The title slide headline placement - Conference Programme IAS ...

The title slide headline placement - Conference Programme IAS ...

Fixed-Dose Combination of Doravirine/Lamivudine/TDF is Non-Inferior to Efavirenz/Emtricitabine/TDF in Treatment-Nave Adults With HIV-1 Infection: Week 48 Results of the Phase 3 DRIVE-AHEAD Study IAS 2017 Abstract TUAB0104LB Kathleen E Squires1, Jean-Michel Molina2, Paul E Sax3, Wing-Wai Wong4, Chloe Orkin5, Otto Sussmann6, Richard Kaplan7, Lisa Lupinacci8, Anthony Rodgers8, Xia Xu8, Gina Lin8, Sushma Kumar8, Peter Sklar8, Bach-Yen Nguyen8, George J Hanna8, Carey Hwang8, Elizabeth Martin8 on behalf of the DRIVE-AHEAD study team 1 Thomas Jefferson University, Philadelphia, PA, USA; 2University of Paris Diderot, Hpital Saint-Louis, Paris, France; 3Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; 4Taipei Veterans General Hospital, Taipei, Taiwan; 5Royal London Hospital, London, UK; 6Asistencia Cientifica de Alta Complejidad SAS, Bogot, Colombia; 7Desmond Tutu HIV Foundation, Cape Town, South Africa; 8 Acknowledgments We thank all the patients who participated in this study. The contributions of the investigators and their staff are also gratefully recognized. Primary investigators (by country): Australia MT Bloch, RJ Finlayson, J McMahon; Belgium S De Wit, I Derdelinckx, E Florence, L Vandekerckhove, B Vandercam; Canada J De Wet, RP LeBlanc, B Lebouche, D Longpre, B Trottier; Chile C Beltran, CE Chahin, W Jensen, C Perez; Colombia JMO Gutierrez, O Sussmann, JD Velez; Denmark J Gerstoft, H Nielsen; Germany K Arasteh, O Degen, S Esser, H-J Stellbrink, C Stephan, A Stoehr; Guatemala EMR Alvarado, E Arathoon, RM Lopez, CR Mejia, LDG Patzan, R Pinzon; Honduras C Parchment; Israel M Chowers, I Levy, E Shahar, Z Sthoeger; Mexico J Andrade, NPQ Perez, BEC Ramirez; Netherlands JG den Hollander, B Rijnders; New Zealand R Handy; Peru N Bonifacio, P Campos, JA Hidalgo, RM Infante, ED Matos, Y Pinedo, ER Ticona; Portugal JGS da Cunha, F Maltez, I Neves, P Pacheco, R Serrao; Puerto Rico S Maldonado-Rivera, I Melendez-Rivera, RO Mendoza-Rodriguez, JO Morales-Ramirez, G OrtizLasanta; Russia S Kizhlo, VV Kulagin, VV Pokrovsky, TE Shimonova, AA Shuldyakov, OA Tsybakova, E Voronin, NG Zakharova; South Africa E Baraldi, LF Fouche, F Hoosen, R Kaplan, JJ Lombaard, AA Mahomed, EA Mitha, L Mohapi, MS Rassool, N Siddique; Spain J Berenguer, HK Freud, SM Guillen, FV Mendez, JS Moreno, DP Palter; Switzerland A Calmy, M Cavassini, J Fehr; Taiwan C-C Hung, W-C Ko, H-H Lin, Y-H Lin, H-C Tsai, WW Wong; Thailand A Avihingsanon, D Changpradub, P Chetchotisakd, S Kiertiburanakul, W Ratanasuwan, K Supparatpinyo; United Kingdom A Clarke, A Fox, MA Johnson, MR Nelson, C Orkin, N Perry, A Ustianowski, IG Williams, A Winston; United States DM Asmuth, NC Bellos, DS Berger, CJ Bettacchi, L Bhatti, T Campbell, RE Campo, KK Casey, JG Castro, GE Crofoot, D Cunningham, E DeJesus, J Feinberg, FA Felizarta, C Fichtenbaum, TT Jefferson, M Johnson, PN Kumar, ST Lewis, RA Loftus, AE Luque, CK McDonald, M Mogyoros, RM Novak, O Osiyemi, DM Parenti, DJ Prelutsky, DJ Riedel, WJ Robbins, PJ Ruane, M Scott, ASY Shon, J Sims, J Slim, L Sloan, DE Sweet, KT Tashima, P Tebas, MA Thompson, WJ Towner, KJ Vigil, BG Yangco, R Zane. Medical writing assistance was provided by Annette Smith, PhD, of Complete Medical Communications,

Macclesfield, UK. This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA. IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Disclosures Dr. Kathleen Squires has received research grants awarded to her institution from Gilead Sciences, and has served on advisory boards for BMS, Gilead Sciences, Janssen, MSD, and ViiV IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Background Doravirine (DOR) is a novel, next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) Unique resistance profile with in vitro activity against wild-type HIV-1 and the most prevalent NNRTI resistance mutations (RT: K103N, Y181C, G190A, K103N/Y181C, and E138K)1 Dosed once daily (QD), without regard to food2 Low potential for drugdrug interactions,3 including with acid-reducing agents4 Being developed as a single entity and fixed-dose combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) In the Phase 2b clinical trial, DOR 100 mg demonstrated favorable efficacy and a superior neuropsychiatric profile vs efavirenz (EFV) 600 mg QD5 In the Phase 3 DRIVE-FORWARD clinical trial, DOR 100 mg showed non-inferior efficacy to ritonavir-boosted darunavir, and a more favorable lipid profile 6 1. Feng M, et al. Antimicrob Agents Chemother. 2016;60:2241-2247; 2. Anderson MS, et al. Antivir Ther. 2015;20:397-405; 3. Behm MO, et al. Clin Drug Investig. 2017;[Epub ahead of print]; 4. Khalilieh S, et al. IAS 2017. Poster MOPEB0334; 5. Gatell JM, et al. J Int AIDS Soc. 2014;17(4 Suppl 3): 19532; 6. Molina JM, et al. CROI 2017. Abstract 45LB IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved DRIVE-AHEAD: Study Design Phase 3, multicenter, double-blind, randomized study in treatment-nave adults with HIV-1 infection Screening begins W0 Key entry criteria:

HIV-1 RNA 1000 copies/mL within 45 days before Day 1 Antiretroviral-naveve No genotypic resistance to any study drugs Stratification factors: HIV-1 RNA >100,000 copies/mL and chronic hepatitis B or C infection status W24 W48 W96 Group 1 N=340 DOR 100 mg/3TC 300 mg/TDF 300 mg QD + PBO 14-day follow-Up Group 2 N=340 EFV 600 mg/FTC 200 mg/TDF 300 mg QD + PBO 14-day follow-Up Primary analysis time point At Week 96, eligible patients may opt to continue for additional 96 weeks (study extension phase) FTC, emtricitabine; PBO, placebo; W, Week IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Study Hypotheses Primary efficacy and safety hypotheses DOR/3TC/TDF QD is non-inferior to EFV/FTC/TDF QD, as assessed by the proportion of participants with HIV-1 RNA <50 copies/mL at Week 48

Considered non-inferior if lower bound of two-sided 95% CI for between-treatment difference is greater than -10 percentage points 90% power with 340 participants in each treatment group assuming a response rate of 80% at Week 48 for both treatment groups (FDA Snapshot approach) DOR/3TC/TDF QD is superior to EFV/FTC/TDF QD, as assessed by the proportion of participants with neuropsychiatric adverse events (AEs) by Week 48 in the categories of dizziness, sleep disorders and disturbances, and altered sensorium (superiority to be tested sequentially within each category) Secondary safety hypotheses DOR/3TC/TDF QD is superior to EFV/FTC/TDF QD, as assessed by the mean change from baseline in LDL-C and nonHDL-C at Week 48 LDL-C, low-density lipoprotein cholesterol; nonHDL-C, nonhigh-density lipoprotein cholesterol IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Disposition, Week 48 Randomized N=734 DOR/3TC/TDF: 368 randomized 364 treated 51 (14%) discontinued 10 (3%) 18 (5%) 8 (2%) 6 (2%) 4 (1%) 2 (1%) 1 (<1%) 1 (<1%) 1 (<1%) EFV/FTC/TDF: 366 randomized 364 treated Adverse event Lack of efficacy Withdrew consent Lost to follow-up Protocol violation Physician decision Death Non-compliance Pregnancy 61 (17%) discontinued 23 (6%) 10 (3%) 11 (3%)

7 (2%) 2 (1%) 2 (1%) 3 (1%) 2 (1%) 1 (<1%) 313 (86%) continuing 303 (83%) continuing IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Baseline Characteristics DOR/3TC/TDF EFV/FTC/TDF (N=364) (N=364) 32.0 (1870) years 30.0 (1869) years Male 84% 85% White 49% 47% Clinical history of AIDS 13% 15% HIV-1 subtype B 64% 70%

4.4 (0.7) log10 copies/mL 4.5 (0.7) log10 copies/mL 20% 23% 435 (218) cells/mm3 416 (211) cells/mm3 12% 13% Median age (range) Baseline HIV-1 RNA Mean (SD) >100,000 copies/mL Baseline CD4+ T-cell count Mean (SD) 200 cells/mm3 SD, standard deviation IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Proportion of Participants with HIV-1 RNA <50 copies/mL (FDA Snapshot Approach) 100 Percentage of Participants (95% CI) 87 77 73 80 81 89 85 60 DOR/3TC/TDF DOR/3TC/TDF isis non-inferior non-inferior

to to EFV/FTC/TDF EFV/FTC/TDF at at Week Week 48 48 49 46 40 Difference Difference (95% (95% CI): CI): 3.5 3.5 (-2.0, (-2.0, 9.0) 9.0) 23 20 20 84 81 DOR/3TC/TDF EFV/FTC/TDF 0; 0 0 00; 0 4 8 16 24 36 Treatment Week

IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved 48 Virologic Outcome at Week 48 (FDA Snapshot Approach) 100 DOR/3TC/TDF DOR/3TC/TDF isis non-inferior non-inferior to EFV/FTC/TDF at to EFV/FTC/TDF at Week Week 48 48 DOR/3TC/TDF EFV/FTC/TDF Percentage of Participants 80 84 81 60 40 20 11 0 HIV-1 RNA <50 copies/mL 10 HIV-1 RNA 50 copies/mL IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved 5 9 No data in window Efficacy by Subgroup (Observed Failurea Approach) HIV-1 RNA <50 copies/mL, % (N)

DOR/3TC/TDF EFV/FTC/TDF 88.7 (346) 88.8 (331) 100,000 90.6 (277) 91.1 (258) >100,000 81.2 (69) 80.8 (73) 200 69.0 (42) 83.7 (43) >200 91.4 (304) 89.6 (288) All participants Treatment difference, % (95% CI) Baseline HIV-1 RNA, copies/mL Baseline CD4+ T-cell count, cells/mm3 0 1 2 3 4

5 6 7 Favors Favors EFV/FTC/TDF DOR/3TC/TDF Discontinuation due to lack of efficacy = failure; data missing for other reasons were excluded a IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Change from Baseline in CD4+ T-cell Count (Observed Failure Approach) 250 DOR/3TC/TDF EFV/FTC/TDF Mean Change (95% CI), cells/mm3 198 200 159 188 150 126 Difference Difference (95% (95% CI): CI): 10.1 (-16.1, 36.3) 10.1 (-16.1, 36.3) 155 100 97 50 0

0 4 8 12 16 20 24 28 32 Treatment Week IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved 36 40 44 48 Resistance Data at Week 48 DOR/3TC/TDF EFV/FTC/TDF 22 (6.0%) 14 (3.8%) (N=364) Participants with PDVF,a n (% of N) (N=364) Non-responder Rebounder Non-responder

Rebounder 6 16 4 10 Participants discontinued without PDVF, n (% of N) 35 (9.6%) 50 (13.7%) Genotype test successfully performed, n 23 24 Primary NNRTI resistance, n (% of N) 6 (1.6%)b 12 (3.3%)c Primary NRTI resistance, n (% of N) 5 (1.4%) b 5 (1.4%)c a Protocol-defined virologic failure (PDVF): - Confirmed HIV-1 RNA 50 copies/mL after initial response of HIV-1 RNA <50 copies/mL; OR - Confirmed HIV-1 RNA 200 copies/mL at Week 24 or Week 36; OR - Confirmed HIV-1 RNA 50 copies/mL at Week 48 In the DOR/3TC/TDF group, NNRTI mutations were RT: Y188L; V106I, F227C; V106V/I, H221H/Y, F227C; F227C; V106A, P225H, Y318Y/F; V106M/T, F227C/R Nucleoside reverse transcriptase inhibitors (NRTI) mutations were RT: M41L, M184V; M184V; M184V; K65R; K65K/R, M184V b In the EFV/FTC/TDF group, NNRTI mutations were RT: K103N; K103N, E138E/G; K103N; G190E; K103N; K103N, M230L; G190E; K103N, V108V/I, T369T/A/I/V; K103N; K103N; K101K/N, K103N, P225P/H NRTI mutations were RT: V118I, M184V; M184V; M184V; M184V, K219K/E; K65K/R, M184M/I

c IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Summary of Clinical Adverse Events DOR/3TC/TDF (N=364) n (%) EFV/FTC/TDF (N=364) n (%) Difference in % estimate (95% CI)a 1 AEs 301 (83%) 330 (91%) -8.0 (-13.0, -3.1) Drug-related AEs 113 (31%) 229 (63%) -31.9 (-38.6, -24.8) Serious AEs 13 (4%) 21 (6%)

-2.2 (-5.5, 0.9) 1 (<1%) 4 (1%) -0.8 (-2.5, 0.5) 11 (3%) 24 (7%) -3.6 (-6.9, -0.5) Drug-related 8 (2%) 21 (6%) -3.6 (-6.7, -0.8) Serious 2 (1%) 4 (1%) -0.5 (-2.3, 1.0) Serious drug-related 1

(<1%) 3 (1%) -0.5 (-2.2, 0.8) 0 (0%) 2 (1%) -0.5 (-2.0, 0.5) Drug-related Discontinued due to AE Deaths 95% CIs were calculated using Miettinen and Nurminens method a IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Most Common Adverse Events (10% in Either Group) DOR/3TC/TDF (N=364) n (%) EFV/FTC/TDF (N=364) n (%) Difference in % estimate (95% CI)a Headache 47 (13%) 45 (12%)

0.5 (-4.3, 5.4) Diarrhea 39 (11%) 49 (14%) -2.7 (-7.6, 2.0) Nasopharyngitis 39 (11%) 31 (9%) 2.2 (-2.1, 6.6) Dizziness 32 (9%) 135 (37%) -28.3 (-34.0, -22.5) Nausea 28 (8%) 39 (11%) -3.0 (-7.3, 1.2)

Abnormal dreams 17 (5%) 42 (12%) -6.9 (-11.0, -3.0) Rash 17 (5%) 44 (12%) -7.4 (-11.6, -3.5) 95% CIs were calculated using Miettinen and Nurminens method a IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Proportion of Participants with Predefined Neuropsychiatric Adverse Events at Week 48 IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Most Commona Laboratory Changes, Grade 3/4b Grade (criteria) DOR/3TC/TDF (N=364) n (%) EFV/FTC/TDF (N=364) n (%) 3 (190 mg/dL) 1 (<1%) 5 (2%)

3 (>5001000 mg/dL) 2 (1%) 8 (3%) 3 (>1.8<3.5 x ULN, or increase of 1.5 to <2.0 x above baseline) 7 (2%) 3 (1%) Aspartate aminotransferase 3 (5.0<10.0 x ULN) 1 (<1%) 5 (1%) Alanine aminotransferase 3 (5.0<10.0 x ULN) 2 (1%) 5 (1%) Lipase 3 (3.0<5.0 x ULN) 3 (1%) 5 (1%) 3 (10.0<20.0 x ULN) 6 (2%) 7 (2%) 4 (20.0 x ULN) 2 (1%)

4 (1%) Fasting LDL-C Fasting triglycerides Creatinine Creatine kinase Reported in 4 participants in either treatment group Grading per Division of AIDS (DAIDS) Version 2 criteria ULN, upper limit of normal a b IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Fasting Lipids: Change from Baseline at Week 48 IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved Conclusions In treatment-nave adults with HIV-1 infection, DOR/3TC/TDF administered once daily demonstrated: Antiviral potency with non-inferior efficacy to EFV/FTC/TDF regardless of baseline HIV-1 RNA Low rate of resistance, with only 1.6% of participants developing resistance to any study drug through Week 48 DOR/3TC/TDF was generally well tolerated and safe: Neuropsychiatric profile superior to EFV/FTC/TDF, as measured by lower proportion of participants with neuropsychiatric AEs in categories of dizziness, sleep disorders and disturbances, and altered sensorium Lipid profile superior to EFV/FTC/TDF, as assessed by difference from baseline in fasting LDL-C and nonHDL-C Doravirine is a novel, once-daily NNRTI for first-line treatment with consistent efficacy regardless of baseline viral load and favorable tolerability and safety profile in 2 Phase 3 clinical trials 11 1. Molina JM, et al. CROI 201. Abstract 45LB IAS 2017, Abstract TUAB0104LB. Copyright 2017 Merck & Co., Inc. All Rights Reserved

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