Deupirfenidone compared with pirfenidone and placebo in idiopathic pulmonary fibrosis (ELEVATE-IPF): a phase 2b randomized placebo-controlled trial

RATIONALE: Deupirfenidone is a strategically deuterated form of pirfenidone that retains pharmacodynamic activity but has a differentiated pharmacokinetic profile that may enable improved efficacy and favorable tolerability in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: To evaluate the efficacy and safety of deupirfenidone compared with placebo and pirfenidone in patients with IPF. METHODS: Patients were randomized 1:1:1:1 to deupirfenidone 550 mg TID, deupirfenidone 825 mg TID, pirfenidone 801 mg TID, or placebo. The primary endpoint was the rate of change in forced vital capacity (FVC) for the combined arms of deupirfenidone versus placebo at 26 weeks. The primary and secondary analyses used Bayesian and frequentist approaches, respectively. MEASUREMENTS AND MAIN RESULTS: A total of 257 patients with IPF were randomized, and the proportion on treatment at the end of the study was 80.0%, 68.3%, 64.6%, and 78.1% for the placebo, pirfenidone, deupirfenidone 550 mg, and deupirfenidone 825 mg arms, respectively. Posterior mean change in FVC for placebo was -110.71 mL (95% credible interval (CI), -148.75, -70.98), and for the combined deupirfenidone arms was -48.42 mL (95% CI, -87.66, -9.04) with a posterior mean difference of 62.29 mL (95% CI l, -6.13, 115.73; posterior probability, 0.985). Using a frequentist approach, the adjusted mean change in FVC for the placebo arm was -112.5 mL (95% CI, -167.2, -57.8), and for the deupirfenidone 825 mg arm was -21.5 mL (95% CI, -78.2, 35.1); the adjusted mean difference was 91.0 mL (95% CI, 12.2, 169.7; P = .02). The most common adverse events for each active treatment arm were gastrointestinal. CONCLUSIONS: In patients with IPF, treatment with deupirfenidone slowed lung disease progression over 26 weeks. TRIAL REGISTRATION: Clinicaltrials.gov number NCT05321420.