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

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

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

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

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

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

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

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)

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

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 N CH 3 CH 3 H 3 C H N N N H CN

Dapivirine gel/ring: Clinical studies StudyStudy NameLocationVolunteersStatus IPM003Gel 002 SafetySA, Tanzania, Rwanda 112completed IPM004Gel 002 PKSouth Africa18completed IPM005BGel 002 Expanded Safety Belgium36completed IPM001PC Ring FeasibilityBelgium12completed IPM008WC Ring FeasibilityBelgium13completed IPM011WC Placebo Ring Safety /Acceptability South Africa, Kenya, Tanzania 200ongoing IPM012Gel 4750 and 4789 pK and Safety Belgium 36November 2007 start IPM018Dapivirine Matrix and Reservoir Ring pK Belgium 24completed

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

UC-781 Ongoing Studies SAFETY STUDIES ENROLLMENT GEL TYPEDURATIONENDPOINTS CDC/Emory36 sexually active women 18 abstinent HIV positive women 0.1, 0.25, placebo 0.25 (12♀) UP (6♀) Twice-daily for 14 days Systemic/local toxicity, absorption, flora, acceptability University of Pittsburgh/NIH 60 abstinent women 0.1% or placebo at 0, 2, 4, and 8 hrs duration Single doseSafety, persistence of UC- 781, systemic absorption, anti-HIV-1 activity, vaginal flora, acceptability CDC/Thailand45 sexually active women 0.1, 0.25, placebo Twice-daily for 14 days Systemic/local toxicity, absorption, flora, acceptability, anti-HIV activity CONRAD/ CFHC 36 abstinent men 0.25 %, placebo Once-daily for 7 days Systemic/local toxicity, absorption UCLA/NIH36 women and men 0.1, 0.25, placebo 2 phases: Single dose; Once-daily for 1 week Systemic/local toxicity, rectal mucosal damage, PK subset

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

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

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

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

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

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

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

Criteria for Moving Forward: Early Clinical Trials Candidates assessed in small numbers of volunteers 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 ACCEPTABILITY Placebo formulations assessed in diverse populations Acceptability measured in all clinical trials PHARMACOKINETICS Where drug goes in body, concentration, duration Preferred dosage: Wide distribution in genital tract Long duration Sufficient concentration

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

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

Drug Discovery, Development and Review Process Adapted from: Pharmaceutical Research and Manufacturers of America, 2006 Phase IPhase IIIPhase II Stage 1 Drug discovery Stage 2 Pre-clinical Stage 3 Clinical trials Stage 4 Regulatory review 7 years 6.5 years1.5 years 5 compounds 250 compounds 1 approved drug 10,000 compounds First clinical trial application submitted Marketing application submitted

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