Preclinical Development of Microbicides How the Most Promising Products Advance to Clinical Trial Evaluation

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1 Preclinical Development of Microbicides How the Most Promising Products Advance to Clinical Trial Evaluation Roberta Black, Ph.D. Microbicide Research Branch Division of AID, National Institute of Allergy and Infectious Diseases NIH/DHH

2 Outline Purpose of preclinical microbicide development Conceptual view of the process Overview of the elements of preclinical drug development PRO 2000

3 Microbicide Preclinical Development Purpose To predict how a microbicide will behave in humans before clinical testing To ensure that the estimated risk/benefit profile of a novel microbicide is reasonable for the proposed use Objective To rationally select the best product and eliminate failures quickly and early

4 Basic Biomedical Research gp41 gp120 V3 V1/2 Virus Define mechanisms of infection ite of infection Vaginal, ectocervical, endocervical mucosa Coreceptor Cell CD4 Rectal mucosa Infectious unit Identify targets for microbicide discovery Discover new microbicide candidates HIV targets TI targets Cellular/tissue targets

5 Discovery and the Product Development Pipeline Discovery Preclinical Virology Preclinical tudies (Critical Path) Pilot tudies I II III Clinical tudies Deployment Product Recycled Into Discovery Product recycled In Pipeline uccessful Microbicide Or Microbicide trategy LEAD Lead Identification And Product Pipeline Development Optimization Eliminated Multiple activities driven by Milestones that may occur sequentially or simultaneously

6 Phase I Development Path In vitro Activity Formulation Inhibits HIV transmission Inhibits other TD pathogens Inhibition of Virus Entry Lactobacillus ensitivity IND-Enabling tudies Product Characterization pectrum of Activity Further Mechanism of Action Rabbit Vaginal Irritation (RVI) cale up Genotoxicity Acute toxicity Repeat dose toxicity ADME tability/purity Condom Compatiblity Reproductive toxicology (eg. I Teratogenicity) GMP manufacture E-11 1 December 1999 Phase I Trials Male, Female Non-human Primate afety & Efficacy

7 What is needed for the Translation from Preclinical to Clinical? Preclinical Virology General Preclinical Virology Antiviral activity Toxicity Cell lines/primary cells Range of Action ubtypes Mechanism of Action Resistance Combination Preformulation GLP Formulation tability terility Homogeneity Purity Must be carried out in accordance with the CFR for GLP and GMP studies Preclinical tudies Microbicide pecific Lab Condom Compatibility GLP Effect on Lactobacilli Effect of Matrices eminal Plasma Cervical fluid Mucin Other TIs Cervical Explants Animal day Rabbit Vaginal Irritation (RVI) GLP Penile Irritation GLP NHP ivag transmission Chemistry Manufacturing and Controls (CMC) GMP Unformulated Formulated Drug Product gel, ring, film tability, terility, Packaging, torage Critical Path PK and Toxicology GLP ystemic Absorbance following ivag admin. Yes ivag AND systemic No ivag, +/ ystemic Maximum tolerated dose (MTD) Acute Toxicity Chronic Toxicity, 90+ days PK and Metabolites (ADME) General Genotoxicity Carcinogenesis Reproductive toxicology eg. I Reproductive performance eg. II Teratology eg. III Perinatal/Post natal Dermal/systemic Hypersensitivity Dermal/ systemic Photosensitivity Applicator GMP election Labeling Acceptability Filling

8 Plan for Microbicide Product Development 1 2 Years Feasibility Formulation Pre/generic Formulation Optimized Formulation Manufacturing Analytical Method Development GMP Production Clinical Batches Pre Clinical tudies (Acute Toxicology etc.) Additional Toxicity studies (Chronic Toc., Repo. Etc.) Pre IND /IND Clinical Trial Activities Protocol Development Phase I Phase II Phase III GO/NO GO Decisions Intermediate GO/NO GO Decisions

9 The Microbicide Development Pipeline 10, ,000 cndts Discovery Preclinical Virology Preclinical tudies (Critical Path) Pilot tudies I II III Clinical tudies Deployment Product Recycled Into Discovery Product recycled In Pipeline uccessful Microbicide Or Microbicide trategy LEAD Lead Identification And Optimization Product Eliminated Pipeline Development Multiple activities driven by Milestones that may occur sequentially or simultaneously

10 Conclusions Discovery research and preclinical development is an iterative, risky, complex task Microbicide preclinical selection algorithms are evolving processes, informed by clinical trial results and state-of-the-art understanding of HIV transmission. The goal is to identify the most promising candidates to advance while eliminating those candidates that are not optimal. To date, it is not possible to validate a microbicide-specific preclinical development path that is predictive for clinical efficacy and safety. Failure is a normal part of the process. There is a substantial body of data on safety and efficacy before any candidate advances to clinical testing.

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