What's the latest update on the ongoing clinical trials related to IL-36R?

Introduction to IL-36R
IL-36R, a receptor that binds the interleukin-36 (IL-36) family of cytokines, has emerged as a pivotal player in inflammation and immune regulation. Over the last decade, research has increasingly recognized its central role in orchestrating immune responses at epithelial barrier sites such as the skin, lung, and gut. IL-36R signaling controls a wide range of downstream processes—from the activation of nuclear factor-kappa B (NF-κB) and MAP kinase pathways to the induction of a diverse array of cytokines and chemokines. This receptor’s functional balance is critical for tissue homeostasis, and its dysregulation is now being linked to several inflammatory and fibrotic diseases including psoriasis, inflammatory bowel diseases, and even certain cancers.

Biological Role and Mechanism
IL-36R is a member of the IL-1 receptor family and binds three agonistic cytokines (IL-36α, IL-36β, and IL-36γ) as well as one natural antagonist, IL-36Ra, which competes for binding without eliciting a signal. Upon agonist binding, the IL-36R heterodimerizes with the IL-1 receptor accessory protein (IL-1RAcP), triggering a MyD88-dependent intracellular signaling cascade. This cascade leads to the activation of transcription factors such as NF-κB and MAP kinases, resulting in the production of proinflammatory mediators. Detailed structural and functional studies have elucidated that post-translational processing and glycosylation of IL-36 cytokines are essential for their full activity, and precise receptor–ligand interactions determine the amplitude and quality of the immune response.

IL-36R in Disease Pathogenesis
Dysregulated IL-36R signaling has been implicated in several chronic inflammatory conditions. For instance, in dermatological disorders like generalized pustular psoriasis (GPP) and palmoplantar pustulosis (PPP), overactivation of IL-36R signaling drives keratinocyte activation, neutrophil recruitment, and the downstream expression of a wide array of inflammatory cytokines, thereby perpetuating the inflammatory cascade. Similarly, in conditions such as inflammatory bowel disease (IBD) and tissue fibrosis, the IL-36/IL-36R axis influences both innate and adaptive immune responses, contributing to persistent inflammation and aberrant tissue remodeling. With these implications, IL-36R has become an attractive target for therapeutic intervention, and several companies have developed monoclonal antibodies to block its signaling.

Current Clinical Trials
The compelling role of IL-36R in multiple inflammatory disorders has sparked considerable interest in clinical development programs. These initiatives are focused on evaluating the safety, tolerability, pharmacodynamics, and therapeutic efficacy of IL-36R antagonists in a variety of conditions that are marked by excessive inflammatory responses.

Overview of Ongoing Trials
Multiple ongoing clinical trials are investigating IL-36R antagonists across different indications. The research focus is mainly on dermatological conditions such as generalized pustular psoriasis, palmoplantar pustulosis, and other skin disorders that are characterized by an overactive inflammatory milieu. For example, anti-IL-36R monoclonal antibodies such as spesolimab and imsidolimab have advanced into clinical trials, with several studies assessing their effect in controlling acute flares of GPP and the potential for preventing disease relapses over extended periods.

Other trials are evaluating the role of IL-36R blockade in non-cutaneous indications such as inflammatory bowel disease and even tissue fibrosis, following promising preclinical results that suggest IL-36 signaling may be integral to the fibrotic process in various organs. While the majority of clinical development has been concentrated on dermatological inflammatory diseases, ongoing clinical studies are expanding the scope to other therapeutic areas, reflecting the wide-ranging impact of the IL-36/IL-36R axis in human disease.

Key Trials and Their Objectives
Among the most notable clinical trials are those evaluating the efficacy and safety of spesolimab, an anti-IL-36R monoclonal antibody that has already demonstrated rapid and sustained responses in patients with GPP. In a proof-of-concept Phase I study, a single intravenous dose of spesolimab led to marked clinical improvement in GPP flares, with patients achieving significant reductions in disease scores maintained for several weeks. A subsequent Phase II/III program, exemplified by the GEMINI-1 trial initiated by ANAPTYSBIO (as detailed in their 2021 Annual report), aims to confirm these findings in a larger patient cohort, with secondary objectives targeting quality-of-life measures and long-term disease control.

Parallel clinical studies are also underway with imsidolimab. This agent is being tested in Phase 3 trials not only in GPP but also in moderate-to-severe acne and hidradenitis suppurativa. Key objectives for these trials include evaluating the time to flare resolution, sustained clinical improvement, and the safety profile of IL-36R blockade over extended treatment durations. Top-line data from the acne trial were anticipated in early 2022, while data from the hidradenitis suppurativa trial were expected in the latter half of the year, indicating a broadening of IL-36R-targeted therapy beyond traditional psoriasis.

Furthermore, preclinical-to-clinical translational studies—such as those involving the anti-human IL-36R antagonist monoclonal antibody MAB92 and its mouse cross-reactive counterpart MAB04—have provided valuable insights into pharmacokinetics and receptor binding dynamics. These studies have contributed to optimizing dosing regimens and understanding interspecies differences that may influence clinical outcomes.

Findings and Implications
The results emerging from ongoing clinical trials and supporting translational studies are starting to clarify the potential of IL-36R antagonism as a novel therapeutic strategy in inflammatory diseases.

Interim Results and Data
Interim outcomes from clinical trials with IL-36R antagonists are encouraging, particularly in the context of GPP. Spesolimab has been shown to induce rapid resolution of skin lesions in patients experiencing acute flares, with many patients achieving a Generalized Pustular Psoriasis Physician Global Assessment score of 0 or 1 within just one week of treatment. This rapid response underscores the drug’s potent anti-inflammatory action through direct modulation of the IL-36/IL-36R axis. Such results are notable given the traditionally challenging treatment landscape of GPP, where systemic corticosteroids and other immunomodulatory agents have been the mainstay therapies with mixed efficacy and significant side effects.

Interim data from imsidolimab trials similarly indicate robust clinical responses. In the GEMINI-1 study, the Phase 3 trial designed for GPP, patients have shown significant improvement in both clinical symptoms and biomarkers indicative of reduced inflammatory activity. For instance, reductions in key proinflammatory cytokines and chemokines that are otherwise elevated in active disease states have been observed, suggesting that IL-36R blockade not only alleviates clinical symptoms but also addresses underlying pathophysiological mechanisms.

From a pharmacokinetic perspective, innovative retrospective model-based predictions of human PK for MAB92 have validated the modeling approach and revealed that integrating target-specific parameters and RNA transcriptome data improves predictability. These findings help inform dosing strategies as well as interspecies translational modeling, critical for bridging preclinical insights to human pharmacodynamics.

Potential Clinical Implications
The emerging data from these trials imply several potential clinical benefits:
- Rapid Onset of Action: The fast response observed in GPP patients treated with spesolimab suggests that IL-36R blockade may offer rapid relief in acute inflammatory episodes, potentially transforming the therapeutic approach in diseases marked by sudden flares.
- Sustained Disease Control: The ability to prevent flares over extended observation periods, as indicated in ongoing trials, implies that IL-36R-targeted therapies could maintain long-term disease remission. This is particularly relevant for chronic inflammatory diseases where sustained control is necessary to prevent tissue damage and improve patient quality of life.
- Broad Therapeutic Applicability: While initial clinical development has been dermatologically focused, the potential extension of these therapies into indications such as inflammatory bowel disease and tissue fibrosis reveals a broader applicability. Given that IL-36R signaling is involved in both pro-inflammatory and fibrotic processes, these therapies might benefit patients with comorbid conditions and reduce overall healthcare burden.
- Favorable Safety Profile: Thus far, IL-36R antagonists appear to be well tolerated in clinical settings. Although some patients have developed anti-drug antibodies or encountered mild adverse effects, the overall safety signals are promising compared to older systemic therapies that have considerable adverse effect profiles.

Collectively, these findings herald a paradigm shift in the management of inflammatory diseases by directly interfering with an upstream driver of immune activation, thereby offering the possibility of more precise and effective disease modulation.

Future Directions and Challenges
Despite the promising interim outcomes, several key questions remain unanswered, and the field faces challenges that will shape future clinical development and research of IL-36R-targeted therapies.

Unresolved Questions
- Long-Term Safety and Immunogenicity: Although early data support a favorable safety profile, long-term studies are required to better understand the immunogenicity of IL-36R antagonists. The development of anti-drug antibodies, as noted in some studies, must be monitored over extended periods to determine if they compromise efficacy or lead to unexpected adverse events.
- Biomarker Identification and Patient Stratification: There is a need to identify robust biomarkers that can predict response to IL-36R blockade. With IL-36 pathway dysregulation observed in a subset of patients with GPP and potentially other inflammatory conditions, stratifying patients based on genetic mutations (e.g., in IL36RN) or circulating cytokine levels could optimize clinical outcomes.
- Mechanistic Insights in Non-Cutaneous Diseases: While the role of IL-36R in skin inflammation is becoming clearer, its involvement in other tissues such as the gut and liver (in fibrosis) requires further investigation. Understanding how IL-36R signaling integrates with other inflammatory pathways in non-cutaneous sites is essential for expanding the therapeutic indications.
- Dose Optimization and Treatment Regimens: The ideal dosing regimens for achieving both rapid flare resolution and sustained remission are still being refined. Studies that incorporate advanced pharmacokinetic/pharmacodynamic modeling are crucial to optimizing these parameters, particularly in light of interspecies differences noted in preclinical models.

Future Research Directions
Future clinical research on IL-36R antagonists is likely to follow several trajectories:

- Expanded Indications: Clinical trials are expected to expand beyond dermatological conditions. Given the involvement of IL-36R in tissue fibrosis and inflammatory responses in organs such as the lung, kidney, and intestine, upcoming trials may investigate these areas. This expansion will not only validate the IL-36/IL-36R axis as a universal mediator of inflammation but also open therapeutic avenues for chronic diseases that currently lack effective treatments.
- Combination Therapy Strategies: There is growing interest in combining IL-36R antagonists with other immunomodulatory agents to enhance efficacy. For example, combining these drugs with agents that target the IL-23/IL-17 axis, which is also central to psoriasis pathogenesis, might offer synergistic benefits. Such combination therapies could potentially address multiple disease mechanisms simultaneously, thereby achieving better clinical outcomes.
- Precision Medicine Approaches: As the understanding of IL-36 signaling deepens, personalized therapeutic approaches based on genetic and molecular profiling of patients will likely emerge. This could involve selecting patients with specific mutations in IL36RN or those with high circulating levels of IL-36 cytokines to ensure that therapy is tailored to those most likely to benefit. Such stratification could improve response rates and reduce unnecessary exposure in non-responders.
- Mechanistic and Translational Studies: Further translational research is required to fully elucidate the receptor’s structure–function relationships, particularly how mutations, post-translational modifications, and receptor interactions influence clinical responses. Mechanistic studies that bridge the molecular insights from preclinical models to the clinical observations will inform the next generation of IL-36R inhibitors.
- Longitudinal and Real-World Evidence: Beyond randomized controlled trials, gathering long-term and real-world evidence on efficacy, safety, and patient-reported outcomes will be critical in establishing the role of IL-36R antagonists in routine clinical practice. Registries and post-market surveillance will provide valuable information to refine treatment guidelines over time.

Conclusion
In summary, the latest updates on ongoing clinical trials related to IL-36R reflect a dynamic and rapidly evolving field. The current clinical programs, principally centered on dermatological conditions such as generalized pustular psoriasis and palmoplantar pustulosis, have demonstrated promising early efficacy with rapid onset of action and sustained remission following IL-36R blockade. Groundbreaking Phase I and Phase II/III studies with anti-IL-36R monoclonal antibodies like spesolimab and imsidolimab are establishing a new therapeutic paradigm by targeting an upstream mediator of inflammation. Moreover, strong translational and PK modeling studies, as exemplified by research with MAB92 and MAB04, are providing confidence in dosing strategies and offering insights to guide subsequent phase trials.

Clinical implications of these findings suggest that IL-36R-targeted therapies may offer rapid relief, improved long-term disease management, and broad applicability to other inflammatory conditions such as inflammatory bowel disease and tissue fibrosis. Nevertheless, challenges remain. Long-term safety, the identification of predictive biomarkers, dose optimization, and the expansion of indications into non-cutaneous fields are key areas for future research. Moreover, there is a compelling need for mechanistic studies to further understand the interplay between IL-36R signaling and other inflammatory pathways, as well as for combination therapy strategies that may enhance overall therapeutic benefit.

Through a combination of rigorous clinical trial designs, personalized medicine approaches, and ongoing translational research, the IL-36/IL-36R axis looks set to become an important target in the treatment of inflammatory diseases. Continued collaboration between industry, academia, and regulatory bodies will be essential to transform these promising early results into widely available, effective therapies for patients suffering from chronic and debilitating inflammatory conditions.

In conclusion, the latest clinical trials on IL-36R have not only validated the biological relevance of this receptor in mediating inflammatory responses but have also paved the way for innovative treatment strategies that are beginning to show impressive clinical results. With multiple trials in advanced phases, the field looks forward to a future where IL-36R antagonists may fundamentally alter the management landscape of inflammatory diseases, offering patients new hope for rapid, effective, and sustained relief.