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Stannsoporfin Briefing Document

InfaCare Pharmaceutical Company FDA Advisory Committee Meeting 03 May, 2018

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FDA ADVISORY COMMITTEE BRIEFING DOCUMENT

Stannsoporfin for the Treatment of Neonatal Hyperbilirubinemia

JOINT MEETING OF GASTROINTESTINAL DRUGS ADVISORY COMMITTEE (GIDAC) AND PEDIATRIC

ADVISORY COMMITTEE (PAC)

MEETING DATE: 03 May, 2018

ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE



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TABLE OF CONTENTS

Table of Contents ...........................................................................................................................2

List of Tables ..................................................................................................................................5

List of Figures .................................................................................................................................9

List of Abbreviations ...................................................................................................................11

1 Executive Summary ..................................................................................................13

1.1 Background and Unmet Need .....................................................................................15

1.2 Clinical Pharmacology ................................................................................................17

1.3 Efficacy .......................................................................................................................18

1.3.1 Study 204 .............................................................................................................19

1.3.2 Study 202 .............................................................................................................24

1.3.3 Rockefeller IND Studies ......................................................................................28

1.4 Safety ..........................................................................................................................28

1.4.1 Neurological Safety .............................................................................................34

1.5 Conclusions .................................................................................................................34

2 Neonatal Hyperbilirubinemia Background and Unmet Need ..............................36

2.1 Neonatal Hyperbilirubinemia Background .................................................................36

2.1.1 Adverse Neuro-motor Sequelae to Neonatal Hyperbilirubinemia ......................37

2.1.2 Risk Factors .........................................................................................................37

2.1.3 Total Serum Bilirubin as a Parameter for the Evaluation Hyperbilirubinemia ..............................................................................................38

2.2 Incidence .....................................................................................................................39

2.3 Current Standards of Care for Hyperbilirubinemia ....................................................40

2.3.1 Limitations of Phototherapy ................................................................................40

2.4 Unmet Need ................................................................................................................41

3 Product Background ................................................................................................42

3.1 Stannsoporfin Overview .............................................................................................42

3.2 Proposed Indication ....................................................................................................42

3.3 Mechanism of Action .................................................................................................42

3.4 Drug Substance ...........................................................................................................43

3.5 Product Description ....................................................................................................44



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4 Clinical Pharmacology .............................................................................................45

4.1 In Vitro Metabolism and Transport Studies ...............................................................45

4.2 Pharmacokinetic Evaluations ......................................................................................45

4.2.1 Dose-Proportion Pharmacokinetics of Stannsoporfin in Healthy Volunteers (Study 64,185-02-1W) ......................................................................45

4.2.2 Pharmacokinetics in Neonates .............................................................................47

4.3 Analysis of Results Across Studies ............................................................................49

4.3.1 Population Pharmacokinetics ..............................................................................49

4.3.2 Exposure-Response .............................................................................................49

5 Overview of Stannsoporfin Development ...............................................................51

5.1 Preclinical Studies ......................................................................................................51

5.2 Regulatory History ......................................................................................................52

5.3 Clinical Development Program ..................................................................................53

6 Clinical Efficacy ........................................................................................................55

6.1 Efficacy Findings: InfaCare IND ................................................................................56

6.1.1 Study 204 .............................................................................................................56

6.1.2 Study 202 .............................................................................................................70

6.1.3 Study 06 ...............................................................................................................78

6.1.4 Study 01-3W ........................................................................................................81

6.2 Efficacy Findings: Rockefeller IND ...........................................................................82

6.3 Efficacy Conclusions ..................................................................................................87

7 Safety Results ............................................................................................................90

7.1 Stannsoporfin Exposure ..............................................................................................90

7.2 Safety Pooling Strategy ..............................................................................................92

7.3 InfaCare IND ..............................................................................................................92

7.3.1 Pivotal Study 204 ................................................................................................92

7.3.2 Acute Pooled Studies (Studies 204, 202, and 01-3W) ........................................95

7.3.3 Long-Term Pooled Extension Studies (Studies 205, 203, and 01C-3W) ..........102

7.3.4 Neurological Assessment of Stannsoporfin .......................................................106

7.3.5 Adverse Events in Subgroups ............................................................................119

7.4 Rockefeller IND ........................................................................................................120

7.4.1 Study 29,462-04 ................................................................................................120

7.4.2 Study 29,462-09 ................................................................................................121

7.4.3 Study 29,462-05 ................................................................................................121

7.4.4 Study 29,462-06 ................................................................................................121



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7.4.5 Study 29,462-07 ................................................................................................121

7.4.6 Study 29,462-08 ................................................................................................122

7.4.7 Neurological Assessments from Pooled Rockefeller Studies ...........................122

7.5 Deaths Across All Studies ........................................................................................126

7.6 Conclusions ...............................................................................................................127

8 Dose Rationale .........................................................................................................129

9 Risk Mitigation ........................................................................................................130

10 Benefit/Risk .............................................................................................................131

10.1 Benefits .....................................................................................................................131

10.2 Risk Assessment .......................................................................................................132

10.3 Benefit Risk Assessment ..........................................................................................133

11 Reference List ..........................................................................................................134

12 Appendix ..................................................................................................................137

12.1 Overview of Rockefeller IND Studies ......................................................................137

12.2 Study 204 Inclusion and Exclusion Criteria .............................................................140

12.3 Other Endpoint Results in Study 204 .......................................................................142

12.4 Study 202 Inclusion and Exclusion Criteria .............................................................146

12.5 Efficacy Results from Rockefeller IND Studies .......................................................148

12.5.1 Study 29,462-04 ................................................................................................148

12.5.2 Study 29,462-09 ................................................................................................149

12.5.3 Study 29,462-05 ................................................................................................149

12.5.4 Study 29,462-06 ................................................................................................150

12.5.5 Study 29,462-07 ................................................................................................152

12.5.6 Study 29,462-08 ................................................................................................152

12.6 Additional Safety Results from Studies 202, 06, and 01-3W ...................................152

12.6.1 Study 202 ...........................................................................................................152

12.6.2 Study 06 .............................................................................................................155

12.6.3 Study 01-3W ......................................................................................................156

12.7 Adverse Events in Study 29,462-06 .........................................................................157

12.8 Narratives ..................................................................................................................157

12.9 Neurological Adverse Event Tables .........................................................................161



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LIST OF TABLES

Table 1: Reasons for Phototherapy Failure in Study 204 (ITT) ....................................................24

Table 2: Proportion of Neonates Requiring Phototherapy in Study 202 (ITT) .............................28

Table 3: Neonates Requiring Rehospitalization in Study 202 (ITT) .............................................28

Table 4: Summary of Adverse Events in Study 204 ......................................................................29

Table 5: Adverse Events Occurring in ≥10% Neonates in Study 204 ...........................................30

Table 6: Serious Adverse Events in Study 204 ..............................................................................30

Table 7: Adverse Events Occurring in ≥2% Neonates in the 4.5 mg/kg Stannsoporfin Group in the Pooled Acute Studies (204, 202, and 01-3W) .......................................31

Table 8: Serious Adverse Events in the Pooled Acute Studies (204, 202, and 01-3W) ................32

Table 9: Common Adverse Events (≥10% Patients in Any Group) in the Long-Term Pooled Extension Studies (205, 203, and 01C-3W) ...................................................33

Table 10: Stannsoporfin Pharmacokinetic Parameters in Healthy Male Subjects following Single IM Doses of Stannsoporfin (Study 02-1W) ....................................46

Table 11: Stannsoporfin PK Parameters in Neonate Population (Study 202) ...............................48

Table 12: Patient Demographic and Baseline Characteristics in Study 204 (ITT) ........................62

Table 13: Age at Qualifying TSB in Study 204 (ITT) ...................................................................63

Table 14: Percent Change from Baseline in Total Serum Bilirubin (mg/dL) at 48 Hours in Study 204 (ITT) ......................................................................................................65

Table 15: Sensitivity Analyses Conducted on Eleven Patients Who Had Not Crossed the AAP-defined Threshold for Initiation of Phototherapy in Study 204 (Primary Endpoint of Percent Change from Baseline in TSB at 48 Hours) ..............................66

Table 16: Time at Which Total Serum Bilirubin Crossed at or Below the Defined Phototherapy Threshold in Study 204 (ITT) ..............................................................67

Table 17: Analysis of Phototherapy Failure in Study 204 (ITT) ...................................................69

Table 18: Analysis of Rebound Hyperbilirubinemia – TSB Level in Study 204 (ITT) ................70

Table 19: Demographic and Other Baseline Characteristics in Study 202 (ITT) ..........................73

Table 20: Change from Baseline in Adjusted TSB at 48 Hours in Study 202 (ITT) .....................75

Table 21: Change from Baseline in Adjusted TSB - MMRM Analysis in Study 202 (ITT) ...........................................................................................................................76

Table 22: Change from Baseline in Actual TSB at 48 Hours in Study 202 (ITT) ........................77

Table 23: Proportion of Neonates Requiring Phototherapy in Study 202 (ITT) ...........................78



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Table 24: Exchange Transfusion after Administration of Study Drug in Study 06 (ITT) .............80

Table 25: Summary of Rockefeller IND Studies ...........................................................................83

Table 26: Exposure to Stannsoporfin, by Dose, in Clinical Trials ................................................91

Table 27: Overall Summary of Adverse Events in Study 204 (Safety Analysis Set) ....................93

Table 28: Treatment-Emergent Adverse Events in at Least 2 Neonates in any Treatment Group, by SOC and Preferred Term in Study 204 (Safety Analysis Set) ...................93

Table 29: Summary of SAEs by SOC and Preferred Term in Study 204 (Safety Analysis Set) ..............................................................................................................................95

Table 30: Summary of Adverse Events in Acute Pooled Studies (01-3W, 202, 204) ...................96

Table 31: Common TEAEs (≥2 Neonates in a Group) in Acute Pooled Studies (01-3W, 202, 204) .....................................................................................................................97

Table 32: SAEs in Acute Pooled Studies (01-3W, 202, 204) ........................................................99

Table 33: Summary of Assessments and Measures in Long-Term Pooled Extension Studies .......................................................................................................................103

Table 34: Summary of Assessment Point Sample Sizes in Long-Term Pooled Extension Studies .......................................................................................................................104

Table 35: Summary of Adverse Events in Long-Term Pooled Extension Studies (01C-3W, 203, 205) ...........................................................................................................104

Table 36: Common Adverse Events (≥10% Patients in a Group) in Long-Term Pooled Extension Studies (01C-3W, 203, 205) ....................................................................105

Table 37: Neurocognitive and Neurodevelopmental AESI in Long-Term Pooled Extension Studies (01C-3W, 203 and 205) ..............................................................107

Table 38: Schedule of Neurodevelopmental Assessments in Long-term Pooled Extension Studies .......................................................................................................................109

Table 39: Mullen Scale of Early Learning: Percentile Rank in Long-Term Pooled Extension Studies (Studies 203 and 205) .................................................................111

Table 40: Mullen Scale of Early Learning: Age Equivalent Scores in Long-Term Pooled Extension Studies (Studies 203 and 205) .................................................................112

Table 41: Bayley Scales of Infant Development: 18 Month T-Scores in Study 01C-3W ...........114

Table 42: Receptive-Expressive Emergent Language Test: 18-Month T-score and Age Equivalent Score in Study 01C-3W ..........................................................................115

Table 43: Conners’ Scales of Early Behavior: T-scores in Long-Term Pooled Extension Studies (203 and 205) ...............................................................................................116

Table 44: Child Behavior Checklist: 18 Months, 3, and 6 Years in Study 01C-3W ...................117

Table 45: Patients with an Adverse Event in Study 29,462-04 ...................................................120



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Table 46: Adverse Events in Study 29,462-05 ............................................................................121

Table 47: Adverse Events of Special Interest (Rockefeller Pooled LT Extensions) (-04, -05, -06, -07, -08, and -09) .........................................................................................123

Table 48: MDI and PDI Assessments – 18 Months (Pooled LT Extensions) (29,462-04, -09, -05, -06, -07, and -08) ....................................................................125

Table 49: Abnormal Neurodevelopmental Assessments (Pooled LT Extensions) (29,462-04, -09, -05, -06, -07, and -08) ....................................................................126

Table 50: Summary of Deaths Across Studies ............................................................................127

Table 51: Stannsoporfin Rockefeller IND Studies ......................................................................137

Table 52: Percent Change from Baseline in Total Serum Bilirubin by Visit (ITT Analysis Set) ............................................................................................................................142

Table 53: Summary of Total Serum Bilirubin (TSB) Area Under the Curve (AUC) for Change from the Baseline Value (ITT Analysis Set) ...............................................144

Table 54: Percent Change From Baseline in Peak Serum Bilirubin (ITT Analysis Set) .............145

Table 55: Total Duration of Phototherapy (ITT Analysis Set; Study 64,185-204) .....................145

Table 56: Maximum Bilirubin Concentration Values .................................................................148

Table 57: Phototherapy Data: By Treatment Groups: Efficacy Population ................................148

Table 58: Efficacy Response Variables .......................................................................................149

Table 59: Comparison of Stannsoporfin and PT –Intergroup Analysis .......................................150

Table 60: Comparison of Stannsoporfin and PT –Intergroup Analysis .......................................150

Table 61: Intergroup Analysis – Primary Efficacy Analysis .......................................................150

Table 62: Intergroup Analysis – Secondary Efficacy Analysis ...................................................151

Table 63: Comparison of Randomized and Non-Randomized Groups .......................................151

Table 64: Comparison of Randomized and Non-Randomized Preventative Use Groups ...........151

Table 65: Summary of TEAEs in Study 202 ...............................................................................153

Table 66: Common TEAEs (≥5% Incidence in a Group) in Study 202 ......................................154

Table 67: Summary of TEAEs in Study 06 .................................................................................155

Table 68: Common TEAEs (≥5% Incidence in a Group) in Study 06 ........................................156

Table 69: Summary of TEAEs in Study 01-3W ..........................................................................156

Table 70: Common TEAEs (≥5% Incidence in a Group) in Study 01-3W .................................157

Table 71: Adverse Events in Study 29,462-06 ............................................................................157

Table 72: Speech-related Adverse Events in Study 01C-3W ......................................................161

Table 73: Speech-related Adverse Events in Study 203 ..............................................................161



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Table 74: Speech-related Adverse Events in Study 205 ..............................................................162



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LIST OF FIGURES

Figure 1: Overview of Stannsoporfin Clinical Development Program .........................................15

Figure 2: Guidelines for Phototherapy Treatment in Infants ≥35 Weeks Gestational Age ...........16

Figure 3: Design of Study 204 .......................................................................................................19

Figure 4: Patient Disposition in Study 204 ....................................................................................20

Figure 5: Qualifying Total Serum Bilirubin Levels vs Bhutani Predictors of Severe Hyperbilirubinemia in Study 204 (ITT) .....................................................................21

Figure 6: Percent Change in Total Serum Bilirubin at 48 Hours in Study 204 (ITT) ...................21

Figure 7: Time at which Total Serum Bilirubin Crosses at or Below the Defined Threshold for Discontinuation of Phototherapy (ITT, Study 204) .............................22

Figure 8: Rate of Phototherapy Failures in Study 204 (ITT) .........................................................23

Figure 9: Design of Study 202 .......................................................................................................25

Figure 10: Change from Baseline in Adjusted TSB at 48 Hours Post-Treatment in Study 202 (ITT) ....................................................................................................................26

Figure 11: Change from Baseline in Actual TSB at 48 Hours Post-Treatment in Study 202 (ITT) ....................................................................................................................27

Figure 12: Change from Baseline in Actual TSB at 48 Hours Post-treatment in Study 202 (ITT) ....................................................................................................................27

Figure 13: Bhutani Nomogram for Risk of Severe Hyperbilirubinemia .......................................38

Figure 14: Guidelines for Phototherapy Treatment in Infants ≥35 Weeks Gestational Age .........39

Figure 15: Stannsoporfin Mechanism of Action ............................................................................43

Figure 16: Stannsoporfin (tin-mesoporphyrin IX dichloride) Chemical Structure ........................44

Figure 17: Plasma Concentrations of Stannsoporfin in Healthy Males following a Single IM Dose of Stannsoporfin (Study 02-1W) .................................................................47

Figure 18: Mean Plasma Concentration vs Time in Neonates (Study 202) ...................................48

Figure 19: Change in Total Serum Bilirubin at 48 Hours vs Stannsoporfin AUC ........................50

Figure 20: Key Studies in Stannsoporfin Development Program ..................................................54

Figure 21: Design of Study 204 .....................................................................................................57

Figure 22: Patient Disposition in Study 204 (ITT) ........................................................................61

Figure 23: Qualifying TSB vs Bhutani Predictors of Severe Hyperbilirubinemia in Study 204 (ITT) ....................................................................................................................64

Figure 24: Primary Efficacy Sensitivity Analyses in Study 204 (ITT) .........................................66



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Figure 25: Time at which Total Serum Bilirubin Crosses at or Below Defined Threshold for Discontinuation of Phototherapy in Study 204 (ITT) ...........................................68

Figure 26: Rate of Phototherapy Failures in Study 204 (ITT) .......................................................69

Figure 27: Design of Study 202 .....................................................................................................71

Figure 28: Patient Disposition in Study 202 ..................................................................................72

Figure 29: Percent Change from Baseline in Actual TSB in Study 202 (ITT) ..............................78

Figure 30: Need for Phototherapy in InfaCare IND Study 202 and Rockefeller IND Studies 29,462-04, -09, -05, and -08 ..........................................................................87

Figure 31: Duration of Phototherapy in InfaCare IND Studies 204 and 202 and Rockefeller IND Studies 29,462-04 and -08 ..............................................................87

Figure 32: Median GGT Values Over 30 Days in Acute Pooled Studies (202 and 204) ............100

Figure 33: Median Serum ALT Values Over 30 Days in Acute Pooled Studies (202 and 204) ...........................................................................................................................101

Figure 34: Median Serum AST Values Over 30 Days in Acute Pooled Studies (202 and 204) ...........................................................................................................................101

Figure 35: Median Creatinine and BUN Over 30 Days in Acute Pooled Studies (202 and 204) ...........................................................................................................................102

Figure 36: Wechsler Preschool Test (Percentile-Rank) in Long-Term Pooled Extension Studies (01C-3W and 203) .......................................................................................110

Figure 37: Bayley Scales of Infant Development at 18 Months (4.5 mg/kg Dose) .....................114



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LIST OF ABBREVIATIONS

Abbreviation Term or Definition

AAP American Academy of Pediatrics ABE Acute bilirubin encephalopathy AE Adverse event AESI Adverse events of special interest ALT Alanine aminotransferase ANCOVA Analysis of covariance ANOVA Analysis of variance AST Aspartate aminotransferase AUC Area under the curve AUC0-inf area under the plasma concentration vs time curve from time 0 to

infinity AUC0-48 area under the plasma concentration vs time curve from time 0 to 48

hours BIND Bilirubin-induced neurologic dysfunction BSID Bayley Scales of Infant [and Toddler] Development BUN Blood urea nitrogen CBCL Child Behaviour Checklist CBE Chronic bilirubin encephalopathy CI Confidence interval Cmax Maximum observed plasma concentration CMC Chemistry, manufacturing, and control CNS Central nervous system CV Coefficient of variation CYP Cytochrome P450 DAT Direct antiglobulin test DSMB Data Safety Monitoring Board ECG Electrocardiogram ECRS Early Childhood Rating Scale ET Exchange transfusion FDA Food and Drug Administration G6PD Glucose-6-phosphate dehydrogenase GA Gestational age h Hour Hb Hemoglobin HO Heme oxygenase IM Intramuscular IND Investigational New Drug ITT Intent-to-treat IVH Intraventricular hemorrhage



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Abbreviation Term or Definition

IVIg Intravenous immunoglobulin LOCF Last observation carried forward LS Least squares MDI Mental development index MedDRA Medical Dictionary for Regulatory Activities MMRM Mixed-effects model for repeated measures MSEL Mullen Scales of Early Learning NDA New Drug Application NEC Necrotizing Enterocolitis NME New molecular entity NNT Number needed to treat PBC Plasma bilirubin concentration PDI Psychomotor development index PK Pharmacokinetic PP Per protocol population PT Phototherapy RDS Respiratory Distress Syndrome REEL Receptive-Expressive Emergent Language test Rh Rhesus SAE Serious adverse event SD Standard deviation SIDS Sudden Infant Death Syndrome SOC System Organ Class TcB Transcutaneous Bilirubin measurement TEAE Treatment-emergent adverse event Tmax Time of maximum concentration TSB Total serum bilirubin ULN Upper limit of normal US United States WPPSI Wechsler Preschool and Primary Scale of Intelligence



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1 EXECUTIVE SUMMARY

Stannsoporfin is a heme oxygenase (HO) inhibitor that is being developed by InfaCare Pharmaceutical Corporation, a Mallinckrodt company, for the treatment of neonates ≥35 weeks of gestational age (GA) with indicators of hemolysis at risk of developing severe hyperbilirubinemia. Stannsoporfin is administered as a single intramuscular (IM) injection of 4.5 mg/kg and has been studied with or without phototherapy (PT).

Stannsoporfin is a first-in-class new molecular entity (NME) with a mechanism of action that provides an innovative approach to the treatment of neonatal hyperbilirubinemia. Unlike PT, the current standard of care, which targets the elimination of excess bilirubin already in the bloodstream and skin, stannsoporfin inhibits bilirubin production at its source. Bilirubin inhibition results in a rapid and sustained reduction in total serum bilirubin (TSB) through the first week of life when neonates are at the highest risk for developing severe hyperbilirubinemia.

Stannsoporfin has not been granted marketing authorization anywhere for any indication. The stannsoporfin development program evolved over several years due to multiple transitions across companies. The first Investigational New Drug Application (IND) for stannsoporfin, IND 029462, was initiated in 1987 at Rockefeller University for the management of jaundice and was later expanded to include newborns. IND 029462 is referred to as the “Rockefeller IND” throughout this briefing document. WellSpring Pharmaceutical Corporation acquired the rights to stannsoporfin in 2002 and submitted a second IND (IND 064185) for the prevention or treatment of neonatal hyperbilirubinemia. This IND was then transferred to InfaCare in 2005. IND 064185 is referred to as the “InfaCare IND” throughout this briefing document.

As shown in Figure 1, the clinical development program for stannsoporfin includes six studies from the Rockefeller IND (Studies 29,462-04, -09, -05, -06, -07, and -08) that are supportive of the use of stannsoporfin in hyperbilirubinemia without PT. Three additional studies (Studies 29,462-01, -02, and -03) were conducted under the Rockefeller IND in populations and indications not relevant to the requested indication and are not detailed in this briefing document. The six studies conducted under the Rockefeller IND to evaluate the safety and efficacy of stannsoporfin for the proposed indication each had a long-term follow-up extension (with the same study number as the acute study) which followed patients for up to five years. These six studies are presented below in order of relevance and robustness of study design:

Study 29,462-04: double-blind, randomized, placebo-controlled, dose-ranging study of five escalating doses of stannsoporfin (1 to 6 µmol/kg [0.75 to 4.5 mg/kg]) that provides supportive data for use of stannsoporfin without PT in preterm (≥210 and ≤251 days GA) neonates at high risk of hyperbilirubinemia.

Study 29,462-09: randomized, open-label safety and efficacy study that provides supportive data for use of stannsoporfin without PT in full-term (≥38 and ≤41 weeks GA) healthy neonates with clinically significant hyperbilirubinemia (plasma bilirubin concentration [PBC] ≥15 and ≤18 mg/dL).

Study 29,462-05: randomized, active-controlled, matched-pairs, safety and efficacy study of stannsoporfin and PT for hyperbilirubinemia that provides supportive data for the use of stannsoporfin without PT in near- and full-term (≥35 and ≥37 weeks GA, respectively) neonates with normal glucose-6-phosphate dehydrogenase (G6PD) activity.



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Study 29,462-06: randomized, controlled, matched-pairs, safety and efficacy study comparing preventive and therapeutic use of stannsoporfin for hyperbilirubinemia that provides supportive data for the use of stannsoporfin without PT in G6PD deficient near- and full-term (>210 days and ≤265 days, and >265 days GA, respectively) neonates.

Study 29,462-07: randomized safety study of preventive and therapeutic uses of stannsoporfin that provides supportive data for the use of stannsoporfin without PT in the treatment of hyperbilirubinemia in near-term (>210 days GA) neonates.

Study 29,462-08: randomized, matched-pairs, safety and efficacy study comparing stannsoporfin with PT for the treatment of hyperbilirubinemia in healthy and sick preterm (≥210 and ≤251 days GA) neonates. This study was discontinued due to slow enrollment after 101 neonates were accrued, and no formal efficacy analyses were performed.

Nine studies were conducted under the InfaCare IND (four acute, four long-term, and one pharmacokinetic [PK]):

Acute and Long-Term Studies

Study 64,185-204 (referred to hereafter as Study 204): pivotal study that provides evidence for the efficacy of stannsoporfin in treating hyperbilirubinemia in near- and full-term (≥35 and ≤43 weeks GA) neonates when used with PT. Study 205 is the long-term follow-up for Study 204.

Study 64,185-202 (referred to hereafter as Study 202): provides evidence for the efficacy of stannsoporfin in treating hyperbilirubinemia in near- and full-term (≥35 and ≤43 weeks) neonates when initiated prior to reaching the threshold for starting PT. Study 203 was the long-term follow-up for Study 202.

Study 64,185-06 (referred to hereafter as Study 06): open-label study that provides efficacy data in near- and full-term (≥35 weeks) neonates at risk for exchange transfusion (ET) who were at significantly higher risk of bilirubin toxicity than in the other studies conducted. Study 06LT was the long-term follow-up for Study 06.

Study 64,185-01-3W (referred to hereafter as Study 01-3W): provides additional safety data. Study 01-3W enrolled healthy near- and full-term (≥35 weeks) newborns without evidence of hemolysis. The study was put on clinical hold after 11% of neonates were enrolled, when the Food and Drug Administration (FDA) requested further discussion regarding the entry criteria, requested further preclinical data, and asked for more chemistry, manufacturing, and control (CMC) data. There were no safety observations in this study that led to the FDA's request. Study 01C-3W was the long-term follow-up for Study 01-3W.

PK Study

Study 64,185-02-1W (referred to hereafter as Study 02-1W): PK study in healthy male subjects evaluating three dose levels of stannsoporfin (20, 40, and 80 mg IM).

To date, 890 neonates have received stannsoporfin in the relevant clinical studies mentioned, as well as 15 who received stannsoporfin under emergency use INDs. Three acute, double-blind, placebo-controlled studies (Studies 204, 202, and 01-3W) under the InfaCare IND, which



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included the 4.5 mg/kg dose, were pooled for safety and provide a broad assessment of short-term safety in neonates of similar GA. The long-term extensions of these studies (Studies 205 [ongoing], 203, and 01C-3W) were pooled and provide safety assessments for up to six years. As previously mentioned, Study 06 was an open-label study, which did not include doses higher than 1.5 mg/kg, conducted in neonates at risk for ET, and the long-term follow-up to this study (Study 06LT) is therefore not included in these pooled safety assessments.

Although studies throughout the development program were conducted in neonates with different characteristics (ABO incompatibility, G6PD deficient, premature infants) and with or without PT, findings have consistently shown the effect of stannsoporfin on TSB and/or PBC (used in the Rockefeller IND studies and equivalent to TSB). The totality of the data demonstrates that stannsoporfin at a dose of 4.5 mg/kg used with or without PT effectively treats neonatal hyperbilirubinemia with a favorable safety profile.

Figure 1: Overview of Stannsoporfin Clinical Development Program

*Studied stannsoporfin without phototherapy NOTE: For the long-term extension studies, the highest N at any visit is represented in the figure.

1.1 Background and Unmet Need

Neonatal hyperbilirubinemia occurs when there is an imbalance in bilirubin production and the neonate’s capacity to eliminate bilirubin. Within the first 96 hours of life, almost all neonates will have bilirubin levels that are above the upper limit of adult normal (1 mg/dL) (Maisels 2006). As the healthy neonate ages, the level of fetal erythrocyte lysis decreases, and the liver matures, eliminating bilirubin more efficiently.

However, neonates with hemolysis have increased bilirubin production and are at greater risk for hyperbilirubinemia. Known risk factors that increase the neonate’s potential for developing severe hyperbilirubinemia include: ABO blood type incompatibility and other alloimmune conditions (eg, antibodies directed against antigens of the Kell blood group, Kidd blood group, [eg, anti-Jka and anti-Jkb], Duffy blood group [eg, anti-Fya], and anti-MNS blood group



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antibodies), Rhesus (Rh) hemolytic disease, G6PD and other enzyme deficiencies, hereditary red blood cell dyscrasias (eg, spherocytosis, elliptocytosis) and extensive bruising, among others.

Untreated hyperbilirubinemia can lead to bilirubin-induced neurologic dysfunction (BIND) when unbound or free bilirubin crosses the blood brain barrier of the neonate (Johnson and Bhutani 2011). The spectrum of BIND includes impaired sensory and sensorimotor integration, central auditory processing, coordination, and muscle tone; these impairments may manifest as learning disabilities, autism spectrum disorder, attention deficit hyperactivity disorder, and non-progressive developmental delay (Shapiro 2010, Johnson and Bhutani 2011). If left untreated, hyperbilirubinemia can lead to significant morbidity and premature mortality. Kernicterus is a rare form of brain damage associated with very high levels of bilirubin exposure that is characterized by motor, auditory, oculomotor, and dental impairments and can result in cerebral palsy or death (Shapiro 2010).

In clinical practice, GA, risk factors such as hemolysis, and TSB level are the key parameters used in the management of hyperbilirubinemia. Total serum bilirubin is the primary laboratory measurement that guides treatment decisions. The current standard of care for hyperbilirubinemia is intensive PT, which utilizes blue light in an attempt to convert unbound or free bilirubin in the bloodstream and skin to less toxic water-soluble photoisomers that are excreted in the urine without need for conjugation. Importantly, however, PT does not affect the production of bilirubin.

The American Academy of Pediatrics (AAP) PT treatment guidelines (Figure 2) use TSB, GA, and various risk factors for bilirubin neurotoxicity to set the thresholds for initiating PT. It is important to note in this figure that neonates at higher risk of developing neurotoxicity need to begin PT at lower TSB levels than neonates at lower risk.

Figure 2: Guidelines for Phototherapy Treatment in Infants ≥35 Weeks Gestational Age

Adapted from AAP, 2004.

While PT is widely accepted as the current standard of care, it is associated with a number of side effects. Studies have shown that PT can cause short-term neonatal side effects including thermal imbalances, dehydration, electrolyte disturbances, and altered circadian rhythms, leading to more frequent crying and jitteriness (Xiong, Qu et al. 2011). Neonatal PT may also inhibit the immune system and place infants at higher risk for asthma, allergic rhinitis, and conjunctivitis



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(Xiong, Qu et al. 2011). In addition, PT produces oxidative stress in the newborn, alters cytokine levels, and damages DNA (Aycicek and Erel 2007, Tatli, Minnet et al. 2008, Procianoy, Silveira et al. 2010). The DNA damage from PT is thought to be correlated with the duration of PT – the longer the duration of PT, the greater the DNA damage (Tatli, Minnet et al. 2008). Importantly, when PT is administered in the neonatal intensive care unit or the newborn nursery, it requires physical separation of the mother and infant and interrupts breastfeeding and maternal-infant bonding (Academy of Breastfeeding Medicine (ABM) Protocol Committee 2010). Therefore, minimizing the need for or duration of PT is a desirable clinical goal.

Because PT does not inhibit the production of bilirubin, studies report that approximately 5% of infants experience rebound hyperbilirubinemia requiring reinitiation of PT following its discontinuation. Furthermore, infants who are failing PT or at risk for severe BIND may undergo ET, a procedure that replaces the newborn’s blood (with elevated bilirubin) with donor blood containing normal levels of bilirubin. Exchange transfusion is associated with a 1-5% mortality risk and a 5-10% risk of significant morbidity (Thilo and Rosenberg 2011) and is used as a last resort.

Although not an FDA approved therapy for the treatment of neonatal hyperbilirubinemia, intravenous immunoglobulin (IVIg) is often used off-label in an attempt to reduce the need for ET. However, conflicting efficacy results have been reported, and administration of IVIg carries the known risks associated with the use of blood products.

Additionally, neonatal hyperbilirubinemia remains a significant public health issue, as jaundice is the leading cause of neonatal hospital readmissions within 30 days of initial discharge (Trudnak Fowler, Fairbrother et al. 2014). None of the currently used treatments for hyperbilirubinemia inhibit the production of bilirubin, but rather attempt to improve the rate of elimination of clinically concerning bilirubin levels. Therefore, a safe treatment that inhibits bilirubin production and generates rapid and sustained decreases in bilirubin, thereby eliminating or decreasing the total need for PT and the rate of PT failures (including restart of PT after discontinuation, hospital readmission for hyperbilirubinemia, use of IVIg, or need for ET) while reducing the interference with maternal/infant bonding or breastfeeding, would be an important addition to the clinical armamentarium for the management of neonatal hyperbilirubinemia.

1.2 Clinical Pharmacology

In vitro assessments showed that stannsoporfin has low drug-drug interaction potential for Phase 1 and 2 enzymes, as it was not found to be a substrate or inducer or inhibitor of the major human cytochrome P450 (CYP) isoenzymes for concomitant neonatal drug use. Stannsoporfin is a full inhibitor of influx transporters OAT1, OAT3 and OATP1B1 and partial inhibitor of OATP1B3, OCT2 and MDR1 at 10 µM. It is anticipated that this interaction is not clinically relevant, due to the intended single use application and high protein binding, peak concentrations of stannsoporfin would be below inhibitory levels in plasma of human neonates.

In healthy male adult subjects (Study 02-1W) who each received three dose levels of stannsoporfin (20, 40, and 80 mg IM) with one-week intervals between dosing, plasma concentrations were detectable in all subjects for all three dose levels within the first 30 minutes. Maximum plasma concentrations were observed between 1-3 hours post-dose before an apparent terminal elimination phase. A linear dose-related increase was observed for maximum observed



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plasma concentration (Cmax), and a slightly more than proportional increase was observed in area under the plasma concentration time curve to 48 hours (AUC0-48).

Pharmacokinetic studies in the intended clinical population of neonates with hyperbilirubinemia demonstrated that after a single IM injection, stannsoporfin was rapidly absorbed with a time of maximum concentration (Tmax) of 1-2 hours. Stannsoporfin has an apparent elimination half-life (t1/2) of about 10 hours. There was a dose-proportional increase in Cmax and a slightly more than dose-proportional increase in area under the plasma concentration time curve (AUC) of stannsoporfin over the dose range of 1.5 mg/kg to 4.5 mg/kg. The generally ≤30% coefficient of variation (CV) in Cmax and AUC parameters of stannsoporfin across dose levels were considered to be relatively low for neonates.

A mixed effects (population) PK model of stannsoporfin was developed using data from Study 202 and Study 02-1W. The data encompassed adults with a four-fold dose range and neonates (GA of 37.3–42.3 weeks) with a three-fold dose range. A satisfactory model of stannsoporfin PK for adults and neonates was developed. The model was a one compartment model with first-order IM absorption, saturable elimination, and allometric coefficients relating kinetics to body size. The PK characteristics of stannsoporfin were found to depend on both dose and body size (and hence neonatal age). For a given body weight, the model-predicted stannsoporfin AUC had a slightly non-linear relationship with dose (slightly more than proportional), with non-linear elimination most evident at the highest (4.5 mg/kg) dose.

Exposure-response analyses were performed using available PK and pharmacodynamic (PD) data from a total of five studies (Studies 204, 202, and 02-1W from the InfaCare IND, and Studies 29,462-04 and -08 from the Rockefeller IND). Total Serum Bilirubin values (percent change from Baseline at 12, 24 and 48 hours) demonstrated a linear relationship with stannsoporfin AUC, with the greatest observed reduction in TSB occurring at 48 h. The 4.5 mg/kg dose of stannsoporfin had a more consistent effect (least variability) on TSB at 48 hours and produced the largest decrease in TSB.

1.3 Efficacy

Efficacy support for 4.5 mg/kg stannsoporfin for the proposed indication is based on Studies 204 and 202 from the InfaCare IND, and Studies 29,462-04, -09, -05, -06, -07, and -08 from the Rockefeller IND. InfaCare IND Study 06 was an open-label evaluation of low doses of stannsoporfin and is considered supportive for efficacy, whereas Study 01-3W enrolled healthy neonates without hemolysis and was therefore excluded from the efficacy analyses. Study 06 and Study 01-3W (InfaCare IND), are discussed in Sections 6.1.3 and 6.1.4, respectively.

The pivotal study, Study 204, showed that stannsoporfin 4.5 mg/kg used with PT was statistically significantly superior to PT used alone. Study 202 was designed to evaluate the use of stannsoporfin to reduce the need for PT and provides data for the use of stannsoporfin without PT. Both studies evaluated similar patient populations: neonates of GA >35 weeks and <43 weeks with blood incompatibilities, rising bilirubin, and positive Coombs test or Coombs negative with one additional risk factor (Study 202) or with reticulocytes >6% (Study 204).



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Additionally, the large body of data in the Rockefeller IND studies provided a foundation for the InfaCare IND and adds significant support for the efficacy of stannsoporfin with and without PT. The findings from each of these studies are supportive of stannsoporfin for the proposed indication.

1.3.1 Study 204

Study 204 was a pivotal double-blind, randomized, placebo-controlled, parallel-group study of two doses of stannsoporfin (3.0 and 4.5 mg/kg). The study included neonates ≥35 weeks GA with indicators of hemolysis at risk of developing severe hyperbilirubinemia. Neonates were to receive study treatment when their TSB level reached the threshold for the initiation of PT according to the AAP guidelines. Underlying risk factors for hemolysis for enrollment included a rising TSB and a positive Coombs test or a negative Coombs test plus reticulocytes >6%.

Study Design

All neonates had rapid rises in TSB and were eligible for randomization within the first 48 hours of life. During the screening period, once the TSB level reached or crossed the AAP age-specific threshold for initiating PT, neonates were randomized in a 1:1:1 ratio to receive stannsoporfin (3.0 or 4.5 mg/kg) or placebo (Figure 3). All neonates were to start PT as soon as it was practical, and within a window of 30 minutes before or after study treatment. Total serum bilirubin levels were to be measured every six hours and at the 48-hour time point, which was the primary endpoint. Additional follow-up visits were conducted on Day 7 and Day 30. The parents or guardians of all neonates who received study drug were asked to participate in a four-year long-term follow-up safety study.

Figure 3: Design of Study 204

The primary efficacy endpoint in Study 204 was the percent change from Baseline in TSB at 48 hours post-treatment. The primary analysis was pre-specified to be performed on the intent-to-treat (ITT) population with the last observation carried forward (LOCF) method used for final TSB values collected for patients discharged prior to the 48-hour time point. Sensitivity analyses were also conducted for the primary endpoint using a mixed-effects model for repeated measures



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(MMRM) without LOCF. In addition, a sensitivity analysis was conducted on the per protocol (PP) population.

Three key secondary endpoints were pre-specified to be tested in hierarchical order. The first was the time at which TSB crossed at or below the defined threshold for discontinuation of PT. The second was PT failure, defined as one of the following: requiring the restart of PT at least six hours after stopping PT, hospital re-admission for hyperbilirubinemia, use of IVIg, or the requirement for ET. The third key secondary endpoint was rebound hyperbilirubinemia, or an increase in TSB that re-crossed the threshold for PT within 54 hours after discontinuation. Bilirubin increases after 54 hours were not captured as rebound hyperbilirubinemia.

Since the primary endpoint analysis was statistically significant for the ITT population (p<0.0001 for both doses), the three key secondary endpoints were analyzed in hierarchical order. If at any point the hypothesis testing for a given dose yielded a non-significant result, the testing was stopped for that dose but could continue for the other dose.

Results

Overall, 91% of neonates completed the study, and disposition was similar across treatment groups (Figure 4). Ninety-one neonates were randomized, and 83 completed the study. Of the eight neonates that discontinued the study, six were lost to follow-up, and two were voluntarily withdrawn by the parent or guardian. Six of these eight patients had a 48-hour TSB sample and therefore did not require imputation. No neonate was withdrawn because of an adverse event (AE) in any group.

Figure 4: Patient Disposition in Study 204

Demographics and other baseline characteristics were balanced across treatment groups. The mean GA was approximately 39 weeks, and the mean age at time of dosing was approximately 24 hours. Mean bilirubin at Baseline was 9.9 mg/dL. Most neonates had a positive direct Coombs test and were ABO incompatible.

The majority of neonates who entered the study had a rapid rise in bilirubin levels after birth. Sixty one of the 91 neonates (67%) had TSB levels that crossed the AAP threshold for PT within the first 24 hours of life, and 78 (86%) within the first 32 hours. Figure 5 shows these data



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plotted on the Bhutani nomogram, which assesses the risk for the development of severe hyperbilirubinemia. The high-risk zone (95th percentile) represents a rate of rise in TSB in the first 36 hours of approximately 0.2 mg/dL/h (5 mg/dL/day), which is a significant indicator for hemolysis and a risk factor for the development of severe hyperbilirubinemia (Maisels, Deridder et al. 2009). All neonates were above the 75th percentile on the Bhutani nomogram. The vast majority were at or above the 95th percentile high-risk zone, and therefore had levels that were rising much more rapidly than 0.2 mg/dL/h.

Figure 5: Qualifying Total Serum Bilirubin Levels vs Bhutani Predictors of Severe Hyperbilirubinemia in Study 204 (ITT)

Primary Endpoint

For the primary efficacy endpoint, both doses of stannsoporfin were superior to placebo in decreasing TSB from Baseline to 48 hours (Figure 6). The least squares (LS) mean difference was statistically significant for both the 3.0 mg/kg and 4.5 mg/kg stannsoporfin groups compared to the difference in the placebo group (p<0.0001 for both). Based on these statistically significant findings for both doses, the prespecified key secondary endpoints were analyzed in a hierarchical order.

Figure 6: Percent Change in Total Serum Bilirubin at 48 Hours in Study 204 (ITT)



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ITT Analysis Set, LOCF

Secondary Endpoints

Time at Which TSB Crossed at or Below Defined Threshold for Discontinuing PT

For the first key secondary endpoint, stannsoporfin 4.5 mg/kg was statistically superior to placebo (median of 10.6 vs 20.9 hours, respectively) in reducing the time when bilirubin levels crossed at or below the defined threshold for discontinuing PT (p=0.003; Figure 7). The difference between stannsoporfin 3.0 mg/kg and placebo was not statistically significant (p=0.232), thus ending the sequential testing in the 3.0 mg/kg dose.

Figure 7: Time at which Total Serum Bilirubin Crosses at or Below the Defined Threshold for Discontinuation of Phototherapy (ITT, Study 204)

Rate of Phototherapy Failure

Phototherapy failure was defined as one of the following: restart of PT >6 hours after stopping, rehospitalization for hyperbilirubinemia, use of IVIg, or the need for ET. The 4.5 mg/kg dose statistically significantly reduced the frequency of PT failure compared with placebo (3.2% vs 26.7%, respectively; p=0.012); whereas, the 3.0 mg/kg dose (10.0%) was not statistically different from placebo (Figure 8). Reasons for PT failure are shown in Table 1. Neonates could have more than one reason for failure, and therefore could appear more than once in a column.



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Figure 8: Rate of Phototherapy Failures in Study 204 (ITT)




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Table 1: Reasons for Phototherapy Failure in Study 204 (ITT)

Neonates Reasons (could be ≥1 per neonate)

Stannsoporfin 3.0 mg/kg + PT

N=30


N=31 Placebo + PT

N=30 n n n

Neonates with failure 3 1 8 Required exchange transfusion 1 0 0 Hospital readmission for hyperbilirubinemia 0 1 3 Restarted phototherapy 1 1 8* IVIg used 1 0 1

* 1 patient was admitted for and restarted phototherapy twice 1 patient not captured in database for restarting phototherapy, but was captured for hospital re-admission

Rebound Hyperbilirubinemia

The third secondary endpoint of rebound hyperbilirubinemia, as defined in the protocol, was not met with statistical significance between groups (p=0.237 for 3.0 mg/kg and p=0.354 for 4.5 mg/kg).

Conclusions

Overall, the data from Study 204 demonstrated that the stannsoporfin 4.5 mg/kg dose was statistically superior to placebo with PT, and that 4.5 mg/kg was the most effective dose. Compared to placebo, both doses were superior in achieving statistically significant decreases in the primary endpoint (percentage change in actual TSB at 48 hours). However, only the 4.5 mg/kg group achieved other clinically relevant secondary endpoints, showing an earlier time to cross below threshold for discontinuing PT, and fewer PT failures compared to placebo with PT.

1.3.2 Study 202

Study 202 was designed to evaluate the efficacy of stannsoporfin without PT when used in neonates who were candidates for PT, according to the AAP guidelines. Stannsoporfin was administered when TSB levels were 1-2 mg/dL below the age-specific threshold for the initiation of PT. The study included neonates ≥35 weeks GA with risk factors for hemolysis, including ABO blood type incompatibility, Rh incompatibility (anti-C, c, D, E, or e), or G6PD deficiency. Neonates could be Coombs positive or Coombs negative with one additional risk factor.

Study Design

Neonates with qualifying TSB levels were randomized within each cohort or dose group (stannsoporfin 1.5, 3.0, or 4.5 mg/kg or placebo) in a 3:1 ratio (Figure 9). Cohorts were enrolled sequentially from the lowest dose, 1.5 mg/kg or placebo, followed by 3.0 mg/kg or placebo, and 4.5 mg/kg or placebo. A Data Safety Monitoring Board (DSMB) review of the safety data was required before the next cohort began.

Since initiation of stannsoporfin was allowed at TSB 1-2 mg/dL below the age-specific AAP guideline threshold for the initiation of PT, Study 202 was stopped prematurely by the FDA due to discussions regarding the most appropriate TSB value to initiate stannsoporfin. The 4.5 mg/kg dose group was approximately 50% enrolled when the study was stopped; there were no safety observations associated with this action by the Agency. See Section 5.2 for full details.



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Study drug was administered within two hours after receipt of the qualifying TSB measurement. The primary endpoint of change in adjusted TSB was assessed at 48 hours, and follow-up visits occurred at 72 hours, 14 days, and 30 days after treatment.

Total serum bilirubin levels were assessed every six hours after study drug injection to determine whether PT was necessary. Phototherapy was initiated if TSB levels crossed the threshold according to the AAP guidelines. When the TSB level decreased to at least 2 mg/dL below the PT threshold, PT was to be stopped. Once PT was stopped, a TSB assessment was performed approximately six hours later to ensure that there was no rebound in the bilirubin level.


The primary endpoint was change in adjusted TSB at 48 hours following study treatment. Because neonates entered Study 202 when TSB was 1-2 mg/dL below the AAP threshold for initiating PT, the difference between the actual measured TSB and the age-specific threshold of PT initiation was calculated to adjust for the difference. This previously untested approach was deemed unnecessary for future studies.

The primary analysis was pre-specified to be performed on the ITT population. The ITT population included all randomized neonates who had at least one TSB measurement during the first 48 hours after treatment. Because neonates could be discharged from the hospital prior to 48 hours, a LOCF method was used to for those who did not have a 48-hour bilirubin draw.

Two sensitivity analyses were also pre-specified for the primary endpoint. The first sensitivity analysis was conducted using the PP population, which included all neonates in the ITT population who completed the clinical study without any major protocol violations. The second sensitivity analysis used an MMRM analysis of variance (ANOVA) in the ITT population using the adjusted Baseline TSB as the only covariate.

Key secondary endpoints included: change from Baseline in actual (measured) TSB at 48 hours after treatment and proportion of neonates requiring PT or ET.

Results

A total of 58 neonates were enrolled to receive treatment with either stannsoporfin (1.5 mg/kg, 17 neonates; 3.0 mg/kg, 18 neonates; 4.5 mg/kg, eight neonates) or placebo (15 neonates). Two



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neonates (one placebo and one 1.5 mg/kg stannsoporfin) were voluntarily withdrawn from the study by their parents or guardians. Demographics and other baseline characteristics were balanced across treatment groups. The mean GA was 39 weeks, and the mean age at time of dosing was between 26 and 33 hours across groups. Although a lower percentage of neonates at the 4.5 mg/kg dose had a positive direct Coombs test, their mean bilirubin level at study entry was slightly higher than the other groups. The majority of neonates across groups were ABO incompatible and direct Coombs positive and were at medium to high risk of developing severe hyperbilirubinemia.

Primary Endpoint

A decrease in adjusted TSB levels from Baseline to 48 hours after treatment was observed in each treatment group: -13.45 (p=0.040) for 1.5 mg/kg, -10.02 (p=0.117) for 3.0 mg/kg, and -14.93 (p=0.057) for the 4.5 mg/kg group, despite the group size being much smaller (Figure 10).

Figure 10: Change from Baseline in Adjusted TSB at 48 Hours Post-Treatment in Study 202 (ITT)

Secondary Endpoints

Change from Baseline in Actual TSB at 48 Hours Post-treatment

For the first key secondary endpoint, change from Baseline in actual TSB at 48 hours post-treatment, there was a statistically significant difference in LS means between the stannsoporfin 4.5 mg/kg and placebo groups (p=0.028; Figure 11). Compared to placebo, all doses of stannsoporfin reduced TSB at 48 hours; however, this difference was only statistically significant for the 4.5 mg/kg group (-2.63 [p=0.028] for 4.5 mg/kg) and not for the 1.5 mg/kg group (-1.81 [p=0.061]) or 3.0 mg/kg group (-1.34 [p=0.163]).



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Figure 11: Change from Baseline in Actual TSB at 48 Hours Post-Treatment in Study 202 (ITT)


For the change from Baseline in actual TSB (Figure 12), the curve began to flatten by six hours post-treatment in the 4.5 mg/kg group, with statistically significant attenuation occurring at 12 hours post-treatment. After 12 hours, stannsoporfin 4.5 mg/kg produced decreases in TSB with levels returning to Baseline by 72 hours post-treatment. Note that returning to Baseline meant achieving a TSB 1-2 mg/dL below the AAP threshold for PT initiation. While both the 1.5 and 3.0 mg/kg doses attenuated the rise in TSB by 12 hours post-treatment compared with placebo, after 12 hours, mean TSB levels plateaued or slightly decreased, remaining 20-30% elevated from Baseline at 72 hours post-treatment. In the placebo group, bilirubin levels continued to rise despite 53% receiving standard of care (PT).

Figure 12: Change from Baseline in Actual TSB at 48 Hours Post-treatment in Study 202 (ITT)

ITT analysis set, LOCF



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Proportion of Neonates Who Required PT/ET

Although the study was not powered to detect differences in the need for PT, 50% fewer neonates in the stannsoporfin 4.5 mg/kg group received PT when compared to placebo (25.6% vs 53.3%, respectively) (Table 2).

Table 2: Proportion of Neonates Requiring Phototherapy in Study 202 (ITT) Stannsoporfin

1.5 mg/kg N=17

Stannsoporfin 3.0 mg/kg

N=18


N=8

Placebo

N=15 n (%) n (%) n (%) n (%)

Phototherapy required 3 (17.6) 6 (33.3) 2 (25.0) 8 (53.3) Exchange transfusion required 0 0 0 0

Additional Analyses

Neonates who require Rehospitalization

There were no rehospitalizations in the stannsoporfin groups, and 13% in the placebo group were rehospitalized despite having received PT (Table 3).

Table 3: Neonates Requiring Rehospitalization in Study 202 (ITT) Stannsoporfin

1.5 mg/kg N=17


N=18


N=8

Placebo

N=15 n (%) n (%) n (%) n (%)

Hospital readmission 0 0 0 2 (13.3)

Conclusions

Overall, Study 202 supports the initiation of stannsoporfin prior to reaching the threshold for PT with the objective of reducing the risk of developing of severe hyperbilirubinemia. Neonates who received stannsoporfin had a greater change from Baseline in both the adjusted and actual TSB compared to the placebo group, and this was confirmed by multiple assessments including prespecified sensitivity analyses. Compared to placebo, fewer neonates in the stannsoporfin groups required PT. The 4.5 mg/kg dose group had an earlier onset of effect, as shown by the blunting of the rise in bilirubin levels between six and twelve hours, with an increasing treatment effect, compared to persistently rising values in the placebo group. Study 202 offers support for use of stannsoporfin without PT.

1.3.3 Rockefeller IND Studies

The six Rockefeller IND studies provide additional efficacy data on stannsoporfin when started without PT. More details on the efficacy findings from these studies can be found in Section 6.2.

1.4 Safety

Overall, 1,433 neonates participated in stannsoporfin development across the Rockefeller and InfaCare INDs in multiple patient populations including premature, near-term, term, G6PD deficient, ABO incompatible, at risk for ET, with and without indicators of hemolysis. Eight hundred and ninety (890) neonates received stannsoporfin in clinical trials, and 543 were



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controls (placebo, no treatment, or PT only). In addition, 59 adults, children, and neonates received stannsoporfin across studies and for other indications that do not directly support the proposed indication. A total of 588 neonates received the 4.5 mg/kg dose of stannsoporfin in clinical studies, and 15 received the 4.5 mg/kg dose in emergency use investigator sponsored INDs.

In the InfaCare IND, the safety assessment of stannsoporfin is based on data from the three acute double-blind, placebo-controlled studies (Studies 204, 202, and 01-3W) pooled to provide the broadest assessment of short-term safety in neonates of similar GA, as well as the three long-term extensions of the acute pooled studies (Studies 205, 203, and 01C-3W) with outcomes up to six years. Because Study 204 is the pivotal trial, the safety data for this study are presented separately before the pooled analysis.

Safety findings from the Rockefeller IND studies, which include both acute and long-term data, are presented individually except for the long-term neurodevelopmental assessments, which are pooled across studies. The six Rockefeller IND studies demonstrated a safety profile that is consistent with findings from the studies conducted under the InfaCare IND. The types of treatment-emergent adverse events (TEAEs) and their occurrence relative to placebo in the Rockefeller IND studies mirror those seen in the acute pooled and long-term pooled extension studies from the InfaCare IND.

The focus of this safety assessment is on the 4.5 mg/kg dose, which had the most favorable benefit/risk ratio. The 4.5 mg/kg dose has the most exposures since the start of the clinical program and is the proposed dose for approval. In Study 204, the overall safety profile was similar between the stannsoporfin 4.5 mg/kg and placebo groups: most TEAEs in all groups were mild in severity, the proportion of neonates with serious adverse events (SAEs) was low and similar in all treatment groups, and there were no discontinuations due to TEAEs or deaths reported during the study (Table 4). The TEAEs shown in this table were collected over the first 30 days in Study 204.

Table 4: Summary of Adverse Events in Study 204


N=30


N=31 Placebo + PT

N=30 n (%) n (%) n (%)

TEAEs 28 (93) 21 (68) 22 (73) SAEs 5 (17) 4 (13) 6 (20) TEAE leading to discontinuation 0 (0) 0 (0) 0 (0) Deaths 0 (0) 0 (0) 0 (0)

The proportion of neonates with TEAEs was comparable between stannsoporfin 4.5 mg/kg and placebo (Table 5). Dermatologic events were among the most commonly reported events in all groups. Although common and expected in neonates, dermatologic TEAEs were considered adverse events of special interest (AESIs). Erythema was the only event that was reported more frequently in the treatment groups vs placebo. All dermatologic events that could be associated to treatment were mild to moderate, transient, and resolved with minor intervention.



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Table 5: Adverse Events Occurring in ≥10% Neonates in Study 204

Preferred terms in ≥10% of neonates


N=30


N=31 Placebo + PT

N=30n (%) n (%) n (%)

Any TEAE 28 (93) 21 (68) 22 (73) Erythema 5 (17) 5 (16) 0 Cardiac murmur 5 (17) 4 (13) 4 (13) Dry skin 2 (7) 3 (10) 3 (10) Reticulocyte increase 2 (7) 3 (10) 1 (3) Erythema toxicum neonatorum 1 (3) 2 (6) 3 (10) Umbilical hernia 4 (13) 1 (3) 0 Rash 3 (10) 1 (3) 3 (10) Seborrheic dermatitis 3 (10) 1 (3) 0 Hyperbilirubinemia 2 (7) 1 (3) 3 (10)

Note: A patient was only counted once per SOC/preferred term. Note: AEs were coded using MedDRA, Version 19.0. TEAE = treatment-emergent adverse event, MedDRA = Medical Dictionary for Regulatory Activities, PT= phototherapy, SOC = system organ class

The proportion of neonates with SAEs was low and similar among treatment groups (Table 6). No individual SAE occurred in more than one neonate except hyperbilirubinemia in the placebo group and medical observation for two neonates in the stannsoporfin 3.0 mg/kg group. The medical observation events were prolonged hospitalizations, one neonate for rule out of sepsis, and one with supraventricular tachycardia with a congenital heart defect, neither of which the investigator considered to be related to study drug. No SAE led to study discontinuation.

Table 6: Serious Adverse Events in Study 204

Preferred Term


N=30


N=31 Placebo + PT

N=30 n (%) n (%) % n (%)

Any SAE 5 (17) 4 (13) 6 (20) Leukocytosis 1 (3) 0 0 Supraventricular tachycardia 1 (3) 0 0 Hyperbilirubinemia 1 (3) 1 (3) 3 (10) ABO incompatibility 0 0 1 (3) Bacterial sepsis 0 1 (3) 0 Meningitis viral 0 1 (3) 0 Sepsis 0 1 (3) 0 Hematocrit decreased 0 0 1 (3) Hemoglobin decreased 0 0 1 (3) Medical observation 2 (7) 0 0 Reticulocyte count increased 0 0 1 (3) Tachypnea 1 (3) 0 0

With regard to the safety results observed in the pooled acute safety set, the proportion of neonates with TEAEs was similar in the stannsoporfin 4.5 mg/kg (42%) and placebo (37%) groups. Adverse events reported in ≥2% of neonates were mild, with a similar frequency across



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groups (Table 7). The most commonly reported TEAEs in the stannsoporfin 4.5 mg/kg group were erythema, cardiac murmur, and candida infection.

Table 7: Adverse Events Occurring in ≥2% Neonates in the 4.5 mg/kg Stannsoporfin Group in the Pooled Acute Studies (204, 202, and 01-3W)

Preferred Term in ≥2% Neonates


N=48


N=126 Placebo N=134

n (%) n (%) % n (%) Any TEAE 38 (79.2) 53 (42.1) 49 (36.6) Erythema 6 (12.5) 7 (5.6) 0 Cardiac murmur 5 (10.4) 5 (4.0) 4 (3.0) Candida infection 0 5 (4.0) 4 (3.0) Thrombocytopenia 2 (4.2) 2 (1.6) 0 Rash 3 (6.3) 3 (2.4) 4 (3.0) Dry skin 2 (4.2) 3 (2.4) 3 (2.2) Reticulocyte increase 2 (4.2) 3 (2.4) 1 (0.7) Nasal congestion 1 (2.1) 3 (2.4) 0 Rash erythematous 1 (2.1) 3 (2.4) 1 (0.7) Diarrhea 0 3 (2.4) 0 Flatulence 0 3 (2.4) 0 Chromaturia 0 3 (2.4) 0

The proportion of neonates in the pooled acute studies with SAEs was low and similar in the 4.5 mg/kg (8%) and placebo (7%) groups (Table 8). There were two SAEs considered related to the drug. One neonate in the 3.0 mg/kg group had prolonged hospitalization due to rule out of sepsis, and the other neonate was given an accidental overdose of 6.4 mg/kg of stannsoporfin and had an erythematous rash receiving PT with the incorrect wavelength of light. The rash was moderate in intensity and resolved in five days without treatment.

No TEAEs led to discontinuation in either group, and there were no deaths during the acute studies. There was one death from sudden infant death syndrome (SIDS) at 4.5 months of age in a neonate who had received stannsoporfin 4.5 mg/kg in Study 01-3W.



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Table 8: Serious Adverse Events in the Pooled Acute Studies (204, 202, and 01-3W)

Preferred term


N=48


N=126 Placebo N=134

n (%) % n (%) n (%) Any SAE 6 (12.5) 10 (7.9) 9 (6.7) Diarrhea 0 1 (0.8) 0 Hyperbilirubinemia 1 (2.1) 1 (0.8) 6 (4.5) Bacterial sepsis 0 1 (0.8)a 0 Meningitis 0 1 (0.8)b 0 Meningitis viral 0 1 (0.8)c 0 Sepsis 0 1 (0.8)d 0 Viral infection 0 1 (0.8)e 0 Incorrect dose administered 0 1 (0.8) 0 Tremor 0 1 (0.8) 0 Wheezing 0 1 (0.8) 0 Anemia 1 (2.1) 0 0 Leukocytosis 1 (2.1) 0 0 Thrombocytopenia 1 (2.1) 0 0 Supraventricular tachycardia 1 (2.1) 0 0 ABO incompatibility 0 0 1 (0.7) Hematocrit decreased 0 0 1 (0.7) Hemoglobin decreased 0 0 1 (0.7) Medical observation 2 (4.2) 0 0 Reticulocyte count increased 0 0 1 (0.7) Tachypnea 1 (2.1) 0 0 a) Gram negative sepsis (Haemophilus parainfluenzae); mother had chorioamnionitis b) CSF culture negative; related to bacterial infection (Group B Streptococcus [GBS]; Streptococcus agalactiae in utero) c) CSF cultures negative; sepsis ruled out d) Blood and CSF cultures negative; no signs/symptoms of sepsis e) Coughing and spitting up; also diagnosed with gastroesophageal reflux disease

In the long-term pooled extension studies, the long-term safety profile was similar between the stannsoporfin 4.5 mg/kg and placebo groups. In the stannsoporfin 4.5 mg/kg group, 75% and 14% of neonates experienced TEAEs and SAEs, respectively, compared with 75% and 9% in the placebo group. There was one death from SIDS at 20 days of age in a neonate who was enrolled in Study 01C-3W but not randomized or treated.

The most frequent TEAEs were similar in both stannsoporfin and placebo groups and included upper respiratory tract infection, otitis media, pyrexia, and cough (Table 9). Speech disorder was seen in 13.7% of neonates who received 4.5 mg/kg and in 2.6% of those who received placebo; however, this observation results entirely from an imbalance in speech disorders from Study 01C-3W.



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Table 9: Common Adverse Events (≥10% Patients in Any Group) in the Long-Term Pooled Extension Studies (205, 203, and 01C-3W) Preferred terms in ≥10% of neonates

Stannsoporfin3.0 mg/kg

N=37


N=73Placebo

N=76 % % %

Any neonate with ≥10% Adverse Events 25 (67.6) 54 (74.0) 62 (81.6) Upper respiratory tract infection 10 (27.0) 35 (47.9) 43 (56.6) Otitis media 2 (5.4) 32 (43.8) 30 (39.5) Pyrexia 10 (27.0) 26 (35.6) 32 (42.1) Cough 5 (13.5) 17 (23.3) 25 (32.9) Diarrhea 4 (10.8) 14 (19.2) 20 (26.3) Conjunctivitis 5 (13.5) 12 (16.4) 17 (22.4) Nasal congestion 6 (16.2) 12 (16.4) 13 (17.1) Speech disorder 0 10 (13.7) 2 (2.6) Eczema 6 (16.2) 10 (13.7) 20 (26.3) Viral upper respiratory tract infection 4 (10.8) 9 (12.3) 7 (9.2) Bronchiolitis 2 (5.4) 9 (12.3) 9 (11.8) Gastroenteritis 2 (5.4) 9 (12.3) 11 (14.5) Rash 1 (2.7) 9 (12.3) 19 (25.0) Pharyngitis 0 9 (12.3) 13 (17.1) Dermatitis diaper 7 (18.9) 9 (12.3) 7 (9.2) Constipation 1 (2.7) 9 (12.3) 12 (15.8) Viral infection 5 (13.5) 8 (11.0) 19 (25.0) Vomiting 6 (16.2) 8 (11.0) 16 (21.1) Asthma 1 (2.7) 7 (9.6) 10 (13.2) Rhinorrhoea 4 (10.8) 7 (9.6) 10 (13.2) Bronchitis 2 (5.4) 7 (9.6) 12 (15.8) Ear infection 5 (13.5) 5 (6.8) 4 (5.3) Impetigo 4 (10.8) 5 (6.8) 2 (2.6) Pneumonia 2 (5.4) 5 (6.8) 9 (11.8) Gastroenteritis viral 1 (2.7) 4 (5.5) 8 (10.5) Otitis media acute 6 (16.2) 2 (2.7) 6 (7.9) Wheezing 2 (5.4) 2 (2.7) 8 (10.5)

Overall, the Rockefeller IND safety profile in over 1,100 neonates is generally consistent with the short- and long-term safety data from the InfaCare IND. With the exception of speech disorders, the types of AEs were comparable to those in the InfaCare IND studies. An imbalance in speech disorders was not seen in the Rockefeller IND studies. Across studies in both INDs, there was a similar rate of AEs compared to placebo. More details on the Rockefeller IND studies can be found in Section 7.4.

In summary, stannsoporfin 4.5 mg/kg was well-tolerated with a similar safety profile to placebo across the two INDs. Most common short-term events were mild to moderate and resolved on their own without intervention. In the long-term studies, there were no unexpected safety signals, and stannsoporfin 4.5 mg/kg was consistently similar to placebo.



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1.4.1 Neurological Safety

As discussed in Section 1.1, untreated hyperbilirubinemia can cause neurotoxicity; however, the exact TSB level where AEs begin to occur is not well understood. Stannsoporfin is unlikely to be associated with neurodevelopmental issues, as it is a large molecule (754 D) with high protein binding (96-99%) and is not expected to cross the blood brain barrier based on animal studies. Additionally, preclinical studies using single and repeat doses of stannsoporfin did not identify any neurological concerns. However, since infants with neonatal hyperbilirubinemia are at greater risk of exposure to unconjugated bilirubin, a known neurotoxin that can cross the blood-brain barrier, long-term neurocognitive and neurodevelopment AEs were identified as events of interest. The stannsoporfin data set provides a long-term cohort, with particular focus on long-term neurological events and neurodevelopmental outcomes.

A variety of well-known and validated tools were used to assess neurocognitive development. The assessments were categorized under three groups: general cognitive development, single cognitive domain-language development, and general behavior issues. Across all assessments and timepoints from three months to six years, these neurological assessments do not suggest that stannsoporfin causes clinically meaningful neurodevelopmental issues. Any perceived early signal did not correlate with a later signal, and the absence of early findings correlated with the absence of later findings.

Overall, neurological AESIs (Studies 01C-3W, 203, and 205) were reported in 27.4% (20/73) of neonates administered 4.5 mg/kg of stannsoporfin and in 17.1% (13/76) of neonates on placebo. In the stannsoporfin group, all events occurred in one or two neonates except speech disorder, which occurred in 13.7% (10/73) neonates in the stannsoporfin 4.5 mg/kg group. Speech disorders led to an imbalance in the overall AE profile. However, this observation in the pooled database results entirely from the imbalance in speech disorders in Study 01C-3W. InfaCare had all neurological AESI data from the program thoroughly reviewed by an independent qualified specialist to provide expert opinion during the evaluation of neurologic outcomes.

The six Rockefeller IND studies provide additional data for long-term neurological safety, including 459 neonates who received the 4.5 mg/kg dose of stannsoporfin. These data show an absence of a dose-response relationship for neurological AEs and a comparable rate of AEs in the 4.5 mg/kg stannsoporfin dose group and placebo. More details on the safety findings from these studies can be found in Section 7.4.

1.5 Conclusions

Phototherapy and ET are the current standard of care for the treatment of hyperbilirubinemia. Phototherapy acts only to break down excess bilirubin from the skin and blood, having no effect on bilirubin production, and requires separation of the infant from the mother (Muchowski 2014). Additionally, PT is not always successful, in which case ET, which has the potential for significant morbidity and mortality, may need to be performed. A therapy that inhibits bilirubin production could enable faster resolution, greater time for maternal bonding in those critical early hours of life, earlier discharge, fewer restarts of PT, and fewer hospital readmissions.



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Stannsoporfin is the first pharmacotherapy that effectively treats neonatal hyperbilirubinemia. Stannsoporfin has been studied with or without PT and has a favorable safety profile. Unlike PT, stannsoporfin inhibits bilirubin production, rapidly lowering TSB.

The totality of the data across studies conducted under both INDs demonstrates that stannsoporfin administered as a single 4.5 mg/kg IM injection (with or without PT) provides significant and clinically relevant benefits when administered to neonates ≥35 weeks GA with indicators of hemolysis at risk for developing severe hyperbilirubinemia.

Efficacy was demonstrated at doses of 3.0 and 4.5 mg/kg; however, the 4.5 mg/kg dose of stannsoporfin demonstrated superior efficacy across the widest range of clinical endpoints. Studies also showed that stannsoporfin 4.5 mg/kg decreased the time to crossing the AAP threshold for discontinuation of PT, decreased the requirement for PT, lowered the total time on PT, reduced the rate of PT failures, and decreased rehospitalizations for hyperbilirubinemia. These consistent efficacy findings support the use of stannsoporfin 4.5 mg/kg as an effective treatment for neonatal hyperbilirubinemia.

Stannsoporfin was safe and well-tolerated. There was no evidence that stannsoporfin causes any adverse hepatic or renal outcomes (see Section 7.3.2.3 for details on laboratory findings). Any AEs potentially associated with photosensitivity were mild or moderate in severity and self-limiting. Moreover, the safety profile of stannsoporfin did not appear to be dose-related, and there was no indication of increased risks associated with the 4.5 mg/kg dose compared with placebo.

Given the robust efficacy results and the favorable safety profile, the potential benefits of the use of stannsoporfin outweigh the possible risks.



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Normal elevation in bilirubin, sometimes described as “physiologic hyperbilirubinemia,” is transient and does not require treatment. In some infants, however, this physiologic hyperbilirubinemia is worsened by co-existing risk factors that aggravate hemolysis, thereby increasing bilirubin production. These infants with neonatal hyperbilirubinemia are at greater risk of exposure to free or unbound bilirubin – a known neurotoxin that can cross the blood brain barrier – and, therefore, need treatment to prevent potential neurotoxicity.

2.1.1 Adverse Neuro-motor Sequelae to Neonatal Hyperbilirubinemia

Unconjugated bilirubin is a known central nervous system (CNS) toxin that injures glial cells and causes a typical inflammatory response (Arif and Bhutta 1999). In the most severe cases of neonatal hyperbilirubinemia, excess bilirubin can build up in the brain and lead to severe neurodevelopment and neurological complications, such as intellectual and developmental delays, hearing loss, cerebral palsy, or death.

Bilirubin-induced neurologic dysfunction was classically characterized by chronic bilirubin encephalopathy (CBE), known as kernicterus, and acute bilirubin encephalopathy (ABE) (Bhutani and Johnson 2004, Shapiro 2010). Kernicterus, although infrequent in the United States (US), has a mortality rate of at least 10% and a long-term morbidity rate of at least 70% (Ip, Chung et al. 2004). More recently, consideration has been given to the potential permanent, but milder, adverse sequelae of hyperbilirubinemia. Thus, BIND is now recognized as a syndrome that encompasses a spectrum of adverse neuro-motor sequelae characterized by impaired audiologic, speech, and language processing, as well as disturbances in visual-motor and cognitive function (Johnson and Bhutani 2011).

With more recent evidence of damage confined to narrower neural pathways, the spectrum of BIND also includes impaired sensory and sensorimotor integration, central auditory processing, coordination, and muscle tone; these impairments may manifest as learning disabilities, autism spectrum disorder, attention deficit hyperactivity disorder, and non-progressive developmental delay (Kemper, Forsyth et al. 1989, Shapiro 2010). Importantly, the sequelae of BIND may be associated with lower levels of total bilirubin than previously thought to be harmful (Johnson and Bhutani 2011); however, the level of bilirubin exposure at which neurological impact begins has yet to be identified. Additionally, “concerns remain that the most vulnerable infants are likely to acquire BIND, either because their exposure to bilirubin is not identified as severe enough to need treatment or is prolonged but slightly below current threshold levels for intervention” (Bhutani and Johnson-Hamerman 2015). For these reasons, clinicians attempt to lower serum bilirubin levels as quickly as possible.

2.1.2 Risk Factors

Neonates with hyperbilirubinemia associated with hemolysis frequently develop rapidly rising levels of bilirubin that reach clinically significant levels and necessitate intervention. Risk factors for hemolysis include ABO blood type incompatibility, other alloimmune conditions (eg, antibodies directed against antigens of the Kell blood group, Kidd blood group, [eg, anti-Jka and anti-Jkb], Duffy blood group [eg, anti-Fya], and anti-MNS blood group antibodies), Rh hemolytic disease of the newborn, G6PD deficiency, hereditary red blood cell dyscrasias (eg, spherocytosis, elliptocytosis) and extensive bruising, among other reasons.



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According to the AAP Guidelines for the management of hyperbilirubinemia in neonates ≥35 weeks GA at birth, known factors that increase the neonate’s risk for developing severe hyperbilirubinemia include: lower GA; jaundice observed in the first 24 hours of life; isoimmune or other hemolytic disease (including neonates with Coombs positive ABO blood type incompatibility, Rh incompatibility, or G6PD deficiency); previous sibling with jaundice and history of PT; cephalohematoma or significant bruising; East Asian race; and pre-discharge total bilirubin in the high- or high-intermediate-risk zone of the Bhutani nomogram (American Academy of Pediatrics 2004, Maisels, Bhutani et al. 2009).

An additional risk factor for the development of severe hyperbilirubinemia is a rise in TSB of more than 5 mg/dL (86 μmol/L) per day, which translates to a rate of rise of ~0.2 mg/dL/h (Maisels, Deridder et al. 2009).

As shown in Figure 13, the Bhutani nomogram is a designation of risk for developing severe hyperbilirubinemia based on hour-specific serum bilirubin values. The zone that a pre-discharge TSB value falls in predicts the likelihood of developing subsequent severe hyperbilirubinemia, or bilirubin levels ≥95th percentile for age in hours (high-risk zone). Infants in the high-risk zone are producing bilirubin at a rate of 0.2 mg/dL/h or greater.

Figure 13: Bhutani Nomogram for Risk of Severe Hyperbilirubinemia

2.1.3 Total Serum Bilirubin as a Parameter for the Evaluation Hyperbilirubinemia

Determining a precise threshold at which bilirubin results in adverse sequelae has not been possible due to inter-related, complex factors. These factors include the relationship between GA at birth and the stage of brain development, the effect of decreasing GA on bilirubin-albumin



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binding capacity and the blood-brain barrier, the presence of neurotoxicity risk factors such as hemolytic disease, hypoalbuminemia, acidosis and sepsis, and the susceptibility to damage the cells in the brain’s grey matter. In addition, the ability to identify a “safe” threshold for unconjugated bilirubin in the neonate is confounded by the absence of a widely available assay to directly measure serum levels of free or unbound bilirubin (Amin and Lamola 2011). Therefore, in the absence of a precise target value for an individual with a given set of risk factors, the reduction of TSB by even 1-2 mg/dL should be considered clinically important.

Therefore, in the absence of superior alternatives, AAP guidelines use TSB in addition to the neurotoxicity risk factors as a basis for clinical decisions regarding the management of hyperbilirubinemia. Figure 14 shows the AAP guideline thresholds for TSB levels where PT should be initiated; neonates at higher risk need to begin PT at lower TSB levels than neonates at lower risk to prevent the development of more severe hyperbilirubinemia and neurotoxicity. Furthermore, as there is no clear predictive marker for the onset of adverse sequelae, TSB is the most clinically relevant parameter that guides evidence of progression, response to treatment, and therefore, clinical decisions (Porter and Dennis 2002).

Figure 14: Guidelines for Phototherapy Treatment in Infants ≥35 Weeks Gestational Age

2.2 Incidence

The extent of neonatal hyperbilirubinemia is dependent upon GA, risk factors, and the presence of some pathologies such as hemolytic disease, and epidemiologic studies have reported differing results regarding the incidence of hyperbilirubinemia.

Severe hyperbilirubinemia (>95th percentile for age in hours) has been reported to occur in 8-11% of infants, with approximately 2-5% requiring readmission to a hospital for treatment (Bhutani, Vilms et al. 2010). Previous reports stated that approximately 1/650-1000 infants >35 weeks GA can develop serum bilirubin values greater than 25 mg/dL, and approximately 1/10,000 can develop levels that exceed 30 mg/dL (FDA Ad. Com. Briefing Doc., 2012). More recently, Bhutani, Meng et al. (2016) reported that based on data in California, the prevalence of



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extreme hyperbilirubinemia (≥25 mg/dL) went from 25.4 in 2009 to 13.3 per 100,000 (assuming a 90% capture rate) in 2012. It is important to note, however, that the AAP guidelines recommend treatments of hyperbilirubinemia based on risk factors and GA. Rarely do clinicians intentionally allow bilirubin to approach extreme levels (≥25 mg/dL). A recent study of infants ≥35 weeks GA enrolled in a single health plan in California (Kaiser Permanente) showed that up to 15.9% received PT (Newman, Wickremasinghe et al. 2016).

2.3 Current Standards of Care for Hyperbilirubinemia

At present, PT is the initial clinical intervention used to treat hyperbilirubinemia. Phototherapy utilizes intensive blue light (430-490 nm at 30 µW/cm2) to convert free or unbound bilirubin in the blood to less toxic water-soluble photoisomers that can be cleared through the liver without the need for conjugation and excreted in the urine. Thus, PT increases bilirubin elimination but has no impact on the production of bilirubin.

Infants who do not respond to PT can be treated with ET, a procedure that replaces an infant's blood containing elevated bilirubin with donated blood in an attempt to quickly lower bilirubin levels. Due to a 5-10% risk of morbidity (ie, apnea, bradycardia, cyanosis, electrolyte imbalance, vasospasm, thrombosis, necrotizing enterocolitis) and 1-5% risk of mortality with ET, it is considered a last resort (Thilo and Rosenberg 2011). Exchange transfusion is only performed in infants who have not responded to other treatments, such as PT and/or off label IVIg, and who have signs of, or are at significant risk of neurologic toxicity due to high bilirubin levels.

Although not an FDA-approved therapy for the treatment of neonatal hyperbilirubinemia, IVIg has been used off-label to treat hyperbilirubinemia in an attempt to prevent the need for ET. While some studies have shown evidence of some efficacy with the use of IVIg, others have not, and the data are inconclusive. Additionally, there are inherent risks associated with the use of blood products.

2.3.1 Limitations of Phototherapy

Although PT is considered the current standard of care, it is associated with a number of side effects that range from self-limiting, mild events to those with more serious long-term implications. Decreasing the total need for PT is a clinically desirable goal for several reasons. First, physical separation of the mother and infant is required when infants are receiving PT in the well baby nursery or neonatal unit, which can interfere with bonding and, more importantly, breastfeeding and its associated benefits (Szucs and Rosenman 2013). Additionally, hospital stays are often prolonged for these neonates after mothers are discharged, further contributing to this separation. Since laboratory evaluations typically occur every 12 hours, mothers must wait for the results from the next evaluation to know whether their newborn is considered a candidate for discharge or must continue PT in the hospital. Twice as many mothers of infants with jaundice stopped breastfeeding at one month compared with those whose infants did not have jaundice (Kemper, Forsyth et al. 1989), and not breastfeeding has been associated with an increased incidence of infectious morbidity, including otitis media, gastroenteritis, and pneumonia, as well as elevated risks of childhood obesity, type 1 and type 2 diabetes, leukemia, and SIDS (Steube 2009).



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A literature review of data from randomized controlled trials showed that PT interferes with maternal-infant interaction and has short-term neonatal side effects including thermal imbalances, dehydration, electrolyte disturbances, and altered circadian rhythms (Xiong, Qu et al. 2011). Neonatal PT may also inhibit the immune system and place infants at higher risk for asthma, allergic rhinitis, and conjunctivitis (Xiong, Qu et al. 2011). In addition, PT produces oxidative stress in the newborn, alters cytokine levels, and produces DNA damage (Aycicek and Erel 2007, Tatli, Minnet et al. 2008, Procianoy, Silveira et al. 2010). The DNA damage from PT is thought to be correlated with the duration of PT – the longer the duration of PT, the greater the DNA damage (Tatli, Minnet et al. 2008).

Studies have also found that parents of infants with significant jaundice report more separation difficulties and are more likely to bring their children in for sick visits than parents of infants with similar health status. A large cohort study found that there was a higher rate of visits to subspecialists and illness visits to primary care physicians during the first 60 days of life in children who had received PT (relative risk=1.07; 95% confidence interval [CI], 1.05 to 1.10) (Muchowski 2014).

2.4 Unmet Need

Standard therapy for neonatal hyperbilirubinemia has not advanced significantly since the 1960s when PT emerged as a treatment for managing neonatal jaundice. Since then, PT has become the standard of care for treatment of hyperbilirubinemia due to the lack of alternatives. However, PT failures are not uncommon, and neonates may need to be re-treated or re-hospitalized for re-treatment. Because of the higher risks associated with ET, that modality is recommended only if TSB continues to rise despite intensive PT or if bilirubin levels are extremely high.

These two AAP recommended methods for managing neonatal hyperbilirubinemia facilitate the elimination of clinically concerning bilirubin in the bloodstream. None of the currently used therapies directly affect the production of bilirubin. Therefore, a therapy that inhibits the production of bilirubin, resulting in a significant decrease in TSB, that reduces the need for PT, rate of PT failures including the total duration of PT and rehospitalization, and that allows for maternal/infant bonding and uninterrupted breastfeeding, would be an important addition to the treatment options for neonatal hyperbilirubinemia.



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Figure 15: Stannsoporfin Mechanism of Action

There is no evidence that acute administration of stannsoporfin forms unusual heme or bilirubin metabolites in vivo. A compensatory increase in biliary heme excretion for at least 48 hours and up to 4 days was observed in some healthy volunteers. The capacity of the liver to excrete excess and untransformed heme directly into bile when heme oxygenase activity is competitively inhibited allows for maintenance of heme levels (Kappas, Simionatto et al. 1985). This heme overflow mechanism via hepatic excretory function is important in patients with acute hemolytic disease, such as jaundiced infants (Berglund, Angelin et al. 1988).

3.4 Drug Substance

The stannsoporfin chemical structure is shown in Figure 16. The molecular formula for stannsoporfin (tin mesoporphyrin IX dichloride) is C34H36Cl2N4O4Sn, and its chemical name is 21H, 23H-Porphine-2,18-dipropanoic acid-7,12-diethyl- 3,8,13,17-tetramethyl tin dichloride. Stannsoporfin has a molecular weight of 754.3 daltons, which is greater than the typical threshold of small molecules penetrating the blood brain barrier (400-500 daltons). Stannsoporfin is also highly protein bound (>96%-99%).



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Figure 16: Stannsoporfin (tin-mesoporphyrin IX dichloride) Chemical Structure

3.5 Product Description

Stannsoporfin is a clear solution that contains 20 mg/mL of stannsoporfin supplied in 2 mL vials each containing 1.5 mL for injection as a single dose. Stannsoporfin is expected to be administered as a single IM injection at a dose of 4.5 mg/kg of body weight.



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Blood (plasma), urine, and fecal samples were collected at pre-determined times and analyzed for stannsoporfin. Plasma samples were obtained at pre-dose, then 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 18, 24, 36, and 48 hours post-treatment. Pharmacokinetic data analysis was performed on plasma concentration vs time data of stannsoporfin using noncompartmental methods and sample collection times.

Plasma concentrations were detectable in all subjects for all three dose levels within the first 30 minutes. Maximum plasma concentrations were observed between 1-3 hours, and then declined in the terminal elimination phase. Estimation of an apparent terminal half-life was complicated by either a long distribution phase or multi-exponential decline in plasma concentrations.

Key stannsoporfin PK parameters are shown in Table 10. A linear dose-related increase was observed for Cmax, and a slightly more than proportional increase in AUC0-48 was observed. The mean plasma concentrations for 48 hours after the dose of stannsoporfin (20, 40, and 80 mg IM) is shown in Figure 17.

Additionally, urine and feces were collected pre-dose, then 0-24 hours and 24-48 hours post-dose; the percentage of dose recovered from these samples was calculated. Stannsoporfin dose recovered in urine over the first 48 hours after administration ranged from 0.22% to 9.85%, with the majority of the drug excreted during the first 24 hours for all subjects. Fecal recoveries were variable and ranged from 0-13.32% of the dose. Fecal excretion was evident within 24 hours of dosing (the first collection interval) but was below quantifiable detection limits for most subjects in all three dose groups (Table 10).

Table 10: Stannsoporfin Pharmacokinetic Parameters in Healthy Male Subjects following Single IM Doses of Stannsoporfin (Study 02-1W)

Parameter

Stannsoporfin Dose Number of Subjects

20 mg N=10

40 mg N=10

80 mg N=12

Cmax, ng/mL 2820 ± 92 4790 ± 236 8430 ± 261 Tmax, h [Range] 1.8 [1.0 to 2.0] 2.0 [1.0 to 3.0] 1.5 [1.5 to 2.0] AUC0-48, h*ng/mL 14900 ± 446 33300 ± 2340 72200 ± 3950 Urine Excretion (0 to 48 h), % of Dose

0.22 to 5.86 0.79 to 8.35 2.37 to 9.85

Fecal Excretion (0 to 48 h), % of Dose

0 to 1.75 0 to 13.32 0 to 5.72

Note: Data presented as Mean ± SEM except for Tmax which is the median [range] and excretion is the range of values. Abbreviations: AUC0-48 = area under the plasma concentration-time curve from 0 to 48 hours post-treatment; Cmax = observed maximum plasma concentration; SEM=standard error of the mean; Tmax = time of Cmax



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Figure 17: Plasma Concentrations of Stannsoporfin in Healthy Males following a Single IM Dose of Stannsoporfin (Study 02-1W)

4.2.2 Pharmacokinetics in Neonates

Study 202 was a Phase 2b, multi-center, double-blind, randomized, placebo-controlled trial of stannsoporfin in neonates ≥35 weeks GA up to 48 hours postnatal age with hyperbilirubinemia and risk factors for hemolytic disease (including neonates with Coombs positive ABO blood type incompatibility, Rh incompatibility, or glucose-6-phosphate dehydrogenase deficiency). Blood samples were collected for PK analysis pre-dose and at 0.75 and 2 hours or 1.5 and 3 hours (depending on PK blood sampling scheme assignment), 6, 12, 24, and 48 hours post-dose.

After a single IM injection, stannsoporfin was rapidly and well absorbed with an apparent elimination half-life of about 10 hours (Figure 18). Plasma stannsoporfin concentrations were still measurable at the last sampling time point of 48 hours after treatment at the 3.0 and 4.5 mg/kg doses, and for at least 24 hours post-treatment in neonates receiving 1.5 mg/kg.



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Figure 18: Mean Plasma Concentration vs Time in Neonates (Study 202)

Pharmacokinetic parameter data were available from 37 neonates (Table 11). The dose-proportional increase in Cmax over the 1.5 to 4.5 mg/kg dose range suggests that the absorption of stannsoporfin from the IM injection site follows first-order linear kinetics. The slightly greater than dose-proportional increase in the AUC0-inf of stannsoporfin, especially in the 1.5 to 3.0 mg/kg dose range, could be partly due to underestimation of the 1.5 mg/kg area under the curve (AUC) from the low plasma stannsoporfin concentrations that fell below the limit of quantitation ≥24 hours post-injection. In the higher dose range of 3.0 to 4.5 mg/kg, the increase in the AUC0-inf of stannsoporfin was 20% to 25% greater than dose-proportional.

The generally ≤30% CV in Cmax and AUC parameters of stannsoporfin across dose levels can be considered relatively low for neonates. This is a desirable characteristic for minimizing variations in the individual neonates’ levels of stannsoporfin and for safety and efficacy of the treatment.

Table 11: Stannsoporfin PK Parameters in Neonate Population (Study 202)

Parameter (units)

Stannsoporfin Dose Number of Neonates

1.5 mg/kg N=15

3.0 mg/kg N=15

4.5 mg/kg N=7

Cmax (ng/mL) 6445 ± 1792 28% [3310 to 9080]

11531 ± 1577 14% [8750 to 15000]

20414 ± 4074 20% [14400 to 25400]

Tmax (h) 1.67 [0.83 to 6.08]

1.58 [0.75 to 3.08]

1.67 [0.75 to 6.18]

AUC0-inf (hng/mL) 70338 ± 21141 30% [18860 to 106700]

206393 ± 46826 23% [141400 to 291300]

377571 ± 106856 28% [252400 to 599700]

Half-life (h) 5.46 ± 1.74 32% [2.98 to 9.99]

10.72 ± 3.60 34% [5.64 to 18.00]

9.86 ± 2.85 29% [6.59 to 14.70]

Note: Data presented as Mean ± SD; %CV; [Range] except for Tmax which is the median and range. Abbreviations: AUC0-inf = area under the plasma concentration-time curve from 0 to infinity; Cmax = observed maximum plasma concentration; %CV = coefficient of variance; SD = standard deviation; Tmax = time of Cmax



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4.3 Analysis of Results Across Studies

4.3.1 Population Pharmacokinetics

Stannsoporfin has been shown to have some evidence of non-linear PK characteristics in adults after IM dosing over a four-fold dose range (Study 02-1W) and in neonates (GA of 37.3-42.3 weeks) over a three-fold dose range (Study 202). To investigate the role of dose, body size (as a function of age) and other patient factors on stannsoporfin exposure, a mixed effects (population) PK model of stannsoporfin was developed based on data from Study 202 and Study 02-1W.

A satisfactory model of stannsoporfin PK for adults and neonates was developed. The model was a one compartment model with first-order intramuscular absorption, saturable elimination, and allometric coefficients relating kinetics to body size. The PK characteristics of stannsoporfin were found to depend on both dose and body size (and hence neonatal age). The stannsoporfin concentration associated with half maximal elimination was 2,730 ng/ml. This value implied that for a given body weight, the model-predicted stannsoporfin AUC had a slightly non-linear relationship with dose (more than proportional) with non-linear elimination most evident at the highest (4.5 mg/kg) dose. The non-linear kinetics were also consistent with the observation that stannsoporfin half-life may vary from study to study depending on the doses used.

The allometric coefficient scaling maximum elimination rate for body weight was 0.858. This value implied that for a given dose (mg/kg), the model-predicted stannsoporfin AUC would be lower as body weight decreased. However, the effect was relatively small as evident from the simulation of predicted stannsoporfin exposure in very premature neonates (32, 33, 34, and 35 weeks GA). This simulation showed exposure decreased slightly with lower GA and smaller body weights despite weight-based dosing. However, the exposure was sufficient to be associated with efficacy. The median simulated stannsoporfin AUC for premature neonates of all ages and a 4.5 mg/kg dose was within the band of AUC values previously associated with substantial reductions in TSB (median 48 hours TSB 19.2% of Baseline).

4.3.2 Exposure-Response

Exposure-response analyses were performed using available PK and pharmacodynamic data from a total of five studies; two PK studies (Studies 202 and 02-1W) and three PD studies without PK (Studies 204, 29,462-04, and 29,462-08). A population PK model was used to infer stannsoporfin exposure up to 48 hours post-treatment (AUC0-48) as a key exposure metric.

Total serum bilirubin values (percent change from Baseline at 48, 24 and 12 hours) all showed a noticeable linear relationship with stannsoporfin AUC, with the greatest observed reduction in TSB occurring at 48 hours. The 4.5 mg/kg dose of stannsoporfin had a more consistent effect (least variability) on TSB at 48 hours and produced the largest decrease in TSB when administered without (Figure 19 upper panel) or with PT (Figure 19 lower panel). When administered without PT, the slope and intercept of this linear model for 48-hour TSB vs AUC were -3.1e-04 (% change per unit AUC) and 134.0 (% change), respectively, and the R2 value was 0.133. The AUC values within the 95% prediction intervals for the 4.5 mg/kg dose group were associated with substantial reductions in the TSB as a percent of Baseline at 48 hours (median change 5.5% of Baseline; untreated change 134.0% of Baseline). These results are



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consistent with efficacy results observed in clinical studies supporting the 4.5 mg/kg dose. The dose of 4.5 mg/kg stannsoporfin was able to produce TSB at 48 hours that was a median of 43.8% of Baseline.

Figure 19: Change in Total Serum Bilirubin at 48 Hours vs Stannsoporfin AUC

Note: Percent change in TSB from Baseline at 48 h plotted against concurrent model predicted stannsoporfin exposure (AUC0-48) for the studies with pharmacodynamic data. Symbol color indicates nominal dose group (mg/kg). A line of linear regression is shown (blue line) with its 95% confidence intervals (grey ribbon). The slope and intercept of the regression line for the data without PT were -0.00031and 134, respectively, and the R2 value was 0.133. With phototherapy, the slope and intercept of the regression line were -8.2 x 10-5 and 31, respectively and the R2 value was 0.08. Simulated PopPK data are from Study 202 Study 204 from the InfaCare IND and 29,462-04 and -08 from the Rockefeller IND.



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5 OVERVIEW OF STANNSOPORFIN DEVELOPMENT

5.1 Preclinical Studies

Biodistribution

Extensive and prolonged-duration tissue distribution of radioactivity was observed in neonatal rats and dogs after IM administration of 119Sn-stannsoporfin. The recovery of radioactivity for adult rats and dogs over 168 hours after IM administration of 119Sn-stannsoporfin was 12% and 18% from urine and 51% and 29% from feces, respectively. The low total recoveries were attributed to tissue retention. In neonatal dogs, the estimated half-life of tissue elimination was 30.5 days, 34.8 days, and 24.4 days for kidney, liver, and spleen, respectively, and elimination of radioactivity was complete in most of the tissues by 42 days post-dose. After a single IM injection, the nonclinical whole-body autoradiography studies in adult and neonatal rats and dogs indicated <0.6% radioactivity detectible in brain tissue, which most likely represents background levels associated with radioactivity in blood within the microvasculature of the brain tissue. Overall, the data from the nonclinical program support a very limited potential for stannsoporfin to distribute to the brain.

Preclinical Safety

Hepatic, renal, and bone marrow effects, local tolerance, phototoxicity, neurodevelopmental outcomes, and reproductive effects were thoroughly assessed in 27 nonclinical toxicology studies. Acute and repeat-dose toxicity studies were conducted in neonatal rats and dogs, and phototoxicity studies were conducted in hairless neonatal guinea pigs. Key findings from preclinical safety studies are as follows:

Non-adverse hepatic pigments and gross organ discoloration were observed at one, three, and six-month necropsies and are consistent with Stannsoporfin accumulation and hepatic uptake.

Minimal to moderate necrosis of individual hepatocytes with associated elevations in alanine aminotransferase, aspartate aminotransferase, and total bilirubin in rats and dogs. However, these findings were observed following 30 days of repeat dose IM administration (not single dose) and were completely reversible following one month of recovery.

No dose- or treatment-related effects on clinical chemistry, including hematologic parameters, or urinalysis at the end of the one-month recovery period.

No dose- or treatment-related effects on CNS function or learning and memory in rats or neurobehavioral effects in dogs after four weeks of treatment with Stannsoporfin.

There were no remarkable local effects at injection sites after repeated IM administration.

Short-term Stannsoporfin treatment from postnatal days four to six had no adverse developmental or reproductive effects in treated rats or their offspring.

Filtration of broad-spectrum operating room light (100W/m2 for 6-hours) in the 360-420 nm range reduced but did not eliminate phototoxicity in neonatal hairless guinea pigs treated with stannsoporfin. Phototoxicity was observed for at least 48 hours after intramuscular administration of Stannsoporfin and was absent when PT began 5 days later.



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Treatment of hairless guinea pigs with 3, 12, and 40 mg/kg of Stannsoporfin and high intensity blue light (425 nm to 475 nm emission spectra) continuously for 3 days induced a dose-related increase in the incidence of minimal (Grade 1) cutaneous erythema.

Stannsoporfin was non-genotoxic when tested in a standard panel of in-vitro and in-vivo studies.

5.2 Regulatory History

Stannsoporfin has been studied in clinical studies since February 1987, when an IND application was filed by Rockefeller University for the management of jaundice. In January 1993, this Rockefeller IND was extended to include management of jaundice in the neonate. Data from six studies conducted under the Rockefeller IND are considered supportive to this New Drug Application (NDA). A new IND was filed by WellSpring in February 2002 for prevention or treatment of hyperbilirubinemia. WellSpring transferred sponsorship of the IND to InfaCare Pharmaceutical Corporation on 1 June 2005.

Key agreements between InfaCare and FDA include the following:

InfaCare was granted Fast-Track Designation/Rolling NDA submission for stannsoporfin on 14 December 2016. The Agency granted Fast-Track Designation based on its determination that stannsoporfin treats a serious condition, with the potential to address an unmet medical need.

InfaCare was granted a waiver for a Thorough QT Study on 12 December 2016.

InfaCare and FDA agreed upon an initial Pediatric Study Plan on 18 May 2017.

During the End-of-Phase 2 meeting for stannsoporfin held on July 19, 2016, the Agency agreed that the completed Study 204 along with the totality of the available data supports the filing of an NDA for FDA review, based on stannsoporfin’s efficacy and safety profiles.

Stannsoporfin received Priority Review on 20 February, 2018.

Study 202 was a dose-ranging, sequential cohort study in which neonates could be enrolled when they became candidates for PT according to the AAP guidelines, when TSB levels were 1-2 mg/dL beneath the AAP age-specific threshold for the initiation of PT. The design of Study 202 was agreed upon and approved by the FDA during a Type C Meeting in 2008. However, during recruitment of the study, InfaCare and FDA revisited the point at which stannsoporfin was initiated. InfaCare voluntarily put the study enrollment on hold while they discussed with the Agency. The discussion revolved around whether stannsoporfin should be commenced when neonates reached the AAP threshold for the initiation of PT or prior to reaching the threshold. However, as a result, the Agency placed a partial clinical hold on the IND due to this topic for Study 202 until further refinement on eligibility criteria completed. There were no safety observations associated with this action by the Agency, and long-term follow-up and emergency use were encouraged to continue; any protocols that enrolled populations for emergency use were not on clinical hold. As any major change in the entry criteria would confound the study outcomes, the decision was made to consider Study 202 complete and conduct the full study analysis. Despite



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the fact that only 50% (8 out of 18) of the planned neonates had been recruited in the 4.5 mg/kg cohort, statistical significance was nearly met (p=0.057).

FDA subsequently held an Advisory Committee meeting in 2012 to discuss Study 202 before InfaCare initiated the conduct of Study 204. The Advisory Committee discussed the study design, population, and results from Study 202. The committee commented that further short- and long-term safety data as well as information on patients with intensive PT would be helpful in making an approval recommendation, and the panel recommended enrolling patients already at the TSB levels for PT initiation in a future study. These important insights were the basis for the design of Study 204.

Additionally, supportive study, Study 01-3W, conducted under the InfaCare IND with WellSpring, was placed on clinical hold by the FDA in 2003 after 11% of the planned 1,600 neonates were randomized and treated. This study was initiated following a 30-day period for protocol review; however, the FDA placed the study on hold because the appropriateness of the target population (ie, otherwise healthy infants without additional risk factors for hemolysis) was questioned, and the Agency requested additional pre-clinical and CMC data. Study 01-3W is included in the safety assessment of the acute pooled studies, and a brief summary of the efficacy findings is included in this briefing document (Section 6.1.4), although the study did not achieve enrollment numbers to provide statistical power to meet its primary endpoint.

5.3 Clinical Development Program

A total of 1,433 neonates participated in stannsoporfin development studies across the Rockefeller and InfaCare INDs, representing multiple patient populations including premature, near-term, term, G6PD deficient, ABO/RH incompatible, with and without hemolysis, and neonates at risk for ET. Eight hundred and ninety (890) neonates received stannsoporfin in clinical trials, and 543 were controls (placebo, no treatment, or PT only). In addition, 59 adults, children, and neonates received stannsoporfin across studies and for indications that do not directly support the proposed indication. A total of 588 neonates received the 4.5 mg/kg dose of stannsoporfin in clinical studies, and 15 received the 4.5 mg/kg dose in emergency use investigator sponsored INDs (Table 26).

The key studies in the stannsoporfin development program are shown in Figure 20. The six relevant Rockefeller IND studies (Studies 29,462-04, -09, -05, -06, -07, and -08), performed in neonates (30 to <43 weeks GA) with a variety of underlying conditions for hemolysis, including ABO or Rh incompatibility and G6PD deficiency identified the initial efficacy and safety characteristics of stannsoporfin and guided the design of the later studies. These six studies are supportive of the use of stannsoporfin without PT. Three additional studies (Studies 29,462-01, -02, and -03) were conducted under the Rockefeller IND in populations (healthy adult volunteers, adults with porphyria, and adults and children with Crigler-Najjar, respectively) not directly related to the proposed indication. These three studies had few patients and are not related to the InfaCare IND and are therefore not included in this briefing document. Table 51 in Appendix 12.1 details the parameters of these Rockefeller IND Studies. Given the consistency of the results throughout the clinical development program, these six Rockefeller IND studies provide additional support for the efficacy and safety of stannsoporfin in the proposed indication. Although causality, severity, and relatedness to study drug of AEs were not captured in the



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Rockefeller IND studies, the type and incidence of AEs relative to placebo mirror the events observed in the studies conducted under the InfaCare IND.

The clinical data supporting stannsoporfin under the InfaCare IND come from nine clinical studies, one of which is still ongoing. These studies include one pivotal acute efficacy study (Study 204), two supportive acute efficacy studies (Studies 202 and 06), three companion long-term safety follow-up studies (Studies 203, 205, and 06LT), one acute efficacy study (Study 01-3W) and its companion long-term safety follow-up study (Study 01C-3W), and one PK study conducted in healthy adult volunteers (Study 02-1W).

Studies 204 (pivotal) and 202 (supportive for efficacy and safety) were randomized, double-blind, placebo-controlled trials, and Study 06 (supportive, efficacy because it was open label, not placebo controlled and only 0.75 mg/kg and 1.5 mg/kg doses were used in patients at risk for Exchange transfusion). Study 01-3W was also conducted as a randomized, double-blind, placebo-controlled trial of 4.5 mg/kg and is supportive for safety.

Figure 20: Key Studies in Stannsoporfin Development Program

*Studied stannsoporfin without PT NOTE: For the long-term extension studies, the highest N at any visit is represented in the figure.



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6.1 Efficacy Findings: InfaCare IND

6.1.1 Study 204

6.1.1.1 Clinical Study Design

Study 204 was a multicenter, single-injection, randomized, double-blind, placebo-controlled, parallel-group study evaluating the safety and efficacy of two doses (3.0 mg/kg or 4.5 mg/kg) of stannsoporfin with PT in neonates (Figure 21). The study enrolled neonates ≥35 weeks GA who were candidates for PT when TSB reached the AAP threshold for the initiation of PT, with indicators of hemolysis, including a rising TSB and a positive Coombs test or a negative Coombs test plus reticulocytes >6%.

Screening Period

Once neonates were enrolled in the study, TSB levels were monitored to determine when the TSB level reached or crossed the age-specific threshold for initiating PT per the AAP guidelines.

Randomization/Treatment Period

Neonates who met the eligibility criteria at the screening visit were immediately randomized 1:1:1 to receive a single IM dose of stannsoporfin 3.0 mg/kg or stannsoporfin 4.5 mg/kg, or placebo within the first 48 hours of life. Phototherapy was to be initiated within a window of 30 minutes before or after the administration of the single IM dose of study drug. Narrow spectrum blue light with a single overhead unit was used for PT, and neonates’ eyes were protected with opaque eye patches.

Post-treatment Period

Assessments were performed at 2, 6, 12, 18, 24, 30, 36, and 48 hours, and 7 and 30 days post-stannsoporfin administration. Total serum bilirubin levels were measured at 6, 12, 18, 24, 30, 36 ± 2 hours, and 48 ± 6 hours after stannsoporfin administration. If a TSB measurement obtained during PT treatment was below the age-specific threshold for PT, the PT was discontinued.

Neonates were eligible for hospital discharge after PT was discontinued and when all safety assessments were considered normal. If discharge was before 48 hours, all assessments required at 48 hours were performed at the time of discharge. An amendment was put in place following study initiation to ensure neonates discharged prior to 48 hours were required to have the 48-hour assessment completed. Neonates were followed-up on Day 7 and Day 30, and a Day 14 visit was required if there were any clinically significant laboratory findings on Day 7.

Long-term follow-up

All neonates who received stannsoporfin were asked to participate in a long-term follow-up trial (Study 205) to evaluate neurocognitive and developmental outcomes.



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Enrollment Criteria

A full list of inclusion and exclusion criteria is in Appendix 12.2. Key enrollment criteria included the following:

Term and near-term neonates ≥35 and ≤43 weeks GA, aged 0-48 hours (at the time the qualifying TSB was drawn) with ABO or Rh incompatibility (anti-C, c, D, E or e) who were direct antiglobulin test (DAT)-positive, or aged 0-72 hours (at the time the qualifying TSB was drawn) with G6PD deficiency as confirmed by a documented blood test

OR

Term and near-term neonates ≥35 and ≤43 weeks GA, aged 0-48 hours (at the time the qualifying TSB was drawn) with ABO or Rh incompatibility (anti-C, c, D, E or e) who were DAT-negative (or status unknown) and had an increased reticulocyte count (>6%).

Birth weight ≥2500 g

A TSB value at or above the age-specific threshold for initiating PT per the AAP guidelines

Direct bilirubin could not be ≥2 mg/dL, or >20% of the TSB

Alanine aminotransferase (ALT) could not be >2 times the upper limit of normal (ULN) and/or aspartate aminotransferase (AST) >3 times ULN

Creatinine and/or blood urea nitrogen (BUN) could not be >2 times the ULN

Apgar score could not be ≤6 at age five minutes



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Efficacy Endpoints

The principal efficacy endpoints in the stannsoporfin clinical development program were based on measures of bilirubin exposure: percent change and change in bilirubin levels from Baseline, peak bilirubin level, and bilirubin AUC.

The principal methods used to manage neonatal hyperbilirubinemia include the use of PT, ET, and IVIg. Therefore, other measures of stannsoporfin efficacy included endpoints that could demonstrate a positive change in standard of care, such as reduced need for PT, ET, or IVIg; reduction in the duration of PT, and reduction in the incidence of PT failures (including restart of PT after discontinuation, hospital readmission for hyperbilirubinemia, use of IVIg, or need for ET).

6.1.1.1.2.1 Primary Endpoint

The primary efficacy endpoint was the percent change from Baseline in TSB (the Baseline TSB was the TSB that qualified for randomization) at 48 hours post-treatment. In addition to patient factors (such as GA and risk factors), TSB has been used as the primary parameter to guide clinical decision-making and has been the standard measurement for monitoring neonatal hyperbilirubinemia. Total serum bilirubin levels have also been the basis for the AAP’s standardized hyperbilirubinemia management guidelines from 1994 to present. The percent change from Baseline in TSB was determined to be the most sensitive endpoint and the one that required the least number of neonates (ie, lower risk of unnecessary exposure) to provide the statistical power necessary to determine whether or not stannsoporfin (with PT) was efficacious compared with placebo (PT alone).

6.1.1.1.2.2 Key Secondary Endpoints

Prespecified, hierarchical key secondary efficacy endpoints included the following:

Time to TSB crossing at or below age-specific threshold to discontinue PT

Phototherapy failure defined as one of:

− Restart of PT >6 hours after stopping

− Rehospitalization for hyperbilirubinemia

− Use of IVIg

− Need for ET

Incidence of rebound hyperbilirubinemia (ie, increase in TSB above the age-specific threshold for initiating PT following the discontinuation of the initial PT) ≤54 hours after discontinuation of PT (increases in TSB after 54 hours were not captured as rebound).

6.1.1.1.2.3 Other Secondary Endpoints

Other secondary efficacy endpoints included:

Change in measured TSB at 48 hours Percent change from Baseline in TSB at 6, 12, 18, 24, 30, and 36 hours post-treatment TSB AUC above the Baseline TSB (0 to 48 hours post-treatment) Peak serum bilirubin



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Duration of clinical requirement for PT

Statistical Analyses

Primary Efficacy Endpoint Evaluation

The primary efficacy analysis was prespecified to be performed for the ITT population using LOCF analysis and an analysis of covariance (ANCOVA) model, with treatment, the stratification factor (ABO/Rh incompatibility vs G6PD deficiency), and Baseline TSB value as the covariates, and an interaction term of treatment by stratification factor (Dobson 2002). Since the interaction term was not significant (p>0.10) in the model, the interaction term was dropped from the final primary efficacy model. All tests were based on the Type III sum of squares.

Sensitivity Analyses

Prespecified sensitivity analyses of missing data assumptions were performed to verify the impact of the LOCF method on the estimates of the treatment effect. The analyses were performed on observed data, using an MMRM that includes the fixed effects of treatment (stannsoporfin 3.0 mg/kg, stannsoporfin 4.5 mg/kg, placebo), TSB measurement (6, 12, 18, 24, 30, 36 and 48 hours), the stratification factor, Baseline TSB value, and treatment-by-visit interaction (McCulloch and Searle 2001). If the unstructured correlation matrix did not converge, other methods were applied (eg, autoregression). Treatment comparisons similar to those for the primary efficacy analyses were performed. No LOCF imputations were used when performing the MMRM analysis.

The same primary efficacy analysis ANCOVA model used for the ITT population with LOCF was applied to the PP population as another sensitivity analysis.

Secondary Efficacy Endpoint Evaluation

If the p-value for the primary endpoint for the ITT population for the highest dose (4.5 mg/kg) was statistically significant (p<0.050, two-sided) then the hypothesis testing for the endpoint was to continue on to the lowest dose (3.0 mg/kg) for the primary endpoint for the ITT population. If the primary endpoint analysis was statistically significant for the primary endpoint for both doses, then secondary efficacy endpoints one through three (below) were analyzed by dose in a hierarchical order. These secondary endpoints were considered clinically meaningful and impactful to the care of the neonates. If at any point the hypothesis testing for a given dose yielded a non-significant result, the testing was to be stopped for that dose, but could continue for the other dose as long as the test for that other dose was significant.

1. Time at Which TSB Crosses at or Below Defined Threshold for Discontinuation of PT: Linear interpolation method was used to estimate the time at which TSB first crosses at or below the defined threshold after initiation of the first PT (post-treatment) in hours. Clinically, this represents the timepoint when PT could be discontinued.

2. Phototherapy Failure: PT was used as a binary variable based on each of four components, (defined below) in which, if any component was a positive event (if any occurs) then PT was considered to have failed. Otherwise, PT was not considered to have failed. There should not be any missing values.



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All neonates in the ITT population were included in this endpoint. PT was considered to have failed if any of the following conditions were met:

Any documented ET started anytime post-drug administration (up to 30 days post-drug administration).

Any documented IVIg drug use started anytime post-drug administration (up to 30 days post-drug administration).

Any documented hospital re-admission for hyperbilirubinemia, with hospital re-admission started anytime post-initial or first hospital discharge (up to 30 days post-drug administration). Adverse events for hyperbilirubinemia without hospital re-admission were not considered a positive event.

Any documented restarting of PT, started any time after PT was discontinued for at least six hours (up to 30 days post-drug administration). If PT was stopped and subsequently restarted before six hours after stopping, then it was not considered a positive event.

Clinically, this represents the requirement for additional intervention to treat hyperbilirubinemia.

3. Rebound Hyperbilirubinemia: Rebound hyperbilirubinemia was defined as an increase in TSB above the age-specific threshold for initiating PT at least six hours following the discontinuation of the initial PT. This variable was analyzed as a binary variable assigned the values of 1, if rebound hyperbilirubinemia occurred ≤54 hours post-treatment, and 0 if rebound hyperbilirubinemia did not occur or occurred >54 hours post-dose. Bilirubin increases that re-crossed the PT threshold after 54 hours from discontinuation of PT were not captured as a rebound, by definition.

6.1.1.2 Patient Disposition

Of 151 screened neonates, 91 (60%) were randomized (30, 31, and 30 neonates to the 3.0 mg/kg, 4.5 mg/kg, and placebo groups, respectively; Figure 22). All 91 (100%) neonates who were randomized received PT and study drug (ie, stannsoporfin or placebo), and 83 (91%) neonates completed the study. Overall, eight (9%) neonates discontinued the study: six (7%) were lost to follow-up (one, three, and two neonates in the 3.0 mg/kg, 4.5 mg/kg, and placebo groups, respectively) and two (2%) were voluntarily withdrawn by the parent/guardian (one each in the 4.5-mg/kg group and placebo group). Six of these eight patients had a 48-hour TSB sample and therefore did not require imputation. No patient was withdrawn because of an AE.



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Figure 22: Patient Disposition in Study 204 (ITT)

6.1.1.3 Patient Demographic and Baseline Characteristics

Neonates’ demographic and baseline characteristics were similar across the three treatment groups (Table 12).

The mean (standard deviation [SD]) age of neonates when randomized was similar in the stannsoporfin 3.0 mg/kg and 4.5 mg/kg and placebo groups (21.66 [11.42], 24.05 [11.020] and 25.92 [12.36], respectively), and the mean (SD) GA was 39.20 (1.17), 39.39 (1.27), and 39.26 (1.11) weeks, respectively. Approximately half of each group was male, and race was similar between groups. The mean (SD) birth weight was 3.33 (0.49), 3.38 (0.47), and 3.38 (0.44) kg, respectively, and mean (SD) Apgar score at five minutes was 8.8 (0.76), 8.9 (0.44), and 8.9 (0.25), respectively.

Comparable proportions of neonates had blood type A (53%) and blood type B (46%). In the 4.5 mg/kg and placebo groups, a majority of neonates had blood type A (58% and 53%, respectively); in the 3.0 kg/kg group the proportion of neonates with blood type A was 47%, and 50% had type B. One neonate in the 3.0-mg/kg group had blood type AB. No neonate had blood type O. Most neonates were Rh positive (95%) and had a positive direct Coombs test (93%). All 91 neonates were stratified during randomization as ABO/Rh incompatible.



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Table 12: Patient Demographic and Baseline Characteristics in Study 204 (ITT)

Assessment Statistic

Stannsoporfin + PT Placebo + PT

(N=30) 3.0 mg/kg

(N=30) 4.5 mg/kg

(N=31) Age1, h Mean (SD) 21.66 (11.417) 24.05 (11.020) 25.92 (12.361) Gestational age, wk Mean (SD) 39.20 (1.172) 39.39 (1.271) 39.26 (1.112)

Female n (%) 15 (50) 15 (48) 13 (43) Male n (%) 15 (50) 16 (52) 17 (57) Hispanic or Latino n (%) 7 (23) 9 (29) 15 (50) Not Hispanic or Latino n (%) 23 (77) 22 (71) 15 (50) White n (%) 9 (30) 13 (42) 12 (40) Black or African American

n (%) 16 (53) 13 (42) 9 (30)

Asian n (%) 0 0 1 (3) American Indian or Alaska Native n (%) 0 0 0 Native Hawaiian or other Pacific Islander n (%) 0 0 0 Other n (%) 4 (13) 5 (16) 8 (27) Not Reported n (%) 1 (3) 0 0

Birth weight, kg Mean (SD) 3.331 (0.4908) 3.381 (0.4731) 3.378 (0.4375) Weight at time of injection of study medication2, kg

Mean (SD) 3.289 (0.4814) 3.341 (0.4516) 3.314 (0.4051)

Apgar Score 1 min Mean (SD) 7.8 (1.46) 8.3 (1.72) 8.4 (1.30) Apgar score 5 min Mean (SD) 8.8 (0.76) 8.9 (0.44) 8.9 (0.25) Blood Group

A n (%) 14 (47) 18 (58) 16 (53) B n (%) 15 (50) 13 (42) 14 (47) AB n (%) 1 (3) 0 0 O n (%) 0 0 0 Unknown n (%) 0 0 0

Rh group Positive n (%) 29 (97) 4 29 (94) 28 (93) Negative n (%) 0 2 (6) 2 (7)

Direct Coombs test result Positive n (%) 29 (97) 29 (94) 27 (90) Negative n (%) 1 (3) 2 (6) 3 (10)

Reticulocyte count increased (%) >6 n (%) 20 (67) 19 (61) 18 (60) ≤6 n (%) 5 (17) 2 (6) 5 (17) Missing n (%) 5 (17) 10 (32) 7 (23)

Tested for G6PD deficiency? Yes n (%) 1 (3) 0 0 Normal n (%) 1 (3) 0 0 Abnormal n (%) 0 0 0 No n (%) 29 (97) 31 (100) 30 (100)

Stratification factor3 ABO/Rh incompatibility n (%) 30 (100) 31 (100) 30 (100) G6PD deficiency n (%) 0 0 0

Nutritional source Breast Milk n (%) 12 (40) 7 (23) 11 (37) Formula n (%) 8 (27) 8 (26) 4 (13)



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Assessment Statistic


(N=30) 3.0 mg/kg

(N=30) 4.5 mg/kg

(N=31) Both n (%) 10 (33) 16 (52) 15 (50)

Feeding Frequency Once every h n (%) 3 (10) 1 (3) 1 (3) Once every 2 h n (%) 5 (17) 5 (16) 6 (20) Once every 3 h n (%) 14 (47) 23 (74) 22 (73) Once every 4 h n (%) 8 (27) 0 1 (3)

Volume per feed, mL n 26 25 26 Mean (SD) 26.3 (13.58) 23.9 (8.85) 20.0 (11.31)

1 Age was calculated relative to the time of injection of study medication. 2 Weight at time of injection (kg) was defined as the weight provided to the pharmacist at injection time of study medication 3 Stratification factor was based on the randomization schedule from the IXRS system. 4 Rh status was unable to be reported for Patient , so total for Rh was 90 instead of 91. G6PD = Glucose-6-phosphate dehydrogenase, h = hours, Max = maximum, Min = minimum, IXRS = interactive voice (or web) response system, SD = standard deviation, Wk = week

The majority of neonates who entered the study had a rapid rise in bilirubin levels after birth. Sixty one of the 91 neonates (67%) had TSB levels that crossed the AAP threshold for PT within the first 24 hours of life, and 78 (86%) within the first 32 hours. Figure 23 shows these data plotted on the Bhutani nomogram which assesses the risk for the development of hyperbilirubinemia. The high-risk zone (95th percentile) represents a rate of rise in TSB in the first 36 hours of approximately 0.2 mg/dL/h (5 mg/dL/day), which is an indicator for hemolysis and a risk factor for the development of severe hyperbilirubinemia (Maisels, Deridder et al. 2009). All neonates were above the 75th percentile on the Bhutani nomogram. The vast majority were at or above the 95th percentile high-risk zone, and therefore had levels that were rising much more rapidly than 0.2 mg/dL/h. These patients were at high risk for developing severe hyperbilirubinemia.

When Baseline qualifying TSB levels were plotted against age and compared to the Bhutani predictors of the risk of severe hyperbilirubinemia (Figure 23), all neonates were above the 75th percentile, and the vast majority of neonates in this study were at or above the 95th percentile, which is a risk factor for developing severe hyperbilirubinemia.

Table 13: Age at Qualifying TSB in Study 204 (ITT)

Category/Group


(N=30) 3.0 mg/kg

(N=30) 4.5 mg/kg

(N=31) ≤12 hours 13 (43.3) 12 (38.7) 10 (33.3) >12 to ≤24 hours 11 (36.7) 8 (25.8) 7 (23.3) >24 to ≤32 hours 3 (10.0) 7 (22.6) 7 (23.3) >32 to ≤40 hours 1 (3.3) 2 (6.5) 3 (10.0) >40 hours 2 (6.7) 2 (6.5) 3 (10.0)

N: number of neonates TSB = total serum bilirubin

(b) (6)



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Figure 23: Qualifying TSB vs Bhutani Predictors of Severe Hyperbilirubinemia in Study 204 (ITT)

6.1.1.4 Primary Endpoint: Percent Change from Baseline in Total Serum Bilirubin at 48 Hours

In the ITT population, the mean percent change in TSB from Baseline at 48 hours (LOCF) was -8.91% in the 3.0 mg/kg group and -5.79% in the 4.5 mg/kg group, compared with 21.97% in the placebo group (Table 14). Mean Baseline TSB values were similar among all treatment groups. The difference in mean TSB from Baseline at 48 hours was -1.34 mg/dL in the 3.0 mg/kg group and -1.11 mg/dL in the 4.5 mg/kg group; in the placebo group, there was an increase of 1.75 mg/dL.

The LS mean percent decrease from Baseline at 48 hours was -9.54% in the 3.0 mg/kg group and -5.30% in the 4.5 mg/kg group, whereas the LS mean percent in the placebo group increased by 22.10%. The LS mean difference was statistically significant for both the 3.0 mg/kg and 4.5 mg/kg groups (-31.64; p<0.0001 and -27.40; p<0.0001, respectively) compared to placebo. The difference between the two doses of stannsoporfin was not statistically significant.

Stannsoporfin Briefing Document InfaCare Pharmaceutical Company FDA Advisory Committee Meeting 03 May, 2018

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Table 14: Percent Change from Baseline in Total Serum Bilirubin (mg/dL) at 48 Hours in Study 204 (ITT)

Primary Efficacy Analyses Total Serum Bilirubin (mg/dL)

Statistic Stannsoporfin + PT

Placebo + PT 3.0 mg/kg 4.5 mg/kg

N=30 N=31 N=30 Baseline Mean (SD) 9.82 (2.641) 9.97 (2.967) 9.92 (2.211) 48 hours LOCF Mean (SD) 8.48 (1.973) 8.86 (2.142) 11.67 (2.337) Percent change from Baseline at 48 hours LOCF

Mean (SD) -8.91 (28.863) -5.79 (29.940) 21.97 (32.338) LS mean (95% CI) -9.54 (-18.281, -0.802) -5.30 (-13.896, 3.297) 22.10 (13.363, 30.838) LS mean diff vs placebo (95% CI) -31.64 (-44.000, -19.283) -27.40 (-39.657, -15.142)p-value vs placebo <0.0001 <0.0001 p-value vs stannsoporfin 4.5 mg/kg 0.493

MMRM Analyses N=23 N=19 N=19 Percent change from Baseline at 48 h

Mean (SD) -13.13 (25.261) 0.67 (31.563) 31.81 (35.626) LS mean (95% CI) -10.02 (-20.487, 0.447) -4.20 (-15.096, 6.698) 25.36 (14.339, 36.373) LS mean diff vs placebo (95% CI) -35.38 (-50.571, -20.180) -29.56 (-45.051, -14.059)p-value vs placebo <0.0001 0.0003 p-value vs stannsoporfin 4.5 mg/kg 0.445

Note: LOCF approach was used in the primary analysis if the TSB at 48 hours (within 40 to ≤54 hours from time of dose) was missing. LOCF was not performed on the data used in the MMRM analysis. Note: For primary efficacy analyses, p-values were based on an analysis of covariance model, which included treatment group (stannsoporfin 3.0 mg/kg, stannsoporfin 4.5 mg/kg, and placebo), stratification factor (ABO/Rh incompatibility vs G6PD deficiency), Baseline TSB as the covariate, and an interaction term of treatment by stratification factor. However, all randomized neonates were from one strata (ABO/Rh incompatibility) so the stratification factor and the interaction term of treatment by stratification factor were removed from the model. Note: For MMRM analyses, p-values were based on a mixed-effects model with the fixed effects of treatment (stannsoporfin 3.0 mg/kg, stannsoporfin 4.5 mg/kg, and placebo), stratification factor (ABO/Rh incompatibility vs G6PD deficiency), TSB visits, and an interaction term of treatment by visit, and Baseline TSB as the covariate assuming a heterogeneous first-order autoregressive variance-covariance structure. However, all randomized neonates were from one strata (ABO/Rh incompatibility) so the stratification was removed from the model. CI = confidence interval, G6PD = glucose-6-phosphate dehydrogenase, h = hours, LS = least squares, LOCF = last observation carried forward, MMRM = mixed-effects model for repeated measures, SD = standard deviation, TSB = total serum bilirubin



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Prespecified sensitivity analyses were also conducted for the primary endpoint using an MMRM without LOCF. In addition, a sensitivity analysis was performed on the PP population. The PP and MMRM analysis results were generally consistent with the results of the LOCF primary analysis (Table 14; Figure 24).

Figure 24: Primary Efficacy Sensitivity Analyses in Study 204 (ITT)

In addition, a sensitivity analysis was conducted excluding 11 neonates in the ITT population of Study 204 who had not crossed the AAP-defined threshold for initiation of PT when study treatment was administered. These neonates were within the AAP guidelines for initiating PT (within 2 mg/dL), and most were within 0.1 mg/dL TSB of the defined threshold. The neonates were considered by the physicians to be eligible for PT based on the clinical picture of each patient, and withholding PT when patients were so close to the threshold was considered clinically impracticable. The sensitivity analysis without these 11 patients showed consistent results with the overall primary endpoint (Table 15).

Table 15: Sensitivity Analyses Conducted on Eleven Patients Who Had Not Crossed the AAP-defined Threshold for Initiation of Phototherapy in Study 204 (Primary Endpoint of Percent Change from Baseline in TSB at 48 Hours)

Analysis Stannsoporfin 4.5 mg/kg

N Placebo

N

Log-rank p-value Stannsoporfin 4.5 mg/kg

vs Placebo

ITT population with LOCF imputation 29 25 0.0000068

ITT population without LOCF 19 19 0.0001950

PP population with LOCF imputation 19 19 0.0000526

PP population without LOCF imputation 19 19 0.0002737



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6.1.1.5 Key Secondary Endpoints

As described in Section 6.1.1.1.3, analysis of the prespecified key, clinically relevant, secondary endpoints followed a hierarchical order to control for Type I error. Since the primary endpoint analysis was statistically significant (p<0.05) for the ITT population, the secondary efficacy endpoints were analyzed in hierarchical order and according to dose (ie, the 4.5 mg/kg first).

Time at Which TSB Crosses at or Below Defined Threshold for Discontinuing PT

In the ITT population, TSB values crossed below the PT threshold statistically significantly earlier in the stannsoporfin 4.5 mg/kg group than in the placebo group (p=0.003; Table 16). In the 3.0 mg/kg group, the difference from placebo was not statistically significant (p=0.232), thereby stopping the hierarchical testing for this dose group.

Figure 25 shows the median time at which TSB crossed at or below the PT threshold.

Table 16: Time at Which Total Serum Bilirubin Crossed at or Below the Defined Phototherapy Threshold in Study 204 (ITT)


Parameter Statistic

3.0 mg/kg 4.5 mg/kg (N=30) (N=31) (N=30)

Time at which TSB crossed at or below defined threshold, (hours) – interpolated

N (%) 30 (100) 31 (100) 28 (93)

50th percentile (95% CI) 11.8 (8.23, 21.82) 10.6 (8.12, 16.35) 20.9 (9.17, 26.54)

Min, Max -3.7, 53.6 -5.5, 28.5 -4.4, 54.0

Log-rank p-value vs placebo 0.232 0.003 —

Cox's model HR (95% CI) 1.5 (0.82, 2.58) 2.5 (1.35, 4.64) —

p-value 0.199 0.004 —

Note: Time at Which TSB Crosses at or Below Defined Threshold was calculated as Date / Time [Serum Bilirubin First crosses at or below the age-specific threshold for PT ≤54 hours posttreatment] - Date / Time of Injection of Study Medication. Neonates whose TSB value never crossed the PT Threshold before or at 54 hours for both analyses, using observed values and interpolated values, were censored at 54 hours or at the time they were discharged from the hospital if before 54 hours (ie, the 6-hour window for the 48-hour time point).

Note: Each event occurring at the various percentiles was estimated using the Kaplan-Meier method and analyzed using the log-rank test.

Note: The HR, CI, and p-value were based on the Cox proportional hazards model, which includes treatment group (stannsoporfin 3.0 mg/kg, stannsoporfin 4.5 mg/kg, and placebo) and stratification factor (ABO/Rh incompatibility vs G6PD deficiency). However, all randomized neonates were from 1 stratum (ABO/Rh incompatibility), so stratification factor was removed from the model.

Note: The interpolated value of when TSB crossed at or below the defined threshold was based on linear interpolation and was estimated to be the time that crossed exactly at the PT threshold line such that both the values and time below and above the PT threshold were considered.

CI = confidence interval; G6PD = glucose-6-phosphate dehydrogenase; HR = hazard ratio; ITT = intent-to-treat; Max = maximum; Min = minimum; PT = phototherapy; TSB = total serum bilirubin



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Figure 25: Time at which Total Serum Bilirubin Crosses at or Below Defined Threshold for Discontinuation of Phototherapy in Study 204 (ITT)

ITT = intent-to-treat; PT = phototherapy; TSB = total serum bilirubin

Phototherapy Failure

Stannsoporfin at 4.5 mg/kg was statistically superior to placebo in reducing the incidence of PT failure (as defined in Section 6.1.1.1.2) in the ITT population (Table 17). Phototherapy failure occurred significantly less frequently among neonates in the 4.5 mg/kg group (one neonate [3%]; p=0.012) than in the placebo group (nine events in eight neonates [27%]). Phototherapy failure occurred in three (10%) of neonates who received 3.0 mg/kg stannsoporfin. Figure 26 shows the differences in rates between the two stannsoporfin doses and placebo (ITT population).

Phototherapy failures were defined as:

ET: one neonate on 3.0 mg/kg (this neonate’s TSB exceeded the threshold for ET at before randomization)

IVIg drug used: one neonate on 3.0.mg/kg and one in the placebo group

Hospital readmission for hyperbilirubinemia: one neonate on 4.5 mg/kg and three in the placebo group (there were four readmissions in three neonates on placebo)

Restarted PT: one neonate in the 3.0 mg/kg group, one in the 4.5 mg/kg group, and eight with placebo (one patient admitted for PT restart twice)



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Table 17: Analysis of Phototherapy Failure in Study 204 (ITT)


N=30


N=31 Placebo + PT

N=30 n n n

Neonates with failure 3 1 8 Required exchange transfusion 1 0 0 Hospital readmission for hyperbilirubinemia 0 1 3 Restarted phototherapy 1 1 8* IVIg used 1 0 1

* 1 patient admitted for phototherapy restart twice 1 patient not captured in database for restarting phototherapy, but was captured for hospital re-admission Note: PT failure was defined as a binary variable based on each of 4 components: exchange transfusion, intravenous immunoglobulin drug used,

hospital re-admission for hyperbilirubinemia, and restarted PT. If any component occurred, then PT failure was considered to have occurred. Otherwise, PT failure was deemed not to have occurred.

Figure 26: Rate of Phototherapy Failures in Study 204 (ITT)

Rebound Hyperbilirubinemia

Rebound hyperbilirubinemia as defined was not met for any neonate in the 3.0 mg/kg group, one (3%) neonate in the 4.5 mg/kg group, and three (10%) neonates in the placebo group (Table 18). It is important to note that neonates who had rebound hyperbilirubinemia >54 hours after treatment were not counted as rebounds.



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Table 18: Analysis of Rebound Hyperbilirubinemia – TSB Level in Study 204 (ITT)

Statistic Stannsoporfin + PT

Placebo + PT N=30

3.0 mg/kg 4.5 mg/kg N=30 N=31

Rebound hyperbilirubinemia TSB ≥Threshold PT Occurred n (%) 0 1 (3) 3 (10) Did not occur n (%) 30 (100) 30 (97) 27 (90) p-value vs placebo 0.237 0.354

p-value vs stannsoporfin 4.5 mg/kg

>0.999

Note: Rebound hyperbilirubinemia was defined as an increase in TSB above the age-specific threshold for initiating PT following the discontinuation of the initial PT. The age was calculated for every TSB value where TSB date and time of specimen collection were after initial PT discontinuation and ≤54 hours posttreatment. If at least one TSB value after initial PT Discontinuation > age-specific threshold for PT, then the patient was considered to have rebound hyperbilirubinemia. Note: Patient (3.0 mg/kg) had a total serum bilirubin that went above the age-specified threshold <=54 hours post-treatment before restart of phototherapy. The site did not enter the initial stop date under PT Stop Date/Time but rather under the PT Modified section. Therefore, this rebound is not captured in the above table. Note: The p-values were computed using Fisher’s exact test. PT = phototherapy, TSB = total serum bilirubin

6.1.1.6 Other Secondary Endpoints

The percent change (reduction) in TSB from Baseline levels at 18, 24, 30, and 36 hours after treatment in the ITT population was statistically significantly greater for both doses of stannsoporfin than for placebo at all time points measured. The magnitude of the median percent change varied between the stannsoporfin doses (Table 52 in Appendix 12.3).

The median AUC for TSB from Baseline to the last observed value within 48 hours post-treatment in the ITT population was 15.28, 9.00, and 42.03 mg·h/dL in the 3.0 mg/kg, 4.5 mg/kg, and placebo groups, respectively (Table 53 in Appendix 12.3). The median AUC measures neonates’ overall exposure to TSB.

Stannsoporfin was effective at both doses in significantly lowering the peak serum bilirubin levels. Regardless of whether this difference from placebo was analyzed by LS mean percent change or by mean peak levels of TSB, the peak serum bilirubin for stannsoporfin-treated neonates never got as high as the level for placebo. The LS mean difference vs placebo for the percent change from Baseline to peak was -12.38 (p=0.018) and -12.20 (p=0.019) for 3.0 and 4.5 mg/kg doses, respectively (Table 54 in Appendix 12.3).

Finally, the difference in mean duration of PT in the ITT population was statistically significant between each dose of stannsoporfin and placebo: 3.0 mg/kg (p=0.0480), 4.5 mg/kg (p=0.0339; Table 55 in Appendix 12.3).

6.1.2 Study 202

6.1.2.1 Clinical Study Design

Study 202 was a Phase 2b, multicenter, single dose, blinded, randomized, placebo-controlled, dose-escalation study of stannsoporfin (1.5, 3.0, and 4.5 mg/kg) in neonates ≥35 weeks GA with risk factors for hemolysis and hyperbilirubinemia. Risk factors for hemolysis included neonates

(b) (6)



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with Coombs positive ABO blood type incompatibility, Rh incompatibility, or G6PD deficiency. The study enrolled neonates who were candidates for PT according to the AAP guidelines, when TSB levels were 1-2 mg/dL below the age-specific threshold for the initiation of PT (full inclusion and exclusion criteria are in Appendix 12.4). Study 202 was stopped prematurely by the FDA due to discussions regarding the point of intervention; there were no safety concerns associated with this action.

The study consisted of a Screening Phase, Treatment Phase, and Post-Treatment Phase including two follow-up visits at 14 and 30 days after treatment (Figure 27). Neonates who met the enrollment criteria were randomized within each cohort and received either stannsoporfin (1.5, 3.0, or 4.5 mg/kg) or placebo. Cohorts were enrolled sequentially from lowest to highest dose after DSMB review of the safety data; enrollment at each dose level had to be completed before initiation of the next higher dose level.

Study treatment had to be administered within two hours of receipt of the qualifying TSB measurement. Total serum bilirubin levels were assessed at six hours after injection of study drug to determine whether PT was necessary. If neonates did not meet the AAP guidelines for starting PT, they continued in the study until the next TSB assessment (at 12, 24, and 48 hours following injection of study drug). In neonates who received PT, determinations to assess whether PT was still required were done every six hours. Phototherapy was stopped after the TSB level had decreased to at least 2 mg/dL below the threshold for PT. A TSB assessment was performed approximately six hours after PT was stopped to ensure that there was no rebound in the bilirubin level.


Efficacy Endpoints and Analyses

Multiple endpoints were explored in this study, and the primary efficacy endpoint was the change in adjusted TSB at 48 hours after study treatment. The adjusted TSB was a calculation of the percentage difference of the TSB concentration from the age-specific threshold in TSB value for PT initiation per the AAP Guidelines, ie, an indication of how far the TSB value was below the PT threshold at the time. The adjusted TSB levels were calculated as follows:



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[(TSB − PT initiation threshold) / PT initiation threshold] × 100%

The primary analysis was prespecified to be performed on the ITT population, which included all randomized neonates who had at least one TSB measurement during the first 48 hours after treatment. Because neonates could be discharged from the hospital prior to 48 hours, a LOCF method was used to handle missing data at 48 hours.

The primary endpoint was analyzed using ANCOVA with treatment, GA group (35 to 37 weeks 6 days or ≥38 weeks), and Baseline adjusted TSB levels as covariates.

Two sensitivity analyses were prespecified for the primary efficacy endpoint. The first sensitivity analysis was performed on the PP population, which included all neonates in the ITT population who completed the study without any major protocol violations. The second sensitivity analysis was an MMRM ANOVA using the Baseline adjusted TSB as the only covariate.

Key secondary endpoints included the change from Baseline in actual TSB at 48 hours post-treatment, the proportion of neonates who required PT or ET, and the total duration of PT.

6.1.2.2 Patient Disposition

A total of 63 neonates were enrolled and randomly assigned to treatment with study drug. Of these, five neonates never received treatment because of physician decision (two neonates), protocol violation (two neonates), or voluntary withdrawal by parents/guardians (one neonate). A total of 58 neonates received treatment with either stannsoporfin (1.5 mg/kg, 17 neonates; 3.0 mg/kg, 18 neonates; 4.5 mg/kg, eight neonates; or placebo, 15 neonates). The 4.5 mg/kg dose group was approximately 50% enrolled when the study was stopped early. Fifty-six neonates completed the study, and two neonates were voluntarily withdrawn by their parents/guardians after treatment (Figure 28).

Figure 28: Patient Disposition in Study 202

*consent withdrawn

6.1.2.3 Patient Demographics

Overall, demographic characteristics were generally well-balanced across treatment groups. The stannsoporfin 3.0 mg/kg group had 67% male neonates, while the 4.5 mg/kg group had 25% males. The mean GA of neonates in each treatment group was approximately 39 weeks. Birth



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weights ranged between 2,614 and 4,490 g, with mean birth weights among the treatment groups ranging from approximately 3,337 to 3,582 g. Most neonates were in the medium- or high-risk category for severe hyperbilirubinemia according to the Bhutani nomogram. There were five Coombs negative and 53 Coombs positive neonates, and there were no G6PD deficient neonates. The majority of neonates were ABO incompatible, and seven neonates were Rh incompatible. Table 19 shows baseline characteristics; Baseline TSB is shown in Table 20.

Table 19: Demographic and Other Baseline Characteristics in Study 202 (ITT) Stannsoporfin

1.5 mg/kg (N=17)


(N=18)


(N=8) Placebo (N=15)

Gestational age (weeks) Mean (SD) 39.1 (0.91) 39.5 (0.99) 39.0 (1.33) 38.9

(1.44) Age categories (weeks [%])

35 to <38 2 (11.8) 0 1 (12.5) 3 (20.0) ≥38 15 (88.2) 18 (100) 7 (87.5) 12 (80.0)

Sex (n [%]) Male 7 (41.2) 12 (66.7) 2 (25.0) 8 (53.3) Female 10 (58.8) 6 (33.3) 6 (75.0) 7 (46.7)

Race (n [%]) White 7 (41.2) 7 (38.9) 6 (75.0) 3 (20.0) Black 5 (29.4) 2 (11.1) 0 2 (13.3) Asian 0 2 (11.1) 0 1 (6.7) American Indian or Alaska Native 0 1 (5.6) 0 0 Native Hawaiian or Other Pacific Islander

4 (23.5) 3 (16.7) 0 4 (26.7)

Other 1 (5.9) 3 (16.7) 2 (25.0) 5 (33.3) Ethnicity (n [%])

Hispanic or Latino 5 (29.4) 6 (33.3) 6 (75.0) 4 (26.7) Not Hispanic or Latino 12 (70.6) 12 (66.7) 2 (25.0) 11 (73.3)

Apgar score (1 minute) Mean (SD) 7.1 (2.30) 7.9 (0.96) 8.1 (0.64) 7.9 (1.41)

Apgar score (5 minute) Mean (SD) 8.8 (0.39) 9.0 (0.00) 9.1 (0.35) 9.0 (0.00)

Blood type (n [%]) A 9 (52.9) 11 (61.1) 5 (62.5%) 7 (46.7) B 6 (35.3) 5 (27.8) 1 (12.5%) 7 (46.7) AB 0 0 0 0 O 2 (11.8) 2 (11.1) 2 (25.0) 1 (6.7)

Birth weight (g) Mean (SD) 3393.5

(503.03) 3582.7

(415.30) 3337.4

(538.62) 3356.5

(514.14) Rh group (n [%])

Positive 16 (94.1) 18 (100) 7 (87.5) 15 (100) Negative 0 0 0 0



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(N=17)


(N=18)



Direct Coombs test (n [%]) Positive 16 (94.1) 18 (100) 5 (62.5) 14 (93.3) Negative 1 (5.9) 0 3 (37.5) 1 (6.7) If negative, major risk factors

Jaundice observed in first 24 hours a 0 0 3 (100) 0 Gestational age 35 weeks 0 days to 37 weeks 6 days a

0 0 0 0

Previous sibling received phototherapya

0 0 0 0

Cephalohematoma or significant bruisinga

0 0 2 (66.7) 0

Exclusive breastfeeding particularly if it is not going well and weight loss is excessive a

0 0 3 (100) 0

G6PD test performed (n=13*) Yes (n [%]) 0 0 0 0 No (n [%]) 0 2 (11.1) 8 (100) 3 (20.0) If performed, result

Positive b 0 0 0 0 Negative b 0 0 0 0

*G6PD testing was added to Protocol Amendment 4.0 in June 2010 (end Cohort 2), 13 neonates enrolled under this amendment and subsequent Protocol Amendment 5.1 in September 2010 Risk category (n [%])

Low 1 (5.9) 0 0 1 (6.7) Medium 14 (82.4) 18 (100) 7 (87.5) 11 (73.3) High 2 (11.8) 0 1 (12.5) 3 (20.0)

a Percentages are based on the number of neonates in each treatment group for whom a negative direct Coombs test was reported. b Percentages are based on the number of neonates in each treatment group in whom a G6PD test was performed. Note: Percentages are based on the number of neonates in each treatment group. G6PD = Glucose-6-phosphate dehydrogenase; Max = maximum; Min = minimum; SD = standard deviation.

6.1.2.4 Primary Endpoint Results

A decrease in adjusted TSB levels from Baseline to 48 hours after treatment was observed in each treatment group (including placebo), with greater numerical decreases seen as the dose of stannsoporfin increased (this greater decrease reflects the TSB value as being farther below the PT threshold at that time). The difference in reduction of LS means for the adjusted TSB changes from Baseline between each stannsoporfin group and the placebo showed the following: p=0.040 for 1.5 mg/kg, p=0.117 for 3.0 mg/kg and p=0.057 for 4.5 mg/kg group (Table 20). Of note is that, as previously mentioned in Section 5.2, the 4.5 mg/kg group enrolled less than 50% (eight out of 18 planned) of the neonates compared to the other groups, including placebo. Post hoc statistical simulations were conducted to estimate the effects of the 4.5 mg/kg dose had this group been fully enrolled (see Section 5.2 for details).



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Table 20: Change from Baseline in Adjusted TSB at 48 Hours in Study 202 (ITT) Stannsoporfin

1.5 mg/kg (N=17)


(N=18)



Baseline adjusted TSB (%) n 17 18 8 15 Mean (SD) -20.24 (7.956) -15.92 (12.002) -9.19 (8.027) -13.41 (8.519) Min, Max -38.1, -4.0 -32.0, 0.0 -22.9, -0.8 -28.1, 1.7

48 Hours/Early termination adjusted TSB (%)

n 17 18 8 15 Mean (SD) -35.09 (19.198) -31.80 (18.214) -34.14 (14.733) -19.43 (14.922) Min, Max -79.2, -17.2 -72.2, -6.6 -64.6, -17.8 -40.5, 9.3

48 Hours/Early termination change from Baseline in adjusted TSB (%)

n 17 18 8 15 Mean (SD) -14.85 (15.442) -15.88 (21.406) -24.95 (19.261) -6.03 (18.659) Min, Max -55.7, 0.3 -54.8, 12.0 -59.0, -5.0 -42.1, 22.2

LS Mean (SEM) -15.03 (5.273) -11.60 (5.612) -16.51 (6.925) -1.58 (5.050) LS Mean difference a -13.45 -10.02 -14.93 95% confidence interval a (-26.27, -0.62) (-22.61, 2.58) (-30.31, 0.44) P-value a 0.040 0.117 0.057

a Pairwise comparison for each stannsoporfin treatment group vs placebo. Note: LOCF is used to impute missing post-Baseline TSB. Least-squares means are from an ANCOVA model for adjusted TSB with treatment and gestational age as fixed effects and Baseline adjusted TSB as a covariate. TSB is calculated as [(TSB − PT threshold/ PT threshold] x 100%. ANCOVA = analysis of covariance; ITT = intent-to-treat; LOCF = last observation carried forward; Max = maximum; Min = minimum; PT = phototherapy; SD = standard deviation; SEM = standard error of mean; TSB = total serum bilirubin.


In the prespecified sensitivity analyses, the primary analysis was repeated using the PP population and an MMRM analysis. The sensitivity analysis in the PP population supported the primary endpoint analysis, with similar decreases in adjusted TSB in all stannsoporfin-treated groups, and the difference between the 4.5 mg/kg stannsoporfin group and placebo at 48 hours was nearly statistically significant (p=0.054). The MMRM analysis on the ITT population showed a trend to significance at 12 hours (p=0.065) and a statistically significant greater reduction in LS Mean between the placebo and stannsoporfin 4.5 mg/kg groups at the 24-hour (p=0.031) and 48-hour (p=0.023) post-treatment time points (Table 21).



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Table 21: Change from Baseline in Adjusted TSB - MMRM Analysis in Study 202 (ITT)

Time point Statistics


(N=17)


(N=18)



6 Hours LS Mean (SEM) 2.94 (2.098) 2.68 (2.252) 2.00 (2.825) 4.37 (1.993) LS Mean difference -1.44 -1.69 -2.38 95% confidence interval

(-6.45, 3.58) (-6.61, 3.23) (-8.56, 3.80)

P-value 0.567 0.493 0.444 12 Hours

LS Mean (SEM) 3.29 (2.731) 0.83 (2.821) -2.41 (3.856) 5.97 (2.728) LS Mean difference -2.67 -5.14 -8.38 95% confidence interval

(-9.84, 4.49) (-12.19, 1.91) (-17.30, 0.55)

P-value 0.457 0.150 0.065 24 Hours

LS Mean (SEM) -5.33 (3.948) -8.57 (3.894) -16.26 (5.495) -1.56 (4.011) LS Mean difference -3.77 -7.01 -14.70 95% confidence interval

(-14.70, 7.16) (-17.70, 3.68) (-28.02, -1.39)

P-value 0.491 0.193 0.031 48 Hours

LS Mean (SEM) -14.94 (5.019) -15.92 (4.919) -27.34 (7.287) -6.68 (5.255) LS Mean differencea -8.26 -9.24 -20.66 95% confidence intervala

(-22.55, 6.03) (-23.26, 4.79) (-38.41, -2.91)

P-valuea 0.251 0.192 0.023 a Pairwise comparison for each Stannsoporfin treatment group vs the placebo group. Note: MMRM analysis is conducted for observed case adjusted TSB with treatment, gestational age group (35-37 weeks 6 days or ≥38 weeks), time point, treatment-by-time point as fixed effects, and observed case adjusted Baseline TSB levels as a covariate. Time point is a repeated factor and an unstructured covariance matrix pattern is applied. TSB is observed case and is calculated as [(TSB − PT threshold)/PT threshold]×100%. ITT = intent-to-treat, LS = least squares, MMRM = Mixed Model Repeated Measures; PT = phototherapy, SEM = standard error of mean, TSB = total serum bilirubin.

6.1.2.5 Key Secondary Endpoint Results

Change from Baseline in actual TSB concentration at 48 hours post-dose (ITT)

As previously mentioned, the primary endpoint was an exploratory assessment to evaluate the applicability of adjusted TSB. However, actual TSB change was prespecified as a key secondary endpoint.

Compared to placebo, all doses of stannsoporfin slowed the increase in TSB at 48 hours with a numerical dose-response, and in the ITT population the LS Mean differences in the TSB between the treatment groups and placebo were 1.81 mg/dL (1.5 mg/kg stannsoporfin), 1.34 mg/dL (3.0 mg/kg stannsoporfin) and 2.63 mg/dL (4.5 mg/kg stannsoporfin). The ANCOVA of the change in actual TSB levels at 48 hours in the ITT population showed a statistically significant difference in LS Means between the stannsoporfin 4.5 mg/kg and placebo groups (p=0.028) despite the smaller sample size in the treatment group (Table 22).



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Table 22: Change from Baseline in Actual TSB at 48 Hours in Study 202 (ITT) Stannsoporfin

1.5 mg/kg (N=17)


(N=18)



Baseline actual TSB (mg/dL) n 17 18 8 15 Mean (SD) 7.59 (1.816) 8.21 (1.577) 9.59 (1.911) 8.31 (2.154) Min, Max 4.3, 12.0 5.5, 10.4 6.4, 12.8 4.6, 11.9

48 Hours/Early termination actual TSB (mg/dL)

n 17 18 8 15 Mean (SD) 9.91 (3.116) 10.68 (2.956) 10.39 (2.650) 12.26 (2.169) Min, max 3.3, 13.5 4.2, 14.1 5.6, 13.4 8.1, 15.8

48 Hours/Early termination change from Baseline in actual TSB (mg/dL)

n 17 18 8 15 Mean (SD) 2.32 (2.560) 2.47 (2.703) 0.80 (2.788) 3.95 (2.711) Min, Max -4.5, 5.2 -3.4, 6.2 -3.4, 3.6 -0.2, 8.7

LS Mean (SEM) 2.43 (0.842) 2.90 (0.886) 1.60 (1.020) 4.24 (0.770) LS Mean difference a -1.81 -1.34 -2.63 95% confidence interval a (-3.71, 0.09) (-3.24, 0.56) (-4.97, -0.30) P-value a 0.061 0.163 0.028

a Pairwise comparison for each Stannsoporfin treatment group vs the placebo group. Note: LOCF is used to impute missing postBaseline TSB. ANCOVA is conducted for TSB including treatment and gestational age as fixed effects and Baseline TSB as a covariate. LS Mean and standard errors (SEM) are estimated for each treatment group and the placebo group. LS Mean difference, 95% Confidence Interval, and p-value are estimated based on LS Mean difference between each stannsoporfin group and the placebo group. ANCOVA = analysis of covariance, ITT = intent-to-treat, LOCF = last observation carried forward, LS = least squares; Max = maximum; Min = minimum; PT = phototherapy, SD = standard deviation, SEM = standard error of mean, TSB = total serum bilirubin

As shown in Figure 29, mean TSB levels in neonates who received placebo (53% of whom also received PT) continued to increase for 48 hours before appearing to start to plateau at ~60% above Baseline between 48 and 72 hours post-treatment. In contrast, stannsoporfin 4.5 mg/kg (25% of neonates received PT) appeared to attenuate the rise in TSB beginning as early as six hours post-treatment, with statistically significant attenuation occurring at 12 hours post-treatment. After 12 hours, stannsoporfin 4.5 mg/kg produced decreases in TSB with levels returning to Baseline by 72 hours post-treatment. Both the 1.5 and 3.0 mg/kg doses attenuated the rise in TSB by 12 hours post-treatment compared with placebo, and after 12 hours mean TSB levels plateaued or slightly decreased.



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Figure 29: Percent Change from Baseline in Actual TSB in Study 202 (ITT)

ITT analysis set LOCF

Proportion of Neonates Who Required PT/ET

No neonates in the study required ET. In the placebo group, 53.3% of neonates received PT, including two infants who were readmitted to the hospital (13%), compared to 25.6% of stannsoporfin neonates (Table 23). This represents a 50% reduction in the need for PT in the stannsoporfin group, and the number needed to treat (NNT) is four for the prevention of the need for PT. In addition, no stannsoporfin-treated neonates were readmitted to the hospital, which represents a NNT of eight for the prevention of rehospitalization.

Table 23: Proportion of Neonates Requiring Phototherapy in Study 202 (ITT) Stannsoporfin

1.5 mg/kg (N=17)


(N=18)



Neonates receiving phototherapy (n [%]) 3 (17.6) 6 (33.3) 2 (25.0) 8 (53.3) P-value a 0.062 0.304 0.379

Neonates receiving exchange transfusion 0 0 0 0 P-value a NA NA NA

a P-value is based on Fisher’s Exact Test. ET = exchange transfusion; ITT = intent-to-treat; NA = not applicable; PT = phototherapy.

6.1.3 Study 06

6.1.3.1 Study Design

Study 06 was an open-label, non-randomized, ascending-dose sequential-cohort study of stannsoporfin 0.75 mg/kg and 1.5 mg/kg designed to evaluate efficacy of stannsoporfin compared with placebo in reducing the need for ET in neonates with severe hyperbilirubinemia. Neonates had to be at medium or high-risk for ET based on their TSB concentration obtained during PT, according to the 2004 AAP Guidelines.



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The risk for ET was based on GA and iso-immune hemolytic disease and defined as follows:

Medium risk: Neonates ≥38 weeks GA with risk factors (iso-immune hemolytic disease) OR GA ≥35 to <38 weeks with no risk factors for ET

High risk: Neonates ≥35 to <38 weeks GA with risk factors (iso-immune hemolytic disease) for ET

It is important to note that the neonates evaluated in Study 06 represented a different stage of hyperbilirubinemia compared with Studies 204 and 202. In Study 06, all neonates had TSB concentrations at or above the threshold for ET despite intensive PT; hence, they were all at risk for serious neurodevelopmental sequelae. Therefore, Study 06 was considered a supportive efficacy study, as the patient population is considered significantly more severe and not directly comparable to that of the proposed indication for stannsoporfin.

Neonates in Study 06 received a single IM injection of stannsoporfin (0.75 or 1.5 mg/kg) or placebo. All neonates received PT.

Efficacy in Study 06 was evaluated by the following endpoints:

Assessment of drug activity in reducing the need for ET

TSB concentration

Kramer’s Rule for clinical evaluation of jaundice (observing the progression of jaundice in five zones of the body from head to toe)

Incidence and duration of PT

6.1.3.2 Results

A total of 55 neonates were treated with either stannsoporfin (0.75 mg/kg, n=19; 1.5 mg/kg, n=18) or placebo (n=18).

Exchange Transfusion

Fourteen neonates required ET during the study; one neonate in the placebo group required two transfusions (one prior to and one after study treatment). Two neonates assigned to stannsoporfin 0.75 mg/kg and one neonate assigned to placebo required ET prior to receiving study drug treatment. Twelve neonates (stannsoporfin 0.75 mg/kg, one neonate; stannsoporfin 1.5 mg/kg, two neonates; placebo, nine neonates) received ET after study treatment. Thus, only three stannsoporfin-treated neonates received ET and were included in the analyses. Statistically significantly fewer neonates required ET in both stannsoporfin dose groups compared to the placebo group (stannsoporfin 0.75 mg/kg, p=0.003; stannsoporfin 1.5 mg/kg, p=0.027). There were no statistically significant differences in total volume transfused and time to ET from drug administration (p=0.595 and p=0.113, respectively).

TSB concentration

When all neonates with or without ET were analyzed, the 1.5 mg/kg group had a statistically significantly lower mean TSB concentration (15.8 mg/dL) at 48 hours post-dose compared with the placebo group (17.7 mg/dL (p=0.05). When analyzed as percentage change from Baseline, the



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1.5 mg/kg group had a significantly greater reduction in TSB at both 24 hours (27.4% vs 14.1%, p=0.0215) and 48 hours (44.1% vs 20.7%, p<0.0001) post-dose for neonates without ET and at 48 hours (45% vs 29%, p<0.001) for all neonates (with or without ET).

Among the 12 neonates who received ET, mean TSB values (mg/dL) immediately before transfusion were highest for the 1.5 mg/kg dose group (stannsoporfin 0.75 mg/kg, 25.9 mg/dL; stannsoporfin 1.5 mg/kg, 40.9 mg/dL; placebo, 28.5 mg/dL, p<0.001; Table 24). Fewer neonates treated with stannsoporfin required ET based on the mean percent change in TSB for the nine placebo-treated neonates who received ET and the three stannsoporfin-treated neonates who received ET.

Table 24: Exchange Transfusion after Administration of Study Drug in Study 06 (ITT)

Parameter Placebo Stannsoporfin

0.75 mg/kg 1.5 mg/kg Exchange transfusion provided

N 18 19 18 Yes 9 (50.0%) 1 (5.3%) 2 (11.1%) No 9 (50.0%) 18 (94.7%) 16 (88.9%)

Time to exchange transfusion from drug administration, h N 9 1 2 Mean 16.7 26.3 8.3 SD 6.7 – 3.3 Median 19.0 26.3 8.3 Range (4, 24) (26, 26) (6, 11)

TSB value immediately before transfusion, mg/dL N 9 1 2 Mean 28.5 25.9 40.9 SD 1.6 – 4.7 Median 28.2 25.9 40.9 Range (26, 31) (26, 26) (38, 44)

ITT = intent-to-treat; SD = standard deviation; TSB = total serum bilirubin

Forty-one neonates did not require ET (0.75 mg/kg, 16; 1.5 mg/kg, 16; placebo, 9) during the study (2 required ET prior to study treatment). Prior to study treatment, there was a statistically significant difference in mean TSB concentration among neonates who did not require ET in the 3 dose groups (0.75 mg/kg, 24.9 mg/dL; 1.50 mg/kg, 28.0 mg/dL; placebo, 22.4 mg/dL, p=0.011). Pre-dose, the 1.5 mg/kg dose group treatment group had a significantly higher mean TSB concentration than did the placebo group (p=0.005)1.

For the 41 neonates who did not require ET, the decrease in mean TSB was statistically significantly greater for the stannsoporfin 1.5 mg/kg group compared with the placebo group at both 24 hours (p=0.0215) and 48 hours (p<0.0001) post-dose. The percentage change in TSB was significantly greater in the 1.5 mg/kg group compared to placebo at 48 hours post-dose (44% vs 21%, p=0.0003). The 0.75 mg/kg group also showed a greater decrease in TSB than placebo

1 p-values are based on one-way ANOVA



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at both 24 and 48 hours post-dose, but this difference did not reach statistical significance at either time point (p≥0.388).

Jaundice

All three treatment groups demonstrated improvement in jaundice based on Kramer’s Rule for clinical evaluation.

Other treatment effects

Stannsoporfin was as effective as ET in reducing TSB and decreased the requirement for ET (n=2 for stannsoporfin 1.5 mg/kg and n=9 for placebo).

6.1.4 Study 01-3W

Study 01-3W was a randomized, placebo-controlled study evaluating the efficacy and safety of 4.5 mg/kg stannsoporfin in reducing PT requirements in healthy newborns ≥35 weeks GA, without indicators of hemolysis. The study was put on clinical hold due to the FDA requiring additional pre-clinical and CMC data. One hundred and seventy-six neonates were randomized and treated out of the intended 1,600 (11%); therefore, only a brief summary of this study is provided in this briefing document. There were no safety observations in this study that led to the FDA hold or discontinuation by the sponsor.

6.1.4.1 Study Design

Neonates ≥35 weeks GA born at the study hospital site and admitted to the well-baby nursery or admitted to the intensive-care nursery for less than 12 hours for post-delivery observation were screened at 12-36 hours of age and were assessed for jaundice. The nursery staff assessed the presence or absence of jaundice every six to 12 hours, along with vital signs of heart rate, respiration and perfusion (capillary filling of the fingernail). If jaundice was noted or suspected, a Transcutaneous Bilirubin (TcB) measurement was obtained. For hour-specific TcB values >75th percentile, neonates were treated with a single injection of stannsoporfin 4.5 mg/kg or sham injection. Mandatory TcB and TSB were repeated at 12 hours after injection. Infants were assessed for TcB and TSB during study evaluations. A phone call questionnaire was administered at 30 days to evaluate safety and efficacy.

The study included in-hospital (36-48 hours) and discharge/follow-up stages. Re-evaluation after discharge was conducted at 24 hours post-discharge, and at 96 and 168 ± 12 hours of age. The study concluded at 168 hours of age. A 30-day follow-up visit was conducted for all neonates.

The primary efficacy variable was the use of PT as treatment for hyperbilirubinemia among those babies who developed severe hyperbilirubinemia prior to 36 hours of age. Severe hyperbilirubinemia was defined as those babies whose TSB was ≥9 mg/dL.

6.1.4.2 Results

A total of 176 neonates completed the study; 87 were treated with stannsoporfin 4.5 mg/kg and 89 were in the control treatment group.



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At the first post-drug administration measurement, which was twelve hours post-treatment, there was a significant difference in the change and percentage change in TcB among the treated as compared to the controls. By 24 hours post-discharge (approximately 48 hours post-drug administration), the difference between groups became greater and was statistically significant for both TSB and TcB and all measures of bilirubin levels as well as change and percentage change in bilirubin levels. At 24 hours post-discharge, TcB levels for treated infants returned to pre-treatment levels.

There was no statistically significant difference in mean time to PT after drug administration.

In addition, the percentage of infants with jaundice, as well as the percentage with severe hyperbilirubinemia (>75th percentile for age in hours), was lower in stannsoporfin neonates vs placebo.

6.2 Efficacy Findings: Rockefeller IND

This section provides an overview of six clinical studies conducted under the Rockefeller IND. The Rockefeller IND studies provided a large body of evidence which served as the foundation for the InfaCare IND and add significant support for the use of stannsoporfin with and without PT. These studies were well-conducted according to the standards of the time and support approval of the current NDA.

The six studies are summarized in Table 25, which provides brief details on study designs, objectives, methodology, treatments, populations enrolled, and efficacy or PK conclusions. Figure 30 and Figure 31 show that stannsoporfin 4.5 mg/kg reduced the need for PT and duration of PT in applicable studies. Additional efficacy results can be found in Appendix 12.5.

In these six Rockefeller IND studies, 659 neonates were treated with stannsoporfin. Of these, 459 received a dose of 4.5 mg/kg. Across studies and in all populations in which efficacy was assessed, treatment with stannsoporfin decreased bilirubin levels.


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Table 25: Summary of Rockefeller IND Studies Study ID/ Location/ No. of Sites/ PT use

Study Design Healthy Subjects or

Diagnosis

Treatments/ Dosage/ Regimen/ Duration/

Route

Number of Neonates in Each Group

Efficacy Endpoints

Efficacy Conclusion

29,462-04/ Greece/ 1 site PT if needed

Phase 2, randomized, double-blind, placebo-controlled, single-center study + 5-yr LTF Comparator: Placebo

Male and female neonates (210 to 251 days GA) (Phase 1 allowed neonates <37 weeks and BW 1500 to 2500 g) at high risk for hyperbilirubinemia to prevent jaundice; G-6-PD normal; negative Direct Coombs Test.

IM injections of: Stannsoporfin Phase 1: 0.75 mg/kg Phase 2: 1.5 &

2.25 mg/kg Phase 3: 1.5 mg/ once or

twice [total 3.0 mg/kg], 24 h apart

Phase 4: 3.0 mg/kg Phase 5: 3.5 mg/kg

followed 24 h later by 1.5 mg/kg

Phase 6: single dose of 4.5 mg/kg

Placebo: 0.25 mL/kg

(Sterile normal saline)

Randomized: 463 0.75 mg/kg: 50

1.5 mg/kg: 59

2.25 mg/kg: 32

3 mg/kg: 59

4.5 mg/kg: 61

Placebo: 202

Primary: Maximum PBC (mg/dL) Key Secondary: Hours of PT per neonate Hours of PT per treated

neonate Percentage of patients

treated with PT

Stannsoporfin significantly decreased mean maximum PBC at 1.5, 3.0, and 4.5 mg/kg doses compared to placebo (P<0.001).

A dose-dependent reduction in the need for PT was demonstrated in preterm neonates.

There was a 50% reduction in the need for PT.

Outcomes are similar to that of Study 202 where stannsoporfin was used first without PT to determine need for PT.

29,462-09/ Argentina/ 1 site PT if needed

Phase 3, randomized, open-label, controlled, single-center study in healthy, full-term neonates; + 18-mo LTF.

Healthy, M&F, full-term (GA: 38-41 weeks), neonates, with BW from 10th to 90th percentiles for GA who developed clinically significant hyperbilirubinemia (PBC ≥15 to ≤18 mg/dL) from 48

Single IM injection of Stannsoporfin: 4.5 mg/kg PT or ET (if required)


Control: 86

Primary: Number of neonates whose

PBC reached 19.5 mg/dL (required PT)

Key Secondary: Maximum PBC Number of PBC

measurements required during study observation

Data demonstrate that stannsoporfin 6 µmol/kg/IM (4.5 mg/kg) was statistically significantly superior to no treatment for almost all endpoints.


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Study ID/ Location/ No. of Sites/ PT use


Diagnosis


Route


Efficacy Endpoints

Efficacy Conclusion

Comparator: No treatment

to 96 hours after birth were eligible.

(enrollment to case closure = PBC ≤13 mg/dL)

Time required for PBC to decrease to ≤13 mg/dL

Hours of PT Number of neonates

requiring ET

None (0/80) of the stannsoporfin-treated infants required PT compared with 22% (19/86) of the untreated infants (p<0.0001).

The total number of heel sticks needed was lower in patients who received stannsoporfin.

29,462-05/ Greece/ 1 site PT if needed (active control)

Phase 3, sequential matched pair design randomized, active-controlled, single-center, + 5 yr LTF Comparator: Phototherapy

M/F neonates (245-265 days GA) and full-term male neonates (≥259 days GA), aged 36 to 96 h, weight ≥1500 g, Direct Coombs Test-, normal G6PD activity in cord blood

Single IM injection of Stannsoporfin: 4.5 mg/kg PT and ET (if required)

Randomized: Phase 1: 44

Phase 2: 40

Primary Analysis Sequential Pairs Difference of ≥24 h

between enrollment and case closure (no. of hours in study)

Need for PT (after stannsoporfin)

Need for ET rescue Intergroup Analysis Need for ET rescue Secondary Intergroup Analyses: Time from enrollment to

case closure (hours in study)

Age at case closure Hours of PT required PBC at case closure

Neonates given stannsoporfin without PT were in the study for a shorter duration vs PT with earlier case closure.

No neonates receiving stannsoporfin required rescue with PT or ET.


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Diagnosis


Route


Efficacy Endpoints

Efficacy Conclusion

29,462-06/ Greece/ 1 site PT if needed

Phase 3, randomized, sequential matched pairs, controlled single-center study comparing preventive (P) and therapeutic (T) uses of stannsoporfin + 5 yr LTF Comparator: Phase 1: Stannsoporfin 4.5 mg/kg, No treatment

Near-term (>210 to ≤265 days GA) and full-term (>265 days GA), G6PD-deficient (≤6.0 U/g Hb [M], ≤8.0 U/g Hb [F] of cord blood activity), neonates, BW >1500 g, Direct Coombs Test (–)

Single IM injection of Stannsoporfin: 4.5 mg/kg PT and ET (if required)

Phase 1: Stannsoporfin (Preventive) = 41 pts Stannsoporfin (Therapeutic) = 19 pts Total N: 60*

Phase 2: Stannsoporfin (Preventive) ≤265 days GA = 163 (163 treated) Total N: 163

Primary: Sequential analysis Difference of ≥1 day in the

age of the pt. at case closing

Need for PT or ET, based on protocol-specified threshold PBC values

Intergroup analysis Age in hours of the patient

at the closing of the case Number of patients

requiring rescue PT Number of patients

requiring rescue ET Key Secondary (Intergroup analysis): Maximum PBC (mg/dL) PBC value at case closure Rate of PBC change from

24 to 48 hours of age (1st to 2nd blood sample)

In the sequential pairs analysis, 22 of the 42 pairs of neonates were in favor of preventive use of stannsoporfin in terms of a >1-day older age at case closure. Eight pairs favored the therapeutic arm.

All secondary endpoints were met with statistical significance demonstrating that stannsoporfin preventative use was favored.

No patients who received stannsoporfin required PT rescue.

29,462-08/ Greece/ 1 site PT if needed (active control)

Phase 3, randomized, sequentially analyzed, matched pairs, single-center study; + 18-mo LTF

Healthy and sick, M&F neonates (GA 210-251 days) with normal G6PD activity, BW >1500 g & hyperbilirubinemia (TSB level sufficient to qualify for PT)

Single IM injection of Stannsoporfin: 4.5 mg/kg or PT

ET (if required)


PT: 27

No Treatment: 44 (did not develop sufficiently elevated TSB levels to require intervention)

24-hour difference in time to case closure for 1 of a matched pair of patients

Need for PT rescue Maximum PBC

Due to slow enrollment, the study was discontinued.


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Diagnosis


Route


Efficacy Endpoints

Efficacy Conclusion

Comparator: Phototherapy, No treatment

*Two patients (1 therapeutic arm, 1 preventive arm) had start and stop dates recorded. For the individual report they were considered as untreated. Due to the fact these 2 patients had start and stop dates and adverse events reported in the long-term follow up at 18 months, these patients were considered as treated for the integrated summary of safety (ISS) and their data included in the ISS datasets and the tables, listings and figures for the supportive long-term follow-up documents.



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Figure 30: Need for Phototherapy in InfaCare IND Study 202 and Rockefeller IND Studies 29,462-04, -09, -05, and -08

a Studies 202 and 08 were discontinued prior to fully enrolling patients. b The active control in Studies 05 and 08 was PT; therefore, all patients received PT according to study design.

Figure 31: Duration of Phototherapy in InfaCare IND Studies 204 and 202 and Rockefeller IND Studies 29,462-04 and -08

a Values based on total number of patients who required PT b Studies 202 and 08 were discontinued prior to fully enrolling patients.

6.3 Efficacy Conclusions

Pivotal Study 204 from the InfaCare IND showed that stannsoporfin at doses of 3.0 mg/kg and 4.5 mg/kg with PT was statistically significantly superior to PT alone in both percent change and actual change in TSB within 48 hours after treatment. While both doses met the primary endpoint, only the 4.5 mg/kg dose met the two prespecified hierarchical secondary endpoints, demonstrating a shorter time for TSB levels to cross the defined AAP threshold for discontinuing PT and fewer PT failures including rehospitalization and restart of PT. Reaching the threshold for discontinuation of PT sooner and decreasing the rates of PT failures could correlate with less separation of infant and mother, earlier discharge, and fewer readmissions to hospital. The highly



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statistically significant results for these key, clinically relevant, secondary efficacy endpoints reinforce the importance of the results seen with the primary endpoint at the 4.5 mg/kg dose.

Study 202 provides data on the efficacy and safety of stannsoporfin when initiated prior to reaching the threshold for initiating PT and supports the use of stannsoporfin with or without PT. Stannsoporfin 4.5 mg/kg attenuated the rise in TSB seen in placebo neonates. The TSB curve began flattening between six and 12 hours, and the difference between placebo patients was statistically significant by 18 hours post-treatment. Total serum bilirubin levels returned to Baseline by 72 hours post-treatment. Fifty percent fewer neonates in the 4.5 mg/kg group required PT compared to placebo, and there were no rehospitalizations in the treatment group vs 13% in the placebo group. Sensitivity analyses strongly corroborated the efficacy of stannsoporfin.

In Study 06, significantly fewer neonates required ET in both stannsoporfin dose groups (0.75 and 1.5 mg/kg) compared with the placebo group (ie, PT alone). The stannsoporfin 1.5 mg/kg dose was statistically significantly better than placebo in reducing TSB at 24 and 48 hours post-treatment. Overall, the data demonstrate that stannsoporfin significantly reduced TSB and the need for ET compared with placebo in neonates at high risk for ET and serious neurodevelopmental sequelae.

The large body of evidence from the Rockefeller IND studies provided a strong foundation for the InfaCare IND and adds significant support for the use of stannsoporfin without PT. Additionally, data from patients who received 4.5 mg/kg and PT is supportive of use of stannsoporfin with PT. Studies in the Rockefeller IND were well-conducted and support approval of the current InfaCare NDA.

Study 29,462-04 in neonates 30 to 36 weeks GA showed a dose-dependent reduction in the need for PT, with the 4.5 mg/kg dose being the most efficacious. These findings are similar to Study 202 where stannsoporfin was shown to eliminate the need for PT in 50% of neonates.

Study 29,462-09 in healthy infants 38-41 weeks GA who were candidates for PT was also supportive of Study 202, as no neonates who received stannsoporfin required PT.

Study 29,462-05 in healthy infants 35-38 weeks GA was supportive of the use of stannsoporfin 4.5 mg/kg without PT; none of the stannsoporfin group required PT as rescue therapy, and time in the study (case closure) was less in the stannsoporfin group. The results of Study 29,462-06 are consistent with those of Study 29,462-05, but Study 29,462-06 was conducted in neonates 30-38 weeks GA with G6PD deficiency.

Study 29,462-08 conducted in premature healthy and sick neonates but was stopped early due to slow enrollment, and the patient population was not comparable with that in Studies 204 and 202. As such, the study is not considered supportive for efficacy.

In summary, stannsoporfin has been studied with and without PT in both the InfaCare IND and Rockefeller IND studies and has been shown to effectively treat neonatal hyperbilirubinemia. The totality of the efficacy data in the clinical trials demonstrates that stannsoporfin 4.5 mg/kg:

Achieves rapid and sustained decreases in TSB

Has the potential to eliminate the need for PT



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Decreases the time to reach the threshold for discontinuing

Reduces rates of PT failures

Reduces rehospitalizations for hyperbilirubinemia

Reduces the total time on PT, if required

The consistency and preponderance of the efficacy data across studies confirms the efficacy of stannsoporfin as an effective treatment for neonatal hyperbilirubinemia and supports the proposed indication.



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7.2 Safety Pooling Strategy

The safety assessment of stannsoporfin was based upon the analysis of the acute studies, long-term studies, and neurodevelopmental assessments from the Rockefeller IND (Section 7.4) and InfaCare IND (Section 7.3) Studies. The data were pooled into four data sets as follows:

Pivotal Study 204 (61 stannsoporfin, 30 control): short-term safety of two doses of Stannsoporfin with PT in neonates.

Acute Pooled Studies (197 stannsoporfin, 137 control): Study 204, Study 202, and Study 01-3W; randomized, double-blind, placebo-controlled studies in neonates of similar gestation ages (range ≥35 and ≤43 weeks) with PT (Studies 204 and 202) and without PT (Studies 202 and 01-3W). Though neonates in Study 01-3W had different baseline characteristics as they had no indicators of hemolysis, they serve as a relevant cohort for exposure and safety. Safety findings from Studies 202, 06, and 01-3W presented individually can also be found in Appendix 12.6.

Long-term Pooled Extension Studies (long-term data were to be collected from 18 months to 6 years): Study 205, Study 203, and Study 01C-3W; companion long-term extension studies that include evaluations of neurological and neurodevelopmental assessments, with outcomes evaluated for up to six years.

Six Rockefeller IND Studies (659 stannsoporfin, 459 control): Studies 29,462-04, -05, -06, -07, -08, and -09; evaluating neurological and neurodevelopmental assessments in the long-term extension phases (Section 7.4).

The Safety Analysis Set includes all randomized neonates who received at least one dose of study medication, based on the treatment received.

In all studies, TEAEs were defined as AEs that started or worsened in intensity during or after the injection of study treatment.

7.3 InfaCare IND

7.3.1 Pivotal Study 204

7.3.1.1 Overall Adverse Events

Safety assessments in Study 204 included incidence of AEs, SAEs, and clinical laboratory findings. Follow-up visits occurred on Days 7, 14, and 30.

Although both doses of stannsoporfin showed a favorable safety profile, the 4.5 mg/kg group had generally fewer AEs than the 3.0 mg/kg group. The proportions of reported TEAEs were similar in the 4.5 mg/kg and placebo groups (68% and 73% respectively), and 93% in the 3.0 mg/kg group (Table 27). Most events in all groups were mild, few were moderate, and none in the 4.5 mg/kg and placebo groups were severe. The proportion of neonates with reported SAEs was similar in all treatment groups: 13%-17% for treated neonates and 20% in the placebo group. There were no deaths or discontinuations due to TEAEs reported during the study.



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Table 27: Overall Summary of Adverse Events in Study 204 (Safety Analysis Set)

Neonates with any

Number (%) of neonates Stannsoporfin + PT Placebo + PT

(N=30) 3.0 mg/kg (N=30) 4.5 mg/kg (N=31) TEAE 28 (93) 21 (68) 22 (73)

Mild 19 (63) 19 (61) 21 (70) Moderate 7 (23) 2 (6) 1 (3) Severe 2 (7) 0 0

TEAEs leading to discontinuation 0 0 0 SAE 5 (17) 4 (13) 6 (20) Death 0 0 0

Note: TEAEs were defined as AEs that started or worsened in intensity on or after the injection of study medication. Note: Related to study medication or trial procedures TEAE was defined as a TEAE with a relationship to study medication as possible or probable AEs = adverse events, PT= phototherapy, SAEs = serious adverse events, TEAEs = treatment-emergent adverse events, SAEs = serious adverse events.

There was a higher incidence of TEAEs in the 3.0 mg/kg dose compared to the 4.5 mg/kg dose in four System Organ Classes (SOCs): Blood and Lymphatic System Disorders; Respiratory, Thoracic, and Mediastinal Disorders; Gastrointestinal Disorders; and Skin and Subcutaneous Disorders. The overall imbalance largely came from Skin and Subcutaneous Disorders (Table 28). Skin-related events occurred with similar frequency in the 4.5 mg/kg (42%) and placebo (47%) groups, and at a higher frequency in the 3.0 mg/kg (67%) group. The most frequently reported TEAEs affecting the skin were erythema in both stannsoporfin groups, rash in the 3.0 mg/kg and placebo groups, and dry skin in all groups. Transient, mild to moderate self-limiting dermatologic reactions, which did not require medical interventions, were reported in all groups. Overall, any Skin and Subcutaneous Disorder TEAEs were comparable between 4.5 mg/kg (42%) and placebo (47%).

Thrombocytopenia was reported in three neonates in the stannsoporfin groups and none in placebo (see Appendix 12.8 for narratives). In the two 3.0 mg/kg neonates, thrombocytopenia was determined by the Investigator to be unlikely related to medication or to PT; the event in the 4.5 mg/kg neonate was mild and classified as probably related to medication and possibly related to PT. All AEs of thrombocytopenia resolved. There were no bleeding events.

Table 28: Treatment-Emergent Adverse Events in at Least 2 Neonates in any Treatment Group, by SOC and Preferred Term in Study 204 (Safety Analysis Set)

System organ class Preferred term

Number (%) of neonatesStannsoporfin + PT

Placebo + PT

(N=30) 3.0 mg/kg (N=30)

4.5 mg/kg (N=31)

Neonates with any TEAE, n (%) 28 (93) 21 (68) 22 (73) Blood and lymphatic system disorders 6 (20) 1 (3) 3 (10)

Anaemia 1 (3) 0 2 (7) Haemolytic anaemia 2 (7) 0 0 Thrombocytopenia 2 (7) 1 (3) 0

Congenital, familial and genetic disorders 2 (7) 3 (10) 3 (10) Congenital naevus 0 2 (6) 2 (7)

Eye disorders 2 (7) 2 (6) 1 (3)



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System organ class Preferred term

Number (%) of neonatesStannsoporfin + PT

Placebo + PT

(N=30) 3.0 mg/kg (N=30)

4.5 mg/kg (N=31)

Gastrointestinal disorders 7 (23) 2 (6) 1 (3) Umbilical hernia 4 (13) 1 (3) 0

General disorders and administration site conditions 0 2 (6) 0 Hepatobiliary disorders 2 (7) 1 (3) 3 (10) Hyperbilirubinaemia 2 (7) 1 (3) 3 (10) Infections and infestations 3 (10) 4 (13) 1 (3) Injury, poisoning and procedural complications 1 (3) 1 (3) 3 (10)

Scratch 0 0 2 (7) Investigations 10 (33) 9 (29) 6 (20)

Cardiac murmur 5 (17) 4 (13) 4 (13) Gamma-glutamyl transferase increased 2 (7) 0 0 Haematocrit decreased 1 (3) 2 (6) 1 (3) Haemoglobin decreased 2 (7) 1 (3) 1 (3) Medical observation 2 (7) 0 0 Reticulocyte count increased 2 (7) 3 (10) 1 (3)

Metabolism and nutrition disorders 2 (7) 3 (10) 0 Respiratory, thoracic and mediastinal disorders 3 (10) 1 (3) 1 (3) Skin and subcutaneous tissue disorders 20 (67) 13 (42) 14 (47)

Acne infantile 1 (3) 1 (3) 2 (7) Dermatitis diaper 2 (7) 0 1 (3) Dry skin 2 (7) 3 (10) 3 (10) Erythema 5 (17) 5 (16) 0 Erythema toxicum neonatorum 1 (3) 2 (6) 3 (10) Milia 1 (3) 1 (3) 2 (7) Rash 3 (10) 1 (3) 3 (10) Rash maculo-papular 2 (7) 1 (3) 0 Seborrhoea 2 (7) 1 (3) 2 (7) Seborrhoeic dermatitis 3 (10) 1 (3) 0

Note: A patient was only counted once per SOC/preferred term. Note: TEAEs were defined as AEs that started or worsened in intensity on or after the injection of study medication. Note: AEs were coded using MedDRA, Version 19.0. MedDRA = Medical Dictionary for Regulatory Activities, PT= phototherapy, SOC = system organ class; TEAEs = treatment-emergent adverse events

7.3.1.2 Serious Adverse Events

A total of 15 neonates (16%) experienced SAEs (Table 29). The proportion of neonates with reported SAEs was similar among the treatment groups (17%, 13%, and 20% in the 3.0 mg/kg, 4.5 mg/kg, and placebo groups, respectively). No individual SAE occurred in more than one neonate except for hyperbilirubinemia in the placebo group (3 neonates) and medical observations in the stannsoporfin 3.0 mg/kg group (two neonates; one for observation of supraventricular tachycardia and one for rule out of sepsis). The medical observation events were prolonged hospitalizations: one neonate with rule out of sepsis, and one neonate with supraventricular tachycardia with a congenital heart defect, which the Investigator did not consider to be related to study drug.



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None of the SAEs led to discontinuation from the study. All SAEs resolved except for three: supraventricular tachycardia in a neonate with a congenital heart defect that was thought to have a re-entry accessory pathway (3.0 mg/kg), hematocrit decreased (placebo), and hemoglobin decreased (placebo).

Table 29: Summary of SAEs by SOC and Preferred Term in Study 204 (Safety Analysis Set)

Number (%) of Neonates

System Organ Class Preferred Term


(N=30) 3.0 mg/kg (N=30)

4.5 mg/kg (N=31)

Neonates with any treatment-emergent serious adverse event

5 (17) 4 (13) 6 (20)

Blood and lymphatic system disorders 1 (3) 0 0 Leukocytosis 1 (3) 0 0

Cardiac disorders 1 (3) 0 0 Supraventricular tachycardia 1 (3) 0 0

Hepatobiliary disorders 1 (3) 1 (3) 3 (10) Hyperbilirubinaemia 1 (3) 1 (3) 3 (10)

Immune system disorders 0 0 1 (3) ABO incompatibility 0 0 1 (3)

Infections and infestations 0 3 (10) 0 Bacterial sepsis 0 1 (3) 0 Meningitis viral 0 1 (3) 0 Sepsis 0 1 (3) 0

Investigations 2 (7) 0 2 (7) Hematocrit decreased 0 0 1 (3) Haemoglobin decreased 0 0 1 (3) Medical observation 2 (7) 0 0 Reticulocyte count increased 0 0 1 (3)

Respiratory, thoracic and mediastinal disorders 1 (3) 0 0 Tachypnoea 1 (3) 0 0

Note: Neonates with multiple occurrences of an event coded to the same SOC or preferred term were counted only once for that SOC or preferred term. Note: AEs were coded using MedDRA, Version 19.0. AEs = adverse events, MedDRA = Medical Dictionary for Regulatory Activities, SAEs = serious adverse events, SOC = system organ class, TEAEs = treatment-emergent adverse events

7.3.2 Acute Pooled Studies (Studies 204, 202, and 01-3W)

Acute safety data also come from the pooled randomized, double-blind, placebo-controlled studies that evaluated a single IM injection of stannsoporfin. In total, Studies 204, 202, and 01-3W (only the 4.5 mg/kg dose was studied in 01-3W) include safety data on stannsoporfin for 38 neonates with 3.0 mg/kg and 126 neonates with 4.5 mg/kg, as well as 134 placebo neonates.


In the acute pooled studies, the proportion of neonates who had TEAEs was similar in the stannsoporfin 4.5 mg/kg and placebo groups (41.3% and 36.6% respectively), and 81% in the 3.0 mg/kg group (Table 30). In these studies, AEs and TEAEs were identical except for 1 patient in the



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3.0 mg/kg group with thrombocytopenia that occurred prior to treatment. The pattern of AEs in the acute pooled studies is similar to that in Study 204.

The proportion of neonates with SAEs was similar in the 4.5 mg/kg and placebo groups (7.9% and 6.7%, respectively), and 13% in the 3.0 mg/kg group. There were no deaths during the studies, and no AEs led to discontinuation. One stannsoporfin 4.5 mg/kg neonate from Study 01-3W died at age 4.5 months of SIDS (3.5 months after completing the study); the death was judged by the investigator to be unrelated to study drug. See Section 7.5 and Appendix 12.8 for details.

Table 30: Summary of Adverse Events in Acute Pooled Studies (01-3W, 202, 204)

Number (%) of neonates Stannsoporfin

Placebo (N = 134)

1.5 mg/kg (N = 17)

3.0 mg/kg (N = 48)

4.5 mg/kg (N = 126)

AEs 8 (47.1) 39 (81.3) 53 (42.1)a 49 (36.6) TEAEs 8 (47.1) 38 (79.2) 53 (42.1) 49 (36.6)

Mild 6 (35.3) 27 (56.3) 40 (31.7) 43 (32.1) Moderate 1 (5.9) 9 (18.8) 12 (9.5) 6 (4.5) Severe 1 (5.9) 2 (4.2) 1 (0.8) 0

TEAEs leading to discontinuation 0 0 0 0 SAE 0 6 (12.5) 10 (7.9) 9 (6.7) Deathb 0 0 0 0 a One AE occurred prior to treatment and is therefore not considered a TEAE. b One death was reported in a neonate who was screened but not randomized or treated. AE = adverse events; SAE = serious adverse events; TEAE = treatment-emergent adverse events

Treatment-emergent adverse events reported in ≥2 neonates were mild, with a similar frequency across groups. The most frequent TEAEs in the 4.5 mg/kg group were erythema (5.6%), cardiac murmur (see Appendix 12.8 for narratives), and candida infection (4.0% each); all other TEAEs were reported in ≤3 neonates (Table 31). As in Study 204, the most common types of events were dermatologic, which had a similar incidence in the 4.5 mg/kg and placebo groups. As mentioned in Section 7.3.1.2, the medical observations in the 3.0 mg/kg stannsoporfin group included one for observation of supraventricular tachycardia and one for rule out of sepsis (both recorded as SAEs, Table 32).



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Table 31: Common TEAEs (≥2 Neonates in a Group) in Acute Pooled Studies (01-3W, 202, 204)

Number (%) of Neonates Stannsoporfin

Placebo (N = 134)

1.5 mg/kg (N = 17)

3.0 mg/kg (N = 48)

4.5 mg/kg (N = 126)

Any neonate with TEAE 8 (47.1) 39 (81.3) 53 (42.1) 49 (36.6) Blood and lymphatic system disorders 0 7 (14.6) 4 (3.2) 3 (2.2)

Anaemia 0 2 (4.2) 2 (1.6) 2 (1.5) Haemolytic anaemia 0 2 (4.2) 0 0 Thrombocytopenia 0 2 (4.2) 2 (1.6) 0

Congenital, familial and genetic disorders 0 2 (4.2) 3 (2.4) 4 (3.0) Congenital naevus 0 0 2 (1.6) 2 (1.5)

Gastrointestinal disorders 0 8 (16.7) 13 (10.3) 5 (3.7) Diarrhoea 0 0 3 (2.4) 0 Flatulence 0 0 3 (2.4) 0 Gastroesophageal reflux disease 0 0 2 (1.6) 1 (0.7) Umbilical hernia 0 5 (10.4) 1 (0.8) 0 Vomiting 0 1 (2.1) 2 (1.6) 2 (1.5)

Hepatobiliary disorders 7 (41.2) 2 (4.2) 2 (1.6) 7 (5.2) Hyperbilirubinaemia 2 (11.8) 2 (4.2) 1 (0.8) 6 (4.5) Jaundice 5 (29.4) 0 1 (0.8) 1 (0.7)

Infections and infestations 0 4 (8.3) 13 (10.3) 10 (7.5) Candida infection 0 0 5 (4.0) 4 (3.0) Oral candidiasis 0 0 0 3 (2.2)

Injury, poisoning and procedural complications 1 (5.9) 1 (2.1) 3 (2.4) 3 (2.2)

Scratch 0 0 0 2 (1.5) Investigations 1 (5.9) 12 (25.0) 12 (9.5) 12 (9.0)

Cardiac murmur 0 5 (10.4) 5 (4.0) 4 (3.0) Gamma-glutamyltransferase increased 0 2 (4.2) 1 (0.8) 5 (3.7) Haematocrit decreased 0 1 (2.1) 2 (1.6) 1 (0.7) Haemoglobin decreased 0 2 (4.2) 1 (0.8) 1 (0.7) Medical observation 0 2 (4.2) 0 0 Reticulocyte count increased 0 2 (4.2) 3 (2.4) 1 (0.7)

Metabolism and nutrition disorders 0 2 (4.2) 5 (4.0) 0 Feeding intolerance 0 0 2 (1.6) 0

Renal and urinary disorders 0 0 3 (2.4) 0 Chromaturia 0 0 3 (2.4) 0

Respiratory, thoracic and mediastinal disorders 0 3 (6.3) 4 (3.2) 1 (0.7)

Nasal congestion 0 1 (2.1) 3 (2.4) 0 Skin and subcutaneous tissue disorders 3 (17.6) 27 (56.3) 23 (18.3) 20 (14.9)

Acne infantile 1 (5.9) 1 (2.1) 1 (0.8) 2 (1.5) Dermatitis diaper 2 (11.8) 3 (6.3) 1 (0.8) 2 (1.5) Dry skin 0 2 (4.2) 3 (2.4) 3 (2.2) Erythema 0 6 (12.5) 7 (5.6) 0



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Placebo (N = 134)

1.5 mg/kg (N = 17)

3.0 mg/kg (N = 48)

4.5 mg/kg (N = 126)

Erythema toxicum neonatorum 0 4 (8.3) 2 (1.6) 3 (2.2) Milia 0 1 (2.1) 1 (0.8) 2 (1.5) Rash 1 (5.9) 3 (6.3) 3 (2.4) 4 (3.0) Rash erythematous 0 1 (2.1) 3 (2.4) 1 (0.7) Rash maculo-papular 0 2 (4.2) 1 (0.8) 0 Rash neonatal 0 1 (2.1) 2 (1.6) 3 (2.2) Rash papular 0 0 1 (0.8) 2 (1.5) Seborrhoea 0 2 (4.2) 1 (0.8) 2 (1.5) Seborrhoeic dermatitis 0 4 (8.3) 1 (0.8) 0

7.3.2.2 Serious Adverse Events

Serious adverse events were reported for 25 neonates during the acute studies (Table 32). The proportion of neonates in the pooled acute studies who had SAEs was similar in the 4.5 mg/kg (7.9%) and placebo groups (6.7%); and 12.5 % in the 3.0 mg/kg group. No SAEs were reported in the 1.5 mg/kg group. The only individual SAE reported for more than one stannsoporfin neonate was prolonged hospitalization for medical observations from Study 204 (two neonates in the 3.0 mg/kg group; one each for supraventricular tachycardia and rule out of sepsis). Serious adverse events were considered related to study drug in two neonates: one due to medical observation for rule out of sepsis, and one due to accidental overdose of study drug and an erythematous rash after receiving PT with the incorrect wavelength of light.



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Table 32: SAEs in Acute Pooled Studies (01-3W, 202, 204)


Placebo (N = 134)

1.5 mg/kg(N = 17)

3.0 mg/kg(N = 48)

4.5 mg/kg(N = 126)

Any neonate with reported SAEs 0 6 (12.5) 10 (7.9) 9 (6.7) Blood and lymphatic system disorders 0 3 (6.3) 0 0

Anaemia 0 1 (2.1) 0 0 Leukocytosis 0 1 (2.1) 0 0 Thrombocytopenia 0 1 (2.1) 0 0

Cardiac disorders 0 1 (2.1) 0 0 Supraventricular tachycardia 0 1 (2.1) 0 0

Gastrointestinal disorders 0 0 1 (0.8) 0 Diarrhoea 0 0 1 (0.8) 0

Hepatobiliary disorders 0 1 (2.1) 1 (0.8) 6 (4.5) Hyperbilirubinaemia 0 1 (2.1) 1 (0.8) 6 (4.5)

Immune system disorders 0 0 0 1 (0.7) ABO incompatibility 0 0 0 1 (0.7)

Infections and infestations 0 0 5 (4.0) 0 Bacterial sepsisa 0 0 1 (0.8) 0 Meningitisb 0 0 1 (0.8) 0 Meningitis viralc 0 0 1 (0.8) 0 Sepsisd 0 0 1 (0.8) 0 Viral infectione 0 0 1 (0.8) 0

Injury, poisoning and procedural complications 0 0 1 (0.8) 0 Incorrect dose administered 0 0 1 (0.8) 0

Investigations 0 2 (4.2) 0 2 (1.5) Haematocrit decreased 0 0 0 1 (0.7) Haemoglobin decreased 0 0 0 1 (0.7) Medical observation 0 2 (4.2) 0 0 Reticulocyte count increased 0 0 0 1 (0.7)

Nervous system disorders 0 0 1 (0.8) 0 Tremor 0 0 1 (0.8) 0

Respiratory, thoracic and mediastinal disorders 0 1 (2.1) 1 (0.8) 0 Tachypnoea 0 1 (2.1) 0 0 Wheezing 0 0 1 (0.8) 0

a Gram-negative sepsis (Haemophilus parainfluenzae); mother had chorioamnionitis b CSF culture negative; related to bacterial infection (Group B Streptococcus [GBS]; Streptococcus agalactiae in utero) c CSF cultures negative; sepsis ruled out d Blood and CSF cultures negative; no signs/symptoms of sepsis e Coughing and spitting up; also diagnosed with gastroesophageal reflux disease

7.3.2.3 Laboratory Findings

Clinical laboratory findings were assessed in the pooled analysis of Studies 202 and 204; clinical laboratory tests other than TSB were not performed in Study 01-3W. Results from liver and kidney function laboratory analyses are shown below. Liver function tests showed no indication of an effect of stannsoporfin. Kidney function tests showed minor decreases over time in all



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groups, but none of these changes were clinically meaningful, and the patterns were similar with stannsoporfin and placebo. These findings are expected in neonates and not indicative of adverse effects of stannsoporfin.

Liver Function Tests

The median values for alkaline phosphatase and GGT were similar at Baseline across the treatment groups. At 48 hours and Day 7, variations across the treatment groups were observed, but no trends were identified (Figure 32). No other liver function tests, including ALT (Figure 33) and AST (Figure 34), gave any indication of an effect of stannsoporfin.

Six liver function test values in five neonates (two, two, and one in the 3.0 mg/kg stannsoporfin, 4.5 mg/kg stannsoporfin, and placebo groups, respectively) were flagged as clinically significant:

One 3.0 mg/kg stannsoporfin neonate had no Baseline AST recorded but a value of 250 IU/L at 48 hours/discharge, and a value of 67 IU/L on Day 7.

The second 3.0 mg/kg stannsoporfin neonate had a Baseline GGT value of 112.0 IU/L (within normal range) and a value of 315 IU/L on Day 7.

One 4.5 mg/kg stannsoporfin neonate had a Baseline AST value of 83 IU/L (flagged as high) and a value of 121 IU/L at 48 hours.

The second 4.5 mg/kg stannsoporfin neonate had a Baseline AST value of 48.0 IU/L (flagged as high) and a value of 183 IU/L at 48 hours/discharge.

The placebo neonate had a Baseline AST value of 68 IU/L (flagged as high) and a value of 46 IU/L at Day 14.

Figure 32: Median GGT Values Over 30 Days in Acute Pooled Studies (202 and 204)

*Harriet Lane normal range for 0-1 months=13-147 U/Ls



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Figure 33: Median Serum ALT Values Over 30 Days in Acute Pooled Studies (202 and 204)

*Harriet Lane normal range for <12 months=13-45 U/L

Figure 34: Median Serum AST Values Over 30 Days in Acute Pooled Studies (202 and 204)

*Harriet Lane normal range for 0-10 days=47-150 U/L; 10 days to 24 months=9-80 U/L

Kidney Function Tests

The median BUN and creatinine levels were similar at Baseline across the treatment groups. Variations over time and across treatment groups were observed; however, no trends were identified, and there was no suggestion of a clinically meaningful relationship of any changes to stannsoporfin. Similar decreases from Baseline in median BUN and creatinine levels were observed at 48 hours and Day 7 in all groups (Figure 35). As previously mentioned, these changes are expected in neonates and are not indicative of any adverse effect of stannsoporfin.



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Figure 35: Median Creatinine and BUN Over 30 Days in Acute Pooled Studies (202 and 204)

*Harriet Lane normal creatinine range for newborns=0.3-1.0 mg/dL; normal BUN range for newborns=2-19 mg/dL

7.3.3 Long-Term Pooled Extension Studies (Studies 205, 203, and 01C-3W)

Long-term extension studies of the three acute pooled studies evaluated outcomes for up to six years, with a focus on evaluations of neurological and neurodevelopmental assessments. Study 205 is the extension of the pivotal Study 204, which ended in 2016. InfaCare is currently collecting data on patients completing their follow-up visits, and the study is planned to continue until four-year data collection is completed. Study 203, the extension of Study 202, followed patients for up to four years. Study 01C-3W, the extension of Study 01-3W, followed patients for up to six years. Table 33 shows a summary of the assessments and safety measures conducted in these studies.


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Table 33: Summary of Assessments and Measures in Long-Term Pooled Extension Studies

Follow-up

Assessments Safety Measures Total Patients Discontinuations

Study 205

2 phone calls (at 6 months and 3 years of age) and 3 clinic visits (at 1, 2, and 4

years of age)

Reported AEs, age-adjusted weight and height percentile, vital signs,

hearing assessments, physical, and neurological/developmental

examinations

68 25 stannsoporfin 3.0 mg/kg, 23 stannsoporfin 4.5 mg/kg,

20 placebo

2: 1 lost to follow-up and 1 voluntarily

withdrawn by parent/guardian)

Study 203 Scheduled assessments from 3 months until 48-

52 months of age

Reported AEs, age-adjusted weight and height percentile, vital signs,

hearing and ophthalmological assessments, physical,

neurological/developmental examinations, and clinical laboratory

assessments

42: 11 stannsoporfin 1.5 mg/kg, 12 stannsoporfin 3.0 mg/kg, 6 stannsoporfin 4.5 mg/kg,

13 placebo

19: 14 lost to follow-up

and 5 voluntarily withdrawn by the parent/guardian)

Study 01C-3W Scheduled assessments at

12 months and 3 years

Medical history and physical evaluations, clinical laboratory tests,

and neurologic and neurodevelopmental examinations

75 at 12 months and three years (37 stannsoporfin 4.5 mg/kg and

38 placebo), 59 at 6 years (30 stannsoporfin 4.5

mg/kg and 29 placebo)



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Table 34: Summary of Assessment Point Sample Sizes in Long-Term Pooled Extension Studies

Long-term Studies

Treatment Group

Follow-up Visit Schedule 3 mo (n)

6 mo (n)

1 yr (n)

18 mo (n)

2 yr (n)

3 yr (n)

4 yr (n)

6 yr (n)

Study 01C-3W (01-3W Extension)

Stann: N=44 Control: N=43

-- -- -- 32 28

-- 31 32

-- 30 29

Study 203 (202 Extension)


26 13

22 11

22 10

-- 21 10

13 5

15 8

--

Study 205* (204 Extension)


-- 43 18

30 14

-- 10 7

1 1

0 0

--

Total Stann: N=121 Control: N=76

26 13

65 29

52 24

32 28

31 17

45 38

15 8

30 29

*Study 205 is ongoing, May 31, 2017 cutoff.


The proportion of patients who had AEs was similar in the stannsoporfin 4.5 mg/kg (78.1%) and placebo (86.8%) groups, and 73.0% in the 3.0 mg/kg group (Table 35). The proportion of patients with SAEs was low and similar in stannsoporfin and placebo groups. There were no deaths during the studies and no AEs that led to discontinuation. One death (SIDS at 20 days) was reported in a patient who was screened but not randomized or treated. See Section 7.5 and Appendix 12.8 for details.

Table 35: Summary of Adverse Events in Long-Term Pooled Extension Studies (01C-3W, 203, 205)

Number (%) of Patients Stannsoporfin

Placebo (N = 76)

1.5 mg/kg (N = 11)

3.0 mg/kg (N = 37)

4.5 mg/kg (N = 73)

AE 7 (63.6) 27 (73.0) 57 (78.1) 66 (86.8) Mild 1 (9.1) 18 (48.6) 26 (35.6) 26 (34.2) Moderate 6 (54.5) 7 (18.9) 25 (34.2) 37 (48.7) Severe 0 2 (5.4) 6 (8.2) 3 (3.9)

AEs leading to discontinuation 0 0 0 0 SAE 0 4 (10.8) 10 (13.7) 7 (9.2) Death 0 0 0a 0

a One death occurred in a stannsoporfin 4.5 mg/kg neonate at 4.5 months after completing the study. Note: Study 205 is ongoing. Table includes safety update; cutoff May 31, 2017

The most frequent AEs in the 4.5 mg/kg and placebo groups were upper respiratory tract infection (52.1% and 63.2% respectively), otitis media (52.1% and 42.1%), pyrexia (37.0% and 39.5%), and cough (20.5% and 28.9%). In the stannsoporfin 3.0 mg/kg group, the most frequent AEs were pyrexia (21.6%), upper respiratory tract infection (16.2%), and vomiting (16.2%). Speech disorder occurred in more stannsoporfin 4.5 mg/kg patients compared with the lower doses and placebo; however, this observation in the pooled database results entirely from the imbalance of this event in Study 01C-3W. Speech disorders were investigated thoroughly on a patient level and are discussed further in Section 7.3.4.1.1. Speech disorders with available data resolved at the subsequent visit or were not confirmed upon referral. Other common AEs were generally similar in the stannsoporfin groups compared to placebo.



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Table 36: Common Adverse Events (≥10% Patients in a Group) in Long-Term Pooled Extension Studies (01C-3W, 203, 205)


1.5 mg/kg (N=11)

3.0 mg/kg (N=37)

4.5 mg/kg (N=73)

Placebo (N=76)

Any neonate with ≥10% AE 7 (63.6) 25 (67.6) 54 (74.0) 62 (81.6) Gastrointestinal disorders 6 (54.5) 13 (35.1) 32 (43.8) 39 (51.3)

Constipation 2 (18.2) 1 (2.7) 9 (12.3) 12 (15.8) Diarrhoea 2 (18.2) 4 (10.8) 14 (19.2) 20 (26.3) Umbilical hernia 2 (18.2) 1 (2.7) 1 (1.4) 3 (3.9) Vomiting 3 (27.3) 6 (16.2) 8 (11.0) 16 (21.1)

General disorders and administration site conditions 4 (36.4) 10 (27.0) 29 (39.7) 35 (46.1) Pyrexia 3 (27.3) 10 (27.0) 26 (35.6) 32 (42.1)

Infections and infestations 6 (54.5) 22 (59.5) 50 (68.5) 61 (80.3) Acute sinusitis 2 (18.2) 0 0 3 (3.9) Bronchiolitis 2 (18.2) 2 (5.4) 9 (12.3) 9 (11.8) Bronchitis 0 2 (5.4) 7 (9.6) 12 (15.8) Conjunctivitis 4 (36.4) 5 (13.5) 12 (16.4) 17 (22.4) Ear infection 3 (27.3) 5 (13.5) 5 (6.8) 4 (5.3) Gastroenteritis 3 (27.3) 2 (5.4) 9 (12.3) 11 (14.5) Gastroenteritis viral 1 (9.1) 1 (2.7) 4 (5.5) 8 (10.5) Impetigo 2 (18.2) 4 (10.8) 5 (6.8) 2 (2.6) Nasopharyngitis 2 (18.2) 3 (8.1) 6 (8.2) 4 (5.3) Otitis media 4 (36.4) 2 (5.4) 32 (43.8) 30 (39.5) Otitis media acute 3 (27.3) 6 (16.2) 2 (2.7) 6 (7.9) Pharyngitis 1 (9.1) 0 9 (12.3) 13 (17.1) Pneumonia 1 (9.1) 2 (5.4) 5 (6.8) 9 (11.8) Upper respiratory tract infection 4 (36.4) 10 (27.0) 35 (47.9) 43 (56.6) Viral infection 4 (36.4) 5 (13.5) 8 (11.0) 19 (25.0) Viral upper respiratory tract infection 2 (18.2) 4 (10.8) 9 (12.3) 7 (9.2)

Injury, poisoning and procedural complications 4 (36.4) 7 (18.9) 22 (30.1) 24 (31.6) Head injury 2 (18.2) 2 (5.4) 4 (5.5) 3 (3.9)

Nervous system disorders 1 (9.1) 2 (5.4) 12 (16.4) 9 (11.8) Speech disorder 1 (9.1) 0 10 (13.7) 2 (2.6)

Respiratory, thoracic and mediastinal disorders 3 (27.3) 9 (24.3) 35 (47.9) 38 (50.0) Asthma 1 (9.1) 1 (2.7) 7 (9.6) 10 (13.2) Cough 2 (18.2) 5 (13.5) 17 (23.3) 25 (32.9) Nasal congestion 1 (9.1) 6 (16.2) 12 (16.4) 13 (17.1) Rhinorrhoea 1 (9.1) 4 (10.8) 7 (9.6) 10 (13.2) Wheezing 1 (9.1) 2 (5.4) 2 (2.7) 8 (10.5)

Skin and subcutaneous tissue disorders 5 (45.5) 12 (32.4) 34 (46.6) 46 (60.5) Dermatitis diaper 2 (18.2) 7 (18.9) 9 (12.3) 7 (9.2) Eczema 1 (9.1) 6 (16.2) 10 (13.7) 20 (26.3) Rash 0 1 (2.7) 9 (12.3) 19 (25.0)

AE = adverse event: in long-term follow-up any adverse event was considered a treatment emergent AE Note: Study 205 is ongoing. Table includes safety update; cutoff May 31, 2017



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7.3.4 Neurological Assessment of Stannsoporfin

Stannsoporfin is a large molecule (754 daltons) that is highly protein bound (>96%-99%), so it is not expected to cross the blood brain barrier in humans. Animal studies showed 0.6% radioactivity in brain after a single IM injection that was isolated to the brain vasculature. Stannsoporfin is not expected to cross the blood brain barrier based on animal studies, and preclinical studies did not identify any neurologic concerns. Stannsoporfin is therefore considered unlikely to have any central neurodevelopment effects in humans. However, since infants with neonatal hyperbilirubinemia are at greater risk of exposure to unbound or free bilirubin, a known neurotoxin that can cross the blood-brain barrier, long-term neurocognitive and neurodevelopment AEs were identified as events of interest.

The Sponsor had a third-party expert conduct an independent review of the long-term studies to assess long-term neurodevelopmental outcomes in newborns treated with stannsoporfin. This review focused on the neurodevelopmental test scores and the clinical judgments made by study site investigators about the presence of adverse neurodevelopmental events.

Across the totality of evidence from the stannsoporfin development program including long-term data up to 6 years, there was no indication of neurocognitive or neurodevelopment effect following single injection of stannsoporfin.

7.3.4.1 Neurocognitive and Neurodevelopmental Adverse Events in Long-term Pooled Extension Studies

Adverse events of special interest were reported for 27.4% of stannsoporfin 4.5 mg/kg patients, 17.1% of placebo patients, and <11% of the 3.0 and 1.5 mg/kg groups (Table 37).



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Table 37: Neurocognitive and Neurodevelopmental AESI in Long-Term Pooled Extension Studies (01C-3W, 203 and 205)


1.5 mg/kg (N=11)

3.0 mg/kg (N=37)

4.5 mg/kg (N=73)

Placebo (N=76)

Any Subject with AESI 1 (9.1) 4 (10.8) 20 (27.4) 13 (17.1) Congenital, familial and genetic disorders 0 0 1 (1.4) 0

Macrocephaly 0 0 1 (1.4) 0 Ear and labyrinth disorders 0 2 (5.4) 5 (6.8) 0

Conductive deafness 0 2 (5.4) 1 (1.4) 0 Deafness 0 0 2 (2.7) 0 Deafness bilateral 0 0 1 (1.4) 0 Hypoacusis 0 0 1 (1.4) 0

General disorders and administration site conditions 0 1 (2.7) 2 (2.7) 1 (1.3) Developmental delay 0 1 (2.7) 2 (2.7) 1 (1.3)

Investigations 0 0 1 (1.4) 0 Neuropsychological test abnormal 0 0 1 (1.4) 0

Nervous system disorders 1 (9.1) 2 (5.4) 10 (13.7) 6 (7.9) Dysarthria 0 0 1 (1.4) 0 Dyspraxia 0 0 1 (1.4) 0 Language disorder 0 0 1 (1.4) 1 (1.3) Psychomotor hyperactivity 0 1 (2.7) 0 0 Seizure 0 0 0 1 (1.3) Speech disorder 1 (9.1) 0 10 (13.7) 2 (2.6) Speech disorder developmental 0 1 (2.7) 0 1 (1.3) Tremor 0 0 0 1 (1.3)

Psychiatric disorders 0 0 5 (6.8) 4 (5.3) Abnormal behaviour 0 0 2 (2.7) 2 (2.6) Agitation 0 0 1 (1.4) 0 Anxiety 0 0 1 (1.4) 0 Anxiety disorder 0 0 0 1 (1.3) Attention deficit/hyperactivity disorder 0 0 0 1 (1.3) Dysphemia 0 0 0 1 (1.3) Learning disability 0 0 0 1 (1.3) Speech sound disorder 0 0 1 (1.4) 0

Respiratory, thoracic and mediastinal disorders 0 0 0 2 (2.6) Apnoea 0 0 0 1 (1.3) Sleep apnoea syndrome 0 0 0 1 (1.3)

Social circumstances 0 0 1 (1.4) 0 Parent-child problem 0 0 1 (1.4) 0

Surgical and medical procedures 0 0 1 (1.4) 0 Psychotherapy 0 0 1 (1.4) 0 AESI = adverse events of special interest Note: Study 205 is ongoing. Table includes safety update; cutoff May 31, 2017

Nervous System Disorders SOC

Nervous system disorders AEs were reported for 13.7% of stannsoporfin 4.5 mg/kg patients, 7.9% of placebo patients, and 5.4% and 9.1% in the 3.0 and 1.5 mg/kg groups.



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Speech disorders occurred more frequently in stannsoporfin treated patients compared with placebo in the pooled dataset, but this observation results entirely from the imbalance of this event in Study 01C-3W that recruited healthy near- and full-term newborns without evidence of hemolysis (10 events for stannsoporfin 4.5 mg/kg and 2 events for placebo, Table 72-Table 74 in Appendix 12.9). No imbalance has been observed in any other stannsoporfin clinical study.

7.3.4.2 Neurodevelopmental Assessments in Long-term Extension Studies

A variety of robust assessment tools were used at various follow-up visits in the studies conducted under both INDs to evaluate physical, neurologic, developmental, behavioral, and psychological status of the patients (Table 38). At the End of Phase 2 meeting, the FDA agreed that neurodevelopmental assessments up to three years would suffice for the application. For stannsoporfin, there are sufficient data up to at least three years, including assessments of general cognitive development, a single cognitive domain of language, and general behavior problems with additional data up to six years post-treatment.

The assessments were categorized under three groups: general cognitive development, single cognitive domain – language development, and general behavior issues. All instruments are normed for the U.S. population of children.

General cognitive development:

Wechsler Preschool and Primary Scale of Intelligence (WPPSI) is an intelligence test designed for children ages two years six months to seven years three months (Edition 3 was used in all assessments except the six-year assessment in 01C-3W which used Edition 4). Higher scores on the WPPSI indicate better performance.

Mullen Scales of Early Learning (MSEL) is a comprehensive measure of cognitive and motor functioning for infants and preschool children from birth through 68 months (assessed in Studies 203 and 205). Higher scores on the MSEL indicate better cognitive and motor functioning.

Bayley Scales of Infant Development (BSID) is used to describe the current developmental functioning of infants and measure development in three domains: psychomotor, behavioral, and mental (assessed in Study 01C-3W). Higher scores on the BSID indicate better cognitive and motor functioning.

Single cognitive domain – language development:

Receptive-Expressive Emergent Language Test (REEL) is a parent-report instrument used to identify whether a young child (0-3 years) is acquiring language at the expected pace and determines if there is a significant discrepancy between receptive and expressive processes of emergent language (assessed in Study 01C-3W). Higher scores on the REEL indicate better language skills.



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General behavior issues:

Conners’ Early Childhood Rating scale (ECRS) is a parent-report instrument used to describe the behavior of children aged two to six years old. Subscales indicate inattention, hyperactivity, defiance, aggression, social functioning and atypical behaviors, anxiety, mood and physical symptoms (assessed in Studies 203 and 205). Lower scores on the ECRS indicate less problematic behavior.

Child Behavior Checklist (CBCL) is a checklist by which parents or other individuals who know the child well rate a child's problem behaviors and competencies (assessed in Study 01C-3W). Lower scores on the CBCL indicate less problematic behavior.

Table 38: Schedule of Neurodevelopmental Assessments in Long-term Pooled Extension Studies

Tool

Follow-up Visit Schedule

3 mo 6 mo 1 yr 18 mo 2 yr 3 yr 4 yr 6 yr

WPPSI 205 01C3W/203 203/205 01C-3W

MSEL 203 203 203/205 203/205

BSID 01C-3W

Conners’ 203/205 203 203/205

REEL 01C-3W

CBCL 01C-3W 01C-3W 01C-3W

Results of Neurocognitive Assessments in Long-term Pooled Extension Studies

Overall, the data indicate that no clinically meaningful signal was detected in long-term follow-up out to six years. Although early events were noted in both the stannsoporfin and placebo groups (eg, Mullen Scales at three months of age), these associations were not apparent at later ages. Thus, any perceived early signal did not correlate with a later signal and, importantly, the absence of early findings correlated with the absence of later findings.

Wechsler Preschool and Primary Scale of Intelligence (WPPSI)

The WPPSI provides scores that represent intellectual functioning in verbal and performance cognitive domains, as well as a composite score that represents a child’s general intellectual ability. Scores can be used in several ways (eg, as an assessment of general intellectual functioning, as part of an assessment to identify intellectual giftedness, and to identify cognitive delay and learning difficulties). The WPPSI was administered at three, four, and six years of age (Study 01C-3W).

The WPPSI Verbal, Performance, and Full-Scale IQ scores of the stannsoporfin group were within the normal range at three years with no significant differences between the scores of the



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stannsoporfin and placebo groups (Figure 36). The four-year data are still being collected in Study 205, but the small number of stannsoporfin patients tested so far are also within the expected range at four years. The scores of the placebo group show a sizeable discrepancy between the Verbal IQ and Performance IQ scores at Year 4.

Figure 36: Wechsler Preschool Test (Percentile-Rank) in Long-Term Pooled Extension Studies (01C-3W and 203)

All not statistically significant Study 01C-3W: 4.5 mg/kg dose at month 18 and year 6 Study 203: 1.5 mg/kg, 3.0 mg/kg, and 4.5 mg/kg doses at year 3

Mullen Scales of Early Learning (MSEL)

The MSEL is a standardized measure of cognitive and motor ability. The MSEL was assessed at three and six months and one and two years in Study 203, and at one and two years in Study 205.

In the MSEL percentile rank results, the three-month findings differ from the findings at six months, one year, and two years, which are quite consistent (Table 39). At Month 3, the mean percentile rank of the stannsoporfin group was lower than the mean of the placebo group on all six scales, and the differences were statistically significant for four of the six scales. This was due to the percentile rank scores of the placebo group being substantially higher than expected and the percentile ranks of the stannsoporfin group being in the expected range. Within both groups, the mean scores at Month 3 tended to be much more similar than the medians, except for the gross motor scale, which suggests that some children in the stannsoporfin group had low scores. Greater within-group variability in the combined stannsoporfin group was confirmed by the much larger standard deviations in this group compared to the placebo group. At six months, one year, and two years, only one of the 18 comparisons revealed a significant difference between groups. At six months, there was no pattern in terms of which group achieved a higher score, and in contrast to the three-month scores, there was less within-group variability in the stannsoporfin group than the placebo group. At one year, the stannsoporfin group had higher mean scores on all six scales (although the differences were not significant) and, at this age, the



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stannsoporfin group tended to have greater within-group variability. At two years, the mean of the placebo group was significantly higher than the mean of the drug group on visual reception. This likely reflects chance, due to the number of comparisons made. Thus, the three-month findings were not predictive of developmental issues at later assessments

Table 39: Mullen Scale of Early Learning: Percentile Rank in Long-Term Pooled Extension Studies (Studies 203 and 205)

Mean (SD), Median

P value Stannsoporfin

Combined Doses Placebo

Month 3 Valid n 24 13 Fine motor 35.54 (24.424), 38.00 46.69 (16.948), 38.00 0.1526 Gross motor 38.96 (28.568), 27.00 51.23 (19.123), 50.00 0.1747 Visual reception 45.33 (33.424), 64.00 70.92 (15.376), 66.00 0.0135 Receptive language 44.5 (33.073), 54.00 66.38 (24.737), 62.00 0.0444 Expressive language 46.25 (27.186), 54.00 67.77 (22.698), 69.00 0.0205 Early learning composite 46.08 (30.987), 49.5 69.92 (20.998), 68.00 0.0183

Month 6 Valid n 22 11 Fine motor 36.36 (24.958), 34.00 31.18 (29.410), 16.00 0.5999 Gross motor 68.55 (24.595), 66.00 56.00 (30.948), 58.00 0.2145 Visual reception 45.45 (25.523), 54.00 49.82 (31.906), 54.00 0.6731 Receptive language 50.18 (24.884), 50.00 44.45 (32.522), 27.00 0.5779 Expressive language 37.41 (19.314), 42.00 42.00 (29.445), 42.00 0.5939 Early learning composite 40.86 (22.639), 36.5 39.09 (31.428), 28.00 0.8536

Year 1 Valid n 50 24 Fine motor 49.56 (34.012), 46.00 48.00 (30.409), 46.00 0.8491 Gross motor 51.6 (31.558), 60.00 43.67 (32.476), 40.00 0.3193 Visual reception 33.94 (29.357), 24.00 34.5 (27.136), 27.00 0.9375 Receptive language 29.56 (24.057), 27.00 21.75 (21.472), 16.00 0.1806 Expressive language 33.66 (29.746), 27.5 24.67 (22.742), 21.00 0.1953 Early learning composite 33.74 (28.541), 29.5 26.25 (20.927), 30.00 0.2561

Year 2 Valid n 29 13 Fine motor 22.17 (25.358), 8.00 31.92 (30.115), 27.00 0.2835 Gross motor 42.52 (30.988), 42.00 34.85 (31.128), 27.00 0.4632 Visual reception 26.00 (27.445), 16.00 53.54 (31.418), 58.00 0.0064 Receptive languagea 42.68 (28.880), 44.00 31.69 (28.622), 27.00 0.2627 Expressive languagea 25.89 (26.953), 15.00 24.54 (17.159), 27.00 0.8693 Early learning compositea 24.39 (21.278), 20.00 32.77 (25.269), 21.00 0.2758

SD = standard deviation Note: Study 205 is ongoing. Table includes safety update; cutoff May 31, 2017 Note: Tests were not performed in 64,185-01C-3W. In 64,185-203 assessments were at 3 and 6 months, and 1 and 2 years. In 64,185-205 assessments were at 1 and 2 years. a: Valid N = 28, 13

In the MSEL age equivalent scores at three months, the stannsoporfin group mean scores were all essentially at the expected three-month level, indicating that they performed as would be expected for a three-month old (Table 40). The placebo group means were significantly higher (well above the level expected for a 3-month-old) than the stannsoporfin group means on two



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scales (visual reception and expressive language). For both scales, however, this was not because the stannsoporfin group performed below the expected level but because the placebo group scored above the expected level on both scales (4.23 and 4.31, respectively). At six months, one year, and two years, there were no significant differences between groups, with no consistent pattern in the direction of group differences (ie, sometimes the stannsoporfin group had a higher score, sometimes the placebo group had a higher score).

Table 40: Mullen Scale of Early Learning: Age Equivalent Scores in Long-Term Pooled Extension Studies (Studies 203 and 205)

Mean (SD), Median

P value Stannsoporfin

Combined doses Placebo Month 3

Valid n 24 13 Fine motor 2.79 (1.532), 3.00 3.15 (1.068), 3.00 0.4544 Gross motor 3.13 (1.624), 3.00 3.23 (0.439), 3.00 0.8202 Visual reception 3.17 (1.466), 4.00 4.23 (0.832), 4.00 0.0230 Receptive language 2.5 (1.504), 2.5 3.46 (1.266), 4.00 0.0583 Expressive language 3.04 (1.122), 3.00 4.31 (1.316), 5.00 0.0040

Month 6 Valid n 21 11 Fine motor 5.76 (1.513), 6.00 5.91 (1.221), 5.00 0.7829 Gross motor 7.67 (2.726), 7.00 7.36 (1.567), 7.00 0.7371 Visual reception 6.00 (1.643), 6.00 6.55 (1.368), 6.00 0.3541 Receptive language 5.71 (1.309), 6.00 6.00 (1.342), 6.00 0.5653 Expressive language 5.43 (1.248), 5.00 6.09 (1.300), 6.00 0.170

Year 1 Valid n 50 24 Fine motor 13.32 (3.461), 13.00 12.92 (2.358), 13.00 0.6078 Gross motor 13.22 (2.597), 14.00 12.58 (2.263), 13.00 0.3077 Visual reception 11.3 (2.978), 12.00 11.42 (2.225), 12.00 0.8653 Receptive language 11.14 (2.879), 10.5 10.29 (2.274), 10.00 0.2099 Expressive language 10.82 (3.397), 10.00 9.88 (3.207), 10.00 0.2580

Year 2 Valid n 29 13 Fine motor 20.86 (3.777), 20.00 21.62 (3.228), 22.00 0.5367 Gross motor 23.28 (4.659), 22.00 21.77 (4.494), 21.00 0.3334 Visual reception 20.72 (4.590), 20.00 23.85 (5.242), 25.00 0.0581 Receptive languagea 22.96 (5.323), 23.5 21.54 (5.158), 23.00 0.4253 Expressive languagea 19.75 (5.386), 20.00 20.62 (3.203), 22.00 0.5958

SD = standard deviation Note: Study 205 is ongoing. Table includes safety update; cutoff May 31, 2017 Note: Mullen Scale Tests were not performed in 64,185-01C-3W. In 64,185-203 assessments were at 3 and 6 months, and 1 and 2 years. In 64,185-205 assessments were at 1 and 2 years. a: Valid N = 28, 13

Overall, children in the stannsoporfin group performed well within the expected range at all ages. Except for the three-month assessment, at which the children in the placebo group scored well above the expected level on this test, there was no consistent pattern of difference between the scores of the stannsoporfin and placebo groups, no indication of an impact on any specific domain of neurodevelopment, and no significant differences in the scores of the groups at the



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one-year or two-year assessments. Given that the predictive validity of assessments increases with age, the absence of a coherent pattern of group differences after three months provides additional assurance that the neurodevelopment of the stannsoporfin group was similar to that of the placebo group.

Bayley Scales of Infant Development

The BSID is often the primary endpoint in studies of neurodevelopmental outcome in children under three-and-a-half years of age. These data are based on well-trained and supervised examiners’ ratings of the behavior of an infant during an assessment. The scores, especially those obtained prior to two years of age, tend not to be highly predictive of longer-term neurodevelopmental status but have excellent concurrent validity (ie, capture a child’s developmental status at the time of assessment). The BSID is widely used both in research and clinical practice.

Overall, lower scores were noted in the stannsoporfin group compared to those with placebo at 18 months, both for the Psychomotor Development Index (statistically significant) and the Mental Development Index (Table 41). The mean scores of the stannsoporfin group are in the low average range while the scores of the placebo group are in the average range (though below the expected mean of 100). The results included two uncooperative stannsoporfin patients; one patient had a Psychomotor Development Index (PDI) standardized score of 70, which is more than two SD below the expected mean score. This PDI was not considered by the investigator to be a valid measure of this child’s motor function. The other patient had a PDI standardized score of 71. The PDI scores in both patients were the lowest scores recorded on the PDI among all patients.

In Study 01C-3W, no significant differences between the stannsoporfin and placebo groups were observed at 18 months on the MSEL, which, like the BSID, provides a global assessment of infants’ development. Thus, the weight of evidence indicates that at 18 months of age, the neurodevelopment of infants who received stannsoporfin does not differ from the neurodevelopment of infants in the comparison groups. Additionally, this finding was not seen in the five Rockefeller IND studies that assessed children at 18 months using the same test. As shown in Figure 37, the stannsoporfin group achieved higher scores in some of the studies. Overall, the data from all six studies combined indicate that the performance of the stannsoporfin and placebo groups did not differ at 18 months of age in terms of mental or motor development.



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Table 41: Bayley Scales of Infant Development: 18 Month T-Scores in Study 01C-3W

Stannsoporfin 4.5 mg/kg (N = 44)

Placebo (N = 43)

Valid N 29 26 Mental development index (MDI) Mean (SD) 89.83 (11.464) 94.85 (11.008) Median 90.00 94.00 Pairwise t-test vs placebo 0.1046 Psychomotor development index (PDI) Mean (SD) 91.07 (9.577) 97.54 (8.664) Median 92.00 98.00 Pairwise t-test vs placebo 0.0116

SD = standard deviation

Figure 37: Bayley Scales of Infant Development at 18 Months (4.5 mg/kg Dose)

*InfaCare IND Study **Rockefeller IND Studies

Receptive-Expressive Emergent Language Test

The REEL is a parent-completed questionnaire, rather than a test administered to a child, that assesses children’s language development. The REEL was completed at 18 months.

The findings show no significant differences between the stannsoporfin and placebo groups at 18 months of age in terms of either receptive or expressive language. The T-score represents a standard distribution analysis to allow comparisons against age-level peers. Children in both groups achieved above the expected mean of 50 and as a result were rated above their 18-month age-expected level for receptive and expressive language.

The age-equivalent scores indicate that children in the stannsoporfin group were rated above their 18-month age-level both in terms of receptive and expressive language (23 month-level for receptive language, 22 month-level for expressive language) (Table 42). These data provide no



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indication that the language development of children in the stannsoporfin group differed from that of children in the placebo group.

Table 42: Receptive-Expressive Emergent Language Test: 18-Month T-score and Age Equivalent Score in Study 01C-3W

T-score Age Equivalent Score (Months) Stannsoporfin

4.5 mg/kg (N = 44)

Placebo (N = 43)

Stannsoporfin 4.5 mg/kg (N = 44)

Placebo (N = 43)

Valid N 29 26 29 26 Receptive language Mean (SD) 54.1 (14.336) 52.54 (8.932) 23.28 (7.869) 21.96 (5.800) Median 58.00 54.00 22.00 20.00 Pairwise t-test vs placebo 0.6338 0.4881 Expressive language Mean (SD) 54.17 (8.913) 50.73 (8.493) 22.41 (5.692) 20.42 (4.456) Median 55.00 51.5 21.00 20.00 Pairwise t-test vs placebo 0.1497 0.1579

SD = standard deviation

Conners’ Early Childhood Rating Scale

The Conners’ ECRS is a widely-used, comprehensive assessment tool, completed by parents, that assesses general behavior with respect to a range of behavioral, emotional, and social concerns, and developmental milestones in preschool-aged children, including cognitive, social-emotional, physical, and health and safety. Ratings were obtained at two, three, and four years. A higher score suggests a greater problem.

The Conners’ ECRS scores provide no evidence that the behavior of the stannsoporfin group differed from the behavior of the placebo group. For both stannsoporfin and placebo groups, the mean scores on many of the scales were above the average range (expected mean is 50 ± 10), sometimes markedly so, especially at ages two and three (Table 43). However, there was no consistent pattern in the direction of group differences (ie, sometimes the stannsoporfin group had a higher score; sometimes the placebo group had a higher score).



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Table 43: Conners’ Scales of Early Behavior: T-scores in Long-Term Pooled Extension Studies (203 and 205)

Stannsoporfin Combined Doses Placebo

P value Mean (SD) Median Mean (SD) Median Year 2 Valid N 21 11 Anxiety 63.38 (15.439) 62.00 60.64 (14.271) 56.00 0.6279 Defiant/aggressive behaviors 66.52 (16.470) 63.00 59.55 (17.426) 57.00 0.2731 Inattention/hyperactivity 52.57 (8.364) 50.00 54.27 (7.747) 53.00 0.5797 Mood and affect 61.52 (15.022) 56.00 58.45 (14.341) 56.00 0.5815 Physical symptoms 57.43 (9.574) 58.00 56.18 (11.522) 54.00 0.7464 Social functioning/atypical behaviors 59.33 (13.847) 58.00 50.91 (12.692) 47.00 0.1033 Year 3 Valid N 11 4 Anxiety 61.55 (10.434) 62.00 62.75 (12.447) 61.00 0.8532 Defiant/aggressive behaviors 62.55 (14.686) 65.00 66.5 (13.772) 70.5 0.6477 Inattention/hyperactivity 55.64 (13.094) 60.00 52.75 (4.193) 53.5 0.6785 Mood and affect 57.73 (13.595) 51.00 62.5 (12.610) 60.5 0.5516 Physical symptoms 50.91 (9.224) 47.00 53.75 (4.717) 55.00 0.5724 Social functioning/atypical behaviors 56.18 (17.186) 47.00 59.00 (14.832) 55.00 0.7768 Year 4 Valid N 14 8 Anxiety 54.64 (17.127) 58.5 54.5 (9.134) 56.00 0.9829 Defiant/aggressive behaviors 57.00 (9.790) 59.00 56.88 (14.990) 50.00 0.9813 Inattention/hyperactivity 57.57 (6.969) 55.00 56.88 (9.250) 58.5 0.8432 Mood and affect 55.71 (9.360) 53.5 57.25 (7.760) 57.00 0.6990 Physical symptoms 48.00 (7.575) 46.00 56.00 (10.664) 56.5 0.0531 Social functioning/atypical behaviors 54.79 (11.026) 54.5 50.38 (7.444) 48.5 0.3278 SD = standard deviation Note: Study 205 is ongoing. Table includes safety update; cutoff May 31, 2017

Child Behavior Checklist

The CBCL is a widely-used questionnaire to assess behavioral and emotional problems in children. Parents or others who interact with the child in regular contexts rate the child's behavior based on the previous two months. Different versions are used for pre-school and school age children, although there is considerable overlap in the scores yielded. The CBCL was administered at 18 months, three and six years. A higher score suggests a greater problem.

The scores of the stannsoporfin and placebo groups did not differ significantly on any CBCL subscale or on either of the two composite scales of Internalizing or Externalizing problem behaviors at 18 months, three or six years (Table 44). The mean z-scores for the stannsoporfin group hover close to zero, with many having negative signs. The median scores tend to be even lower (ie, better) than the mean scores. This was true in both the stannsoporfin and placebo groups. There was one subscale mean score that was somewhat elevated in the stannsoporfin group (0.41; Attention Problems at 18 months), but the median score in this group was -0.2. This suggests that the mean score was unduly affected by a small subset of children who had



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high scores (ie, suggesting attention problems). This pattern was not observed at three or six years, when the mean z-scores for the stannsoporfin group were essentially 0 (0.03 and -0.06, respectively). The mean scores of the stannsoporfin and placebo groups on the two scales that are expressed as T-scores (Social Problems, Vocabulary) did not differ statistically significantly.

Table 44: Child Behavior Checklist: 18 Months, 3, and 6 Years in Study 01C-3W Norm Based Z-Scores unless otherwise noted 18 months 3 years 6 years

Stannsoporfin

4.5 mg/kg Placebo Stannsoporfin


4.5 mg/kg Placebo Anxious depressed Valid N 29 26 31 32 28 29 Mean (SD) -0.07 (0.871) -0.19 (0.582) 0.06 (1.142) -0.15 (0.94) -0.11 (1.013) -0.12 (1.295) Median -0.56 -0.39 -0.39 -0.56 -0.66 -0.73 Somatic complaints/problems Valid N 29 26 31 32 28 29 Mean (SD) -0.04 (0.964) 0.13 (1.084) -0.13 (1.009) -0.1 (0.799) -0.08 (0.888) -0.05 (0.987) Median -0.69 -0.39 -0.69 -0.69 -0.43 -0.61 Attention problems Valid N 29 26 31 32 28 29 Mean (SD) 0.41 (1.243) -0.15 (0.733) 0.03 (1.125) -0.3 (0.788) -0.06(0.856) -0.01(1.365) Median -0.2 -0.38 -0.55 -0.55 -0.41 -0.46 Aggressive problems Valid N 29 25 31 32 28 29 Mean (SD) -0.13 (0.868) -0.16 (0.64) 0.07 (1.108) -0.28 (1.298) 0.05 (1.146) -0.09 (0.935) Median -0.37 -0.53 -0.37 -0.7 -0.47 -0.39 Withdrawn Valid N 26 24 28 30 28 29 Mean (SD) 0.23 (1.424) 0.05 (1.083) 0.37 (1.351) 0.26 (1.096) 0.09 (1.039) -0.18 (1.079) Median -0.53 -0.49 -0.06 -0.23 -0.41 -0.76 Vocabulary T-scores Valid N 29 25 Mean (SD) 41.9 (24.943) 34.2 (22.898) Median 35.00 25.00 Emotionally reactive Valid N 29 26 31 32 Mean (SD) -0.04 (0.973) 0.02 (0.969) -0.07 (0.954) -0.44 (0.673) Median -0.53 -0.61 -0.44 -0.7 Sleep problems Valid N 29 26 31 32 Mean (SD) -0.1 (1.172) -0.08 (0.756) -0.16 (0.788) 0.14 (1.171) Median -0.56 -0.43 -0.47 -0.21 Thought problems Valid N 28 29 Mean (SD) -0.14 (1.074) -0.05 (1.247) Median -0.58 -0.57 Rule breaking behavior Valid N 28 29 Mean (SD) 0.07 (1.002) -0.05 (0.871)



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Norm Based Z-Scores unless otherwise noted 18 months 3 years 6 years

Stannsoporfin



4.5 mg/kg Placebo Median -0.43 -0.58 Social problems T-scores Valid N 28 29 Mean (SD) 54.29 (5.943) 54.14 (7.165) Median 52.5 51.00 Internalizing (composite) Valid N 29 26 31 32 28 29 Mean (SD) -0.09 (1.038) 0.00 (0.954) -0.07 (1.163) -0.34 (1.089) -0.03 (0.947) -0.24 (1.153) Median -0.1 0.00 0.1 -0.51 -0.12 -0.42 Externalizing (composite) Valid N 29 26 31 32 28 29 Mean (SD) 0.00 (0.958) -0.06 (0.986) -0.1 (1.212) -0.31 (1.014) 0.08 (1.001) 0.02 (0.9) Median 0.00 0.1 0.1 -0.3 0.1 0.09 SD = standard deviation Note: Pre-school normative data were used for 18-month and 3-year visits; school aged empirically-based normative data were used for 6-year visits. In contrast to the other scales and subscales, a higher T-score on Vocabulary is better

7.3.4.3 Conclusions from Neurological Assessments

Across all assessments and timepoints from three months to six years, a variety of robust indices of general cognitive development, language development, and general behavior issues used in the long-term pooled extension studies provide no evidence that stannsoporfin impairs neurodevelopment. Any perceived early signal did not correlate with a later finding and the absence of early findings correlated with the absence of later findings. The absence of group differences at later time points suggests there are no clinically meaningful differences with placebo in the stannsoporfin treated infants.

The Wechsler Preschool and Primary Scale of Intelligence, a measure of general cognitive development, showed no differences between the scores of the stannsoporfin and placebo groups in Verbal IQ, Performance IQ, or Full-scale IQ at 3 or 4 years of age, or in any of the five composite scores, including Full-Scale IQ, at 6 years of age. Overall, the central tendencies of distributions of scores in the stannsoporfin group were similar to the placebo group. Importantly, the frequencies of extreme or outlier scores were also similar between groups.

When the Mullen Scales of Early Learning were administered at three months of age, stannsoporfin patients scored in the normal range but statistically significantly lower than patients in the placebo group, who tended to score higher than expected on most scales. At the next assessment three months later (at six months of age), however, no statistically significant differences were found between the scores of the two groups on any of the six scales. Only one statistically significant difference between groups was found at the one-year or two-year assessments, with the stannsoporfin patients scoring lower on the visual reception scale. This might reflect chance due to the number of comparisons made. The



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differences observed at three-months did not persist and thus were not predictive of developmental issues at later assessments.

The Bayley Scales of Infant Development, which describes the current developmental functioning of infants and measures development in the psychomotor, behavioral, and mental domains, was administered only at 18 months. The mean scores of the children in the stannsoporfin group for the mental and psychomotor development indices were well within the normal range, but statistically significantly lower than those of the children in the placebo group. Also, there were two uncooperative stannsoporfin patients; when data were re-analyzed excluding these patients, there were no statistically significant differences.

The Receptive-Expressive Emergent Language test is a parent-completed measure of the pace at which young children acquire receptive and expressive language. The assessment at 18 months showed similar language development in the stannsoporfin and placebo groups.

The Conners’ Early Childhood Rating scale is a parent rating scale and was one of two assessments of general behavior problems. For both stannsoporfin and placebo patients, mean scores on many scales were above the average range, sometimes markedly so, especially at ages two and three. However, there was no consistent pattern in the direction of group differences.

On the Child Behavior Checklist, another assessment of general behavior, scores of the stannsoporfin and placebo patients did not differ statistically significantly on any subscale or on the two composite scales (internalizing and externalizing behavior problems) at 18 months, three years, or six years. The mean scores in the stannsoporfin group were also very similar to normative values, with differences within 10% of one standard deviation for both scales at all three ages.

7.3.5 Adverse Events in Subgroups

For the acute pooled studies (Studies 204, 202, and 01-3W, subgroup analyses were performed based on sex, GA (<38 weeks vs ≥38 weeks), and AAP Clinical Practice Guideline risk categories, examining possible trends in clinical laboratory tests, vital signs, and physical examinations findings. There were no trends in changes for male or female neonates treated with stannsoporfin vs those treated with placebo. Likewise, there were no trends in changes by GA for either group of stannsoporfin-treated neonates vs those treated with placebo though the number of neonates <38 weeks was too small to draw conclusions about that group (n=19). Analysis by risk categories (low, medium, and high risk) did not reveal any trends for changes associated with high or medium risk neonates treated with stannsoporfin vs those treated with placebo. The low-risk group had too few neonates to draw conclusions (n=2).

Subgroup analyses for long-term-extension studies were based on neurodevelopmental assessments. Risk levels remained in the average range for all assessments. In the Mullen Scales of Early Learning assessment, there were some differences between stannsoporfin 4.5 mg/kg and placebo patients at three months due to higher than normal scores in the placebo group, but the differences were diminished at six months and absent at one and two years.



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7.4 Rockefeller IND

The Rockefeller IND consisted of six studies relevant for the assessment of the safety profile of stannsoporfin in neonates (Table 25). Although these studies were conducted prior to the establishment of the Medical Dictionary for Regulatory Activities (MedDRA) coding system, the studies were conducted in a robust manner consistent with standards at that time. MedDRA coding was subsequently applied to the Rockefeller safety data in order to allow comparisons to the InfaCare safety data.

In these studies, 659 neonates were treated with stannsoporfin. Of these neonates, 459 received a dose of 4.5 mg/kg. These exposures add to the overall body of evidence that the stannsoporfin safety profile is favorable and consistent in all populations studied.

7.4.1 Study 29,462-04

Stannsoporfin at doses from 1 to 6 umol/kg (0.75 to 4.5 mg/kg) in preterm neonates administered during the first day of life was safe and well tolerated. Overall, more neonates experienced AEs in the 3.0 mg/kg stannsoporfin group compared with placebo.

Table 45: Patients with an Adverse Event in Study 29,462-04 Treatment Group

Stannsoporfin Control N=202

0.75 mg/kg N=50

1.5 mg/kg N=59

2.25 mg/kg N=32

3.0 mg/kg N=59

4.5 mg/kg N=61

Total N=261

Patients with an AE, n (%)

142 (70.3)

33 (66.0) 45 (76.3) 21 (65.6) 54 (91.5) 47 (77.1) 200 (76.6)

p-value -- 0.5548 0.3704 0.5933 0.0009 0.3040 0.1241

The incidence of cutaneous erythema was higher in stannsoporfin treated neonates (6.9%) compared with placebo (1%). Erythema events were usually mild, transient, and self-limited. In addition to the erythema, there was a greater incidence of pneumothorax of all treated neonates compared to placebo (5.0% vs 1.5%). Additionally, compared to no cases in the placebo group, in the treated groups there were four cases of convulsions, three cases of bradycardia, three cases of abdominal distention, three cases of ventricular hemorrhage, and three cases of cyanosis.

There were eight deaths in the study (five stannsoporfin, one tin protoporphyrin2, and two placebo). All deaths were judged to be related to complications of prematurity and unrelated to study drug. See Section 7.5 and Appendix 12.8 for details.

The long-term safety follow-up study at three and 18 months showed no safety issues among treatment groups. Differences in spleen and liver measurements were found at month three but did not exist at 18 months.

2 Stannsoporfin (tin-mesoporphyrin IX dichloride) is a metalloporphyrin of tin-protoporphyrin in which the vinyl groups at C2 and C4 have been reduced to ethyl groups. Tin mesoporphyrin and tin protoporphyrin were both studied in the first cohort of Study 29,462-04. However, because the incidence of dermatological AEs was significantly higher, and the efficacy was similar, tin protoporphyrin was no longer studied in subsequent cohorts or studies



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7.4.2 Study 29,462-09

The safety profile of stannsoporfin was comparable to that of PT in this study. There were no systemic or local AEs observed in either the stannsoporfin or control groups. There were no deaths, SAEs, or adverse dropouts. There were no differences in clinical laboratory test values between the two treatments groups and no clinically significant laboratory results.

The three- and 18-month follow-up assessments showed normal physical, psychomotor, neurological, and cognitive development in both stannsoporfin treated patients and the control group.

7.4.3 Study 29,462-05

Stannsoporfin was safe and well tolerated in full-term male neonates (Phase 1) and near- and full-term male and female neonates (Phase 2) in this study. In Phase 1, the rate of AEs was similar among groups (Table 46). In Phase 2, the PT group experienced more AEs due to an excess of neonatal jaundice in this group. There were two cases of mild, transient erythema observed in this study during Phase 1: one stannsoporfin neonate and one placebo neonate. There were no adverse dropouts, deaths, or serious AEs.

Table 46: Adverse Events in Study 29,462-05 Incidence of Patients in Phase 1 with Specific AEs

AE, n (%) Stannsoporfin

N=22 Phototherapy

N=22 Polycythemia 1 (4.5) 4 (18.2) Jaundice 1 (4.5) 1 (4.5) Erythema 1 (4.5) 1 (4.5) Anemia 1 (4.5) 0

Incidence of Patients in Phase 2 with Specific AEs

AE, n (%) Stannsoporfin

N=22 Phototherapy

N=20 Neonatal Jaundice 1 (4.5) 8 (40.0) Polycythemia 3 (13.6) 0 Anemia 0 1 (5.0)

7.4.4 Study 29,462-06

Overall, stannsoporfin was safe and well tolerated in this study. Table 71 in Appendix 12.7 shows TEAEs that occurred during the study. There were no deaths, SAEs, discontinuations due to AEs or other significant AEs in either phase of this study.

7.4.5 Study 29,462-07

During the acute portion of the study, no TEAEs or clinically significant physical examination abnormalities developed with the exception of jaundice in five neonates in the therapeutic arm who then received successful treatment with stannsoporfin. There were no deaths, SAEs, discontinuations due to AEs, or other significant medical events during the acute portion of this study.



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A long-term safety follow-up evaluation was conducted at approximately 18 months of age evaluating number of pediatrician visits for illness, number of clinic visits for illness, number of hospital admissions, weight, height, head circumference, physical examination abnormalities, neuromotor abnormalities, cognitive development (mental IQ), motor skills (motor IQ), neurological status abnormalities, visual abnormalities and hearing abnormalities. There were no statistically significant differences between the stannsoporfin and placebo groups for any of these variables.

7.4.6 Study 29,462-08

During the acute portion of the study, no TEAEs or clinically significant physical examination abnormalities occurred except jaundice as neonates’ TSB levels increased to a point at which intervention was required, thereby qualifying them for randomization into a treatment group.

A long-term safety follow-up evaluation was conducted when patients were approximately 18 months old evaluating physical development, neuromotor skills, neurological status, sensory status, and cognitive development. There were no statistically significant differences between the three groups (stannsoporfin, PT, and no treatment) for any of the variables evaluated.

7.4.7 Neurological Assessments from Pooled Rockefeller Studies

Reported adverse event terms for the six Rockefeller IND Studies (29,462-04, -05, -06, -07, -08, and -09) were manually summarized with the MedDRA system and organ classes. Neurodevelopment assessments were performed up to 18 months; thereafter, developmental assessments were performed. Follow-up visits included any visit beyond the first 30 days (acute portion) of the studies, including any three-month, 18-month, three-year, and five-year visits. The three- and five-year visits were phone interviews.

The incidence of neurological AESIs was similar in all groups; 5.1% of stannsoporfin 3.0 mg/kg patients, 4.1% of stannsoporfin 4.5 mg/kg patients, and 3.8% of placebo patients (Table 47). Most event types occurred in only one or two patients. Event types that occurred in more than two patients included learning and speech problems, though rates were still less than 2% in all groups. Rates of speech disorders were comparable between stannsoporfin (2.6%) and control (2.6%) groups.



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Table 47: Adverse Events of Special Interest (Rockefeller Pooled LT Extensions) (-04, -05, -06, -07, -08, and -09)

Number (%) of Subjects

Controla

(N=391)

Stannsoporfin (mg/kg)0.75

(N=50)1.5

(N=59)2.25

(N=32)3.0

(N=59) 4.5

(N=459) Any subject with any reported AESI 2 (4.0) 2 (3.4) 3 (9.4) 3 (5.1) 19 (4.1) 15 (3.8) Aggressive 0 0 0 0 0 1 (0.3) Cerebral palsy 0 0 0 0 0 1 (0.3) Convulsions 0 0 0 1 (1.7) 1 (0.2) 2 (0.5) Dilatations of forebrain gyri 0 0 0 0 1 (0.2) 0 Epilepsy 0 0 0 0 1 (0.2) 0 Hearing disability 0 0 0 0 0 1 (0.3) Hyperkinetic 0 0 0 0 1 (0.2) 0 Hypertonic lower limp 0 0 0 0 1 (0.2) 0 Hypertonic right arm 0 0 0 0 1 (0.2) 0 Learning and speech problem 0 0 0 1 (1.7) 6 (1.3) 1 (0.3) Learning/speech problem/hyperkinetic 1 (2.0) 0 0 0 0 0 Learning/speech problem/does not participate in the class

0 0 0 0 0 1(0.3)

Learning/speech problem/poor concentration

0 0 0 0 1 (0.2) 0

Learning/speech problem/teacher concerned

0 0 0 0 0 1 (0.3)

Learning problems/mental retardation 0 0 0 1 (1.7) 0 1 (0.3) Learning problems/mental retardation (mild)

1 (2.0) 0 0 0 0 0

Learning problems/mental retardation/ stuttering

0 0 0 0 0 1 (0.3)

Learning problems/mental retardation/ hyperkinetic

0 0 0 0 0 1 (0.3)

Marked learning and speech problem & learning problems - mental retardation

0 0 0 0 2 (0.4) 0

Mental retardation 0 0 0 0 0 1 (0.3) Microcephaly 0 0 0 0 0 1 (0.3) Mild diplegia - high IQ 0 1 (1.7) 0 0 0 0 Myopia (High) 0 0 1 (3.1) 0 0 0 Not interested in school 0 0 0 0 1 (0.2) 0 Optic nerve atrophy 0 0 0 0 1 (0.2) 0 Physiotherapy for hypotomia 0 0 0 0 1 (0.2) 0 Pseudotumor cerebri 0 0 0 0 0 1 (0.3) Psychological problem 0 0 0 0 1 (0.2) 0 Psychological problems (after birth of sibling)

0 0 0 0 1 (0.2) 0

Right hemiplegia 0 0 0 1 (1.7) 0 0 Right hemiplegia/speech problem/ epilepsy

0 0 0 1 (1.7) 0 0

Right spastic monoplegia 0 0 0 0 0 1 (0.3) Seizures 0 0 0 0 1 (0.2) 0 Sensorineural hearing loss 0 0 1 (3.1) 0 0 0 Severe learning and speech problem & learning problems - mental retardation

0 0 0 0 1 (0.2) 0



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Number (%) of Subjects

Controla

(N=391)

Stannsoporfin (mg/kg)0.75

(N=50)1.5

(N=59)2.25

(N=32)3.0

(N=59) 4.5

(N=459) Shy does not participate in class - psychological problem

0 0 0 0 1 (0.2) 0

Special school learning problems - mental retardation hyperkinetic

0 0 0 0 1 (0.2) 0

Speech not clear speech problem 0 0 0 0 0 1 (0.3) Speech problem 0 1 (1.7) 0 1 (1.7) 3 (0.7) 2 (0.5) Speech problem delayed speech development

0 0 0 0 0 1 (0.3)

Speech problem improved 0 0 0 0 0 1 (0.3) Speech problem improving speech 0 0 0 0 0 1 (0.3) Speech problem psychological problem 0 0 0 0 0 1 (0.3) Teacher-difficult to communicate, IQ rexam 10/25/95=normal

0 0 1 (3.1) 0 0 0

Tip toe walking 0 0 0 0 0 1 (0.3) AESI = adverse events of special interest a Includes placebo, no treatment, or PT only

7.4.7.1 Long-Term Neurodevelopmental Assessments from Pooled Rockefeller Studies

Long-term neurodevelopmental safety for patients assessed in Studies 29, 462-04, -09, -05, -06, -07, and -08 is summarized below:

Long-term extension studies conducted under the Rockefeller IND met clinical practice standards at the time they were conducted, which were established by ICH guidelines in 1990. In addition to physical and neurologic examinations, assessment tools used in the supportive LT extension studies to evaluate developmental, behavioral, and psychological status included:

BSID Mental Development Index (MDI): is a global measure of developmental status in infancy that assesses and aggregates the timely attainment of relatively fundamental milestones in infancy and early childhood.

BSID Psychomotor Development Index (PDI): measures the progressive acquisition of skills involving both mental as well as motor activities. It is used with infants to assess overall physical and motor skill ability and to confirm whether the infant's development in these areas is on track with their age.

At 18 months of follow-up, the BSID MDI and PDI showed that fewer than 2% of stannsoporfin 4.5 mg/kg and placebo patients scored abnormally low on either index (Table 48). No consistent pattern of difference was found between the stannsoporfin groups and the placebo/control groups. In terms of mental development, the scores of the stannsoporfin group were greater in three studies (29,462-06, -07, and -08) and lower in two studies (29,462-04 and -05). In terms of motor development, the scores of the stannsoporfin group were greater in two studies (29,462-06 and -



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07) and lower in three studies (29,462-04, -05, and -08). However, the differences in group means were all modest in magnitude.

Table 48: MDI and PDI Assessments – 18 Months (Pooled LT Extensions) (29,462-04, -09, -05, -06, -07, and -08)

Number (%) of Patients Stannsoporfin (mg/kg)

Controla (N = 391)

0.75 (N = 50)

1.5 (N = 59)

2.25 (N = 32)

3.0 (N = 59)

4.5 (N = 459)

MDI Valid N 37 39 20 41 242 193 Mean (SD) 99.8 (15.71) 100.7 (14.16) 106.5 (17.58) 100.0 (14.75) 104.3 (15.01) 105.6 (16.74) Median 100.0 102.0 103.5 98.0 104.0 105.0 Minimum 60.0 63.0 75.0 60.0 50.0 50.0 Maximum 138.0 124.0 150.0 140.0 145.0 150.0 PDIb Valid N 37 39 20 40 242 192 Mean (SD) 98.2 (10.34) 96.6 (9.73) 98.8 (9.01) 96.2 (5.08) 96.2 (6.90) 98.0 (8.48) Median 100.0 96.0 100.0 96.0 96.0 100.0 Minimum 56.0 53.0 68.0 87.0 70.0 56.0 Maximum 113.0 113.0 113.0 107.0 115.0 119.0 MDI = Mental Developmental Index, PDI = Psychomotor Developmental Index a Includes placebo, no treatment, or PT only b A value of 34 (29,462-04) was handled as unknown in the table but presented as 34 in the listing; patients with a percentile rank >99% were removed.

The stannsoporfin 4.5 mg/kg and placebo patients were similar with respect to most neurodevelopmental assessments. No patient in the stannsoporfin 4.5 mg/kg or placebo group had an abnormal assessment for eye movements or any of the fine or gross motor measures (Table 49).



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Table 49: Abnormal Neurodevelopmental Assessments (Pooled LT Extensions) (29,462-04, -09, -05, -06, -07, and -08)

Number (%) of Patients Stannsoporfin (mg/kg)

Controla (N = 391)

0.75 (N = 50)

1.5 (N = 59)

2.25 (N = 32)

3.0 (N = 59)

4.5 (N = 459)

Month 3 Movement overall 3 (6.0) 0 1 (3.1) 0 0 4 (1.0) Tone overall 7 (14.0) 5 (8.5) 3 (9.4) 3 (5.1) 5 (1.1) 18 (4.6) Reflexes overall 5 (10.0) 5 (8.5) 2 (6.3) 1 (1.7) 5 (1.1) 12 (3.1) Babinski Response 9 (18.0) 1 (1.7) 2 (6.3) 0 2 (0.4) 12 (3.1) Eye Movements overall 8 (16.0) 0 0 0 1 (0.2) 11 (2.8) Month 18 Movement overall 0 0 0 1 (1.7) 3 (0.7) 1 (0.3) Tone overall 0 1 (1.7) 0 1 (1.7) 3 (0.7) 4 (1.0) Reflexes overall 0 1 (1.7) 0 1 (1.7) 3 (0.7) 5 (1.3) Babinski Response 2 (4.0) 1 (1.7) 2 (6.3) 3 (5.1) 4 (0.9) 8 (2.0) Eye Movements overall 2 (4.0) 2 (3.4) 0 0 3 (0.7) 6 (1.5) Parachute Response (yes) 8 (16.0) 0 0 1 (1.7) 5 (1.1) 14 (3.6) Overall Neurologic Status 0 0 1 (3.1) 1 (1.7) 1 (0.2) 3 (0.8) Cranial Nerve Motor Func Overall 4 (8.0) 2 (3.4) 0 1 (1.7) 16 (3.5) 11 (2.8) Posture Abnormalities Overall 0 0 1 (3.1) 1 (1.7) 1 (0.2) 1 (0.3) Fine Motor Abnormalities Fine Pincer Grasp R 0 0 0 0 0 0 Fine Pincer Grasp L 0 0 0 1 (1.7) 0 0 Finger Exploration of Toy R 0 0 0 1 (1.7) 0 0 Finger Exploration of Toy L 0 0 0 0 0 0 Gross Motor Abnormalities Crawling 0 0 0 0 0 0 Cruising 0 0 0 0 0 0 Running 0 0 0 0 0 0 Standing Alone 0 0 0 0 0 0 Stooping to Retrieve Object 0 0 0 0 0 0 Walking 0 0 0 0 0 0 a Includes placebo, no treatment, or PT only

Long-term Developmental Safety Conclusions

Review of the data from the long-term studies under the Rockefeller IND revealed no signal of neurodevelopmental safety concerns in patients treated with stannsoporfin. Patients in this pool were followed for 5 years with in-person visits up to 18 months. The numbers of patients with abnormally low scores on standard test instruments were uniformly low, and there was no pattern in AESIs possibly connected with neurodevelopmental safety.

7.5 Deaths Across All Studies

A total of 10 deaths occurred in the InfaCare and Rockefeller IND studies (Table 50). No deaths were considered related to stannsoporfin treatment. Two deaths occurred in the InfaCare IND (one in Study 01-3W from SIDS and one in Study 01C-3W from SIDS) and eight in the Rockefeller IND.



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All deaths in the Rockefeller IND were in Study 29,462-04, which enrolled pre-term newborns at high risk for hyperbilirubinemia with a birth weight of 1,500 to 2,500 grams and GA <37 weeks. All deaths were a result of complications of prematurity. In three cases, the patient did not receive stannsoporfin. It is important to note that there were approximately 2.5 times the number of exposures for stannsoporfin than control.

Narratives for all deaths can be found in Appendix 12.8.

Table 50: Summary of Deaths Across Studies

GA/ Gender

Age at Death (days) Description

Treatment Stannsoporfin

(mg/kg) Related to Treatment

Acute Studies

33/M 9 Severe RDS, pneumothorax, IVH 4.5 No

32/F 3 RDS, pneumothorax, massive IVH 3.0 No

30/F 5 Severe RDS, pneumothorax 3.0 No

30/M 15 Severe RDS, IVH 1.5 No

34/F 16 RDS, IVH, seizures, multiple pneumothoraxes Placebo No

29/F 3 Pulmonary interstitial emphysema and pneumothorax 0.75 tin protoporphyrin No

Long-term Follow-up

40/M 126 SIDS 4.5 No

31/F 252 Short bowel syndrome secondary to extensive NEC 1.5 No

30/F 90 RDS, bilateral pneumothorax Placebo No

-/F 20 SIDS Not enrolled No

IVH = intraventricular hemorrhage; NEC = necrotizing enterocolitis; RDS = respiratory distress syndrome N=1510 stannsoporfin, N=614 control

7.6 Conclusions

The safety profile of stannsoporfin has been well characterized. A total of 955 patients have been exposed to stannsoporfin (896 in clinical trials of neonatal hyperbilirubinemia and 59 in other uses). The AE profile of the proposed stannsoporfin dose (4.5 mg/kg) has been consistent across trials and similar to placebo. The incidence of AEs compared to placebo and the types of safety observations from the Rockefeller studies, were consistent with those seen in the InfaCare studies. Adverse events in the InfaCare IND studies were further characterized for severity, duration, and relationship to study drug. The consistency of the totality of stannsoporfin data from both the InfaCare IND and Rockefeller IND studies serve to support its overall safety profile.

The numbers of patients treated with stannsoporfin are sufficient to provide appropriate characterization of optimal dosing and stannsoporfin’s safety profile. A total of 588 neonates received the 4.5 mg/kg dose of stannsoporfin in clinical trials and via investigator held INDs (Table 26).



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Stannsoporfin was safe and well tolerated, with a safety and tolerability profile similar to placebo for the 4.5 mg/kg dose.

AEs were mild to moderate, self-limiting, and resolved spontaneously.

No differences from placebo were noted in laboratory values.

No trends were identified, and there was no suggestion of a clinically meaningful relationship of any changes in vital signs to stannsoporfin.

In long-term follow-up out to six years, using a wide range of assessment instruments, patients treated with stannsoporfin were consistently within the normative range for age and no clinically meaningful difference from placebo was observed.



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8 DOSE RATIONALE

Rockefeller IND Study, Study 29,462-04, was the first dose-ranging study of stannsoporfin for the treatment of hyperbilirubinemia in neonates, and the results from that study influenced the dose strategy for the studies conducted under the InfaCare IND, as well as the basis for testing the 4.5 mg/kg dose in all subsequent clinical studies conducted under the Rockefeller IND. Study 29,462-04, which encompassed doses between 0.75 and 4.5 mg/kg stannsoporfin and was conducted in 463 premature infants and neonates with a GA of 30 to 36 weeks, demonstrated that the 4.5 mg/kg dose offered the maximum efficacy without indication of any dose-related adverse effects. Study 202, the dose escalation study of 1.5, 3.0 and 4.5 mg/kg, also indicated a clear drug effect with evidence of a more rapid and greater magnitude of effect in neonates treated with the 3.0 and 4.5 mg/kg doses.

Stannsoporfin was rapidly and well absorbed from an IM injection and was eliminated from the body with an elimination half-life of approximately 10 hours. Peak stannsoporfin concentrations were typically observed within an hour in almost all patients across dose levels. The dose-proportional increase in Cmax over the 1.5 to 4.5 mg/kg dose range suggests that the absorption of stannsoporfin from the injection site follows first-order linear kinetics. Slightly more than dose-proportional increases (20-25%) were seen in the AUC0-inf of stannsoporfin, particularly from the 3.0 to 4.5 mg/kg dose range, which is not considered clinically meaningful. Total Serum Bilirubin as percent change from Baseline at 12, 24 and 48 hours post-dose all showed a strong relationship with exposure as represented by stannsoporfin AUC, with larger decrease from Baseline being associated with higher AUC values, suggesting the higher doses would provide more benefit than the lower doses studied.

In Study 204, stannsoporfin at 4.5 mg/kg was statistically superior to placebo for the primary endpoint of percent change in bilirubin at 48 hours and two clinically relevant prespecified hierarchical secondary endpoints (time to crossing the threshold for discontinuation of PT [p=0.003], and reduction in PT failures [p=0.0125]). The 3.0 mg/kg dose of stannsoporfin was statistically superior to placebo for the primary endpoint but not for the prespecified secondary endpoints. The 4.5 mg/kg dose offers the best balance between efficacy and safety because, in addition to achieving statistically significant decreases in both percent change and actual change in bilirubin levels by 18 hours through 48 hours: 1) there was shorter time to reach the threshold for discontinuation of PT; and 2) there was a lower rate of PT failures including restart of PT and rehospitalizations for hyperbilirubinemia which, for those neonates, may correlate with decreased length of hospital stay and less separation of mother and child for the management of PT failures.

Collectively, the results from these three studies demonstrate that single IM injections of stannsoporfin 4.5 mg/kg (with or without PT) consistently produce statistically and clinically significant improvements across the broadest number of endpoints, and these results are consistent regardless of sex or GA (ie, <37 weeks in Study 29,462-04 or ≥35 weeks in Studies 202 and 204).

The overall safety profile of stannsoporfin 4.5 mg/kg was similar to that of placebo.



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9 RISK MITIGATION

The proposed indication for stannsoporfin is for a single IM injection in neonates ≥35 weeks GA. Chronic use will not be indicated. The proposed stannsoporfin label specifically will indicate that stannsoporfin is not indicated in neonates with a GA of <35 weeks’ gestation and that stannsoporfin has not been approved in this age group.

The proposed label includes precautions to minimize risk: stannsoporfin is a porphyrin and exposure to broad spectrum white light or direct exposure to sunlight within the first few days following use may cause self-limiting photosensitivity. In clinical trials with stannsoporfin, if PT was used, blue light phototherapy was administered. Special filters that block wavelengths from 360-420 nm, such as those used in patients with porphyria, should be placed over Operating Room lights when surgery is required. During surgery, the patient should be draped as much as possible to reduce the light exposure and eye protection should be used.

Stannsoporfin is not metabolized by CYP enzymes in vitro, and therefore drug interactions via modulation of CYP isoenzymes are unlikely. Stannsoporfin does inhibit probe transport via OAT1, OAT3, and OATP1B1 in vitro at high concentrations (10 µM); however, peak concentrations of stannsoporfin are below inhibitory levels in plasma at all times during the dosing period. Therefore, there is no evidence that suggests that there would be a potential risk for drug interactions from either the CYP or transporter systems.

Of note, tissue bio-distribution studies demonstrate that stannsoporfin does not significantly cross the blood brain barrier, a fact of interest in relation to the potential use and safety of this compound clinically (Bundock, Drummond et al. 1996, Bashir and LiuPerez 2006, Bashir and LiuPerez 2007). The final risk mitigation actions will be discussed with the FDA prior to approval.



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10 BENEFIT/RISK

10.1 Benefits

Stannsoporfin 4.5 mg/kg demonstrated clinical benefit across a spectrum of efficacy assessments, including a rapid (effect onset ~6-12 hours) followed by a sustained reduction in TSB, thus reducing the risk for developing severe hyperbilirubinemia and associated adverse sequelae and the frequency of PT failures. This was demonstrated by:

Attenuating the rate of rise of TSB (without PT) beginning at six hours post-treatment as observed in Study 202. Stannsoporfin’s ability to attenuate the rise in TSB is confirmed by results across studies.

Significant reductions compared with placebo in mean TSB beginning at 12 hours (Study 202 without PT) to 18 hours (Study 204 with PT) post-treatment and lasting through the last measurement at 48 hours (Study 204) or 72 hours (Study 202). Although no statistical comparison was performed at Day 14 in Study 202, TSB levels showed a reduction from Baseline in the 4.5 mg/kg group compared with placebo. These results are supported by statistically and clinically significant reductions compared with placebo in mean PBC observed through ~144 hours post-treatment in Study 29,462-04.

Statistically and clinically significant reductions compared with placebo in mean TSB at the primary efficacy analysis time point (48 hours) post-treatment; these results were consistent using LOCF and non-LOCF methods and MMRM sensitivity analyses for percent change from Baseline and for absolute change from Baseline (Studies 204 and 202)

Statistically significant reduction compared with placebo in the time from study drug administration until TSB crossed the threshold for discontinuation of PT (Study 204).

Statistically significant (pairwise t-test) reduction compared with placebo in overall bilirubin exposure as measured by TSB AUC(0-48hr) when stannsoporfin was administered without PT (Study 202) and with PT (Study 204); the robustness of this result was confirmed by MMRM analysis in the pivotal study, which was fully enrolled. A reduction in overall exposure is clinically meaningful, because no one measure of increase in bilirubin has been associated with BIND.

A reduction in the number of neonates who failed PT including restarting of PT and in the number of hospital readmissions for hyperbilirubinemia.

Additionally, stannsoporfin produced a rapid and sustained (up to 14 days) reduction in exposure to bilirubin that reduced the need for and duration of PT and the frequency of PT failures and associated sequelae (ie, need for PT restart, hospital readmissions, and use of second-line therapies), thereby also increasing the amount of time for mother/baby skin-to-skin contact, breastfeeding, and maternal-neonate bonding. This was demonstrated by:

Clinically meaningful reduction in the need for PT when stannsoporfin 4.5 mg/kg was administered without PT (53.3% of placebo neonates required PT vs 25.6% of neonates across 3 stannsoporfin dose groups) (Study 202).



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Statistically and clinically significant reduction (>12 hours) compared with placebo in the total duration of administered PT that translated into a reduction equal to one hospital nursing shift, which may reduce the duration of hospitalization by one day (Study 204).

Statistically significant reduction compared with placebo in the frequency of PT failure, demonstrated by fewer PT restarts, fewer hospital readmissions, (Studies 202 and 204).

Statistically and clinically significant reduction compared with placebo in the need for ET in neonates at risk for ET (Study 06).

To further examine the clinical benefit of stannsoporfin from Studies 202 and 204, the NNT was calculated to identify the number of patients needed to treat at a selected dose to have an impact on one patient. For prevention of rehospitalization, the NNT for 4.5 mg/kg stannsoporfin was 15 in Study 204 and eight in Study 202. In Study 202, the NNT for the prevention of needing PT was four. In Study 204, the NNT for PT failure was four and PT restart was five. These values highlight the clinical benefit of stannsoporfin from a public health perspective.

10.2 Risk Assessment

A total of 1,433 patients have participated in the clinical development of stannsoporfin; 949 have received stannsoporfin (890 in clinical studies and 59 under emergency use INDs, other indications, or healthy adult subjects) and 543 served as controls (placebo, sham, no treatment, or PT alone). The overall exposure database is adequate to thoroughly characterize the general short- and long-term safety profile of a single dose of stannsoporfin for use in the intended indication.

The totality of data across studies conducted under both INDs demonstrates that stannsoporfin administered as a single 4.5 mg/kg IM injection (with or without PT) is safe and well tolerated. Potential risks evaluated based on either nonclinical data or stannsoporfin’s mechanism of action included: adverse hepatic or renal effects, photosensitivity, and adverse neurodevelopmental outcomes. These were carefully assessed during the clinical studies with stannsoporfin with no evidence that stannsoporfin causes any adverse hepatic, renal, hematologic, or neurodevelopmental outcomes. Any AEs potentially associated with photosensitivity were mild or moderate in severity and self-limiting.

The overall incidence of TEAEs was similar between neonates who received stannsoporfin 4.5 mg/kg (41.3%) and those who received placebo (36.6%). In long-term follow-up out to six years, no clinically meaningful AE observation was detected.

There are no acute or long-term data that suggest that stannsoporfin is associated with any clinically significant adverse hematologic effects (including anemia); hepatic or renal effects; or cardiac effects (including QT prolongation).

No deaths in the clinical program were considered to be related to stannsoporfin, and most were related to prematurity.



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10.3 Benefit Risk Assessment

The totality of data across studies conducted under both INDs demonstrates that stannsoporfin administered as a single 4.5 mg/kg IM injection (with or without PT) provides statistically significant and clinically relevant benefits. Moreover, the 4.5 mg/kg dose was safe and well tolerated. Treatment-emergent AEs potentially associated with photosensitivity were mild or moderate in severity and self-limiting.

The totality and overall consistency of the efficacy and safety data included in this briefing document support a positive profile where the potential benefits of stannsoporfin significantly outweigh the potential risks.



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Maisels, M. J., V. K. Bhutani, D. Bogen, T. B. Newman, A. R. Stark and J. F. Watchko (2009). "Hyperbilirubinemia in the newborn infant > or =35 weeks' gestation: an update with clarifications." Pediatrics 124(4): 1193-1198.

Maisels, M. J., J. M. Deridder, E. A. Kring and M. Balasubramaniam (2009). "Routine transcutaneous bilirubin measurements combined with clinical risk factors improve the prediction of subsequent hyperbilirubinemia." J Perinatol 29(9): 612-617.

McCulloch, C. E. and S. R. Searle (2001). Generalized, linear, and mixed models. New York.

Morioka, I., R. J. Wong, A. Abate, H. J. Vreman, C. H. Contag and D. K. Stevenson (2006). "Systemic effects of orally-administered zinc and tin (IV) metalloporphyrins on heme oxygenase expression in mice." Pediatr Res 59(5): 667-672.

Muchowski, K. E. (2014). "Evaluation and treatment of neonatal hyperbilirubinemia." Am Fam Physician 89(11): 873-878.

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Szucs, K. A. and M. B. Rosenman (2013). "Family-centered, evidence-based phototherapy delivery." Pediatrics 131(6): e1982-1985.

Tatli, M. M., C. Minnet, A. Kocyigit and A. Karadag (2008). "Phototherapy increases DNA damage in lymphocytes of hyperbilirubinemic neonates." Mutat Res 654(1): 93-95.

Thilo, E. H. and A. A. Rosenberg (2011). Chapter 1: The Newborn Infant. CURRENT Diagnosis & Treatment: Pediatrics. 20th ed. W. W. Hay, M. J. Levin, J. M. Sondheimer and R. R. Deterding. New York, McGraw-Hill.

Trudnak Fowler, T., G. Fairbrother, P. Owens, N. Garro, C. Pellegrini and L. Simpson (2014). "Trends in complicated newborn hospital stays & costs, 2002-2009: implications for the future." Medicare Medicaid Res Rev 4(4).

Wong, R. J., V. K. Bhutani, H. J. Vreman and D. K. Stevenson (2007). "Tin mesoporphyrin for the prevention of severe neonatal hyperbilirubinemia." NeoReviews 8(2): e77-e84. Review.

Xiong, T., Y. Qu, S. Cambier and D. Mu (2011). "The side effects of phototherapy for neonatal jaundice: what do we know? What should we do?" Eur J Pediatr 170(10): 1247-1255.


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12 APPENDIX

12.1 Overview of Rockefeller IND Studies

Table 51: Stannsoporfin Rockefeller IND Studies

Descriptor

Study Number

29,462-04 29,462-09 29,462-06 29,462-07 29,462-08 29,462-05

Study Design Randomized, double-blind, acute + 5-yr LTF

Randomized, open-label, acute + 18-mo LTF

Randomized, open-label, acute + 5-yr LTF



Randomized, open-label, acute + 5-yr LTF

Countries (No. Sites)

Greece (1 site)

Argentina (1 site)

Greece (1 site)

Greece (1 site)

Greece (1 site)

Greece (1 site)

Stannsoporfin a Dose(s), mg/kg (N)

Phase 1: 0.75 (N=50)

Phases 2-6: 1.5 (N=59) 2.25 (N=32) 3.0 (N=59) 4.5 (N=61) N=261 total

4.5 (N=80)

Phase 1: 4.5 (N=42)

Phase 2: 4.5 (N=163) N=205 total (preventative tx)

Period A: 4.5 (N=14) Period B: 4.5 (N=20) N=34 total

(preventative tx)

4.5 (N=30)

4.5 (N=48) b

Comparator (N) placebo (N=202)

no treatment (N=86)

Phase 1: IMP 4.5 mg/kg (N=20)

(therapeutic tx) no treatment (N=24) c

N=44 total

Phase 2: historical (N=168 G6PD normal) (N=58 G6PD deficient)

Period A: IMP 4.5 mg/kg (N=5) (therapeutic tx) no treatment (N=8) d

Period B: none (N=0)

phototherapy (N=27) no treatment (N=44) N=71 total

phototherapy (N=44) b

When Treated 1st 24 h of life 48-96 h of life Px: 24-36 h of life Tx: PBC threshold

Px: 1st day of life Tx: PBC threshold

TSB threshold for PT

PBC threshold for PT


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Diagnosis

Phases 1-6: Neonates at high risk for hyperbilirubinemia

Healthy neonates with clinically significant hyperbilirubinemia

Phase 1 & 2: G6PD-deficient neonates

Period A: Direct Coombs Test + Period B: ABO incompatibility and elevated TSB

Healthy and sick pre-term neonates (normal G6PD) with hyperbilirubinemia who need PT

Neonates who were Direct Coombs Test with normal G6PD activity (cord blood)

Key Inclusion Criteria

Phase 1: GA: <37 wks + BW: 1500-2500 g

Phases 2-6: GA: 30 to <36 wks (210-251 days)

GA: 38 to 41 wks

BW: 10th to 90th %tile for GA

PBC 15-18 mg/dL between 48-96 h of life

GA: 30 to <38 wks (210-265 days)

GA: 38 wks

Hb (cord blood) 6.0 U/g (M) 8.0 U/g (F)

Direct Coombs Test+ (Period A)

Direct Coombs Test (Period B)

ABO-HDN, not clinically severe

GA: 30 to <36 wks (210-251 days)

BW: >1500 g

GA: 37 wks (259 days) + M GA: 35 (245 days) + M or F BW: 1500 g

Phototherapy if needed if needed if needed if needed if needed and (active control)

if needed and (active control)

Key Endpoint(s) Maximum PBC Need for PT (PBC reached 19.5 mg/dL)

Phase 1: Randomized Px vs Tx Matched Pairs & Intergroup

Diff. 1 day in age of pt. at case closure

Need for PT

Need for ET

Phase 2: Non-randomized Px Only

Age at case closure

Need for PT

Need for ET

Maximum TSB

Need for PT rescue

Matched Pairs

Diff. 24 h to case closure for 1 of pair

Intergroup

Need for PT rescue

Maximum TSB

Matched Pairs

Diff. 24 h between enrollment and case closure

Need for PT after IMP

Need for ET rescue

Intergroup

Need for ET rescue

Included for: Note: P-LTF = pooled analysis across studies for long-term neurologic data; CSR = data from original CSR Efficacy yes: CSR yes: CSR yes: CSR no no yes: CSR


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a Study 29,462-04 also enrolled 53 patients who received tin-protoporphyrin (SnPP); these patients were excluded from analysis of the acute study results (efficacy and safety) and are not tabulated in the LTF results. The numbers in this table reflect only those control and stannsoporfin-treated patients in Study 29,462-04.

b In Study 29,462-05, 6 patients (4 active and 2 placebo) were removed from analyses in the CSR because they were subsequently diagnoses with G6PD. As these data were not used in the integrated efficacy analyses, efficacy data presented in Module 2.7.3 and in this document are based on the data as presented in the CSR (N=44 stannsoporfin and N=42 placebo). However, where included in this submission for safety, the database includes all treated patients (N=48 active and N=44 placebo).

c In Phase 1 of Study 29,462-06, patients were randomized to receive stannsoporfin as a preventative therapy (active treatment arm) or as a therapeutic treatment (only administered if PBC reached threshold) (control arm). Of the 44 patients randomized to the control arm (therapeutic treatment), 19 had PBC levels that reached the threshold for treatment and they received stannsoporfin 4.5 mg/kg, and plasma bilirubin levels in 25 patients did not meet the threshold and they received no treatment. In the CSR, Module 2.7.4, and this document, all 44 patients randomized to the control arm are included as control patients (based on pooled data from the SAS datasets) regardless of whether or not they received stannsoporfin.

d In Part A of Study 29,462-07, patients were randomized to receive stannsoporfin as a preventative therapy (active treatment arm) or as a therapeutic treatment (only administered if PBC reached threshold) (control arm). Of the 13 patients randomized to the control arm (therapeutic treatment) in Part A, 5 had PBC levels that reached the threshold for treatment and they received stannsoporfin 4.5 mg/kg, and 8 patients did not meet the threshold and they received no treatment. This study was discontinued prematurely due to poor enrollment and no formal efficacy analyses were performed. In the CSR, the 5 control patients who received stannsoporfin therapeutically are combined with the 34 patients who received stannsoporfin prophylactically (14 in Part A and 20 in Part B) for safety analyses (N=39) compared with the 8 patients who received no treatment. However, where included in this submission for safety, all 13 patients randomized to the control arm are included in the control group (regardless of whether or not stannsoporfin was administered).

Abbreviations: = not applicable; %tile = percentile; ABO = blood group; ABO-HDN = ABO hemolytic disease of the newborn; BW = body weight; diff. = difference; CSR = clinical study report; DCT/+ = direct Coombs test negative or positive; ET = exchange transfusion; F = female; G6PD = glucose-6-phosphate dehydrogenase; GA = gestational age; Hb = hemoglobin; h = hours; Hx = historical; IM = intramuscular; IMP = investigational medicinal product; LTF = long-term follow-up; M = male; mo. = month; PBC = plasma bilirubin concentration; pt. = patient; PT = phototherapy; Px = prevention/preventative; TSB = total serum bilirubin; Tx = treatment; wks = weeks; yr = year

Safety yes: CSR, P-LTF yes: CSR, P-LTF yes: CSR, P-LTF yes: CSR, P-LTF yes: CSR, P-LTF yes: CSR, P-LTF

PK no no no no no no



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12.2 Study 204 Inclusion and Exclusion Criteria

Inclusion Criteria

Patients were eligible to participate in the study if they met all of the following criteria:

1. Term and near-term neonates ≥35 and ≤43 weeks GA, aged 0-48 hours (at the time the qualifying TSB was drawn) with ABO or Rh incompatibility (anti C, c, D, E or e) who were DAT-positive, or aged 0-72 hours (at the time the qualifying TSB was drawn) with G6PD deficiency as confirmed by a documented blood test

OR

Term and near-term neonates ≥35 and ≤43 weeks GA, aged 0-48 hours (at the time the qualifying TSB was drawn) with ABO or Rh incompatibility (anti C, c, D, E or e) who were DAT-negative (or status unknown) and had an increased reticulocyte count (>6%)

2. Birth weight ≥2500 g

3. A TSB value at or above the age-specific threshold for initiating PT per the AAP guidelines

4. Parent/guardian written consent

Parents agreed to observe light precautions for 10 days posttreatment

Exclusion Criteria

Patients were ineligible to participate in the study if they met any of the following criteria:

1. Elevated direct bilirubin ≥2 mg/dL, or >20% of the TSB

2. ALT >2 times the ULN and/or AST >3 times ULN

3. Abnormal renal function defined as creatinine and/or BUN >2 times the ULN

4. Any clinically significant abnormalities on electrocardiogram (ECG) or other screening laboratory evaluation that in the opinion of the Investigator makes the patient unsuitable for the clinical trial

5. Apgar score ≤6 at age 5 minutes

6. An unexplained existing rash or skin erythema

7. Prior exposure to PT

8. Clinical suggestion of neonatal thyroid disease or current uncontrolled thyroid disease in the mother (maternal Hashimoto’s disease was not excluded)

9. Cardio-respiratory distress, defined as a respiratory rate >60 breaths per minute at the time of enrollment



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10. Any clinically significant abnormal auditory or ophthalmologic findings on screening physical exam

11. Electrocardiogram finding of prolonged QT interval corrected for heart rate using Bazzett’s formula (QTcB) during the three screening ECGs: average QTcB >480 ms for neonates on Day 1 (0-24 hours) or Day 2 (>24-48 hours) of life or an average QTcB >460 ms for neonates on Day 3 (>48-72 hours) of life

12. Treatment or need for treatment of the neonate with medications that might prolong the QT interval, or family history of Long QT syndrome

13. Known porphyria or risk factors for porphyria, including family history

14. A maternal history of systemic lupus erythematosus

15. Maternal use of phenobarbital within 30 days before, or after delivery if breast-feeding

16. Maternal current drug or alcohol abuse, or maternal history of drug or alcohol abuse that, in the opinion of the Investigator, would not make the patient a suitable candidate for participation in the clinical trial

17. Significant congenital abnormalities or infections

18. Risk of requiring surgery or exposure to operating room lights in the first 2 weeks of life

19. Persistent hypoglycemia unresponsive to medical intervention defined as 3 consecutive readings of blood glucose <40 mg/dL over a 3-hour period

20. Current temperature instability defined as 3 consecutive readings <36ºC and/or >37.5ºC (axillary) over a 3-hour period

21. Use of IVIg or albumin prior to study-drug administration

22. Use of photosensitizing drugs or agents

23. Post-delivery treatment with medications that were known or suspected to displace bilirubin from albumin

24. Exposure to any investigational medications or devices after delivery, or participation in another clinical trial while participating in this trial

25. Any other concurrent medical condition, which in the opinion of the Investigator makes the patient unsuitable for the clinical trial.



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12.3 Other Endpoint Results in Study 204

Table 52: Percent Change from Baseline in Total Serum Bilirubin by Visit (ITT Analysis Set)

Statistic

Stannsoporfin Placebo

N=30

3.0 mg/kg

N=30

4.5 mg/kg

N=31 Total Serum Bilirubin (mg/dL)

TSB at 6 h N 30 31 30

Mean (SD) 10.92 (2.430) 10.95 (2.765) 10.92 (1.901)

Percent change from Baseline at 6 hours

Mean (SD) 13.40 (13.937) 11.99 (16.356) 12.15 (15.431)

LS mean (95% CI) 13.21 (8.440,

17.792) 12.21 (7.611,

16.810) 12.20 (7.530,

16.880)

LS mean diff vs placebo (95% CI)

0.91 (-5.710, 7.523) 0.01 (-6.553,

6.563)

p-value vs placebo 0.785 0.999


0.784

TSB at 12 h N 29 30 28 Mean (SD) 10.47 (2.389) 10.62 (2.597) 10.93 (2.003) Percent change from Baseline at 12 hours Mean (SD) 7.38 (15.354) 7.94 (20.020) 14.32 (20.058)

LS mean (95% CI) 7.35 (1.487,

13.221) 8.52 (2.750,

14.293) 13.73 (7.760,

19.708)


-6.38 (-14.753, 1.993)

-5.21 (-13.524, 3.099)



0.779

TSB at18 h N 24 23 27

Mean (SD) 9.31 (2.297) 9.48 (2.311) 10.91 (2.176)

Percent change from Baseline at 18 hours Mean (SD) -1.86 (23.656) -3.73 (24.998) 12.61 (23.494)

LS mean (95% CI) -2.51 (-10.524,

5.506) -2.59 (-10.787,

5.600) 12.21 (4.658,

19.769)


-14.72 (-25.735, -3.710)

-14.81 (-25.957, -3.657)



0.988

TSB at 24 h N 21 28 22



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Statistic


N=30

3.0 mg/kg

N=30

4.5 mg/kg

N=31 Total Serum Bilirubin (mg/dL) Mean (SD) 8.90 (2.156) 8.85 (2.337) 11.07 (2.210) Percent change from Baseline at 24 hours Mean (SD) -11.51 (19.378) -9.42 (19.918) 16.44 (19.638)

LS mean (95% CI) -10.37 (-17.719, -

3.012) -9.30 (-15.653, -

2.940) 15.19 (8.006,

22.382)


-25.56 (-35.864, -15.255)

-24.49 (-34.088, -14.893)



0.827

TSB at 30 h N 16 15 14 Mean (SD) 8.81 (2.556) 8.47 (2.286) 11.43 (2.364) Percent change from Baseline at 30 hours Mean (SD) -4.40 (31.338) -14.28 (24.038) 26.29 (16.045)

LS mean (95% CI) -3.98 (-14.689,

6.727) -11.91 (-23.022, -

0.789) 23.27 (11.732,

34.810)


-27.25 (-43.013, -11.491)

-35.18 (-51.305, -19.048)



0.305

TSB at 36 h N 14 14 16 Mean (SD) 8.44 (2.379) 8.38 (2.503) 11.56 (2.455) Percent change from Baseline at 36 hours Mean (SD) -14.68 (23.511) -10.61 (30.011) 17.11 (20.532)

LS mean (95% CI) -13.55 (-24.963, -

2.131) -11.37 (-22.774,

0.042) 16.78 (6.109,

27.443)


-30.32 (-45.952, -14.693)

-28.14 (-43.756, -12.528)



0.786

TSB at 48 h N 23 19 19 Mean (SD) 8.53 (1.972) 9.29 (1.884) 12.73 (2.137) Percent change from Baseline at 48 hours Mean (SD) -13.13 (25.261) 0.67 (31.563) 31.81 (35.626)

LS mean (95% CI) -12.03 (-21.435, -

2.623) -0.71 (-11.057,

9.644) 31.85 (21.511,

42.197)



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Statistic


N=30

3.0 mg/kg

N=30

4.5 mg/kg

N=31 Total Serum Bilirubin (mg/dL)


-43.88 (-57.864, -29.903)

-32.56 (-47.193, -17.927)

p-value vs placebo <0.00001 0.0000396


0.111

Note: p-values were based on an analysis of covariance model, which included treatment group (stannsoporfin 3.0 mg/kg, stannsoporfin 4.5 mg/kg, and placebo), stratification factor (ABO/Rh incompatibility vs G6PD deficiency), Baseline TSB as the covariate, and an interaction term of treatment by stratification factor. However, all randomized patients were from one strata (ABO/Rh incompatibility) so the stratification factor and the interaction term of treatment by stratification factor were removed from the model. CI = confidence interval, G6PD = glucose-6-phosphate dehydrogenase, h = hours, LS = least squares, SD = standard deviation, TSB = total serum bilirubin

Table 53: Summary of Total Serum Bilirubin (TSB) Area Under the Curve (AUC) for Change from the Baseline Value (ITT Analysis Set)

Statistic Stannsoporfin

Placebo N=30 3.0 mg/kg

N=30 4.5 mg/kg

N=31

AUC from 0 to observed last value ≤48 hours (+ 6 hours) (mg.h/dL)

Mean (SD) 21.07 (26.155) 26.91 (37.469) 64.75 (64.790)

Median 15.28 9.00 42.03 Min, Max 0.0, 93.6 0.0, 150.5 0.0, 227.9

Note: The TSB AUC (0 to last observed posttreatment TSB ≤48 hours +6 hours) was calculated as the positive change from Baseline using the normal trapezoid rule. AUC = area under the curve, h = hours, Max = maximum, Min = minimum, SD = standard deviations, TSB = total serum bilirubin



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Table 54: Percent Change From Baseline in Peak Serum Bilirubin (ITT Analysis Set)

Statistic Stannsoporfin

Placebo N=30 3.0 mg/kg

N=30 4.5 mg/kg

N=31 Baseline total serum bilirubin, mg/dL Mean (SD) 9.82 (2.641) 9.97 (2.967) 9.92 (2.211) Peak posttreatment serum bilirubin, mg/dL Mean (SD) 11.30 (2.275) 11.35 (2.452) 12.56 (2.323) Min, Max 7.6, 16.7 6.9, 18.8 8.2, 16.6 Percent change from Baseline to peak posttreatment serum bilirubin Mean (SD) 18.51 (20.219) 17.81 (22.233) 30.29 (30.270)

LS mean (95% CI) 18.01 (10.790, 25.234) 18.19 (11.084, 25.292) 30.39 (23.168,

37.609)

LS mean diff vs placebo (95% CI) -12.38 (-22.590, -

2.165) -12.20 (-22.330, -

2.072)

p-value vs placebo 0.018 0.019 p-value vs stannsoporfin 4.5 mg/kg 0.972

Note: Peak serum bilirubin was calculated as the maximum TSB posttreatment value ≤48 hours (+6 hours). All data, regardless of windowing used for the by-visit TSB analyses, would be considered ≤54 hours after study treatment. Note: p-values were based on an analysis of covariance model, which included treatment group (stannsoporfin 3.0 mg/kg, stannsoporfin 4.5 mg/kg, and placebo), stratification factor (ABO/Rh incompatibility vs G6PD deficiency), Baseline TSB as the covariate, and an interaction term of treatment by stratification factor. However, all randomized patients were from one strata (ABO/Rh incompatibility) so the stratification factor and the interaction term of treatment by stratification factor were removed from the model. CI = confidence interval, LS = least squares, Max = maximum, Min = minimum, SD = standard deviation, TSB = total serum bilirubin

Table 55: Total Duration of Phototherapy (ITT Analysis Set; Study 64,185-204) Stannsoporfin Placebo

Duration of Phototherapy 3.0 mg/kg 4.5 mg/kg

Statistic N=30 N=31 N=30

No. analyzed 30 31 30

Mean values, h 24.34 23.7 36.07

Mean p-value 0.0480 0.0339 —

Mean 95% CI 17.06, 31.62 16.54, 30.86 28.79, 43.35 Duration of PT was calculated as total PT time postdose. Note: The total time (hours) under lights for phototherapy is defined as Date / Time of PT Stop - Date / Time of Initiation of PT. The records collected at the unscheduled visits are not considered. Dunnett p-values were derived from a generalized linear model. No covariates used. CI = confidence interval; h = hour; ITT = intent-to-treat; PT = phototherapy



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12.4 Study 202 Inclusion and Exclusion Criteria

1. Term and late preterm neonates (≥35 and <43 weeks GA)

2. Risk factors for hemolytic disease, including ABO blood type incompatibility, Rh incompatibility (anti-C, c, D, E, or e), or, per amendment, G6PD deficiency

3. A minimum birth weight of 2500 g (5.5 lbs)

4. Coombs positive or Coombs negative

- Per amendment, if Coombs negative, one or more additional risk factors must also be present

5. Serum bilirubin within 1 mg/dL below the threshold for PT up to 12 hours of age or within 2 mg/dL below the threshold for PT at ≥12 to 48 hours of age, inclusive (per amendment, changed to 2 or 3 mg/dL below the PT threshold, and additional amendment, changed back to 1 or 2 mg/dL below the PT threshold) or

- Per amendment, serum or TcB within 2 mg/dL below the threshold for PT up to 12 hours of age or within 3 mg/dL below the threshold for PT at ≥12 to 48 hours of age to initiate enrollment and screening.

Note: Randomization/treatment cannot take place until the infant is within 1 to 2 mg/dL of the PT threshold based on age

6. Willingness for parents/guardians to adhere to recommendations regarding light precautions

7. Written informed consent obtained from parents/guardians Exclusion Criteria

1. (Deleted per amendment) Family history of G6PD deficiency

2. Clinical suggestion of neonatal thyroid disease or current uncontrolled thyroid disease in the mother (maternal Hashimoto disease is not exclusionary)

3. Treatment or need for treatment in the neonate with medications that may prolong the QT interval (erythromycin ointment for eye prophylaxis is permitted), family history of long QT syndrome, or family history of sudden infant death syndrome

4. Known porphyrias or risk factors for porphyrias, including family history

5. A maternal history of systemic lupus erythematosus

6. Maternal use of phenobarbital 30 days before, or after delivery, if breastfeeding

7. Maternal current drug or alcohol abuse or maternal history of drug or alcohol abuse that, in the opinion of the investigator, would not make the neonate a suitable candidate for participation in the clinical trial

8. Apgar score ≤6 at age 5 minutes

9. Per amendment, significant congenital anomalies or infections

10. (Deleted per amendment) Acidosis or sepsis

11. (Deleted per amendment) Hepatitis

12. (Deleted per amendment) Any excess risk of requiring surgery or exposure to operating room lights in the foreseeable future



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13. Cardiorespiratory distress, defined as a respiratory rate >60 breaths per minute at the time of enrollment unless a diagnosis of transient tachypnea of the newborn has been made

14. Any abnormal auditory or ophthalmologic findings at screening

- Patients who fail initial auditory screen may be rescreened

15. Any excess risk of requiring surgery or exposure to operating room lights in the foreseeable future

16. Clinically significant abnormalities on screening laboratory evaluation

17. Elevated direct or conjugated bilirubin (>1.0 mg/dL if the TSB is <5.0 mg/dL or >20% of the TSB if the TSB is ≥5.0 mg/dL)

18. Persistent hypoglycemia (blood glucose <40 mg/dL) despite standard-of-care treatment

19. Liver diseases (per amendment, defined as ALT and/or AST >2 times the ULN)

20. Abnormal renal function defined as creatinine and/or blood urea nitrogen >2 times the ULN

21. Any blood smear finding of structural red cell abnormalities, such as spherocytosis, not caused by isoimmune hemolysis

22. Temperature instability defined as temperature consistently (3 consecutive times) <36°C and/or >37.5°C axillary

23. Use of photosensitizing drugs or agents

24. (Deleted per amendment) Dehydration, defined by hypernatremia, serum sodium >ULN

25. Use of intravenous immunoglobulin (IVIG) or albumins

26. Postdelivery treatment with medications that are known or suspected to displace bilirubin from albumin (eg, ceftriaxone or sulfa-based antibiotics)

27. Other serious morbid conditions (eg, pulmonary disease, cardiovascular disease)

28. Exposure to any investigational medications or devices after delivery, or participation in another clinical trial while participating in this trial

29. Any other concurrent medical condition that, in the opinion of the investigator, makes the neonate unsuitable for the clinical trial

30. Unwillingness for parents/guardians to adhere to recommendations regarding light precautions



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12.5 Efficacy Results from Rockefeller IND Studies

12.5.1 Study 29,462-04

The mean maximum PBC value was significantly decreased (p<0.05) by stannsoporfin at dose 2 mol/kg (1.5 mg/kg) and at 4 (3.0 mg/kg) and 6 mol/kg (4.5 mg/kg) (p<0.001) compared to placebo for the Efficacy Analysis Population as shown in the table below:

Table 56: Maximum Bilirubin Concentration Values

Variables (Mean ±SD)

Control (n=181)

Stannsoporfin1

(n=40) Stannsoporfin2




(n=55)

Initial PBC 4.481.38 4.020.99 4.711.56 4.371.32 4.751.32 4.801.34

Initial Age (h)

14.536.82 13.276.32 15.136.95 14.507.44 15.596.36 15.586.58

Maximum PBC (h)

11.662.07 11.482.08 10.342.58

P<0.05 vs 10.272.01

9.982.48

P<0.001 vs

9.322.45

P<0.001 vs

Age at Maximum PBC (h)

94.2225.23 97.6528.15 97.6629.04 102.8430.56 101.5936.42 95.8030.73

Stannsoporfin1 1 μmol/kg of Stannsoporfin; Stannsoporfin2 2 μmol/kg of Stannsoporfin; Stannsoporfin3 3 μmol/kg of Stannsoporfin; Stannsoporfin4 4 μmol/kg of Stannsoporfin; Stannsoporfin6 6 μmol/kg of Stannsoporfin

Stannsoporfin also was statistically significantly superior to placebo at the 2, 4 and 6 µmol/kg (4.5 mg/kg) doses for the secondary efficacy variables.

Table 57: Phototherapy Data: By Treatment Groups: Efficacy Population

Variables (Mean±SD) Control (n=181)

Stannsoporfin1





(n=55)

Newborns Treated (%) 114 (0.63) 23 (0.58) 23 (0.41) 10 (0.37) 17 (0.32) 13 (0.24)

P-value % of Newborns requiring PT vs Placebo 0.5179* 0.0037 0.0104 <0.0001 <0.0001

Hours of Phototherapy per treated neonates**

77.1±41.1 55.3±24.5

NS

65.7±31.7

NS

57.2±25.3

NS

49.8±33.5

NS

47.8±24.2

NS

Hours of Phototherapy per neonates (PT Treated plus PT untreated)***

48.6±49.6 31.8±33.2

NS

27.0±38.1

P<0.05

21.2±31.8

NS

16.0±29.9

P<0.001

11.3±23.4

P<0.001

*Chi-squared vs placebo ** Overall ANOVA, P-value=0.0024, No significant differences among any groups using Scheffe’s Test. *** No therapy equals 0.0 hours of therapy. Overall ANOVA P-value <0.0001. Several significant differences among groups using Scheffe’s Test as listed.

Stannsoporfin1 1 μmol/kg of Stannsoporfin; Stannsoporfin2 2 μmol/kg of Stannsoporfin; Stannsoporfin3 3 μmol/kg of Stannsoporfin; Stannsoporfin4 4 μmol/kg of Stannsoporfin; Stannsoporfin6 6 μmol/kg of Stannsoporfin



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12.5.2 Study 29,462-09

This study compared a single dose of stannsoporfin, 6 µmol/kg/IM (4.5 mg/kg) with no treatment in male and female, full-term, breast-fed, otherwise healthy neonates with clinically significant hyperbilirubinemia (15 to 18 mg/dL) developing from 48 to 96 hours of age. No patient receiving stannsoporfin required PT. The results are summarized in the tables below for the primary and secondary efficacy variables.

Table 58: Efficacy Response Variables

Variable Stannsoporfin

n=80 Control

n=86 p-value

Number (%) of neonates requiring PT

0 19 (22.1) <0.0001*

Maximum PBC (mg/dL)

Mean (SD) 16.7 (±1.1) 17.6(±1.9) 0.0002

Median (min-max) 16.4(15- 17.7 (15-24) 0.0043

Numbers of PBC measurements required

Mean (SD) 3.6 (±2.2) 5.0 (±2.2) <0.0001

Median (min-max) 3 (1-16) 5 (1-12) <0.0001

Hours between enrollment and case closure

Mean (SD) 86.4 123.4 (±58.5) <0.0001

Median (min-max) 72.0 (24-384) 120.0 (24-336) <0.0001

Hours of PT required Mean (SD) 0 77.1 (±31.6) ---

Median (min-max) 0 72.0 (48-120) ---

ET Required

Numbers of Patients. Requiring ET 0 0 NS

*Fisher’s Exact Test

12.5.3 Study 29,462-05

The intergroup analysis of Phase 1 demonstrated statistical superiority for the stannsoporfin group as shown in the table below:



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Table 59: Comparison of Stannsoporfin and PT –Intergroup Analysis

Variable Stannsoporfin use

p-value* Stannsoporfin n=22

PT n=22

Hours in study 32.8 64.7 <0.001 Age at case closure 91.6 123.6 <0.001 PBC at case closure, mg/dL 12.4 12.1 0.559 Hours of PT required 0 33.2 <0.001

*p-values are from one-way ANOVA

The intergroup analysis of Phase 2 demonstrated statistical superiority for the stannsoporfin group as shown in the table below:

Table 60: Comparison of Stannsoporfin and PT –Intergroup Analysis

Variable Stannsoporfin use

p-value* Stannsoporfin

n=22 PT

n=20

Hours in study 51.8 83.0 <0.003 Age at case closure 113.8 146.4 <0.004 PBC at case closure, mg/dL 13.0 12.4 0.188 Hours of PT required 0 48.6 <0.001

*p-values are from one-way ANOVA

12.5.4 Study 29,462-06

In the intergroup analysis for the randomized phase of this study, the preventive group had a statistically significantly lower age at case closure as shown below.

Table 61: Intergroup Analysis – Primary Efficacy Analysis

Variable

Stannsoporfin Use

Preventive N=41 Therapeutic N=19 p-value Age (hours) at case closure 89.4 (35.98) 115.6 (19.18) 0.0043 Patients w/PT 0 0 Patients w/ET 0 0 * Mistakenly given PT instead of stannsoporfin as per protocol.

The results of the secondary efficacy variables in the randomized intergroup analysis are shown in the table below.



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Table 62: Intergroup Analysis – Secondary Efficacy Analysis

Variable (SD)

Stannsoporfin Use

p-value Preventive N=41 Therapeutic N=19 Maximum PBC (mg/dL) 8.12 (3.126) 12.72 (1.628) <0.0001 PBC Value (mg/dL) at case closure 6.99 (2.848) 10.86 (1.96) <0.0001 PBC Value (mg/dL) of 2nd venous blood sample 6.91 (2.544) 10.94 (1.558) <0.0001 Rate of PBC change from 1st to 2nd blood sample (mg/dL)

0.94 (1.521) 3.9 (1.58) <0.0001

Age (hours) at Maximum PBC 65.5 (36.40) 82.6 (23.86) 0.0681

The 172 pooled, randomized full-term preventive-use neonates had outcomes similar to the randomized preventive group as shown in the table below.

Table 63: Comparison of Randomized and Non-Randomized Groups Stannsoporfin Use

Variable Preventive (randomized)

n=42

Preventive (Total Phases I & II >265 days GA)

n=172

Therapeutic (randomized)

n=20

p-Value

Age (hours) at Case Closure (SD) 89.1 (35.6) 82.2 (31.8) 110.8 (23.6) <0.0001*

Maximum PBC (mg/dL) (SD) 8.20 (3.13) 7.81 (3.04) 10.88 (2.8) <0.0001*PBC Value (mg/dL) at case closure 7.20 (2.87) 6.87 (2.82) 9.58 (2.5) <0.0001*PBC Value (mg/dL) of 2nd venous blood sample (SD)

7.08 (2.73) 6.81 (2.64) 9.12 (2.21) <0.0001*

Rate of PBC change from 1st to 2nd

blood sample (mg/dL) (SD) 1.02 (1.60) 0.63 (1.44) 2.99 (1.65) <0.0001*

Age (hours) at maximum PBC (SD)

63.5 (34.8) 56 (29) 82.2 (24.7) <0.0001*

*ANOVA

Table 64: Comparison of Randomized and Non-Randomized Preventative Use Groups

Variable

Stannsoporfin Use

Preventive (randomized) N=41

Preventive (Total Phases I & II

>265 days GA) N=172

Mean (SD) Mean (SD)

Age (hours) at Case Closure 89.4 (35.98) 82.2 (31.8)

Maximum PBC (mg/dL) 8.12 (3.126) 7.81 (3.04)

PBC Value (mg/dL) at case closure 6.99 (2.848) 6.87 (2.82)

PBC Value (mg/dL) of 2nd venous blood sample 6.91 (2.544) 6.81 (2.64)

Rate of PBC change from 1st to 2nd

blood sample (mg/dL)

0.94 (1.521)

0.63 (1.44)

Age (hours) at maximum PBC 65.5 (36.40) 56 (29)



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12.5.5 Study 29,462-07

No formal efficacy analysis of this study was performed because of the small number of neonates enrolled. None of the neonates who received stannsoporfin required PT.

12.5.6 Study 29,462-08

No formal efficacy analyses were performed due to the small number of neonates entered in each of the six stratification groups.

12.6 Additional Safety Results from Studies 202, 06, and 01-3W

12.6.1 Study 202

The proportions of patients that had TEAEs in Study 202 were similar in the stannsoporfin 4.5 mg/kg and placebo groups, and higher in the stannsoporfin 1.5 and 3.0 mg/kg groups (Table 65). Most TEAEs were mild, few were moderate, and none in the 4.5 mg/kg and placebo groups were severe; one in the 1.5 mg/kg group was severe (contusion from a forceps delivery). The proportion of patients that had SAEs was low and similar in all treatment groups. There were no deaths or discontinuations due to AEs reported during the study.



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Table 65: Summary of TEAEs in Study 202 Number (%) of Patients

Stannsoporfin

1.5 mg/kg (N = 17)

3.0 mg/kg (N = 18)

4.5 mg/kg (N = 8)

Placebo (N = 15)

TEAEs 8 (47.1) 10 (55.6) 3 (37.5) 5 (33.3) Mild 6 (35.3) 8 (44.4) 1 (12.5) 2 (13.2) Moderate 1 (5.9) 2 (11.1) 2 (25.0) 3 (20.0) Severe 1 (5.9) 0 0 0 SAEs 0 1 (5.6) 1 (12.5) 2 (13.3) TEAE leading to study discontinuation 0 0 0 0 Deaths 0 0 0 0 Note: The total number of AEs counts all AEs for patients. At each level of patient summarization, a patient is counted once if the patient reported one or more events. Percentages are based on the number of patients in each treatment group. TEAE = treatment-emergent adverse event; SAE = serious adverse event

Treatment-emergent AEs involving the skin were expected, and the most common events occurred in 13.3% in the placebo group, 12.5% in the stannsoporfin 4.5 mg/kg group, 38.9% in the 3.0 mg/kg group, and 17.6% in the 1.5 mg/kg group (Table 66). Most rashes in all groups were expected neonatal rashes such as diaper dermatitis, erythema toxicum, and seborrheic dermatitis. All of these events resolved and were considered mild and unrelated to study drug except for one case of erythema (4.5 mg/kg patient), one case of erythema toxicum neonatorum (3.0 mg/kg patient) most likely from ECG lead placement, and one rash (1.5 mg/kg patient).



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Table 66: Common TEAEs (≥5% Incidence in a Group) in Study 202 Number (%) of Patients

Stannsoporfin

Placebo (N = 15)

1.5 mg/kg (N = 17)

3.0 mg/kg (N = 18)

4.5 mg/kg (N = 8)

Patients with any TEAE 8 (47.1) 10 (55.6) 3 (37.5) 5 (33.3) Total number of TEAEs 17 16 8 8 Blood and lymphatic system disorders 0 1 (5.6) 2 (25.0) 0 Anaemia 0 1 (5.6) 1 (12.5) 0 Leukocytosis 0 0 1 (12.5) 0 Thrombocytopenia 0 0 1 (12.5) 0 Cardiac disorders 0 0 1 (12.5) 0 Bradycardia 0 0 1 (12.5) 0 Gastrointestinal disorders 0 1 (5.6) 0 1 (6.7) Umbilical hernia 0 1 (5.6) 0 0 Vomiting 0 0 0 1 (6.7) Hepatobiliary disorders 7 (41.2) 1 (5.6) 0 3 (20.0) Hyperbilirubinaemia 2 (11.8) 1 (5.6) 0 2 (13.3) Jaundice 5 (29.4) 0 0 1 (6.7) Infections and infestations 0 1 (5.6) 1 (12.5) 2 (13.3) Anal abscess 0 1 (5.6) 0 0 Meningitis 0 0 1 (12.5) 0 Oral candidiasis 0 0 0 2 (13.3) Injury, poisoning and procedural complications 1 (5.9) 0 0 0 Contusion 1 (5.9) 0 0 0 Investigations 1 (5.9) 1 (5.6) 1 (12.5) 0 Blood glucose decreased 0 1 (5.6) 0 0 Blood sodium increased 0 1 (5.6) 0 0 C-reactive protein increased 1 (5.9) 0 0 0 Carbon dioxide decreased 0 1 (5.6) 0 0 Haemoglobin increased 0 0 1 (12.5) 0 Neoplasms benign, malignant and unspecified 1 (5.9) 0 0 0 Haemangioma 1 (5.9) 0 0 0 Nervous system disorders 0 0 1 (12.5) 0 Depressed level of consciousness 0 0 1 (12.5) 0 Skin and subcutaneous tissue disorders 3 (17.6) 7 (38.9) 1 (12.5) 2 (13.3) Acne infantile 1 (5.9) 0 0 0 Dermatitis contact 1 (5.9) 0 0 0 Dermatitis diaper 2 (11.8) 1 (5.6) 0 1 (6.7) Erythema 0 1 (5.6) 1 (12.5) 0 Erythema toxicum neonatorum 0 3 (16.7) 0 0 Rash 1 (5.9) 0 0 0 Rash neonatal 0 1 (5.6) 0 0 Rash papular 0 0 0 1 (6.7) Seborrhoeic dermatitis 0 1 (5.6) 0 0 Skin exfoliation 1 (5.9) 0 0 0 Vascular disorders 0 1 (5.6) 0 0 Flushing 0 1 (5.6) 0 0 TEAE = treatment-emergent adverse event.



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Four SAEs unrelated to treatment were reported; anemia in a patient diagnosed with hemolytic disease of the newborn at birth (3.0 mg/kg), meningitis (4.5 mg/kg), and two cases of hospital re-admission due to hyperbilirubinemia (placebo), all of which all of which resolved.

Overall, this study showed that stannsoporfin administered at a dose of 1.5, 3.0 or 4.5 mg/kg, was safe and well tolerated in neonates with hyperbilirubinemia. The safety profile of stannsoporfin 4.5 mg/kg was similar to that of placebo.

12.6.2 Study 06

The proportions of patients that had TEAEs in Study 06 were similar across treatment groups, and all were mild or moderate (Table 67). The proportion of patients that had SAEs was low and similar in all treatment groups. There were no deaths or discontinuations due to AEs reported during the study. One (5.6%) neonate in the placebo treatment group experienced a non-treatment-related SAE (moderate meningitis), which resolved within two months.

Table 67: Summary of TEAEs in Study 06 Number (%) of Patients

Stannsoporfin

Placebo (N = 18)

0.75 mg/kg(N = 19)

1.5 mg/kg (N = 18)

TEAEs 13 (68.4) 15 (83.3) 15 (83.3) Mild/Moderate 13 (68.4) 15 (83.3) 15 (83.3) Severe 0 0 0 SAEs 0 0 1 (5.6) AE leading to study discontinuation 0 0 0 Deaths 0 0 0

TEAE = treatment-emergent adverse event.

The most frequently occurring adverse events were decreased hemoglobin occurring in 28 neonates (0.75 mg/kg, 10; 1.50 mg/kg, 10; Placebo, 8) and acidosis, which occurred in five neonates (1.50 mg/kg, 1; Placebo, 4).



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Table 68: Common TEAEs (≥5% Incidence in a Group) in Study 06 Number (%) of Patients

Stannsoporfin

0.75 mg/kg(N = 19)

1.50 mg/kg (N = 18)

Placebo (N = 18)

Patients with any TEAE 13 (68.4) 15 (83.3) 15 (83.3) Infections and infestations 0 1 (5.6) 1 (5.6) Skin infections 0 1 (5.6) 0 Meningitis 0 0 1 (5.6) Investigations 12 (63.2) 11 (6.1) 8 (44.4) Blood calcium decreased 1 (5.3) 0 0 Blood potassium increased 1 (5.3) 0 0 Haemoglobin decreased 10 (52.6) 10 (55.6) 8 (44.4)

Platelet count decreased 0 1 (5.6) 0 Metabolism and nutrition disorders 0 3 (1.7) 6 (33.3) Acidosis 0 1 (5.6) 4 (22.2)

Hypoglycaemia 0 2 (11.1) 1 (5.6) Hypokalaemia 0 0 1 (5.6)

Skin and subcutaneous tissue disorders 1 (5.3) 0 0 Rash 1 (5.3) 0 0

TEAE = treatment-emergent adverse event.

12.6.3 Study 01-3W

The proportions of patients that had TEAEs in Study 06 were similar in the stannsoporfin 4.5 mg/kg and placebo groups (Table 69). Six SAEs were reported, all were unrelated to treatment; five hospitalizations (four stannsoporfin 4.5 mg/kg, one placebo) and one accidental overdose. There were no deaths during the study. One death (SIDS at 20 days) was reported in a neonate who was screened but not randomized or treated.

Table 69: Summary of TEAEs in Study 01-3W Stannsoporfin 4.5 mg/kg

(N = 87) Placebo (N = 89)

TEAEs 29 (33.3%) 22 (24.7%) SAEs 5 1 Death 0 0

Treatment-emergent AEs involving the skin were expected, and the most common events occurred with similar frequency in the 4.5 mg/kg and placebo groups (Table 70). The most frequently reported TEAEs affecting the skin were mild or moderate erythema (10 stannsoporfin and five placebo).



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One patient in the 4.5 mg/kg group experienced two TEAEs of cardiac murmur/heart murmur 1 day and 32 days post-treatment. The events were both mild, non-serious, and unlikely related to study drug. The first TEAE resolved, and the outcome of the second TEAE is ongoing.

One patient in the 4.5 mg/kg group experienced a TEAE of cardiac murmur/heart murmur 7 days post-treatment. The event was mild, non-serious, and unlikely related to study drug. The outcome of this TEAE is ongoing.

One patient in the 4.5 mg/kg group experienced a TEAE of cardiac murmur/small murmur 6 days post-treatment. The event was mild, non-serious, and unlikely related to study drug. The outcome of the TEAE is resolved.

One patient in the 3.0 mg/kg group experienced TEAEs of supraventricular tachycardia/supraventricular tachycardia (two episodes) and ventricular hypertrophy/combined ventricular hypertrophy 6 days and 25 days post-treatment, respectively. The supraventricular tachycardia event was mild, serious, and unlikely related to study drug. The ventricular hypertrophy/combined ventricular hypertrophy event was mild, non-serious, and unlikely related to study drug. The outcomes of these TEAE are not resolved.

One patient in the 3.0 mg/kg group experienced a TEAE of cardiac murmur/heart murmur 27 days post-treatment. The event was mild, non-serious, and unlikely related to study drug. The outcome of the TEAE is not resolved.

One patient in the 3.0 mg/kg group experienced a TEAE of cardiac murmur/heart murmur 1 day post-treatment. The event was mild, non-serious, and unlikely related to study drug. The outcome of the TEAE is ongoing.

One patient in the 3.0 mg/kg group experienced a TEAE of cardiac murmur/heart murmur 30 days post-treatment. The event was mild, non-serious, and unlikely related to study drug. The outcome of the TEAE is not resolved.

One patient in the 3.0 mg/kg group experienced a TEAE of cardiac murmur/systolic murmur – GR 1-2/V1 with radiation 2 days post-treatment. The event was mild, non-serious, and unlikely related to study drug. The outcome of the TEAE is resolved.

One patient in the 3.0 mg/kg group experienced a TEAE of cardiac murmur/heart murmur 30 days post-treatment. The event was mild, non-serious, and unlikely related to study drug. The outcome of the TEAE is ongoing.

Study 202

One patient in the 4.5 mg/kg group experienced a TEAE of bradycardia/bradycardia 2 days post-treatment. The event was mild, non-serious, and unlikely related to study drug. The outcome of the TEAE is resolved.

Study 01-3W

One patient in the 4.5 mg/kg group experienced a TEAE of cardiac murmur/heart murmur 1 day post-treatment. The event was mild, non-serious, and not related to study drug. The outcome of the TEAE is resolved.

Study 01-3CW



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One patient in the 4.5 mg/kg group experienced a TEAE of cardiac murmur/Grade 1 mid-systolic heart murmur 4.6 years post-treatment. The event was mild and non-serious, and the outcome of the TEAE is not resolved.

One patient in the 4.5 mg/kg group experienced two TEAEs of cardiac murmur/heart murmur 21 days post-treatment. The events were mild and non-serious. The outcome of one TEAE is resolved, and the other is not resolved.

One patient in the 4.5 mg/kg group experienced TEAEs of cardiac murmur/6 still murmur at L sternal border, cardiac murmur/cardiac murmur, and cardiac murmur/cardiac murmur 1, all occurring at 6 months post-treatment. The events were mild and non-serious, and the outcomes of the TEAEs are not resolved.

One patient in the 4.5 mg/kg group experienced a TEAE of heart rate increased/rapid heartbeat 2.8 years post-treatment. The event was mild and non-serious, and the outcome of the TEAE is resolved.

Thrombocytopenias

Study 204

One patient in the 3.0 mg/kg group had a TEAE of thrombocytopenia at 22.7 hours post-treatment. The event was mild and unlikely related to stannsoporfin or PT. A clinically significant platelet count of 102 x 103/µL was reported at 48 hours. Platelets returned to normal range without any treatment. The patient had recovered on Day 7. This TEAE was not considered an SAE.

One patient in the 3.0 mg/kg group had a TEAE of thrombocytopenia at 15.5 hours post-treatment of moderate intensity after receiving a double volume exchange transfusion. The thrombocytopenia was considered unlikely related to stannsoporfin. Clinically significant platelet counts of 36 x 103/µL and 68 x 103/µL were also reported at 48 hours and at Day 7. The patient had recovered on Day 30. Infants that receive exchange transfusions receive red blood cells in plasma without platelets. This TEAE was likely related to the exchange transfusion, which is a recognized cause of thrombocytopenia.

One patient in the 4.5 mg/kg group had a TEAE of thrombocytopenia at 13.3 hours posttreatment (platelet count: 94 x 103/µL) of mild intensity, probably related to stannsoporfin and possibly related to PT. A clinically significant platelet count of 87 x 103/µL was reported at Day 7. The count was 384 x 103/µL on Day 30.

Deaths

Study 01-3W

One patient with GA of 40 weeks, treated with stannsoporfin 4.5 mg/kg at 29 hours (no PT), died at 4.5 months of SIDS by exclusion. The infant’s mother was 18 years old with a history of smoking in the first trimester and had a vaginal delivery without complication. The infant’s birth weight was 2750 g, with an Apgar of 9 at 1 and 5 minutes. The infant had S1 and S6 cardiac murmurs deemed normal by the pediatrician, and a medical history significant for eczema to the face. The death was judged by the Investigator to be unrelated to study drug.

Study 01C-3W



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One patient with GA of 40 weeks, enrolled in the study but not randomized or treated, died at 20 days of age from SIDS. The infant’s mother was 21 years old with a history of anemia, no prenatal care, and a vaginal delivery with no complications; the father was a household smoker and user of alcohol. The infant’s birth weight was 3455 g, with an Apgar of 8 at 1 minute and 9 at 5 minutes. The infant’s TSB was 5.6 mg/dL at 19 hours, with no jaundice noticed.

Study 29,462-04

One patient with GA of 30 weeks, treated with stannsoporfin, 1.5 mg/kg at 11 hours, died on day 15 of severe respiratory distress syndrome (RDS), bilateral pneumonia and intraventricular hemorrhage (IVH) and renal failure. The death was judged unrelated to study drug. In the acute database.

One patient with GA of 32 weeks, treated with stannsoporfin, 3.0 mg/kg at 18 hours, died on day 3 of RDS, pneumothorax and massive IVH. The death was judged unrelated to study drug. In the acute database.

One patient with GA of 30 weeks, treated with stannsoporfin, 3.0 mg/kg at 13 hours after birth died at 98 hours (day 5) of severe RDS and pneumothorax. This infant was part of a triplet pregnancy related to in vitro fertilization. The death was judged unrelated to study drug. In the acute database.

One patient with GA of 33 weeks, treated with stannsoporfin, 4.5 mg/kg at 23 hours after birth died on day 9 of severe RDS, pneumonia and IVH. The infant weighed 1100 grams at birth. The death was judged unrelated to study drug. In the acute database.

One patient with GA of 29 weeks, treated with tin stannsoporfin 0.75 mg/kg at 9 hours after birth, died at 68 hours of age (day 3) of RDS, pulmonary interstitial emphysema (PIE) and pneumothorax. The death was judged unrelated to study drug. This case is listed as having a cardiac arrest, but the death is not in the database.

One patient with GA of 34 weeks, treated with placebo at 22 hours after birth, died on day 16 of RDS, IVH, seizures and multiple pneumothoraxes. The infant weighed 1150 grams at birth. The death was judged unrelated to study drug. In the acute database.

One patient with GA of 30 weeks, treated with placebo one hour after birth died at 3 months of RDS, bilateral pneumonia and IVH. This infant was part of a twin pregnancy. The death was judged unrelated to study drug. In the acute database.

One patient with a GA of 31 weeks, treated with stannsoporfin 1.5 mg/kg at 19 hours after birth, died at 9 months of short bowel syndrome secondary to extensive necrotizing enterocolitis (NEC) at 18 days of life. The death was judged unrelated to study drug. This death is not in the database.


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12.9 Neurological Adverse Event Tables

Table 72: Speech-related Adverse Events in Study 01C-3W Study Group Stann: n=44, Placebo: n=43 Sex

AE Preferred Term AE Severity Age at AE Onset AE status Mother’s Age

Confounding Factors

4.5 mg/kg M Speech Disorder Mod 23 mo Lost to follow-up 17 Otitis media 4.5 mg/kg M Speech Disorder Mod 18 mo Lost to follow-up 18 Atopic dermatitis

4.5 mg/kg M Speech Disorder

Language Disorder Dyspraxia

Mild Mild Mild

2 yr 4 mo 2 yr 6 mo 2 yr 6 mo

Resolved Lost to follow-up Lost to follow-up

32

Deafness

4.5 mg/kg M Speech Disorder Mild 3 yr Resolved 39 Contusion head, Bilateral ear infection;

Bilateral otitis media (5x); Ear disorder; Otitis media (2x); Head injury (3x)

4.5 mg/kg M Speech Disorder Mild 3 yr 1 mo Lost to follow-up 19 None reported 4.5 mg/kg M Speech Disorder Mild 3 yr 2 mo Lost to follow-up 32 Otitis media

4.5 mg/kg F Speech Sound

Disorder Speech Disorder

Mild Mod

3 yr 3 yr 11 mo

Resolved Ongoing

17 Otitis media (2x), Bilateral otitis media,

Hand/foot/mouth disease (10 days before speech disorder, Abnormal WPPSI

4.5 mg/kg M Dysarthria

Speech Disorder Mod Mod

4 yr 7 mo Ongoing Ongoing

20 Otitis media, bilateral otitis media, Left head

bump, Iron deficiency anemia, Eczema

4.5 mg/kg M Speech Disorder Mod 4 yr Ongoing 18 Otitis media (2x), bilateral otitis media, child

neglect, febrile seizure, Eczema

Placebo M Language Disorder Mild 22 mo Lost to follow-up 24 Eczema Placebo F Speech Disorder Mild 5 yr 6 mo Ongoing 40 None reported

Unique patients

Table 73: Speech-related Adverse Events in Study 203

Study Group Stann: n=29 Placebo: n=13 Sex

AE Preferred Term

AE Severity Age at AE Onset AE status Mother’s Age

Confounding Factors 1.5 mg/kg M Speech Disorder Mild 2 yr 1 mo Resolved 27 Eczema, Ear infection 4.5 mg/kg F Speech Disorder Mild 2 yr Resolved 38 Trauma of the soft tissue of head


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Placebo F Speech Disorder Mild 16 mo Resolved 30 Dermatitis atopic, Ear infection

Placebo M Speech Disorder

Developmental Mild 16 mo Resolved 28

Otitis media, Hand/foot/mouth disease

Unique patients

Table 74: Speech-related Adverse Events in Study 205 Study Group Stann: n=48 Placebo: n=20 Sex

AE Preferred Term

AE Severity AE Onset Visit AE Status Mother’s Age

Confounding Factors

3.0 mg/kg M Speech Disorder Developmental

Mild 23 mo Ongoing* 23 Hand/foot/mouth

disease, Otitis media *Patient continues in long-term follow-up study. Resolution not yet determined. Note: Study 205 is ongoing. Table includes safety update; cutoff May 31, 2017

stannsoporfin for the treatment of neonatal …€¦ · figure 8: rate of phototherapy failures in...

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