International Partnership for Microbicides Vaginal Rings and Microbicides Mark Mitchnick, MD. October 30, 2007

Microbicide Delivery System Goals n Safe n Effective n Coitally Independent  Daily  Monthly n Affordable  Ease of manufacture  Broadly stable  Long shelf life n Acceptable n Versatile  Forgiving PK  Multiple actives

Microbicide Delivery: Choice will be Key to Widespread Adoption of Microbicides n Diversity of delivery systems  Semisolids/Solids p Gels p Emulsions p Films p Tablets  Devices p Vaginal rings p Sponges p Physical barriers  Other?

n Most developers are focusing on ARV’s n HIV specific n Highly active n Affordable n Can be formulated to be Coitally independent n Safe, lots of experience with most classes n Stable in relevant climatic zones Antiretroviral (ARV) Microbicides

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

IPM Drug Product Grid: Medium Term  API NNRTI Dapivirine NRTI PMPA R5 Blocker Merck 167 Maraviroc (pending) GP 120 binding BMS 793  Delivery Formats Semisolids Gels Emulsions Gel caps Vaginal Rings Matrix Reservoir Films Dissolving Tablets

DapivirineDapivirine  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, very cheap  Stable drug substance  IP clarity  Multiple dosage forms

Sustained Release: Vaginal Rings n Attractive technology:  30+ days of drug delivery  Potentially reduces compliance burden  Easy to use  “Low” cost n Unknowns:  Acceptability in relevant populations  Scale up manufacture  Regulatory path in multiple countries  Feasibility of multi-drug combinations  Environmental impact

Addressing the Unknowns  Acceptability in relevant populations p Acceptability studies ongoing  Scale up manufacture p Survey of methods with scale-up of each investigated p Redundant capacity being installed  Regulatory path in multiple countries p Priority p Engaging regulators  Feasibility of multi-drug combinations p Multiple groups engaged to tackle p Several novel approaches  Environmental impact p Being quantified, primary concern is control over HIV p Additional matrix materials being investigated

Types of Vaginal rings: Reservoir & Matrix Courtesy or Karl Malcolm, QUB Matrix-type Core-type Cross-sectional profiles Dapivirine Raman maps Drug

-Sink conditions: Release medium is 50% IPA. Daily vaginal gel dose= 500  g (red line) In-Vitro Daily Release of Dapivirine From a Silicone Elastomer Matrix Vaginal Ring  g Dapivirine Days

Human Experience with Vaginal Rings To Date n Several marketed products  Hormone releasing  FemRing p Vagianl menapuse symptoms p Silicone reservoir  NuvaRing p Birth control p EVA reservoir n Microbicide containing rings  In development  Several Phase I studies p PK looking very promising p No safety issues to date

Dapivirine Levels in Clinical Samples <50 pg/mL Dapivirine ng/mL EC 50 = 0.33 ng/mL

Next Steps n Complete manufacturing development n Install manufacturing capacity n Larger safety studies in 2008 n Phase III study with Dapivirine ring in 2010  Part of larger multi-arm study n Strong efforts in additional development  Multiple actives in single ring  Additional Matrix materials