LPA1 antagonist BMS-986278 for idiopathic pulmonary fibrosis: Preclinical pharmacological in vitro and in vivo evaluation

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal fibrosing lung disease with limited approved treatment options. The bioactive lysophospholipid lysophosphatidic acid (LPA) and the LPA₁ receptor have been implicated in the etiology and pathogenesis of IPF, positioning LPA₁ as a promising therapeutic target for IPF and other fibrotic diseases. The LPA₁ antagonist BMS-986020 600 mg BID was efficacious in a 6-month placebo-controlled Phase 2 clinical trial in IPF patients by slowing lung function decline as measured by rate of decline of forced vital capacity (FVC) (CHEST, 154, p1061–69, 2018). BMS-986278 is a novel next generation LPA₁ antagonist currently in Phase I clinical trials. BMS-986278 is a potent and complete antagonist of LPA action at LPA₁-mediated G_i, G_q, G₁₂, and β-arrestin signaling pathways in both cells heterologously expressing human LPA₁ and in primary human lung fibroblasts. In vivo, BMS-986278: 1) inhibits LPA-stimulated histamine release in mice; 2) demonstrates antifibrotic activity, as shown by decreases in picrosirius red staining area of the lung in the chronic rodent bleomycin model. BMS-986278 demonstrates excellent pharmacokinetics in preclinical species: 1) oral bioavailability = 70% (mouse); 100% (rat); 79% (monkey) and 2) clearance (mL/min/kg) = 37 (mouse); 15 (rat); 2 (monkey). BMS-986278 has negligible activity at bile acid and other clinically relevant drug transporters (BSEP, MDR3 IC₅₀ = >100 μM; OATP1B1 IC₅₀ = 35.5 μM). BMS-986278 represents a novel promising LPA1 antagonist for the treatment of multiple fibrotic diseases.