Inhaled Vasodilator Slows Lung Function Decline in Idiopathic Pulmonary Fibrosis

In idiopathic pulmonary fibrosis (IPF), the trajectory of declining lung function and clinical worsening was less drastic with the use of inhaled treprostinil (Tyvaso), the placebo-controlled TETON-2 trial found.

With a year on the inhaled prostacyclin vasodilator therapy, the median change in absolute forced vital capacity (FVC) was -49.9 mL from baseline to week 52 compared with -136.4 mL with inhaled placebo (P<0.001).

Clinical worsening occurred in 27.2% of patients in the treprostinil group versus 39% of those in the placebo group (HR 0.71, 95% CI 0.53-0.95), reported Steven Nathan, MD, of Inova Fairfax Hospital in Falls Church, Virginia, and colleagues in the New England Journal of Medicine.

“Treprostinil targets multiple prostacyclin receptors that modulate fibrogenetic pathways in the lungs, a mechanism that provides a biologic rationale for the potential antifibrotic role of this agent,” they wrote.

“A potential advantage of administering antifibrotic agents by inhalation is the opportunity for greater drug deposition at the alveolar interface, possibly with fewer systemic toxic effects,” the authors noted. “The most common adverse event reported with inhaled treprostinil was cough [48.3% vs 24.1%].”

Other common adverse events were headache (19.8% vs 11.9%) and diarrhea (13.8% vs 16.9%).

Inhaled treprostinil emerged as a potential preserver of lung function among patients with fibrotic lung disease in the INCREASE trial, in which FVC benefits were reported at 16 weeks.

IPF, a rare progressive disease characterized by fibrosis in the alveoli of the lungs, has a poor prognosis, with a median survival of 3 to 5 years if left untreated, according to Nathan and colleagues.

However, there was no benefit to inhaled treprostinil when it came to time to acute exacerbation or mortality.

“Because these secondary endpoints were ranked higher in the prespecified hierarchical analysis plan, no statistical inference was drawn with respect to subsequent secondary endpoints,” including patient-reported outcomes, the percentage of predicted FVC, and the diffusing capacity of the lungs for carbon monoxide, the authors noted.

More answers are anticipated from TETON-2’s open-label extension study and its sister trial of inhaled treprostinil in IPF, TETON-1, from the U.S. and Canada. TETON-1 has been completed but its results are yet to be reported.

TETON-2 was a phase III, double-blind trial that enrolled patients from 2022 to 2024 in 16 countries in Asia, Europe, and South America. The researchers randomized 593 patients with IPF to inhaled treprostinil or placebo (12 breaths four times daily) over a year (463 patients completed the study through week 52). Treprostinil inhalation solution or placebo was administered with the TD-300 ultrasonic nebulizer.

Mean age was 71.7, and 80.1% were men. Mean FVC at baseline was 76.8%, and 75.4% of patients were receiving background antifibrotic therapy.

Discontinuation of assigned treatment occurred in 33.6% and 24.7% of the treprostinil and placebo groups, respectively, with adverse events cited as the primary reason for discontinuation in about half of the cases.

The high rates of discontinuation were a major limitation to the trial, the authors cautioned, as was the lack of assessment of long-term mortality. Another limitation was the possibility that patients changed their use of nintedanib (Ofev) or pirfenidone (Esbriet) during the trial, which may have affected the results.

Nintedanib and pirfenidone have been deemed standard of care for IPF, though their efficacy is limited, and many patients can’t tolerate them. In October 2025, the FDA approved nerandomilast (Jascayd), the first new product for IPF in over a decade.

Of note, inhaled treprostinil is also being investigated for progressive pulmonary fibrosis in the TETON-PPF trial.