Nonclinical Safety Profile of BMS-986001, a Nucleoside Transcriptase Inhibitor for Combination Retroviral Therapy.
Nucleoside reverse transcriptase inhibitors (NRTIs)/nucleotide reverse transcriptase inhibitors are key components of combination antiretroviral therapy for HIV infection. First-generation NRTIs are associated with mitochondrial toxicity in patients, mainly due to inhibition of human DNA polymerase γ (hDNA polγ) that manifests as adverse events such as lipodystrophy, lactic acidosis, myopathy, cardiomyopathy, or nephropathy in patients. In chronic nonclinical studies in rodents and nonrodents, eukaryotic (host) mitochondrial toxicity manifests as some drug-specific toxicities similar to human toxicity. BMS-986001, a novel thymidine analog with minimal hDNA polγ inhibition, has demonstrated antiretroviral activity in early clinical studies. The primary toxicity of BMS-986001 in rats and monkeys is bone marrow dyserythropoiesis with associated decreases in red blood cell mass. Additionally, at high doses, severe platelet reductions accompanied by cutaneous petechiae began during weeks 8 and 11 in 3 of 60 monkeys in chronic toxicity studies. In a 6-month study, platelet reductions required euthanasia of the 2 affected monkeys (300 mg/kg/d) at week 14, but with dose reduction (200 mg/kg/d) remaining monkeys had no platelet changes. One affected monkey (200 mg/kg/d) in a 9-month study completed dosing and its platelet counts recovered during a 1-month recovery. Formation of platelet-bound immunoglobulin in the presence of BMS-986001, together with rapid and complete platelet recovery in the absence of BMS-986001, suggested that platelet decreases in monkeys may be immune mediated. No findings indicative of mitochondrial toxicity were observed in rats or monkeys given BMS-986001, suggesting an improved safety profile compared to marketed NRTI or tenofovir disoproxil fumarate.
Research and Development, Bristol-Myers Squibb Company, Mt Vernon, IN, USA.
Guha
G
Mausumee
Research and Development, Bristol-Myers Squibb Company, Mt Vernon, IN, USA.
Simutis
S
Frank
Research and Development, Bristol-Myers Squibb Company, Mt Vernon, IN, USA.
Clark
C
Shawn
Research and Development, Bristol-Myers Squibb Company Lawrenceville, NJ, USA.
Hawthorne
H
Dara
Research and Development, Bristol-Myers Squibb Company Lawrenceville, NJ, USA.
Yue
Y
Zhao
Charles River Laboratories, Senneville, Quebec, Canada.
Piche Marie
PM
Soleil
Research and Development, Bristol-Myers Squibb Company, Mt Vernon, IN, USA thomas.sanderson@bms.com.
Thomas P
TP
Sanderson
Research and Development, Bristol-Myers Squibb Company Lawrenceville, NJ, USA.
Graziano
G
Michael
Research and Development, Bristol-Myers Squibb Company Lawrenceville, NJ, USA.
Davies
D
Marc
D000748:Anemia, Macrocytic / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development; D006207:Half-Life; D008252:Macaca fascicularis; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011696:Purpura, Thrombocytopenic / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism; D016019:Survival Analysis; D013936:Thymidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D036401:Toxicity Tests, Chronic; D066007:Toxicokinetics
D019380:Anti-HIV Agents; C583040:BMS-986001; D015507:Drugs, Investigational; D018894:Reverse Transcriptase Inhibitors; D013936:Thymidine
BMS-986001; HIV type 1; human DNA polymerase γ; mitochondrial; nucleoside reverse transcriptase inhibitor