Treprostinil is a prostacyclin analog with inhaled, intravenous, and subcutaneous formulations used for the treatment of pulmonary arterial hypertension since its approval in 2009 from the US Food and Drug Administration.1 The INCREASE trial, published in 2021, evaluated inhaled treprostinil as a treatment for patients with pulmonary hypertension (PH)-associated interstitial lung disease (ILD), demonstrating improvements in 6-minute walk distance over 16 weeks.2 Subsequent data from the open-label extension study reported increases in FVC, leading to interest in its potential as a treatment for fibrotic lung disease.3
Supporting evidence from both in vitro and animal studies have suggested that treprostinil may have additional antifibrotic effect in the lung.4 First, treprostinil has been shown to antagonize transforming growth factor-ß and platelet-derived growth factor, preventing fibroblast proliferation and extracellular matrix deposition in both normal human lung fibroblasts and lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF).5–7 Second, treprostinil reduced lung inflammation and fibrosis when instilled prophylactically in the lungs of mice with bleomycin-induced lung injury.8
The results from the TETON-1 trial of inhaled treprostinil for IPF were recently presented.9 TETON-1 was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in the United States and Canada. A total of 598 patients with IPF were enrolled in the study. Patients in the treatment arm received three breaths (18 mcg) of treprostinil titrated to a goal of 12 breaths (72 mcg) four times daily, or the maximum tolerated dose, with 84% patients achieving this milestone by week 16 of treatment.
Compared with placebo, nebulized treprostinil met its primary efficacy end point over 52 weeks of treatment by demonstrating a median change in absolute FVC of -43.3 mL (95% CI, -92.1 to -9.1 mL) compared with -196.2 mL (95% CI, -227.1 to -155.6 mL). Most of the secondary end points—improvement in the time to first exacerbation, percent change in Dlco, and King’s Brief ILD questionnaire—demonstrated a trend to less clinical worsening in the treprostinil group but were not statistically significant. These findings surpass the results of the TETON-2 trial, which had the same study design but recruited patients from Asia, Europe, and Latin America.10
The prospect of inhaled treprostinil as a potential therapy for IPF is exciting since therapies for IPF have been historically limited to pirfenidone and nintedanib, both antifibrotics that slow the rate of FVC decline in affected patients at the cost of frequently intolerable gastrointestinal side effects. Nerandomilast was approved in 2025, based on the positive findings of the FIBRONEER-IPF trial, which investigated the novel drug as a monotherapy and add-on therapy.11 It increases intracellular cyclic adenosine monophosphate, which, interestingly, is also an effect of treprostinil.11 If inhaled treprostinil is approved specifically for IPF, there will be a fourth option to slow the rate of FVC decline for patients and the options for combination therapy may broaden. However, important questions remain about which patients with IPF should receive monotherapy vs combination antifibrotic therapies and what the real-world efficacy and tolerability of these new medications will be on their own and in combination.
In the current study, concomitant use of antifibrotics had synergistic effects. Roughly 40% of patients discontinued treprostinil due to cough, which poses significant limitation to its use in the real word. It is also important to note that there were no assessments for PH, the original indication for inhaled treprostinil, in the TETON studies, which leaves unanswered questions concerning whether IPF patients with and without PH respond differently to treatment. Finally, clinical guidance will be needed for the providers who will be prescribing inhaled treprostinil if it is approved for IPF to ensure that patients are properly assessed for left heart disease and other conditions that could potentially result in harm if treated with this potent pulmonary vasodilator.12
Despite these outstanding questions, the positive results from the TETON trials and expanding treatment options are encouraging for pulmonologists who are accustomed to working with a limited tool kit for slowing disease progression for their patients with IPF.
References
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2. 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
3. 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
4. Nathan SD, Behr J, Cottin V, et al. Study design and rationale for the TETON phase 3, randomised, controlled clinical trials of inhaled treprostinil in the treatment of idiopathic pulmonary fibrosis. BMJ Open Respir Res. 2022;9(1):e001310. doi:10.1136/bmjresp-2022-001310
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7. Roberts MJ, May LT, Keen AC, et al. Inhibition of the proliferation of human lung fibroblasts by prostacyclin receptor agonists is linked to a sustained cAMP signal in the nucleus. Front Pharmacol. 2021;12:669227. doi:10.3389/fphar.2021.669227
8. Nikitopoulou I, Manitsopoulos N, Kotanidou A, et al. Orotracheal treprostinil administration attenuates bleomycin-induced lung injury, vascular remodeling, and fibrosis in mice. Pulm Circ. 2019;9(4):2045894019881954. doi:10.1177/2045894019881954
9. Nathan SD, Smith P, Deng C, et al. Phase 3 trials of inhaled treprostinil for idiopathic pulmonary fibrosis. N Engl J Med. Published online May 18, 2026. doi:10.1056/NEJMoa2501488
10. 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
11. Richeldi L, Azuma A, Cottin V, et al. Nerandomilast in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2025;392(22):2193-2202. doi:10.1056/NEJMoa2414108
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