Inhaled Treprostinil Benefit Affirmed in Idiopathic Pulmonary Fibrosis

Nebulized treprostinil (Tyvaso) reduced lung function decline from idiopathic pulmonary fibrosis (IPF) in the pivotal TETON-1 trial, mirroring positive results from the parallel TETON-2 trial.

Declines from baseline to week 52 for the primary endpoint of median change in forced vital capacity (FVC) came out significantly smaller with multiple daily doses of the prostacyclin vasodilator compared with placebo (-43.3 vs -196.2 mL, P<0.001), Steven Nathan, MD, of Inova Fairfax Hospital in Falls Church, Virginia, reported at the American Thoracic Society (ATS) annual meeting in Orlando. The findings were published simultaneously in the New England Journal of Medicine.

The findings of TETON-1, conducted in the U.S. and Canada, appeared somewhat more impressive than of the similarly designed TETON-2 trial done outside North America. When the two trials were pooled, the between-group difference in FVC from baseline to week 52 favored treprostinil by 111.8 mL (95% CI 79.7-144.0, P<0.0001).

Along with the recent nerandomilast (Jascayd) approval, the new findings come as “a sigh of relief” for the pulmonary community, said ATS session study discussant Darren Taichman, MD, PhD, an editor at the NEJM.

After a slew of disappointing phase III results — including some with signals of harm — that followed promising phase II studies, such as with ziritaxestat and pamrevlumab, “we’re finally seeing positive results and that we can do something for these patients beyond the antifibrotics,” he said.

“We would love to see a halting of progression, but just slowing progression is obviously important,” Taichman added, noting that FVC correlates with prognosis, so the slowing in decline seen in the trials is expected to change prognosis. “We don’t know that yet. These aren’t long enough trials to show that,” he cautioned.

Treprostinil currently carries indications for improving exercise ability in pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease, but drugmaker United Therapeutics said it plans to seek priority FDA review this summer for an expanded label indication in IPF based on data from the TETON studies.

TETON-1 randomly assigned 598 patients with IPF to receive inhaled treprostinil or placebo (12 breaths, four times daily), with 434 completing the assessments through week 52. Participants averaged 73 years of age, and 77.3% were men. Percent predicted FVC averaged 74.6% at baseline. An FVC greater than 45% predicted was necessary to enroll in the trial.

The first hierarchical secondary endpoint, clinical worsening (the first occurrence of death from any cause, hospitalization for a respiratory cause, or a relative decline of ≥10% in percent predicted FVC) favored treprostinil (31.8% vs 44.5%; HR 0.67, 95% CI 0.52-0.88, P=0.003). The next secondary endpoint, acute exacerbation of IPF, didn’t differ significantly between groups.

However, after pooling together the 1,191 total patients across TETON-1 and TETON-2, treprostinil did reduce acute exacerbation of IPF (3.2% vs 6.1%; HR 0.52, 95% CI 0.30-0.91). Mortality also trended the same direction in the pooled analysis, although without statistical significance (6.9% vs 9.4%; HR 0.71, 95% CI 0.47-1.06).

The biggest between-group difference was seen among patients on pirfenidone (Esbriet) at the time of trial entry (144.9 mL median change in FVC at week 52) followed by those on nintedanib at enrollment (108.7 mL), and the smallest difference was among the patients who were not receiving background antifibrotic therapy at entry (70.5 mL).

“I think the wrong message from this is that if you look at the no background therapy, where it’s borderline statistical significance [in TETON-1], the wrong message is that the drug does not work by itself. Clearly it does,” Nathan said. “The treatment effect is very much the same across the three groups.”

The exciting benefits “do come at a cost,” Taichman said, pointing to the some one-third of patients who had to discontinue treatment. While serious adverse event rates were similar between groups, the most frequent adverse events with treprostinil were cough and headache, and cough was the most common reason for discontinuation (5.9% vs 1.2% with placebo).

“Do we have any clue, do we have any data to help guide us as to the presence or absence of pulmonary hypertension, as an example, in these patients and whether that can help us target the drug to those patients who are most likely to benefit sufficiently to warrant the extra cough, the syncope that might come with that cough, for example?” he asked.

No factor has yet been seen, including pulmonary hypertension, Nathan noted. “As far as I’m concerned, any patient with IPF should be eligible for this medication, much like they were in the context of the clinical trial.”

A bigger concern for patients than cough might have been “nebulizer fatigue” from using it four times a day without knowing that it was active drug that would help them, Nathan suggested.

“And I think it also is dependent on hand-holding the patients through this,” he added. At his center, the discontinuation rate was only 18%. “So I think with experience and increased motivation, knowing what the benefits of the drug are will enable more patients to see salient therapy.”

For severe cases, “the nice thing about this is it gives you two shots on goal, it has antifibrotic properties and we know it’s effective for [pulmonary hypertension] related to IPF or [interstitial lung disease] as well. So I think that’s another attractive option with this particular medication,” Nathan said.