Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study

Summary

Background

INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest.

Methods

In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316.

Findings

Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI −30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; −25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI −32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; −20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea.

Interpretation

In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study.

Funding

United Therapeutics Corporation.

Introduction

Interstitial lung diseases (ILDs) encompass a broad range of conditions that are categorised by varying amounts of inflammation and fibrosis. Idiopathic interstitial pneumonias are a category of ILD, of which idiopathic pulmonary fibrosis is the most common form.¹ Clinical trials of idiopathic pulmonary fibrosis treatments have resulted in approval in many countries of two so-called antifibrotic agents, pirfenidone and nintedanib.2, 3, 4 Both drugs have been shown to slow loss of lung function, as measured by forced vital capacity (FVC). Results of clinical trials for both drugs in other forms of fibrotic lung disease—including scleroderma-associated ILD, ILDs characterised by progressive fibrosis, and unclassifiable ILD—indicate that both agents have antifibrotic effects beyond idiopathic pulmonary fibrosis.5, 6, 7 These results suggest that once lung fibrosis supervenes, there are pathways common to various forms of ILD that might be targets for therapy.

Treprostinil is a stable analogue of prostacyclin, which promotes vasodilation of pulmonary and systemic arterial vascular beds and inhibits platelet aggregation.⁸ The inhaled formulation of treprostinil is approved in the USA for the treatment of WHO group 1 pulmonary hypertension.8, 9 In addition to its effects on the pulmonary vasculature, there are data to suggest that treprostinil has antifibrotic properties. Specifically, treprostinil has been shown to affect extracellular matrix remodelling and fibrosis in vitro by reducing recruitment of fibrocytes to sites of vascular remodelling, as well as suppressing profibrotic fibroblast activity and the synthesis and deposition of collagen and fibronectin in mice.10, 11

Research in context

Evidence before this study

Clinical trials in patients with chronic fibrosing interstitial lung diseases (ILDs) have led to the development of two antifibrotic agents, nintedanib and pirfenidone. These therapies have been shown to reduce the rate of decline in lung function and are now recommended in clinical practice guidelines for patients with idiopathic pulmonary fibrosis. The INCREASE study was a randomised clinical trial of patients with ILD and pulmonary hypertension that evaluated the safety and efficacy of inhaled treprostinil. The study met its primary endpoint of change in the peak 6-min walk distance at week 16. Pulmonary function testing was obtained as a safety parameter in this study. Somewhat unexpectedly, this study also showed that inhaled treprostinil was associated with improvements in forced vital capacity (FVC) over a 16-week period. We searched PubMed on June 9, 2021, using the search terms “treprostinil” and “lung function” for all articles published from database inception up to June 9, 2021, with no language restrictions. One retrospective study of 22 patients with interstitial lung disease and associated pulmonary hypertension treated with inhaled treprostinil assessed lung function. No significant changes were observed in percentage predicted FVC but this study was limited by its observational, uncontrolled design. The effects of inhaled treprostinil on lung function in this disease population have otherwise not been studied.

Added value of this study

In this post-hoc analysis of the INCREASE trial, inhaled treprostinil was associated with significant improvements in the percentage of predicted FVC at week 8 and week 16. Improvement in FVC was greatest among patients with idiopathic interstitial pneumonia, particularly those with idiopathic pulmonary fibrosis. These results suggest that inhaled treprostinil might have independent antifibrotic properties beyond traditional vasodilatory effects. Whether this will be substantiated in a study of patients with interstitial lung disease, with or without pulmonary hypertension, remains to be determined.

Implications of all the available evidence

The present study serves as proof of concept that inhaled treprostinil can have a beneficial effect on the loss of lung function in patients with ILDs and associated pulmonary hypertension. These findings were most pronounced in patients with idiopathic pulmonary fibrosis. Further studies are needed to investigate the clinical benefits of inhaled treprostinil in this patient population, with or without associated pulmonary hypertension, and to explore potential mechanisms of action.

The INCREASE study was a 16-week randomised controlled trial that was designed to evaluate the safety and efficacy of inhaled treprostinil in patients with ILD and pulmonary hypertension documented by right heart catheterisation. Patients received inhaled treprostinil, up to 12 breaths (72 μg) four times daily, or placebo.¹² The dose of drug or placebo was adjusted, with dose escalation (an additional breath, four times daily) occurring as often as every 3 days, with a target dose of nine breaths four times daily and a maximum dose of 12 breaths four times daily. Investigators adjusted the dose for each individual patient to achieve the maximum tolerated dose. The study met its primary endpoint of change in the peak 6-min walk distance, a measure of exercise capacity, at week 16. Secondary endpoints, including change in N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration at week 16 and time to clinical worsening, were also met. Pulmonary function testing was done as a safety assessment at baseline, week 8, and week 16, and was previously reported.¹²

The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC among the overall study population and in various subgroups of interest, including specific disease subgroups and patients stratified by median baseline clinical characteristics.