XIX International AIDS Conference 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 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 Slide last updated: 18 July 2012 Mention injectable methods on this slide (not pictured) since TMC278 is discussed at the end of the presentation. The delivery vehicle for a drug is just as critical as the active substance itself. Scientists developing microbicides must consider the various characteristics of the product that may affect use over prolonged periods as well as issues such as cost and women’s and their partners’ preferences. History has taught that the more product choices people have, the more likely they are to use one of them for protection. Some people might prefer a gel used around the time of sex; or a once-daily gel, film or tablet; or a vaginal ring that could be used monthly or longer. A product’s effectiveness depends on its acceptability to women and their male partners. Even the most efficacious microbicide will not work if it is not used correctly or consistently. Feedback from clinical trials in many developing countries points to the need for microbicides that are not perceived to interfere with sexual intercourse and that can be used discreetly. It is crucial that cultural differences surrounding sexual practices are considered when developing novel delivery methods for microbicides. Mention IPM product acceptability studies: PAS I, PAS II, IPM 011 (all these studies assessed acceptability among women, and also included interviews/focus groups with a smaller number of male partners – in various African countries and communities). Vaginal gel applicator Vaginal tablet, soft gel capsule, film Vaginal ring

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

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 Slide last updated: 19 July 2012 Dapivirine or TMC120, is a highly potent ARV that belongs to the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which stop the HIV virus at the replication stage. Dapivirine was developed by Janssen R&D Ireland (previously Tibotec Pharmaceutials) which then licensed the drug to IPM. Janssen initially tested dapivirine as an oral therapeutic in 11 Phase I clinical trials, among more than 200 participants. These studies included assessments of safety, PK and clinical efficacy. The 15 dapivirine ring and gel studies include: Gel: Completed (1 Tibotec study; IPM 003, 004, 005B, 012); in data analysis (IPM 014A, 014B, 020 and IPM 010/ MTN 012) Ring: Completed (IPM 001, 008, 018, 024, 013); in data analysis (IPM 015) IPM and MTN will be starting long-term safety and efficacy studies of the dapivirine ring in 2012 (The Ring Study and ASPIRE) IPM 026/MTN-013, a Phase I study of the first combination microbicide (dapivirine-maraviroc ring) compared to a dapivirine ring; maraviroc ring; and placebo ring. Study is now ongoing at 3 MTN-affiliated sites in US

Dapivirine Vaginal Ring 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 Important potential new option for women Dapivirine vaginal rings are the lead dapivirine candidate for Phase III testing and licensure. Dapivirine is a potent ARV, safe and well tolerated as tested in over 20 Phase I and I/II clinical trials to date (in oral, gel and ring form) Vaginal rings are a promising technology, used safely for contraception (i.e. NuvaRing) and hormone therapy for post-menopausal women (i.e. Femring) in developed countries An acceptability study conducted by IPM in Africa shows good acceptability and a high willingness to use the vaginal ring for HIV protection (IPM 011) The rings are flexible, can be self-inserted, easy to use, are rarely felt by women during their daily activities, and pose little or no interference with sexual activity Dapivirine rings are designed as long-acting products, with the potential to improve product adherence, which in turn could lead to better effectiveness of the product in preventing infection In PK studies conducted to date, there was steady drug release from matrix-type rings over one month, and very low systemic absorption The manufacturing cost of the rings is relatively low, and therefore rings would be suitable for distribution in developing countries.

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 Slide last updated: 30 September 2011 Data presented is from IPM 011 Open-label placebo ring, randomized crossover design; N = 170 women Study Sites: Tanzania (1) South Africa (3) 12 weeks of placebo ring, 12 weeks of no product Safety assessed by pelvic/speculum examination, colposcopy, and AE monitoring Adherence assessed through self-report at each of three 4-weekly visits during ring use period Qualitative data collected from women and male partners at study exit Ring was used continuously for 3 months in this study, followed by an observational safety period (with no ring) of 3 months (or vice-versa) In addition to questionnaires at each study visit: participant focus groups (n=6 groups, 49 women) and male partner interviews (n=19) conducted at end of study - Preliminary data presented at the Microbicides 2010 Conference, Pittsburgh, and additional final data presented at CROI 2011, Boston

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

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

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 Slide last updated: 16 July 2012

The ASPIRE Study (MTN-020) A Study 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 Slide last updated: 16 July 2012

Dapivirine Ring Timelines 2012 2013 2014 2015 2016 DPV Ring Regulatory Consultations Regulatory submissions for product approval The Ring Study (IPM 027) ASPIRE (MTN-020) Drug-drug interaction study Adolescent and pre-/peri-menopausal women safety studies Slide last updated: 18 July 2012 DPV Ring Regulatory Consultations include: Parallel Scientific Advice procedure (Q3 2011-Q1 2012); FDA/EMA consultations on CMC, design of safety trials (Q2 2012-Q4-2012) IPM 027 Regulatory Submissions: South Africa RCs received all approval to start v1.0 of IPM 027 protocol by Feb 2012. IPM submitted V1.0, amend. 1 of the protocol beginning in South Africa January 2012. Submissions in Rwanda are expected in Q3 2012. IPM 027 estimated timelines: Inv. Mtg - mid (Feb 2012), first SIVs in SA (Feb-Mar 2012), first participant enrolled (Q1 2012) all participants enrolled (Q4 2012), last participant visit (Q1 2015), final study report (Q3 2015) MTN-020 estimated timelines: first approvals received (Q1/Q2 2012), first SIVs (May 2012) all participants enrolled (Q2 2013), last participant visit (Q2 2014), final study report (Q4 2014) Condom compatibility study Open-label / post-marketing studies

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

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 Slide last updated: 18 July 2012 Why combination microbicides? Precedent of HAART & PMTCT Potential increased efficacy against resistant virus Coverage of multiple transmission pathways Maraviroc – unique mechanism of action

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 Data last updated: 18 July 2012 Study Locations: Boston, MA (Fenway Institute); Birmingham, AL (University of Alabama at Birmingham); Pittsburgh, PA (University of Pittsburgh Medical Center) Population: Healthy, HIV-negative, sexually abstinent, 18-40 years of age Pharmacokinetics (PK) Drug concentrations in plasma, cervicovaginal fluid & cervical tissue Safety Self-reported genital symptoms Pelvic/colposcopic examination findings (including vaginal flora and vaginal pH) Adverse Event/Serious Adverse Event reports Laboratory evaluations of hematology, and liver and renal function First clinical trial of a combination microbicide & first clinical trial of maraviroc for HIV prevention 14

TMC278 Injectable Developed by Janssen Clinical development 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 Ian McGown’s study- MWRI-01. It is undergoing significant design modifications since the grant was funded (mainly due to IRB responses). It will now enroll women and men (2:1 ratio) in sequential cohorts looking at single (1200 mg and 600 mg) doses of TMC278 and then in subsequent cohorts multiple doses at 2 month or 1 month intervals. The study will assess safety, acceptability, and PK/PD. We will use ex vivo explant challenge (cervicovaginal and colorectal) and rectal / cervical secretions as the PD models. Total enrollment = 90, single site (Pittsburgh). We hope to start screening Q3 2012.

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 Info pulled from PopCouncil website PopCouncil has developed both silicone and EVA rings, though focus seems to be shifting to EVA because PC studies showed EVA rings released 5x as much MIV-150 MIV-150 originally developed as an HIV therapeutic Per the Pop Council website, “Based on current progress, Phase 1 trials testing the MIV-150/zinc acetate gel versus the zinc acetate alone are projected to commence in early 2012.” And per the AVAC database, the Phase I trial is planned by PC/USAID in October 2012.

Microbicides: What’s Next New drugs, new mechanisms of action DS 003 Darunavir Integrase inhibitors 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 Slide last updated: 30 April 2012 MPTs: The Pop Council is developing multipurpose prevention technologies that combine antiviral and contraceptive ingredients into one product for on-demand or long-term use. A dual-protection gel for women who have sex irregularly combines LNG, a contraceptive agent, with two antiviral agents (MIV-150 and zinc acetate). The Council is also developing this combination of drugs as an intravaginal ring for long-term use