Shalabh Singhal1, Ihab G Girgis2, Jenny Xie3, Santanu Dutta4, Diane E Shevell5, John Throup6. 1. Immunology and Fibrosis, Bristol Myers Squibb, Princeton, NJ, USA. 2. Research and Animal Development, Bristol MyersSquibb, Princeton, NJ, USA. 3. Discovery Biology, Bristol MyersSquibb, Princeton, NJ, USA. 4. Global Biostatistics, Bristol MyersSquibb, Princeton, NJ, USA. 5. Precision Medicine and Companion Diagnostics, Bristol MyersSquibb, Princeton, NJ, USA. 6. Immunology and Fibrosis, Bristol MyersSquibb, Princeton, NJ, USA.
Abstract
Background: Safety, pharmacokinetics and pharmacodynamics of BMS-986166, a novel sphingosine-1-phosphate receptor 1 modulator, were assessed.Research design and methods: Two double-blind, placebo-controlled, randomized Phase l studies were conducted in healthy participants. In the single ascending dose study (N = 70), BMS-986166 was administered as a single dose, upwardly titrated daily doses or a single dose in participants who were fed, fasted or administered famotidine. In the multiple ascending dose study (N = 32), BMS-986166 was administered daily for 28 days. Safety, pharmacokinetics and pharmacodynamics (absolute lymphocyte count [ALC]) were assessed. Results:BMS-986166 was generally well tolerated; treatment-related adverse events were mild. Dose-related, clinically insignificant reductions in time-matched heart rate were recorded versus placebo. Pharmacokinetics were linear and stationary with approximately dose-related increases in blood exposure of BMS-986166. Decreases in ALC percent change from baseline with multiple doses of BMS-986166 versus placebo were dose-related. Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14-21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg.Conclusions: BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711.
RCT Entities:
Background: Safety, pharmacokinetics and pharmacodynamics of BMS-986166, a novel sphingosine-1-phosphate receptor 1 modulator, were assessed.Research design and methods: Two double-blind, placebo-controlled, randomized Phase l studies were conducted in healthy participants. In the single ascending dose study (N = 70), BMS-986166 was administered as a single dose, upwardly titrated daily doses or a single dose in participants who were fed, fasted or administered famotidine. In the multiple ascending dose study (N = 32), BMS-986166 was administered daily for 28 days. Safety, pharmacokinetics and pharmacodynamics (absolute lymphocyte count [ALC]) were assessed. Results:BMS-986166 was generally well tolerated; treatment-related adverse events were mild. Dose-related, clinically insignificant reductions in time-matched heart rate were recorded versus placebo. Pharmacokinetics were linear and stationary with approximately dose-related increases in blood exposure of BMS-986166. Decreases in ALC percent change from baseline with multiple doses of BMS-986166 versus placebo were dose-related. Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14-21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg.Conclusions: BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711.
Authors: Zili Xiao; Michael G Yang; T G Murali Dhar; Hai-Yun Xiao; John L Gilmore; David Marcoux; Kim W McIntyre; Tracy L Taylor; Hong Shi; Paul C Levesque; Anthony M Marino; Georgia Cornelius; Arvind Mathur; Ding Ren Shen; Mary Ellen Cvijic; Lois D Lehman-McKeeman; Huadong Sun; Jenny H Xie; Percy H Carter; Alaric J Dyckman Journal: ACS Med Chem Lett Date: 2020-08-11 Impact factor: 4.345