TRPA1 Antagonist Shows Delayed but Meaningful Effect on IPF Cough

A phase 2a/2b trial of BI 1839100, a selective oral transient receptor potential ankyrin 1 (TRPA1) antagonist, missed its week-4 primary endpoint for cough reduction in idiopathic pulmonary fibrosis (IPF) but showed a clinically meaningful effect by week 12, according to Marlies Wijsenbeek, MD, PhD, professor of interstitial lung diseases and chair of the Academic Centre of Excellence for Interstitial Lung Diseases and Sarcoidosis at Erasmus MC, University Medical Centre Rotterdam. Wijsenbeek discussed the late-breaking abstract, presented at the European Respiratory Society (ERS) Congress 2026 in Barcelona, Spain, held September 5 to 9, in an interview with HCPLive.

Of 85 randomized patients with IPF-related chronic cough, 28 received the high dose of BI 1839100 (150 mg twice daily) and 29 received placebo, with 26 and 27, respectively, completing treatment.1 Median baseline cough burden was approximately 20 coughs per hour. The trial was designed with co-primary 24-hour cough-count endpoints at weeks 4 and 12; a prespecified interim analysis after the week-4 assessment led to termination for futility, since the high dose produced only a 5.7% relative reduction in cough count from baseline at that point. By week 12, however, the same dose showed a 45.5% reduction in 24-hour cough count relative to placebo, along with reductions in daytime cough count (48.8% vs 18.6% with placebo) and cough bouts (36.8% vs a 17.9% increase with placebo); forced vital capacity was unaffected, and the drug's safety profile was acceptable.1

Wijsenbeek said the mismatch between the 2 timepoints likely reflects the drug being assessed too early rather than a lack of effect.

“This is the first drug that is not in that category that shows something,” she said, contrasting BI 1839100 with the centrally acting, opioid-based antitussives, including morphine and nalbuphine, that have previously shown benefit in IPF cough.

Nalbuphine extended-release, a kappa-agonist, mu-antagonist opioid, reduced objective cough frequency compared with placebo in the phase 3 CORAL trial published earlier this year.2 Wijsenbeek said she could only speculate on the mechanism behind BI 1839100's delayed onset, but noted preclinical data suggesting the drug also has antifibrotic properties, raising the possibility that its effect depends on longer-term neuroplastic or fibro-inflammatory changes rather than acute receptor blockade alone.

Mechanistically, Wijsenbeek said TRPA1 is a sensory ion channel expressed on airway afferent nerves that contributes to cough hypersensitivity and has been shown in preclinical models to be upregulated in fibrotic lung tissue; BI 1839100 works as an antagonist of that channel, a pathway she said the cough research field has considered promising for years. She said the findings support designing a new trial with a later primary endpoint to properly capture the drug's apparent delayed benefit.

References

1. Wijsenbeek M, Smith J, Adegunsoye A, et al. Selective TRPA-1 antagonist in patients with chronic cough and idiopathic pulmonary fibrosis: a phase IIa/IIb randomized, double-blind, placebo-controlled study (BI 1839100). Late-breaking abstract presented at: European Respiratory Society (ERS) Congress 2026; September 5-9, 2026; Barcelona, Spain.

2. Molyneaux PL, Mogulkoc N, Gunen H, et al; CORAL Study Group. Oral nalbuphine in idiopathic pulmonary fibrosis-associated cough: the CORAL randomized clinical trial. JAMA. 2026;335(12):1050-1059. doi:10.1001/jama.2025.26179