A week 4 futility gate closed on a TRPA1 antagonist whose cough effect appeared at week 12

What was tried

Boehringer Ingelheim ran NCT06360094 (study 1490-0004), a Phase IIa/IIb randomised, quadruple-blind, placebo-controlled, parallel-group dose-finding study of oral BI 1839100 over 12 weeks in adults aged 40 and over with idiopathic pulmonary fibrosis or progressive pulmonary fibrosis and clinically meaningful cough. Entry required chronic cough of more than eight weeks attributed to the fibrotic disease and refractory to treatment of known causes, a cough severity visual analogue scale score of at least 30 mm, forced vital capacity at or above 45 percent of predicted, and diffusing capacity above 25 percent of predicted. Stable nintedanib or pirfenidone was allowed, as was no antifibrotic.

Three dose levels were compared with placebo. The Phase IIa primary endpoint was change from baseline in 24-hour cough frequency at week 4, and the Phase IIb primary endpoint was the same measure at week 12, analysed by a mixed model for repeated measures on log-transformed cough counts per hour. The study opened on 28 August 2024 and closed on 2 September 2025 as terminated, with no reason posted. Results are posted.

Eighty-five participants with idiopathic pulmonary fibrosis were randomised: 14 low dose, 14 medium dose, 28 high dose, 29 placebo. Mean age was 71.5 years, 64 of 85 were male, and mean baseline 24-hour cough frequency was 29.9 coughs per hour.

The biological hypothesis

TRPA1 is a ligand-activated, calcium-permeable non-selective cation channel on airway sensory nerves, and Open Targets records its role in pain detection and in cough. The rationale for blocking it in fibrotic lung disease is that cough hypersensitivity is driven by sensitised vagal afferents, that TRPA1 transduces irritant stimuli reaching those afferents, and that the channel is reported to be upregulated in fibrotic lung tissue. A 2017 review set out that case.

The Open Targets evidence shows where the anchor sits. TRPA1 and cough as a phenotype score 0.601, with a clinical datatype score of 0.985. TRPA1 and idiopathic pulmonary fibrosis score 0.019, carried entirely by a literature datatype score of 0.154. The target was anchored to the symptom, not the disease.

What actually happened

At week 4 drug and placebo were not distinguishable. Estimated treatment differences versus placebo in 24-hour cough frequency were -18.30 percent for low dose (95 percent confidence interval -45.42 to 22.30), +6.69 percent for medium dose (-28.41 to 58.99) and -5.67 percent for high dose (-31.88 to 30.63). Every interval crossed zero.

At week 12 the picture changed: -57.93 percent for low dose (-73.29 to -33.75), -32.39 percent for medium dose (-56.68 to 5.53) and -45.53 percent for high dose (-62.24 to -21.45). The proportion reaching at least a 30 percent reduction was 80.0, 63.6 and 71.4 percent across the three doses against 39.1 percent on placebo, with adjusted odds ratios of 5.52 (1.05 to 43.34), 3.04 (0.69 to 15.23) and 4.86 (1.34 to 20.24).

Reporting at a September 2026 clinical meeting, summarised by HCPLive, states that a prespecified interim analysis after week 4 triggered termination for futility, and that the high dose was 150 mg twice daily. The week 12 data came from participants already randomised.

Safety was unremarkable at this size. Serious adverse events occurred in 0 of 14, 3 of 14 and 3 of 28 on drug versus 4 of 29 on placebo, with no deaths. Forced vital capacity change at week 12 numerically favoured drug in all three arms, with every interval crossing zero.

Failure mechanism, best guess

This was a decision-rule failure rather than a pharmacology failure. The futility gate sat at week 4 and the effect emerged after it.

Two features of the week 4 data explain why the gate closed. The placebo arm had already improved by a least-squares mean of 25.93 percent at week 4, then gave that back, standing at 12.57 percent at week 12. A large early placebo response followed by regression is documented in cough trials, and it compresses any early treatment contrast toward zero. With 14 participants in each smaller arm, the week 4 intervals spanned more than 60 percentage points, too wide to separate a real 20 percent effect from nothing.

The underlying assumption looks borrowed. Antitussives acting on P2X3, such as gefapixant and camlipixant, act on refractory chronic cough within weeks, which makes an early endpoint reasonable there. Fibrotic cough may not behave the same way if the channel contribution sits downstream of slowly reversing airway sensitisation. Nothing in the record shows the week 4 timing was validated in this population before it was used as a stopping rule.

The dose ordering cautions against overreading the positive side. The low dose produced the largest week 12 effect and the medium dose the smallest, which is not a monotonic exposure response and is consistent with chance in arms of 14.

How to prevent this next time

Endpoint-level data are available, so the levers are concrete.

The first is to validate the timing of an interim gate before using it. A futility rule belongs where the pharmacodynamic model says the effect will be observable and where prior trials show placebo behaviour has stabilised. Neither condition was demonstrated for week 4 in fibrotic cough.

The second is to size the gate, not just the trial. Baseline cough frequency had a standard deviation of roughly 30 coughs per hour against a mean of 30, a coefficient of variation near 1. A 14-participant arm cannot support a futility decision at that variance, and any interim rule should require arms large enough that the decision interval is narrower than the effect worth detecting.

The third is to model the placebo trajectory rather than assume it is flat. The observed placebo path, -25.93 percent at week 4 and -12.57 percent at week 12, would have inverted the sign of any early futility comparison.

The single highest leverage change would have been placing the futility gate at week 12 rather than week 4, with the week 4 read used only to confirm safety and exposure.

What this means for similar programs

The Claidex mechanism risk score for TRPA1 opens at 45 out of 100, in the yellow band, driven by the genetic deficit component at 14.72 of a possible 15, reflecting an Open Targets association of 0.019 with idiopathic pulmonary fibrosis. Saturation is low because Open Targets lists only four drug and clinical candidates against TRPA1, of which one selective antagonist, GRC-17536, reached Phase 2 in neuropathic pain.

For other TRPA1 programmes, this trial did not falsify the mechanism. It is closer to an unfinished experiment, and the transferable lesson for cough programmes is about gate placement rather than about the channel.

One contrary signal belongs in the record. A 2023 report in the American Journal of Respiratory Cell and Molecular Biology describes an inhibitory function of TRPA1 in transforming growth factor beta 1-driven fibroblast to myofibroblast differentiation, raising the possibility that sustained blockade could work against the fibrotic process even while relieving cough. The forced vital capacity data here cannot speak to that.

Open questions

Whether the sponsor will run a confirmatory study with a later primary endpoint is unknown, and the registry gives no reason for termination. Whether the progressive pulmonary fibrosis cohort in the protocol was ever recruited is not visible in the posted results, which report only idiopathic pulmonary fibrosis groups. Whether the low dose result is real or a small-sample artefact can be settled only by a study powered at week 12.

Sources

1. • ClinicalTrials.gov, NCT06360094, BI 1839100 in idiopathic pulmonary fibrosis or progressive pulmonary fibrosis with cough, protocol and posted results, accessed 24 September 2026: https://clinicaltrials.gov/study/NCT06360094 - Wijsenbeen M, TRPA1 antagonist shows delayed but meaningful effect on IPF cough, HCPLive, 14 September 2026: https://www.hcplive.com/view/trpa1-antagonist-shows-delayed-but-meaningful-effect-on-ipf-cough - BI 1839100's termination raises questions for TRPA-1 targeting in IPF cough, GlobalData, 2026: https://www.globaldata.com/media/pharma/bi-1839100s-termination-raises-questions-for-trpa-1-targeting-in-ipf-cough-says-globaldata/ - TRPA1 receptors in chronic cough, Pulmonary Pharmacology and Therapeutics, 2017,- Role of transient receptor potential ankyrin 1 in idiopathic pulmonary fibrosis: modulation of M2 macrophage polarisation, Cellular and Molecular Life Sciences, 2024,- An inhibitory function of TRPA1 channels in TGF-beta1-driven fibroblast-to-myofibroblast differentiation, American Journal of Respiratory Cell and Molecular Biology, 2023,- Decoding the impact of the placebo response in clinical trials for chronic cough, ERJ Open Research, 2024,- Camlipixant in refractory chronic cough: a phase 2b randomised placebo-controlled trial (SOOTHE), American Journal of Respiratory and Critical Care Medicine, 2025,- Oral nalbuphine in idiopathic pulmonary fibrosis-associated cough: the CORAL randomized clinical trial, JAMA, 2026,- Open Targets Platform, TRPA1 (ENSG00000104321) association records for idiopathic pulmonary fibrosis (EFO_0000768) and cough (HP_0012735), and drug candidate list, queried 24 September 2026: https://platform.opentargets.org - openFDA drug event API, queried 24 September 2026, no FAERS records for BI 1839100: https://api.fda.gov/drug/event.json.