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

Vaginal Rings and Microbicides Mark Mitchnick, MD. October 30, 2007. Microbicide Delivery System Goals. Safe Effective Coitally Independent Daily Monthly Affordable Ease of manufacture Broadly stable Long shelf life Acceptable Versatile Forgiving PK Multiple actives.

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

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  1. Vaginal Rings and Microbicides Mark Mitchnick, MD. October 30, 2007

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

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

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

  5. 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

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

  7. Dapivirine • 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

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

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

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

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

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

  13. Dapivirine Levels in Clinical Samples EC50= 0.33 ng/mL Dapivirine ng/mL <50 pg/mL

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

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