What s in the Biomedical Prevention Pipeline

Transcription

1 What s in the Biomedical Prevention Pipeline HIV Endgame: Closing Gaps in the Care Cascade Toronto, 24 th October 2016 Ian McGowan MD DPhil FRCP University of Pittsburgh Pittsburgh, PA, USA

2 Presenter Disclosure Presenter: Ian McGowan Relationships with commercial interests Grants/Research support: Janssen R & D Speakers Honoraria: ABIVAX Consulting Fees: Aelix Therapeutics, Novicol Life Sciences, Other: Employee of the University of Pittsburgh Medical Center

3 Overview The need for biomedical approaches to HIV prevention Oral PrEP Topical PreP Vaginal microbicides Rectal Microbicides Long Acting antiretroviral PrEP Injectable agents and implants Vaccines and monoclonal antibodies for HIV prevention

4 The HIV/AIDS Epidemic in million people were accessing antiretroviral therapy 36.7 million people globally were living with HIV 2.1 million people became newly infected with HIV 1.1 million people died from AIDS related illnesses UNAIDS 2015 Data

5 The HIV Prevention Tool Box in 2016 Available Sexual health education, delayed sexual debut, STI diagnosis & treatment, and condoms Male circumcision Treatment as prevention Oral Pre exposure prophylaxis (PrEP) In development Injectable PrEP Microbicides Vaccines and monoclonal antibodies

6 The HIV Prevention Tool Box in 2016 Available Sexual health education, delayed sexual debut, STI diagnosis & treatment, and condoms Male circumcision Treatment as prevention Oral Pre exposure prophylaxis (PrEP) In development Injectable PrEP Microbicides Vaccines and monoclonal antibodies

7 Oral PrEP

8 The Good News Clear evidence for PrEP effectiveness iprex study: 44% Proud (UK) & IperGay (France) studies: 86% WHO recommends PrEP for all population groups at substantial risk of HIV infection Populations with an HIV incidence of about 3 per 100 person years or higher

9 The Bad News

10 The Discover Trial Emtricitabine/TFV versus Emtricitabine/TFV MSM & Transgender women (N = 5,000) Key endpoints Bone & renal safety HIV infection 96 week follow up period Study completion anticipated in 2020

11 Topical PrEP

12 Microbicides Microbicides are products that can be applied to the vaginal or rectal mucosa with the intent of preventing or significantly reducing the risk of acquiring STIs including HIV

13 Topical Microbicides Deliver antiretrovirals directly to the site of infection High concentrations of antiretrovirals locally Minimal systemic antiretroviral exposure Vaginal microbicide formulations Gels, vaginal rings, and vaginal films Rectal microbicide formulations Gels, enemas, and solid dose formulations

14 Vaginal Microbicides Multiple gel based products have been evaluated but only tenofovir 1% gel was found to be effective in the CAPRISA 004 study (39%) Attention is now focused on the development of intravaginal rings (IVRs) Single antiretroviral IVR Combination antiretroviral IVR Multipurpose IVR (antiretroviral & contraceptive)

15 Why a Vaginal Ring for HIV Prevention? Longer Acting: Used monthly or longer sustained release of drug May help with consistent use Higher adherence increased effectiveness Ease of Use: Flexible ring women insert and remove the ring themselves Little or no impact on sexual activity Safety: Studies have shown the ring is safe to use and has very few side effects Privacy: Vaginal rings can be inserted and removed in private Rarely felt by women or male partners Vaginal rings are used in the US and Europe to deliver contraception

16 The ASPIRE Study Overall 27% reduction in HIV (statistically significant) 27% reduction 71 women acquired HIV in the dapivirine ring group (3.3% annual incidence) 97 women acquired HIV in the placebo ring group (4.5% annual incidence)

17 HIV Protection Differed by Age Women age 25 or older had substantial HIV protection while those younger than age 25 had no significant reduction in HIV incidence < 25 years >25 years 10% reduction 61% reduction

18 Rectal Microbicides Individuals practicing receptive anal sex often use lubricants A lubricant based antiretroviral microbicide might provide a highly acceptable form of HIV prevention Animal studies have demonstrated the feasibility of this approach

19 Would This Approach Work? HIV ( 99m Tc SC) in Ejaculate Microbicide ( 111 In DTPA) CHARM 02 Study (Hiruy H et al. AIDS Res Hum Retroviruses 2015)

20 The MTN 017 Study

21 MTN 017 Study Design Open label crossover design, Each participant was randomized to follow all study regimens for eight weeks, with a one week wash out period between regimens Study regimens Rectal RG 1% TFV gel used daily Rectal RG 1% TFV gel used before and after receptive anal intercourse (RAI) FTC/TDF tablet taken daily 4 weeks 4 weeks Visit 1 Screening Visit 2 Enrollment Initiate Period 1 Visit 3 Mid Period Visit 4 Period 1 End Washout Visit 5 Initiate Period 2. Visit 10 Period 3 End Period 1 Period 2 Period 3

22 Key Findings From MTN 017 Rectal tenofovir gel was safe and acceptable compared to oral Truvada Participants preferred using gel before and after sex rather than on a daily base Participants did not like using the vaginal applicator to insert the gel

23 In Response to Community Concerns The Microbicide Trials Network (MTN) will conduct two Phase 1 studies MTN 033 to determine whether digital / phallic insertion equivalent to applicator insertion of dapivirine gel MTN 039 to determine the safety and acceptability of a combination antiretroviral rectal insert Elvitegravir & tenofovir

24 Moving Forward with Rectal Products DREAM Program PREVENT Program Tenofovir prodrug enemas PI: Craig Hendrix, JHU Griffithsin rectal gel PI: Kenneth Palmer, University of Louisville

25 Long Acting Antiretroviral PrEP

26 Requirements for LA ARV Infrequent dosing (~ 2 3 months) Practical injection volume (~ 4mL) Stable formulation ideally without cold chain requirements Potential LA antiretroviral products TMC278 LA (Rilpivirine) GSK 744 (Cabotegravir) EFdA

27 Long Acting Antiretroviral PrEP Candidates

28 Rilpivirine LA NNRTI licensed as Edurant for the treatment of chronic HIV infection (25 mg) PA EC 90 : 12.2 ng/ml Plasma trough levels in successful treatment populations: ~70 ng/ml Formulation: 300 mg / ml PrEP doses evaluated mg QD & Q8 weeks

29 Rilpivirine Levels in Plasma 160 RPV (ng/ml) mg 600 mg 300 mg PA EC 90 Time (days) Jackson A et al. Clinical Pharmacology & Therapeutics 2014

30 MWRI 01 Rilpivirine PK/PD McGowan I et al. Lancet HIV 2016

31 Cabotegravir Integrase inhibitor analogue of dolutegravir Oral dose 30mg Highly protein bound PA IC 90 : 166ng/mL Formulation: 200 mg/ml Dosing varies by indication PrEP: 600 mg Q4 x 2 then Q8 weeks Treatment: 400 mg Q4 weeks

32 ÉCLAIR Study Phase 2A study in which 127 HIVuninfected participants were randomized to receive cabotegravir or placebo (5:1) Oral cabotegravir (30mg) or matching placebo tablet for four weeks followed by 800mg cabotegravir LA or placebo dosed once every 12 weeks for three cycles. Markowitz M et al. CROI 2016

33 ÉCLAIR Study Results Well tolerated through Week 41 Faster absorption from the depot site resulted in mean Ct below the minimum target of 4x PA IC90. An alternative dosing strategy of 600mg Q8 weeks is being investigated with the aim of achieving targeted exposure prior to conduct of Phase 3 efficacy trials. Markowitz M et al. CROI 2016

34 HPTN 083 Study

35 Potent nucleoside RTI derived from soy 10 mg dose associated with 1.64 log reduction in viral load Allows for once weekly dosing T 1/2 in PBMC 103 hours LA formulation might last 1 year EFdA

36 The Patient s Perspective It seems to me that it s much better because you simply don t have to worry about anything. If you go on a trip, you don t have to bring your pills or take anything at all along. It s just that. You come once a month and you re done. You follow your normal life. You come once a month. You get the shot and it s over. You don t have to be thinking everyday oh I forgot to take the pill. Or when did I take it last... You just don t worry about anything. In reality, taking the pill everyday keeps it present [HIV] you have it more present and the shot is just once a month you remember it when you come in and the rest of the time you can basically forget it. Spain, MSM LATTE-2 Study

37 Tolerability of LA Antiretrovirals

38 Patient Reported Outcomes 100% 80% 14% How satisfied are you with your current treatment? 1% 1% 1% 4% 1% 20% 29% 100% 80% How satisfied would you be to continue with your present form of treatment? 11% 1% 13% 1% 1% 8% 2% 2% 60% 60% 33% 40% 40% 20% 20% 0% 83% 79% 67% Q8W (n=109) Q4W (n=103) Oral CAB (n=49) 0% 88% 85% 55% Q8W (n=109) Q4W (n=103) Oral CAB (n=49) very satisfied very dissatisfied LATTE-2 Study. Margolis D et al. AIDS 2016

39 Injection Site Reactions Over Time Overall ISR AE Incidence Subjects at visit Day 1 W 4 W 8 W 12 W 16 W 20 W 24 W 28 W 32 W 36 W 40 W 44 W 48 Weeks Q8W IM Q4W IM LATTE-2 Study. Margolis D et al. AIDS 2016

40 Challenges of LA PrEP Safety Acceptability Adherence Pharmacokinetics Resistance Operational complexity

41 Persistence of Rilpivirine LA RPV was detectable in 7/7 (100%) of plasma samples collected a mean of 541 days after single dose exposure to 1200 mg of RPV LA McGowan I et al. AIDS 2016

42 Resistance HIV infection during periods of declining drug exposure may result in the development of resistance NNRTI resistance seen in a SSAT040 study participant who received a 300 mg dose of rilpivirine and who seroconverted 1 Loss to follow up during implementation may generate large pool of individuals at risk of HIV infection and the development of resistance 1 Penrose K et al. JID 2016

43 Operational Complexity One month oral run in phase Exposure to LA PrEP every 2-3 months Two IM injections PrEP Cessation 12 months of Oral PrEP HPTN-083

44 Delivery of LA PrEP

45 Vaccine Research HVTN702 Phase 3 randomized controlled trial assessing efficacy and safety aimed at licensure of ALVAC/gp120 (Clade C) with MF59 adjuvant (N = 5,400 in South Africa) HVTN701 will start in early 2018 Phase 2b non licensure down selection study of novel vaccines candidates currently being evaluated in Phase 1 studies

46 Monoclonal Antibody Research The Antibody Mediated Prevention (AMP) studies Phase 2b evaluation of VRCo1 mab infusions for HIV prevention Participants will receive 10 IV infusions of VRC01 at monthly intervals HVTN704/HPTN 085: MSM & TGW in North/South America and Switzerland (N = 2,700) HVTN703/HPTN 081: Women in Sub Saharan Africa (N =1500)

47 Summary The safety and efficacy of oral PrEP has been established but global access is still problematic Oral PrEP adherence maybe suboptimal especially in adolescent MSM so other options are needed The safety and efficacy of topical PrEP has been established for IVRs and rectal microbicide research is ongoing Cabotegravir LA is moving towards Phase 3 licensure studies for both treatment and prevention New vaccine and monoclonal antibody studies will be initiated in 2016

48 Thank You