Dapivirine Vaginal Ring for HIV Prevention: Overview and Considerations

1. OVERVIEW Jared Baeten, MD PhD Thesla Palanee, PhD Site trainings 2012

2. Overview • Background and rationale • Dapivirine for HIV prevention • MTN-020/ASPIRE overview • MTN-020/ASPIRE sites, timelines, goals • MTN-020 and IPM 027 • Lessons learned and thinking ahead

3. Background and Rationale

4. MTN-020 / ASPIRE • A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase III Safety and Effectiveness Trial of a Vaginal Matrix Ring Containing Dapivirine for the Prevention of HIV-1 Infection in Women

5. MTN-020 / ASPIRE AStudy to Prevent Infection with a Ring for Extended Use

6. Antiretrovirals for HIV prevention • Right drug (safe, effective, ideally not overlapping treatment) • Right place (sufficient concentrations at site of exposure) • Right time (present when exposed, user-independent adherence)

7. Tenofovir for HIV prevention: successes and challenges • During the past two years, large studies of oral and topical tenofovir-based PrEP have demonstrated efficacy for HIV protection:

8. Tenofovir for HIV prevention: successes and challenges • However, not all trials of tenofovir-based PrEP have found HIV protection: • No efficacy for daily oral FTC/TDF in FEM-PrEP trial and for daily tenofovir gel and daily TDF in VOICE study, both studies of women with high HIV incidence • Across PrEP studies, adherence is likely an important driver of HIV protection

9. Developing a range of options for antiretroviral-based HIV prevention Pill Gel Vaginal film Vaginal ring Injectable • Landmark health research is a process of continued development. Tenofovir is critical first proof on a future pathway. • Goals: long acting, safe, effective, low cost and user-friendly • Maximize choice & optimize effectiveness

10. Vaginal ring for HIV prevention: advantages and considerations • 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 male partners • Little or no impact on sexual activity • Suitable for a wide range of settings • Relatively low manufacturing cost • Good safety and acceptability data • Potential for drug combinations • For example, contraception, in the future

11. Dapivirine Vaginal Ring for HIV Prevention

12. Dapivirine (TMC 120) • Dapivirine is a di-amino-pyrimidine (DAPY) substituted highly potent non-nucleoside reverse transciptase inhibitor (NNRTI) of HIV-1 replication • Initially developed and tested as oral antiretroviral treatment agent by Tibotec • Potent activity both in vitro and in vivo

13. Dapivirine ring • Flexible ring made of an elastic silicone material • Off white, platinum-catalyzed • Measures 56 mm (about 2 ½”) in diameter and 7.7 mm (3/4”) thick • Designed for monthly use • Developed by the International Partnership for Microbicides (IPM)

14. Dapivirine vaginal ring composition Tested for description, weight, tensile strength, ID, assay, content uniformity, impurities, dissolution and microbial limits

15. Dapivirine safety studies • 11 oral dosing studies, for HIV treatment (N=211) • 9 studies in healthy volunteers • 2 studies in HIV-infected patients • 8 vaginal gel studies, for HIV prevention (N=774) • 6 vaginal ring studies, for HIV prevention (N=393) • Ring-001: 1 trial • Ring-002: 2 trials • Ring-003: 1 trial • Ring-004: 3 trials

16. IPM dapivirine Ring-004 trials

17. Ring-004 safety and pharmacokinetic studies • IPM 024 : Phase 1 Study, 16 Women, 4 weeks, Belgium (2009) • Desired sustainable release, PK properties, no safety concerns • Vaginal fluid levels on Day 28 at least 4000 times higher than the in vitro inhibitory concentration in cervical tissues; plasma levels <1 ng/mL • IPM 013 : Phase 1 study, 48 women, 8 weeks, Belgium (2010) • Multiple dosing of monthly rings well tolerated, no safety concerns • PK data support sustained release over a 35-day period • Vaginal fluid levels on Day 35 at least 3000 times higher than the in vitro 99% inhibitory concentration in cervical tissue, Plasma levels < 1ng/ml • IPM 015: Phase I/II study, 280 women, 12 weeks, Africa (2010- 2011) • Active and placebo rings safe and well tolerated. Adverse events probably or possible related to ring use were similar for dapivirine and placebo • Plasma levels <1ng/mL; ring residual levels found that ~4mg dapivirine is released from Ring-004 over 28 days

18. IPM 015: ring acceptability • Ring was comfortable : 97% • Ring not felt during daily activities : 89% • Willing to use if effective : 97% • Prefer to wear ring every day : 97% • Prefer ring use during menses : 69% • Concerned ring might fall out : 16% • Concerned ring might get lost in body : 22% • Male partner did not feel ring during sex : 63% • Male partner felt ring, but no problem: 22% • Male partner felt ring might be or definitely a problem : 1%

19. IPM 015: safety data

20. IPM 015: ring adherence • Frequency of ring use • Perfect adherence (ring never came out for >1 day) : 92% • Ring removals • Median number of times ring came out : 1 time per visit interval • Frequency decreased over time • Most frequent activity for involuntary expulsion: urination/ defecation • Most common reason for removal: cleaning • Had sex during the time that the ring was out : 17% - 36%

21. Dapivirine ring for HIV prevention: Ring-004 • SAFETY: • Safe and well-tolerated • No related SAEs, AEs similar in treatment and placebo groups • PK: • High vaginal, low systemic concentrations • Sustained release for at least 35 days • Acceptability • High willingness, good adherence, most common reason for removal = menses

22. ASPIRE: Design, Objectives, and Overview

23. ASPIRE Study Design

24. Primary Objectives EFFECTIVENESS • To determine the effectiveness of dapivirine (25 mg) administered in a silicone elastomer vaginal matrix ring, when inserted once every 4 weeks, in preventing HIV infection among healthy sexually active HIV-uninfected women • Primary Effectiveness Outcome: HIV seroconversion

25. Primary Objectives SAFETY • To assess the safety of dapivirine (25 mg) administered in a silicone elastomer vaginal matrix ring, when inserted once every 4 weeks over the investigational product use period • Primary Safety Outcomes: • Grade 2 adverse events (AEs) judged to be related to study product • Grade 3 and 4 AEs • All serious adverse events

26. Secondary Objectives • Acceptability • Self-report • Adherence • Including ring expulsions & removals • Drug resistance • In HIV-1 seroconverters • Relationship between drug concentrations and HIV-1 seroconversion • Concentrations of dapivirine in blood and self-collected vaginal swabs

27. Exploratory Objectives • Describe changes in the genital microenvironment • Changes in candidate biomarkers of safety and efficacy • Assess correlation of steady-state drug concentrations and adherence measures • Assess delayed seroconversion • 4 week post-product completion visit

28. Behavioral components • Quantitative assessments • CRFs • ACASI • Qualitative component • Subset of 6 sites (35-40♀/site) / ~5% sub-sample (~n=200) • Serial IDIs (M3; Y1 and/or PUEV) • Single IDIs with serconverters/ product discontinuers • Post PUEV FGDs (2 per site) • Adherence Counseling & Education (ACE) • Modeled after NSC and VASP (use experience, needs focused) • Integrates product adherence and visit retention

29. Participants • 3476 sexually active HIV-uninfected women who are non-pregnant, contracepting, and 18-45 years of age • Accrual will require approximately 12 months, with total study duration approximately 24 months • Designed so that all participants will achieve 12 months on study product

30. Follow-up • Monthly follow-up, including: • HIV serologic testing • Contraceptive counseling and provision • Clinical safety assessment • Study produce provision and adherence counseling • Physical and pelvic examination, laboratory safety assessment (every 3-6 months)

31. Pregnancy • Women who become pregnant while in the study will need to stop using the ring but can remain in the study to continue with follow-up visits • Women will be referred for appropriate care and invited to join MTN-016, an observational registry study that aims to understand if product use has an effect on pregnancy outcomes • She may be able to rejoin ASPIRE after her pregnancy

32. HIV acquisition Sites are required to have procedures for care and support for participants who acquire HIV and referral agreements with HIV primary care and ART providers The study product will be discontinued immediately Antiretroviral resistance testing will be done Seroconverters will be invited to join MTN-015 MTN-015 is a long-term observational study / registry of seroconverters from MTN studies

33. Sites, Timelines, and Goals

34. Proposed sites Blantyre Lilongwe Malawi Cape Town Durban (8 sites) Johannesburg South Africa Kampala Uganda Lusaka Zambia Harare (3 sites) Zimbabwe

35. Timeline 2011 2012 2013 2014 2015 • Initiate site IRB and regulatory approval process • IRB/regulatory approvals, trainings, • enrollments begin Q3 • Enrollments and follow-up continue • End of participant follow-up • Results

36. The Big Five Accrual Retention Adherence Clinical and Laboratory Participant Safety Data Quality and Timeliness

37. Design efficiencies • Accrual • Large number of sites, modest sample size = achievable number of recruitments • Focus will be on protocol adherence during screening and enrollment – i.e., really trying to enroll only those who will return as scheduled for follow-up • Follow-up • Streamlined data collection and study procedures = reduced time spent in clinic • Allowances for efficiencies for individual women – protocol provisions for extra ring dispensing and off-site visits

38. Design efficiencies (2) • Retention • Focus from day one from participant one : resource and attention allocation will be critical • No retention = no adherence • Provision of services on-site • Contraception : expanding method mix and convenience • Partner HIV testing, STI evaluation/referral

39. MTN-020 and IPM 027

40. MTN-020 and IPM 027

43. Similarities • Very similar primary, secondary, and exploratory objectives and endpoints

44. Similarities • Very similar primary, secondary, and exploratory objectives and endpoints • Key goals are identical: efficient enrollment, high retention, promotion of product use/adherence, definitively testing whether this product is safe and effective

45. Differences • Sample size (3476 vs. 1650) • Follow-up (open-ended vs. fixed 24 months) • Randomization (1:1 vs. 1:2) • Sample collection (somewhat different repositories), laboratory testing (027 has more tests), pregnancy (027 will terminate at pregnancy)

46. Coordination • MTN-020 and IPM 027 teams have worked tirelessly to ensure that data collection, counseling/clinical management, oversight are moving in parallel • MTN-020 and IPM 027 are coordinated within single regulatory/investigational new drug applications (FDA, EMA)

48. Dapivirine ring for HIV prevention • Dapivirine ring has shown safety and acceptability in phase I and phase II trials but its large-scale safety and its effectiveness for HIV protection are unknown • These studies will provide the definitive data to determine whether dapivirine vaginal ring will have the strength of evidence to support potential licensure

49. Key Considerations for Optimization of Implementation

50. Numbers that matter • 3476 = total number of women enrolled • >95% = retention, product distribution • 100% = attention to data quality, safety Everything else flows from these