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State of the Field: Microbicide Science and Trials M2008 Preconference Workshop Delhi, India Sharon Hillier, PhD University of Pittsburgh Microbicide Trials Network February 24, 2008 A microbicide is a product that can be applied to the vaginal or rectal mucosa with the intention of preventing or significantly reducing the transmission of sexually transmitted infections including HIV infection Topical Microbicides Ideal if option available for use with sex or daily (independent of sex) Local drug levels can be high and systemic exposure low Maximum drug:virus level Lower chance for adverse events related to systemic drug No one prevention option will satisfy all; multiple approaches needed to address acceptability preferences Types of Microbicide Delivery Platforms Vaginal applicator for gel Vaginal ring Vaginal film Ideally long acting, safe, effective, low cost and user-friendly Potential for combinations of drugs to increase effectiveness How Does the Virus Get In? How Could Microbicides Prevent Infection? McGowan I, Biologicals, 2006 Who is Developing Microbicides? Microbicide Manufacturers Gilead Sciences Inc. StarPharma Holdings Ltd Indevus Pharmaceuticals Inc. Reprotect LLC Tibotec Pharmaceuticals Ltd The Microbicide Trials Network NIH funded network PI: Dr. Sharon Hillier Founded in 2006 Based in Pittsburgh Domestic (n=5) and international (n=10) sites funded directly by NIH Conducting Phase 1, 2 and 2B microbicide studies http://www.mtnstopshiv.org/ MTN does not do any product development or formulation MTN Clinical Trials Year Study Phase N HPTN-035 2/2B 3220 HPTN-059 2 200 MTN-001 2 144 MTN-002 1 40 MTN-003 2B 4200 MTN-004 1 60 MTN-015 HIV+ Registry 225 MTN-016 Pregnancy registry Ongoing Studies 06 07 08 09 10 11 Planned Studies 12 13 CONRAD Established in 1986 Executive Director: Henry Gabelnick Strategic focus: Contraception Prevention of sexual transmission of HIV/AIDS and other infections. http://www.conrad.org/ Product Portfolio • • • Cellulose sulfate Tenofovir UC-781 International Partnership for Microbicides (IPM) IPM is a non-profit product development partnership (PDP) established in 2002 to prevent HIV transmission by accelerating the development and availability of a safe and effective microbicide for use by women in developing countries CEO: Zeda Rosenberg http://www.ipm-microbicides.org Product Portfolio • • TMC-120 Tenofovir IPM does product formulation and scale-up research United Kingdom Microbicides Development Program (MDP) Funded through grants from the UK Medical Research Council (MRC) and the UK government Department for International Development (DFID) Conducting the microbicide trial of PRO-2000 Lead investigators- Charles Lacey, Sheena McCormack http://www.mdp.mrc.ac.uk/ MRC MDP Trial Sites • • • • South Africa Tanzania Zambia Uganda Population Council Conducts research worldwide to improve policies, programs, and products in three areas HIV and AIDS Poverty, gender, and youth Reproductive health. Just released data from Phase 3 study of Carraguard® Ongoing research program with combination microbicide – PC 815 Director-Naomi Rutenberg Carraguard® Gel http://www.popcouncil.org/ Microbicide Trial Design Safer sex counseling Diagnosis & treatment of STIs Condom provision Randomization Active Drug 1 Active Drug 2 Primary Endpoint HIV seroconversions Placebo DSMB Review Process Safety • Adverse events • Laboratory tests • HIV infection Trial conduct • Accrual • Retention • Adherence DSMB Decision Continue Continue with study Modification: • Drop a study arm Pause/stop study • Futility • Success • Safety concerns Reasons for Premature Study Discontinuation Overwhelming evidence of efficacy Safety concerns Futility Inability to achieve primary study endpoint New treatments or prevention strategies emerge that change clinical equipoise Economic considerations Social or political issues Why Were Some Studies Stopped by the DSMB? C31G (Savvy™) Stopped due to futility Insufficient HIV seroconversions (endpoints) to determine whether product effective Cellulose sulfate (CS) studies CONRAD study stopped because of safety concerns • Unequal distribution of HIV endpoints • CS group had more endpoints than anticipated • CS might increase risk of HIV transmission FHI study showed no increased risk of HIV acquisition but also no evidence of efficacy (benefit) http://www.global-campaign.org/CS-background.htm#interim Population Council Study of Carraguard USAID & Gates Foundation Carraguard vs placebo S Africa (Durban; Cape Town and Medunsa) 6203 women enrolled First phase 3 trial of microbicides to be completed Safe but not effective Can now be used as a delivery vehicle for next generation product Effectiveness Studies of Savvy (C31G), Cellulose Sulfate, and Carraguard PRODUCT STUDY OUTCOME Savvy (C31G) Trial stopped due to futility, trend toward harm in frequent users Cellulose Sulfate CONRAD FHI Carraguard Stopped, evidence of harm No evidence of harm Trial completed, no benefit Drug Discovery, Development and Review Process 250 compounds 10,000 compounds 6.5 years Stage 3 Clinical trials Phase I Phase II 5 compounds 7 years Phase III Marketing application submitted Stage 2 Pre-clinical First clinical trial application submitted Stage 1 Drug discovery Stage 4 Regulatory review 1 approved drug 1.5 years Adapted from: Pharmaceutical Research and Manufacturers of America, 2006 HPTN 035: BufferGel and PRO2000 (0.5%) Objective:To estimate the safety and effectiveness of BufferGel and 0.5% PRO2000/5 (P) when applied intravaginally by women at risk for sexually-transmitted HIV infection 7 sites (1 US, 6 Africa) Full accrual of 3100 women July 2007 Follow-up to be completed July/August 2008 MDP-301 Study of PRO2000 PRO 2000 0.5% and 2% Sponsored by the Microbicide Development Programme (MDP) of the UK Intended sample size: 9,590 First enrollment: 25 Oct. 2005 16 years or older, except in S Africa and Zambia: 18years Last SDMC meeting: Feb 2008 resulting in closure of 2% PRO 2000 Estimated complete enrollment: July 08, results late 09 or early 2010 HPTN-035 / MDP-301 HPTN-035 MDP-301 PRO-2000 (0.5%) PRO-2000 (0.5%) BufferGel PRO-2000 (2%) Condom Placebo Placebo The Ideal HIV Prevention Drug PrEP = Pre-Exposure Prophylaxis oral, vaginal, rectal Specific antiretroviral microbicide One dose daily – or less Potent, good tissue penetration at site of infection Well tolerated, safe (including pregnancy) Minimal drug interactions Minimal resistance, preserve options Affordable: drug cost and monitoring Topical Microbicides Containing Antiretroviral Drugs = Topical PrEP Products that can be applied topically for prevention of HIV . Ideal if option available for use with sex or daily (independent of sex) Local drug levels can be high and systemic exposure low Maximum drug:virus level Lower chance for adverse events related to systemic drug May be safer for pregnant or breastfeeding women ARV-Based Microbicides Tenofovir UC-781 MIV TMC120 (Dapivirine) 1% Tenofovir Vaginal Gel Active ingredient is tenofovir, an antiretroviral Has specific action against HIV and proven safety and activity as a therapeutic agent Provided in pre-filled applicators Low levels of drug in the blood Low frequency of side effects Tenofovir Gel Studies 2006 2007 2008 HPTN 050 Phase I Safety HPTN 059 Phase II Expanded Safety Male Tolerance Tissue PK MTN-002 Pregnancy MTN-001 Oral vs. Topical PK MTN-003 VOICE STUDY CAPRISA 004 Study CAPRISA 004 Study of Tenofovir Funded by USAID Tenofovir 1% gel vs placebo Proof-of-concept trial (Phase 2b) Sample size: 980 women in Durban 18 years and older Family planning attendees, STI clinic clients and sex workers (3/2/1) Required to use contraception Screening started on 18 May 2007 Gel use within 12 hours before and 12 hours after sex, max. 2 applications within 24 hours Coital Dosing in CAPRISA 004 Participants advised to use gel which is in single-use, pre-filled applicators, as follows: Coitally dependent use - 2 doses of gel per sex act Participants asked to apply the first dose of the assigned gel within 12 hours prior to coitus and to apply a second dose as soon as possible, within 12 hours, after coitus. Not more than two doses of gel in a 24-hour period. The VOICE Study: Vaginal and Oral Interventions to Control the Epidemic Phase IIb trial with five study groups testing two different HIV prevention approaches in women: - A once-a-day antiretroviral tablet (PrEP) - A once-a-day application of a vaginal gel 4,200 women to be enrolled at 10 centers in Africa Target start date Fall 2008 The VOICE Study Safety and effectiveness study of tenofovir gel, tenofovir tablet and Truvada tablet for prevention of HIV infection in 4,200 women Randomized trial with 5 study groups. Two sequential randomizations. Women will use product for average of 21 months TOTAL SAMPLE (4200) Oral Pill (2520) Truvada (840) Tenofovir (840) Vaginal Gel (1680) Oral Placebo (840) Tenofovir Gel (840) Placebo Gel (840) VOICE and CAPRISA-004 Status VOICE* CAPRISA-04 Planned start Q3 2008 Ongoing 4200 980 Tenofovir gel Viread® Truvada® Placebo gel/tablet Tenofovir gel Placebo gel No Yes Enrollment Arms Coital dosing *Protocol in development Why VOICE? Tenofovir Tenofovir Gel Truvada Which is safer? Which is effective? Which will women use? Why a head to head trial or oral vs vaginal regimens? Each approach carries specific theoretical and operational advantages vaginal use may confer less systemic toxicity oral use is less closely linked to sexual practices, and can be administered by the woman without knowledge of her partner Theoretical reasons to favor either approach for efficacy and/or selection of resistance Only a head-to-head trial of these two approaches will answer this question TMC120 (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, cheap Stable drug substance H C CH CN N IP clarity N N N CH H H Multiple dosage forms 3 3 3 Dapivirine gel/ring: Clinical studies Study Study Name Location IPM003 Gel 002 Safety SA, Tanzania, Rwanda 112 completed IPM004 Gel 002 PK South Africa 18 completed Gel 002 Expanded Safety Belgium 36 completed IPM001 PC Ring Feasibility Belgium 12 completed IPM008 WC Ring Feasibility Belgium 13 completed IPM011 WC Placebo Ring Safety /Acceptability South Africa, Kenya, Tanzania 200 ongoing IPM012 Gel pK and Safety Belgium 36 11-07 start IPM018 Matrix and Reservoir Ring pK Belgium 24 completed IPM005B Volunteers Status Planned trial: International Partnership for Microbicides TMC 120 – no final decision on formulation yet: gel or ring or both Directly monitored treatment No sample size calculations yet Planned start at the end of 2008 UC-781 Carboxanilide type of NNRTI Potent anti-HIV-1 activity (nM range) Tight binding to HIV-1 RT Active against cell-free and cellassociated virus Little to no cytotoxicity (>M) Active against RT inhibitor resistant strains Reduced likelihood for resistance selection Exhibits so-called “Memory Effect” UC781 Gel: Clinical Studies 2006 2007 2008 Phase I Safety n=48 Phase 1 Safety 14 day-US & Thailand Male Tolerance Vaginal pK and Safety N=60 Rectal Safety n=36 MIV-150: A Combination PC-815, Carraguard plus MIV-150 (NNRTI) Phase 1 crossover study (Dominican Republic, PC-815 and Carraguard 20 women, 1 week single dose/day followed by 1 week twice dosing/day Safety and pK Planned start 2008 Phase I male tolerance Safety and pharmacokinetic for systemic absorption of MIV-150 10 circumcised and 10 uncircumcised males IRB approved; Planned start following Phase I in women Rectal Microbicides Receptive Anal Intercourse Common Country Ever Experienced RAI Source (%) Brazil 31.0 Guimares MD et al. 1995 Peru 12.0 Caceres C et al. 1997 South Africa 42.8 Karim SS and Ramjee G 1998 Kenya 40.8 Schwandt M et al. 2006 Rectal Safety Phase 1 Studies Product Status Timeline Sponsor UC-781 Ongoing Q2 2008 NIAID/DAIDS Tenofovir gel Planned Q3 2008 NIAID/DAIDS PRO-2000 Gel Planned ? Q1 2008 MDP MRC-UK UC-781 (Rectal formulation) Possible Q4 2010 TBD State of the Field and Science First generation products have been evaluated in efficacy studies with no level of effectiveness detected to date Potent antiretroviral microbicides (topical PrEP) now in efficacy studies Oral versus topical microbicide use is a key scientific question Rectal safety studies have started Community engagement in research agenda is more critical than ever Ten years ago, 1 percent of women in South Africa had contracted HIV; today the number is 25 percent. These women are living a nightmare, but we in rich countries are the ones who have to wake up. We need to develop prevention tools that can give women a chance to defend themselves. We need to deliver them as soon as they’re available, and we need to deploy now the prevention tools we already have. Melinda French Gates, Newsweek, May 15, 2006