BMS-986278, a lysophosphatidic acid 1 (LPA1) receptor antagonist, in healthy participants: A single/multiple ascending dose (SAD/MAD) phase 1 study

Introduction: The LPA1 receptor is implicated in IPF pathogenesis. BMS-986278 is a potent small molecule LPA1 receptor antagonist being investigated for IPF. This study evaluated the safety, tolerability, and PK of oral BMS-986278 in healthy participants (ppts). Methods: IM027-009 is a phase 1, double-blind, placebo (PBO)-controlled, randomized study in healthy adults. In SAD evaluation (with sentinel dosing), ppts received BMS-986278 or PBO (6:2) at doses 3, 10, 30, 100, 150, or 250mg; food and pH effects were analyzed with 100mg. The 250-mg SAD was terminated due to dose-limiting AEs (sentinel cohort). In MAD evaluation, ppts received BMS-986278 or PBO (6:2) for 14d at doses QD (10 or 30mg) or BID (30, 60, or 125mg). Results: SAD: 37 ppts received BMS-986278 and 11 received PBO; MAD: 30 ppts received BMS-986278 and 10 received PBO. Baseline demographics were similar between BMS-986278 and PBO groups in SAD and MAD. Most AEs were mild; the most common AE was headache. Decreases in blood pressure were seen in SAD and MAD cohorts and were not associated with discontinuation. No clinically significant elevations in liver function tests were seen. In both SAD and MAD cohorts, BMS 986278 Cmax and AUC appeared dose proportional with a half-life of approximately 10h; Tmax was slower after a high-fat meal vs fasted state with no exposure difference. Gastric pH had no notable effect on BMS-986278 PK. Conclusions: BMS-986278 was generally well tolerated; blood pressure reductions were reported without treatment discontinuation. Dose-proportional PK was seen and dosing is supported with/without food. Further study of BMS‑986278 in IPF is warranted.