23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA 1 The Aaron Diamond AIDS Research Center, an affiliate of the Rockefeller University, New York, NY; 2 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3 Institute of Virology & Immunology, Gladstone Institutes, San Francisco, CA; Department of Medicine, University of California, San Francisco, CA; 4 The Fenway Institute, Fenway Health, Boston, MA; Beth Israel Deaconess Medical Center, Boston, MA; Harvard Medical School, Boston, MA; 5 ViiV Healthcare, Research Triangle Park, NC; 6 PAREXEL International (formerly employed by GlaxoSmithKline), Research Triangle Park, NC ECLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men Martin Markowitz, 1 Ian Frank, 2 Robert M. Grant, 3 Kenneth H. Mayer, 4 David A. Margolis, 5 Krischan J. Hudson, 5 Britt S. Stancil, 6 Susan L. Ford, 6 Alex R. Rinehart, 5 William R. Spreen 5

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Dr. Martin Markowitz has received research grants from GSK/ViiV and Gilead Sciences awarded to his institution Dr. Markowitz has served as a consultant to Merck Dr. Markowitz is a speaker on behalf of Gilead Sciences Disclosures Markowitz et al. CROI 2016; Boston, MA. Abstract 106.

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Daily oral PrEP has proven effective in randomized clinical trials in MSM, discordant couples, and IDUs, but less so in other populations Efficacy strongly related to adherence LA injections may overcome barriers to adherence CAB is a potent INSTI that has been formulated in an LA suspension Introduction Markowitz et al. CROI 2016; Boston, MA. Abstract 106. CAB, cabotegravir; IDU, intravenous drug user; INSTI, integrase strand transfer inhibitor; LA, long-acting; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis.

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA 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 Objectives Markowitz et al. CROI 2016; Boston, MA. Abstract 106. IM, intramuscular.

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA 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 half-lives Current or chronic history of liver disease Study Population Markowitz et al. CROI 2016; Boston, MA. Abstract 106. ART, antiretroviral therapy; PEP, post-exposure prophylaxis.

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA ECLAIR Study Design Markowitz et al. CROI 2016; Boston, MA. Abstract 106. PO, orally; Q12W, every 12 weeks; QD, once daily. Phase IIa, randomized, multi-site, 2-arm, double-blinded study in men at low risk of acquiring HIV 5:1 Randomization CAB 30 mg PO QD CAB 30 mg PO QD Placebo PO QD Placebo PO QD CAB LA 800 mg IM Q12W Follow-up Saline placebo IM Q12W Follow-up D1 W2 W4 W5 W17 W29 W41 W53 W65 W77 W81 Injection phase Oral phase Follow-up phase Note: not all scheduled study visits are shown in this study schematic.

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA 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) ECLAIR Study Disposition Markowitz et al. CROI 2016; Boston, MA. Abstract 106. Screened (N=205) Entered oral phase (n=105, 99%) Adverse event (n=7, 7%) Decision by subject (n=3, 3%) Investigator discretion (n=1, 1%) CAB (N=106) Decision by subject (n=1, 1%) Placebo (N=21) Not randomized (N=78) Completed injection phase (n=87, 82%) Entered injection phase (n=94, 89%) Subject decision (n=3, 3%) Investigator discretion (n=3, 3%) Lost to follow-up (n=1, 1%) Entered oral phase (n=21, 100%) Completed injection phase (n=20, 95%) Randomized (N=127) Entered injection phase (n=21, 100%) Reached protocol-defined stopping criteria (n=1, 5%)

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Baseline Characteristics of the Randomized Population Markowitz et al. CROI 2016; Boston, MA. Abstract 106. BMI, body mass index; PBO, placebo. PBO (N=21) CAB (N=106) Median age, years (min-max) 30 (21-57)31 (20-61) Race White African American/African 57% 33% 56% 31% 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% 85% 21% 2%

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Adverse Events—Oral Phase Markowitz et al. CROI 2016; Boston, MA. Abstract 106. a Grade 2 (n=1), Grade 4 (n=2). b Grade 2 (n=2), Grade 3 (n=1). c Grade 2. PBO (N=21) n (%) CAB (N=105) n (%) Grade 2-4 adverse events4 (19)24 (23) Drug-related adverse events (by maximum toxicity) Grade 23 (14)9 (9) Grade 301 (1) Grade 402 (2) Serious adverse events00 Adverse events leading to withdrawal07 (7) Blood creatine phosphokinase increased 03 (3) a Neutropenia 03 (3) b Fatigue 01 (<1) c

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Adverse Events—Injection Phase (Primary Safety Evaluation) Markowitz et al. CROI 2016; Boston, MA. Abstract 106. a PBO: deep vein thrombosis (drug-related); CAB: appendicitis. PBO (N=21) n (%) CAB (N=94) n (%) Grade 1-4 adverse events19 (90)92 (98) Grade 2-4 adverse events (>5% in CAB arm)10 (48)75 (80) Injection site pain 1 (5)55 (59) Pyrexia 07 (7) Injection site pruritus 06 (6) Injection site swelling 06 (6) Serious adverse events a 1 (5)1 (<1) No laboratory adverse events, including liver laboratory abnormalities, led to discontinuation throughout the injection phase

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA No subjects discontinued due to AEs during the injection phase; 4 subjects who withdrew consent cited injection tolerability as a reason ISR Symptoms—Injection Phase Markowitz et al. CROI 2016; Boston, MA. Abstract 106. a Percentages are out of total number of injections. With the exception of Grade 3 pain, all ISRs listed were Grade 1-2. b Subject was misdosed with CAB on third injection. PBO (N=21) n (%) CAB (N=94) n (%) Subjects with any ISR event12 (57)87 (93) Total number of injections62272 ISR events by maximum toxicity a Number of events (%) Mean duration (days) Number of events (%) Mean duration (days) Pain17/62 (27)2.0250/272 (92)5.4 Grade 116 (26)122 (45) Grade 21 (2) b 101 (37) Grade 3027 (10) Pruritus4 (6)1.826 (10)2.5 Swelling022 (8)3.8 Nodule/Bump021 (8)9.7 Warm to touch019 (7)3.2 Bruising1 (2)2.016 (6)3.3 Induration015 (6)4.3

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Predicted and Observed Mean (SD) CAB Concentration Markowitz et al. CROI 2016; Boston, MA. Abstract 106. C T, concentration at the end of the dosing interval; PA-IC 90, protein binding–adjusted 90% inhibitory concentration; SD, standard deviation.

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Numbers of Subjects in CAB Concentration Ranges by Injection Visit (ECLAIR) Markowitz et al. CROI 2016; Boston, MA. Abstract 106. Percentages shown as percentage of reportable troughs at each injection visit within window.

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Subject reported unprotected sex with a casual partner between the visits at Weeks 41 and 53 Concomitant transaminitis at Week 53 (Grade 3 ALT/Grade 2 AST) No pheno/genotype resistance mutations to INIs (DTG, RAL, EVG, or CAB), NNRTIs, or NRTIs for samples collected at Weeks 53 and 65 Subject was referred to ID provider, and initiated on darunavir+ritonavir, emtricitabine/tenofovir HIV Seroconversions Markowitz et al. CROI 2016; Boston, MA. Abstract 106. ALT, alanine aminotransferase; AST, aspartate aminotransferase; DTG, dolutegravir; EVG, elvitegravir; ID, infectious disease; INI, integrase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NQ, not quantifiable; PK, pharmacokinetic; RAL, raltegravir. Case 1: 24-year-old man, PBO arm, HIV seroconversion at Week 23; referred to ID provider Case 2: 22-year-old man, CAB LA injection arm, HIV seroconversion at Week 53 (24 weeks after final injection) Study week HIV rapid test result HIV-1 RNA (c/mL) PK value (μg/mL) 29 (pre-dose, final injection)Negative< Negative< Negative3,820,820NQ 65Positive4142NQ

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Also see Poster #471: Tolerability and acceptability of cabotegravir LA injection: results from ECLAIR study; Presenter: Miranda Murray; Session date: Wednesday, February 24, 2016, 2:45 PM to 4:00 PM Study Medication Satisfaction Questionnaire (Week 18 LA Compared With Oral) Markowitz et al. CROI 2016; Boston, MA. Abstract 106. 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)

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA Both CAB oral and LA were well tolerated, permitting continued development of CAB for PrEP The absorption rate following CAB LA injection was faster than predicted by early PK population models, leading to higher peak and lower trough exposures 15% to 31% of trough concentrations were <PA-IC 90, whereas 30% to 37% were ≥4 × PA-IC 90 across injection visits, below initial predictions Given observed trough levels, an 8-week dosing interval is currently under evaluation Participant satisfaction with IM CAB LA injections was high, including a preference for injections Q12W compared with oral CAB once-daily tablets ECLAIR Conclusions Markowitz et al. CROI 2016; Boston, MA. Abstract 106.

23rd Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA We thank everyone who has contributed to the success of this study, including – All study participants and their families – The ECLAIR clinical investigators and their staff – The GSK and ViiV Healthcare study team – PPD – Quest, Covance, and Monogram Biosciences This study was funded by ViiV Healthcare Acknowledgments Markowitz et al. CROI 2016; Boston, MA. Abstract 106. InvestigatorClinical siteCity, State Martin Markowitz (PI)ADARCNew York, NY Rick Elion/Deborah GoldsteinWhitman Walker HealthWashington, DC Chester FisherHealth Research of Hampton Roads, IncNewport News, VA Ian FrankUniversity of PennsylvaniaPhiladelphia, PA Joel GallantSouthwest Care CenterSanta Fe, NM Robert GrantGladstone, UCSFSan Francisco, CA Beryl Koblin/Hong Van TieuNew York Blood CenterNew York, NY Ken MayerHarvard/Fenway InstituteBoston, MA Magdalena SobieszczykColumbia University Medical CenterNew York, NY Winkler WeinbergKaiser PermanenteAtlanta, GA