Transcript Document
International Partnership for Microbicides 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 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? 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 Microbicides in Product Development Lactin-V Invisible Condom Free virus BufferGel Locus small molecules S-DABO Dapivirine (TMC120) UC781 Tenofovir (PMPA) PC815 (MIV150 + Carraguard) Attachment Fusion Carraguard PRO2000 SPL7013 (VivaGel) Monoclonal antibodies DS003 (BMS) DS001 (Merck) DS006 (Maraviroc) Pyrimidinediones (Samjin) Replication (RT) Integration Protein synthesis and assembly Budding Maturation 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 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 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 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 Types of Vaginal rings: Reservoir & Matrix Cross-sectional profiles Drug Core-type Courtesy or Karl Malcolm, QUB Matrix-type Dapivirine Raman maps In-Vitro Daily Release of Dapivirine From a Silicone Elastomer Matrix Vaginal Ring 1000 g Dapivirine 900 800 700 25 mg 600 20 mg 500 15 mg 400 10 mg 300 200 100 0 0 5 10 15 Days 20 25 30 -Sink conditions: Release medium is 50% IPA. Daily vaginal gel dose= 500 g (red line) Human Experience with Vaginal Rings To Date Several marketed products Hormone releasing FemRing Vagianl menapuse 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 Dapivirine Levels in Clinical Samples 1.E+06 EC50= 0.33 ng/mL Dapivirine ng/mL 1.E+05 1.E+04 4 hours 24 hours 1.E+03 7 days 1.E+02 1.E+01 <50 pg/mL 1.E+00 introitus (T) cervix (T) ring (T) introitus (S) cervix (S) ring (S) plasma 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