title: Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Bristol-Myers Squibb.
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: sgupta1@iu.edu.
authors.forename: Samir K
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Grace A
authors.initials: GA
authors.lastname: McComsey
authors.affiliation: JOSHA Research, Bloemfontein, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Lombaard
authors.affiliation: Hospital Nacional Cayetano Heredia, Lima, Peru.
authors.forename: Juan
authors.initials: J
authors.lastname: Echevarría
authors.affiliation: Desmond Tutu HIV Foundation, Cape Town, South Africa.
authors.forename: Catherine
authors.initials: C
authors.lastname: Orrell
authors.affiliation: HIV-NAT, Thai Red Cross AIDS Research Centre and Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Anchalee
authors.initials: A
authors.lastname: Avihingsanon
authors.affiliation: Triple O Research Institute, West Palm Beach, FL, USA.
authors.forename: Olayemi
authors.initials: O
authors.lastname: Osiyemi
authors.affiliation: Centro Glucomedi, Mexico City, Mexico.
authors.forename: Mario
authors.initials: M
authors.lastname: Santoscoy
authors.affiliation: Bristol-Myers Squibb, Princeton, CT, USA.
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Ray
authors.affiliation: Bristol-Myers Squibb, Wallingford, NJ, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stock
authors.affiliation: Bristol-Myers Squibb, Wallingford, NJ, USA.
authors.forename: Samit R
authors.initials: SR
authors.lastname: Joshi
authors.affiliation: Bristol-Myers Squibb, Princeton, CT, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Hanna
authors.affiliation: Bristol-Myers Squibb, Wallingford, NJ, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
mesh_terms: D000293:Adolescent; D000328:Adult; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D013936:Thymidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: C583040:BMS-986001; D018894:Reverse Transcriptase Inhibitors; D013936:Thymidine