TUPE041 - Poster Exhibition
Absence of renal and bone toxicity in non-clinical studies of BMS-986001, a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus (HIV)
M. Guha1, G. Pilcher2, J. Moehlenkamp2, F. Wang2, S. Clark2, F. Simutis2, O. Flint3, R. Bunch2, T. Sanderson2, G. Hanna3, M. Davies4
1Bristol Myers Squibb, Drug Safety Evaluation, Trabuco Canyon, United States, 2Bristol-Myers Squibb Pharmaceuticals Ltd, Evansville, United States, 3Bristol-Myers Squibb Pharmaceuticals Ltd, Lawrenceville, United States, 4Bristol-Myers Squibb Pharmaceuticals Ltd, Princeton, United States
Background: Pre-clinical toxicity studies of tenofovir disoproxil fumarate (TDF), a commonly used NRTI in the treatment of HIV, have shown changes indicative of both renal and bone toxicity at high exposures. These same organ toxicities are also associated with clinical use of TDF. BMS-986001, a novel selective NRTI with a favorable in vitro mitochondrial safety profile, has demonstrated potent antiviral activity in a proof-of-concept clinical study. The major pre-clinical toxicity with BMS-986001(up to 6-month duration) at high exposures were dyserythropoesis in the bone marrow with lower myeloid to erythroid ratios and decreased red blood cells, and thrombocytopenia.
Methods: Chronic oral 6-month toxicity studies were conducted in rats (50-300 mg/kg/day) and cynomolgus monkeys (50-200 mg/kg/day) with BMS-986001. In addition to standard end points, we assessed several parameters of renal function and toxicity, as well as parameters of bone toxicity (including markers of bone formation and resorption).
Results: There were no BMS-986001-related changes in renal function (serum and/or urine urea, creatinine, total protein and excretion, albumin, phosphorus, calcium, and glucose) or biomarkers of renal toxicity (serum cystatin C and renal b2-microglobulin, clusterin, and NGAL) at any dose tested compared to control group. There were no BMS-986001-related changes in serum phosphate and calcium or in biomarkers of bone formation (serum osteocalcin) or bone resorption (serum free deoxypyridinoline and C-terminal cross-linking telopeptide of type I collagen [C-Tx]; and urine N-Tx). All changes were not considered drug related because they were either not dose related or were within the range of biological variation or the study control range.
Conclusions: In contrast to published data with TDF, no evidence of renal or bone toxicity was noted with BMS-986001 in 6-month studies in 2 species. BMS-986001 has a favorable preclinical renal and bone safety profile, warranting further clinical development for treatment of HIV.
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