Dr Max Lataillade. Bristol-Myers Squibb Pharmaceuticals THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014

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2 THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Dr Max Lataillade Bristol-Myers Squibb Pharmaceuticals 1-4 April 2014, Arena and Convention Centre Liverpool

3 BHIVA 2014 (Abstract O2) HIV-1 Attachment Inhibitor Prodrug in Antiretroviral-Experienced Subjects: Week 24 Analysis AI438011: A Phase IIb, Randomized, Controlled, Partially-Blinded Trial to Investigate the Safety, Efficacy and Dose-response of BMS in Treatment-Experienced HIV-1-positive Subjects Lalezari J, Latiff GH, Brinson C, Echevarría J, Treviño-Pérez S, Bogner JR, Stock D, Joshi SR, Hanna GJ, and Lataillade M for the AI study team

4 Financial Disclosures This study was funded by Bristol-Myers Squibb Max Lataillade, DO MPH, Bristol-Myers Squibb, Wallingford, CT Executive Director, HIV Drug Development Employee and shareholder of Bristol Myers-Squibb

5 BMS Overview Prodrug metabolized to BMS , a first-in-class attachment inhibitor that binds to HIV-1 gp120, preventing initial viral attachment and entry into the host CD4+ T cell 1,2 Conversion of BMS to BMS In vitro activity against HIV-1 viruses, with the exception of subtype AE and Group O, irrespective of co-receptor tropism 3 Unique resistance profile with no in vitro crossresistance to other classes of antiretrovirals 4 In the POC study, substantial declines in plasma HIV- 1 RNA ( log 10 c/ml) in treatment-naïve and experienced subjects after 8 days of monotherapy 5 Generally well tolerated in clinical studies 5 1. Brown J et al. J Pharm Sci 2013: 102(6): ; 2. Langley DL et al. Manuscript in development; 3. Nowicka Sans B et al. AAC 2012: 56: ; 4. Li Z et al. AAC 2013: 57(9): ; 5. Nettles R et al. J Infect Dis 2013: 206:

6 BMS Attachment Inhibitor: Proposed Mechanism of Action No drug BMS gp41 gp41 gp120 gp120 BMS binding Conformational changes Conformational changes inhibited CD4 binding site CD4 binding CD4 binding Blocked Cell surface CD4 receptor CCR5 co-receptor 1. Langley DL et al. Manuscript in development.

7 AI438011: Key Inclusion Criteria Antiretroviral treatment-experienced (defined as current or previous exposure to 1 antiretroviral for 1 week) Plasma HIV-1 RNA 1000 c/ml CD4+ T-cell count >50 cells/mm 3 Susceptibility to RAL, TDF and ATV BMS IC 50 <0.1 μm (100 nm) as determined by screening Phenosense entry assay (Monogram Biosciences LabCorp)

8 Partial Blind AI438011: Study Design BMS mg BID + RAL + TDF BMS mg BID + RAL + TDF BMS mg QD + RAL + TDF BMS mg QD + RAL + TDF ATV/r 300/100 mg QD + RAL + TDF BMS Monotherapy Substudy: 10 patients per study arm Day 1 Primary study - start of combination therapy Week 8 Data monitoring committee assessment Week 24 Primary endpoint Week 48/96 Long-term follow-up through Week 48/96

9 AI438011: Baseline Characteristics BMS TDF + RAL ATV/r +TDF + RAL 400 mg BID 800 mg BID N= mg QD N= mg QD 300 mg/100 mg QD N= 51 Median age, years Male, % Non-white, % HIV subtype, % B C Other HIV-1 RNA mean, log 10 c/ml >100,000 c/ml, % CD4+ T-cell count mean cells/µl <200 cells/µl, % % % % % % % % % % % BMS IC 50 median, nm Baseline Resistance (N=251): M184V/I, 29%; K103N, 29%; TAMS, 13%; Major PI mutations, 2%.

10 AI438011: Subject Disposition* BMS mg BID + RAL + TDF BMS mg BID + RAL + TDF BMS mg QD + RAL + TDF BMS mg QD + RAL + TDF ATV/r 300/100 mg QD + RAL + TDF Randomized Treated 50 (96.2%) 49 (98.0%) 51 (100%) 50 (100%) 51 (100%) Discontinued 6 (11.5%) 11 (22.0%) 7 (13.7%) 8 (16.0%) 9 (17.6%) 1 AE 1 consent withdrawal 2 lost to FU 1 poor/ noncompliance 1 other 2 AEs 2 consent withdrawals 2 pregnancies 1 no longer met study criteria 3 lack of efficacy 1 poor/ noncompliance 1 pregnancy 1 lost to FU 2 no longer met study criteria 2 poor/ noncompliance 1 other 1 AE 1 consent withdrawal 3 lost to FU 1 subject request 1 no longer met study criteria 1 lack of efficacy 2 AEs 3 consent withdrawals 2 pregnancies 1 admin-related 1 poor/ noncompliance *581 patients screened

11 AI438011: BMS Monotherapy Substudy: Mean Change in HIV-1 RNA from Baseline* *Error bars represent standard error of the mean.

12 AI438011: Proportion of Subjects Achieving HIV-1 RNA <50 or < 400 c/ml (Week 24 Snapshot): mitt BMS TDF + RAL ATV/r + TDF + RAL 400 mg BID 800 mg BID N= mg QD N= mg QD 300 mg/100 mg QD N=51 HIV-1 RNA <50 c/ml, % 80.0% 69.4% 76.5% 72.0% 74.5% HIV-1 RNA 50 c/ml, % 16.0% 20.4% 21.6% 26.0% 17.6% No virologic data at Week 24 Discontinued due to AE or death, n (%) 1 (2.0%) 2 (4.1%) 0 1 (2.0%) 2 (3.9%) Discontinued for other reasons, n (%) 1 (2.0%) 3 (6.1%) 1 (2.0%) 0 2 (3.9%) Missing data during window but on-study, n (%) HIV-1 RNA <400 c/ml, % 92% 80% 90% 80% 82% mitt population: all subjects receiving 1 dose of study drug

13 AI438011: Proportion of Subjects Achieving HIV-1 RNA <50 or <400 c/ml (Week 24 Window): Observed BMS TDF + RAL ATV/r + TDF + RAL Observed (data within Week 24 window) 400 mg BID N= mg BID N= mg QD 1200 mg QD N= mg/100 mg QD N=44 HIV-1 RNA <50 c/ml, % 87% 81% 78% 84% 86% HIV-1 RNA <400 c/ml, % 100% 93% 92% 93% 96% Observed population: subjects receiving 1 dose of study drug and with plasma HIV RNA data within the Week 24 window

14 AI438011: Proportion of Subjects Achieving HIV-1 RNA <50 c/ml by Baseline BMS IC 50 Category: Observed BMS TDF + RAL ATV/r +TDF + RAL Subgroup 400 mg BID N= mg BID N= mg QD 1200 mg QD N= mg/100 mg QD N=44 Baseline BMS IC 50 category, n (%) <0.1 nm 0.1 nm 2/2 (100%) 38/44 (86%) 1/1 (100%) 33/41 (81%) 3/3 (100%) 36/47 (77%) 2/2 (100%) 34/41 (83%) 0 38/44 (86%) <1.0 nm 1.0 nm 23/27 (85%) 17/19 (90%) 20/22 (91%) 14/20 (70%) 26/34 (77%) 13/16 (83%) 18/21 (86%) 18/22 (82%) 24/26 (92%) 14/18 (78%) <10.0 nm 10.0 nm 32/38 (84%) 8/8 (100%) 31/36 (86%) 3/6 (50%) 33/43 (77%) 6/7 (86%) 31/37 (84%) 5/6 (83%) 36/40 (90%) 2/4 (50%)

15 AI438011: Safety Summary BMS TDF + RAL ATV/r +TDF + RAL Total number of subjects BMS : 13 subjects reported 15 SAEs, none related to BMS No BMS related AEs led to discontinuation No trend for Grade 2-4 related clinical adverse events or laboratory abnormalities 4 AEs leading to discontinuation: 1 non-specific EKG changes*, 2 TB cases, 1 TDF ARF ATV: 400 mg BID 800 mg BID N= mg QD N= mg QD Grade 2 4 ATV/r-related AEs were mostly secondary to GI disorders 300 mg/100 mg QD N=51 SAEs, n (%) 4 (8.0%) 4 (8.2%) 3 (5.9%) 2 (4.0%) 5 (9.8%) Grade 2 4 related AEs, n (%) 6 (12.0%) 3 (6.1%) 2 (3.9%) 6 (12.0%) 14 (27.5%) AEs leading to discontinuation, n (%) 1 (2.0%) 2 (4.1%) 0 1 (2.0%) 2 (3.9%) *Corrected as not related (drug abuser)

16 AI438011: Summary Through week 24, response rates were similar across all BMS arms and with ATV/r in treatment-experienced, HIV-positive subjects 69 80% on BMS and 75% on ATV/r had HIV-1 RNA <50 c/ml (mitt Snapshot algorithm) 78-87% on BMS and 86% on ATV/r had HIV-1 RNA <50 c/ml (observed) Seven days of monotherapy resulted in mean decreases in plasma HIV-1 RNA of log 10 c/ml across BMS doses Response rates were comparable regardless of BMS IC 50 category BMS was generally well tolerated across all arms without any dose response safety signal These results support the continued development of BMS

17 Author Affiliations Jacob Lalezari, Quest Clinical Research, San Francisco, CA, USA Gulam H Latiff, Maxwell Clinic, Durban, South Africa Cynthia Brinson, Central Texas Clinical Research, Austin, TX, USA Juan Echevarría, Hospital Nacional Cayetano Heredia, Lima, Peru Sandra Treviño-Pérez, Mexico Centre for Clinical Research, Mexico City, Mexico Johannes Bogner, Hospital of the University of Munich, Munich, Germany Max Lataillade, Samit R Joshi, David Stock, Bristol-Myers Squibb, Wallingford, CT, USA George J Hanna, Bristol-Myers Squibb, Princeton, NJ, USA

18 Acknowledgments We would like to thank all of the AI clinical trial participants and their families AI Investigators: JD Altclas, PE Cahn, SH Lupo, MD Martins, AI Arango-Duque, OA Sussmann-Pena, G Amaya-Tapia, JF Andrade-Villanueva, ER Granados-Reyes, J G Sierra-Madero, SC Trevino-Perez, WM Casapia-Morales, JI Echevarria, JR Lama-Valdivia, MY Leon-Paredes, FC Mendo-Urbina, Y Pinedo-Ramirez, MR Salazar-Castro, R Bardinas-Rodriguez, C Brinson, E Dejesus, R Elion, J Ernst, J Feinberg, S Hassler, C Hicks, J Lalezari, AR Scribner, L Sloan, M Thompson, K Arastéh, J Bogner, J Rockstroh A Stoehr, IG Diaconescu, LJ Prisacariu, S Rugina, OA Tsybakova, EE Voronin, AA Yakovlev, NG Zakharova, J Fourie, D Johnson, R Kaplan, G Latiff, B Clotet Bristol-Myers Squibb: Anna Rightmire, Michelle DeGrosky, John Coumbis, Neela Ray, Nancy Cusack, Mark Krystal, Carey Hwang and Todd Correll Other: Peter Lill and John Riefler (ICON CRO) Professional medical writing and editorial assistance was provided by Anna Shirazi at MediTech Media and was funded by Bristol-Myers Squibb

19 Questions?

20 Back up slides

21 AI438011: Proportion of Subjects Achieving HIV-1 RNA <50 c/ml by Baseline Viral Load: Observed

22 AI438011: Mean Change in CD4+ T-cell Counts from Baseline through Week 24: Observed* *Error bars represent standard error of the mean.

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