The IL-36 pathway: why it matters for inflammatory skin disease

The IL-36 pathway is a branch of the broader IL-1 superfamily of cytokine signalling, and its dysregulation drives a distinct class of neutrophil-rich, pustular inflammatory skin diseases that respond poorly to biologics designed for plaque psoriasis. Three pro-inflammatory agonist cytokines — IL-36α, IL-36β, and IL-36γ — bind the interleukin-36 receptor (IL-36R), a heterodimeric complex formed by IL-36R and the co-receptor IL-1RAcP. This binding recruits MyD88 adaptor protein and activates downstream NF-κB and MAPK signalling cascades, triggering keratinocyte activation, upregulation of antimicrobial peptides, and release of secondary mediators including IL-17, IL-8, and GM-CSF — all of which amplify neutrophil recruitment and the characteristic pustule formation seen in generalised pustular psoriasis (GPP).

A critical genetic observation underpins the therapeutic rationale: gain-of-function mutations in IL36RN — the gene encoding the endogenous antagonist IL-36Ra — are a validated monogenic cause of GPP. IL-36Ra normally competes with the agonist cytokines for IL-36R binding, dampening signal amplitude. When IL-36Ra function is lost, unopposed IL-36 signalling produces the explosive neutrophilic inflammation characteristic of a GPP flare. This human genetic validation, confirmed through multiple cohort studies published in journals indexed by Nature, provides the kind of mechanistic credentialing that drug developers and investors look for before committing to a biologic programme.

Beyond GPP, elevated IL-36 expression has been detected in lesional skin biopsies from patients with atopic dermatitis (AD), palmoplantar pustulosis (PPP), and hidradenitis suppurativa (HS), as well as in airway epithelium in asthma. This breadth of IL-36 involvement across diverse inflammatory conditions is what makes the IL-36R an attractive target for platform-style pipeline construction — a single antibody blocking a shared receptor can, in principle, address multiple diseases with a common pathogenic thread.

Spesolimab’s mechanism and the GPP approval that validated IL-36R as a target

Spesolimab is a humanised IgG1 monoclonal antibody that binds selectively to the extracellular domain of IL-36R, sterically blocking the binding of all three IL-36 agonist cytokines and thereby silencing the entire IL-36 signalling axis at the receptor level. Unlike cytokine-directed antibodies — which must individually neutralise each agonist — receptor blockade with spesolimab provides comprehensive pathway inhibition regardless of which IL-36 isoform predominates in a given disease context. This mechanistic breadth is a key commercial and scientific advantage for a programme targeting multiple indications.

“Receptor-level blockade with spesolimab silences all three IL-36 agonist cytokines simultaneously — a mechanistic breadth that cytokine-directed antibodies cannot replicate without combination dosing.”

The pivotal clinical evidence came from the Effisayil-1 trial, a randomised, double-blind, placebo-controlled Phase II/III study in adults experiencing a GPP flare. Spesolimab demonstrated rapid and significant clearance of pustules: at week 1, 54% of spesolimab-treated patients achieved a Generalised Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation sub-score of 0 (no visible pustules), compared with 6% of placebo patients. This dramatic early separation — driven by the speed of neutrophil-dependent pustule resolution — was the key efficacy signal that supported the FDA’s September 2022 approval under the brand name Spevigo. The approval was granted to Boehringer Ingelheim and made spesolimab the first biologic approved anywhere in the world that specifically targets the IL-36 pathway.

The subcutaneous maintenance formulation of spesolimab was subsequently studied in the Effisayil-2 trial, which evaluated whether regular subcutaneous dosing could prevent GPP flares from occurring — shifting the therapeutic paradigm from flare rescue to chronic disease prevention. This two-pronged approach (intravenous for acute flares, subcutaneous for maintenance) mirrors the strategy Boehringer Ingelheim has employed across its broader immunology portfolio and reflects the company’s intent to build spesolimab into a durable commercial franchise rather than a single-indication niche product.

Boehringer Ingelheim’s pipeline expansion: from GPP to atopic dermatitis and beyond

Boehringer Ingelheim’s decision to expand spesolimab beyond GPP rests on a growing body of translational evidence showing that IL-36 signalling is not confined to pustular psoriasis. The company has identified at least five indications where IL-36 pathway activation has been mechanistically implicated and where clinical development is either active or planned: generalised pustular psoriasis (approved), palmoplantar pustulosis (PPP), atopic dermatitis (AD), hidradenitis suppurativa (HS), and asthma.

Atopic dermatitis: the largest commercial opportunity

Atopic dermatitis represents the most commercially significant expansion target. AD affects approximately 10–20% of children and 1–3% of adults globally, according to data published by the World Health Organization, making it one of the most prevalent chronic inflammatory skin conditions worldwide. Transcriptomic and immunohistochemical studies of AD lesional skin have identified elevated IL-36γ expression, particularly in the acute and subacute phases of disease, suggesting that the IL-36 axis contributes to keratinocyte hyperactivation and the amplification of type-2 and type-17 inflammation that characterise AD. Boehringer Ingelheim has initiated clinical studies of spesolimab in AD, positioning the drug against an established but still-evolving competitive field dominated by dupilumab (anti-IL-4Rα) and the emerging JAK inhibitor class.

Palmoplantar pustulosis and hidradenitis suppurativa

Palmoplantar pustulosis, a chronic relapsing condition characterised by sterile pustules on the palms and soles, shares histological and molecular features with GPP — including elevated IL-36γ expression in lesional skin — making it a logical early expansion target for spesolimab. Hidradenitis suppurativa, a more complex and debilitating condition involving recurrent abscesses and sinus tracts in apocrine gland-bearing skin, has a more heterogeneous cytokine milieu but IL-36 expression has been detected in HS abscess tissue, providing a rationale for clinical investigation. Both conditions represent populations with high unmet need and limited approved biologic options beyond adalimumab (HS) and secukinumab (PPP).

Asthma: extending the IL-36 platform beyond dermatology

The inclusion of asthma in Boehringer Ingelheim’s spesolimab pipeline reflects emerging evidence that IL-36 cytokines are expressed in bronchial epithelium and may contribute to airway inflammation and remodelling. If validated clinically, an asthma indication would substantially broaden the addressable market for spesolimab and position Boehringer Ingelheim’s IL-36R franchise as a cross-tissue-type platform rather than a dermatology-specific asset. The company’s existing respiratory portfolio — which includes the LAMA/LABA combination tiotropium/olodaterol — gives it established commercial infrastructure in this therapeutic area.

The competitive landscape for anti-IL-36R and adjacent biologics

Spesolimab currently holds a first-mover advantage as the only approved anti-IL-36R biologic, but the competitive landscape is evolving rapidly. Izokibep, a small antibody fragment targeting IL-17A developed by Affibody/Acelyrin, and imsidolimab, an anti-IL-36R antibody from Anaptysbio, are among the assets in clinical development that compete directly or adjacently with spesolimab’s expansion indications. Imsidolimab in particular represents a direct mechanistic competitor, as it targets the same receptor as spesolimab; its clinical programme in GPP and AD will provide important comparative data on whether anti-IL-36R efficacy is class-wide or molecule-specific.

In the atopic dermatitis space, spesolimab faces a more established competitive environment. Dupilumab (Sanofi/Regeneron), which blocks the shared IL-4Rα receptor subunit used by both IL-4 and IL-13, remains the dominant biologic in moderate-to-severe AD with more than $10 billion in annual sales as reported in company filings. Tralokinumab (LEO Pharma), lebrikizumab (Eli Lilly), and the JAK inhibitors abrocitinib (Pfizer) and upadacitinib (AbbVie) have further fragmented the market. Spesolimab’s differentiation in AD will depend on demonstrating either superior efficacy in a specific AD endotype, a favourable safety profile relative to JAK inhibitors, or additive benefit in combination with existing standard-of-care agents. According to clinical guidelines from NIH-funded research consortia, AD endotyping is increasingly recognised as essential for matching patients to the most appropriate targeted therapy.

The patent landscape around IL-36R blockade is also relevant for competitive intelligence. Boehringer Ingelheim has filed composition-of-matter patents covering spesolimab’s antibody sequence, as well as method-of-treatment patents covering GPP and the expansion indications. Competitors seeking to develop anti-IL-36R antibodies must navigate this IP estate, and the expiry timeline of Boehringer Ingelheim’s core composition patents will shape the biosimilar entry window. Patent databases indexed by EPO and WIPO are the primary sources for tracking these filings across jurisdictions.

IP and R&D implications for the IL-36 axis

The validation of IL-36R as a drug target has generated a substantial and growing body of patent activity that extends well beyond Boehringer Ingelheim’s own estate. Understanding this landscape is essential for R&D teams evaluating whether to pursue anti-IL-36 programmes, for business development professionals assessing licensing opportunities, and for IP attorneys advising on freedom-to-operate in the IL-36 space.

Composition-of-matter vs. method-of-treatment claims

Boehringer Ingelheim’s core IP protection for spesolimab rests on composition-of-matter claims covering the antibody’s specific variable region sequences — the strongest form of patent protection for a biologic. These claims prevent competitors from making, using, or selling antibodies with the same or substantially similar sequences, regardless of the indication. Method-of-treatment claims, which cover the use of spesolimab in specific disease contexts, provide an additional layer of protection and are particularly relevant for the expansion indications: even if a competitor’s anti-IL-36R antibody has a different sequence, Boehringer Ingelheim’s method claims could cover the treatment of GPP, AD, or PPP with any anti-IL-36R antibody if the claims are drafted broadly enough. The scope and enforceability of such claims is a matter of active legal interpretation across jurisdictions.

Biomarker and patient selection patents

A strategically important category of secondary IP involves biomarker patents — claims covering the use of specific genetic markers (such as IL36RN mutation status), serum cytokine levels, or histological features to select patients most likely to respond to IL-36R blockade. As the spesolimab programme expands into heterogeneous conditions like AD and HS, where the IL-36 axis is one of several pathogenic drivers rather than the dominant mechanism, patient selection tools will become critical for demonstrating clinical efficacy in Phase III trials. Companies that file and prosecute biomarker patents in this space can create durable competitive moats that extend beyond the expiry of composition-of-matter claims.

Combination therapy opportunities

The multi-cytokine nature of AD and HS pathogenesis raises the question of whether IL-36R blockade will be most effective as monotherapy or in combination with agents targeting complementary pathways — for example, IL-4Rα blockade (dupilumab) for the type-2 component of AD, or TNF inhibition for the type-1/17 component of HS. Combination patents, which cover the co-administration of spesolimab with a second agent, represent a route to extending the commercial life of the franchise and creating new data packages that competitors cannot easily replicate. The PatSnap Life Sciences intelligence platform provides tools to map combination patent activity across the IL-36 and adjacent cytokine spaces, helping R&D and IP teams identify white spaces and potential freedom-to-operate risks before committing to clinical investment.

For drug hunters evaluating the IL-36 space from a competitive intelligence perspective, the key strategic questions are: which indications beyond GPP will spesolimab’s Phase III data read out first and with what effect size; whether imsidolimab’s clinical programme will confirm class-wide efficacy or reveal molecule-specific differentiation; and how Boehringer Ingelheim will position spesolimab’s safety profile relative to JAK inhibitors in the context of evolving regulatory guidance from agencies including the PatSnap Insights team continues to monitor. The answers to these questions will determine whether spesolimab becomes a multi-billion-dollar franchise or remains a well-validated but commercially narrow GPP asset.