Microbicides Trial Network Safety and acceptability trial of the dapivirine vaginal ring in U.S. adolescents K. Bunge, L. Levy, D. Szydlo, J. Zhang, A. Gaur, D. Reirden, K. Mayer, D. Futterman, C. Hoesley, S. Hillier, M. Marzinke, C. Dezzutti, C. Wilson, L. Soto-Torres, B. Kapogiannis, A. Nel, K. Squires, MTN-023/IPM 030 Protocol Team Microbicides Trial Network July 25, 2017 K. Bunge1, L. Levy2, D. Szydlo3, J. Zhang3, A. Gaur4, D. Reirden5, K. Mayer6, D. Futterman7, C. Hoesley8, S. Hillier9, M. Marzinke10, C. Dezzutti9, C. Wilson8, L. Soto-Torres11, B. Kapogiannis12, A. Nel13, K. Squires14, MTN-023/IPM 030 Protocol Team

HIV and adolescent girls Young women ages 15-25 years are disproportionately affected by the HIV epidemic Among girls 10-19 AIDS is the leading cause of death (UNAIDS 2016-AIDS by the numbers) In Sub-Saharan Africa, 25% of new infections occur among young women in the 15-24 year age group (UNAIDS 2016 estimates)

HIV Prevention in ASPIRE and The Ring Study 27% reduction 31% reduction AN Overall 31% reduction in HIV (statistically significant) 77 infections out of 1300 women in active group (4.1% incidence rate) 56 infections out of 650 women in placebo group (6.1% incidence rate) Explain the randomisation again. Why 77 vs 56 (confusing to civil society sometimes) Baeten et al, N Engl J Med 2016 Nel et al, N Engl J Med 2016

In ASPIRE, HIV protection differed by age Among women who were 25 and older when they enrolled, 61% fewer acquired HIV in the dapivirine ring group compared to the placebo ring group Further analysis of data found the age cutoff for HIV protection was age 21 Age 18-21 – no protection (and lowest adherence) Age 22-45 – 56% fewer HIV infections among women in the dapivirine ring group vs. placebo group Our question: is the ring safe and acceptable in 15-17 year olds? Is there a reason to be concerned about safety? In a pre-planned analysis, we looked at different characteristics of women, one of which was age -- older and younger than 25. This was the only characteristic in which there was a statistically significant difference between women in the placebo group and women in the dapivirine group. Among women who were 25 and older when they enrolled, 61% fewer acquired HIV during the study in the dapivirine ring group compared to the placebo ring group. And this was highly statistically significant. Additional analyses were performed to further explore these results. Participants were stratified by age and divided into three groups with approximately equal numbers of HIV infections to balance statistical power. These results were also statistically significant - and you can see that the difference is really for those older than 21, that in fact women ages 22, 23, 24, 25 had significant reduction in HIV. If asked: Age 18-21: -27% effective (95% CI -133-31%) p=0.45 451 women, 44 HIV infections, placebo annual incidence 5.4% (95% CI 3.2-8.4) Age 22-26: 56% reduced risk of HIV (95% CI 19-76%) p = 0.009 752 women, 51 HIV infections, placebo annual incidence 6.1% (95% CI 4.3-8.3) Age 27-45: 51% reduced risk of HIV (95% CI 8-74%) p =0.028 1,192 women, 44 infections, placebo annual incidence 3.0% (95% CI 2.0-4.4) Baeten et al, N Engl J Med 2016

MTN023/IPM 030 Project iMatter Phase 2a randomized, double-blind placebo controlled trial of a dapivirine vaginal ring in 15-17 year olds in the US Collaboration between Adolescent Trials Network and Microbicide Trials Network Dapivirine vaginal ring was developed and supplied by IPM 6 sites ATN Denver Bronx Boston Memphis MTN Birmingham Pittsburgh

Randomization and participant criteria Randomized 3:1 to dapivirine or placebo ring Inserted monthly for 6 months Key inclusion criteria Participant assent and guardian consent Ages 15-17 Healthy, HIV-negative History of sexual activity Using an effective method of contraception at enrollment

Primary objective and endpoint To assess the safety of dapivirine (25 mg) administered via a silicone vaginal ring in HIV-uninfected adolescent females, when inserted once every 4 weeks during 24 weeks of study product use Primary endpoints Grade 2 adverse events (AE) deemed related to study product Grade 3 or higher adverse events

Secondary objectives and endpoints Acceptability Participant self report of acceptability via ACASI Adherence Frequency of VR expulsions and removals by self report Pharmacokinetics (local and systemic) Dapivirine concentrations in plasma and vaginal fluid

Exploratory objectives Adherence: To investigate the association between systemic and local drug concentration, ring residual drug levels and self-reported adherence measures Vaginal microenvironment: To describe the genital microenvironment over 24 weeks of study product use

Visit schedule / sample collection Screen Enrollment Phone contact Clinical evaluation Clinical evaluation Phone contact ≤56 Days Day 0 1 week 2 weeks q4 week x 6 25 weeks Each visit: AE assessment, adherence, acceptability 2, 4, 12 and 24 weeks: blood and vaginal fluid for drug level Each month: returned ring for residual drug level Ask SLH- PK instead of drug

Demographics Dapivirine (n=73) Placebo (n=23) Age, mean (SD) Range 16.3 (0.8) (15-17) 16.2 (0.7) Age at first menses 11.7 (8-15) (10-14) Latina or Hispanic 22% 17% Race Black or African American White Other 47% 27% 26% 57% Lifetime sexual partners, median 3 (1-23) (1-12) No condom last sex 49% Anal sex no condom, ever 21% 0%

Primary endpoint: Safety assessment Dapivirine (n=73) Placebo (n=23) Odds Ratio P-Value Participants with one or more Grade 2 related AE 8 (11%) 2 (9%) 1.29 (0.25, 6.57) 1.00 Grade 3 or higher AE 3 (4%) 0 (0%) -- Total 11 (15%) 1.86 (0.36, 18.55) 0.73

Product hold: none due to product toxicity Dapivirine (n=73) Placebo (n=23) Total (n=96) Number with at least one product hold 7 (10%) 2 (9%) 9 (9%) Total no. of product holds 8 2 10 Total no. of permanent discontinuation 2 (25%) 1 (50%) 3 (30%) Reasons for product hold AE Pregnancy Other 4 (50%) 0 (0%) 2 (50%) 4 (40%) AEs prompting hold: PID (2), trichomonas, IUD expulsion Fill in “other”?

Adherence: biologic measures and self-report Dapivirine plasma drug concentration > 95 pg/mL 87% of plasma samples with levels suggestive of adherence to study product in the day prior to visit Dapivirine residual drug levels in used rings <23.5 mg 95% of returned vaginal rings with levels suggestive of adherence over the past month Self report 42% (95% CI, 32, 52) of participants reported that they never removed the ring except to replace it monthly. Most removals were brief

Spaghetti plot of residual dapivirine concentration over time Better figure from SCHARP

Acceptability: assessed at 3 and 6 months Since your last visit… % visits It was easy or very easy to use the ring 95% Never experienced any physical discomfort because of the ring 87% Never aware of the ring during normal activities 74% Never felt the ring inside you when you had vaginal or anal sex 63% ….if you felt the ring, how much did it bother you? Not at all A little 76% 13% Did your sex partner feel the ring when you had sex? Never Not at all …if your partner was aware, did it bother him/her A little Unknown 41% 18% 49% 17% Did you like the ring? Yes, liked it 93% Choose a couple to emphasize?

Conclusions The dapivirine vaginal ring is safe and acceptable in 15-17 year old US girls Both plasma and residual vaginal ring drug levels indicated high adherence Consistency between dapivirine plasma levels and residual dapivirine levels in used rings supports appropriate study product use

Next steps Dapivirine licensure package has been submitted to the European Medicines Agency; SA MCC and FDA to follow Safety data among adolescents are required to support product labelling of new prevention products in this at risk group MTN-034 to begin in Q4, 2017 A Phase 2a crossover trial evaluating the safety of and adherence to a vaginal matrix ring containing dapivirine and oral emtricitabine/tenofovir disoproxil fumarate in 16-21 year olds 4 sites: S Africa, Uganda, Kenya, Zimbabwe A Phase 2a Crossover Trial Evaluating the Safety of and Adherence to a Vaginal Matrix Ring Containing Dapivirine and Oral Emtricitabine/Tenofovir Disoproxil Fumarate in an Adolescent Female Population

Funding The Microbicide Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The Adolescent Medicine Trials Network (ATN) for HIV/AIDS intervention is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 040533).

Acknowledgements Most especially, THANK YOU to the participants MTN 023/IPM030 study staff: Aditya Gaur, Daniel Reirden, Kenneth Mayer, Donna Futterman, Craig Hoesley International Partnership for Microbicides: Annalene Nel Dapivirine vaginal rings were developed and supplied by IPM SCHARP: Elizabeth Brown, Daniel Szydlo, Jingyang Zhang FHI360: Lisa Levy, Sherri Johnson MTN: Sharon Hillier, Jared Baeten, Devika Singh, Charlene Dezzutti, Mark Marzinke, Craig Hendrix ATN: Craig Wilson, Pamina Gorbach NIH: Lydia Soto-Torres, Roberta Black, Bill Kapogiannis Most especially, THANK YOU to the participants and their guardians