Journal Article

Safety profile of HIV‐1 attachment inhibitor prodrug BMS‐663068 in antiretroviral‐experienced subjects: week 24 analysis

Latiff, Gulam H, Brinson, Cynthia, Bogner, Johannes R, Lalezari, Jacob, Stock, David, Hanna, George J, Echevarria, Juan, Treviño‐Pérez, Sandra, Lataillade, Max, Joshi, Samit R

2014

Overview

Introduction BMS‐663068 is a prodrug of BMS‐626529, an attachment inhibitor that binds directly to HIV‐1 gp120, preventing initial viral attachment and entry into the host CD4+ T‐cell. AI438011 is an ongoing, Phase IIb, 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‐positive subjects. At Week 24, response rates across the BMS‐663068 arms were consistent with ATV/r. Materials and Methods Antiretroviral TE subjects (exposure to ≥1 antiretroviral for ≥1 week) with susceptibility to all study drugs (including BMS‐626529 IC50 100 nM) were randomized equally to four BMS‐663068 arms (400 or 800 mg, BID; 600 or 1200 mg, QD) and a control arm (ATV/r 300/100 mg QD), with tenofovir disoproxil fumarate (TDF) + raltegravir (RAL). The complete safety profile through Week 24 is reported. Results In total, 251 subjects were treated (BMS‐663068, 200; ATV/r, 51). No BMS‐663068‐related adverse events (AEs) led to discontinuation. Grade 2–4 drug‐related AEs occurred in 17/200 (8.5%) subjects across the BMS‐633068 arms; however, these events were mostly single instances and no dose‐relationship was seen. Similarly, no noticeable trend for Grade 3–4 laboratory abnormalities was seen and Grade 3–4 hematologic changes and liver chemistry elevations were uncommon (neutropenia, 2.5%; AST/ALT elevations, 1% (n=196)). In the ATV/r arm, Grade 2–4 drug‐related AEs occurred in 14/51 (27.5%) subjects and were mostly secondary to gastrointestinal and/or hepatobiliary disorders. Serious adverse events (SAEs) occurred in 13/200 (6.5%) and 5/51 (9.8%) subjects receiving BMS‐663068 and ATV/r, respectively; most were secondary to infections and none were related to study drugs. The most common AE reported for BMS‐663068 was headache (28/200, 14%), occurring in 5/51 (10%) subjects in the ATV/r arm; in the BMS‐663068 arms, this was not dose‐related. There were no deaths. Conclusions BMS‐663068 was generally well tolerated across all arms, with no related SAEs or AEs leading to discontinuation and no dose‐related safety signals. There were no trends for Grade 2–4 AEs or clinical laboratory abnormalities. These results support continued development of BMS‐663068. Note Previously submitted at IDWeek, Philadelphia, PA, 8 October 2014.

• Publisher: International AIDS Society,John Wiley & Sons, Inc
• Subject: Acquired immune deficiency syndrome / AIDS / Antiretroviral agents / Antiretroviral drugs / Drug dosages / HIV / Human immunodeficiency virus / Laboratories / Ritonavir / Safety