Taking a shot at HIV with longacting injectable ARVs for treatment and prevention

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1 Taking a shot at HIV with longacting injectable ARVs for treatment and prevention Martin Markowitz M.D. Clinical Director and Staff Investigator Aaron Diamond AIDS Research Center Aaron Diamond Professor at The Rockefeller University

2 Objectives Introduction to long acting injectable ARVs in clinical development Rilpivirine Cabotegravir Treatment of HIV infection with long acting ARVs LATTE studies Prevention of HIV-1 infection with long acting ARVs as PrEP

Rilpivirine is an HIV-1 NNRTI Oral 25 mg tablet

3 Long acting injectable ARVs in clinical development Cabotegravir is an HIV-1 integrase inhibitor Oral 30 mg tablet (t½, ~40 hours) LA nanosuspension 200 mg/ml (t½, ~20-40 days) Rilpivirine is an HIV-1 NNRTI Oral 25 mg tablet (t½, ~50 hours) LA nanosuspension 300 mg/ml (t½, ~30-90 days)

4 PK of long acting rilpivirine Williams et al Current Opinions HIV/AIDS 2015

5 PK of long acting cabotegravir Trezza et al Current Opinions HIV/AIDS 2015

6 The HIV Cascade in the US-2011 Kilmarx et al Current Opinions in HIV/AIDS 2012

7 Development Plan for Treatment LATTE 1 3-drug oral induction followed by a 2-drug oral maintenance to establish the feasibility of a 2-drug maintenance regimen LATTE 2 3-drug oral induction followed by either monthly or bimonthly 2-drug injectable maintenance therapy to establish proof-of-principle of the first long acting HIV treatment regimen Phase 3 3-drug oral induction/2-drug injectable maintenance in ARV naïve Switch from oral to 2-drug injectable therapy

8 LATTE 1: Study Design Margolis et al. CROI 2015; Seattle, WA. Poster 554LB

9 Margolis et al. CROI 2015; Seattle, WA. Poster 554LB LATTE 1: Baseline Characteristics CAB 10 mg n=60 CAB 30 mg n=60 CAB 60 mg n=61 EFV 600 mg n=62 Age Median (y) Gender Male 95% 97% 93% 98% Race White 62% 65% 59% 63% African American/African 35% 28% 30% 32% Ethnicity Hispanic/Latino 15% 27% 23% 19% Baseline HIV-1 RNA Median (log 10 c/ml) Median (c/ml) 19,099 15,066 22,336 22, ,000 c/ml 13% 12% 20% 13% Baseline CD4+ Median (cells/mm 3 ) <200 cells/mm 3 3% 7% 3% 2% Hepatitis coinfection HCV Ab + 0% 8% 7% 2% Investigator-selected dual NRTIs at Day 1 TDF/FTC 62% 62% 61% 61% ABC/3TC 38% 38% 39% 39% 243 patients were randomized and treated (ITT-E): 96% male, 38% non-white, 14% >100,000 c/ml HIV-1 RNA, 61% TDF/FTC

10 Week 96 Treatment Outcomes Margolis et al. CROI 2015; Seattle, WA. Poster 554LB Outcome at Week CAB 10 mg CAB 30 mg CAB 60 mg CAB total EFV 600 mg % <50 c/ml at W96 Snapshot (ITT-E) 41/60 (68%) 45/60 (75%) 51/61 (84%) 137/181 (76%) 39/62 (63%) Protocol-defined virologic failure 3 (5%) 2 (3%) 1 (2%) 6 (3%) 6 (10%) Failure - adverse event 1 (2%) 1 (2%) 4 (7%) 6 (3%) 9 (15%) Failure - HIV-1 RNA 50 c/ml 5 (8%) 1 (2%) 2 (3%) 8 (4%) 2 (3%) Failure - other + reasons while 50 c/ml 2 (3%) 2 (3%) 1 (2%) 5 (3%) 3 (5%) Failure - other + reasons while <50 c/ml 8 (13%) 9 (15%) 2 (3%) 19 (10%) 3 (5%) % <50 c/ml at W96 Snapshot (ITT- ME) 41/52 (79%) 45/53 (85%) 51/55 (93%) 137/160 (86%) 39/47* (83%) Protocol-defined virologic failure 2 (4%) 1 (2%) 0 3 (2%) 2 (4%) Failure - adverse event 1 (2%) 0 1 (2%) 2 (1%) 2 (4%) Failure - HIV-1 RNA 50 c/ml 4 (8%) 1 (2%) 1 (2%) 6 (4%) 2 (4%) Failure - other + reasons while 50 1 (2%) 1 (2%) 1 (2%) 3 (2%) 0 c/ml Failure - other + reasons while <50 c/ml 3 (6%) 5 (9%) 1 (2%) 9 (6%) 2 (4%) ++ W96 represents a 24-week Induction Phase followed by a 72-week Maintenance Phase. HIV-1 RNA 50 c/ml reasons include HIV-1 RNA 50 c/ml at Week 96 or discontinued while not suppressed ( 50 c/ml) for lack of efficacy. + Other reasons include missing data, protocol deviation, non-compliance, lost to follow-up, withdrawn consent, investigator discretion, ART change and ineligible for Maintenance Phase. *EFV patients with a W24 visit (n=47). Subcategories are a slight variation on FDA Snapshot Study Outcomes categories.

11 Protocol defined Virologic Failure Induction phase Seven subjects total: CAB 10 mg, n=1 Week 8; 30 mg, n=1 Week 4; 60 mg, n=1 Week 8; EFV 600 mg, n=4 Weeks 4 (n=2), 8 and 16 No treatment-emergent genotypic or phenotypic resistance Maintenance phase Five subjects total: CAB 10 mg, n=2 Weeks 48 and 72; CAB 30 mg, n=1 Week 36; EFV 600 mg, n=2 Weeks 36 and 60 Treatment-emergent resistance 3 subjects through W96 CAB 10 mg NNRTI (E138Q) and IN (Q148R) in one subject with PDVF at Week 48. CAB FC = 3; RPV FC = 2. CAB and RPV exposures <50% of predicted concentrations at PK assessments CAB 10 mg NNRTI K101K/E and E138E/A in one subject with PDVF at Week 72 with RPV FC = 4.6. No treatment-emergent integrase resistance One additional subject on CAB 10 mg + RPV with suspected virologic failure (without confirmatory lab draw; lost to follow-up) developed treatment-emergent NNRTI K101K/E and E138E/K at Week 48. RPV FC = 2.18 Margolis et al. CROI 2015; Seattle, WA. Poster 554LB

12 Conclusions: LATTE 1 Following induction therapy, oral CAB + RPV maintained virologic suppression at a rate similar to EFV + NRTIs through 96 weeks (ITT-E) - 76% of CAB + RPV and 63% of EFV + NRTIs subjects had HIV-1 RNA <50 c/ml (ITT-ME) - 86% of CAB + RPV and 83% of EFV+NRTIs subjects had HIV-1 RNA <50 c/ml Numerically lower response rate of CAB 10 mg and 30 mg, relative to 60-mg arm is largely due to non-virologic discontinuations, with a low PDVF rate across all arms CAB + RPV was well tolerated CAB 30-mg once-daily dose was selected for further oral development These regimen POC results support evaluation of long-acting injectable regimens of CAB LA + RPV LA as maintenance therapy Margolis et al. CROI 2015; Seattle, WA. Poster 554LB

Positive for hepatitis B ALT 5 ULN Creatinine clearance <50 ml/min Qualification for maintenance

13 LATTE 2: Study Design (1) Induction period CAB 30 mg + ABC/3TC for 20 weeks (N=309) Inclusion criteria >18 years old Naive to antiretroviral therapy CD4+ >200 cells/mm 3 Exclusion criteria Positive for hepatitis B ALT 5 ULN Creatinine clearance <50 ml/min Qualification for maintenance HIV-1 RNA <50 c/ml between Week -4 and Day 1 Add RPV 4 weeks Margolis et al CROI 2016; Boston, MA. Abstract 31LB

LATTE 2: Study Design(2) Induction period CAB 30 mg + ABC/3TC for 20 weeks Maintenance period a CAB 400 mg IM + RPV 600 mg IM Q4W (n=115) CAB loading dose at Day 1 CAB 600 mg IM + RPV 900 mg IM Q8W

14 LATTE 2: Study Design(2) Induction period CAB 30 mg + ABC/3TC for 20 weeks Maintenance period a CAB 400 mg IM + RPV 600 mg IM Q4W (n=115) CAB loading dose at Day 1 CAB 600 mg IM + RPV 900 mg IM Q8W (n=115) CAB loading doses at Day 1 and Week 4 CAB 30 mg + ABC/3TC PO QD (n=56) Day 1 Randomization 2:2:1 Week 32 Primary analysis Dosing regimen selection Week 48 Analysis Dosing regimen confirmation Margolis et al CROI 2016; Boston, MA. Abstract 31LB

15 LATTE 2: Baseline Characteristics Q8W IM (n=115) Q4W IM (n=115) Oral CAB (n=56) Total (N=286) Median age, years Female, n (%) 8 (7) 6 (5) 10 (18) 24 (8) African American/African heritage, n (%) 17 (15) 12 (10) 15 (27) 44 (15) CDC class C, n (%) 1 (<1) 2 (2) 0 3 (1) Median HIV-1 RNA, log 10 c/ml ,000, n (%) 16 (14) 28 (24) 7 (12) 51 (18) Median CD4+, cells/mm Margolis et al CROI 2016; Boston, MA. Abstract 31LB

16 LATTE 2: Induction Outcomes 91% Oral CAB Day 1 Snapshot outcome (N=309) Virologic success 282 (91%) Virologic non-response 14 (5%) Data in window not <50 c/ml 9 (3%) Discontinued for lack 2 (<1%) of efficacy Discontinued for other reason 3 (<1%) while not <50 c/ml No virologic data in window 13 (4%) Discontinued due to AE 6 (2%) or death Discontinued for other reasons 7 (2%) ITT-E Snapshot <50 c/ml Day 1 drug-related AEs Oral CAB (N=309) Preferred term 3% Nausea 27 (9%) Dyspepsia 9 (3%) Headache 9 (3%) Fatigue 8 (3%) Margolis et al CROI 2016; Boston, MA. Abstract 31LB

17 Proportion of patients with virological suppression, % LATTE 2: Week 32 Results Snapshot success: D1 Q4W 99% Q8W 95% Oral CAB 98% 0 BL W-16 W-12 W-8 W-4 D1 W4 W8 W12 W16 W20 W24 W28 W32 Study visit Margolis et al CROI 2016; Boston, MA. Abstract 31LB

18 Margolis et al CROI 2016; Boston, MA. Abstract 31LB LATTE 2: Week 32 Primary Endpoint Virologic outcomes Treatment differences (95% CI) * * Oral IM Q8W Q4W Both Q8W and Q4W comparable to oral CAB at Week 32 *Met pre-specified threshold for concluding IM regimen is comparable to oral regimen (Bayesian posterior probability >90% that true IM response rate is no worse than -10% compared with the oral regimen).

19 LATTE 2: Week 32 Snapshot Outcomes Week 32 outcome Q8W IM (n=115) Q4W IM (n=115) Oral CAB (n=56) Virologic success 109 (95%) 108 (94%) 51 (91%) Virologic non-response 5 (4%) 1 (<1%) 2 (4%) Data in window not <50 c/ml a 3 (3%) 1 (<1%) 1 (2%) Discontinued for lack of efficacy 1 (<1%) 0 1 (2%) Discontinued for other reason while not <50 c/ml 1 (<1%) 0 0 No virologic data in window 1 (<1%) 6 (5%) 3 (5%) Discontinued due to adverse event or death b 0 4 (3%) 1 (2%) Discontinued for other reasons c 1 (<1%) 2 (2%) 2 (4%) a Week 32 HIV-1 RNA Q8W: 53 c/ml, 70 c/ml, 91 c/ml; Q4W: 70 c/ml; oral CAB: 243 c/ml. All 5 are still in the study. b Q4W: hepatitis C, rash, depression, and psychosis; oral CAB: hepatitis C. c Q8W: ISR; Q4W: pregnancy and prohibited medication; oral CAB: lost to follow-up, relocation. Margolis et al CROI 2016; Boston, MA. Abstract 31LB

20 LATTE 2: Adverse Events ITT-ME population, n (%) Q8W IM (n=115) Q4W IM (n=115) Oral CAB (n=56) IM subtotal (N=230) Drug-related AEs, excluding ISRs ( 3%) Pyrexia 3 (3) 5 (4) 0 8 (3) Fatigue 2 (2) 4 (3) 1 (2) 6 (3) Influenza-like illness 3 (3) 2 (2) 0 5 (2) Grade 3 and 4 AEs, excluding ISRs 10 (9) 12 (10) 1 (2) 22 (10) Drug-related Grade 3/4 AEs a, excluding ISRs 3 (3) 4 (3) 0 7 (3) Serious AEs b 7 (6) 6 (5) 3 (5) 13 (6) AEs leading to withdrawal c 2 (2) 6 (5) 1 (2) 8 (3) Grade 3 and 4 labs d 17 (15) 20 (17) 8 (14) 37 (16) a Q8W: influenza-like illness, chills and pain, and lipase; Q4W: influenza-like illness, rash, depression, and psychosis. b None drug related; one death (epilepsy) evaluated as not likely related to study drug. c Q8W: ISR 2; Q4W: Churg Strauss vasculitis, hepatitis C, depression, epilepsy, psychosis, and rash; oral CAB: hepatitis C. d Maintenance emergent. AE, adverse event; ISR, injection-site reaction. Margolis et al CROI 2016; Boston, MA. Abstract 31LB

21 LATTE 2: Injection Site Reactions Q8W IM (n=115) Q4W IM (n=115) IM subtotal (N=230) Number of injections Number of ISRs (events/injection) 1054 (0.65) 1228 (0.46) 2282 (0.53) Grades Grade (80%) 1021 (83%) 1860 (82%) Grade (19%) 197 (16%) 399 (17%) Grade 3 12 (1%) 10 (<1%) 22 (<1%) Grade Duration, days (89%) 1121 (91%) 2064 (90%) Median Most common ISR events overall were pain (67%), swelling (7%), and nodules (6%) Number of subjects reporting ISRs decreased over time, from 86% (Day 1) to 33% (Week 32) a 2/230 subjects (1%) withdrew as a result of injection reactions (Q8W) Margolis et al CROI 2016; Boston, MA. Abstract 31LB

LATTE 2: Pharmacokinetics 1000 500 Q4W Cτ Cτ Mean

1 4 8 12 16 20 24 25 28 32 10 0 1 4 8 12 16 20 24 25 28

22 LATTE 2: Pharmacokinetics Q4W Cτ Cτ Mean plasma RPV ± SD, ng/ml 100 Q8W PA-IC90 25 mg PO CT Cτ Week Margolis et al CROI 2016; Boston, MA. Abstract 31LB

23 Acceptability: LATTE 2 How satisfied are you with your current treatment? 1% 3% 3% 2% How satisfied would you be to continue with your present form of treatment? 1% 1%

24 LATTE 2: Conclusions LATTE-2 results successfully demonstrate the potential to maintain HIV-1 viral load <50 c/ml with LA IM CAB + RPV, dosed once Q4W or Q8W Two subjects met PDVF criteria Q8W (n=1), oral CAB (n=1); both without evidence of resistance at failure Injection tolerability Majority of ISRs were Grade 1 to 2 pain, with a median duration of 3 days Few subjects had an ISR that led to discontinuation, with high overall reported satisfaction Regimen selection criteria Neither Q4W IM or Q8W IM dosing was ruled out on the basis of pre-specified criteria Upcoming Week 48 analysis will contribute to final dose selection for phase III studies Margolis et al CROI 2016; Boston, MA. Abstract 31LB

25 Regional HIV and AIDS statistics and features: 2014 Adults and children living with HIV Adults and children newly infected with HIV Adult prevalence (15 49) [%] Adult & child deaths due to AIDS Sub-Saharan Africa 25.8 million [24.0 million 28.7 million] 1.4 million [1.2 million 1.5 million] 4.8% [4.5% 5.1%] [ ] Middle East and North Africa [ ] [ ] 0.1% [<0.1% 0.1%] [ ] Asia and the Pacific 5.0 million [4.5 million 5.6 million] [ ] 0.2% [0.2% 0.2%] [ ] Latin America 1.7 million [1.4 million 2.0 million] [ ] 0.4% [0.4% 0.5%] [ ] Caribbean [ ] [ ] 1.1% [0.9% 1.3%] 8800 [ ] Eastern Europe and Central Asia 1.5 million [1.3 million 1.8 million] [ ] 0.9% [0.7% 1.0%] [ ] Western and Central Europe and North America 2.4 million [1.5 million 3.5 million] [ ] 0.3% [0.2% 0.5%] [ ] TOTAL 36.9 million [34.3 million 41.4 million] 2.0 million [1.9 million 2.2 million] 0.8% [0.7% - 0.9%] 1.2 million [ million] UNAIDS Core Epidemiology Report 2015

26 Clinical Trial Evidence for Oral Tenofovir-Based Prevention (March 2015) Serodiscordant couples Partners PrEP - daily oral TDF/FTC (Discordant couples - Kenya, Uganda) Partners PrEP - daily oral tenofovir (Discordant couples - Kenya, Uganda) Effect size (95% CI) 75% (55; 87) 67% (44; 81) Men who have sex with men iprex - daily oral TDF/FTC (MSM - North and South America, Thailand, South Africa) 44% (15; 63) PROUD - daily TDF/FTC (MSM - UK) 86% (58; 96) (90% CI) IPERGAY - intermittent TDF/FTC (MSM France, Canada) 86% (40; 99 ) Heterosexual men and women TDF2 - daily TDF/FTC (Heterosexual men and women - Botswana) 62% (22; 84) Heterosexual women FEMPrEP - daily oral TDF/FTC (Women - Kenya, South Africa, Tanzania) MTN 003/VOICE - daily oral TDF/FTC (Women - South Africa, Uganda, Zimbabwe) MTN 003/VOICE - daily oral tenofovir (Women - South Africa, Uganda, Zimbabwe) 6% (-21; 40) -4% (-49; 27) -49% (-129; 3) People who inject drugs Bangkok Tenofovir Study - daily oral tenofovir (IDUs - Thailand) 49% (10; 72) Effectiveness (%) Adapted from Salim S. Abdool Karim, CAPRISA

27 Effectiveness (%) Effectiveness and Adherence in Trials of Oral and Topical Tenofovir-Based PrEP CAPRISA 004 (tenofovir gel, BAT-24 dosing) iprex TDF2 Partners PrEP (TDF) Partners PrEP (TDV/FTC) FEM-PrEP Participants samples that had detectable drug levels (%) VOICE (TDF) VOICE (TDF/FTC) VOICE (tenofovir gel, daily dosing) Source: Salim S. Abdool Karim, CAPRISA

28 Benefits of Long Acting Reversible Contraception Secura et al; N Engl J Med 2014

29 Attitudes toward PrEP: NYC MSM Meyers et al, PLOS ONE; 2015

30 Development of cabotegravir for prevention Preclinical evaluations SHIV162P3/macaque model Clinical studies ÉCLAIR- Phase 2A Safety and PK Study of CAB LA in HIV-Uninfected Men (target 60% MSM) HPTN 077-Phase 2A Safety and PK Study of CAB LA in HIV-Uninfected Men and Women (target 60% women) HPTN 083-A Phase 2b/3 Double Blind Efficacy Study Of CAB LA Compared to Daily TDF/FTC For PrEP in MSM and TGW

31 CAB plasma concentrations in protected macaques are comparable to those achieved in humans GSK744 LA Plasma GSK744 (mg/ml) Time (weeks) 4X PAIC 90 Macaques (50, 50 mg/kg) Humans (800 mg) Andrews et al Science 2014: 343

32 CAB LA Is Effective at Preventing SHIV Infection in Preclinical Studies Mimicking Sexual Transmission Species Viral Challenge Route SHIV162P3 Challenge Dose % Protection Rhesus Macaque IR 50 TCID Rhesus Macaque IVAG (with Depo) 300 TCID 50 >90 2 Pigtail Macaque IVAG 50 TCID C.D. Andrews, et al, Science (2014) 2 C.D. Andrews, et al, Science Translational Medicine (2015) 3 J. Radzio, et al, Science Translational Medicine (2015)

33 CAB plasma concentrations >3X PAIC 90 result in 100% protection, while 1XPAIC 90 are 97% effective Andrews et al Science 2014: 343

34 Phase 2A Safety and PK Study of CAB LA in HIV- Uninfected Men: ÉCLAIR Primary To evaluate the safety and tolerability of IM CAB LA injections through Week 41 Secondary To evaluate the pharmacokinetics of CAB LA injection through Week 41 To evaluate the safety and tolerability of oral CAB To assess the acceptability of CAB LA injections

35 Pharmacokinetic evaluation of a single intramuscular CAB-LA injection in human volunteers Plasma GSK744 (µg/ml) mg 400 mg 800 mg 4X PAIC 90 1X PAIC Time (weeks)

36 Dose rationale for ECLAIR Markowitz et al, CROI 2016 Boston MA. Abstract 106

Q12W Saline placebo IM Q12W Follow-up Follow-up Note: not all scheduled study

37 Study Design Oral phase Injection phase Follow-up phase D1 W2 W4 W5 W17 W29 W41 W53 W65 W77 W81 CAB 30 mg PO QD Placebo PO QD 5:1 Randomization CAB LA 800 mg IM Q12W Saline placebo IM Q12W Follow-up Follow-up Note: not all scheduled study visits are shown in this study schematic. Markowitz et al, CROI 2016 Boston MA. Abstract 106

38 Study population Key Inclusion Criteria Healthy men 18 to 65 years of age At low risk of acquiring HIV, defined as having at least one casual sex partner in the past 24 months Key Exclusion Criteria At high risk for HIV infection Recent use of ART (eg, for PEP or PrEP) in the past 30 days or 5 halflives Current or chronic history of liver disease

39 Baseline Characteristics of the Randomized Population PBO CAB (N=21) (N=106) Median age, years (min-max) 30 (21-57) 31 (20-61) Race White African American/African 57% 33% Hispanic/Latino ethnicity 14% 15% Median height, cm (min-max) 175 ( ) 176 ( ) Median weight, kg (min-max) 79 (48-132) 81 (52-167) Median BMI, kg/m 2 (min-max) 25 (18-40) 26 (18-48) Risk factors for HIV acquisition Homosexual contact Heterosexual contact Occupational exposure 76% 29% 5% 56% 31% 85% 21% 2% Markowitz et al, CROI 2016 Boston MA. Abstract 106

40 ECLAIR Study Disposition Screened (N=205) Randomized (N=127) Not randomized (N=78) CAB (N=106) Decision by subject (n=1, 1%) Entered oral phase (n=105, 99%) Adverse event (n=7, 7%) Decision by subject (n=3, 3%) Investigator discretion (n=1, 1%) Entered injection phase (n=94, 89%) Subject decision (n=3, 3%) Investigator discretion (n=3, 3%) Lost to follow-up (n=1, 1%) Placebo (N=21) Entered oral phase (n=21, 100%) Entered injection phase (n=21, 100%) Reached protocol-defined stopping criteria (n=1, 5%) Completed injection phase (n=87, 82%) Completed injection phase (n=20, 95%) 87 of 94 (93%) who received CAB LA injection and 20 of 21 (95%) who received placebo injections completed the injection phase 4 subjects withdrew from CAB LA injections due to injection intolerability (n=3, subject decision; n=1, investigator discretion) Markowitz et al, CROI 2016 Boston MA. Abstract 106

41 Adverse Events Injection Phase (Primary Safety Evaluation) PBO (N=21) n (%) CAB (N=94) n (%) Grade 1-4 adverse events 19 (90) 92 (98) Grade 2-4 adverse events (>5% in CAB arm) 10 (48) 75 (80) Injection site pain 1 (5) 55 (59) Pyrexia 0 7 (7) Injection site pruritus 0 6 (6) Injection site swelling 0 6 (6) Serious adverse events a 1 (5) 1 (<1) Markowitz et al, CROI 2016 Boston MA. Abstract 106

42 ISR Symptoms Injection Phase PBO CAB (N=21) (N=94) n (%) n (%) Subjects with any ISR event 12 (57) 87 (93) Total number of injections ISR events by maximum Number of events Mean duration Number of events toxicity a (%) (days) (%) Pain 17/62 (27) /272 (92) 5.4 Grade 1 16 (26) 122 (45) Grade 2 1 (2) b 101 (37) Grade (10) Pruritus 4 (6) (10) 2.5 Swelling 0 22 (8) 3.8 Nodule/Bump 0 21 (8) 9.7 Warm to touch 0 19 (7) 3.2 Bruising 1 (2) (6) 3.3 Induration 0 15 (6) 4.3 Mean duration (days) Markowitz et al, CROI 2016 Boston MA. Abstract 106

43 Predicted and Observed Mean (SD) CAB Concentration Markowitz et al, CROI 2016 Boston MA. Abstract 106

44 Numbers of Subjects in CAB Concentration Ranges by Injection Visit (ECLAIR) Markowitz et al, CROI 2016 Boston MA. Abstract 106

45 CAB LA Acceptability in ECLAIR How satisfied are you with your current study medication? How satisfied would you be to continue with your present form of study medication? PBO (n=21) CAB (n=91) PBO (n=21) CAB (n=91)

46 Cabotegravir as PrEP: subsequent clinical development HPTN076 soon to be completed Includes a 600 mg q 8-week dosing schedule HPTN083 Randomized, placebo controlled study of CAB-LA versus Truvada in high risk MSM and TGW HPTN086 Study in high risk women in South Africa Planned regimen for CAB LA PrEP studies Oral lead-in for 5 weeks 600 mg (3mL) at day 0, week 4, and every 8 weeks thereafter

47 Long acting rilpivirine (TMC-278) as Phase 1 PrEP SSAT 040 study- dose ranging study with collection of plasma, tissue, and cervical/rectal fluids MWRI-01- dose ranging with plasma and tissue collection Phase 2a HPTN-076- safety and PK study in HIV-unifected women in US, South Africa, and Zimbabwe

48 Phase 1 SSAT 040: Study design Jackson et al Clin Pharm and Therapeutics, 2014

49 Plasma and genital PK in females plasma CVF Vaginal tissue Jackson et al Clin Pharm and Therapeutics, 2014

50 Incident HIV-1 infection with selection for drug resistance to RPV Penrose et al J. Inf Diseases 2016

51 MWRI-01 Study: A Phase I Open Label Safety, Acceptability, PK, and ex Vivo Pharmacodynamic Study of TMC-278 LA Administered Intramuscularly to HIV-1 Seronegative Participants Study Group TMC278 LA dosing Study Group TMC 278 LA dosing 1A- 12 females 1200 mg single dose 1B- 6 males 1200 mg single dose 2A-12 females 600 mg single dose 2B- 6 males 600 mg single dose 3A- 12 females every 2 months 4A- 12 females every 2 months 5A- 12 females every 2 months 3B- 6 males every 2 months 4B- 6 males every 2 months 5B- 6 males every 2 months McGowan CROI 2016 Boston MA

52 MWRI-01: Pharmacokinetics of RPV-LA McGowan, CROI2016 Boston MA

53 MWRI-01: Tissue explant results McGowan CROI 2016 Boston MA

54 Long acting injectable antivirals for prevention CABOTEGRAVIR RILPVIRINE Preclinical development Macaque/SHIV162P3 Tissue Explant model Likely dosing intervals Every 2 months Every 2 months Barrier to resistance Use as initial therapy Need for maintenance of cold chain Unknown, but likely to be high InSTIs more common in resource rich settings No Current status Phase 2b/3 to start in 2016 in MSM; females 2017 Low NNRTIs more common in settings with limited resources Yes No current development plans beyond Phase 2a

Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 32 Results

Slide 1 Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 32 Results David A. Margolis, 1 Juan Gonzalez-Garcia, 2 Hans-Jürgen Stellbrink, 3 Joe Eron, 4 Yazdan Yazdanpanah, 5 Sandy