The Basics of Drug Development Science - Nothing to be scared of! Or Which Way to the Clinic?

1. The Basics of Drug Development Science - Nothing to be scared of!OrWhich Way to the Clinic? IRMA Webinar September 28, 2010 Jim A. Turpin, Ph. D. Preclinical Team Leader Topical Microbicide Branch Prevention Science Program NIAID, Division of AIDS,

2. DHHS/NIH Required Disclaimer The views expressed are those of the presenter and do not necessarily reflect the official policies of the Department of Health and Human Services (HHS), nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government DHHS/NIH/NIAID/DAIDS

3. Today's talk Touch on the following : What is drug development? Basic Science behind drug development Will use prevention and microbicides as a context for discussion Everything I say can be applied to other drug development efforts with appropriate modifications A complex process but will take the 20,000 ft view DHHS/NIH/NIAID/DAIDS

4. Definition Lead or Candidate A compound or proposed new chemical entity (NCE) with properties or characteristics that make it appropriate for further development The terms can be applied interchangeably to any stage of the drug development process Emphasize that a selection (elimination) has occurred DHHS/NIH/NIAID/DAIDS

5. In a Nutshell What is drug development? • Identifying candidates/leads for clinical testing that will improve health or meet a medical need • To accomplish this we must integrate and balance: • Scientific knowledge • FDA Requirements DHHS/NIH/NIAID/DAIDS

6. Drug Development: Opposing Forces 1 or 2 100,000 To 1,000,000 Number of Compounds I II III Preclinical Studies (Critical Path) Preclinical Virology Deployment Clinical Studies Discovery $.01 to $1.00 Cost of Development Per Compound $ millions DHHS/NIH/NIAID/DAIDS

7. Drug Development : Thy Name is Attrition FACTOIDS Average time from Discovery to Phase III trials : 12 years Probabilities of Success Discovery to Clinical Testing: ~11 % Initial lead identification, i.e. screen random library Chances of success ~ 1: 10,000 that a compound will go to clinical testing Can raise to 1:100 to 1:1000 if working on a series of compounds Clinical testing: 38% drop out in Phase I 60% percent drop out in Phase II 40% fail in Phase III Of successful Phase III candidates only 23% are approved as drugs by the FDA DHHS/NIH/NIAID/DAIDS

8. Where Do We Lose Candidates/Leads? Ismail Kola & John Landis Nature Reviews Drug Discovery 3, 711-716 (August 2004) DHHS/NIH/NIAID/DAIDS

9. Drug Development and the Pipeline Concept Everyone talks about pipelines --- Adjectives galore: robust, vibrant, sustainable A pipeline is a way to describe and conceptualize a drug development process involving many candidates/leads DHHS/NIH/NIAID/DAIDS

10. Pipelines are Defined by Their Goal Microbicides as the Example • Must protect healthy and HIV infected men and women when used vaginally, penile and/or rectally without harm • Harm= any effect that increases infection susceptibility or changes disease course for the worse, directly or indirectly May be used episodically or continually by individuals for decades Drug development strategy is used to identify suitable compounds to meet the above requirements proactively and efficiently tocreate a sustainable effort that: Generates new candidates/leads Eliminates the unsuitable DHHS/NIH/NIAID/DAIDS

11. The Drug Development Pipeline Example: Microbicide Development Pilot Studies Preclinical Studies (Critical Path) I III II Preclinical Virology Deployment Discovery Clinical Studies Product recycled In Pipeline Product Recycled Into Discovery Successful Microbicide Or Microbicide Strategy LEAD Lead Identification And Optimization Drug Development Multiple activities driven by Milestones that may occur sequentially or simultaneously Product Eliminated DHHS/NIH/NIAID/DAIDS

12. Preclinical Virology Formulation Pre/generic Formulation Optimized Formulation Manufacturing Analytical Method Development GMP Production Clinical Batches Pre Clinical Studies (Acute Toxicology etc.) Additional Toxicity studies (Chronic Toc. , Repo. Etc.) Pre IND /IND Clinical Trial Activities Protocol Development Phase I Phase II Phase III Intermediate GO/NO-GO Decisions GO/NO GO Decisions S Gantt Charts—A Tool of Industry 1 Years 4 5 6 7 8 9 10 2 3 Discovery S S S S S S S S S DHHS/NIH/NIAID/DAIDS

13. Drug Development and Pipelines are not Uni-Dimensional Primary Path Lead Expansion Path Targeted Expansion Path New Target Time Library of Compounds >100,000 to 1,000,000 Successful Failure Discovery Iterative Screen Library of Compounds >100,000 to 1,000,000 1000 100 New Limited Synthesis 10 1000 Lead(s) 100 Toxicology 100 10 Lead(s) Pharmacology Preclinical 10 Formulation Toxicology 10 Lead(s) Pharmacology Lead(s) Manufacturing Toxicology Lead(s) Formulation Toxicology Pharmacology Phase I Toxicology Pharmacology Manufacturing Phase II Formulation Clinical Pharmacology Formulation Phase III Phase I Manufacturing X Phase IV Manufacturing Phase II Phase I Phase III Product Phase I Phase II Phase IV Phase II Phase III Phase III Product Phase IV Phase IV Product Product DHHS/NIH/NIAID/DAIDS

14. The Challenge of the Basic Science of Drug Development is Finding the right needle in the right hay stack And once it is found confirming the needle you found is the one you were looking for Doing all of this in sustainable fashion DHHS/NIH/NIAID/DAIDS

15. The Foundation of Drug Development is: Scientific knowledge We must understand the disease to be able to find candidates/leads to prevent or treat it DHHS/NIH/NIAID/DAIDS

16. HIV drug development has to account for: What we do not know In HIV Infection • What form of the virus infects? • Cell –free • Cell-associated • Both • How does virus get to its target cells? • Micro-trauma • Translocation • Permeation • Cell capture • What is the first cell infected? DHHS/NIH/NIAID/DAIDS

17. HIV drug development must also account for: What we think we know The data, models and observations we use to describe the process of HIV transmission and infection are subject to change as we learn more DHHS/NIH/NIAID/DAIDS

18. Multi-Spliced Singly Spliced Un spliced HIV Replication Cycle and Prevention Targets Other Membrane targets Rafts, lipids, etc. Entry X APOBEC 3G Trim 5a Coreceptor Reverse Transcription X X Integrase Attachment RNA Integration X Translation Transcription X Protease Genomic RNA Pr 160 gag/pol Pr55gag Infectivity gp120/gp41 gp160 Immature Virion DHHS/NIH/NIAID/DAIDS

19. Target Tissues Female Genital Tract GI Tract Uterus Cervix Rectum Anus Vagina Transition Zone Colon Transition Zone Introitus Endocervix Ectocervix DHHS/NIH/NIAID/DAIDS

20. Duration of Effectiveness? Microbicides Point of no return? Haase Nature Reviews 2010 464:217 DHHS/NIH/NIAID/DAIDS

21. Complex Microenvironment • Mucous • pH • Osmolarity • Microbiota • Innate defenses • Target cell activation • Distribution and coverage Hendrix et al. Ann,. Rev. Pharmacol. Toxicol. 2009 49:349 DHHS/NIH/NIAID/DAIDS

22. How do we decide what testing to do? DHHS/NIH/NIAID/DAIDS

23. First must ask: What Are the Optimal “Drug” Characteristics of a Candidate/Lead? • Ultimately driven by regulatory requirements to conduct clinical trials • FDA enforces regulations and provides guidance • No FDA guidance specific to microbicides • Most relevant FDA preclinical guidance is for antivirals: • Guidance for Industry Antiviral Product Development • http://www.fda.gov/OHRMS/DOCKETS/98fr/05d-0183-gdl0002-01.pdf • The needed properties can be divided into 4 general categories • 1. Safety 3. Acceptability • 2. Efficacy 4. Feasibility/Delivery DHHS/NIH/NIAID/DAIDS

24. Selected Properties of an Ideal Topical Microbicide (FDA guidance) • low in vitro toxicity and no systemic toxicity • Efficacy, In vitro --- In vivo (?) • Easily formulated and stable under likely storage conditions • Active in semen/seminal, cervicovaginal and rectal secretions • Low systemic uptake • GMP and industrial scale production compatible • Lack of effect on the microbiota: Lactobaclli • Compatible with rectal use • Acceptable to user • Color, odor and taste compatible • Overall ease of use- negotiable • Does not negatively impact intercourse • Compatible with condoms and other mechanical barriers Safety Efficacy Acceptability Feasibility/Delivery DHHS/NIH/NIAID/DAIDS

25. How do you Guidance into Drug Development? The Role of the Algorithm Algorithm: A set of rules or steps that results in achieving the right answer in the shortest period of time • Algorithms and the Basic Science of Drug Development • Use best assays to pick the best candidates/leads • Basic Science driven • May include approaches to address gaps in knowledge • In Prevention---everyone has one • Tailored to the objectives and goals of the individual drug development program DHHS/NIH/NIAID/DAIDS

26. Finding Candidates/Leads: NIAID Screening Algorithm Objective: Proof-of –feasibility as a proposed microbicide candidate DHHS/NIH/NIAID/DAIDS Antimicrob Agents Chemother. 2008 52:1768-81.

27. Algorithms Addressing FDA Requirements CONRAD Algorithm IPM Algorithm Courtesy of Gustavo Doncel Courtesy of Joe Romano DHHS/NIH/NIAID/DAIDS

28. Common Themes? Safety and Activity • Safety- In vitro cytotoxicity • Activity---Efficacy • Effect in Ex Vivo Tissue Model (Explants)--Safety and Efficacy • Animal Model--Efficacy • FDA required testing—Safety (Critical Path) DHHS/NIH/NIAID/DAIDS

29. Lets Develop a Microbicide Candidate! UC781 NNRTI Tenofovir (TFV, PMPA) NRTI Dapivirine (TMC120) NNRTI Maraviroc CCR5 VivaGel™ (SPL7013) Entry DHHS/NIH/NIAID/DAIDS

30. Microbicide Candidate? • Safety- In vitro Cytotoxicity • Safety = cytotoxicity--Usually determined simultaneously with efficacy • General guidelines (any cytotoxicity is a concern) • No toxicity Cell lines, Primary cells, i.e. PBMCs • No toxicity on genital and GI epithelial cells • No toxicity to endogenous H2O2 producing Lactobacilli DHHS/NIH/NIAID/DAIDS

31. Microbicide Candidate? • Activity in: • General anti-HIV activity • Is the mechanism of action compatible with microbicide use? • Effect of: • Cervical mucous/secretions and/or GI and secretions • Semen/Seminal fluid • Environmental pH • Inhibits multiple HIV clades/subtypes of virus • Resistance • How quickly generate • Effect on antiviral activity • Cross Resistance • Severity • Combinations with other candidates or drugs DHHS/NIH/NIAID

32. Microbicide Candidate? • Effect in Ex Vivo Tissue Model • First chance for tissue exposure to unformulated or formulated microbicide • Toxicity • Metabolic viability—MTT assay • Histology • Activity • Inhibition of HIV replication Tissue on support matrix Microbicide Virus Wash DHHS/NIH/NIAID/DAIDS

33. Microbicide Candidate? • Animal model testing (efficacy) • Humanized mice • NHP • Role of efficacy • Researcher--argument for “Biological Plausibility” • FDA--optional but preferred to be active DHHS/NIH/NIAID/DAIDS

34. Microbicide Candidate? SAFETY: The Critical Path Studies required by FDA International Conference on Harmonization (ICH) guidance are also used Goal of the Critical Path: Prepare for testing in humans by looking for any issues that will affect safety and/or feasibility DHHS/NIH/NIAID/DAIDS

35. PK and Toxicology GLP Systemic Absorbance? iVag. or iR. . No Yes • Genotoxicity • Acute Toxicity • Maximum tolerated dose (MTD) • Chronic Toxicity, 90+ days • PK and Metabolites (ADME) • Carcinogenesis • Reproductive toxicology • Seg. I Reproductive performance • Seg. II Teratology • Seg. III Perinatal/Post natal • Dermal/systemic Hypersensitivity • Dermal/ systemic Photosensitivity • Others, if applicable-Lung, CNS, Heart etc. Critical Path: Translation from Preclinical to Clinical Testing? Preclinical Studies • Microbicide Specific • Lab • Condom Compatibility GLP • Effect on Lactobacilli • Effect of Matrices • Seminal Plasma • Cervical fluid • Mucin • Other STIs • Cervical Explants • NHP iVag transmission • Animal GLP • Rabbit Vaginal/Rectal Irritation testing • Systemic Absorption by iVag or iR. • Penile Irritation • General Preclinical Virology • Antiviral activity • Toxicity Cell lines/Primary cells • Range of Action--Subtypes • Mechanism of Action • Resistance • Combination • Relevant Matrices • Preformulation • ↓GLP • Formulation • Stability • Sterility • Release Chemistry Manufacturing and Control (CMC) GMP UnformulatedFormulated Active Pharmaceutical Gel or Ring Ingredient (API) Stability, Sterility, Purity, Packaging Must be carried out in accordance with the CFR for GLP and GMP studies ApplicatorGMP Selection Compatibility Acceptability Filling DHHS/NIH/NIAID/DAIDS

36. Take Home Messages • Drug development is a process • The process is controlled by multiple factors • FDA regulations and guidances • Basic science of HIV infection • Evolving knowledge of what might work • The basic science of drug development is a process to select the candidate(s) with the best chance of success DHHS/NIH/NIAID/DAIDS

37. AND FINALLY: • Jim Turpin’s slightly twisted final thoughts on the • Basic Science of Drug Development • A challenge --not for the faint-hearted • Must embrace the Zen of Candidate Reduction • It is never too early or late to eliminate a candidate • and if you do-- kill it dead---put a stake through its heart, and bury it at midnight at a crossroads –No Regrets Allowed • The process is ever evolving—flexibility of mind is good! • Seems complicated but the roadmap is there, just gotta follow it • Sometimes its one of the most rewarding things you can do because it can change the world DHHS/NIH/NIAID/DAIDS

38. Thank You Questions? Timbuk3 –The future is so bright I gotta wear shades! DHHS/NIH/NIAID/DAIDS