Recent data from the TETON program investigating inhaled treprostinil for idiopathic pulmonary fibrosis (IPF) show smaller declines in FVC and fewer clinical worsening events compared with placebo in global (TETON-2) and North American (TETON-1) populations. Phase 3 results from the TETON-2 trial were published in the New England Journal of Medicine in March, and top-line results from the phase 3 TETON-1 trial were announced later that month.1–2
Lead author Steven D. Nathan, MD, FCCP, Medical Director of the Advanced Lung Disease and Transplant Program at Inova Fairfax Hospital, said he hopes the results lead to expanded approval of inhaled treprostinil for IPF.
“For now, treprostinil is not approved for IPF, but it is approved for pulmonary hypertension in interstitial lung disease and is available,” Dr. Nathan said. “If patients have pulmonary hypertension, they should be able to get the drug right away. This drug gives us two shots on goal: It treats pulmonary hypertension and slows or prevents the worsening of fibrosis.”
The TETON program emerged from the INCREASE study of pulmonary hypertension in interstitial lung disease (PH-ILD).3 Lung function was a safety end point in INCREASE, Dr. Nathan said, and treprostinil showed a surprising trend toward improved lung function. The unexpected finding prompted a series of post hoc analyses. One analysis, a 16-week open-label portion of INCREASE, showed an increase in FVC associated with treprostinil.4
The INCREASE findings and existing literature prompted the TETON program to compare treprostinil with placebo for 52 weeks in patients with IPF. TETON-1 enrolled 598 patients across multiple centers in the United States and Canada, while TETON-2 enrolled 593 patients across 107 centers in 14 other countries.
TETON-2 concluded first because of its broader geographical reach, Dr. Nathan said. Most participants were male (80.1%), and the mean age was 72 years old. The majority (83.8%) were White, and 26.8% were Hispanic or Latino. The mean time since IPF diagnosis was 3.9 years. Nearly a third of patients (28.3%) had no history of tobacco smoking, while 69.5% had previously smoked tobacco. The mean FVC at baseline was 2,695 mL, 76.8% of predicted value. A quarter of patients (24.6%) were not on any background therapy, 36.1% were taking nintedanib, and 39.3% were taking pirfenidone.
The median change in FVC at week 52 was -49.9 mL in the treprostinil arm (95% CI, -79.2 to -19.5) and -136.4mL in the placebo arm (95% CI, -172.5 to -104.0). Clinical worsening occurred in 27.2% of the treprostinil group compared with 39.0% of the placebo group, with an HR of 0.71 (95% CI, 0.53-0.95; P = .02). There were no substantial differences in time to first IPF exacerbation between groups.
The most commonly reported adverse event was cough, at 48.3% in the treprostinil group and 24.1% in the placebo group. Discontinuation was observed in 33.6% of the treprostinil group and 24.7% of the placebo group, with adverse events cited as the primary reason for discontinuation by about half of the patients in both arms.
Top-line results from TETON-1 show a placebo-corrected difference in FVC change favoring inhaled treprostinil of 130.1 mL at 52 weeks. Treprostinil also demonstrated a significant reduction in the risk for clinical worsening and numerical improvements in time to first acute exacerbation of IPF. Detailed results have not been published yet.
Dr. Nathan said a combined analysis of TETON-1 and TETON-2 showed a difference in change in FVC of 111.8 mL at 52 weeks favoring inhaled treprostinil. There were also significant improvements in time to first clinical worsening, time to first acute exacerbation of IPF, change in predicted FVC, and other secondary end points, according to the analysis.
Dr. Nathan reiterated that he hopes expanded approval for treprostinil comes soon. Until then, its use will continue to require a pulmonary hypertension diagnosis.
“Getting physicians to think about doing right heart catheterization in patients with ILD is an ongoing struggle,” he said. “The TETON results provide further impetus and rationale for doing right heart catheterization because if the patient has pulmonary hypertension, you can get the drug for them.”
References
1. Nathan SD, Smith P, Deng C, et al. Inhaled treprostinil for idiopathic pulmonary fibrosis. N Engl J Med. Published online March 11, 2026. doi:10.1056/NEJMoa2512911
2. 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. United Therapeutics. 2026.
3. Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med. 2021;384(4):325-334. doi:10.1056/NEJMoa2008470
4. Nathan SD, Waxman A, Rajagopal S, et al. Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study. Lancet Respir Med. 2021;9(11):1266-1274. doi:10.1016/S2213-2600(21)00165-X
