Phase 3 Trials of Inhaled Treprostinil for Idiopathic Pulmonary Fibrosis

BACKGROUND: Two phase 3, randomized trials of inhaled treprostinil for idiopathic pulmonary fibrosis (IPF) were conducted on the basis of preclinical and clinical evidence of an antifibrotic mechanism. TETON-2 was completed first, and results were published; the results of TETON-1 and of both trials combined are reported here. METHODS: In the double-blind TETON-1 trial, we randomly assigned patients with IPF to receive inhaled treprostinil or placebo (12 breaths four times daily). The primary end point was the change in forced vital capacity (FVC) at week 52. Secondary end points, which were analyzed in a prespecified order to control for multiplicity, were clinical worsening (the first occurrence of death from any cause, hospitalization for a respiratory cause, or a relative decline of ≥10% in the percentage of predicted FVC) and acute exacerbation of IPF (each assessed in a time-to-event analysis), survival, change in percentage of predicted FVC, quality of life, and change in diffusion capacity of the lungs for carbon monoxide at week 52. RESULTS: A total of 598 patients underwent randomization and received at least one dose of treprostinil (299 patients) or placebo (299 patients). Of these, 434 completed the assessments through week 52 (218 in the treprostinil group and 216 in the placebo group). The mean age of the patients was 73.0 years, 77.3% were men, and 77.6% were receiving background antifibrotic therapy; the percentage of predicted FVC at baseline was 74.6%. The median change in FVC at week 52 was -43.3 ml (95% confidence interval [CI], -92.1 to -9.1) with treprostinil and -196.2 ml (95% CI, -227.1 to -155.6) with placebo (difference, 130.1 ml; 95% CI, 82.2 to 178.1; P<0.001). Clinical worsening occurred in 95 patients (31.8%) with treprostinil and in 133 patients (44.5%) with placebo (hazard ratio, 0.67; 95% CI, 0.52 to 0.88; P = 0.003). No significant difference was observed in the time to an IPF exacerbation, and no further inferences regarding secondary end points were made. The most frequent adverse event was cough (reported in 54.8% of the patients in the treprostinil group and 33.1% patients in the placebo group). Discontinuation of treprostinil or placebo occurred in 40.5% and 32.8% of the patients, respectively, with adverse event being the primary reason (20.7% and 14.7%). Efficacy and safety outcomes were similar in analyses of the combined trial data. CONCLUSIONS: In patients with IPF, treatment with inhaled treprostinil led to a smaller decline in FVC and fewer clinical-worsening events than placebo over the course of 52 weeks. (Funded by United Therapeutics; TETON-1 ClinicalTrials.gov number, NCT04708782.).