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Attachment Inhibitor Prodrug BMS–663068 in ARV-Experienced Subjects: Week 48 Analysis
Melanie Thompson1, Jay Lalezari2, Richard Kaplan3, Yvette Pinedo4, Otto Sussman Pena5, Pedro Cahn6, David A. Stock7, Samit R. Joshi7, George J. Hanna8, Max Lataillade7
1 AIDS Research Consortium of Atlanta, Atlanta, GA, United States. 2 Quest Clinical Research, San Francisco, CA, United States. 3 Desmond Tutu HIV Foundation, Cape Town, South Africa. 4 Asociacion Civil Via Libre, Lima, Peru. 5 Asistencia Cientifica de Alta Complejidad SAS, Bogotá, Colombia. 6 Fundacion Huesped, Buenos Aires, Argentina. 7 Research and Development, Bristol-Myers Squibb, Wallingford, CT, United States. 8 Research and Development, Bristol-Myers Squibb, Princeton, NJ, United States.
Background: BMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T-cells. AI438011 is an ongoing Phase 2b, randomized, active-controlled trial investigating the safety, efficacy and dose–response of BMS-663068 vs atazanavir/ritonavir (ATV/r) in treatment-experienced (TE) HIV-1-infected patients (pts). At Week 24, BMS”‘663068 arms had similar response rates to ATV/r and were generally well tolerated with no BMS-663068-related SAEs or AEs leading to discontinuation (D/C). Here we report the Week 48 results.
Methods: TE adults (≥1 week exposure to ≥1 ARV) with viral load (VL) ≥1,000 c/mL and susceptibility to all study drugs (including a conservative cut-off for BMS-626529 IC50 <100 nM) were randomized equally to four BMS-663068 groups (400 or 800 mg BID; 600 or 1200 mg QD) and a control group (ATV/r 300/100 mg QD), each with a background of raltegravir (RAL) 400 mg BID + tenofovir disoproxil fumarate (TDF) 300 mg QD. Efficacy and safety at Week 48 were assessed as secondary endpoints.
Results: 254 pts were randomized and 251 were treated across all arms. At baseline (BL), demographics were similar across arms: median age=39 yrs, male=60%, non-white=62%, median BL VL=4.85 log10 c/mL (43% had VL ≥100,000 c/mL), median CD4 count=230 cells/µL (38% had <200 CD4 cells/µL). Approximately 50% of pts had ≥1 major NRTI, NNRTI or PI resistance-associated mutation at BL. Through Week 48, 61–82% of BMS-663068 pts and 71% of ATV/r pts had HIV-1 RNA <50 c/mL (Table, mITT FDA Snapshot). Similarly, 77–95% of BMS-663068 pts and 88% of ATV/r pts had HIV-1 RNA <50 c/mL in the observed analysis (Table). Mean increase in CD4 counts from baseline were 141–199 cells/µL across BMS-663068 arms and 179 cells/µL for the ATV/r arm. Observed virologic response rates across the BMS-663068 and ATV/r arms by BL VL <100,000c/mL were 74–100% vs 96%, respectively and by BL VL ≥100,000c/mL were 60–91% vs 71%, respectively. All BMS-663068 doses were generally well tolerated and no BMS-663068-related AEs led to D/C.
Conclusions: Through Week 48, BMS-663068 continues to show similar efficacy to ATV/r in TE pts. Virologic response rates (mITT and observed) and immunologic reconstitution were similar across the BMS-663068 and ATV/r arms through Week 48. All BMS-663068 doses were generally well tolerated with no dose response safety signals reported. These results support the continued development of BMS-663068.