11/8/2016. Moving Beyond Truvada: The (Current) Future Pipeline for PrEP. Prevention Modalities

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1 Moving Beyond Truvada: The (Current) Future Pipeline for PrEP Raphael J. Landovitz, MD MSc Associate Professor of Medicine UCLA Center for Clinical AIDS Research & Education November 18, Million New Infections in ,600 New Infections per Day New HIV Infections 13,000 [9,600 17,000] 22,000 [13,000 33,000] 85,000 [48, ,000] 87,000 [70, ,000] 140,000 [110, ,000] 340,000 [240, ,000] 1.4 million [ million] UNAIDS. Fact Sheet: 2014 Statistics; Prevention Modalities Condoms PEP Voluntary Male Circumcision Needle Exchange Vaccine Abstinence HIV Treatment PrEP Microbicides HIV & STI Testing STI Treatment Harm Reduction 1

2 Clinical Trial Evidence for HIV Prevention Options (February 2016) Prevention of sexual transmission PROUD daily oral TDF/FTC (MSM United Kingdom) IPERGAY event-driven TDF/FTC (MSM Canada, France) Partners PrEP daily oral TDF/FTC (Serodiscordant couples Kenya, Uganda) Partners PrEP daily oral TDF (Serodiscordant couples Kenya, Uganda) TDF2 daily TDF/FTC (Heterosexual men and women Botswana) iprex daily oral TDF/FTC (MSM North and South America, South Africa, Thailand) Effect size (CI) 86% (58; 97) 86% (44; 99) 75% (55; 87) 67% (44; 81) 62% (22; 84) 44% (15; 63) CAPRISA 004 BAT-24 dosing vaginal tenofovir gel (Women South Africa) RV 144 six injectable ALVAC/AIDSVAX (Heterosexual men and women Thailand) The Ring Study monthly vaginal ring containing dapivirine (Women South Africa, Uganda) ASPIRE monthly vaginal ring containing dapivirine (Women Malawi, South Africa, Uganda, Zimbabwe) MTN 003/VOICE daily dosing vaginal tenofovir gel (Women South Africa, Uganda, Zimbabwe) FEM-PrEP daily oral TDF/FTC (Women Kenya, South Africa, Tanzania) FACTS 001 event-driven vaginal tenofovir gel (Women South Africa) MTN 003/VOICE daily oral TDF/FTC (Women South Africa, Uganda, Zimbabwe) MTN 003/VOICE daily oral TDF (Women South Africa, Uganda, Zimbabwe) R R R 39% (6; 60) 31% (1; 51) 31% (1; 51) 27% (1; 46) 15% (-21; 40) 6% (-21; 40) 0% (-40; 30) -4% (-49; 27) -49% (-129; 3) Prevention in Bangkok Tenofovir Study daily oral TDF people who (PWID Thailand) inject drugs DELIVERY SYSTEM ACTIVE DRUG % (10; 72) Vaccine Vaginal gel Oral pills Vaginal ring ALVAC/AIDSVAX Tenofovir Tenofovir/ emtricitabine (TDF/FTC) Dapivirin e Tenofovir disoproxil fumarate (TDF) Effectiveness (%) Adapted from: Salim S. Abdool Karim, CAPRISA 9000 Total Incidence and Growth Trend of FTC/TDF for PrEP 523% 8482 Unique individuals Individuals initiating FTC/TDF for PrEP, n Q20123Q20124Q20121Q20132Q20133Q20134Q20131Q20142Q20143Q20144Q20141Q20152Q20153Q2015 Quarter 49,148 Unique individuals initiated FTC/TDF for PrEP in the US 2Q2012 3Q Bush S, et al. ASM/ICAAC 2016; Boston, MA. #2651 FTC/TDF for PrEP Utilization Compared With Population and New HIV Infections Estimated Population Distribution by Race/Ethnicity, 2014, US a Total FTC/TDF for PrEP Utilization by Race/Ethnicity, Sept 2015, US b Estimated New HIV Infections, 2014, US c % 10% 12% % AA White Hispanics Asians Multiracial/Other FTC/TDF for PrEP use among AA and Hispanics is low relative to the rate of new HIV infections a. b. These data represent 43.7% (n=21,463) of unique individuals who have started TVD for PrEP from Q2015. c. Other indicates American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander. CDC. HIV Surveillance Report, Bush S, et al. ASM/ICAAC 2016; Boston, MA. #2651 2

3 The PrEP Pipeline: Looking past TDF/FTC Maraviroc HPTN 069/ACTG A TAF Macaque protection (?) but low tissue levels 2 Long Acting Therapies Rilpivirine (TMC278) HPTN 076 Cabotegravir (GSK ) HPTN 077/HPTN 083/ ÉCLAIR 3 Immunotherapies VRC01 Implantable devices More on Intermittent (i)prep Special populations HPTN 073 BMSM 4 ATN 110/113 Youth 5,6 Combinations of interventions 1. Gulick RM, CROI Garrett K, CROI Markowitz M, CROI Wheeler D, CROI Hosek S, IAS 2016; Mulligan K Compl HPTN 069 / ACTG A5305 A phase 2 safety study designed to answer: Could daily oral maraviroc, a CCR5 receptor antagonist, be a next-gen PrEP agent for men and/or women? HPTN 069 / ACTG A5305: Participants N = 406 individuals enrolled 100% male at birth; 7 (2%) transgender Median age 30 (range 18, 70) 28% black, 22% Latino, 62% white, 10% other (participants could report more than one) 20% high school education or less, 67% some college or more, 13% advanced degrees 31 (8%) had 34 STIs during study screening: 15 (4%) chlamydia, 5 (1%) gonorrhea, 14 (3%) syphilis 3

4 HPTN 069 / A5305: Results No differences by study arm in: proportion who discontinued study drugs (p=0.6) time to permanent study drug discontinuation (p=0.6) There were 67 grade 3-4 AEs No differences in occurrence or rate among the study arms (p>0.05 in pairwise comparisons) 90 (22%) had 115 STI diagnosed during study f/u Plasma Drug Concentrations: Random subset across 4 study arms (n=160) All study drugs in regimen detectable in 83% (week 24) and 77% (week 48) No differences between the study arms (p>0.3) HPTN 069 / A5305: HIV Infections 5 new HIV infections during the study Annual incidence rate 1.4% [95% CI: 0.8%, 2.3%] # Demos. (age, race/ ethnicity, HIV risk) 1 20, black MSM 2 61, Asian MSM 3 21, mixed MSM 4 35, white MSM 5 36, black MSM Study arm MVC+ TDF MVC alone MVC alone MVC alone First reactive HIV+ test (week) HIV RNA (cps/ml) CD4 cells (/mm 3 ) HIV tropism Genotypic drug resistance Plasma drug conc. at seroconversion visit (ng/ml)* 4 122, R5 none MVC=0 = R5 none MVC= , R5 none MVC= , R5 none MVC=6.7 MVC alone * expected pre-dose steady state MVC = 32 ng/ml undetectable plasma drug concentrations at every study visit 48 52, R5 none MVC=0.7 HPTN 069 / A5305: Study Drug Concs. in New HIV Infections MVC 32 ng/ml Note: 2 others with new HIV infection had undetectable study drug at every visit. 4

5 Pre-Clinical and Animal Models of TAF for PrEP Will it be equi-efficacious as TDF-based PrEP? Perhaps Perhaps not Prodrug Pharmacology of TDF and TAF GI TRACT TDF TAF RENAL TUBULAR CELL PLASMA LESS PLASMA STABILITY 91% LESS PLASMA 1 GREATER PLASMA STABILITY RENAL TUBULAR CELL OAT 1 & 3 OAT 1 & 3 LYMPHOCYTE HIV Sax P, et al. Lancet 2015 Wohl D, et al. CROI Boston, MA. #681 TAF 25 mg results in >90% lower plasma levels OAT, organic anion transporter; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate;, tenofovir. Concentrations of and -DP in Female Mucosal Tissues After Single Dose of TAF TAF 25mg, Tissue Samples BLQ, % n TDF 300mg Tissue Samples BLQ, % -DP -DP CVF 58 n/a n/a 95 Genital Tissue Rectal Tissue n BLQ=below the level of quantification. 0=all the samples had detectable (none were BLQ) Garrett K, et al. CROI Boston, MA. #102LB 5

6 F/TAF for PrEP in SHIV-Challenged Macaques Treatment arm (n=6) Placebo arm (n=6) 24h SHIV +2h FTC/TAF 24h SHIV +2h PBO SHIV challenge repeated weekly for up to 19 weeks F/TAF prevents rectal SHIV infection in macaques to a degree similar to that previously found with F/TDF but with a substantially reduced dose 1 F/TAF protected 100% of macaques (N=6) challenged with SHIV in a similar, pre-clinical trial 2 1. Massud I, et al. CROI Boston, MA. # Heneine W, et al. CROI Denver, CO. #32LB Percent protected SHIV challenges (weeks, n) FTC/TAF Placebo 0% 100% RILPIVIRINE: HPTN 076 A phase 2 safety study designed to answer: Could injectable rilpivirine, a FDA-approved NNRTI in its oral formulation, be a useful sustained-release PrEP agent? Long Acting Rilpivirine (TMC278) HPTN 076: Phase 2 Safety TMC278 LA is a novel poloxamer 338- containing formulation of TMC278. TMC278 LA is long-acting suspension and well-suited for delivery via IM injection HPTN 076 enrolling at 4 sites, low-risk HIVuninfected women (NY, NJ, Zim, SA) Fully enrolled, Data available

7 HPTN 076: Safety and acceptability of injectable rilpivirine(tmc278 LA) for PrEP 136 HIV-uninfected, women ages years WEEKS ARM 1 N = 91 ARM 2 N = 45 Daily oral TMC278 Daily oral placebo Six injections of TMC278 LA 1200 mg every 8 weeks Six injections of TMC278 LA placebo every 8 weeks Follow-up phase (tail phase) HPTN 076 STUDY SITES AND STATUS US Sites Bronx, NY Newark, NJ International Sites Cape Town, South Africa Harare, Zimbabwe Primary Endpoint September, 2016 Last Study Visit February,

8 CABOTEGRAVIR Formerly known as GSK Or 744 Cabotegravir (GSK ) development Early Phase Indication Phase 2a Phase 2b ± 3 NHP Models Treatment LATTE-1 LATTE-2 Pivotal Phase 3 First-inhuman/Phase 1 Prevention cis women HPTN 077* HPTN 084 Cardiac Safety, DDI Prevention MSM/TGW ECLAIR HPTN 083 *INCLUDES BOTH MEN AND WOMEN CAB LA PrEP Phase 2 Safety and PK Studies 1 analysis D1 W3 W4 W5 W9 W17 W25 W29 W33 W41 W53 W65 W77 W81 CAB 30 mg PO qd Placebo PO qd CAB LA 200mg/mL gluteal IM Placebo (0.9% saline) gluteal IM Follow Up Phase ECLAIR all subjects 800mg q12 wks (2 x 2mL) HPTN 077 Cohort 1 800mg q12 wks (2 x 2mL) HPTN 077 Cohort 2 600mg q8 wks (1 x 3mL) HIV negative, at risk adults (excluding high risk) Drug PK sampling (blood plasma) in all study participants ViiV ECLAIR Study (NCT ) n=126 (all injections complete) 800 mg IM 5:1 randomization Men including MSM US only (10 sites) HPTN 077 Study (NCT ) n=200 (110 Cohort 1; 90 Cohort 2) Two Cohorts (800 and 600mg IM) 3:1 randomization 67% enrolment of women US, Brazil, SA, Malawi (8 sites) 8

9 Plasma CAB Conc-Time Profiles following 800mg IM Q12W in ÉCLAIR 10 Plasma CAB ( g/ml) Simulated CAB 800mg IM Q12W (males, n=663) Observed CAB 800mg IM Q12W (ECLAIR, n=94) 8x PA-IC90 (1.35 g/ml) 4x PA-IC90 (0.664 g/ml) 1x PA-IC90 (0.166 g/ml) Time (Weeks) HPTN 083 A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir HPTN 083 Sites Phase 2b/3 45 Sites in 8 Countries Compared to Daily Oral TDF/FTC, for Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men Target enrollment: 4,500 HIVuninfected cisgender men and transgender women who have sex with men and who are at risk of HIV acquisition Primary outcome: HIV Prevention effectiveness of cabotegravir compared to daily oral TDF/FTC United States India Vietnam Thailand ClinicalTrials.gov Identifier: NCT Peru Brazil Argentina South Africa Anticipated Start Q32016 US Sites Non US Sites TBD* *Based on local regulatory approvals Screening Arm A Week 2 HPTN 083: Study Schema Blinded Injections & Safety Visits Week 4 Week 5 Week 9 Week 17 Week 25 Week 33 Week 41 Injections: Every 8 Week 49 Week 187 weeks Week 6 Week 10 Week 19 Week 27 Week 35 Week 43 Safety visits: Two weeks after each injection CAB LA 600 mg IM at Weeks 5, 9, and Q8 Weeks thereafter Plus Daily Oral Placebo for TDF/FTC + W W W W W Arm B + Daily Oral TDF/FTC Plus Placebo for CAB LA IM at Weeks 5, 9, and Q8 Weeks thereafter Step 1 Step 2 Step 3 Oral Phase Injection/Oral Phase Open Label Follow Up Key Cabotegravir oral Cabotegravir Oral placebo TDF/FTC oral TDF/FTC placebo Cabotegravir injection Cabotegravir placebo injection 9

10 Immunotherapies: VRC01 Slides adapted from Shelly Karuna/HVTN and Phil Andrew/HPTN The AMP Study (HVTN 704/HPTN 085) AMP is the first trial to assess if antibodies can be used to prevent HIV infection, similar to how antibodies are used to prevent other infectious diseases. Study Schema for The AMP Study REGIMEN MSM & TG in the Americas Women in sub Saharan Africa TOTAL VRC01 10 mg/kg VRC01 30 mg/kg Control Total infusions total & Infusions every 8 weeks Study duration: ~22 months 30 10

11 AMP Study Research Sites 31 Pre-Clinical and Animal Models of TAF for PrEP Will it be equi-efficacious as TDF-based PrEP? Perhaps Perhaps not Prodrug Pharmacology of TDF and TAF GI TRACT TDF TAF RENAL TUBULAR CELL PLASMA LESS PLASMA STABILITY 91% LESS PLASMA 1 GREATER PLASMA STABILITY RENAL TUBULAR CELL OAT 1 & 3 OAT 1 & 3 LYMPHOCYTE HIV Sax P, et al. Lancet 2015 Wohl D, et al. CROI Boston, MA. #681 TAF 25 mg results in >90% lower plasma levels OAT, organic anion transporter; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate;, tenofovir. 11

12 Concentrations of and -DP in Female Mucosal Tissues After Single Dose of TAF TAF 25mg, Tissue Samples BLQ, % n TDF 300mg Tissue Samples BLQ, % -DP -DP CVF 58 n/a n/a 95 Genital Tissue Rectal Tissue n BLQ=below the level of quantification. 0=all the samples had detectable (none were BLQ) Garrett K, et al. CROI Boston, MA. #102LB F/TAF for PrEP in SHIV-Challenged Macaques Treatment arm (n=6) Placebo arm (n=6) 24h SHIV +2h FTC/TAF 24h SHIV +2h PBO SHIV challenge repeated weekly for up to 19 weeks F/TAF prevents rectal SHIV infection in macaques to a degree similar to that previously found with F/TDF but with a substantially reduced dose 1 F/TAF protected 100% of macaques (N=6) challenged with SHIV in a similar, pre-clinical trial 2 1. Massud I, et al. CROI Boston, MA. # Heneine W, et al. CROI Denver, CO. #32LB Percent protected SHIV challenges (weeks, n) FTC/TAF Placebo 0% 100% Conclusions We did not stop with drug development when we had AZT for HIV treatment We have only experienced first generation PrEP to date The many exciting pharmaco-chemical and bio-engineering/delivery opportunities are being investigated We need better insights into how to market, equally (appropriately) deploy, and scale up these interventions 12

13 Thank you! Questions? 13