Inhaled Treprostinil Treats Pulmonary Hypertension Due to Interstitial Lung Disease
Presenter: Steven D. Nathan, MD, Director, Advanced Lung Disease Program, Medical Director, Lung Transplant Program, Inova Fairfax Hospital, Falls Church, VA.
A summary of Treatment of pulmonary hypertension in IPF and lessons learned from the INCREASE study, presented October 19, 2021.
Treatment with inhaled treprostinil is associated with improved exercise capacity and a lower risk of clinical worsening in patients with pulmonary hypertension (PH) due to interstitial lung disease (ILD), according to results from the INCREASE trial published in 2021. The INCREASE trial, a phase 3, multicenter, randomized, double-blind, placebo-controlled, 16-week trial, evaluated the safety and efficacy of inhaled treprostinil in patients with ILD and associated PH. Investigators assigned 163 patients to receive inhaled treprostinil administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths 4 times daily. Another group of 163 patients received placebo. The primary end point was the change in 6-minute walk distance from baseline to week 16.
The baseline demographics of the 2 groups were well-matched. Regarding the etiology of PH-ILD, about one-half had idiopathic interstitial pneumonia (39.9% of treprostinil recipients and 49.7% of placebo recipients) and about one-quarter had combined pulmonary fibrosis and emphysema (25.8% and 24.5%, respectively) (Nathan Lancet Respir Med 2021).
According to Steven D. Nathan, lead author of the Lancet Respiratory Medicine article on the INCREASE trial, “This was a sick group of patients, with almost three-quarters on supplemental oxygen. They had moderate to severe PH. In terms of lung function, they had moderately restrictive physiology.”
The study’s primary endpoint—mean change from baseline in peak 6-minute walk distance—was significantly improved by 31 meters in the treprostinil group compared with placebo recipients (P < .001) (Waxman N Engl J Med 2021). “This was mostly driven by improvement in the treatment arm vs deterioration in placebo arm,” Nathan said.
“An important secondary endpoint was time to clinical worsening,” he said. “This occurred in 22.7% in the treprostinil group as compared with 33.1% in the placebo group, which was a statistically significant difference. The biggest driver for this change was a decrease in walk distance in the placebo arm.”
Nathan added that “Biomarkers also supported the clinical endpoints. There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo. This underscores that what we saw clinically was a real difference.”
He noted that higher doses of inhaled treprostinil were associated with a lower risk of clinical worsening, suggesting that there is a dose-response for clinical outcomes. Patients who took at least 9 breaths per session had a significantly lower rate of clinical worsening (P < .0001) than those who took fewer than 9 breaths per session. Patients who took 12 or more breaths per session from the treprostinil inhaler had the most benefit, with a walk distance of 33.7 meters (Waxman Chest 2021).
A safety endpoint in terms of lung function showed that treprostinil caused no harm to patients’ underlying disease. Also, patients who used inhaled treprostinil did better in terms of forced vital capacity. “This may be due to the antifibrotic properties of treprostinil,” Nathan added.
“A post-hoc analysis study asked what happens after clinical worsening?” he said. “Types of events included in this analysis were death, hospitalization due to cardiopulmonary indications, decline in walk distance, exacerbation of underlying lung disease, or lung transplantation. Patients had to have at least 2 events to qualify for analysis. Many more multiple events occurred in the placebo arm.”
“One of the clinical messages is that even if patients have clinical worsening on inhaled treprostinil, it does not mean the drug is not working,” Nathan said. “They should continue on the drug to avert or reduce risks of subsequent worsening events.”
In March 31, 2021, the FDA approved inhaled treprostinil for the treatment of PH associated with ILD. “This represents a real paradigm shift regarding how we approach ILD patients,” he said. “We really have to lower the threshold to look for PH. We now have another medication to offer these patients who have complicating or superimposed PH.”
Disclosures
Steve Nathan, MD: Altavant (Consultant), Bayer (Consultant), Bellerophon (Research Funding), Boerhinger-Ingelheim (Consultant, Speaker’s Bureau, Research Funding), Galapagos (Consultant), Roche (Consultant), Roche-Genentech (Speaker’s Bureau), Third Pole (Consultant), United Therapeutics (Consultant, Speaker’s Bureau, Research Funding).
References
Nathan SD. Treatment of pulmonary hypertension in IPF and lessons learned from the INCREASE study. Presented virtually at: CHEST 2021; October 19, 2021.
Nathan SD, Waxman A, Rajagopal S, et al. Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study. Lancet Respir Med 2021; Jun 29:S2213–2600(21)00165-X. doi: 10.1016/S2213-2600(21)00165-X
Waxman A, Nathan S, Fisher M, et al. Dose response analysis of inhaled treprostinil in pulmonary hypertension associated with interstitial lung disease and its effects on clinical worsening. Chest 2021; 160(4)(suppl): A2279–A2280. doi: 10.1016/j.chest.2021.07.1995
Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med 2021; 384(4):325–334. doi: 10.1056/NEJMoa2008470