Presentation Given at Regional AAPS DDDI Meeting in Baltimore. Similar to previous talks BUT updated to include a discussion of BIA 10-2474 and extended discussion of risk

1. 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 Pharmacology
Office of Translational Sciences
US Food and Drug Administration

2. 2
Disclaimer
• The presentation should not be considered, in whole or in part as being
statements of policy or recommendation by the United States Government or
the US Food and Drug Administration.
• Throughout the presentation representative products or organizations may be
used as examples to emphasize a point, no endorsement is either intended or
implied.

3. 3
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

4. 4
ATTRITION IN DRUG DEVELOPMENT

5. 5
The US Drug Development Process
Nature Reviews and Drug Discovery, 2003, Volume 2, Page 71

6. 6
Lengthy Process to Reach Market

7. 7
Updated Drug Development Cost Figures
J Health Econ. 2016 May;47:20-33. doi: 10.1016/j.jhealeco.2016.01.012

8. 8
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

9. 9
Industry Reported Success Rates
2007-2011
https://speakingofresearch.files.wordpress.com/2013/01/drug-development-92-animal-tests.jpg

10. 10
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

11. 11
Work Streams for First-in-Human (FIH)
Study Design
Risk Assessment
Preclinical Safety
Evaluation
Biomarker Development
Research
Pharmacology
PK/PD
Modeling
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

12. 12
APPROACHES TO DOSE SELECTION

13. 13
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 concern
for the observed toxicity in the animal species (e.g., a steep dose-response
curve for the appearance of severe toxicity or death in animals)
• the safety factor can be decreased (<10) when there is a low level of concern
for the identified toxicity in animals (e.g., mild adverse effects that can be
monitored 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

14. 14
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.

15. 15
ICH Guidance on Approaches to Selection
• The selection of the starting dose for healthy
volunteers is often based on the NOAEL
determined in pivotal toxicology studies.
–ICH Guidance M3(R2), “Nonclinical Safety Studies for the Conduct of
Human Clinical Trials and Marketing Authorization for
Pharmaceuticals
• Normally, two species prior to and during the clinical testing of
investigational products.
• In some cases, toxicity testing in a single species can be justified, especially
for biotechnology-derived products (ICH Guidance S6(R1), Preclinical Safety
Evaluation of Biotechnology-Derived Pharmaceuticals).

16. 16
FDA Guidance
• The FDA guidance on safe starting dose selection in
healthy volunteers provides an algorithm for
determining the MRSD (maximum recommended
starting dose). This algorithm includes the selection of a
most appropriate species for determining the MRSD.
http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf

17. 17
Guidance Algorithm
The provided algorithm is a “GUIDANCE”,
clinical judgement must be used at all
times in selecting starting doses for patient
safety

18. 18
THE HIGH RISK TRIAL-GENERAL PROCEDURES

19. 19
In general, the higher the potential risk associated with an investigational medicinal
product (IMP) and its pharmacological target, the greater the precautionary measures that
should be exercised in the design of the first-in-human study. The protocol should describe
the strategy for managing risk including a specific plan to monitor for and manage likely
adverse events or adverse reactions as well as the procedures and responsibilities for
modifying or stopping the trial if necessary. The sponsor should arrange for peer review of
the protocol and the associated risk factors and to assure that they have been properly
considered and planned for.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002988.pdf

20. 20
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

21. 21
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
Effect

22. 22
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

23. 23
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

24. 24
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

25. 25
A TALE OF TWO PROGRAMS

26. 26
TGN1412

27. 27
TGN1412
TGN1412 was developed as a therapeutic agent for various
diseases in which T cells are involved in the pathogenesis of
chronic inflammation or hematological malignancies such as
leukemia.
TGN1412 was genetically engineered by transfer of the
complementarity determining regions (CDRs) from a monoclonal
mouse anti-human CD28 antibody into human heavy and light
chain variable region frameworks. These variable regions were
subsequently recombined with a human gene coding for the IgG4
chain.
–The human constant domain and variable domain framework structures were
expected to confer decreased immunogenicity and an optimum of antibody
effector functioning within the human immune system.

28. 28
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

29. 29
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

30. 30
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

31. 31
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

32. 32
TGN1412-What Went Wrong?
Animal-Human Pharmacology
• Potential differences between humans and
monkeys
 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

33. 33
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

34. 34
TGN1412-What Went Wrong?
Receptor Dynamics & Occupancy
TGN1412
Anti-CD28 mAb
CD28
T-Cell membrane
TGN1412:CD28
Complex
Kd = 1.88 nM
0.1 mg/kg IV at 2 mg/min
MW= 150,000 Daltons
Plasma 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

35. 35
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

36. 36
BIA 10-2474

37. 37
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.

38. 38
Trial Design
J Pharmacol Pharmacother. 2016 Jul-Sep; 7(3): 120–126. doi: 10.4103/0976-500X.189661

39. 39
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

40. 40
RISK RECOGNITION AND
MANAGEMENT

41. 41
EMA First-in-Human Study Guideline
Revised July 25, 2017
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/07/WC500232186.pdf

42. 42
EMA First-in-Human Study Guideline
Revised July 25, 2017

43. 43
Risk
• Drug Development is an inherently risky
business
• Attrition at each stage of the program is
due to a combination of factors
• EARLY attrition is preferred over late
attrition due to the associated financial
and “opportunity” cost

44. 44
Risk Tolerance Evolves
Lack of Appropriate
Head Gear
Lack of Protective
Clothing No Safety
Rigging
Hard Hats
Safety Rigging
High Visibility
Clothing
RCA Building-1932 Heron Tower in central London-2011
Bottle of Whisky
Milk Tea?

45. 45
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

46. 46
Post-TGN1412
And BIA 10-2474
• The events surrounding both drugs has been a wake-up call to
the drug development industry to the recognition that we
needed to re-examine both our processes and our tools.
• We need to pay more attention to the use of in vitro binding
and inhibition assays
• We need to take the “world view” of information and not view
disparate data sets separately
• As we use more and more targeted therapies, we must never
relax our dedication to safety, but by the same token never
allow us to have “paralysis of will” in determining reasonable
risk.

47. 47
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
Selection
Best Proposed Dose
Population PK
Modeling

48. 48
Development of Safe and Effective
Drugs Requires a Team Effort
Academia
Industry
International
Collaboration
Patient
Advocacy
Regulators
Benefits
To All

49. 49
As drugs become more potent we
must 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 in
class”
• Identify potential weaknesses in
our programs
• Control the flow of the study
according to the protocol
• Mitigate in a real-time active
manner any unforeseen adverse
events
Elements of a Risk Mitigation
Planning Process

50. 50
Closing Thought
Risk 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

51. 51
Contact Information
CAPT Edward D. Bashaw, PharmD.
Director, Div. of Clinical Pharmacology -3
US FDA
10903 New Hampshire Ave
Building 51, Rm 3134
Edward.Bashaw@fda.hhs.gov

52. 52
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