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Zeda Rosenberg , Sc.D. XIX International AIDS Conference Washington, DC 26 July 2012

Expanding the Method Mix: Current and planned trials of different ARV-based approaches for women. Zeda Rosenberg , Sc.D. XIX International AIDS Conference Washington, DC 26 July 2012. Need for Multiple Drugs & Formulations. Vaginal tablet, soft gel capsule, film.

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Zeda Rosenberg , Sc.D. XIX International AIDS Conference Washington, DC 26 July 2012

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  1. Expanding the Method Mix:Current and planned trials of different ARV-based approaches for women Zeda Rosenberg, Sc.D. XIX International AIDS Conference Washington, DC 26 July 2012

  2. Need for Multiple Drugs & Formulations Vaginal tablet, soft gel capsule, film Vaginal ring Vaginal gel applicator More drug choices, more options for protection Different women, different preferences Vaginal gels, rings, films, tablets, soft gel capsules – all found to be acceptable in IPM studies in Africa

  3. Film Ring Prioritizing Products Gel Tablet/ capsule Formulation Potential Adherence/ Acceptability DPV DS 003 MAR MIV-150 Human experience Redundancy Dev. partners Potency Cost & resource needs Mechanism of action TFV Stage of development Manufacturing

  4. Dapivirine (TMC120) • Highly potent ARV (NNRTI) • Developed by Janssen • Originally tested as oral therapeutic in 11 studies • Licensed to IPM in 2004 • Development as topical microbicide for HIV prevention • 15 Phase I/II safety studies (dapivirine ring or gel) • Good safety profile in 15 studies to date • Data on more than 700 study participants before efficacy studies • Dapivirine Ring Licensure Program started in 2012

  5. Dapivirine Vaginal Ring Important potential new option for women • Dapivirine • Potent NNRTI • Local distribution, low systemic absorption • Potential for drug combinations • Long-acting: monthly (or longer) • Could potentially improve adherence • Better adherence → better effectiveness • Easy to use, comfortable • Flexible ring, can be self-inserted • Rarely felt by women or their male partners • Little or no impact on sexual activity • Suitable for developing world • Relatively low manufacturing cost • Stability / shelf-life

  6. Vaginal Ring Acceptability Acceptability among women • Ring was very comfortable: 95% • Ring not felt during daily activities: 99% • Willing to use if effective: 100% Most favorable characteristics • Potential for HIV prevention • Ring does not alter sexual experience • Ring is worn every day Male partner involvement • Important that partner accepts ring: 84% • Would use without telling partner: 63% • Most men reported not feeling ring during sex; no impact on sexual pleasure; and no side effects

  7. Vaginal Ring Adherence (IPM 015) • Cumulative adherence over 12 weeks (N=261) • 84% had perfect adherence (ring never out) • 92% had 100% daily adherence (ring never out for ≥1 day) • Ring “ever out” reported in 5% of 1082 visit intervals • Expulsions= 2%; Removals= 3% • Sex occurred without the ring at 1.2% of visit intervals

  8. Summary of Social-Behavioral Data (IPM 015) • Ring was highly acceptable and women reported preferring continuous use • Ring had minimal impact on sex for women participants or male partners • High reported adherence to monthly use of ring • Expulsions were rare and decreased over time • Mostly associated with urination and bowel movement • Removals were rare but increased over time • Mostly to clean ring

  9. The Ring Study (IPM 027) • Dapivirine vaginal ring long-term safety and efficacy study • Double-blind, placebo-controlled, randomized (2:1) • Targeted enrollment: 1650 women, ages 18-45 • 5 sites South Africa, Rwanda • Rings inserted every 4 weeks • Length of participant follow-up: 2 years • Sites initiated in South Africa: Q1-2012; Results in 2015 • Study objectives • Primary: Long-term safety and efficacy of dapivirine ring when inserted once every 4 weeks over a period of 24 months • Secondary: Incidence of HIV-2; incidence of STIs; pregnancy; adherence and acceptability; frequency of drug resistance

  10. The ASPIRE Study (MTN-020) • AStudy to Prevent Infection with a Ring for Extended Use • Dapivirine vaginal ring safety and efficacy study • Double-blind, randomized (1:1) • Targeted enrollment: 3476 women, ages 18-45 • Rings inserted every 4 weeks • Length of participant follow-up: 1 year min, 2 years max • 17 planned sites in Malawi, Uganda, S.Africa, Zambia and Zimbabwe • First sites initiated: July 2012 (S. Africa and Uganda); Results in 2014 • Study objectives • Primary: Efficacy and safety of dapivirine ring when inserted once every 4 weeks • Secondary: acceptability; adherence; frequency of HIV-1 drug resistance; relationship between drug levels and seroconversions

  11. Dapivirine Ring Timelines 2016 DPV Ring Regulatory Consultations Regulatory submissions for product approval 2012 2013 2015 2014 The Ring Study (IPM 027) ASPIRE (MTN-020) Drug-drug interaction study Adolescent and pre-/peri-menopausal women safety studies Condom compatibility study Open-label / post-marketing studies

  12. Dapivirine in other formulations • FAME 02: Dapivirine Gel and Film • Phase I safety and pharmacokinetics • 60 women, ages 18-45 • 4 study arms • Dapivirine film, placebo film, dapivirine gel, placebo gel • Conducted by Magee Women’s Research Institute • Initiating Q3 2012

  13. Maraviroc • CCR5 blocker with established safety profile as marketed oral therapeutic (Selzentry™) • Developed by Pfizer • Licensed to IPM in 2008 for microbicide indication in developing world • Clinical development: • Maraviroc rings alone and in combination with dapivirine • Preclinical development: • Maraviroc gel (rectal use)- Magee Women’s Research Institute • Maraviroc/tenofovir combination in early preclinical development

  14. Dapivirine/Maraviroc Ring Trial • MTN-013 / IPM 026: Phase 1 PK & safety vaginal ring • 3 research centers in the United States • Study design: • 4 arms: dapivirine-maraviroc ring, dapivirine ring, maraviroc ring, placebo ring • N = 48 women • 28 days on product + 24 days of follow-up • Fully enrolled • Results expected Q4 2012 First clinical trial of a combination microbicide & first clinical trial of maraviroc for HIV prevention 14

  15. TMC278 Injectable • Developed by Janssen • NNRTI approved for therapeutic use in 2011 (Edurant ™) • Clinical development • St. Stephen’s AIDS Trust • Phase I safety and PK • MWRI-01 • Magee Women’s Research Institute (U. of Pittsburgh) • Phase I safety, acceptability and PK/PD • 90 women and men (2:1); sequential cohorts • Planned study start: Q3 2012

  16. MIV-150 • NNRTI • Developed by Medivir AB • Licensed to Population Council in 2003 • Preclinical development • MIV-150 monthly ring • Combination rings: MIV-150/zinc acetate and MIV-150/contraceptive • Combination gel: MIV-150, zinc acetate

  17. Microbicides: What’s Next • New drugs, new mechanisms of action • DS 003 • Darunavir • Integraseinhibitors • Multipurpose Prevention Products • HIV prevention plus additional indication (i.e. pregnancy prevention, prevention of other STIs, etc.) • ARVs and hormonal contraceptives • IPM, CONRAD, Pop Council

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