Inhaled Treprostinil Improves IPF Outcomes in Phase 3 TETON-1 Trial

Phase 3 results from the TETON-1 trial, presented at the American Thoracic Society (ATS) 2026 International Conference in Orlando, demonstrated that nebulized treprostinil (Tyvaso; United Therapeutics) significantly slowed lung function decline and reduced clinical worsening events in patients with idiopathic pulmonary fibrosis (IPF) over 52 weeks.^1,2

The findings, alongside combined analyses of TETON-1 and the previously completed TETON-2 trial, represent what investigators are calling an unprecedented efficacy profile for a 52-week IPF study, with the program meeting endpoints that have not been achieved in prior trials.¹ HCPLive spoke with Steven D. Nathan, MD, Schar Chair of the Advanced Lung Disease and Lung Transplant Program at Inova Fairfax Hospital and chair of the TETON Steering Committee, about key efficacy findings, tolerability challenges, and what the data mean for pulmonologists managing IPF.

Why Test a Prostacyclin Mimetic in IPF? The Antifibrotic Rationale Behind the TETON Program

The TETON program was built on a signal observed in the INCREASE trial, which evaluated inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD).² In that 16-week study, patients who received active drug vs placebo showed better lung function at study end, raising the question of whether treprostinil carries independent antifibrotic properties beyond its established vasodilatory effects.

"There's very good biologic plausibility as to how treprostinil, specifically inhaled treprostinil, might have independent antifibrotic properties, aside from its known vasodilatory effects," Nathan told HCPLive. "And so, this was the underpinning of the TETON program."

TETON-1 Primary Endpoint: 130 mL FVC Difference at 52 Weeks

TETON-1 enrolled 598 patients in the US and Canada; TETON-2 enrolled patients across 14 countries outside North America. Both were 52-week, double-blind, placebo-controlled studies. TETON-2 reported first, showing a ~96 mL FVC difference in favor of treprostinil.²

In TETON-1, 598 patients were randomized 1:1 to nebulized treprostinil or placebo. The median change in FVC at week 52 was -43.3 mL in the treprostinil group compared with -196.2 mL in the placebo group, a between-group difference of 130.1 mL (95% CI, 82.2 to 178.1; P <.001). More than 3 quarters of enrolled patients were receiving background antifibrotic therapy, nintedanib, pirfenidone, or both, and benefits were observed across all subgroups.²

Nathan emphasized that while 130 mL represents a population-level estimate, the magnitude carries clinical weight.

"There's no one cut point, and 130 mL represents the population as a whole…but the fact that we could show that amount of difference between placebo and the treatment arm is quite meaningful,” he said.

Treprostinil also reduced the risk of a clinical worsening event by 33% relative to placebo (HR, 0.67; 95% CI, 0.52 to 0.88; P =.003). The composite endpoint captured three outcomes: a 10% or greater relative decline in percent predicted FVC, respiratory hospitalization, and all-cause mortality.²

"We know that patients who have a reduction in FVC, that's a pretty good surrogate for subsequent mortality. Respiratory hospitalization is also a very good surrogate for subsequent mortality. And the third component was mortality itself," Nathan said.

Combined TETON-1 and TETON-2 Analysis: Five of Six Secondary Endpoints Met

In the combined analysis of > 1000 patients, nebulized treprostinil achieved statistical significance in 5 of 6 secondary endpoints, a first for any IPF trial program. Among the most notable secondary findings was a 48% reduction in acute IPF exacerbations (HR, 0.52; 95% CI, 0.30 to 0.91; P =.0223).

"Acute exacerbations in and of itself carries a very high mortality in these patients, in excess of around 80%," he said. "The fact that we could reduce that with inhaled treprostinil is quite meaningful.”

The combined data also demonstrated statistically significant improvements in percent predicted FVC, quality of life as measured by the King's Brief Interstitial Lung Disease (K-BILD) questionnaire, and diffusion capacity of the lungs for carbon monoxide (DLCO), marking the first time an IPF therapy has demonstrated a significant DLCO effect in a phase 3 trial.

Overall survival trended in favor of treprostinil but did not reach statistical significance, a result Nathan called unsurprising given the 52-week window and a mild-to-moderate patient population.

Tolerability of Inhaled Treprostinil in IPF: Cough, Discontinuation, and Patient Counseling

Cough occurred in 54.8% of the treprostinil group versus 33.1% with placebo. Discontinuation rates were 40.5% versus 32.8%.¹ Nathan attributed much of the dropout to logistical burden rather than intolerance alone.

"A lot of the discontinuations probably were from what we term 'nebulizer fatigue,'“ Nathan said. “3 months, 6 months, 9 months into the study, they just got tired of doing the [nebulizer] four times a day, and perhaps coupled with a little bit of cough, [it] was enough to cause them to discontinue.

What an IPF Approval for Inhaled Treprostinil Would Mean for Treatment

United Therapeutics plans to submit a supplemental New Drug Application (NDA) to the FDA by the end of summer 2026, seeking priority review to add IPF to the labeled indications for nebulized Tyvaso. Both the FDA and the European Medicines Agency have granted orphan designation for treprostinil in IPF. If approved, it would be the first inhaled therapy indicated for IPF.

"Getting more drug locally down to the alveoli to me makes a lot of sense in terms of the evolving treatment paradigm in IPF," he said. "There hasn't been another IPF study to have achieved all of these different endpoints."

Editor’s note: Relevant disclosure for Nathan includes Boehringer Ingelheim Pharmaceuticals, United Therapeutics Corporation, Merck Sharp & Dohme , AstraZeneca UK Limited, ABBVIE INC., and E.R. Squibb & Sons, L.L.C.

References

1. Nathan SD, Smith P, Deng C, et al; for the TETON-1 Trial Investigators. Phase 3 trials of inhaled treprostinil for idiopathic pulmonary fibrosis. N Engl J Med. 2026. doi:10.1056/NEJMoa2501488. https://www.nejm.org/doi/full/10.1056/NEJMoa2501488
2. United Therapeutics Corporation. United Therapeutics Corporation announces TETON-1 study of Tyvaso published in The New England Journal of Medicine and presented at ATS 2026. Published May 18, 2026. Accessed June 4, 2026. https://ir.unither.com/press-releases/2026/05-18-2026-211528317