THIRD JOINT CONFERENCE OF BHIVA AND BASHH 2014 Dr Max Lataillade Bristol-Myers Squibb Pharmaceuticals 1-4 April 2014, Arena and Convention Centre Liverpool
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-663068 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 AI438011 study team
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
BMS-663068 Overview Prodrug metabolized to BMS-626529, 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-663068 to BMS-626529 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 (1.21 1.73 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):1742 512; 2. Langley DL et al. Manuscript in development; 3. Nowicka Sans B et al. AAC 2012: 56:3498 507; 4. Li Z et al. AAC 2013: 57(9):4172 80; 5. Nettles R et al. J Infect Dis 2013: 206:1002 11.
BMS-626529 Attachment Inhibitor: Proposed Mechanism of Action No drug BMS-626529 gp41 gp41 gp120 gp120 BMS-626529 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.
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-626529 IC 50 <0.1 μm (100 nm) as determined by screening Phenosense entry assay (Monogram Biosciences LabCorp)
Partial Blind AI438011: Study Design BMS-663068 400 mg BID + RAL + TDF BMS-663068 800 mg BID + RAL + TDF BMS-663068 600 mg QD + RAL + TDF BMS-663068 1200 mg QD + RAL + TDF ATV/r 300/100 mg QD + RAL + TDF BMS-663068 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
AI438011: Baseline Characteristics BMS-663068 + TDF + RAL ATV/r +TDF + RAL 400 mg BID 800 mg BID N=49 600 mg QD N=51 1200 mg QD 300 mg/100 mg QD N= 51 Median age, years 38.1 38.4 40.1 39.2 39.6 Male, % 62.0 57.1 56.9 68.0 56.9 Non-white, % 60.0 61.2 66.7 68.0 55.0 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, % 70.0 16.0 14.0 4.76 46.0% 252.9 38.0% 59.2 24.5 16.2 4.85 51.0% 264.3 32.6% 68.6 21.6 9.9 4.95 45.1% 241.5 41.2% 64.0 20.0 16.0 4.65 36.0% 247.7 42.0% 66.7 17.6 15.6 4.69 35.3% 265.4 37.3% BMS-626529 IC 50 median, nm 0.68 0.65 0.43 0.82 0.73 Baseline Resistance (N=251): M184V/I, 29%; K103N, 29%; TAMS, 13%; Major PI mutations, 2%.
AI438011: Subject Disposition* BMS-663068 400 mg BID + RAL + TDF BMS-663068 800 mg BID + RAL + TDF BMS-663068 600 mg QD + RAL + TDF BMS-663068 1200 mg QD + RAL + TDF ATV/r 300/100 mg QD + RAL + TDF Randomized 52 49 51 50 51 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
AI438011: BMS-663068 Monotherapy Substudy: Mean Change in HIV-1 RNA from Baseline* *Error bars represent standard error of the mean.
AI438011: Proportion of Subjects Achieving HIV-1 RNA <50 or < 400 c/ml (Week 24 Snapshot): mitt BMS-663068 + TDF + RAL ATV/r + TDF + RAL 400 mg BID 800 mg BID N=49 600 mg QD N=51 1200 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 (%) 0 0 0 0 0 HIV-1 RNA <400 c/ml, % 92% 80% 90% 80% 82% mitt population: all subjects receiving 1 dose of study drug
AI438011: Proportion of Subjects Achieving HIV-1 RNA <50 or <400 c/ml (Week 24 Window): Observed BMS-663068 + TDF + RAL ATV/r + TDF + RAL Observed (data within Week 24 window) 400 mg BID N=46 800 mg BID N=42 600 mg QD 1200 mg QD N=43 300 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
AI438011: Proportion of Subjects Achieving HIV-1 RNA <50 c/ml by Baseline BMS-626529 IC 50 Category: Observed BMS-663068 + TDF + RAL ATV/r +TDF + RAL Subgroup 400 mg BID N=46 800 mg BID N=42 600 mg QD 1200 mg QD N=43 300 mg/100 mg QD N=44 Baseline BMS-626529 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%)
AI438011: Safety Summary BMS-663068 + TDF + RAL ATV/r +TDF + RAL Total number of subjects BMS-663068: 13 subjects reported 15 SAEs, none related to BMS-663068 No BMS-663068-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=49 600 mg QD N=51 1200 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)
AI438011: Summary Through week 24, response rates were similar across all BMS-663068 arms and with ATV/r in treatment-experienced, HIV-positive subjects 69 80% on BMS-663068 and 75% on ATV/r had HIV-1 RNA <50 c/ml (mitt Snapshot algorithm) 78-87% on BMS-663068 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 0.7 1.47 log 10 c/ml across BMS-663068 doses Response rates were comparable regardless of BMS-626529 IC 50 category BMS-663068 was generally well tolerated across all arms without any dose response safety signal These results support the continued development of BMS-663068
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
Acknowledgments We would like to thank all of the AI438011 clinical trial participants and their families AI438011 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
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Back up slides
AI438011: Proportion of Subjects Achieving HIV-1 RNA <50 c/ml by Baseline Viral Load: Observed
AI438011: Mean Change in CD4+ T-cell Counts from Baseline through Week 24: Observed* *Error bars represent standard error of the mean.