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LPA1 Antagonism in Lung Fibrosis
Ashfaq A Parkar1, Brandon Elpers1, Aryeh Fischer1, Gerald Horan1, Anne Minnich1
1Bristol Myers Squibb, 3401 Princeton Pike, Lawrenceville, NJ 08648 USA
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening disease characterized by scarring in the lung parenchyma, breathlessness, cough, exertional fatigue and a decline in lung function (measured by forced vital capacity [FVC]). Two approved anti-fibrotic drugs (nintedanib and pirfenidone) can slow the progression of FVC decline in IPF, but each has significant side effects (particularly gastrointestinal) that often limit their use. Patients with IPF have a median survival of 3-5 years from diagnosis, emphasizing the need for more effective treatments. Lysophosphatidic acid (LPA) is reported to be increased in the lungs of patients with IPF and signaling through LPA receptor-1 (LPA1), which is expressed on fibroblasts, alveolar epithelial cells and endothelium, has been implicated in the development of IPF.
Aims and Methods: Randomized placebo-controlled Phase 2 efficacy and safety studies in patients with IPF have been performed with two LPA1 antagonists, BMS-986020 (NCT01766817) and BMS-986278 (NCT04308681). BMS-986278 is a second generation LPA1 antagonist, designed to alleviate hepatobiliary toxicity associated with the first generation LPA1 antagonist, BMS-986020. The primary endpoint in both studies evaluated the FVC decline at 26 weeks. BMS-986020 was evaluated in the absence of background therapies, whereas BMS-986278 was evaluated in a population in which two thirds were on stable background anti-fibrotic therapies.
Results: Both LPA1 antagonists demonstrated a clinically meaningful slowing of the decline in FVC, and in the case of BMS-986278 there was a treatment effect irrespective of the presence or absence of background therapy. Furthermore, LPA1 antagonism with BMS-986020 reduced serum extracellular matrix-neoepitope biomarkers, which have been previously associated with IPF prognosis. The overall safety profile was favorable for BMS-986278 including an absence of hepatobiliary findings that were associated with the first-generation molecule BMS-986020.
Conclusion: These findings suggest that LPA1 antagonism is a promising approach to the treatment of IPF and provide support for the continued development of BMS-986278 into phase 3 studies.