Inhaled treprostinil improves outcomes in ILD-associated pulmonary hypertension

Inhaled treprostinil was well tolerated and significantly improved exercise capacity and other clinical outcomes over 16 weeks in patients with pulmonary hypertension associated with interstitial lung disease, according to results of the INCREASE study.

“INCREASE is the largest and most comprehensive study of this patient group to date,” Steven D. Nathan, MD, director of the Advanced Lung Disease Program and the lung transplant program at Inova Fairfax Hospital in Virginia, said during a presentation at the American Thoracic Society’s Breaking News: Clinical Trial Results in Pulmonary Medicine virtual briefing. “Patients experienced significant improvements in exercise capacity with effects sustained throughout the 16-week treatment period. Patients also demonstrated improvements in other clinically meaningful outcomes including improvements in NT-proBNP and decreased risk of clinical worsening as well as a decreased risk of exacerbations of the underlying lung disease.”

The phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled 326 patients with WHO group 3 pulmonary hypertension associated with ILD. Primary endpoint was change in 6-minute walk distance at 16 weeks. Secondary endpoints were change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) time to clinical worsening, which was calculated as the time from randomization until hospitalization due to cardiopulmonary indication, 15% or greater decrease in 6-minute walk distance, all-cause mortality or lung transplantation; change in peak 6-minute walk distance at week 12; and change in trough 6-minute walk distance at week 15.

Patients were randomly assigned to receive inhaled treprostinil (Tyvaso, United Therapeutics; n = 163; mean age, 65.6 years) at 6 µg per breath or placebo (n = 163; mean age 67.4 years) four times per day. Patients began treatment with three breaths (18 µg) of treprostinil or placebo with dose escalations that could occur up to every 3 days, with a target dose of nine breaths (54 µg) four times per day and a maximum dose of 12 breaths (72 µg) four times per day, Nathan said during the presentation.

Of the 326 enrolled patients, 80% completed the 16-week study period. At week 16, patients in the inhaled treprostinil group had a placebo-corrected median improvement from baseline in 6-minute walk distance of 21 m (95% CI, 7-37; P = .004, Hodges-Lehmann estimate). Using a different statistical approach, mixed-model repeated measurement, treatment with inhaled treprostinil increased 6-minute walk distance by 31 m (95% CI, 16.85-45.39; P < .001) at week 16, Nathan said.

The researchers also reported differences in secondary outcomes with inhaled treprostinil compared with placebo, including a 38% reduction in NT-proBNP (P < .001), a 34% reduction in risk for exacerbation of ILD (P = .03) and a 39% reduction in time to first clinical worsening event (P < .001), Nathan reported.

The benefits of inhaled treprostinil were observed across several key subgroups, including etiology of pulmonary hypertension associated with ILD, disease severity, age, sex, baseline hemodynamics and dose.

Inhaled treprostinil was well tolerated and the safety profile was consistent with previous studies. Most events that occurred during the INCREASE study were mild to moderate. Serious adverse events occurred in 23.3% of the inhaled treprostinil group compared with 25.8% of the placebo group. In addition, there were no clinically relevant treatment-related changes in pulse oximetry or supplemental oxygen in either group during the study period.

There was evidence of an improvement in forced vital capacity with inhaled treprostinil, Nathan said. The median improvement in percent predicted FVC at week 16 was 1% in the inhaled treprostinil group vs. a 1% reduction in the placebo group. The placebo-corrected improvement in FVC was 28.47 mL at week 8 and 44.4 mL at week 16. In patients with idiopathic pulmonary fibrosis treated with inhaled treprostinil, the placebo-corrected improvement in FVC was 84.52 mL at week 8 and 168.52 mL at week 16, according to results presented.

“These results support an additional treatment avenue and might herald a shift in the clinical management of patients with interstitial lung disease,” Nathan said.