Among patients with pulmonary hypertension and interstitial lung disease (ILD), treatment with the inhaled prostacyclin vasodilator treprostinil was associated with highly significant improvements in exercise capacity in phase III findings from the multicenter, randomized INCREASE trial.
Compared with placebo-treated patients, patients treated with treprostinil (Tyvaso) showed increases in 6-minute walk distance (6MWD) of 21 meters after 16 weeks (P=0.0043, Hodges-Lehmann estimate), reported Steven D. Nathan, MD, director of the Advanced Lung Disease Program and the Lung Transplant Program at Inova Fairfax Hospital in Annandale, Virginia.
- These findings were reported at a meeting, and have not been published in a peer-reviewed journal.
He presented the findings at an American Thoracic Society 2020 virtual session on clinical trials held in advance of the full virtual program scheduled for August.
The patients in the treprostinil arm of the study also showed improvements in other clinically meaningful outcomes, including plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to week 16 and decreased risk of clinical worsening and exacerbation of underlying lung disease.
Treprostinil is approved for the treatment of patients with pulmonary hypertension, and the drug has been shown to improve exercise capacity in these patients.
The phase III INCREASE study included 326 ILD patients with pulmonary hypertension randomized 1:1 to either treprostinil (6 mcg per breath) or placebo for 16 weeks, with the primary endpoint the change in 6MWD measured at peak exposure from baseline to week 16.
All participants started the drug at a dose of three breaths (18 mcg) four times a day during waking hours or placebo four times a day. Dose escalations (additional one breath four times daily) could occur up to every 3 days with a target dose of nine breaths (54 mcg) four times daily and a maximum dose of 12 breaths (72 mcg) four times daily, as tolerated.
Secondary endpoints included change in plasma concentration of NT-proBNP during the course of the study; time to clinical worsening, determined by hospitalization due to cardiopulmonary cause; decrease in 6MWD greater than 15% from baseline at two consecutive visits at least 24 hours apart; death or lung transplantation; change in peak 6MWD from baseline to week 12; or change in trough 6MWD from baseline to week 15.
The mean patient age was 65.6 in the inhaled treprostinil group and 67.4 in the placebo group; 73% and 70%, respectively, used supplemental oxygen.
Baseline median 6MWD was 254 meters in the inhaled treprostinil patients and 265 meters in the placebo group.
Nathan reported that at 16 weeks, inhaled treprostinil patients had a placebo-corrected median difference from baseline peak 6MWD of 21 meters; with the improvement from baseline of four meters at week 4, 15 meters at week 8, 20 meters at week 12, and 21 meters at week 16 (Hodges-Lehmann estimate 95% CI 7-37; P=0.004).
No significant differences in patient-reported quality of life or peak distance saturation product were observed.
Inhaled treprostinil resulted in a 38% reduction in NT-proBNP when compared with placebo at week 16 (P<0.001) and a 39% reduction in risk of clinical worsening (log rank P=0.04).
A total of 37 patients treated with inhaled treprostinil (22.7%) and 54 patients in the placebo group (33.1%) had clinical worsening during the trial, with 11% and 14.7% of the treprostinil and placebo groups, respectively, needing hospitalization due to cardiopulmonary causes.
A total of 10% of the treprostinil group and 8% of the placebo group discontinued treatment due to adverse events, and 23.3% of the active treatment group and 25.8% of placebo-treated patients had serious adverse events. The most frequently occurring adverse events were cough, headache, dyspnea, dizziness, and nausea.
Treprostinil’s manufacturer, United Therapeutics, which funded the trial, recently submitted an application to the FDA seeking to revise the drug’s label to reflect the INCREASE data.
“Results support an additional treatment avenue and might herald a shift in the clinical management of patients with interstitial lung disease,” Nathan said.
Asked for his perspective, Martin Kolb, PhD, of McMaster University in Ontario, the facilitator for the presentation, said the findings offer more evidence that targeting the blood vessels can be an effective strategy for addressing fibrosis.
The pathobiology underlying the remodeling and fibrosis of the parenchyma in ILD and the mechanisms leading to structural and functional alteration of the pulmonary vasculature are closely intertwined, Kolb told MedPage Today. “The lung is made up of both air tubes and blood vessels, and much of the research has been focused on either one or the other. But there is close interaction between the two.”
He added that the trial findings support the concept of targeting the blood vessels to treat lung fibrosis.
The INCREASE study was funded by United Therapeutics Corporation.
Nathan reported financial relationships with United Therapeutics, Bellerophon Therapeutics, Boehringer-Ingelheim, Biogen, Roche-Genentech, Merck, and Pliant.