clinical topic updates

Research on Pulmonary Hypertension–Specific Therapeutics for Patients With Chronic Lung Disease

by Steven D. Nathan, MD


Research continues to unfold on possible new treatments for pulmonary hypertension (PH) in patients with chronic lung disease (CLD), including those with interstitial lung disease (ILD). Although results of past trials with pulmonary arterial hypertension (PAH)–targeted therapy in patients with CLD-PH have been mixed, there is hope that continued research efforts will lead to therapeutic advancements for patients with pulmonary vascular disease and presumed ILD-PH.

Expert Commentary

Steven D. Nathan, MD

Medical Director
Advanced Lung Disease and Transplant Program
Inova Fairfax Hospital
Falls Church, VA

“Current research on therapeutics for ILD-PH is at a similar point as PAH-related research in the early 1990s—prior to which no treatments for PAH had been available.”

Steven D. Nathan, MD

Over the last decade or so, randomized controlled trials exploring the use of PAH-targeted therapy for patients with CLD have had mixed results. These trials have been performed in populations with ILD-PH, chronic obstructive pulmonary disease (COPD)–PH, and sarcoidosis-PH. While there has been the suggestion of a positive response in trials with sildenafil in COPD-PH and ILD-PH at secondary end points, other trials of PAH-directed therapy in CLD have had neutral or negative results. For instance, riociguat is contraindicated in patients with idiopathic interstitial pneumonia–PH based on data from the RISE-IIP trial, while ambrisentan is contraindicated in idiopathic pulmonary fibrosis–PH based on data from the ARTEMIS study.

Today, treprostinil inhalation solution and inhaled nitric oxide represent 2 promising PH-specific agents being developed for patients with CLD-PH. Current research on therapeutics for ILD-PH is at a similar point as PAH-related research in the early 1990s—prior to which no treatments for PAH had been available. I have been involved in a very interesting study with inhaled treprostinil—a randomized placebo-controlled study that has completed enrollment, with results to be reported in the near future. There is also an ongoing investigational program of ambulatory inhaled nitric oxide, which is employing a novel primary end point of actigraphy. Actigraphy arguably is a better measure of functional ability, since it reflects what patients are actually doing outside the clinical setting.

Composite end points of time to clinical worsening with some variations in the individual components are now used often in PH research. A good example of a composite end point would be one constituted by death, the need for hospitalization due to PH, a 10% decrease in the 6-minute walk distance, the need for parenteral therapy, atrial septostomy, or lung transplantation. Part of the reason for transitioning to the use of composite end points in PAH has resulted from the availability of multiple agents, and, hence, the ability to show incremental differences in a single end point may be increasingly diminished. For example, patients in trials for PAH today are on at least 1 or 2 drugs—and sometimes even 3—in addition to the experimental agent or the placebo, and there can be a ceiling effect where it is difficult to show benefit with additional treatment based on the 6-minute walk test. At this point, however, since there is no approved agent as of yet for ILD-PH, the 6-minute walk test remains a good and appropriate end point for ILD-related PH studies.

With respect to delivery systems, inhaled routes of delivery for CLDs beyond COPD have not been extensively explored. The advantage of inhaled medications is that the lung can be targeted directly with greater precision; therefore, there is the potential to deliver higher doses to actionable areas with less systemic toxicity.

References A safety and efficacy study of pulsed inhaled nitric oxide in pulmonary hypertension associated with pulmonary fibrosis. Accessed June 19, 2020. Safety and efficacy of inhaled treprostinil in adult PH with ILD including CPFE. Accessed June 19, 2020.

Hoeper MM, Behr J, Held M, et al. Pulmonary hypertension in patients with chronic fibrosing idiopathic interstitial pneumonias. PLoS One. 2015;10(12):e0141911. doi:10.1371/journal.pone.0141911

Nathan SD, Barbera JA, Gaine SP, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J. 2019;53(1):1801914. doi:10.1183/13993003.01914-2018

Nathan SD, Behr J, Collard HR, et al. Riociguat for idiopathic interstitial pneumonia–associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study. Lancet Respir Med. 2019;7(9):780‐790. doi:10.1016/S2213-2600(19)30250-4

Prins KW, Duval S, Markowitz J, Pritzker M, Thenappan T. Chronic use of PAH-specific therapy in World Health Organization group III pulmonary hypertension: a systematic review and meta-analysis. Pulm Circ. 2017;7(1):145-155. doi:10.1086/690017

Raghu G, Behr J, Brown KK, et al; ARTEMIS-IPF Investigators. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial [published correction appears in Ann Intern Med. 2014;160(9):658]. Ann Intern Med. 2013;158(9):641-649. doi:10.7326/0003-4819-158-9-201305070-00003

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