Microbicide Products in the Pipeline

1. Microbicide Products in the Pipeline Regional Meeting on Regulatory Issues in Microbicide Research Dr. Zeda F. Rosenberg International Partnership for Microbicides 29 October 2007 New Delhi, India

2. Microbicides in Product Development Lactin-V Invisible Condom Free virus BufferGel Carraguard PRO2000 SPL7013 (VivaGel) Monoclonal antibodies DS003 (BMS) DS001 (Merck) DS006 (Maraviroc) Attachment Locus small molecules Fusion S-DABO Dapivirine (TMC120) UC781 Tenofovir (PMPA) PC815 (MIV150 + Carraguard) Pyrimidinediones (Samjin) Replication (RT) Integration Protein synthesis and assembly Budding Maturation

3. Microbicide Options • Multiple delivery types: – gel – intravaginal ring – film – tablet – sponge Vaginal applicator Vaginal ring • Ideally long acting, safe, effective, low cost and user-friendly • Potential for combinations of drugs to increase effectiveness

4. Rationale for Vaginal Dosing Local drug levels can be high and systemic exposure low Maximum drug:virus level Lower chance for systemic related side effects Precedent in contraception No one prevention option will satisfy all; multiple approaches available to address acceptability preferences Women-initiated

5. Early-Generation Microbicides • Non-specifically block HIV from interacting with target cells • Polyanions recently or currently in HIV efficacy trials (Carraguard, CS, PRO 2000, Buffergel) • Some polyanions are also acid-buffering agents • Partial, low or no effectiveness

6. Early Generation Microbicides • Advantages • inexpensive • broad activity • lack of systemic absorption • some are contraceptive • Disadvantages • reduced or no activity against R5 viruses • coitally dependent • may not be at the right place at the right time • activity reduced in seminal plasma

7. Next-Generation Anti-retroviral (ARV) Microbicides • Advantages • Highly potent and HIV-specific • Documented safety and efficacy as therapeutics • Can be formulated for sustained protection • Once a day or less frequent • Gels, intravaginal rings, others • Disadvantages • Potential for resistance • Lack of activity against other STDs

8. Topical Tenofovir • Nucleotide reverse transcriptase inhibitor • Viread marketed as a therapeutic • Preclinical development began in late 1990s • HPTN 050 Phase I Safety Study completed in US (NIH) • Well tolerated • Low serum levels in 56% of subjects • HPTN 059 Phase II Safety Study ongoing in US and India (NIH) • CONRAD PK study of 1% Tenofovir gel to determine systemic and local tissue levels – ongoing (IPM)

9. Topical Tenofovir (cont.) • CAPRISA 004 Phase IIb study began in May 2007 (USAID) • Dosing regimen: coitally +/- 12 hours • MTN 001 Comparison of once daily tenofovir oral and gel pK, adherence and acceptability in 120 women • Planned in Uganda, SA, and US • MTN 003 Phase IIb Vaginal Tenofovir and Oral Tenofovir and Truvada in 4200 women • Dosing regimen: once per day • Planned in SA, Malawi, Uganda, Zambia and Zimbabwe

10. TMC120 (Dapivirine): Background • NNRTI developed by Tibotec/J&J, licensed to IPM (2004) • Developed originally as therapeutic, 11 clinical studies conducted via oral administration • Highly potent ARV • Low cytotoxicity, non-mutagenic, non-teratogenic • Easily manufactured, cheap • Stable drug substance • IP clarity • Multiple dosage forms H C C H C N 3 3 N N N N C H H H 3

11. Dapivirine gel/ring: Clinical studies

12. UC-781 Background • Carboxanilide type of NNRTI • Potent anti-HIV-1 activity (nM range) • Tight binding to HIV-1 RT • Active against cell-free and cell-associated virus • Little to no cytotoxicity (>M) • Active against RT inhibitor resistant strains • Reduced likelihood for resistance selection • Exhibits so-called “Memory Effect” • Phase I safety study in 48 women completed

13. UC-781 Ongoing Studies

14. MIV-150 Background • PC-815, Carraguard plus MIV-150 (NNRTI) • Phase 1 crossover study (Dominican Republic, Profamilia) PC-815 and Carraguard • 20 women, 1 week single dose/day followed by 1 week twice dosing/day • Safety and pharmacokinetic for systemic absorption of MIV-150 • Planned start Nov 2007 • Phase I male tolerance, (South Africa, Setshaba Research Center) • Safety and pharmacokinetic for systemic absorption of MIV-150 • 10 circumcised and 10 uncircumised males • IRB approved; • Planned start following Phase I in women

15. HIV Entry HIV HIV gp120 Coreceptor Binding gp120 CD4 Binding HIV gp41 CD4 gp120 gp41 gp120 CCR5 CXCR4 CD4 gp120 Gp41 Mediated Fusion CCR5 CXCR4 gp41 Host Cell

16. HIV-Specific Entry/Fusion Inhibitors • Act on virus: gp120 or gp41 blockers • DS003 (BMS793), cyanovirin, FI peptides • Disadvantages • current gp41 blockers are peptides • Act on target cell: CCR5 blockers • DS001 (M167), Maraviroc, PSC-Rantes • Disadvantages • lack of activity against X4 virus

17. Next-Generation Product Development Tenofovir Gel Dapivirine Gel & Ring UC781 Gel MIV150 + Carraguard Gel Monoclonal antibodies DS001 (M167) DS001 (M167) + Dapivirine Dapivirine Tablet & Film S-DABO Pyrimidinediones DS003 (BMS793) Maraviroc Early Preclinical Preclinical Phase I/II Phase III Filing Approval 1-2 years 1-2 years 2+ years 3 years 1 year

18. Future Pipeline • New mechanisms of action • Integrase inhibitors • Small molecule fusion inhibitors ?? • Need to add back-up drugs to hedge against drop-out • Need to add better options • In late stage development or marketed therapeutic

19. Combination Microbicides • Advantages • potential increased efficacy against resistant virus • coverage of multiple transmission pathways • potential synergy and need for less drug • Disadvantages • unclear regulatory pathway • possible difficulties in co-formulation • possible increased cost • increased potential for toxicity • cross company/institutional agreements

20. Criteria for Moving Forward: Pre-Clinical • Compounds assessed to identify best candidates for clinic MECHANISMS OF ACTION • Earlier in life cycle is better • New mechanism of action • Comparison with other candidates with same mechanism of action LABORATORY STUDIES • Toxicity / Potency • Pre-formulation • Stability • BUSINESS CASE • IP access to compound • Cost • Drug synthesis process • Ease of manufacture

21. Criteria for Moving Forward: Early Clinical Trials • Candidates assessed in small numbers of volunteers PHARMACOKINETICS • Where drug goes in body, concentration, duration • Preferred dosage: • Wide distribution • in genital tract • Long duration • Sufficient concentration ACCEPTABILITY • Placebo formulations assessed in diverse populations • Acceptability measured in all clinical trials SAFETY • Drug, formulation, delivery assessed for prolonged use • Product safety evaluated in diverse populations • Early clinical trials cannot fully predict risk of enhancing HIV transmission

22. Criteria for Moving Forward: Efficacy Trials • Top candidates move into efficacy trials BEST-IN-CLASS Essential criteria: • Potency • Safety • PK • Acceptable formulation Secondary criteria: • Mechanism of action • Cost • Ease of manufacture • Access / IP

23. Will Microbicides Work? • Predicated on getting the RIGHT drug at the RIGHT levels in the RIGHT place at the RIGHT time • Right Drugs and Right Levels • Highly potent ARVs acting early in HIV lifecycle • Right Place and Right Time • Formulations to keep drug(s) in vaginal lumen and/or in tissue depending on drug’s MOA • Long acting sustained release

24. Drug Discovery, Development and Review Process Stage 4 Regulatory review Stage 1 Drug discovery Stage 2 Pre-clinical Stage 3 Clinical trials Phase I Phase II Phase III 250 compounds First clinical trial application submitted 1 approved drug 5 compounds 10,000 compounds Marketing application submitted 6.5 years 7 years 7 years 1.5 years Adapted from:Pharmaceutical Research and Manufacturers of America, 2006

25. Lessons Learned from HIV/AIDS Treatment 1981 1997 1987 2003 1983 1995 2002 2006 Three-drug therapy: HAART Brazil offers free universal access to treatment Drug combinations/ reducing pill burden “3 by 5” Initiative & PEPFAR launched First AIDS case reported in the US AZT mono-therapy approved for use 26 FDA-approved drugs and research continues HIV virus identified Global Fund established Two-drug therapy becomes available