Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease
Open accessAbstract
BACKGROUND: No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear. METHODS: We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 μg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening. RESULTS: A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea. CONCLUSIONS: In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE ClinicalTrials.gov number, NCT02630316.).
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A phase 2 trial of BMS-986278 (admilparant) in 278 IPF patients showed a 62% relative reduction in the rate of change of percent predicted FVC in the 60 mg group versus placebo, with no significant difference in the 30 mg group.
“A phase 2 trial (NCT04308681) comparing placebo versus 30 mg versus 60 mg in a 1:1:1 distribution of a new LPA1 antagonist BMS-986278 or Admilparant in 278 patients with IPF diagnosed within seven years demonstrated a 62% relative reduction in rate of change of percent predicted FVC (95% CI 0.2 – 3.4) in the 60 mg group in comparison to placebo and no significant difference in the 30 mg group when”
From Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF) (2024) · cites this paper as [94]
The Methods and Patients sections describe a different trial: 326 patients with interstitial lung disease and pulmonary hypertension were assigned to inhaled treprostinil or placebo. Its primary endpoint was six-minute walk distance, not percent-predicted FVC. The cited paper therefore contradicts the claim’s identification of its drug, trial population, treatment groups, and endpoint; it does not report the claimed BMS-986278 result. Page numbers were not available for these passages. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredThe LPA1 receptor has a significant role in the pathogenesis of pulmonary fibrosis.
“The LPA1 receptor has been found to have a significant role in the pathogenesis of pulmonary fibrosis [94,95].”
From Emerging pharmacological options in the treatment of idiopathic pulmonary fibrosis (IPF) (2024) · cites this paper as [94]
The Discussion describes a trial of inhaled treprostinil for pulmonary hypertension associated with interstitial lung disease, not the pathogenesis of pulmonary fibrosis. Searches for “LPA1 receptor” and “lysophosphatidic acid receptor” found no passage in our copy addressing the receptor’s role. (LLM, conf=0.78)
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“In line with previous reports on inhaled drugs in IPF 31 , cough was also the most frequently reported TEAE for 44% of participants receiving LTI-03, as compared to the 33% receiving placebo, and the only study drug-related TEAE experienced by more than 1 participant.”
- Authors
- Waxman, A., Restrepo-Jaramillo, R., Thenappan, T., Ravichandran, A., Engel, P., Bajwa, A., Allen, R., Feldman, J., Argula, R., Smith, P., Rollins, K., Deng, C., Peterson, L., Bell, H., Tapson, V., & Nathan, S. D.
- Affiliations
- Brigham and Women's Hospital (US)
- From Brigham and Women’s Hospital, Boston (A.W.); the University of South Florida, Tampa (R.R.-J.), and St. Vincent’s Lung, Sleep, and Critical Care Specialists, Jacksonville (A.B.) — both in FL; the University of Minnesota, Minneapolis (T.T.); St. Vincent Medical Group, Indianapolis (A.R.); the Carl and Edyth Lindner Research Center at the Christ Hospital, Cincinnati (P.E.); University of California Davis Medical Center, Sacramento (R. Allen), and Cedars–Sinai, Los Angeles (V.T.); Arizona Pulmonary...
- Cedars-Sinai Medical Center (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-01-28
- Volume
- 384
- Issue
- 4
- Pages
- 325-334
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3119793303
- Cited by
- 666
- References
- 16
- Citations by year
- 2026: 116 · 2025: 139 · 2024: 133 · 2023: 120 · 2022: 95 · 2021: 61 · 2020: 2
- FWCI
- 66.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- United Therapeutics Corporation
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Keywords
- inhaled treprostinil, pulmonary hypertension, interstitial lung disease, 6-minute walk distance, NT-proBNP, exercise capacity, clinical deterioration, adverse events, phosphodiesterase-2 inhibitor, pulmonary arterial hypertension treatment, right heart catheterization, clinical trial safety and efficacy, pulmonary arterial hypertension
- MeSH terms
- Walk Test, Administration, Inhalation, Adult, Aged, Aged, 80 and over, Antihypertensive Agents, Double-Blind Method, Female, Humans, Hypertension, Pulmonary, Male, Middle Aged, Epoprostenol, Quality of Life, Least-Squares Analysis, Exercise Tolerance, Lung Diseases, Interstitial
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