Samit R Joshi

Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial

BACKGROUND BMS-663068 is an oral prodrug of BMS-626529, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 cells. AI438011 is an ongoing trial investigating the efficacy, safety, and dose-response of BMS-663068 in treatment-experienced, HIV-1-infected patients. Herein we present the results of the primary analysis. METHODS AI438011 is a phase 2b, randomised, active-controlled trial, at 53 hospitals and outpatient clinics across ten countries in North and South America, Europe, and Africa. Individuals with an HIV-1 RNA viral load of at least 1000 copies per mL and a BMS-626529 half-maximum inhibitory concentration lower than 100 nmol/L were randomly assigned (1:1:1:1:1) to receive either BMS-663068 at 400 mg twice daily, 800 mg twice daily, 600 mg once daily, or 1200 mg once daily or ritonavir-boosted atazanavir (300 mg of atazanavir and 100 mg of ritonavir once daily), each with 400 mg of raltegravir twice daily and 300 mg of tenofovir disoproxil fumarate once daily as a backbone. The sponsor, participants, and investigators were masked for BMS-663068 dose but not for allocation. Primary endpoints were the proportion of patients with an HIV-1 RNA viral load less than 50 copies per mL (response rate) at week 24 and the frequency of serious adverse events and adverse events leading to discontinuation, up to the week 24 analysis. The primary analyses included all patients who received at least one dose of study drug (modified intention-to-treat population). This study is registered at ClinicalTrials.gov, NCT01384734. FINDINGS Between July 26, 2011, and July 16, 2012, 581 participants were assessed for eligibility. Of these, 254 patients were randomly assigned to receive either BMS-663068 (n=52 for the 400 mg twice daily group, n=50 for the 800 mg twice daily group, n=51 for the 600 mg once daily group, and n=50 for the 1200 mg once daily group) or ritonavir-boosted atazanavir (n=51). 200 patients received at least one dose of BMS-663068, and 51 patients received at least one dose of ritonavir-boosted atazanavir. At week 24, 40 (80%) of 50 patients in the BMS-663068 400 mg twice daily group, 34 (69%) of 49 patients in the 800 mg twice daily group, 39 (76%) of 51 patients in the 600 mg once daily group, and 36 (72%) of 50 patients in the 1200 mg once daily group had an HIV-1 RNA viral load less than 50 copies per mL, compared with 38 (75%) of 51 patients in the ritonavir-boosted atazanavir group. Serious adverse events were noted in 13 (7%) of 200 patients in the BMS-663068 groups and five (10%) of the 51 patients in the ritonavir-boosted atazanavir group. Four (2%) of the 200 patients in the BMS-663068 groups and two (4%) of the 51 patients in the ritonavir-boosted atazanavir group discontinued because of adverse events. No serious adverse events or adverse events leading to discontinuation were BMS-663068-related. Grade 2-4 adverse events related to study drug(s) occurred in 17 (9%) of 200 patients across the BMS-663068 groups and 14 (27%) of 51 patients in the ritonavir-boosted atazanavir group. For the BMS-663068 groups these events were mostly single instances with no dose relation and for the ritonavir-boosted atazanavir group these were mostly gastrointestinal or hepatobiliary disorders associated with hyperbilirubinaemia. INTERPRETATION In a comparison with ritonavir-boosted atazanavir, efficacy and safety of BMS-663068 up to the week 24 analysis support continued development of BMS-663068, which is being assessed in a phase 3 trial in heavily treatment-experienced individuals. FUNDING Bristol-Myers Squibb.

Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial

BACKGROUND BMS-986001 is a thymidine analogue nucleoside reverse transcriptase inhibitor (NRTI) designed to maintain in-vitro antiviral activity while minimising off-target effects. We assessed the efficacy and safety of BMS-986001 versus tenofovir disoproxil fumarate in treatment-naive patients with HIV-1. METHODS In this phase 2b, randomised, active-controlled trial (AI467003), we recruited treatment-naive (no current or previous exposure to an antiretroviral drug for >1 week) adults (aged at least 18 years) with HIV-1 from 47 sites across Asia, Australia, Europe, North America, South Africa, and South America. Patients with plasma HIV-1 RNA greater than 5000 copies per mL and CD4 counts greater than 200 cells per μL were randomly assigned (2:2:2:3) to receive BMS-986001 100 mg, 200 mg, or 400 mg once a day or to receive tenofovir disoproxil fumarate 300 mg once a day; each allocation was given with efavirenz 600 mg once a day and lamivudine 300 mg once a day. Both patients and investigators were masked to BMS-986001 dose (achieved with similar looking placebo tablets), but not allocation up to and including week 48. The primary endpoints were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL and safety events (serious adverse events and adverse events leading to discontinuation) through week 24; the main analysis was with a modified intention-to-treat population. Resistance analysis was a secondary endpoint, and additional safety parameters were exploratory endpoints. This trial is registered with ClinicalTrials.gov, number NCT01489046, and the European Clinical Trials Database, number EudraCT 2011-003329-89. FINDINGS Patients were recruited between Jan 25, 2012, and Oct 3, 2012; 757 patients were assessed for eligibility and 301 were randomly assigned to receive either BMS-986001 once a day (67 patients to 100 mg, 67 to 200 mg, and 66 to 400 mg) or tenofovir disoproxil fumarate (n=101). 297 patients received at least one dose of study drug. At week 24, 57 (88%) of 65 patients for whom there were data in the 100 mg group, 54 (81%) of 67 in the 200 mg group, 62 (94%) of 66 in the 400 mg group achieved HIV-1 RNA less than 50 copies per mL, compared with 88 (89%) of 99 in the tenofovir disoproxil fumarate group (modified intention-to-treat population). BMS-986001 was generally well tolerated through week 48. Two patients had BMS-986001-related serious adverse events (atypical drug eruption and thrombocytopenia) and two in the tenofovir disoproxil fumarate group had study drug-related serious adverse events (potential drug-induced liver injury and depression or lipodystrophy) that led to discontinuation. NRTI resistance-associated mutations were reported in four (2%) of 198 patients, and non-NRTI mutations in 17 (9%) of 198 patients receiving BMS-986001 versus none of 99 and one (1%) of 99 patients receiving tenofovir disoproxil fumarate, respectively. Compared with tenofovir disoproxil fumarate, individuals in the BMS-986001 groups showed a smaller decrease in lumbar spine and hip bone mineral density but greater accumulation of limb and trunk fat, subcutaneous and visceral adipose tissue, and increased total cholesterol. INTERPRETATION BMS-986001 had similar efficacy to that of tenofovir disoproxil fumarate and was associated with a smaller decrease in bone mineral density; however, greater resistance and gains in both peripheral and central fat accumulation were recorded for the investigational drug. Bristol-Myers Squibb has discontinued its involvement in the development of BMS-986001, and future decisions on development will be made by Oncolys BioPharma. FUNDING Bristol-Myers Squibb.

Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

ABSTRACT BMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4+ T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n = 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8+ T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the loge-transformed concentration at the end of a dosing interval (Ctau) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC50) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level of >0.5 or >1.0 log10 copies/ml as a function of the loge-transformed PBAIC50-adjusted Ctau after 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600- and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers NCT01009814 and NCT01384734, respectively.)

Safety Profile of HIV-1 Attachment Inhibitor Prodrug BMS-663068 in Antiretroviral-Experienced Subjects: Week 24 Analysis

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.

540HIV-1 Attachment Inhibitor Prodrug BMS-663068 in Antiretroviral-Experienced Subjects: Week 24 Subgroup Analysis

540. HIV-1 Attachment Inhibitor Prodrug BMS-663068 in AntiretroviralExperienced Subjects: Week 24 Subgroup Analysis Cynthia Brinson,; Jacob Lalezari,; Gulam H Latiff,; Melanie Thompson, MD; Juan Echevarría,; Sandra Treviño-Pérez,; David Stock,; Samit R Joshi,; George J Hanna,; Max Lataillade,; study team,; Central Texas Clinical Research, Austin, TX; Quest Clinical Research, San Francisco, CA; Maxwell Clinic, Durban, South Africa; AIDS Research Consortium of Atlanta, Atlanta, GA; Hospital Nacional Cayetano Heredia, Lima, Peru; Mexico Centre for Clinical Research, Mexico City, Mexico; Bristol-Myers Squibb, Wallingford, CT; Bristol-Myers Squibb, Princeton, NJ