International Partnership for Microbicides

Transcription

1 International Partnership for Microbicides Advancing HIV Prevention Options for Women GNP+ Consultation on NPTs Thomas Mertenskoetter July 2010, Amsterdam

2 Leading Causes of Death in Women (Age 15 44)

3 Existing and Potential Interventions in HIV Prevention Male and female condoms Prevention of mother-to-child transmission Male circumcision (protection for men) Post-exposure ARV pills (healthcare workers) HIV vaccines Pre-exposure Prophylaxis (PrEP) Microbicides Treatment as prevention Male condoms Female condom

4 ARV-based Methods for Treatment and Prevention of HIV/AIDS Existing ARV options in use Currently being researched Treatment PMTCT PEP PrEP Microbicides Drugs used 25+ approved ARVs Nevirapine, AZT and 3TC Multiple ARVs tenofovir, Truvada, TMC278 LA tenofovir, dapivirine, UC-781, maraviroc.. Drug regimen Combinations (triple drug) 2 drugs (WHO) 2 or 3 drugs Single or dual drug Single drugs or combinations Delivery formulation Oral pill, injection Oral pill, dropper Oral pill Oral pill, injection Vaginal & rectal gels, vaginal rings & films Frequency of use At least daily 28 wks before to 7 days post Daily for 4 weeks Daily, intermittent or monthly Around time of sex, daily, or monthly Resistance potential If inadequate suppression of replication Frequent with NVR but little impact > 6 mths Depends on regimen, adherence No data, under research No data, under research Source: MMCI / MTN / GCM / IPM

5 Results to date from HIV prevention trials 37 efficacy trials conducted between interventions tested in these trials: Microbicides: 12 Male circumcision: 4 Vaccines: 4 STI treatment: 9 PrEP : 1 Behavioral: 7 Diaphragm: 1 Microfinance: 1 Only 5 trials of 3 interventions showed a protective effect on HIV incidence in over 2 decades of research Padian NS, et al. Weighing the gold in the gold standard challenges in HIV prevention research. AIDS 2010

6 What are Microbicides? Topical products to prevent HIV transmission to women Could be delivered in many forms: Gel applicator Ring Tablet, capsule, film Ideally safe, effective, low cost, user friendly

7 The Case for Microbicides Vaginal dosing establishes high drug levels where virus enters body Topical dosing causes low systemic exposure Reduced chance of systemic side effects Theoretically, less chance of selection of resistance Precedent for vaginal dosing in contraception and treatment of infections No one prevention option will satisfy all Microbicides, PrEP, vaccines, etc.

8 Microbicide Efficacy Trials Summary 7 products tested in efficacy trials to date N9, Savvy, CS, Carraguard, BufferGel, PRO 2000 (2%), PRO 2000 (0.5%) All early-generation, non-specific candidates None found to be effective in preventing HIV infection 2 products in ongoing or planned efficacy trials Next-generation, ARV-based candidates Tenofovir gel (CAPRISA, VOICE) analysis / ongoing Dapivirine vaginal ring (IPM) planned Other ARV compounds in earlier stages of development

9 Lessons Learned from Prior Trials Lessons learned Prioritization Safety Adherence Incidence Futility Pregnancy Regulatory Locations What can be done going forward Advance best-in-class product only into Phase III Continue early looks for harm and ability to stop Multiple data reviews during the trial Longer acting formulations Product acceptability studies Explore novel adherence strategies/technologies Epi studies conducted in advance Early stop if unlikely to show efficacy Contraceptives and counseling provided on site where feasible Obtain feedback/input in advance of trial Diversify in terms of countries and sites Address co-enrollment concerns

10 Early & Next Generation Microbicides Early Generation Next Generation First microbicides tested, none found to be effective Newer products in different stages of preclinical and clinical research Non-specific to HIV Specific to HIV (ARV-based) Primarily gel formulations Various forms: gel, ring, film, other Applied vaginally within a few hours before sex Tissue exposure and longer duration of action: daily gels, monthly rings, etc. No concern about potential resistance ARV resistance is a possible issue that is being investigated

11 Current Microbicide Efficacy Trials Product /Trial Phase MoA Sponsors Countries Status/Results Tenofovir gel CAPRISA 004 IIB N = 892 NRTI SA govt USAID CONRAD FHI South Africa Data analysis Results July 2010 Tenofovir gel MTN-003 (VOICE) IIB N = 4950 NRTI NIH CONRAD South Africa Uganda Zimbabwe Malawi (TBD) Zambia (TBD) Ongoing since 2009 Results 2013 Dapivirine ring IPM 009 III N = 6000 to 8000 NNRTI IPM Africa Planned 2011

12 Product Acceptability Studies Placebo vaginal gels (PAS I) Kenya, South Africa, Zambia Completed 2006 (543 women) Placebo vaginal ring (IPM 011) South Africa, Tanzania Completed 2010 (170 women) Placebo vaginal tablet, film, soft gel capsule (PAS II) Burkina Faso, Zambia, Tanzania Completed 2010 (526 women)

13 IPM Partnerships With Industry Compound License Year Type/Stage Development Status Dapivirine Tibotec 2004 NNRTI Phase I/II DS001 (L-860,167) DS004 (L-860,872) DS005 (L-860,882) Merck 2005 CCR5 blockers Early preclinical DS003 (BMS ) BMS 2005 gp120 binder Preclinical Tenofovir (IPM & CONRAD) Gilead 2006 NRTI Phase I (CONRAD / IPM) Phase IIB (CAPRISA / CONRAD) Phase IIB (MTN) Maraviroc Pfizer 2008 CCR5 blocker Advanced preclinical DS007 (L ) Merck 2008 gp41 binder Early preclinical Non-exclusive, royalty-free licenses to develop, manufacture and distribute compounds as microbicides in developing countries

14 IPM Clinical Trials of Dapivirine PK PK/Feasibility Safety/ Feasibility Safety Expanded safety Ring Gel Male tolerance Seroconverter protocol dapivirinemaraviroc Phase III efficacy Clinical trials in Africa, Europe, United States

15 Women Urgently Need Microbicides A microbicide could mean the difference between life and death for millions of women. Let us do everything in our power to accelerate its development. Mrs. Graça Machel, March 2008

16 Towards an HIV+ Women s Microbicide Agenda 6 month consultation 2006/2007 Dialogue with scientists Report June 2007 Some topics addressed: Drug safety in HIV+ women HIV testing requirements Usage when HIV-infection undiagnosed Protection against re-infection of HIV+ women Bidirectional protection female/male Development of drug resistance in infected women Follow-up of sero-converters

17 For discussion What updates can be given to the previously posed questions? Where do you think there are opportunities to engage people living with HIV in the research process and in advocacy?

18 Backup

19 HIV Prevalence by Age Group

20 Past Microbicide Efficacy Trials Microbicide Sponsors Countries Results / Reasons for Closure Nonoxynol-9 NIH, AMFAR, FHI / Univ of Washington Kenya Sponge trial cancelled (1990) More HIV+ in N-9 arm (not statistically significant) USAID, NIH / FHI Cameroon Film trial completed (1996) No efficacy against HIV NIH / FHI Kenya Gel trial cancelled (1998) Slow enrollment & follow up WHO, UNAIDS Thailand, Benin, Cote d Ivoire, SA Gel trial completed (2000) Trend towards harm Savvy USAID / FHI Ghana Gel trial cancelled (2005) Low HIV incidence No safety concerns USAID / FHI Nigeria Gel trial cancelled (2006) Futility (no efficacy) More HIV+ in Savvy arm (not statistically significant)

21 Past Microbicide Efficacy Trials (cont d) Microbicide Sponsors Countries Results / Reasons for Closure Cellulose Sulfate Gates, USAID, Polydex / CONRAD Benin, India, SA, Uganda, Zimbabwe Gel trial cancelled (2007) More HIV+ in CS arm (not statistically significant) USAID, Polydex / FHI Nigeria Gel trial cancelled (2007) No safety concerns (precaution) Carraguard Gates, USAID / PopCouncil South Africa Gel trial completed (2007) No efficacy against HIV Good safety profile BufferGel & PRO 2000 (0.5%) NIAID / HPTN (MTN) Malawi, South Africa, Zambia, Zimbabwe, United States Gel trial completed (2009) PRO 2000: 30% efficacy against HIV (not statistically significant) BufferGel: No efficacy against HIV Both gels safe for use as tested Gels not effective against other STIs PRO 2000 (2%, 0.5%) UK MRC, DFID / MDP SA, Tanzania, Uganda, Zambia 2% arm dropped (2008) Futility (no efficacy) Gel trial completed (2009) 0.5% arm safe for use as tested but showed no efficacy against HIV

22 Microbicide Development Process Research & Development Site Development Clinical Trials Regulatory Approval Launch & Access Intellectual Property rights Formulation Lab safety Community engagement Capacity building HIV incidence studies Safety Efficacy Acceptability Clinical trials Licensure Post-licensure studies Manufacturing Service delivery Marketing Drug development approach consistent with regulatory path

23 Guidelines for Clinical Trials Informed consent process Risk reduction counseling Provision of condoms STI screening and treatment Family planning Management of pregnancy Counseling & referrals for treatment If HIV-positive at screening Long-term access to care & treatment For participants who become HIV-positive during clinical trials Treatment / referrals For any medical condition that arises during the study Provisions for study staff Post-trial access to products

24 IPM s Work Across the Globe 20+ clinical research centre partners in 9 countries Kenya: Kisumu, Suba Malawi: Blantyre, Lilongwe Rwanda: Kigali South Africa: Brits, Edendale, Ladysmith, Masiphumelele, Mbekweni, Nyanga, Pinetown Tanzania: Moshi Zambia: Lusaka, Ndola Zimbabwe: Mutare

25 IPM Donors

26 Clinical Research Centers in Africa Be Part Yoluntu Centre More than 15 local partners in 7 countries conduct research studies on behalf of IPM

27 Capacity Building at Research Centers Community engagement Referral networks for medical care, treatment, support Infrastructure and equipment Staff training and development Communications, messaging, tools Financial management support HIV incidence studies