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Monthly Long-Acting Cabotegravir and Rilpivirine is Noninferior to Oral MOPEB257 ART as Maintenance Therapy for HIV-1 Infection: Week 48 Pooled Analysis From the Phase 3 ATLAS and FLAIR Studies Edgar T. Overton,1 Chloe Orkin,2 Susan Swindells,3 Keikawus Arasteh,4 Miguel Górgolas Hernández-Mora,5 Vadim Pokrovsky,6 Pierre-Marie Girard,7 Shinichi Oka,8 Jaime-Federico Andrade-Villanueva,9 Gary J. Richmond,10 Giuliano Rizzardini,11 Axel Baumgarten,12 Maria Del Mar Masiá,13 Gulam Latiff,14 Sandy Griffith,15 Conn M. Harrington,15 Krischan J. Hudson,15 Marty St. Clair,15 Christine Talarico,15 Veerle Van Eygen,16 Ronald D’Amico,15 Joseph M. Mrus,15 Sterling Wu,17 Ken Chow,18 Jeremy Roberts,18 Simon Vanveggel,16 David A. Margolis,15 Peter Williams,16 Wim Parys,16 Kimberly Smith,15 William R. Spreen15 1University of Alabama at Birmingham, Birmingham, AL, USA; 2Queen Mary University, London, UK; 3University of Nebraska Medical Center, Omaha, NE, USA; 4EPIMED GmbH, Berlin, Germany; 5Fundación Jiménez Díaz, Madrid, Spain; 6Central Research Institute of Epidemiology, Moscow, Russia; 7Hôpital Saint Antoine, Paris, France; 8National Center for Global Health and Medicine, Tokyo, Japan; 9University of Guadalajara, Guadalajara, Mexico; 10Broward Health Medical Center, Fort Lauderdale, FL, USA; 11Fatebenefratelli Sacco Hospital, Milan, Italy; 12MIB Infectious Disease Medical Center, Berlin, Germany; 13Hospital General de Elche, Alicante, Spain; 14Maxwell Centre, Durban, South Africa; 15ViiV Healthcare, Research Triangle Park, NC, USA; 16Janssen Research & Development, Beerse, Belgium; 17GlaxoSmithKline, Collegeville, PA, USA; 18GlaxoSmithKline, Mississauga, Ontario, Canada

Background Figure 3. Virologic Snapshot Outcomes at Week 48 for ITT-E Table 4. ATLAS and FLAIR Confirmed Virologic Failures*:  Despite the success of daily oral therapy, considerable interest Noninferiority Achieved for Primary and Secondary Endpoints CAB + RPV LA Arm exists in long-acting (LA) treatment options for HIV-1 infection. 1,2 SVF  Cabotegravir (CAB) is an HIV-1 integrase strand transfer inhibitor. Viral A Virologic Outcomes Baseline Timepoint  Sex, Load at Drug Oral 30 mg tablet: half-life (t½) ≈ 40 hours. RAMs† RAMs  LA intramuscular (IM) injection, 200 mg/mL: t ≈ 40 days. Country, SVF / Sensitivity ½ 94.4 CAB + RPV LA (n=591) HIV-1 Previous CVF at SVF (Fold 100 93.1  Rilpivirine (RPV) is an HIV-1 non-nucleoside reverse CAR (n=591) Study Subtype CAR RT INSTI (c/mL) RT INSTI‡ Change)§ 1,2 transcriptase inhibitor (NNRTI). 80 RPV (2.4)  F, Russia, 3TC, AZT, E138E/ 79,166 / Oral 25 mg tablet: t½ ≈ 50 hours. None E138A None CAB (0.8) 60 A/A1 LPV/r A 25,745  LA IM injection, 300 mg/mL: t½ ≈ 90 days. DTG (0.9)  1 2 ATLAS (NCT02951052) and FLAIR (NCT02938520) are two 40 3TC, AZT, randomized, open-label, international Phase 3 studies which RPV (3.7) F, France, NVP to V108V/I 695 / V108I 20 None None CAB (1.2) evaluate switching to monthly IM injections. 5.1 3.9 ATLAS AG 3TC, ABC, E138K 258 E138K 1.9 1.7 DTG (1.0) NVP 0

Objective and Endpoints (%) Participants of Proportion Virologic Virologic No Virologic FTC, RAL, Nonresponse Success Data RPV (6.5) Objective M, Russia, TDF to 544 / E138E/ (≥50 c/mL) (<50 c/mL) None None N155H CAB (2.7) A/A1 ABC, EFV, 1841 K  Establish noninferior antiviral activity of monthly IM CAB + RPV DTG (1.2) LA vs continuing current antiretroviral regimen (CAR) in 3TC RPV (7.1) treatment-experienced (ATLAS) and previously treatment-naïve B Adjusted Treatment Difference (95% CI)* F, Russia, 373 / E138E/ – None None Q148R CAB (5.2) (FLAIR) participants. A1 456 A/K/T DTG (1.0) Primary Endpoint CAB + RPV LA CAR Primary Endpoint: 0.2 RPV (2.6)  Proportion of participants with HIV-1 RNA ≥50 c/mL at Week 48 LA noninferior to M, Russia, 287 / FLAIR¶ – None None K101E G140R CAB (6.7) CAR (HIV-1 RNA A1 299 using the U.S. Food and Drug Administration (FDA) Snapshot -1.4 1.7 4% NI DTG (2.2) margin ≥50 c/mL) at algorithm (4% noninferiority margin on difference between Week 48 -10 -8 -6 -4 -2 0 2 4 6 8 10 RPV (1.0) groups). F, Russia, 488 / Difference (%) – None None E138K Q148R CAB (9.4) A1 440 Selected Secondary and Exploratory Endpoints CAR CAB + RPV LA Key Secondary DTG (1.1)  HIV-1 RNA <50 c/mL at Week 48 (Snapshot). -1.4 Endpoint: -10% NI *In the CAR arm, there were seven CVFs. In ATLAS, there were 4 CVFs in the CAR arm, where RT  Safety and tolerability. mutations M184I, M184V+G190S, and M230M/I were detected in HIV-1 RNA samples from one margin -4.1 1.4 LA noninferior to  Treatment satisfaction and preference. CAR (HIV-1 RNA participant each, and one had no mutations. In FLAIR, there were 3/4 CVFs in the CAR arm without -10 -8 -6 -4 -2 0 2 4 6 8 10 treatment-emergent resistance mutations or phenotypic changes.  <50 c/mL) at Resistance analysis of confirmed virologic failure (CVF). Difference (%) †Baseline RAMs were determined using DNA for ATLAS and RNA for FLAIR; ‡L74I was present at baseline in 5/6 subjects and is not *Adjusted for sex and baseline third agent class. Week 48 considered an INSTI RAM by IAS-US guidelines and has no impact on CAB activity; §Monogram biological cutoffs are: RPV=2.0, CAB=2.5, and the Monogram clinical cutoff for DTG=4.0; ¶FLAIR had oral CAB/RPV dosing interrupted due to a false-positive Figure 1. ATLAS and FLAIR Study Design pregnancy test and upon re-initiation of oral therapy, had suspected VF that was confirmed. Figure 4. Treatment Difference in Proportion (95% CI) Snapshot HIV-1 RNA <50 c/mL at Week 48 by Subgroup Table 5. Summary of the Prevalence of L74I at Baseline* Screening Phase Maintenance Phase Extension Phase‡ by Subtype in FLAIR Participants

† CAB +

1 PI, NNRTI, or INSTI Extension CAR CAR CAB + RPV LA ART-experienced Current daily oral ART n=308 RPV LA CAB + RPV LA CAR Phase or N=705 Overall 550/591 558/591 -1.4 † † PI-, NNRTI-, or INSTI- Randomization transition to the L74I Within L74I Within (1:1) n=618 ‡ ‡ based regimen with CAB LA (400 mg) + ATLAS-2M Gender Male 400/429 399/423 -1.1 Subtype Subtype, n/N (%) Subtype, n/N (%) ATLAS Oral CAB + 2 NRTI backbone* RPV LA (600 mg)§ study Female 150/162 159/168 -2.1 RPV n=308 Total L74I Present / Total tested 54/243 (22) 47/240 (20) IM monthly n=303 Race African American/ 105/109 119/133 6.9 African heritage A 32/38 (84) 28/32 (88) ‖ 52 Day 1 4 48 96 100 Asian 29/34 27/28 -11.1 A1 5/8 (63) 3/4 (75) Induction Phase White 399/430 391/408 -3.0 AE 0/0 0/3 Other 17/18 19/20 -0.6 AG 3/10 (30) 3/13 (23) <30 kg/m2 457/491 460/488 ART-naïve DTG/ABC/3TC BMI -1.2 B 12/165 (7) 11/161 (7)

2 N=629 2 N=809 Oral daily n=283 DTG/ABC/3TC ≥30 kg/m 93/100 98/103 -2.2 HIV-1 RNA ≥1000 C 0/2 0/4 single-tablet <50 years old 457/492 438/466 Any CD4 count Age -1.1 regimen for 20 Undetermined 0/5 0/5 HBsAg-negative Oral CAB + CAB LA (400 mg) + RPV LA (600 mg)§ ≥50 years old 93/99 120/125 -2.1 FLAIR ¶ weeks** Extension NNRTI RAMs excluded RPV n=283 IM monthly n=278 BL CD4 <350 39/42 52/54 -3.4 Other 2/15 (13) 2/18 (11) (cells/μL) 350 to <500 109/120 109/117 -2.3 *Baseline values taken at Week –20 in participants that were randomized; †L74I is not considered an INSTI RAM by IAS-US ‡ ≥500 402/429 397/420 -0.8 guidelines and has no impact on CAB activity; Results pending for 40 and 43 samples, respectively. Study Week −20 −4 Day 1 4‖ 48 52 96 100 BL ART PI 47/51 51/54 -2.3 class at INSTI 361/385 359/382 -0.2  101/483 subjects tested had the L74I substitution, with the randomization NNRTI 142/155 148/155 Confirm Randomization Primary Endpoint -3.9 majority of subjects with L74I (64/101, 63.4%) coming from the HIV-1 RNA (1:1) n/N <50 c/mL -30 -25 -20 -15 -10 -5 0 5 10 15 20 25 Russian Federation. In contrast, 5/84 (6.0%) subjects from the Unadjusted Treatment Difference

† in Proportion (95% CI) United States had the L74I substitution. *Uninterrupted ART ≥ 6 months and VL <50 c/mL at Screening, 2× VL <50 c/mL ≤12 months; INSTI-based regimen capped at 40% Dashed line represents the overall difference in proportion. of enrollment; Triumeq excluded from study; ‡Optional switch to CAB + RPV LA at Week 52 for those on CAR; §Participants who  withdraw/complete IM CAB + RPV LA must complete 52 weeks of follow-up; ‖Participants received initial loading dose of CAB LA (600 L74I was most commonly observed in Subtype A (60/70; 85.7%) mg) and RPV LA (900 mg) at Week 4. From Week 8 onwards, participants received CAB LA (400 mg) + RPV LA (600 mg) injections ¶ ( ). every 4 weeks; NNRTI RAMs, but not K103N, were exclusionary; **DTG plus two alternative non-ABC NRTIs was permitted if Table 3. Safety Overview, Excluding ISRs, Through Week 48 Table 5 participant was intolerant or HLA-B*5701-positive. in Maintenance Phase  Subtype B (326/483, 67.5%) was the most prevalent subtype observed in the FLAIR subjects. Results CAB + RPV LA CAR N=591 N=591 Table 6. Effect of L74I on Virologic Suppression at Week 48 in Table 1. Baseline Characteristics: ITT-E Population Any AE 506 (86%) 444 (75%) FLAIR Participants Any Grade 3/4/5 AE* 44 (7%) 35 (6%) Number of HIV-1 CAB + RPV LA CAR Any drug-related AE 165 (28%) 35 (6%) L74I Polymorphism RNA <50 c/mL / Difference in N=591 N=591 Any Grade 3/4/5 drug-related AE* 8 (1%) 1 (<1%) at Induction BL Treatment Total Assessed (%) Proportion* (95% CI) Median age, years (range) 38 (19–74) 38 (18–82) Any AEs leading to withdrawal 17 (3%) 9 (2%) CAB + RPV LA 50/54 (93) Yes –1.0 (–12.7, 11.0) Age ≥50 years, n (%) 99 (17) 125 (21) Any serious AE 24 (4%) 25 (4%) CAR 44/47 (94) Female, n (%) 162 (27) 168 (28) Serious AEs related to study treatment† 1 (<1%) 1 (<1%) CAB + RPV LA 177/189 (94) No 0.4 (–4.9, 5.6) Race, n (%) Common AEs (≥5%) CAR 180/193 (93)

White 430 (73) 408 (69) Nasopharyngitis 108 (18%) 90 (15%) *Difference (unadjusted): Proportion on CAB + RPV LA – Proportion on CAR. Black or African American 109 (18) 133 (23) Headache 73 (12%) 38 (6%) Other 52 (9) 50 (8) Upper respiratory tract infection 70 (12%) 53 (9%)  The presence of L74I IN polymorphism had no impact on overall Median BMI (range), kg/m2 24.9 (15.3–50.9) 24.8 (12.6–57.7) Diarrhea 54 (9%) 40 (7%) treatment outcomes: Median CD4+ cell count (IQR), cells/mm3 645 (487–824) 641 (480–821) Back pain 43 (7%) 23 (4%)  HIV-1 RNA <50 by Snapshot (Table 6). Influenza 42 (7%) 34 (6%) HIV-1–HCV co-infection, n (%) 42 (7) 40 (7)  HIV-1 RNA ≥50 by Snapshot (CAB + RPV LA 3/54 [5.6%]; CAR 1/47 Pyrexia 43 (7%) 13 (2%) [2.1%], treatment difference of 3.4 [95% CI –6.8, 13.5]). *Baseline for FLAIR was Day 1 (Maintenance Phase). AEs of special interest Anxiety 27 (5%) 20 (3%) Figure 6. Participant Satisfaction (HIVTSQs) and Preference for Figure 2. Summary of ITT-E Participants by Region and Country Depression 16 (3%) 14 (2%) Injectable Therapy Suicidal ideation/behavior 4 (<1%) 5 (<1%) *There was only one (<1%) participant with Grade 5 AE in the CAR arm; †Serious AEs related to study treatment: LA arm – arthritis; HIVTSQs Total Score* Improvement 2.2 CAR arm – suicidal ideation. Europe n=696 Difference (95%CI) 4.9 Spain n=219 The pooled data 8.7 Russian Federation n=199 Figure 5. Pooled Injection Site Reactions reported a significant +4.2 Germany n=92 increase among Week 24* 3.9 (3.0–4.8), p<0.001 France n=75 ISR Incidence by Week CAB + RPV LA study participants in +0.3 Italy n=66 100 Event N=591 treatment satisfaction Participants receiving 25.3 UK n=25 581 of injectable therapy 80 injections, n 58.9 Sweden n=15 compared with Injections given, n 14682 +3.9 3.4 (2.5–4.3), p<0.001 Netherlands n=5 60 ISR events, n (%) 3663 (24.9) participants receiving Week 44* Pain 3087 (21.0) oral therapy at +0.5 40 North America n=299 Nodule 140 (1.0) Weeks 24 and 44 CAB + RPV LA CAR USA n=242 Induration 136 (0.9) 20 Canada n=57 Swelling 86 (0.6) Asia/Australia n=58 Grade 3 ISR pain 32 (0.2) Patient Preference Survey (LA Arm)

South Africa n=103 with ISRs (%) Participants 0 Japan n=20 Median duration of ISRs, days 3 Latin America n=26 4 8 12 16 20 24 28 32 36 40 44 48 Single-item question on participants’ preference at Week 48 Australia n=19 Participants with ISR leading Argentina n=16 Study Week 6 (1)  Republic of Korea n=19 to withdrawal, n (%) ITT-E population: 88% (523/591) preferred LA; 2% (9/591) preferred Mexico n=10 daily oral therapy Bars represent incidence of onset ISRs relative to the most recent IM injection visit.  Responding participants: 98% (523/532) preferred the LA regimen over previous oral therapy  Table 2. Pooled Snapshot Outcomes at Week 48 (ITT-E) The majority (99%, 3628/3663) of ISRs were Grade 1–2 and *Adjusted mean change from baseline; adjusted for baseline score, sex, age, and race. Error bars show 95% CI. n=557 for most (88%) resolved within ≤7 days CAB + RPV LA at Week 24 and Week 44; n=543 for CAR at Week 24 and n=552 at Week 44.

CAB + RPV LA CAR N=591 N=591 Conclusions HIV-1 RNA <50 c/mL 550 (93.1%) 558 (94.4%)  Monthly injections of CAB + RPV LA were noninferior to daily oral CAR for key virologic endpoints at Week 48. 11 (1.9%) 10 (1.7%) HIV-1 RNA ≥50 c/mL  1 2 Data in window not below threshold 3 (0.5%) 3 (0.5%) Primary and secondary outcomes in ATLAS and FLAIR analyzed separately were similar to the results in the pooled analysis. Discontinued for lack of efficacy 7 (1.2%) 5 (0.8%)  Low CVF (1.2%) was seen across both treatment arms. Discontinued for other reason while 1 (0.2%) 2 (0.3%)  Injection site reactions in the LA arm were common but mainly Grade 1 or 2, with few associated discontinuations. not below threshold Change in background therapy 0 0  L74I polymorphism alone had no impact on overall efficacy among FLAIR participants; further research on the interplay No virologic data 30 (5.1%) 23 (3.9%) between L74I and HIV sub-type is ongoing. Discontinued study due to AE 19 (3.2%) 7 (1.2%)  Discontinued study due to death 0 1 (0.2%) High treatment satisfaction reported among those receiving CAB + RPV LA. Discontinued study for other reasons 11 (1.9%) 16 (2.7%)  Overall, ATLAS and FLAIR show that CAB + RPV LA offers individuals with HIV-1 infection a well-tolerated, novel, On study but missing data in window 0 0 long-acting two-drug regimen without an increased risk of virologic failure.

Abbreviations 3TC, lamivudine; ABC, abacavir; AE, adverse event; ART, antiretroviral therapy; AZT, azidothymidine; BL, baseline; BMI, body mass index; CAB, cabotegravir; CAR, current antiretroviral; CI, confidence interval; CVF, confirmed virologic failure; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIVTSQs, HIV Treatment Satisfaction Questionnaire (Status); HLA, human leukocyte antigen; INSTI, integrase strand transfer inhibitor; IQR, interquartile range; ISR, injection site reaction; ITT-E, intention-to-treat exposed; LA, long-acting; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; r, ritonavir; RAL, raltegravir; RAM, resistance-associated mutation; RPV, rilpivirine; RT, reverse transcriptase; SVF, suspected virologic failure; TDF, tenofovir disoproxil fumarate; VL, viral load. References 1. Swindells S, et al. Abstract 1475. Presented at: Conference on Retroviruses and Acknowledgments Opportunistic Infections; March 4-7, 2019; Seattle, WA; We thank everyone who has contributed to the success of the study: All study participants and their families, the FLAIR and ATLAS clinical investigators and their staff. ATLAS and FLAIR are funded by 2. Orkin C, et al. Abstract 3947. Presented at: Conference on Retroviruses and ViiV Healthcare and Janssen R&D. Professional medical writing and editorial assistance was provided by Nicole Ogbonnaya at Articulate Science, funded by ViiV Healthcare. Opportunistic Infections; March 4-7, 2019; Seattle, WA.

10th IAS Conference on HIV Science; July 21–24, 2019; Mexico City, Mexico