Inspiring HIV Prevention Innovations for Women IPM Satellite Event Durban, 13 th June 2017 Annalene Nel
HIV Infection: Where We Are Today 30+ years since the US CDC reported the first cases of AIDS 25.5 out of 36.7 million people living with HIV in 2015 are in Africa Progress is being made New UNAIDS data show the drop in new infections worldwide has leveled off since 2010 Key populations, including women and girls in Africa, still at high risk of HIV infection - o Leading cause of death globally among women ages 15-44 o In parts of sub-saharan Africa, young women are more than twice as likely be infected with HIV as young men 2 June 2017
Women s Vulnerability to HIV Gender inequities, including gender-based and intimate partner violence Condom use can be difficult to negotiate Financial dependence on male partners Young women at even higher risk Early marriage, intergenerational sex and concurrent partnerships Limited access to SRH information and health services Higher male-to-female transmission Biological Economic Socio- Cultural
HIV Prevention Toolkit Male and female condoms Behavior change Prevention of mother-to-child transmission Voluntary medical male circumcision Post-exposure prophylaxis (PEP) Treatment as prevention (TasP) Oral pre-exposure prophylaxis (PrEP) Vaginal rings Rectal microbicides Injectable ARVs HIV vaccines 4 June 2017
HIV Prevention Trials: Efficacy Results Male circumcision men South Africa MCB -Savvy gel women West Africa Male circumcision men Kenya Male circumcision men Uganda MCB -CS gel women Africa, India Male Circumcision MCB Carraguardwomen South Africa MCB -PRO 2000 gel and BufferGel women Africa, USA Vaccine -RV144 men and women Thailand MCB -PRO 2000 gel women Africa PrEP- oral Truvada (FEM-PrEP) women Africa TasP-HPTN 052 couples Global PrEP-oral Truvada and TFV (Partners PrEP) couples Africa PrEP-oral Truvada men, women Botswana Oral PrEP PrEP-Oral tenofovir IDUs Thailand PrEP- oral Truvada (VOICE) women Africa Vaccine VRC DNA/rAd5 MSM, transgender USA PrEP- Oral Truvada (iprexole) MSM, transgender Global MCB -Tenofovir gel (FACTS 001) women Africa PrEPand ART Oral Truvada (Partners PrEPdemo) couples Dapivirine Africa Vaginal Ring Dossier in progress MCB -Dapivirine Vaginal Ring (ASPIRE) women Africa Male circumcision women Uganda MCB -tenofovir gel (CAPRISA 004) women South Africa PrEP- oral tenofovir (VOICE) women Africa PrEP-Oral Truvada (PROUD) MSM United Kingdom Vaccine - Step/Phambili men and women Global PrEP-oral Truvada (iprex) MSM Global MCB -tenofovir gel (VOICE) women Africa PrEP-oral Truvada (Ipergay) MSM Canada, France MCB -Dapivirine Vaginal Ring (The Ring Study) women Africa 2005-07 2008-10 2011 2012-14 2015-16 5 June 2017
Dapivirine Ring Development Path Dapivirine Dapivirine licensed to IPM in 2004 from Janssen Sciences Ireland UC; expanded to exclusive worldwide rights in 2014 Dapivirine Ring IPM developed and manufactured the first dapivirine ring IPM regulatory sponsor Product Development Plan Regulatory Path Regulatory Dossier Regulatory Approval Access Plan Drug Development Plan consistent with Regulatory Path World Medical Association Declaration of Helsinki International Conference on Harmonisation Guideline for Good Clinical Practice US Food and Drug Administration Country Specific Regulatory Authority Guidelines & Regulations 6 June 2017
Clinical Development Dapivirine Ring: Clinical Development Plan Phase I Phase II Phase III Phase IIIB IPM 024 First Ring-004 in Women IPM 013 Multiple Rings in Women IPM 034 Extended Ring use in Women IPM 035 Menses and Tampon Use IPM 036 DDI with Clotrimazole* MTN-029/IPM 039 PK in lactating women* IPM 011 Single Placebo Ring over 3 months in Women in Africa IPM 015 Multiple Rings in Women in Africa MTN-024/IPM 031 Post Menopausal IPM 027 (The Ring Study) Open-Label* Amendment 5.0 MTN-020 (ASPIRE) IPM 032 (DREAM) Open label extension+ Cohorts of ring naïve young women (18 25 years) MTN-025 (HOPE) Open label extension+ IPM 028 DDI with Miconazole Nitrate MTN-012/IPM 010 Male tolerance study (Gel 4759) MTN-023/IPM 030 Adolescents in US* IPM 029 & IPM 033 Condom Functionality *In analysis +Ongoing #Planned Additional arm, measuring PK levels with intermittent ring use 7 June 2017 MTN/IPM Pregnant and Breast feeding women # MTN-034/IPM 045 Ring naïve young women in Africa# (16-21 years)
Dapivirine Vaginal Ring, 25 mg Approximately 4 mg dapivirine is released during continuous use over a month Dapivirine residual levels in used rings decrease with the duration of ring use High dapivirine vaginal fluid concentrations: Achieved by 24 hours Maintained throughout the entire month of use Very low plasma concentrations 8 June 2017
Phase III Dapivirine Vaginal Ring Reduces HIV-1 infection risk in two independent wellcontrolled Phase III clinical trials in women ages 18-45 years in sub-saharan Africa 31% reduction 9 June 2017 P < 0.05, statistically significant
Phase III Dapivirine Vaginal Ring Reduces HIV-1 infection risk in two independent wellcontrolled Phase III clinical trials in women ages 18-45 years in sub-saharan Africa 27.4% HIV reduction CI: 8.6%; 42.3% p=0.007 10 June 2017 Based on HIV-1 Seroconversion (HIV Rapid Test Result)
HIV Prevention Trials: Varying Levels of Efficacy Study Effect size (CI) TDF/FTC (Partners PrEP Demo) 94% (85, 98) TasP (HPTN052) 93% (78, 98) TDF/FTC (PROUD) 86% (58, 96)* TDF/FTC (Ipergay) 86% (40, 99) TDF/FTC (Partners PrEP) 75% (55, 87) TDF (Partners PrEP) 67% (44, 81) TDF/FTC (TDF2, CDC) 62% (22, 83) Medical male circumcision 57% (29, 76) (Orange Farm, Rakai, Kisumu) TDF (Bangkok TDF Study) 49% (10, 72) TDF/ FTC (iprex) 44% (15, 63) Tenofovir gel (CAPRISA 004) 39% (6, 60) Prime-boost Vaccine (Thai RV144) 31% (1, 52) Dapivirine ring (The Ring Study) 31% (1, 52) Dapivirine ring (ASPIRE) 27% (1, 46) TDF/ FTC (FEM-PrEP) 6% (-52, 41) Prime-boost Vaccine -25%(-121, 29) (HVTN 505) Tenofovir gel 15% (-20, 40) TDF -4%(-49, 27) TDF/FTC -49%(-122, 3) Tenofovir gel (FACTS 001) 0% (-60, 40) (VOICE) *90% confidence interval 11 June 2017
Dapivirine Vaginal Ring, 25 mg: Efficacy Adherence to Use Objective measures of non-adherence to ring use: Dapivirine residual levels in used rings Dapivirine plasma and vaginal fluid concentrations All measures are imperfect as they cannot distinguish different patterns of ring use during the month None of the measures indicate if the ring was used during the time of an HIV risk event No HIV-1 infection risk reduction is observed when women do not adhere to ring use (dapivirine residual levels >23.5mg or plasma concentrations <95pg/ml) Higher HIV-1 risk reduction is achieved with increased adherence to product use Continuous use, including during menses is very important If removed, the ring should immediately be replaced by a new ring 12 June 2017
Dapivirine Vaginal Ring: Safety Dapivirine vaginal ring is safe No difference between the dapivirine and placebo groups in the number of:» pregnancies and pregnancy outcomes» adverse events (side effects / health problems)» sexually transmitted infections and bacterial vaginosis No significant HIV-1 drug resistance Male and Female condoms can be used with the ring 13 June 2017 Vaginal miconazole can be used concomitantly with the ring
The Next Step for the Dapivirine Vaginal Ring? Regulatory Pathway Public Health Pathway Applications for regulatory approval will be submitted starting mid 2017 Two open-label extension trials to support consistent use Access 14 June 2017
Open-Label Extension Trials Activated in July 2016 for former Phase III participants Assessment of adherence to ring use and long-term safety profile Adolescentclinical trial planned for 2017: Assess safety of and adherence to Dapivirine Vaginal Ring and oral PrEP among 300 young women, 16-21 years, in Kenya, South Africa, Uganda, Zimbabwe (MTN-034/IPM 045) 15 June 2017
Open-Label Extension Trials (Phase IIIb) DREAM (IPM 032) HOPE(MTN-025) Treatment Regimen 25 mg Dapivirine Vaginal Ring, replaced monthly Design Follow-up regimens Product use period Phase III former Participants, Open-label Follow-up visit one month after enrolment up to three months 3-monthly visit schedule: three rings dispensed to the participant two additional to take home, or dispensing will take place as arranged with the participant Approx. 1-year follow-up with extension Approx. 1-year 16 June 2017
DREAM (IPM 032): Ring-use Naïve Participant Cohorts No HIV risk reduction was observed in younger women in the Phase III program, a protocol amendment includes: two additional cohorts of young women 18 to 21 years and >21 to <25 years who have not used the Dapivirine Vaginal Ring-004 previously 300 participants per cohort BETTER UNDERSTANDING OF UNIQUE CHALLENGES Additional data will be collected to gain a better understanding of younger women s unique challenges in using HIV prevention methods 17 June 2017
Qualitative Component In-depth interviews: Decliner population Ring users Ring non-users Cases of interest Male partners Male community members DVR-naïve cohorts: Baseline behavioural assessment ACCEPTABILITY AND INFLUENCERS OF RING USE Behavioural data will support the potential introduction of a microbicide as a public health intervention and assist with future program development. 18 June 2017
Women Need Multiple Options Women-initiated technologies are a key component of a comprehensive prevention package No one option will suit everyone To end the HIV epidemic, women need multiple options that meet their various needs, including daily oral PrEP, long-acting vaginal rings and one day, rectal microbicides, injectablesand vaccines 19 June 2017
Regulatory Pathway European Medicines Agency (EMA) Article 58 eligibility reconfirmed 2016 (Co) Rapporteur meetings Jan 2017 Pre-submission meeting Feb 2017 Target submission end Q2 2017 World Health Organization (WHO) Why WHO Prequalification? Process to evaluate whether a drug meets global standards o Quality o Safety o Efficacy Many African regulatory agencies use WHO prequalification to determine which new products to approve, and review EMA decisions Sub-Saharan NRAs Following WHO PQ, first round of submissions to Kenya, Malawi, Rwanda, Tanzania, Uganda, Zambia and Zimbabwe Medicines Control Council (MCC, SA) Target submission Q4 2017 US Food and Drug Administration (FDA) Target submission 2018 20 June 2017
It takes a village to develop the Dapivirine Ring Trial Participants Research Centre Teams and Leadership Partners, Vendors and Collaborators National and Local Leaders and Stakeholders MTN, DAIDS, NIH Colleagues Colleagues of Janssen Sciences Ireland UC IPM Board, Management and Colleagues Our Family and Friends 21 June 2017
Current IPM Donors The contents of this presentation are the responsibility of IPM and do not necessarily reflect the views of its donors. 22 June 2017
Contact Information: Dr Annalene Nel International Partnership for Microbicides Tel: +27 21 860 2300 / +27 83 657 0733 Email: anel@ipmglobal.org.za Website: www.ipmglobal.org