Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA1) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA_1-6). Signalling via LPA₁ appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA₁ antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD.

Methods and analysis: This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort.

Ethics and dissemination: This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication.

Trial registration number: NCT04308681.

Keywords: interstitial fibrosis.

Figure 1

Study Design: (A) IPF and (B) PF-ILD Cohorts. ^aRandomisation will be stratified (1) by country (Japan vs rest of world); and (2) according to concomitant use of approved IPF therapy (pirfenidone vs nintedanib vs none). ^bPatients receiving 30 mg or 60 mg BMS-986278 two times per day or placebo two times per day in the main study or OTE who meet low BP criteria may have their dosage reduced to 10 mg BMS-986278 two times per day (or matching placebo for 10 mg two times per day in main study). ^cRandomisation will be stratified by (1) UIP pattern (typical or probable UIP vs inconsistent with UIP) of lung injury on either centrally read HRCT, surgical lung biopsy, or cryobiopsy; and (2) according to background therapy (immunosuppression (azathioprine, mycophenolate mofetil, mycophenolic acid and/or tacrolimus) vs antifibrotic agents (pirfenidone or nintedanib) vs none). BID, two times per day; BP, blood pressure; HRCT, high-resolution CT; IPF, idiopathic pulmonary fibrosis; OTE, optional active-treatment extension; PF-ILD, progressive fibrotic interstitial lung disease; PO, per os (by mouth); R, randomisation; UIP, usual interstitial pneumonia.