Spesolimab in hidradenitis suppurativa: an IL-36 receptor program that worked in pustular psoriasis and stalled here

What was tried

Boehringer Ingelheim tested spesolimab, a humanized IgG1 antibody against the interleukin-36 receptor (IL-36R, gene IL1RL2), in moderate-to-severe hidradenitis suppurativa. The molecule is the same one approved as Spevigo for generalized pustular psoriasis, where it blocks IL-36R signaling driven by IL-36 alpha, beta, and gamma (J Dermatol 2024, 10.1111/1346-8138.17449). The hidradenitis program ran a placebo-controlled Phase 2a proof-of-concept study (NCT04762277, 52 patients randomized 2:1 over 12 weeks) and then a Phase 2/3 evaluation with a long-term extension. The extension trial covered here, NCT06241573 (Lunsayil LTE), enrolled 39 patients under quadruple masking and was terminated with posted results and an actual primary completion date of 11 April 2025 (ClinicalTrials.gov).

The biological hypothesis

The IL-36 axis has clean human validation in one disease. Loss-of-function mutations in IL36RN, which encodes the IL-36 receptor antagonist, cause generalized pustular psoriasis through unopposed IL-36R signaling and neutrophilic skin inflammation (BioDrugs 2023, 10.1007/s40259-023-00587-5). Spesolimab works in that setting because IL-36R is the dominant, rate-limiting node. Hidradenitis suppurativa is also a neutrophil-rich, abscess-forming skin disease, and IL-36 cytokines are detectable in lesional tissue, so the program reasoned that blocking the same receptor would lower HS lesion counts. The biology looked transferable on the surface: shared keratinocyte-driven IL-36 expression, shared neutrophilic histology, and an approved antibody already in hand.

What actually happened

The controlled data separated from placebo, but inconsistently. In the Phase 2a study at Week 12, mean change in draining tunnels was -1.30 with spesolimab versus +1.07 with placebo, and the total abscess, nodule, and draining tunnel count fell -4.87 versus -0.86 (Br J Dermatol 2024, NCT04762277). Abscess counts moved -0.53 versus +3.07. The nodule count went the other way, -3.00 with spesolimab versus -5.00 with placebo. Most patients, 45 of 52 (86.5%), rolled into the open-label extension, which kept the program alive into the Phase 2/3 stage. The long-term extension NCT06241573 was then terminated. No free-text reason was posted on that record, and the program did not advance to a registrational HS indication. Open Targets scores the IL1RL2 to hidradenitis suppurativa association at 0.248, and that number is carried almost entirely by clinical and drug evidence (0.406) rather than human genetics (literature component 0.048, no genetic datatype score). FAERS for spesolimab is dominated by underlying pustular disease terms and drug-ineffective or off-label reports across 53 serious cases (openFDA), with no novel receptor-related safety signal.

Failure mechanism, best guess

This reads as translational mismatch rather than a broken molecule or a safety stop. Spesolimab engages IL-36R exactly as designed, and it remains effective in generalized pustular psoriasis. The problem is that the target sits at a different position in the two diseases. In pustular psoriasis, IL-36R is the dominant driver, anchored by IL36RN human genetics. In hidradenitis suppurativa, the dominant validated pathways run through TNF, IL-17, and IL-1 beta, with IL-36 acting as one contributor among several (Biomolecules 2024, 10.3390/biom14020175). When a target is secondary, blocking it produces partial and endpoint-dependent effects, which is what the inconsistent tunnel, abscess, and nodule numbers show. The Open Targets profile is the quantitative tell. An association built on drug trials rather than genetics is what a secondary, non-rate-limiting target looks like before a confirmatory trial reads out (Int J Mol Sci 2022, 10.3390/ijms23169479).

How to prevent this next time

Two quantitative changes would have de-risked the jump from pustular psoriasis to HS.

First, a Bayesian interim with an explicit posterior probability of success. Define success as a clinically meaningful HiSCR response gap over placebo, set a futility boundary, and compute

PP(success)=∫θ​P(final success∣θ,interim data)⋅π(θ∣interim data)dθ

with a prior anchored on the pustular psoriasis effect size and then discounted by the weaker HS genetic support. With nodule counts already favoring placebo at Week 12, that posterior would have crossed a futility boundary early and capped extension spend.

Second, biomarker-enriched enrollment combined with historical base-rate adjustment. HS is heterogeneous, and only a subset of lesions show high IL-36 expression. Stratifying or enriching on lesional IL-36 alpha and IL-36 gamma protein, then powering the trial on that enriched subgroup, would have raised the effective effect size and shrunk the sample needed to detect it. Setting the design assumptions to the published HS base rate, where IL-17 and TNF agents define the efficacy bar (Expert Opin Drug Saf 2025, 10.1080/14740338.2025.2484022), would have prevented an optimistic powering carried over from pustular psoriasis.

The single highest leverage change would have been to gate the expansion into HS on a prespecified lesional IL-36 biomarker readout, so that capital advanced only if the human target evidence in HS matched the strength it already had in pustular psoriasis.

What this means for similar programs

The lesson generalizes to any asset moving between diseases that share histology but not genetics. Shared neutrophilic appearance is not shared causal architecture. IL-36R, IL-1, and IL-17 programs in inflammatory skin disease should treat human genetic anchoring as a target-by-indication property, not a target property. The Claidex Mechanism Risk Score for IL1RL2 stands at 34 of 100 (yellow band), with the genetic-deficit component contributing 11.28 of its possible 15 points, which flags exactly this gap between pharmacological and genetic validation in HS.

Open questions

Did the Phase 2/3 data contain a biomarker-defined subgroup with a larger effect that a future sponsor could enrich on? Would a higher or more frequent subcutaneous dose have shifted the nodule and abscess endpoints, or is the ceiling set by IL-36 being secondary in HS? And does combination with an IL-17 or TNF backbone recover the partial single-agent signal, or does it add cost without changing the causal bottleneck?

Sources

1. • ClinicalTrials.gov, NCT06241573, Lunsayil long-term extension, TERMINATED, enrollment 39, primary completion 2025-04-11: https://clinicaltrials.gov/study/NCT06241573 - Phase 2a proof-of-concept RCT of spesolimab in moderate-to-severe HS (52 patients, 2:1, Week 12 lesion-count changes), Br J Dermatol 2024, NCT04762277: https://academic.oup.com/bjd/article/191/4/508/7641056 - Spesolimab, the first-in-class anti-IL-36R antibody: from bench to clinic, J Dermatol 2024: https://- Targeting IL-36 in inflammatory skin diseases (IL36RN genetics in GPP), BioDrugs 2023: https://- Therapeutic potential of IL-1 antagonism in hidradenitis suppurativa, Biomolecules 2024: https://- IL-1 family cytokines in inflammatory dermatoses, Int J Mol Sci 2022: https://- Off-label applications of spesolimab in inflammatory skin diseases, J Dermatolog Treat 2025: https://- Updated safety review of hidradenitis suppurativa treatment options (HS efficacy bar), Expert Opin Drug Saf 2025: https://- Open Targets, IL1RL2 to hidradenitis suppurativa association (overall 0.248, clinical 0.406, literature 0.048): https://platform.opentargets.org/evidence/ENSG00000115598/EFO_1000710 - openFDA FAERS, spesolimab reaction terms and serious case count (53): https://api.fda.gov/drug/event.json?search=patient.drug.medicinalproduct:spesolimab.