Early Phase Development and Population PK and Its Value

Navigating the Transition from Animal to Man

CAPT E. Dennis Bashaw, Pharm.D. Dir. Division of Clinical Pharmacology-3

Office of Clinical PharmacologyOffice of Translational Sciences

US Food and Drug Administration

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Disclaimer

• The presentation should not be considered, in whole or in part as beingstatements of policy or recommendation by the United States Government orthe US Food and Drug Administration.

• Throughout the presentation representative products or organizations may beused as examples to emphasize a point, no endorsement is either intended orimplied.

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Outline

•Attrition in Drug Development–What is it really?

•Approaches For Dose Selection–General Approaches

•The High Risk Trial-General Procedures

•A Tale of Two Programs–TGN-1412

–BIA 10-2474

•Risk Recognition and Management

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ATTRITION IN DRUG DEVELOPMENT

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The US Drug Development Process

Nature Reviews and Drug Discovery, 2003, Volume 2, Page 71

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Lengthy Process to Reach Market

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Updated Drug Development Cost Figures

J Health Econ. 2016 May;47:20-33. doi: 10.1016/j.jhealeco.2016.01.012

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The Cost of Research vs Ease of Conduct

High

Low

Single Center Randomized Trials

Low

Single Case

Reports

Cohort Studies

Case-Control Studies

Case Series

HighEase of conduct

Multi-Center Randomized Trials

Cost

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Industry Reported Success Rates 2007-2011

https://speakingofresearch.files.wordpress.com/2013/01/drug-development-92-animal-tests.jpg

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Reasons for Lack of Success in Drug Discovery

Lack of fundamental knowledge regarding the causes of CNS disorders

Absence of biomarkers for diagnosing and monitoring these conditions

A paucity of animal models that are congruent with the human disease state

The likelihood that CNS conditions are multifactorial in their etiology

These factors are true for most therapeutic areas.

They are also factors that we can IMPACT.

Williams, Michael & Enna, S J “Prospects for neurodegenerative and psychiatric disorder drug discovery” Expert Opin. Drug Discov. (2011) 6(5):457-463

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Work Streams for First-in-Human (FIH)Study Design

Risk Assessment

Preclinical Safety Evaluation

Biomarker Development

ResearchPharmacology

PK/PDModeling

First-in-Human

Study Design

Adapted from “Gibbs, JP-, “Prediction of Exposure–Response Relationships to Support First-in-Human Study Design”, The AAPS Journal, Vol. 12, No. 4, December 2010, pg 750-758

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APPROACHES TO DOSE SELECTION

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General Approaches to Starting Dose Selection

• Classic approach: NOAEL/safety factor (≥10)–Usually derived from doses rather than exposures (i.e., NOEL, PAD)

• the safety factor can be increased (>10) when there is a high level of concernfor the observed toxicity in the animal species (e.g., a steep dose-responsecurve for the appearance of severe toxicity or death in animals)

• the safety factor can be decreased (<10) when there is a low level of concernfor the identified toxicity in animals (e.g., mild adverse effects that can bemonitored and/or were shown to be reversible).

• Allometric Methods–Human equivalent dose (HED) based on animal NOAELs

• NOAEL-HED Approach–Combine NOAELs with HED and a safety Factor.

Guidance for industry and reviewers: Estimating the safe starting dose in clinical trials for therapeutics in adult healthy volunteers, July 2005, http://www.fda.gov/CDER/guidance/5541fnl.pdf

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Definitions and their Relationship

• NOAEL – no observed adverse effect level,

• PAD – pharmacologically active dose,

• MABEL – minimum anticipated/acceptable biological effect level,

• HED – human equivalent dose, AUC – area under the concentration-time curve,

• Cmax – maximum concentration,

• MRSD – maximum recommended starting dose.

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ICH Guidance on Approaches to Selection

• The selection of the starting dose for healthyvolunteers is often based on the NOAELdetermined in pivotal toxicology studies.–ICH Guidance M3(R2), “Nonclinical Safety Studies for the Conduct of

Human Clinical Trials and Marketing Authorization forPharmaceuticals

• Normally, two species prior to and during the clinical testing ofinvestigational products.

• In some cases, toxicity testing in a single species can be justified, especiallyfor biotechnology-derived products (ICH Guidance S6(R1), Preclinical SafetyEvaluation of Biotechnology-Derived Pharmaceuticals).

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FDA Guidance

• The FDA guidance on safe starting dose selection inhealthy volunteers provides an algorithm fordetermining the MRSD (maximum recommendedstarting dose). This algorithm includes the selection of amost appropriate species for determining the MRSD.

http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf

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Guidance Algorithm

The provided algorithm is a “GUIDANCE”, clinical judgement must be used at all times in selecting starting doses for patient safety

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THE HIGH RISK TRIAL-GENERAL PROCEDURES

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In general, the higher the potential risk associated with an investigational medicinalproduct (IMP) and its pharmacological target, the greater the precautionary measures thatshould be exercised in the design of the first-in-human study. The protocol should describethe strategy for managing risk including a specific plan to monitor for and manage likelyadverse events or adverse reactions as well as the procedures and responsibilities formodifying or stopping the trial if necessary. The sponsor should arrange for peer review ofthe protocol and the associated risk factors and to assure that they have been properlyconsidered and planned for.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002988.pdf

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MABEL Approach

• Recommended for high-risk, first-in-man trials

–Usually done in patients where risk tolerance is different and in whom the prospect of therapeutic benefit must be considered

• Minimal Anticipated Biological Effect Level (MABEL)

–Based on all RELEVANT in-vitro and in-vivo PK/PD data including•Receptor binding studies

•Concentration/response data

• Exposure at pharmacologic doses in a relevant animal model/species

–Starting Dose=MABEL dose/Safety Factor• If NOAEL-HED dose is lower, use this dose instead

•Patient Safety is always a concern

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Characteristics of a Starting Dose

• A Safe Starting Dose

–Does not cause any clinical measurable effects

•no pharmacodynamic effects

•nor toxic effects

•dose prior MED / PAD (minimal effective dose, pharmacologically active dose)

–The next higher dose causes first pharmacological effects (if detectable in healthy volunteers) without toxic effects

•MED

Log Dose

Effe

ct

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General Procedures

• Cohort Size

– Larger cohorts allow for better estimates and earlier refinement of escalation strategy

– Larger cohorts put more subjects at risk and increase the costs of clinical development programmes

–Common standard is an A + P design

• A = 6 to 10 subjects on active therapy

• P = 2 to 4 subjects receiving placebo

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General Procedures

• Dose Escalation-Relevant factors

–Steepness of the slope of dose/effect and dose/toxicity relationship

•Greatly affected by cohort size

–Therapeutic range in non-clinical models

–Predictability of the effects of the next dose step

–Potential pharmacodynamic effects (if any)

–Potential toxic effects

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Dosing in High-Risk Trials

• Initial sequential dose administration design within each cohort

• Adequate period of observation between the administration of each subject depending on estimated PK and PD data

• Before administration of the next cohort all results from all subjects of the subsequent cohort(s) must be reviewed

• PK and PD data from the previous cohorts should be compared to known non-clinical PK, PD and safety information

• Patient Safety is always a concern

• Stopping rules must be clear and unambiguous

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A TALE OF TWO PROGRAMS

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TGN1412

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TGN1412

TGN1412 was developed as a therapeutic agent for variousdiseases in which T cells are involved in the pathogenesis ofchronic inflammation or hematological malignancies such asleukemia.

TGN1412 was genetically engineered by transfer of thecomplementarity determining regions (CDRs) from a monoclonalmouse anti-human CD28 antibody into human heavy and lightchain variable region frameworks. These variable regions weresubsequently recombined with a human gene coding for the IgG4chain.

–The human constant domain and variable domain framework structures wereexpected to confer decreased immunogenicity and an optimum of antibodyeffector functioning within the human immune system.

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Clinical Trial Chronology

• TeGenero “first in human” (FIH) study of TGN1412–Direct immune stimulation

• Trial initiated March 13, 2006• Four single doses of 0.1, 0.5, 2.0 and 5.0 mg/kg planned

in 4 groups of 8 subjects • 1st cohort: –0.1 mg/kg IV at 2 mg/min to 6 subjects in the course of one

hour (i.e., one subject dosed every 10 minutes)–Placebo: 2 subjects

G. Suntharalingam, et al., “Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412” NEJM, 355;10, pg 1018-1028

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Clinical Course

• Within 90 min dosing–Severe headache, lumbar myalgia, pyrexia, rigors–Nausea, vomiting, diarrhea–Amnestic episodes, restlessness–Erythema, desquamation–Peripheral vasodilation, hypotension, tachycardia

• Subjects/patients admitted to ICU 12-16 hours after dosing–Multisystem failure–Metabolic acidosis, Disseminated Intravascular Coagulation–Respiratory failure, bilateral infiltrates

• Cytokine storm–Lymphopenia, monocytopenia–↑ ↑ TNF α–↑ IL-2, IL-6, IL-10–↑ IFN-γ

G. Suntharalingam, et al., “Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412” NEJM, 355;10, pg 1018-1028

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Therapy

• Aggressive supportive management–Steroids

–Daclizumab (anti-IL2 receptor antagonist)

–Pulmonary support, dialysis, fresh frozen plasma

–Irradiated cells to decrease GVHD

EXPERT SCIENTIFIC GROUP ON PHASE ONE CLINICAL TRIALS, www.tsoshop.co.uk

Time Course of Immunologic Effects

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Follow-up at 30 days

• 4 patients better after 48 hours

• 1 has gangrenous digits

• 5 with late myalgia, HA, difficulty concentrating, short-term word-finding problems

• 3 with delayed hyperalgesia

• 2 with peripheral numbness

G. Suntharalingam, et al., “Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412” NEJM, 355;10, pg 1018-1028

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TGN1412-What Went Wrong?Animal-Human Pharmacology

• Potential differences between humans andmonkeys CD28 structure difference in three

transmembrane residues CD28SA binding kinetics and calcium

response (sustained in humans) Immunological Synapse (IS) formation

involving CD28 crosslinking Greater T-cell adhesion to endothelial

cells in humans Greater immunoregulation in animals

Hansel, T., et al, “The Safety and Side Effects of Monoclonal Antibodies”, Nature Reviews Drug Discovery, 2010 Apr; 9(4): 325-38

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TGN1412-What Went Wrong?Animal-Human Pharmacology

Summary of in vitro activation and proliferation responses of human and Cynomolgus macaque lymphocytes to immobilized TGN1412

EXPERT SCIENTIFIC GROUP ON PHASE ONE CLINICAL TRIALS, www.tsoshop.co.uk

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TGN1412-What Went Wrong?Receptor Dynamics & Occupancy

TGN1412Anti-CD28 mAb

CD28T-Cell membrane

TGN1412:CD28Complex

Kd = 1.88 nM

0.1 mg/kg IV at 2 mg/minMW= 150,000 DaltonsPlasma Volume= 2.5L

18.7 nM post-dosing

Using Standard Blood Values

T-cells 1.9x106 mL-1

CD28 receptors per cell ~150,000

CD28 ~ 0.95nM

0.86 nM at Equilibrium

0.86/0.95 = 90.5% Occupancy!

EXPERT SCIENTIFIC GROUP ON PHASE ONE CLINICAL TRIALS, www.tsoshop.co.uk

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General Information Flow for Determining a FIH Dose: TGN1412

Tibbits J., et al, “Practical approaches to dose selection for first-in-human clinical trials with novel biopharmaceuticals” Regulatory Toxicology and Pharmacology, Volume 58, Issue 2, 2010, 243 - 251

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BIA 10-2474

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BIA 10-2474

*By Roadster29 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=46531418

BIA 10-2474 is an experimental fatty acid amide hydrolase inhibitor developed by the Portuguese pharmaceutical company Bial-Portela & Ca. SA. It interacts with the human endocannabinoid system. A Phase I trial incorporating single dose, multiple dose, and a food effect study was underway in Rennes, France, in January 2016, in which serious adverse events occurred affecting five participants, including the death of one man.

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Trial Design

J Pharmacol Pharmacother. 2016 Jul-Sep; 7(3): 120–126. doi: 10.4103/0976-500X.189661

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What Happened?Minutes of the Temporary Specialist Scientific Committee (TSSC)

meeting on "FAAH(Fatty AcidAmideHydrolase) Inhibitors”15 February 2016.

FULL REPORT (28 pages)http://ansm.sante.fr/var/ansm_site/storage/original/application/744c7c6daf96b141bc9509e2f85c227e.pdf

MINUTES/SUMMARY (14 pages)http://ansm.sante.fr/content/download/86439/1089765/version/1/file/CR_CSST- FAAH_15-02-2016_Version-Anglaise.pdf

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RISK RECOGNITION AND MANAGEMENT

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EMA First-in-Human Study GuidelineRevised July 25, 2017

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC500232186.pdf

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EMA First-in-Human Study GuidelineRevised July 25, 2017

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Risk

• Drug Development is an inherently riskybusiness

• Attrition at each stage of the program isdue to a combination of factors

• EARLY attrition is preferred over lateattrition due to the associated financialand “opportunity” cost

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Risk Tolerance Evolves

Lack of Appropriate Head Gear

Lack of Protective Clothing No Safety

Rigging

Hard HatsSafety Rigging

High VisibilityClothing

RCA Building-1932 Heron Tower in central London-2011

Bottle of Whisky

Milk Tea?

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Patrick Muller and Mark Milton, “The Determination and Interpretation of the Therapeutic Index in Drug Development” Nature Reviews Drug Discovery,2012, vol. 11, pg 751-751

TGN 1412

Modified from:

Idealized Efficacy and Safety vs. TGN1412 and BIA 10-2474

BIA 10-2474

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Post-TGN1412And BIA 10-2474

• The events surrounding both drugs has been a wake-up call tothe drug development industry to the recognition that weneeded to re-examine both our processes and our tools.

• We need to pay more attention to the use of in vitro bindingand inhibition assays

• We need to take the “world view” of information and not viewdisparate data sets separately

• As we use more and more targeted therapies, we must neverrelax our dedication to safety, but by the same token neverallow us to have “paralysis of will” in determining reasonablerisk.

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Confluence of Decision-making in FIH

Understanding

of Disease

How well do we truly understand the underlying biological

system?

Risk Tolerance

Given the potential benefit what level of risk are we willing to

consider

Animal Data

MABEL, HED, NOAEL,PAD,

FIH Dose

SelectionBest Proposed Dose

Population PKModeling

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Development of Safe and Effective Drugs Requires a Team Effort

Academia

IndustryInternational

Collaboration

Patient

AdvocacyRegulators

Benefits

To All

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As drugs become more potent wemust all work to properly• Assess the risk to the patient• Monitor the patient appropriately• Review our tools to make sure

they are up to date and “best inclass”

• Identify potential weaknesses inour programs

• Control the flow of the studyaccording to the protocol

• Mitigate in a real-time activemanner any unforeseen adverseevents

Elements of a Risk Mitigation Planning Process

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Closing ThoughtRisk Mitigation via Sherlock Holmes

“…If you should find yourself in doubt or in danger --"

"Danger! What danger do you foresee?"

Holmes shook his head gravely. "It would cease to be a danger if we could define it," said he.

The Adventure of the Copper Beeches

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Contact Information

CAPT Edward D. Bashaw, PharmD.Director, Div. of Clinical Pharmacology -3US FDA10903 New Hampshire AveBuilding 51, Rm 3134Edward.Bashaw@fda.hhs.gov

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Acknowledgements• The Staff of the Division of Clinical Pharmacology-3

• The Office of Clinical Pharmacology

• The Office of Translational Sciences

• Hazem E. Hassan, PHD, MS, RPH, RCDS and the other organizers of this meeting