TETON-2 Supports Antifibrotic Benefit of Inhaled Treprostinil in IPF, With Steven Nathan, MD

Inhaled treprostinil (Tyvaso; United Therapeutics) significantly preserved lung function and reduced the risk of clinical worsening compared with placebo over 52 weeks in patients with idiopathic pulmonary fibrosis (IPF) — findings that Steven D. Nathan, MD, FCCP, argues position the drug as a first inhaled antifibrotic therapy and validate a years-long hypothesis derived from an earlier pulmonary hypertension trial.

Nathan, medical director of the Advanced Lung Disease and Lung Transplant Program at Inova Fairfax Hospital in Falls Church, Virginia, and chair of the TETON steering committee, was the presenting author of the TETON-2 results at the European Respiratory Society meeting in Amsterdam in September 2025., and later the full paper published in the New England Journal of Medicine in March 2026.

HCPLive spoke with Nathan to learn more about TETON-2, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial enrolling 593 patients with IPF across sites in Asia-Pacific, Europe, and Latin America. Patients in the trial were randomly assigned 1:1 to receive nebulized treprostinil or placebo, titrated from 3 breaths 4 times daily to a target regimen of 12 breaths 4 times daily over 52 weeks. The mean patient age was 71.7 years, 80.1% were men, mean baseline forced vital capacity (FVC) was 76.8% predicted, and 75.4% were receiving background antifibrotic therapy with nintedanib or pirfenidone.

The trial met its primary endpoint: the median change in absolute FVC at week 52 was −49.9 mL (95% CI, −79.2 to −19.5) in the treprostinil group versus −136.4 mL (95% CI, −172.5 to −104.0) in the placebo group, yielding a between-group difference of 95.6 mL (95% CI, 52.2 to 139.0; P <.001). Treprostinil also significantly reduced the risk of clinical worsening, with events occurring in 81 patients (27.2%) in the treprostinil group versus 115 (39.0%) in the placebo group (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; P = .02), a 29% risk reduction. These benefits were observed across all analyzed subgroups, including patients with and without background antifibrotic therapy, across smoking histories, and in those using supplemental oxygen. No substantial between-group difference in time to acute IPF exacerbation was observed, precluding formal inference on subsequent prespecified secondary endpoints per the hierarchical testing procedure. The most common adverse event was cough, reported in 48.3% of treprostinil-treated patients versus 24.1% of those receiving placebo; the overall safety profile was consistent with prior Tyvaso experience and known prostacyclin-related adverse events, with no new safety signals identified.

Nathan described the conceptual underpinning of the TETON program as originating from an ad hoc analysis of the INCREASE trial — a phase 3 study of inhaled treprostinil in pulmonary hypertension associated with interstitial lung disease (PH-ILD), published in the New England Journal of Medicine in March 2021, which supported the drug's approval for that indication. Although FVC was assessed in INCREASE as a safety measure rather than an efficacy endpoint, patients who received inhaled treprostinil demonstrated better lung function at week 16 than those on placebo, and patients who crossed over to open-label treprostinil from placebo showed subsequent FVC gains — a signal Nathan characterized as suggesting independent antifibrotic properties beyond vasodilation. That hypothesis became the foundation for the TETON program, which also includes a third study, TETON-PPF, evaluating inhaled treprostinil in progressive pulmonary fibrosis beyond IPF.

TETON-1, the North American sister study enrolling 598 patients in the United States and Canada, reported positive topline results in March 2026, with treprostinil demonstrating superiority over placebo for absolute FVC change from baseline to week 52 by 130.1 mL (Hodges-Lehmann estimate, 95% CI, 82.2 to 178.1 mL; P <.0001) — a treatment effect exceeding that observed in TETON-2. TETON-1 also achieved statistical significance for reducing the risk of clinical worsening. United Therapeutics plans to submit a supplemental New Drug Application to the FDA by the end of summer 2026 seeking to add IPF to the labeled indications for nebulized Tyvaso, with integrated analyses of both TETON studies to be presented at the American Thoracic Society Annual Meeting in Orlando in May 2026.

“In fact, when the placebo arm got converted to open label with treprostinil, the FVCs went up. So this gave us some kind of indication that maybe treprostinil had independent anti fibrotic properties, and that was the foundation and underpinning for the TETON program,” Nathan said.

Nathan’s reported disclosures include AstraZeneca, Avalyn Pharma, Boehringer Ingelheim, Pliant, and United Therapeutics.

References

1. Nathan SD, Smith P, Deng C, et al; TETON-2 Trial Investigators. Inhaled treprostinil for idiopathic pulmonary fibrosis. N Engl J Med. Published online March 11, 2026. doi:10.1056/NEJMoa2512911

2. United Therapeutics Corporation. United Therapeutics Corporation announces TETON-1 pivotal study of Tyvaso® meets primary endpoint for treatment of idiopathic pulmonary fibrosis, exceeding impressive treatment effect seen in TETON-2. Press release. March 30, 2026. Accessed April 10, 2026. https://ir.unither.com/press-releases/2026/03-30-2026-120037465