Inhaled treprostinil ups exercise capacity in pulmonary hypertension

Inhaled treprostinil significantly improves exercise capacity in terms of 6-minute walking distance (6MWD) over 16 weeks compared with placebo in patients with pulmonary hypertension associated with interstitial lung disease (ILD), according to the INCREASE trial presented at ATS 2020.

Patients treated with treprostinil had significantly greater improvement from baseline in the primary endpoint of 6MWD compared with placebo, which was sustained throughout the 16-week treatment period (placebo-corrected median difference from baseline, 21 m; p=0.004).

Analysing 6MWD using mixed model repeated measurements yielded further validation to the above finding, with an even greater placebo-corrected difference from baseline of 31.12 m (p<0.001).

“This is the largest and most comprehensive study of this patient group to date,” said principal investigator Dr Steven Nathan from Inova Fairfax Hospital in Falls Church, Virginia, US. “The results support an additional treatment avenue and might herald a shift in the clinical management of patients with ILD.”

The phase III, double-blind, multicentre study involved 326 (mean age ~66 years) patients with CT-scan confirmed pulmonary hypertension and signs of diffuse parenchymal lung disease. They were randomized in a 1:1 ratio to receive inhaled treprostinil 6 µg/breath four times daily or a matching inhaled placebo. [ATS 2020, session B12]

Any form of ILD or combined emphysema and pulmonary fibrosis were considered eligible for inclusion. Dose escalations by adding one extra breath four times daily were permitted up to every 3 days, with a target dose of nine breaths (54 µg) up to a maximum of 12 breaths (72 µg) four times daily.

“Patients [also] demonstrated improvements in other clinically meaningful outcomes, including improvements in NT-proBNP and decreased risk of clinical worsening and exacerbation of underlying lung disease,” reported Nathan.

At week 16, treprostinil led to a reduction in NT-proBNP by 38 percent compared with placebo (p<0.001).

In addition, the treprostinil arm had 34 percent less frequent exacerbations of underlying lung disease than the placebo arm (26.4 percent vs 38.7 percent; p=0.03).

Patients treated with treprostinil also had 39 percent reduced risk of clinical worsening compared with those on placebo (22.7 percent vs 33.1 percent; p=0.04).

Overall, inhaled treprostinil was well tolerated, with the safety profile being consistent with previous studies of inhaled treprostinil, observed Nathan. Most treatment-related adverse events (AEs) were mild to moderate in intensity. Cough, headache, and dyspnoea were the most adverse events of any grade.

In addition, 10 percent of patients in the treprostinil arm discontinued treatment due to an AE compared with 8 percent in the placebo arm. Serious AEs occurred in 23.3 percent of patients receiving inhaled treprostinil and 25.8 percent of patients on placebo.

“There was no evidence of worsened oxygenation or lung function, thus allaying the concerns about V/Q mismatch,” Nathan pointed out.

In fact, there was evidence of improved lung function, as indicated by forced vital capacity (FVC), which became significantly different between the two arms in favour of treprostinil, when measured as percent predicted FVC at weeks 8 (1.79 percent; p=0.01) and 16 (1.80 percent; p=0.03).