What drugs are in development for Hidradenitis Suppurativa?

Introduction to Hidradenitis SuppurativaDefinitionon and Symptoms
Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by recurrent painful nodules, deep-seated abscesses, draining sinus tracts, and eventual scarring. The condition most frequently affects intertriginous regions such as the axillae, groin, inframammary areas, and buttocks. Patients typically suffer from persistent pain, malodorous discharge, and significant disfigurement, which in combination lead to social stigma and reduced quality of life. Several studies have indicated that while the disorder was once considered rare, its prevalence may be in the range of 0.2% to 4% worldwide, with a strong female predominance and onset usually after puberty.

Current Treatment Landscape
Traditionally, HS management has relied on nonbiologic medical therapies that include antibiotics, systemic anti-inflammatory drugs (such as corticosteroids) and hormonal therapies, and surgical options when medical management fails. Adalimumab, a TNF-α inhibitor, has been the only FDA-approved biologic in the United States for moderate-to-severe HS since 2015. However, real-world outcomes show that only about 50% of patients achieve clinical response with adalimumab. Given the chronic-recurrent nature of HS and the limited long-term efficacy of conventional treatments, there is a high unmet need for novel therapeutics aimed at new inflammatory pathways or offering improved efficacy/safety profiles.

Drugs in Development

Overview of Drug Development Process
The drug development process for HS predominantly focuses on immune modulation and targeting specific inflammatory cytokines. In preclinical studies, researchers have identified various molecular signals such as IL-1, IL-17, IL-23, and components of the complement cascade as key drivers in HS pathogenesis. Based on these discoveries, a number of drugs have advanced to Phase 2 and Phase 3 clinical trials. The pipeline includes both biologics (monoclonal antibodies and nanobodies) and small molecule inhibitors, with the development process evaluated in randomized controlled trials to determine efficacy using clinically relevant endpoints (for example, HiSCR, or Hidradenitis Suppurativa Clinical Response) and patient-reported outcomes. Importantly, many of these clinical investigations also try to overcome issues such as high placebo response rates by refining clinical scores and targeting additional hallmarks like draining tunnels and abscess counts.

Current Drugs in Clinical Trials
Several drugs are driving innovation in the field of HS. The current candidates in clinical development include:

• Sonelokimab – A next-generation nanobody targeting IL-17A and IL-17F has been evaluated in a Phase 2 study (often labeled as MIRA) using HiSCR75 as the primary endpoint. Early data have shown that sonelokimab can elicit robust anti-inflammatory responses and, because of its novel Nanobody® design, may offer improved tissue penetration and a favorable safety profile compared to conventional monoclonal antibodies.

• Bimekizumab – This biologic is a dual inhibitor of IL-17A and IL-17F. Phase 2 and Phase 3 data indicate that bimekizumab provides improvements in HiSCR and quality-of-life metrics in patients with moderate-to-severe HS, with some studies suggesting that it achieves clinical responses superior to placebo. While bimekizumab has been successfully used in psoriasis, its application in HS is still being refined.

• Povorcitinib (INCB054707) – A Janus kinase (JAK) 1 inhibitor, povorcitinib has been studied in a randomized, placebo-controlled Phase 2 trial in HS patients. It is designed to block JAK1-mediated signaling, which is implicated in the cytokine cascade of HS. Early trial results presented evidence of dose-ranging efficacy and acceptable safety profiles, with the drug reducing abscess and inflammatory nodule counts and improving quality-of-life scores.

• LTA4H Inhibitors – These compounds target leukotriene A4 hydrolase (LTA4H), an enzyme involved in neutrophilic inflammation. Two separate patents have been filed describing LTA4H inhibitors as a novel therapeutic approach. Although clinical data are still emerging, these inhibitors promise to modulate neutrophilic chemotaxis and reduce the inflammatory burden in HS.

• IL-1 Inhibitors (e.g., Bermekimab) – Bermekimab, a monoclonal antibody targeting IL-1α, has shown encouraging results in two clinical trials. Although not every HS patient responds equally, bermekimab has reduced lesion counts and inflammation in some studies, making IL-1 inhibition an attractive target in the setting of HS beyond the currently approved anti-TNF agents.

• Other Emerging Targets – There are also drugs that target complementary pathways and newer markers emerging from translational research. Some examples include:
  – CD38 antagonists. One recently disclosed patent suggests that therapeutic inhibition of CD38 could be beneficial, potentially by reducing pro-inflammatory cellular interactions.
  – IL-36 inhibitors, such as spesolimab – though the clinical trial results are pending, this approach is based on the role of IL-36 in neutrophil recruitment and skin inflammation, fitting within the autoinflammatory concept of HS.
  – Anti-complement therapies – Targeting complement component 5a (C5a) or its receptor has been explored, especially in patients with severe HS, though clinical benefits have been less consistent than with cytokine-targeting agents.
  – Other JAK inhibitors – While povorcitinib is the prominent agent currently in HS trials, additional JAK inhibitors are under early-phase investigation to broaden the spectrum of cytokine blockade.

Mechanisms of Action

Biological Targets for Hidradenitis Suppurativa
The pathogenesis of HS has been linked with multiple inflammatory mediators. Several key targets have been identified:

• TNF-α – Inhibition of TNF-α via agents like adalimumab remains the cornerstone of current biologic therapy. However, due to variability in patient response, alternatives targeting other nodes in the inflammatory network are needed.

• Interleukin (IL)-17 – Both IL-17A and IL-17F have been implicated in the downstream cascade that leads to keratinocyte hyperproliferation and neutrophilic inflammation. Drugs such as secukinumab and bimekizumab directly block these cytokines. The novel nanobody sonelokimab further expands the therapeutic options by offering dual IL-17A/17F inhibition with potentially enhanced tissue penetration.

• IL-1 – IL-1α, a pivotal switch in initiating and propagating inflammation in HS, is targeted by agents such as bermekimab and anakinra in early-phase trials. Although these drugs have shown promise in reducing inflammatory lesion counts, further investigation is needed to confirm long-term efficacy.

• JAK-STAT Pathway – Dysregulation of the JAK-STAT signaling pathway leads to an amplification of inflammatory cytokine production. Inhibitors such as povorcitinib are designed to interrupt these signals selectively, thereby reducing inflammation in HS lesions.

• Leukotriene A4 Hydrolase (LTA4H) – By inhibiting LTA4H, these agents aim to reduce the generation of pro-inflammatory leukotrienes, which mediate neutrophil chemotaxis and activation—a crucial aspect of HS pathology.

Innovative Approaches
Beyond targeting established cytokines, innovative therapeutic strategies are being explored:

• Nanobody Technology – Sonelokimab is an example of a nanobody, a small antibody fragment that combines stability and deep tissue penetration with the ability to block multiple cytokines. Its design offers potential advantages such as reduced immunogenicity and improved administration schedules.

• Broad Immune Modulation – Drugs under development are increasingly designed to target multiple nodes within the inflammatory cascade simultaneously. For instance, bimekizumab’s dual inhibition of IL-17A and IL-17F offers a broader blockade against the IL-17 inflammatory axis than single-target antibodies.

• Combination Strategies – In some clinical trial designs, drugs in development are being used in combination with surgical interventions or as adjuncts to established therapies. For example, studies exploring neoadjuvant biologic therapy (with adalimumab) before surgical excision have revealed potential synergies in reducing recurrence rates and improving healing times.

• Targeting Novel Molecules – Additional approaches include targeting CD38, implicated in immune cell activation, and blocking IL-36, which has a strong association with neutrophilic inflammation. These molecules represent newer avenues that might improve outcomes for patients who do not respond to conventional immunomodulators.

Clinical Trial Insights

Key Clinical Trial Phases and Results
The stage of clinical development for HS drug candidates varies:

• Phase 1/2 Trials – Early-phase trials aim to assess safety, tolerability, pharmacokinetics, and preliminary efficacy. Drugs like povorcitinib, sonelokimab, and early IL-1 inhibitors have been evaluated in this phase with promising results in terms of dose‐dependent reduction in abscess and inflammatory nodule counts, as measured by HiSCR. These trials are crucial for establishing a safe starting dose and identifying early signals of clinical benefit.

• Phase 2b/3 Trials – More advanced trials, such as those conducted for bimekizumab and sonelokimab, are designed to test the therapeutic efficacy against placebo and to compare active treatments in larger cohorts. For example, trials using HiSCR thresholds (e.g., HiSCR50 and HiSCR75) as primary endpoints have shown that these novel agents can significantly reduce the inflammatory burden compared with placebo. The use of multiple endpoints, including DLQI and IHS4 scores, has helped to establish a more comprehensive picture of drug efficacy.

• Combination Therapy Trials – There are also studies that evaluate drug efficacy in combination with other interventions. One study compared recurrence rates after surgery between patients receiving neoadjuvant biologic therapy and those managed with surgery alone. Results indicate that biologic therapy may improve some surgical outcomes, though issues like prolonged healing times can arise.

Regulatory Challenges and Approvals
Regulatory agencies worldwide have been evaluating the promising candidates for HS with varying levels of success:

• Adalimumab – Although not in development now (being the first approved agent), its variable clinical response spurred the development of next-generation agents. The approval of adalimumab was based on pivotal Phase 3 trials that demonstrated HiSCR improvements; however, approval differences between regions have led to ongoing efforts to identify drugs with more consistent efficacy profiles.

• Expanding Labels – Recently, Cosentyx (secukinumab) has received an expanded label from the FDA to include HS, thereby introducing competition from agents with alternative mechanisms (IL-17A blockade). Such regulatory decisions encourage further investigations of similar agents.

• Approval Pathways for Innovative Modalities – The emergence of nanobodies (such as sonelokimab) and small molecules (like povorcitinib) has necessitated careful regulatory consideration of their unique pharmacologic profiles. Regulatory authorities are placing emphasis on robust clinical trial endpoints (such as HiSCR75) and comprehensive patient-reported outcome measures when assessing these novel treatments.

• Bridging Evidence Gaps – Many trials are designed not only to demonstrate efficacy but also to address heterogeneity in clinical responses by capturing detailed clinical endpoints (e.g., changes in draining tunnels, abscess counts, and quality-of-life measures). High-quality randomized controlled trials (RCTs) and meta-analyses are required to provide the evidence numbers agencies need to approve these new therapies.

Future Directions and Research Opportunities

Emerging Therapies
Novel therapies for HS remain a vibrant field with several promising candidates on the horizon:

• Dual Cytokine Inhibitors – Drugs like bimekizumab, with dual action on IL-17A and IL-17F, represent a trend toward broader anti-inflammatory activity that may translate into improved clinical outcomes for HS patients who do not benefit sufficiently from single-cytokine blockade.

• Nanobody-Based Agents – The development of sonelokimab marks a new era in biologics utilizing nanobody technology. This innovative design permits simultaneous blockade of multiple cytokines while potentially minimizing adverse reactions, positioning it as one of the most promising agents in the pipeline.

• Targeting Inflammatory Enzymes and Novel Receptors – LTA4H inhibitors, CD38 antagonists, and IL-36 inhibitors are among the emerging candidates that aim to modulate unique aspects of HS pathogenesis. While data remain preliminary, targeting these molecules provides opportunities to affect neutrophil recruitment and immune cell activation in novel ways.

• JAK Inhibitors – With the success of povorcitinib in early trials, further exploration of the JAK-STAT pathway in HS is underway. This modality could be particularly useful in patients with a pronounced systemic inflammatory profile, providing an oral alternative to injectable biologics.

Gaps in Current Research
Despite these advances, several gaps remain that drive future research priorities:

• Clinical Heterogeneity and Endpoints – HS is a highly heterogeneous disease and existing clinical endpoints such as HiSCR, while widely used, may not capture all aspects of improvement or disease burden (for instance, drainage tunnels or pain scores). There is a need for standardized, universally accepted outcome measures that incorporate both objective and subjective parameters.

• Long-Term Safety and Efficacy – Many current trials are of relatively short duration (weeks to months). Given the chronic nature of HS, long-term studies are essential to assess sustained efficacy, development of anti-drug antibodies, and safety over years, rather than months. This is particularly true for novel modalities that use advanced protein engineering techniques such as nanobodies.

• Patient-Reported Outcomes – Incorporating patient perspectives through rigorous quality-of-life metrics remains a challenge. Future studies should expand the use of validated patient-reported outcome tools alongside clinical measures such as IHS4 and DLQI, thus ensuring that treatments not only reduce clinical lesion counts but also meaningfully improve daily functioning and wellbeing.

• Biomarker Development – There is a significant need for biomarkers that can predict response to specific therapies. This would enable a more personalized approach in a field currently characterized by trial-and-error treatment methods. Investigations into the molecular signature of HS lesions and systemic inflammatory markers might pave the way for patient stratification in clinical trials.

• Combination Therapy Approaches – While several biologics are being developed as monotherapies, there is growing interest in combining systemic therapies with surgical interventions or other modalities. Trials exploring neoadjuvant strategies or the use of biologics as maintenance therapy following surgical excision are still in early stages, and more research is required to define optimal protocols.

• Economic Evaluations and Accessibility – As more expensive biologics enter the market, studies should also focus on cost–benefit analyses and real-world effectiveness. Access disparities remain a significant barrier in many regions, and health economic studies will be critical in supporting future approval and reimbursement decisions.

Detailed Conclusion

In summary, the pipeline for drugs in development for Hidradenitis Suppurativa is robust and multifaceted. The current landscape extends far beyond the sole TNF-α inhibitor adalimumab, incorporating innovative biologics such as sonelokimab and bimekizumab, targeted small molecule inhibitors like povorcitinib, and emerging candidates working through novel mechanisms including LTA4H inhibition, IL-1 blockade, and even CD38 antagonism. These agents are being developed through an iterative process that incorporates state‐of‐the-art clinical trial design, evolving clinical endpoints, and a deeper understanding of HS pathogenesis gleaned from translational studies.

The drug development process is rigorously tested in Phase 1 through Phase 3 trials, with early-phase studies demonstrating promising dose-dependent efficacy and acceptable safety profiles, and more advanced studies beginning to confirm clinical benefits using endpoints such as HiSCR75, improvements in quality-of-life indices and objective lesion counts. Innovative approaches, including nanobody technology, dual cytokine inhibition and combination therapy regimes, mark a new era in HS therapeutics that aims to address the significant unmet medical needs in this debilitating condition.

Various regulatory challenges persist, notably the need for standardized outcome measures and the demonstration of long-term safety and efficacy in a chronic condition. Nevertheless, recent regulatory approvals (for example, the expansion of the Cosentyx label to include HS) underscore that progress is being recognized and that future drugs may soon join the limited arsenal available for this disease.

Finally, future research must continue to explore emerging therapies while addressing current gaps: there is a clear call for precise biomarkers, longer-duration studies, and standardized patient-reported outcome tools to help refine treatment selection. Advancements in novel targets such as IL-36, CD38, and further JAK inhibitors provide promising yet underexplored avenues. Moreover, combination therapies integrating surgical approaches with systemic biologics may ultimately redefine best practices for management.

The convergence of these diverse drug development strategies, clinical trial insights, and emerging research priorities suggests that the future of HS treatment is poised to become more personalized and effective, thereby improving clinical outcomes and quality of life for a patient population that has historically had very few satisfactory treatment options. This multi‐layered development process and the depth of research underscore an optimistic future for HS therapy and set the stage for a significant transformation in how this chronic inflammatory condition is managed worldwide.

Each candidate and pathway brings its own set of challenges, but together they represent a broad-based attack on the complex immunopathology of HS. Continued collaboration between researchers, clinicians, and industry partners (as evidenced by multiple clinical trial results and patents) will be essential to bring these drugs from development into clinical practice and ultimately expand the therapeutic landscape for HS.

In conclusion, drugs in development for Hidradenitis Suppurativa span a wide spectrum—from innovative nanobody constructs to novel small molecule inhibitors and cytokine blockers—each targeting different aspects of the dysregulated immune response that underlies the disease. These multifaceted approaches, combined with emerging insights from long-term clinical trials and patient-centered research, provide hope for more effective and durable therapies. Future research priorities include refining clinical endpoints, establishing biomarkers for personalized treatment, and exploring the potential of combination regimens, all of which are critical to fully addressing the unmet needs of HS patients.