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Microbicides: State of the Art and Its Evolution

Microbicides: State of the Art and Its Evolution. Sharon L. Hillier, Ph.D. Professor Department of Obstetrics, Gynecology and Reproductive Sciences University of Pittsburgh Magee-Womens Hospital USA. Microbicides for Prevention of HIV-1 Transmission.

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Microbicides: State of the Art and Its Evolution

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  1. Microbicides: State of the Art and Its Evolution Sharon L. Hillier, Ph.D. Professor Department of Obstetrics, Gynecology and Reproductive Sciences University of Pittsburgh Magee-Womens Hospital USA

  2. Microbicides for Prevention of HIV-1 Transmission Shattock RJ and Moore JP. Nature Reviews Microbiology, vol. 1 Oct/2003

  3. Microbicide Active HIV Activity Low toxicity In vitro Activity against other STI’s Activity against sperm +/-

  4. HIV Activity Toxicity In vitro Activity against other STI Activity against sperm +/- Nonoxynol-9

  5. The Road to Development • Scale-up manufacture of active molecules • Formulation • Pharmacokinetic and pharmacodynamic studies to identify how much active is available in the lumen and the epithelium • Phase 1, 2 and 3 clinical trials • Complexities of access (storage and cost)

  6. LONG STRAIGHT ROAD

  7. H C O ( C H ) C H 2 2 7 3 H O H C H C O H 2 New Surface Active Agents Octylglycerol (OG) Invisible condom Savvy™ (C31G)

  8. Membrane Disruption Agents

  9. The State of the ArtMembrane Disruption Agents • Newer surfactant agents identified having low toxicity and contraceptive potential • Savvy trial (USAID funded, FHI implementation) ongoing for prevention of HIV • CAP being developed by CDC and NIH • These agents have lower toxicity than N-9 and could replace N-9 as a topical contraception • A study comparing Savvy and Tenofovir gel vs. placebo is being planned by CAPRISA/FHI/CONRAD

  10. Acid/Buffering Agents

  11. The State of the ArtAcid/Buffering Agents • May be used with cervical barriers for HIV and STI prevention • May replace N-9 for topical contraception • May be combined with other hi-potency microbicides as combination products

  12. Fusion Inhibitors Cellulose sulfate PRO 2000 Carraguard

  13. Fusion Inhibitors

  14. The State of the Art:Fusion Inhibitors • PRO 2000 in two effectiveness trials (HPTN 035 and MDP) • Cellulose sulfate in effectiveness studies (CONRAD and Gates, FHI funded by Gates and USAID) • Carraguard in late phase effectiveness studies (Pop Council) • These may be considered as secondary actives for combination products

  15. ART’s Molecular Structure of TMC120 Tenofovir MIV TMC120 UC-781

  16. ART’s

  17. The State of the ArtART’s • Tenofovir being evaluated as oral agent for prevention of HIV • Tenofovir gel moving forward into expanded phase 2 testing (HPTN 059) • TMC 120 gel in expanded phase 2 testing (IPM) • TMC 120 vaginal ring in phase 1 (IPM) • Several NNRTI’s moving forward in early clinical studies, some incorporating sustained release technology • Richest pipeline of products ready to move into effectiveness studies

  18. CCR5 Antagonists SCH-D SH-D GSK-873140 Aplaviroc Merck-167 Pfizer Maraviroc (UK 427857)

  19. CCR5 Antagonists

  20. The State of the ArtCCR5 Antagonists • None of these agents are in human trials as topical microbicides to date • PSC-RANTES is being developed specifically for vaginal application- formulation challenges considerable • Merck 167 and two related molecules have recently been licensed and royalty-free for microbicide development (IPM) • CCR5 antagonists developed as therapeutics have had safety signals which may limit their further development as topical microbicides

  21. GP120 Binders Cyanovirin-N Dendrimers SPL BMS78806 BMS599,793

  22. GP 120 Binders

  23. The State of the ArtGP120 Binders • Dendrimers (SPL, VivaGel) in phase 1 clinical trials and beginning studies for STI prevention • Cyanovirin formulation may be complex, being considered for delivery through genetically-modified organisms • BMS599, 793 recently licensed royalty-free for microbicide development (IPM)

  24. Cervical Barrier Delivery Systems

  25. Cervical Barrier Delivery Systems

  26. Cervical Barrier Delivery Systems Current Status: • Phase 1 acceptability of Duet completed in early 2006 N=24, CONRAD • Post-coital testing (phase 1) for SILC’s completed 2005 The Future: • SILC moving to contraceptive effectiveness study with N-9 (CONRAD, USAID) non-comparative, to begin July 2006

  27. Sustained Release Delivery Systems: Rings

  28. Sustained Release Delivery Systems: Rings

  29. Sustained Release Delivery Systems: Rings • Current Status • Multiple technologies being evaluated • Reservoir and matrix type • Phase I trials with reservoir type rings with TMC120 demonstrated safety and good tissue levels (IPM) • New ring technologies in development • Biodegradable; multi-drug delivery capable; hydrophilic drug compatible, etc.

  30. Genetically Modified Bacteria

  31. Genetically Modified Live Organism Vectors

  32. Genetically Modified Live Organism Vectors:Lactobacillus Current Status: Lactobacillus • Lactobacillus sCD4 and 17b hybrid protein developed by Dr. Ed Berger, Chief of NIAID Laboratory of Viral Disease • Lactobacillus has been genetically modified to express sCD4 and 17b by Osel • Cyanovirin-N, an antiviral protein developed at NCI has also been expressed in Lactobacillus • Some animal studies underway for Lactobacillus expressing these protein

  33. Genetically Modified Live Organism Vectors:E. coli Current Status: E. coli • Dean Hamer (NCI Biochemistry Lab) has genetically engineered a strain of E. coli to secrete an antiviral peptide in the gut • HIV C-peptide binds to gp41 • Capacity of this genetically modified organism to colonize the mouse gut following ampicillin treatment documented • Similar model studies with SHIV challenge underway

  34. Combination Products

  35. The State of the ArtCombinations • Combinations of cervical barriers and non-specific microbicides will be the first combinations available if proven efficacious • Combinations based on acid buffer gels with a hi-potency active can be developed with low regulatory barrier because of formulation excipients that can be used • Combining hi-potency actives will be challenging, but preliminary animal model studies have confirmed the feasibility of this approach

  36. Microbicide Active Early consideration of Pharmacology HIV Activity Toxicity In vitro Activity against other STI Activity against sperm +/- Early consideration of formulation challenges

  37. The State of the Art of Microbicides • In the pipeline of microbicide candidates there is a broad diversity in mechanism of action • Each of the approaches has significant strengths and challenges • The near-term pipeline of molecules ready to enter phase 1 testing is modest and should be expanded rapidly • Need to better define the TARGET for each active and whether the ACTIVE can be successfully delivered to the target

  38. Acknowledgements • Ian McGowan • Zeda Rosenberg • Ward Cates • Joe Romano • Fulvia Veronese • Saliya Senevirantne • Marianne Callahan • Larry Severy • Ed Tramont • Lisa Rohan

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