Inhaled Treprostinil in pulmonary hypertension associated with interstitial lung disease: hope on the horizon

Pulmonary hypertension associated with interstitial lung disease (PH-ILD) is one of the deadliest pulmonary conditions and is associated with poor survival and high morbidity (1). The disease is characterized by abnormalities in both the lung interstitium and pulmonary vasculature, which has made finding a treatment challenging (2, 3). Clinical studies evaluating pulmonary vasodilators approved for pulmonary arterial hypertension in patients with PH-ILD have had mixed results with some studies showing no benefit or even demonstrating harm (4).

The INCREASE study, a 16-week randomised, placebo-controlled study of inhaled treprostinil in patients with PH-ILD, was the first positive study in this patient population and led to US FDA approval of inhaled treprostinil as the first and only therapy for PH-ILD (5). The study met its primary endpoint of change in peak 6-minute walk distance (6MWD) at week 16, as well as numerous secondary endpoints including change in N-terminal pro-B-type natriuretic peptide, a marker of myocardial dysfunction, and time to clinical worsening.

In the INCREASE study, pulmonary function testing was obtained as a safety parameter. Somewhat unexpectedly, the study showed that inhaled treprostinil was associated with improvements in the forced vital capacity (FVC). In a post-hoc analysis, patients receiving inhaled treprostinil demonstrated significant improvements in percentage of predicted FVC at week 8 and week 16 in comparison to placebo, with the greatest FVC improvements seen in patients with idiopathic interstitial pneumonia, in particular idiopathic pulmonary fibrosis (IPF) (6). 

It is noteworthy that the magnitude of difference at 16 weeks was comparable to the 52 week difference seen in studies of the two approved antifibrotic agents, pirfenidone and nintedanib (7,8). Additionally, the difference in INCREASE was driven by both improvements in FVC in the treatment arm and decline in the placebo arm. It remains to be seen whether the FVC benefit is a durable response and whether this can be replicated in IPF patients without PH. 

Nonetheless, when combined with in vitro and animal data suggesting antifibrotic effects from treprostinil, this analysis generates optimism from physicians and patients alike and hopefully extends beyond just those with complicating PH (9,10). This is currently being investigated in the global phase III TETON trials of inhaled treprostinil in patients with IPF (NCT04708782; NCT05255991).

Changes in the 6-minute walk test and FVC are accepted as clinical trial endpoints and are important in PH-ILD given patients’ limitations with exercise capacity and progressive loss of lung function. Clinical worsening is also important and has been employed as an endpoint in numerous pulmonary hypertension trials. Typically, only the time to first disease progression event is evaluated. While the first event is undoubtedly important, subsequent events are also meaningful. Therefore, a post-hoc analysis was performed evaluating all disease progression events in the INCREASE study defined as 15% decline in 6MWD, 10% decline in FVC, acute exacerbation, cardiopulmonary hospitalisation, lung transplantation, or death (11). 

This holistic analysis demonstrated that patients on inhaled treprostinil experienced significantly fewer disease progression events, and significantly fewer patients receiving inhaled treprostinil had multiple disease progression events compared to those receiving placebo. In clinical practice, physicians often consider changing or discontinuing therapies when there are signs of worsening PH-ILD. Results from this analysis suggest that continuation of inhaled treprostinil treatment in spite of disease progression conveys ongoing beneficial effects.

For far too long, patients with PH-ILD have had few options and little hope. Results from the INCREASE study and these secondary analyses are encouraging and support a numerous positive effects associated with inhaled treprostinil treatment. Forthcoming results from the INCREASE open-label extension (NCT02633293) will provide additional data on how durable these benefits are. 

Additionally, an analysis of the effects of inhaled treprostinil dose on clinical improvement is underway. A recent Delphi consensus from ILD experts has been published, with the goal of aiding physicians in identifying PH in patients with ILD (12). With a therapy for PH-ILD now available to clinicians, the early screening and diagnosis of PH in patients with ILD is paramount to detect and treat this condition.

By Steven Nathan and Eric Shen on behalf of the Pulmonary Vascular Research Institute.

Pulmonary Hypertension Group III Workstream