1. ART containing vaginal microbicides in the clinical pipeline: A status of the studies Salim S. Abdool Karim Director: CAPRISA Pro Vice-Chancellor (Research): University of KwaZulu-Natal Professor in Clinical Epidemiology, Columbia University Executive Committee Member, Microbicide Trials Network

2. Outline  Is there still a need for microbicides?  Past & current microbicide clinical trials  ARV microbicides in clinical and pre- clinical development  Challenges in ARV microbicides  Conclusion

3. Vaginal gel applicator Vaginal ringVaginal film A microbicide is a product that can be applied to the vaginal or rectal mucosa with the intention of preventing the transmission of sexually transmitted infections including HIV Microbicides containing antiretroviral drugs = Topical PrEP (Pre-exposure prophylaxis)

4. Is there still a need for microbicides?

5. Source: Abdool Karim Q, Abdool Karim SS, Singh B, Short R, Ngxongo S. AIDS 1992; 6: 1535-9 Age and gender distribution of HIV infection in South Africa 0 <910-14 Prevalence (%) 15-1920-2425-2930-3940-49 2 4 6 8 10 Female Male >49

6. Source: Data from South African Department of Health Antenatal Surveys. www.doh.gov.za/ 0 5 10 15 20 25 30 35 1989199119931995199719992001200320052007 HIV Prevalence (%) The HIV epidemic in South Africa HIV prevalence in pregnant women attending public antenatal clinics in South Africa 1989-2006

7. Past & Current Microbicide Clinical Trials Stopped for futility Safe but not effective Increased HIV infection Zena Stein publishes seminal article “HIV prevention: the need for methods women can use” Kenya N-9 sponge trial FHI N-9 film trial UNAIDS COL-1492 trial CONRAD CS trial FHI SAVVY trial PopCouncil Carraguard trial HPTN PRO2000 & BufferGel trial 1 st class: Surfactants eg. N9, SAVVY 2 nd class: Polymers eg. PRO2000, Carraguard, Cellulose Sulfate (CS) 3 rd class: ARVs eg. Tenofovir gel, Dapivirine gel/ring 4 th class: Co-receptor Blockers eg. CD4 blocker, CCR5 Blockers CAPRISA Tenofovir gel trial MTN Tenofovir gel & tablet trial MDP 0.5% PRO2000 trial ‘90 ‘92 ’98 ’00 ‘03 ‘04 ‘04 ’05 ’05 ’07 ’09 ‘10 IPM Dapivirine gel & ring trial FHI CS Trial 2% PRO2000

8. ARV microbicides

9. Tenofovir gel  nRTI from Gilead Sciences, licensed to CONRAD & IPM  Effective & licensed therapeutic agent  Very good safety profile with long half life  Shows protection in several animal challenge studies  Multiple genetic changes needed for resistance

10. Gel --Cervicovaginal Fluid Gel-- Vaginal Tissue Tablet-- Cervicovaginal Fluid Tablet --Blood Plasma Gel --Blood Plasma CONRAD PK Study Results Information courtesy of Jill Schwartz, CONRAD Tablet data: Dumond et. al AIDS 2007

11. Tenofovir Clinical Development Pathway 1995 // 2006 2007 2008 2009 2010 1995 // 2006 2007 2008 2009 2010 HPTN Phase I safety & PK HPTN Phase IIa safety &PK CONRAD tenofovir gel male tolerance MTN Phase I gel and tablet PK MTN Phase I safety in pregnancy MTN VOICE Phase IIb trial CAPRISA Phase IIb Test of Concept trial 1 st Macaque challenge study 20 th Macaque challenge study CONRAD gel PK

12. CAPRISA 004 Tenofovir gel trial: Status  Phase IIb randomized, double-blind, ToC trial  845 of 1250 participants enrolled  Overall 12 month retention rate: 91%  Gel adherence: 88% & Condom use: 74%  Pregnancy rate: 2.8 per 100 person-years  Challenge: co-enrolled participants – 183 terminated  Quarter of total HIV endpoints reached (on target)  Estimated completion: 1 st quarter 2010

13.  V aginal and O ral I nterventions to C ontrol the E pidemic  Five-arm, multi-site, randomized trial  Status: Protocol approved – accrual to start in mid-2009 TOTAL SAMPLE (4200) ORAL (2520) Truvada (840) Viread (840) Placebo tablet (840) TOPICAL (1680) Tenofovir Gel (840) Placebo Gel (840) MTN-VOICE : Phase IIb Tenofovir gel Viread tablet & Truvada tablet trial Information courtesy of Jeanne Marrazzo, MTN

14. Dapivirine (TMC120)  NNRTI developed by Tibotec, licensed to IPM  Developed originally as therapeutic - highly potent ARV  Low toxicity  Easily manufactured, stable & cheap  Also as combination: Dapivirine + Maraviroc N C H 3 N C H 3 C 3 HC H NN H N Information courtesy of IPM

15. Dapivirine Clinical Development Pathway 2007 2008 2009 2010 2011 IPM Dapivirine gel male tolerance IPM Dapivirine ring PK IPM Dapivirine ring safety & PK IPM Dapivirine gel PK IPM Dapivirine gel safety (mulitple studies) IPM Dapivirine gel & ring efficacy trial Information courtesy of IPM

16. IPM: Phase III trial design  Adaptive trial design with multiple arms Only the best in class moves forwardOnly the best in class moves forward  Strong focus on safety (early looks for harm)  Early stop for futility  Powered for licensure  Improved adherence Daily participant contactDaily participant contact Smart applicatorSmart applicator Longer-acting formulationsLonger-acting formulations  Anticipated start date: mid 2010 Information courtesy of IPM

17. UC-781  Licensed to CONRAD  NNRTI with potent anti-HIV activity  Low toxicity  Also as combination: UC-781 + Tenofovir

18. UC-781 Clinical Development Pathway 200620072008 Phase I Safety Phase 1 Safety (14 day) Male Tolerance Vaginal pK and safety Rectal Safety Information courtesy of Sharon Hillier, MTN

19. MIV-150  NNRTI licensed to the Population Council  Combination (PC-815): MIV-150 + Carraguard  Trials starting in 2008/9: Phase 1 safety and PKPhase 1 safety and PK Male toleranceMale tolerance Information courtesy of Louise Pedneault, PopCouncil

20. MaravirocMaraviroc  Licensed to IPM  Being developed as a gel and ring as combination product: Dapivirine + Maraviroc  Currently in pre-clinical assessment: Animal vaginal dosing studies ongoing Animal vaginal dosing studies ongoing Information courtesy of IPM

21. CompoundLicenseYearType/Stage Development Status M167, M872, M882 Merck2005CCR5 blockers Pre-clinical (on hold) BMS793BMS2005gp120 binder Early pre-clinical L’644 peptide Merck2008gp41 binderEarly pre-clinical IPM pipeline: other compounds Information courtesy of IPM

22. Challenges in ARV microbicide trials  Criteria for selection of candidates: No validated animal model - so multiple criteria usedNo validated animal model - so multiple criteria used Promising new approach: ex-vivo challenge modelPromising new approach: ex-vivo challenge model  No surrogate markers of safety & protection HIV endpoint: only gold standard for safety & efficacyHIV endpoint: only gold standard for safety & efficacy  Real world adherence to daily or coital use esp. over years (eg. daily acyclovir use at 12 months = 34.5%) #  Potential for drug resistance - will this affect their subsequent care and choice of ARV treatment?  Trial design challenges (IOM report): # Source: Watson-Jones, Weiss, Rusizoka, et al: NEJM 2008; 358: 1560-71

23. Conclusion  3 RTI ARVs (Tenofovir, Dapivirine & UC-781) are well along in the clinical development pathway  First ARV microbicide effectiveness trial underway  Two large effectiveness trials (VOICE & IPM-009) to start within next 2 years  New ring formulation – important advance  Two other ARVs (MIV-150: NNRTI) and (Maraviroc: CCR5 inhibitor) are in advanced pre-clinical testing  Combination microbicides are being developed

24. Acknowledgement My appreciation to the following people who provided information for this presentation: My appreciation to the following people who provided information for this presentation:  Sharon Hillier, Jeanne Marrazzo, Lisa Noguchi  Pam Norick, Zeda Rosenberg  Henry Gabelnick, Jill Schwartz, Chris Mauck  Louise Pedneault  Quarraisha Abdool Karim  Leya Hassanally