treating the pain with gmi-1070 - home -...

Treating the Pain with GMI-1070

Timothy L. McCavit, M.D., M.S. UT Southwestern Medical Center

Dallas, TX

Click to edit Master title style

Click to edit Master text styles

• Second level

- Third level

- Fourth level

- Fifth level

Acute Pain Crises are the Clinical Hallmark of Sickle Cell Disease (SCD)

“Ten, Redefined” by H. Nazaire

http://kreyolicious.com/wp-content/uploads/2013/12/nazaire-art.jpg



• Second level

- Third level

- Fourth level

- Fifth level

Vaso-occlusive Crises (VOC) in Sickle Cell Disease

Epidemiology: widely variable, most common cause of ED visits and hospitalizations

Risk factors: • Exposure & stress • Age in childhood • Fetal hemoglobin • Hematocrit

Duration: hours to many days

Treatment (Palliative):

• Opioids • Anti-inflammatory • Intravenous fluid



• Second level

- Third level

- Fourth level

- Fifth level

The Biology of Pain in SCD

1. Endothelial activation by RBC’s & others

2. Recruitment of adherent leukocytes

3. Activation of recruited neutrophils & other leukocytes

4. Interaction of sickle RBC’s with neutrophils

5. Vascular clogging by heterotypic cellular aggregates (± platelets)

6. Increased transit time of RBC’s

7. Local ischemia creates feedback loop – worsens much of the above

Manwani & Frenette. Blood. 122:3892-8; 2013.



• Second level

- Third level

- Fourth level

- Fifth level

Selectin Inhibition for VOC in SCD

• GMI-1070 – Rationally designed

– Pan-selectin inhibitor

– Maximally inhibits E-selectin

– Decreases leukocyte adhesion

– Increases leukocyte rolling

Manwani & Frenette. Blood. 122:3892-8; 2013.

Adherent Neutrophil

Erythrocyte



• Second level

- Third level

- Fourth level

- Fifth level

Vehicle Control GMI-1070

*As seen by intravital microscopy; Dr. Paul Frenette, Mt. Sinai.

Murine model of sickle cell anemia with VOC induced by TNF-a

Once VOC is established, GMI-1070 is administered

Treatment resulted in significant improvements

Increased survival

Improved blood flow

Reduced leukocyte/endothelial interactions

Reduced leukocyte/SSRBC interactions

GMI-1070 for VOC in SCD

Chang et al, Blood, 116:1779-1786; 2010.



• Second level

- Third level

- Fourth level

- Fifth level

GMI-1070 – early phase studies

Phase 1 clinical trials

• Healthy adult volunteers

• Adult SCD patients at baseline

Pharmacokinetics: Established dose

No major dose-limiting toxicity



• Second level

- Third level

- Fourth level

- Fifth level

Study Aims Primary Aim

To evaluate the efficacy of GMI-1070 in reducing the duration of

VOC in a phase 2 clinical trial

Secondary Aims

(1) To evaluate the safety and pharmacokinetics of GMI-1070 in

the setting of acute pain

(2) To compare baseline characteristics and efficacy of GMI-

1070 between pediatric and adult subjects



• Second level

- Third level

- Fourth level

- Fifth level

Study Design

Prospective, multicenter, randomized, placebo-

controlled, double-blind, adaptive clinical trial of 76

adult and pediatric SCD patients

• Subjects enrolled at the time of admission to the hospital

• GMI-1070 or placebo given in addition to institutional

standard care for VOC

• Interim analyses for PK and safety were built in



• Second level

- Third level

- Fourth level

- Fifth level

Eligibility Inclusion Criteria:

1. Hb SS or Sb0 thal

2. Diagnosis of VOC at time of enrollment

3. Hospitalized or in process of admission at enrollment

4. Age 12-60 years

5. 1st dose of study drug given within 18 24 hours of presentation



• Second level

- Third level

- Fourth level

- Fifth level

Eligibility Exclusion Criteria:

1. Infection – diagnosed or strongly suspected

• Fever > 39°C

• Fever > 38.5°C with positive cultures or radiographs, or determination by treating physician that serious infection was likely

2. SCD pain atypical of VOC (e.g., cholecystitis, splenic / hepatic pain)

3. Major surgery in the past 30 days

4. Hb < 5g/dL; Plt < 100,000/mm3

5. Creatinine >1.2 mg/dL if age 16-60; > 1.0 if 12-15; ALT >2x ULN

6. Systemic steroid therapy in 48 hrs prior to enrollment

7. For those on long-acting opioids, no dose change in past 14 days



• Second level

- Third level

- Fourth level

- Fifth level

Adaptive Design

Characteristic Study Beginning

Study End

INCLUSION CRITERIA

Age, years 16-45 12-60

Time from initial medical eval to 1st study drug 18 hours 24 hours

EXCLUSION CRITERIA

Timing of most recent PRBC transfusion < 60 days < 14 days

Frequent, recent hospitalizations for VOC > 6 in 12 months > 5 in 6 months

Timing of recent hospitalization or parenteral treatment for VOC

within 14 days within 2 days



• Second level

- Third level

- Fourth level

- Fifth level

Methods - Intervention • GMI-1070 or placebo

20 minute IV infusions every 12 hrs for up to 7 days

Dosing:

Loading Dose - 20 mg/kg

Maintenance Doses - 10 mg/kg (up to 14 total maint doses)

Pre-specified interim PK analysis

• First 11 subjects (1 pediatric)

• Dosing doubled to 40mg/kg loading dose and 20mg/kg maintenance doses

• Daily lab monitoring

• Pain intensity measured every 4 hours on visual-analog scale (VAS)

• Other clinical care at discretion of treating physicians

• Follow-up visits 36 hours, 7 days, and 28 days after last dose



• Second level

- Third level

- Fourth level

- Fifth level

Methods - Outcomes Primary Outcome

Time to resolution of VOC defined as:

1) Sustained decrease in VAS pain score by 1.5cm from baseline with concurrent cessation in parenteral opioids

or

2) Agreement about readiness for discharge by patient and physician

or

3) Hospital discharge

Secondary Outcomes

• time to discharge

• time to transition from IV to oral analgesics

• parenteral opioid usage (by hospital day) in morphine equivalent units per kilogram (MEU/kg)

• safety profile



• Second level

- Third level

- Fourth level

- Fifth level

Analyses • Median time-to-outcome (for primary and secondary outcomes)

compared between arms using Kaplan-Meier (KM) method

• Analysis of covariance compared mean hourly opioid use, by hospital day

• Fisher’s exact test and Wilcoxon rank-sum test used to compare pediatric and adult hospitalization features



• Second level

- Third level

- Fourth level

- Fifth level

Baseline Subject Characteristics GMI-1070 (N=43) Placebo (N=33)

Age (years), mean (SD) 25.4 (10.8) 25.0 (10.2)

Gender Male 18 (41.9%) 13 (39.4%)

Genotypes

HbSS 39 (90.7%) 30 (90.9%)

Hb Sβ0 thalassemia 1 (2.3%) 3 (9.1%)

HbSC 3 (7%) 0

Hydroxyurea therapy 22 (51.2%) 23 (69.7%)

Daily out-patient pain meds 18 (41.9%) 19 (57.6%)

≥3 VOC admissions in previous 12 months 13 (30.2%) 14 (42.4%)

ACS in previous 12 months 5 (11.6%) 6 (18.2%)

VAS at presentation, mean (SD) 8.3 (1.6) 9.0 (1.5)

Hemoglobin g/dL, mean (SD) 8.3 (1.4) 8.2 (2.1)

WBC x 103, mean (SD) 12.8 (5.0) 13.6 (5.6)

ANC x103/ml, mean (SD) 7.3 (3.9) 8.3 (5.1)



• Second level

- Third level

- Fourth level

- Fifth level

Features of Pediatric Subjects

Characteristic Pediatric Subjects

Number enrolled (of 76 total) 20

Age, years, median (range) 14 (12-17)

Genotype, % SS 100

Gender, % Female 40

Concurrent hydroxyurea, % 55

Primary Outcome Component, %* Sustained decrease in VAS Readiness for discharge agreement Hospital discharge

45 40 20

* One subject met both readiness and hospital discharge criteria simultaneously.



• Second level

- Third level

- Fourth level

- Fifth level

Primary Outcome

Time to Resolution of VOC All Subjects Pediatric Subjects

Time to Resolution of VOC

GMI-1070 Hours, Median (95% CI)

Placebo Hours, Median (95% CI)

P

All Subjects 69.6 (44.3-115.5) 132.9 (67.0-164.2) 0.187

Pediatric Subjects 72.2 (46.3-128.0) 132.9 (47.5-181.0) 0.061



• Second level

- Third level

- Fourth level

- Fifth level

Secondary Outcome

Time to Transition to Oral Analgesics All Subjects Pediatric Subjects

Time to Transition to Oral Analgesics

GMI-1070 Hours, Median (95% CI)

Placebo Hours, Median (95% CI)

P

All Subjects 128.0 (57.7-156.9) 181.0 (97.7-217.0) 0.20




• Second level

- Third level

- Fourth level

- Fifth level

Secondary Outcome

Time to Discharge All Subjects Pediatric Subjects

Time to Discharge GMI-1070

Hours, Median (95% CI) Placebo

Hours, Median (95% CI) P

All Subjects 72.2 (59.9-121.0) 156.1 (75.4-185.8) 0.09


Pediatric vs Adult Primary and Secondary Outcomes



• Second level

- Third level

- Fourth level

- Fifth level

Mean Hourly Opioid Use By Hospital Day H

ou

rly

IV O

pio

ids

An

alge

sic

Use

0.0

0.2

0.4

0.6

0.8

1.0

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

GMI-1070

Placebo

48 hour reduction p=0.067

24 hour reduction p<0.001 ***

‡ ***

‡



• Second level

- Third level

- Fourth level

- Fifth level

SCD-Related Adverse Events

Complication GMI-1070

(N=43) N (%)

Placebo (N=33) N (%)

Acute Chest Syndrome 6 (14) 3 (9)

RBC Transfusion 15 (35) 17 (52)

ICU Admission 0 1 (3)

Death 0 0

Readmission for VOC (14 days) 4 (9) 3 (9)

Readmission for VOC (30 days) 9 (21) 7 (21)

All Subjects



• Second level

- Third level

- Fourth level

- Fifth level

Treatment Emergent (Related) Adverse Events

*One patient developed acute generalized exanthematous pustulosis after discharge; this resolved without intervention.

Complication GMI-1070

N=43 N (%)

Placebo N=33 N (%)

Gastrointestinal Disorders 18 (42) 12 (36)

Rash 6 (14) * 2 (6)

Hepatobiliary 2 (5) 2 (6)

Renal / Urinary 3 (7) 2 (6)

Pyrexia 8 (19) 6 (18)

Headache 8 (19) 4 (12)

All Subjects



• Second level

- Third level

- Fourth level

- Fifth level

Pediatric Safety

No severe or unusual infections

7 pediatric serious adverse events (SAE’s) 4 VOC recurrence

1 VOC with acute chest syndrome (ACS)

1 cholelithiasis

1 gastroenteritis

• 4/13 (30%) on GMI-1070

• 3/7 (43%) on placebo



• Second level

- Third level

- Fourth level

- Fifth level

Safety – Acute Chest Syndrome (ACS)

GMI-1070 ACS / Total %

Placebo ACS / Total %

Pediatric 4 / 13 31% 0 / 7 0%

Adult 2 / 30 6% 3 / 26 11%

Total 6 / 43 14% 3 / 33 9%

Of 4 pediatric ACS cases: - 3 occurred within 24 hours of admission - 1 received transfusion - 0 received intensive care



• Second level

- Third level

- Fourth level

- Fifth level

Pediatric vs Adult – Pain Features Characteristic

Pediatric N=20

Adult N=56

P

Patient controlled analgesia (PCA) usage, % 80 86 0.65

Opioid agent used in PCA, % Morphine Hydromorphone

80 20

20 80

0.003

Cumulative IV opioid, mean (SD), MEU/kg 5.7 (7.0) 41.6 (86.3) 0.10

VAS pain score at presentation, mean (SD) 7.9 (1.9) 8.8 (1.4) 0.10

VAS pain score at resolution, mean (SD) 5.2 (2.9) 4.2 (2.6) 0.15

Difference in VAS from presentation to resolution, mean (SD) -1.86 (2.1) -2.44 (2.3) 0.36



• Second level

- Third level

- Fourth level

- Fifth level

Pediatric vs Adult – Other Features Characteristic

Pediatric N=20

Adult N=56

P

Hydroxyurea use (at enrollement), % 55 61 0.78

Daily long-acting opioid use (at enrollment), % 5 43 0.003

Time from first medical evaluation to 1st study drug, hours, mean (SD) 14.8 (5.6) 15.5 (5.3) 0.46

Antibiotics within 24 hours of 1st study drug, % 55 25 0.015

PRBC transfusion during hospitalization, % 25 45 0.17

SAE occurrence, % 35 29 0.59

7 day VOC readmission, % 10 0 0.086





• Second level

- Third level

- Fourth level

- Fifth level

Comparison - other novel agents for VOC

Study or Agent Duration of VOC, Hours % Change

Active Agent Placebo

Poloxamer-188 – Phase II1 67 80 – 16

Poloxamer-188 – Phase III2 (Overall) 133 141 – 6

Poloxamer-188 – Phase III2 (Pediatric)

127 149 – 14

Inhaled Nitric Oxide3 73 66 + 10

GMI-1070 – Phase II (Overall) 67 133 – 50

GMI-1070 – Phase II (Pediatric) 72 133 – 46

1 – Adams-Graves et al. Blood. 90:2041-6, 1997 2 – Orringer et al. JAMA. 286:2099-2106, 2001 3 – Gladwin et al. JAMA. 305:893-902, 2011



• Second level

- Third level

- Fourth level

- Fifth level

The Need for Phase III

Variability of response – (large 95% CI) • Duration of VOC

- GMI-1070 – 70 hrs, 95% CI 44-116 - Placebo – 133 hrs, 95% CI 67-164

Potential differences between groups (peds & adult)

• Hydroxyurea usage - 51% - GMI-1070 - 70% - Placebo

• Daily pain meds - 42% - GMI-1070 - 58% - Placebo

P = 0.187

Ongoing & Planned Studies for VOC Study or Agent Mechanism Age Phase Location Primary Outcome Status

Rivipansel (aka GMI-1070)

Selectin Inhibition Children & Adults

III Multi-center ? Late 2014

IVIG Decreased RBC & neutrophil adhesion

12 – 65 yrs I/II Albert Einstein

Time to resolution of VOC

Enrolling

MST-188 (Poloxamer)

Rheologic agent 4 – 65 yrs III Multi-center Time to resolution of VOC

Enrolling

Abciximab Glycoprotein IIb/IIIa receptor antagonist

5 – 25 yrs I St. Louis Univ.

Duration of hospitalization

Enrolling

Intranasal Fentanyl

Opioid pain agent 3 – 21 yrs N/A Montefiore Pain score 20 min after intervention

Enrolling

Mag Sulfate RBC hydration 4 – 21 yrs III Multi-center Duration of hospitalization

Enrollment Completed

Regional Analgesia

Femoral nerve block > 18 yrs N/A Mount Sinai Pain score 2-4 hrs after intervention

Enrolling

Regadenoson Inhibition of iNKT function

10 – 70 yrs II Multi-center iNKT cell reduction

Enrolling

Gabapentin Neuropathic pain agent

1 – 20 yrs N/A St. Jude 33% reduction in pain score at 3 hrs

Enrolling

As per clinicaltrials.gov on 3/28/14



• Second level

- Third level

- Fourth level

- Fifth level

Conclusions Use of GMI-1070 during VOC improved multiple outcomes:

• Time to resolution

• Length of hospital stay

Improvements were seen in every efficacy endpoint explored and across every subgroup

evaluated.

GMI-1070 had a benign safety profile.

Pediatric and adult subjects differed:

• analgesia agents and usage

• antibiotic usage

• PRBC administration in VOC treatment

These results support phase III clinical trial of Rivipansel (formerly GMI-1070) for VOC.



• Second level

- Third level

- Fourth level

- Fifth level

Acknowledgements

GlycoMimetics • Helen Thackray, M.D.

• Lauren Berning

• Mark Crisanti (INC)

• Henry Flanner

• Kristen Hahn

• Martina Hemmer

• LaTonya Hendricks

• Maria Lempicki

• Christine Kolata Nietubicz

• Shanti Rodriguez

Investigators and Research Staff M. Telen – Lead Investigator (also at Duke) O. Alvarez, T. Hustace, University of Miami Miller School of Medicine B. Andemariam, M. Parente, University of Connecticut Health Center R. Bellevue, E. Colon, New York Methodist Hospital L. De Castro, J. Jonassaint, Duke University Medical Center C. Driscoll, C. Bell, Children’s Hospital at Montefiore V. Gordeuk, L. Krauz, M. Girotti, University of Illinois at Chicago W. Hagar, M. Macarewich, S. Murphy, Alta Bates Summit Medical Center/Children’s Hospital at Oakland K. Hassell, J. McAfee, University of Colorado Denver Health Sciences Center T. Howard, L. Eskridge, J. Dumas, University of AL, Birmingham L. Hsu, J. Handy, Children’s National Medical Center L. Krishnamurti, M. Byrne, K. Stiegler, D. Ross, Children’s Hospital of Pittsburgh of UPMC A. Kutlar, L. Wells, L. Bowman, N. Barrett, Georgia Health Sciences University S. Lanzkron, C. Williams, Johns Hopkins School of Medicine L. McMahon, A. Akinbami, Boston University Medical Center I. Odame, M. Merelles-Pulcini, The Hospital for Sick Children C. Quinn, K. Thueneman, Cincinnati Children’s Hospital Medical Center M.G. Smith, G. Thomas, University of Mississippi Medical Center W. Smith, M. Madu, Virginia Commonwealth University Medical Center K. Smith-Whitley, H. Enninful-Eghan, The Children’s Hospital of Philadelphia P. Swerdlow, K. Kaulaskar, Karmanos Cancer Institute T. Wun, M. Garcia, D. Tsai, University of CA Davis Medical Center

This study was supported by GlycoMimetics, Inc.

From UT Southwestern: Michael Henson, CRA Ruth Merryman, PharmD Leah Adix, CRA Zora Rogers, MD George Buchanan, MD Janna Journeycake, MD Jonathan Wickiser, MD Martha Stegner, MD



• Second level

- Third level

- Fourth level

- Fifth level

Save the Date: May 5-9, 2015

28th Annual Meeting

Phoenix, AZ

treating the pain with gmi-1070 - home -...

Documents