Inhaled treprostinil delivers promising phase 3 results in idiopathic pulmonary fibrosis

Inhaled treprostinil is a synthetic analogue of prostacyclin approved for the treatment of pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD). Its potential antifibrotic effects have prompted evaluation in TETON-1 (NCT04708782), a randomized, double-blind, placebo-controlled phase 3 trial in patients with idiopathic pulmonary fibrosis (IPF).

In this interview, we spoke with Dr Steven Nathan (Inova Fairfax Hospital, Falls Church, VA, USA) about the unmet needs in the treatment paradigm for IPF, and the rationale for investigating inhaled treprostinil in this indication. Dr Nathan also explores the aims, design and findings from the TETON-1 study which he presented at ATS 2026.

Abstract: TETON-1 Phase 3 Clinical Trial of Inhaled Treprostinil for the Treatment of Idiopathic Pulmonary Fibrosis. ATS 2026, May 15–20, 2026; Orlando, Florida, USA.

1. What are the unmet needs in the treatment paradigm for IPF? (0:19)
2. What was the rationale for investigating inhaled treprostinil in this indication? (0:58)
3. What were the aims, design, and inclusion criteria of the TETON-1 trial? (1:58)
4. How well did the study meet its primary and secondary endpoints? (2:46)
5. What was the safety profile of treprostinil in the study and how does this compare to previous findings? (4:26)

Transcript

What are the unmet needs in the treatment paradigm for IPF?

In the treatment paradigm for IPF, we now have three approved antifibrotics, pirfenidone, nintedanib, and most recently nerandomilast. Despite having three therapies available, none of them are the panacea, and most of them come with some kind of side effects and tolerability issues. All of them work to slow the rate of decline in lung function, but I think there’s certainly room to go with other therapies needed, more tolerable therapies and more efficacious therapies. So I think it’s still a wide open field in terms of potential new therapies for IPF.

What was the rationale for investigating inhaled treprostinil in this indication?

Inhaled treprostinil was investigated as a treatment for IPF based on a somewhat surprising finding from the prior INCREASE study. The INCREASE study looked at inhaled treprostinil for the treatment of pulmonary hypertension associated with interstitial lung disease. We looked at spirometry as a safety endpoint in that study, but it turned out to be more of an efficacy endpoint because those patients who received inhaled treprostinil had significantly better lung function at the end of the 16 week study.

That really formed the underpinnings for the TETON program, which consists of three separate studies. TETON-1 looking at inhaled treprostinil over 52 weeks in the US and Canada. TETON-2 looked at treprostinil for IPF in 14 other countries around the world, and TETON PPF, which is still ongoing, is looking at inhaled treprostinil for progressive pulmonary fibrosis, and that’s also a global study.

What were the aims, design, and inclusion criteria of the TETON-1 trial?

The TETON-1 trial was a typical IPF study where patients could qualify by having a confirmed diagnosis of IPF. The CAT scans, the HRCTs, needed to be centrally read to verify that they had a lung function that included an FVC of more than 45%, and they couldn’t have any significant comorbidities coming into the study. Notably, they could come into the study on either of the two existing approved antifibrotics, namely pirfenidone or nintedanib. But it was a pretty broad inclusion criteria and that resulted in very successful recruitment into the clinical trial, much like we saw in the TETON-2 study.

How well did the study meet its primary and secondary endpoints?

The study did very well, it actually surprised me to be quite honest, in terms of meeting its primary endpoint. The primary endpoint was the placebo corrected change in FVC at 52 weeks and that came out at 130.1 mLs. So there was a difference of 130 mLs at 52 weeks in terms of the change in FVC in favour of inhaled treprostinil. There were six secondary endpoints in the TETON-1 clinical trial and it missed one of them, which was clinical worsening. It came very close to all the others in terms of numerically favouring inhaled treprostinil, but it didn’t quite reach statistical significance.

Now, just to add to that, there was a prior TETON-2 study that was previously released and the purpose of having the two studies, aside from making this a more global endeavour, was to be able to combine the two studies together. That was also presented at the ATS, the combined TETON 1 and TETON 2 studies. This obviously merits a primary endpoint as well, when you look at the two studies together. The difference in FVC was 112 mLs at 52 weeks. But together both studies achieved statistical significance in five of the six secondary endpoints – the only one missed out on was mortality, but there was a strong trend towards a mortality benefit from the study.

I think the study results were pretty remarkable in terms of being able to achieve not only the primary, but five out of six secondary endpoints at 52 weeks.

What was the safety profile of treprostinil in the study and how does this compare to previous findings?

The safety profile didn’t reveal any surprises in terms of inhaled treprostinil. The biggest side effect or adverse event was cough, and this was seen in a good number [54.87%] of the patients, but that was not unexpected with an inhaled drug given to a patient population that has a propensity to cough. The rest of the side effects were mostly related to what we know about prostanoid therapy in terms of headaches, flushing, and a little bit of GI upset. But inhaled treprostinil has been around for a decade and a half, and the adverse event profile is pretty well known, so there were no surprises necessarily.

The discontinuation rate was quite high at around 40%, but I think that was due to a combination of things, not necessarily cough. There were only 7% of patients who discontinued because of cough. When we put patients into the study, it was a big ask of them. Specifically, we were asking patients to take a nebuliser treatment four times a day for 52 weeks, not knowing if they were getting placebo or the real deal, and not knowing if the real deal worked or not. I think what happens over the course of 52 weeks in a fairly sick population is an element of nebuliser fatigue. If patients are coughing a little bit or they are not feeling well from their disease and they have to take a nebuliser four times a day, eventually a proportion of them are going to not want to continue. I think that contributed to that 40% discontinuation rate.