Long Acting Injectable Agents for HIV Prevention Nyaradzo M Mgodi (MBChB, MMed) On behalf of the HPTN-076 Team UZ-UCSF Annual Research Day May 05, 2017 Harare

Outline Background Introduction to Rilpivirine (TMC 278) HPTN-076 Study Design Methods Results Conclusions Chemoprophylaxis for the prevention of HIV infection has been revolutionized by recent studies showing high-levels of protection against rectal exposures in MSM and vaginal exposures in sero-discordant couples by daily oral tenofovir/emtricitabine Robust efficacy data led to the approval of daily oral TDF/FTC by the US Food and Drug Administration in 2012, for men and women who are at high risk of becoming HIV infected. Indicate a clear dose-response relationship of protection and adherence protection afforded by daily oral use of TDF/FTC has been modelled to be 99% when taken 7 days per week as prescribed modelled data and clinical cohorts suggest some forgiveness of missed doses for protection against rectal exposures – as few as 4 doses per week appears to preserve high levels of protective efficacy Protection against vaginal exposures has been less rigorously described, but is modelled to be much less forgiving of missed doses than are rectal exposures Attributable to differential tissue pharmacokinetics of the components of TDF/FTC in rectal and cervico-vaginal matrices Challenges of daily or near-daily oral dosing strategies, and the long-term maintenance of such dosing have driven interest in PrEP agents that have more convenient dosing schedules.

Background Daily oral tenofovir/emtricitabine is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). Adherence to daily oral PrEP is difficult for many Long-term maintenance of such dosing is a challenge Oral PrEP is one option May not be suitable for everyone Finding alternative PrEP strategies is a priority. Urgent need to develop PrEP agents that have more convenient dosing schedules, such as: Long acting (LA) injectable agents Chemoprophylaxis for the prevention of HIV infection has been revolutionized by recent studies showing high-levels of protection against rectal exposures in MSM and vaginal exposures in sero-discordant couples by daily oral tenofovir/emtricitabine Robust efficacy data led to the approval of daily oral TDF/FTC by the US Food and Drug Administration in 2012, for men and women who are at high risk of becoming HIV infected. Indicate a clear dose-response relationship of protection and adherence protection afforded by daily oral use of TDF/FTC has been modelled to be 99% when taken 7 days per week as prescribed modelled data and clinical cohorts suggest some forgiveness of missed doses for protection against rectal exposures – as few as 4 doses per week appears to preserve high levels of protective efficacy Protection against vaginal exposures has been less rigorously described, but is modelled to be much less forgiving of missed doses than are rectal exposures Attributable to differential tissue pharmacokinetics of the components of TDF/FTC in rectal and cervico-vaginal matrices Challenges of daily or near-daily oral dosing strategies, and the long-term maintenance of such dosing have driven interest in PrEP agents that have more convenient dosing schedules.

Background LA injectable agent precedence Anti-psychotics Contraception Antibiotics Analgesia LA injectable agents for HIV prevention Obviate the need for daily pill taking, Raise novel challenges regarding adherence, safety, and optimizing starting and stopping mechanisms. Chemical entities in advanced stages of clinical development for LA prophylactic use include Rilpivirine (RPV) The field of long acting (LA) injectable agents has substantial precedent among antipsychotics (e.g., paliperidone palmitate) and contraception (e.g., medroxyprogesterone acetate). Removable depots of contraceptive agents (Norplant), and transdermal patches for sustained drug delivery are attractive, but are limited by molecular size and chemical properties including hydrophobicity and charge. Technologies are evolving rapidly, and a recent presentation of an implantable system appears capable of delivering tenofovir alafenamide (TAF) in sustained fashion in a dog model [11]. HIV chemoprophylaxis - LA agents have the potential advantage of requiring less-than-daily dosing intervals, some dosed as infrequently as every 2 to 3 months. All LA HIV antiviral agents currently in development require parenteral injections – via subcutaneous, intramuscular (IM), or intravenous routes of administration.

Rilpivirine (TMC278) Favorable attributes for PrEP: Generally safe and well tolerated High concentrations found in genital tract Novel parenteral nanosuspension formulation (TMC278 LA) allows 8 weekly dosing Well-suited for delivery via IM injection NNRTI Rilpivirine (RPV, Edurant, Janssen Scientific) was approved by the FDA in May 2011 for the treatment of HIV-1 infection at an oral dose of 25 mg daily. It is a small-molecule non-nucleoside reverse transcriptase inhibitor with picomolar activity against HIV-1 primary clinical isolates [16]. Oral RPV is indicated for HIV-1-infected individuals with viral loads <100,000 c/mL, and is being developed as a LA injectable preparation (also referred to as TMC278LA or RPV LA) [17]. The RPV LA has undergone a series of formulation revisions in order to optimize pharmacokinetics: It is a liquid formulation that must be injected into muscle Three PK, safety and tolerability studies have been completed More than 150 humans have been given TMC278 LA Injections have been well tolerated and safe Injection site reactions are the most common adverse events Rilpivirine - a small molecule non-nucleoside reverse transcriptase inhibitor (NNRTI) Potent antiviral activity against HIV. Approved by the FDA in May 2011 for the treatment of HIV-1 infection at an oral dose of 25 mg daily. Effective as part of treatment for ARV-naïve HIV-infected patients as rilpivirine 25 mg tablets. Also co-formulated with TDF and FTC for use as a once-daily single fixed-dose combination (Complera™) TMC278 LA is long-acting suspension, well-suited for delivery via IM injection Currently being considered for both ART and HIV prevention.

Are long-acting injectable PrEP agents safe? Questions Is the use of injections for HIV prevention acceptable in diverse populations? Are long-acting injectable PrEP agents safe?

HPTN 076 Phase II Safety and Acceptability of an Investigational Injectable Agent, TMC278 LA, for HIV Pre-Exposure Prophylaxis

Study Sites SpilhausTeam Harare, Zimbabwe US Sites Newark, NJ International Sites Cape Town, South Africa Harare, Zimbabwe Bronx, NY HPTN 076 is a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg TMC278 LA (LA) to placebo (P). Injectable product was administered to low risk, sexually active HIV-uninfected women in two gluteal, intramuscular (IM) injections every eight weeks over a 48-week period. Injections followed 28-days of self-administered daily oral rilpivirine (RPV, 25mg). Acceptability, safety and pharmacokinetic data were collected throughout the study. Product was paused for any participant with Grade (Gr) >2 related or Gr >3 unrelated adverse events (AEs).  

Methods HPTN 076 is a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg TMC278 LA to placebo Injectable product was administered to low risk, sexually active HIV-uninfected women Injectable product was administered in two gluteal, IM injections on 6 occasions, 8 weeks apart at study Weeks 4, 12, 20, 28, 36, and 44 during the Injection Phase. All study participants are followed to Week 76, 32 weeks after the last injection visit, the Tail Phase.

Methods Prior to injections, participants received either placebo or 25mg rilpivirine (RPV) for 28 days. Participants were observed taking the oral product up to six times in clinic. The remaining oral doses were self-administered during study Weeks 0 – 4 (Oral Run-in Phase). Acceptability, safety and pharmacokinetic data were collected throughout the study. Product was paused for any participant with grade >2 related or grade >3 unrelated adverse events (AEs). either placebo or 25mg rilpivirine (RPV). Participants were observed taking the oral product up to six times in clinic. The remaining doses were self-administered during study Weeks 0 –4 (Oral Run-in Phase). •Events (AEs) during the Oral Run-in phase did not progress to the Injection Phase. On a case-by-case basis, participants with Grade 3 or 4 UNRELATED AEs were permitted tomove into the Injection Phase. •the same criteria. Product was re-started in specific instances after review and consensus by study clinicians.

HPTN 076 Study Design 136 HIV-uninfected, ages 18-45 ARM 1 N = 91 WEEKS 4 52 76 ORAL RUN-IN INJECTION PHASE ARM 1 N = 91 Daily Oral TMC278 Six doses of injections of TMC278 LA every 8 weeks Follow-up phase (Tail phase) ARM 2 N = 45 Daily oral placebo Six doses of injections of TMC278 LA placebo HPTN 076 is a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg TMC278 LA (LA) to placebo (P). Injectable product was administered to low risk, sexually active HIV-uninfected women in two gluteal, intramuscular (IM) injections every eight weeks over a 48-week period. Injections followed 28-days of self-administered daily oral rilpivirine (RPV, 25mg). Acceptability, safety and pharmacokinetic data were collected throughout the study. Product was paused for any participant with Grade (Gr) >2 related or Gr >3 unrelated adverse events (AEs).   Primary objective: Evaluate the safety of TMC278 LA, through 48 weeks after initial injection in women in sub-Saharan Africa and the U.S.

Methods Participants presenting with Grade 2 or greater RELATED Adverse Events (AEs) during the oral run-in phase did not progress to the Injection Phase. On a case-by-case basis, participants with Grade 3 or 4 UNRELATED AEs were permitted to move into the Injection Phase. The Fisher Exact test was used to compare the number of AEs between the two arms. Boxplots were used to summarize the distribution of plasma RPV concentration at each visit. either placebo or 25mg rilpivirine (RPV). Participants were observed taking the oral product up to six times in clinic. The remaining doses were self-administered during study Weeks 0 –4 (Oral Run-in Phase). •Events (AEs) during the Oral Run-in phase did not progress to the Injection Phase. On a case-by-case basis, participants with Grade 3 or 4 UNRELATED AEs were permitted tomove into the Injection Phase. •the same criteria. Product was re-started in specific instances after review and consensus by study clinicians.

Methods Drug concentrations were determined via a validated liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method Participants identified one or more attributes of injectable prevention they liked and disliked at baseline. Participants’ interest in future injectable PrEP use was measured at Week 44 by level of agreement with six items. Comparisons by arm were made between participants who “agreed a lot” to each statement. either placebo or 25mg rilpivirine (RPV). Participants were observed taking the oral product up to six times in clinic. The remaining doses were self-administered during study Weeks 0 –4 (Oral Run-in Phase). •Events (AEs) during the Oral Run-in phase did not progress to the Injection Phase. On a case-by-case basis, participants with Grade 3 or 4 UNRELATED AEs were permitted tomove into the Injection Phase. •the same criteria. Product was re-started in specific instances after review and consensus by study clinicians.

Timeline for Major Milestones March, 2015 All sites activated September, 2015 Enrollment completed September, 2016 Primary Endpoint February, 2017 Last study visits

Results A total of 136 (100 African, 36 US) women were enrolled. During the Oral Run-in Phase, ten women withdrew (8 active arm, 2 placebo arm) and four had product discontinued (3 active arm, 1 placebo arm). During the Injection Phase, 1 withdrawal and 16 product discontinuations (10 active arm, 6 placebo arm). 6 (8%) active arm and 2 (5%) placebo arm were due to AEs

Participant Characteristics Overall (N=136) African Sites (N= 100) US Sites (N=36) Median Age 31 years (IQR: 25,38) 31 years (IQR: 22,37) 32 years (IQR: 28,40) Median Weight 75 kg (IQR: 64,89) 72 kg (IQR: 63,87) 83 kg (IQR: 72,100) Marital Status 46% married 56% married 19% married Race 94% Black 100% 78% Employment Status 60% unemployed 65% unemployed 47% unemployed

Injection Phase: Safety Data A total of 122 (80 active arm, 42 placebo arm) women received > one injection; 98 participants (64 active arm and 34 placebo arm) received all six injections. Transient grade >2 liver abnormalities occurred in 9 (11%) of active arm participants compared with 4 (10%) in the placebo arm. Three active arm participants developed grade >3 injection site reactions compared with none in the placebo arm. The differences in AEs observed between the two arms were not statistically significant. Of the 16 product discontinuations during Injection Phase, 6 (8%) active arm and 2 (5%) placebo arm were due to AEs including one placebo arm participant with prolonged QTc interval.

Active Arm Participants Receiving at Least One Injection (N=80) Injection Phase: Drug Concentration Active Arm Participants Receiving at Least One Injection (N=80) The solid line connects the median concentration over time. The dashed line is the PA-IC90 for RPV (=12.5 ng/mL). The variability seen in Figure 2a is reflective of participants receiving between one and six injections. For categorical variables, # (%) was reported and for continuous variables, median (IQR) was reported. The Fisher Exact test was used to compare the number of AEs between the two arms. Boxplots were used to summarize the distribution of plasma RPV concentration at each visit, where the mid-line of the box denotes the median and the ends of the box denote the 25th and 75th percentiles, with whiskers extended to the extreme data points that are no more than 1.5 times the inter-quartile range, and the diamond denotes for the mean. test was used to compare the number of AEs between the two arms. Boxplots summarize the distribution of plasma RPV concentration at each visit, where the mid-line of the box denotes the median and the ends of the box denote the 25thand 75thpercentiles, with whiskers extended to the extreme data points that are no more than 1.5 times the interquartile range (IQR), and the diamond denotes for the mean.

Injection Phase: Drug Concentration In participants receiving at least one injection: The median trough concentration (CTrough) of RPV during the injection phase was 68.2 ng/mL. The concentration two weeks (C2WK) after the first and second injections (at Weeks 6 and 14) was 85.5 ng/mL and 113 ng/mL, respectively.  At Week 52 (eight weeks after last injection), the CTrough was 91.9 ng/mL. a measure of the concentration of drug needed to inhibit 50% or 90%, respectively, of viral growth

Injection Phase: Drug Concentration Participants receiving all six injections (N=64) < 2% had RPV concentrations below the PA-IC90 at any given time point after Week 4 when injections began. a measure of the concentration of drug needed to inhibit 50% or 90%, respectively, of viral growth

Acceptability Data The majority of participants liked that the injectable was: Easier to use (>80%) Provided longer-term protection (>73%) Some participants disliked that the injectable was: Painful (~30%) Had side effects (31-37%) Acceptability did not differ by arm. At the last injection visit 61% of women strongly agreed that they would definitely use and 73% that they would think about using a PrEP injectable in the future. At the last injection visit, only 3% of participants “strongly agreed” that they would NOT use an injectable PrEP agent if it were available. Participants reported strongest interest in future use of an injectable that prevented both HIV and pregnancy.

Acceptability Data

Acceptability Data

Acceptability Data At the last injection visit, 73% of women strongly agreed that they would think about using – and 61% that they would definitely use – a PrEP injectable in the future.

Are long-acting injectable PrEP agents safe? Questions Is the use of injections for HIV prevention acceptable in diverse populations? Are long-acting injectable PrEP agents safe?

And it all comes together… Conclusions TMC278 LA IM injections administered every eight weeks in this clinical trial cohort of African and US women were safe, overall well tolerated and acceptable. Data from this study support further development of injectable agents for PrEP. And it all comes together…

Congratulations! 988 scheduled visits – 100% retention rate Spilhaus representatives receiving retention award – HPTN Annual Meeting, April 2017, Washington DC

Thank you! We sincerely thank the 136 participants, especially the 52 women from Zimbabwe, and their families/communities CAB Study site staff Protocol Leadership And all of you for your invaluable support 076 Festivities…

Acknowledgements The HIV Prevention Trials Network is sponsored by the U.S. National Institute of Allergy and Infectious Diseases, the U.S. National Institute of Mental Health, and the U.S. National Institute on Drug Abuse, all components of the U.S. National Institutes of Health.