International Partnership for Microbicides Microbicides: Developing HIV-Prevention Options for Women World Bank Briefing Dr. Zeda Rosenberg 5 December 2006

World Bank Photos The Face of HIV Globally Increasingly female, young – In Sub-Saharan Africa, 74% of young adults (aged years) living with HIV are female – In South Africa: 1 in 4 women infected by age 22 – HIV infections also on the rise in women and girls in Eastern Europe, Asia, Latin America and the Caribbean Married, monogamous Married, monogamous – In India: 22% of cases in housewives with single partner Mothers Mothers – In Swaziland: 56% of pregnant women from ages 25 to 29 are HIV positive – highest prevalence in 5 years

Women’s Vulnerability Women’s susceptibility to HIV infection results from a combination of biological, economic and socio-cultural factors –Male-to-female transmission higher –Young women at even higher risk –Financial dependence on male partners –Inequality of women (exploitation and violence) –Cultural practices such as early marriages, intergenerational sex and marital infidelity

Microbicides: A Human Rights Issue for Women Microbicides would provide women with a prevention tool consistent with their right to self-protection and personal autonomy Over time, microbicides could be developed with both contraceptive and non-contraceptive properties

Microbicides would offer a woman-initiated method to reduce HIV transmission Microbicides Prevention Time of ExposurePrior to Exposure Treatment and Care  Behavior change  STI treatment  Male circumcision  Pre-exposure prophylaxis  HIV vaccines  Male and female condoms  Cervical barriers  Antiretroviral rx (mother-to-child)  Post-exposure prophylaxis  Antiretroviral therapies  Opportunistic infection therapies  Basic care Comprehensive Approaches to HIV/AIDS

Vaginal applicatorVaginal ring Vaginally applied substance that prevents or reduces transmission of HIV Could potentially be delivered in many forms: Ideally, safe, effective, low cost and user-friendly What is a Microbicide? – gel or cream – sponge – film, tablet – suppository – diaphragm – intravaginal ring

Mechanisms of Action Free virus C31G SLS Buffer Gel BMS 793 Merck 167 CD4 mAbs PSC-rantes T1249 DC-SIGII CV-II Mannan Carragiard Cellulose sulfate PRO 2000 Dendrimers SPL PMPA Dapivirine MIV 150 UC 781 DABO Attachment Fusion Replication (reverse transcriptase) Protein synthesis and assembly Budding Maturation

Candidate Microbicide Mechanism of Action Sponsor/FunderTrial Location CarraguardEntry InhibitorPopulation Council/Gates, USAID South Africa – Gugulethu, Isipingo, Durban, Gorankuwa, Shoshanguve Cellulose Sulfate Trial 1 Entry InhibitorGlobal Microbicide Program/Gates, USAID Nigeria – Port Harcourt, Lagos Cellulose Sulfate Trial 2 Entry InhibitorGlobal Microbicide Program/Gates, USAID South Africa – Durban Uganda, Kenya Zimbabwe (Feb 2007) PRO 2000Entry InhibitorUK Medical Research Council/DFID South Africa – Mtubatuba, Durban, Johannesburg Uganda – Masaka Tanzania – Mwanza PRO 2000 Buffer Gel Entry Inhibitor Vaginal Defense Enhancer NIAIDZimbabwe – Harare, Chitungwiza Zambia – Lusaka Malawi – Blantyre, Lilongwe South Africa – Durban, Hlabisa Current Clinical Efficacy Trials

Next-Generation Microbicides Antiretroviral-based Future of microbicides likely in combinations – two or more mechanisms of action in one product to increase effectiveness Advanced delivery mechanisms – non-coitally dependent –Long-acting gels –Intravaginal rings

Realistic Expectations First generation of microbicides likely to be only partially effective Microbicide development path similar to that of AIDS therapeutics IPM hopes to condense the development process and expedite access First AIDS case reported in the US HIV virus identified AZT mono-therapy approved for use Two-drug therapy becomes available Three-drug therapy: HAART Brazil offers free universal access to treatment 26 FDA-approved drugs and research continues 2002 Global Fund established 2003 Drug combinations/ reducing pill burden “3 by 5” initiative 2006

IPM Mission & Donors IPM is a non-profit product development partnership (PDP) established in 2002 whose mission is to prevent HIV transmission by accelerating the development and availability of safe and effective microbicides for use by women in developing countries. Donors: World Bank, Belgium, Canada, Denmark, France, Ireland, Norway, Netherlands, Sweden, United Kingdom, United States, European Commission, Rockefeller Foundation, Bill & Melinda Gates Foundation

IPM Infrastructure Formulation GMP Manufacturing Phase I/II Animal Models Screening

IPM Clinical Trials StudyStudy nameLocationVolunteersStatus IPM 001Dapivirine vaginal ring PK/safety trialBelgium12Completed IPM 003Dapivirine gel safety trialSouth Africa, Rwanda, Tanzania 112 Completed IPM 004Dapivirine gel pK trialSouth Africa18Completed IPM 005BDapivirine gel expanded safety trialBelgium36Completed IPM 007Seroconverter protocol (Phase III)Various sitesN/APlanned, 2008 IPM 008Dapivirine vaginal ring PK/safety trialBelgium13Completed IPM 009Dapivirine gel efficacy trial (Phase III)Various sitesTBDPlanned, 2008 IPM 010Dapivirine gel male tolerance trialBelgium36Planned IPM 011Vaginal ring acceptability studySouth Africa, Kenya, Tanzania 200Q1, 2007 IPM 012Dapivirine vaginal gel PK trialTBD Q2, 2007 IPM 013Dapivirine vaginal ring PK trialBelgiumTBDQ1, 2007 IPM 014Dapivirine vaginal gel safety trialSouth Africa, TBDTBDQ2, 2007 IPM 015Dapivirine vaginal ring safety trialSouth Africa, TBDTBDQ1, 2007

GMP Manufacture Applicator Filling Line Pennsylvania, US Delivery: Manufacture of Semi-Solid Formulations

IPM has acquired non-exclusive royalty-free licenses to develop, manufacture and distribute antiviral compounds as microbicides in developing countries from several major drug companies – TMC 120: NNRTI licensed from Tibotec – M 167: CCR5 blocker licensed from Merck – BMS 793: gp120 binder licensed from Bristol- Meyers Squibb – PMPA: NRTI, license pending from Gilead Partnership with Industry

Product Attribute Study Gel acceptability study - completed Sept country market research study of gel preferences among 543 women in Kenya, South Africa and Zambia Supported by the World Bank Primary conclusions: – Participants and male partners liked using gels (focus groups) – Suggest less viscous formulation than current IPM gel BUT also that viscosity is not a primary driver of decision to use Publication strategy for 1 st /2 nd quarter 2007

Site Development Identify promising new sites (dependent on incidence) – At least 10 sites needed for pivotal phase III trials Build research capacity Establish links for community-based HIV/AIDS care and support services Conduct site preparedness studies Community participation and advisory process

IPM Approach to Site Development Non SA: 8 countries 11 sites SA: 12 sites

Site Development Trial Locations & Partners CountryCurrent & Planned LocationsIn-Country Partners South AfricaGauteng (3 sites) KwaZulu Natal (5 sites) North West Province (2 sites) Western Cape (2 sites) Reproductive Health Research Unit (RHRU) – Univ. of Witswatersrand, Tembisa Hospital, Stanza Bopape Clinic - Clinical Research Center Medical Research Council, RHRU, The Dream Centre, Private Madibeng Center for Research Drakenstein Hospice, Desmond Tutu HIV Center – Univ. of Cape Town KenyaMombasa Nairobi International Center for Reproductive Health (Belgium) Family Health International (US), Kenya Medical Research Institute, Urban Research and Development Center for Africa RwandaKigaliProjet Ubuzima, Int’l Antiviral Therapy Evaluation Center (IATEC) TanzaniaMoshiHarvard School of Public Health, Kilimanjaro Christian Medical Center NigeriaAbujaInnovative Biotech Ltd. MozambiqueMaputoMozambican National Institute of Health, Microbicides Development Programme (UK) ZimbabweBulawayoUniv. of Zimbabwe Faculty of Medicine, IATEC (Netherlands) NamibiaWalvis Bay, Katima MuliloSociety for Women and AIDS in Africa, Deseret Int’l Foundation Namibia BelgiumAntwerp, GentTibotec Pharmaceuticals, SGS Life Science Services, Univ. of Ghent, Institute of Tropical Medicine

IPM visit to Kigali The Laboratory Makeover Community Advisory Group Premises Clinic and lab Offices and reception Counseling rooms Kigali, Rwanda Projet Ubuzima

Moshi, Tanzania KCMC - HSPH The Laboratory

Informed consent Family planning counseling Pre/Post HIV-testing counseling Referrals for women becoming pregnant Referrals for those screening HIV positive Treatment of STIs Treatment of those who become HIV-infected during the trial Treatment of adverse reactions Resistance Ethics of HIV Prevention Trials

Urgency and Access Historically, it can take decades for benefits of scientific innovation to reach the developing world Microbicide field committed to expediting widespread availability of any effective product, reaching those most in need first Microbicides must be widely available and affordable

Access Objectives Maximize health impact of microbicides for women in developing countries –Situate microbicides as part of comprehensive response to HIV –Address components of access: availability, acceptability, accessibility and affordability –Mobilize partnerships

Access Timeline Clinical & Regulatory Manufacturing Behavioral Research Delivery Research Policy & Advocacy Marketing Safety TrialsEfficacy TrialsRegulatory Approval Post-Licensure Studies Community Trial Engagement & Participation Pilot Manufacturing Efficacy Trial Manufacturing Demand Forecasting & Production Planning Commercial Scale Production Trial Support & Acceptability ResearchIntroduction Support Research Operations ResearchService Delivery Mechanisms Branding Impact Modeling Mobilization of Scale-Up Financing Mobilization of Political Support Advertising SCALE UP Market Research Launch and Pilot

IPM Access-Related Efforts ProgramExample Activity R&D Intellectual property rights Manufacturing capacity survey Clinical Clinical trial cost model Community trial engagement Regulatory Country case studies FDA/EMEA engagement Social and Behavior Trial - IC/enrolment video (Pop Council) Vaginal practices research (WHO) Delivery Lessons from reproductive health technologies introduction Country profiles (overview of system capacity) Modeling introduction strategies (Africa/India) Policy and Advocacy Country profiles (political challenges) Global/country impact modeling Financing profile and instruments Investment case (link costs with public health benefits and potential market returns) Marketing Product acceptability studies

Post-Trial Access “IPM is committed to the principle that all participants in an IPM-sponsored trial will have access to the product studied if the product has been proven to be safe and effective, and has been approved for domestic use in the country.” (Guidelines for the Conduct of IPM Clinical Trials, IPM, April 2006)

World Bank Contribution to Microbicides Donor to IPM since 2002 through the Population and Reproductive Health Capacity Building Program Political leadership, including support for access to microbicides, once licensed Grants supported: – Launch of IPM in Europe – Two IPM Access Advisory Committee meetings – Country preparedness/capacity building in South Africa & Zambia – Product attribute study to determine gel preferences

ConclusionConclusion With leadership, sufficient financial resources, collaborative efforts and product development expertise, women in developing countries could have access to effective microbicides within the next five to seven years.