Phase 3 Antifibrotic-Directed Therapy Outcomes in Idiopathic Pulmonary Fibrosis: Beyond FVC Decline

Phase 3 evidence for antifibrotic-directed therapies in idiopathic pulmonary fibrosis (IPF) has expanded, but direct head-to-head trials are lacking. Forced vital capacity (FVC) decline remains the principal trial outcome, although it may not fully capture clinically relevant differences among therapies.

We systematically reviewed phase 3 randomized placebo-controlled trials of antifibrotic-directed therapies in IPF. FVC effects versus placebo were descriptively summarized using standardized 48-52-week estimates. All-cause treatment discontinuation and all-cause mortality were analyzed using placebo-controlled odds ratios. Sensitivity analyses assessed follow-up duration, background antifibrotic therapy, and trial-level consistency.

Ten trials including 5,386 randomized participants were included. Pirfenidone and nintedanib showed consistent reductions in FVC decline versus placebo. Inhaled treprostinil showed a favorable FVC signal in the combined TETON-1/2 evidence, largely as add-on therapy with background antifibrotic treatment. Without background antifibrotic therapy, several therapies showed directionally favorable but imprecise FVC effects, without evidence of equivalence. Nintedanib and inhaled treprostinil were associated with higher odds of all-cause treatment discontinuation versus placebo: OR 1.39 (95% CI, 1.02-1.88) and OR 1.39 (95% CI, 1.08-1.78), respectively. Pirfenidone was the only therapy associated with lower odds of all-cause mortality (OR, 0.50; 95% CI, 0.31-0.83), based on published pooled ASCEND/CAPACITY mortality data and the Japanese phase 3 trial.

FVC decline remains essential but may not fully distinguish antifibrotic-directed therapies in IPF. Integrating FVC effects, background therapy, treatment continuation, and mortality provides a cautious, context-dependent framework for interpreting expanding phase 3 evidence.