Steven D. Nathan, MD, is the director of the Advanced Lung Disease Program and medical director of the lung transplant program at Inova Fairfax Hospital

Steven D. Nathan, MD, FCCP

A post hoc analysis of the phase 3 TETON-2 trial presented at the 

 in Phoenix found inhaled treprostinil (Tyvaso) reduced total and recurrent disease progression events compared with placebo in patients with 

In the primary TETON-2 analysis, inhaled treprostinil produced a smaller decline in forced vital capacity (FVC) and a lower hazard of clinical worsening compared with placebo across 52 weeks (hazard ratio [HR], 0.71; log-rank 

 =.02).¹,² Clinical worsening was a composite of death, respiratory hospitalization, or a ≥ 10% relative decline in percent predicted FVC, measured as time to the first event. Because the endpoint stops at the first event, a less severe outcome such as an FVC decline can close out a patient’s contribution before later hospitalizations, exacerbations, or deaths are counted.

“Once someone has one of those events, it kind of draws a curtain on what happens subsequently,” said investigator Steven D. Nathan, MD, director of the Advanced Lung Disease Program and medical director of the lung transplant program at Inova Fairfax Hospital, in an interview with 

 “If you look at just one progression event, it’s, for want of a better analogy, running a half marathon. But what happens if you run the full marathon?”

Inhaled Treprostinil Reduces Recurrent IPF Events, With Steven Nathan, MD

Inhaled Treprostinil and Multiple Disease Progression Events in TETON-2

Nathan and colleagues analyzed patients in the TETON-IPF program for every disease progression event occurring during the 52-week study period, not only the first.¹ Qualifying events included a ≥10% relative decline in percent predicted FVC, adjudicated respiratory-related hospitalization, adjudicated acute exacerbation of IPF, concurrent exacerbation plus respiratory hospitalization, and death.

TETON-2, a randomized, double-blind, placebo-controlled phase 3 trial, enrolled 597 patients, and results from the 598-patient TETON-1 study were pending at the time of abstract submission.¹ Baseline characteristics were balanced between the inhaled treprostinil and placebo groups.

In TETON-2, 126 total events occurred in 82 patients receiving inhaled treprostinil, compared with 161 events in 115 patients receiving placebo (

 =.003).¹ A numerically greater proportion of patients in the placebo group experienced > 1 progression event (39% [n = 36] vs 28% [n = 26]; 

 <.166). According to Nathan, patients with 1 event tended to go on to accumulate additional events, a pattern more pronounced in the placebo group.

Waterfall Plot of Recurrent IPF Progression Events by Type

In a TETON-2 post hoc analysis, inhaled treprostinil was associated with fewer total progression events vs placebo (126 vs 161; 

The difference was driven primarily by fewer ≥ 10% FVC declines (54 vs 86) and concurrent exacerbations with hospitalization (6 vs 18).

Investigators say the findings support continuing inhaled treprostinil after a progression event; an sNDA decision is expected in late April 2027.

The investigators displayed recurrent events in a waterfall plot, which accounts for both first and subsequent occurrences of progression within each patient.¹ Nathan described the color-coded plot as an outcomes heat map, showing both the total burden of events in each arm and the specific type of each event.

The most frequent events in the inhaled treprostinil and placebo groups were ≥ 10% relative decline in percent predicted FVC (54 vs 86 events), concurrent IPF exacerbation with respiratory hospitalization (6 vs 18 events), and death (17 vs 23 events).¹ Adjudicated respiratory hospitalizations were numerically more frequent with inhaled treprostinil (45 vs 34 events). The investigators attributed the difference in total events primarily to FVC decline and concurrent exacerbation with hospitalization.

Nathan also pointed to mortality following a first progression event, which he said was approximately halved with inhaled treprostinil, at roughly 22 deaths in the treatment arm vs 44 with placebo. The abstract did not report safety outcomes.

“Patients and providers need to persist with the therapy because there are going to be benefits beyond the initial progression events,” said Nathan. The investigators concluded the results support continuing inhaled treprostinil after any clinical worsening event.¹

The FDA has accepted a supplemental New Drug Application (sNDA) for nebulized inhaled treprostinil in IPF based on TETON-1 and TETON-2, with a decision anticipated in late April 2027, according to United Therapeutics.³ TETON-1 results, presented at ATS 2026, showed a 33% reduction in the risk of clinical worsening with inhaled treprostinil (HR, 0.67).⁴ Inhaled treprostinil remains investigational for IPF.

Editor’s note: Reported disclosures for Nathan include Boehringer Ingelheim Pharmaceuticals, United Therapeutics Corporation, and more.

Nathan SD, Cottin V, Flaherty KR, et al. Efficacy of inhaled treprostinil on multiple disease progression events in patients with idiopathic pulmonary fibrosis in the TETON-IPF program. Presented at: CHEST 2026 Annual Meeting; October 20, 2026; Phoenix, AZ. 

Nathan SD, Smith P, Deng C, et al. Inhaled treprostinil for idiopathic pulmonary fibrosis. 

Application accepted for inhaled pulmonary fibrosis treatment. Respiratory Therapy. Accessed October 26, 2026. 

https://respiratory-therapy.com/products-treatment/pharmaceuticals/us-pharmaceuticals/application-accepted-for-inhaled-pulmonary-fibrosis-treatment/

TETON-1: Treprostinil preserved lung function in idiopathic pulmonary fibrosis. HCPLive. 

https://www.hcplive.com/view/teton-1-treprostinil-preserved-lung-function-idiopathic-pulmonary-fibrosis

. Published May 20, 2026. Accessed October 26, 2026.

Videos

A TETON-2 post hoc analysis at CHEST 2026 found 126 progression events with inhaled treprostinil vs 161 with placebo across 52 weeks.

TETON-2 Supports Antifibrotic Benefit of Inhaled Treprostinil in IPF, With Steven Nathan, MD

Inhaled treprostinil (Tyvaso; United Therapeutics) significantly preserved lung function and reduced the risk of clinical worsening compared with placebo over 52 weeks in patients with idiopathic pulmonary fibrosis (IPF) — findings that Steven D. Nathan, MD, FCCP, argues position the drug as a first inhaled antifibrotic therapy and validate a years-long hypothesis derived from an earlier pulmonary hypertension trial.

Nathan, medical director of the Advanced Lung Disease and Lung Transplant Program at Inova Fairfax Hospital in Falls Church, Virginia, and chair of the TETON steering committee, was the presenting author of the TETON-2 results at the European Respiratory Society meeting in Amsterdam in September 2025., and later the full paper published in the 

spoke with Nathan to learn more about TETON-2, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial enrolling 593 patients with IPF across sites in Asia-Pacific, Europe, and Latin America. Patients in the trial were randomly assigned 1:1 to receive nebulized treprostinil or placebo, titrated from 3 breaths 4 times daily to a target regimen of 12 breaths 4 times daily over 52 weeks. The mean patient age was 71.7 years, 80.1% were men, mean baseline forced vital capacity (FVC) was 76.8% predicted, and 75.4% were receiving background antifibrotic therapy with nintedanib or pirfenidone.

The trial met its primary endpoint: the median change in absolute FVC at week 52 was −49.9 mL (95% CI, −79.2 to −19.5) in the treprostinil group versus −136.4 mL (95% CI, −172.5 to −104.0) in the placebo group, yielding a between-group difference of 95.6 mL (95% CI, 52.2 to 139.0; 

 <.001). Treprostinil also significantly reduced the risk of clinical worsening, with events occurring in 81 patients (27.2%) in the treprostinil group versus 115 (39.0%) in the placebo group (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; 

 = .02), a 29% risk reduction. These benefits were observed across all analyzed subgroups, including patients with and without background antifibrotic therapy, across smoking histories, and in those using supplemental oxygen. No substantial between-group difference in time to acute IPF exacerbation was observed, precluding formal inference on subsequent prespecified secondary endpoints per the hierarchical testing procedure. The most common adverse event was cough, reported in 48.3% of treprostinil-treated patients versus 24.1% of those receiving placebo; the overall safety profile was consistent with prior Tyvaso experience and known prostacyclin-related adverse events, with no new safety signals identified.

Nathan described the conceptual underpinning of the TETON program as originating from an ad hoc analysis of the INCREASE trial — a phase 3 study of inhaled treprostinil in pulmonary hypertension associated with interstitial lung disease (PH-ILD), published in the 

 in March 2021, which supported the drug's approval for that indication. Although FVC was assessed in INCREASE as a safety measure rather than an efficacy endpoint, patients who received inhaled treprostinil demonstrated better lung function at week 16 than those on placebo, and patients who crossed over to open-label treprostinil from placebo showed subsequent FVC gains — a signal Nathan characterized as suggesting independent antifibrotic properties beyond vasodilation. That hypothesis became the foundation for the TETON program, which also includes a third study, TETON-PPF, evaluating inhaled treprostinil in progressive pulmonary fibrosis beyond IPF.

TETON-1, the North American sister study enrolling 598 patients in the United States and Canada, reported positive topline results in March 2026, with treprostinil demonstrating superiority over placebo for absolute FVC change from baseline to week 52 by 130.1 mL (Hodges-Lehmann estimate, 95% CI, 82.2 to 178.1 mL; 

 <.0001) — a treatment effect exceeding that observed in TETON-2. TETON-1 also achieved statistical significance for reducing the risk of clinical worsening. United Therapeutics plans to submit a supplemental New Drug Application to the FDA by the end of summer 2026 seeking to add IPF to the labeled indications for nebulized Tyvaso, with integrated analyses of both TETON studies to be presented at the American Thoracic Society Annual Meeting in Orlando in May 2026.

“In fact, when the placebo arm got converted to open label with treprostinil, the FVCs went up. So this gave us some kind of indication that maybe treprostinil had independent anti fibrotic properties, and that was the foundation and underpinning for the TETON program,” Nathan said.

Nathan’s reported disclosures include AstraZeneca, Avalyn Pharma, Boehringer Ingelheim, Pliant, and United Therapeutics.

Nathan SD, Smith P, Deng C, et al; TETON-2 Trial Investigators. Inhaled treprostinil for idiopathic pulmonary fibrosis. 

. Published online March 11, 2026. doi:10.1056/NEJMoa2512911

United Therapeutics Corporation. 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. Press release. March 30, 2026. Accessed April 10, 2026. 

https://ir.unither.com/press-releases/2026/03-30-2026-120037465

Treprostinil significantly slowed FVC decline and reduced clinical worsening events over 52 weeks in patients with IPF.


Some practical tips to share with community physicians. IPF [idiopathic pulmonary fibrosis] can be a difficult diagnosis. Sometimes it’s black and white, clearly IPF or clearly not. But most of the patients fall in that gray zone of uncertainty. What I would say is if you’re uncertain, and this might be self-serving, contact your local ILD [interstitial lung disease] center. Get a second opinion and see what they have to say. I look to my colleagues all the time in our clinic, and I say, what do you think of this CT, or what do you make of this or that?

Talking among ourselves and putting these patients before multidisciplinary discussion, which typically happens at ILD centers, can be very important for validation of the diagnosis. Because probably the most difficult aspect of IPF is to make an accurate diagnosis first. The value of sending folks to ILD centers is that they can be looked at for clinical trials. Many ILD centers, such as ours, are transplant centers as well.

It becomes 1-stop shopping. You can get validation of the diagnosis concurrently. If you don’t want to start the therapy yourselves and leave it to the ILD docs, you can do it. They get looked at for clinical trials, and they get evaluated even in a cursory fashion as a potential lung transplant candidate.

To the community docs out there, don’t feel like you’re flying alone. I think I speak for all the ILD centers out there. We’re only too happy to partner with you in taking care of your patients and making sure they have the best possible outcomes.

I believe strongly that the primary care clinician should be the principal player in guiding patients and their caregivers through any disease process. I’ve had strong bias all along. I trained as a primary care physician years ago. My sense is that the primary care clinician needs to understand these disorders because of their severity and the implication for patient and their family members. That includes having a high index of suspicion of when this disease may be present.
So there have been a series of studies that are lovely and demonstrate that an older person presenting with a chronic cough is a tip-off to the primary care clinician that they should consider these disorders, and IPF in particular, as a potential diagnosis. Because it’s our suspicion that earlier diagnosis, particularly with these effective drugs, is likely going to be better in the long term. It makes sense, and the data would support that. Trying to work with our primary care clinicians to have a higher index of suspicion of when these disorders are present is crucial. The same thing for our radiologists, because we have a sense that early changes on a CT scan can be very instructive with regard to the early diagnostic process. 

That interaction has improved. If you think about how we consider optimizing the patient’s quality of life and survival, the importance of being able to address the potential tolerability issues of the drugs and how to manage them. The comorbid conditions and their interaction. In the middle of all that is a primary care clinician.

When we develop therapeutic plans with our patients and their caregivers, when we have a disease-management plan, it’s immediately transmitted to their primary care clinician, ideally by a phone call or a video chat, so the primary care clinician is fully aware of where we are at each stage and can aid the patient in making decisions at each stage.

The primary care clinician is a crucial player from the early diagnosis to the management at the end stage of disease. They are the quarterback in most of what happens with these patients.

Steven D. Nathan, MD, FCCP, and Fernando J. Martinez, MD, MS, share clinical pearls and advice for the management of IPF.

Clinical Pearls for the Management of IPF

Pirfenidone and nintedanib have been around for 7 years. What’s going to come down the pike next? I mentioned inhaled treprostinil is approved to treat complicating PH [pulmonary hypertension] being studied as a potential antifibrotic. There are many other drugs in various stages of development.

Drug development takes awhile, and inhaled treprostinil is in phase 3. There’s the drug that was owned by Promedior and is now owned by Roche, PRM-151. That’s being studied in a phase 3 clinical trial by Roche. There was the Galapagos study [ISABELA phase 3 trial], which got halted earlier this year for some reason. Data still have to be presented, but that was halted early so it’s not going to bear out as a therapy. There’s FibroGen’s anticonnective tissue growth factor infusion that’s being studied in a phase 3 trial as well.

It takes awhile for these drugs to go through phase 3, for the data to be scrubbed and analyzed, for patients to be followed, to go before the FDA. If any of the 3 agents I just mentioned that are on phase 3 do bear fruit and are shown to work in IPF, then it’s probably a minimum of another 2 years to maybe 4 years before 1 of them becomes available for clinical practice.

Many other drugs in phase 2 are even further behind. Many who will go on to phase 3 will depend on the phase 2 results, obviously. The next wave after these 3 that I mentioned is probably 7 to 10 years down the road. At this point, therefore, we have pirfenidone, nintedanib, and inhaled treprostinil that we can give our patients who have IPF [idiopathic pulmonary fibrosis]. We have to be patient, and our patients have to be willing to get enrolled and recruited into clinical trials. That’s important in our global management of these patients: the opportunity of being enrolled in a clinical trial because the availability of pirfenidone, nintedanib, and inhaled treprostinil is only through the good graces of the patients previously who were willing to participate in randomized controlled, placebo-controlled clinical trials.

There’s a tremendous push. It’s amazing to see how much advance is taking place in IPF over the last decade. It’s unbelievable. We have 2 agents that work, and dozens of clinical trials are ongoing with agents that span the spectrum of how the lung is injured and how it responds to that injury. Several drugs are in advanced-stage development, in phase 3, the traditional large, blinded, placebo-controlled trials.

There’s a drug being tested that specifically targets a very downstream pathway in the fibrotic pathway, which is pamrevlumab. It’s had impressive phase 2 results. It’s in a phase 3 program now. We’re all excited about how that looks. There’s a drug called ataxin-2 that targets a particular inflammatory process that’s been associated with progressive fibrosis, also with very impressive phase 2 data and in a phase 3 program. I’m 1 of the co–PIs [principal Investigators] of that study, so I’m biased. That study is now global and enrolling patients.

There was a recent study of inhaled treprostinil, which was more targeted to the pulmonary hypertension complication of ILD [interstitial lung disease]. But it suggested that it may improve lung function, so that’s being tested. There are 27 or 28 earlier-stage phase 2 studies that are ongoing. It’s dramatic how much advance we’ve made. The discussions that we have with patients at our center [Weill Cornell Medicine] are about not only the antifibrotics but the 5 or 6 active clinical trials that are present at any given time.

My suspicion is that within the next 2 or 3 years, the situation will be much more hopeful with combinations of these agents targeted to a specific patient. The overall approach and prognosis of patients is going to be markedly improved, and it’s not going to be 20 years. It’s going to be within the next few years. I am absolutely convinced that’s going to be the case.

Stem cells have been looked at for IPF, mostly just feasibility and tolerability. I know 

 sounds sexy for everything, but we don’t have efficacy data yet. There’s some promise to using stem cells, but I cannot endorse this in any way, shape, or form outside a clinical trial until we have the appropriate clinical trials to show that this is a strategy that works.

Expert pulmonologists comment on emerging therapies in the pipeline for the treatment of IPF.

Steven D. Nathan, MD, FCCP

Articles