IL-17

The family of interleukin-17 (IL-17) cytokines (IL-17A-F) signal through multiple IL-17 receptors formed from six unique IL-17 receptor subunits that exist as homodimers or heterodimers. While not critical for differentiation, IL-23 plays an important role in sustaining T _H 17 differentiation and promoting IL-17 and IL-22 production. In addition, IL-17A and IL-17F act synergistically with IL-1 and TNF-α to augment and perpetuate the inflammatory cascade triggered by these pro-inflammatory cytokines. IL-17A activates keratinocyte proliferation and produces AMPs and numerous neutrophil-attracting chemokines, including IL-8 (also referred to as CXCL8). IL-17F has similar functions biologically as IL-17A, signaling through the same receptor and forming a heterodimeric complex with IL-17A. Multiple studies have demonstrated significantly increased IL-17 levels in HS lesions and perilesional tissue, compared to control skin. ²⁹ The elevated levels of IL-17 in perilesional tissue may suggest an early role in HS pathogenesis. In addition, IL-17 has also been found to be elevated in the serum of HS patients, which correlates with disease activity.

Secukinumab is a human IgG1 monoclonal antibody that binds IL-17A, preventing its interaction with the IL-17 receptor. Initially, several case reports were published demonstrating benefit to HS patients. However, an in vitro study using HS skin lesions showed that secukinumab did not significantly lower overall cytokine (TNF-α, IFN-γ, IL-1β, IL-6, and IL-17A) levels compared with prednisolone, TNF-α inhibitors, or ustekinumab. More recently, there has been increased enthusiasm for this approach after three open-label 16- to 24-week prospective studies for moderate to severe HS demonstrated benefit, with 67% to 75% achieving HiSCR. Two core phase III multicenter, randomized, double-blinded placebo-controlled studies with two secukinumab dose regimens (300 mg every 2 or 4 weeks) are currently underway for moderate to severe HS. A randomized withdrawal extension study for the two core trials is already recruiting. The goal of the study is to assess the long-term maintenance of HiSCR out to week 104. Those participants that achieve HiSCR by week 52 of the two core studies will be randomized (2:1) to continue their regimen or placebo until week 104 to evaluate the loss of response. Those participants that either did not achieve HiSCR by week 52 in the core studies or lose response in the extension trial or complete the 104-week extension trial maintaining HiSCR will be offered to enroll in the open-label treatment study to week 260.

CJM112 is a fully human IgG1 monoclonal dual anti-IL-17A and anti-IL-17F antibody. It has higher potency compared with secukinumab, achieving similar results for psoriasis, but at significantly lower doses. In addition, in vitro studies have demonstrated that dual IL-17A/F inhibition significantly lowers inflammatory mediators more than either IL-17A or IL-17-F alone. Recently, a phase II randomized placebo-controlled trial for HS showed 32% (10/32) participants had a two-point drop in HS physician global assessment (HS-PGA) score, compared to only 12.5% (4/32) in the placebo group.

Bimekizumab is also a human IgG1 monoclonal dual anti-IL-17A/F antibody. Phase II proof-of-concept and dose-ranging studies have already shown significant improvements in both plaque psoriasis and psoriatic arthritis at higher doses compared to controls. A phase II randomized, double blind trial comparing two different doses of bimekizumab against adalimumab and placebo was recently completed. Results from this study have not been released, but two phase III randomized, placebo-controlled trials are currently being planned.

Brodalumab is a human monoclonal IgG2 antibody that binds with high affinity to the IL-17 receptor A, competitively inhibiting IL-17A, C, E, and F. As the responses to direct IL-17A inhibition with secukinumab can take up to 12 to 24 weeks for HS, the faster response rates seen for brodalumab in psoriasis makes it an attractive potential treatment for HS. Initially, a case report of brodalumab for HS showed rapid improvement in draining tunnels, global assessment, and quality of life over 12 weeks. More recently, results from an open-label early Phase I study of 10 participants with moderate to severe HS showed that using the FDA-approved dose for psoriasis resulted in all 10 participants achieving HiSCR by 12 weeks. Although there is a black box warning for suicidal ideation and behavior for brodalumab, no episodes of self-harm or suicidality were experienced by HS patients in this small study.

IL-12/23

Interleukin-12 (IL-12) and interleukin-23 (IL-23) are cytokines secreted by macrophages and dendritic cells in response to wound healing and infection. While IL-12 promotes T _H 1 cell differentiation of naïve CD4 T cells, IL-23 contributes to the IL-17 producing T helper (T _H 17) cell response. Both cytokines are highly expressed by infiltrating macrophages in lesional HS skin, and share a p40 subunit. IL-12 is a heterodimer composed of the IL-12p40 and IL-12p35 subunits which signal through the IL-12 receptor. IL-23 is a heterodimer composed of the IL-12p40 and IL-23p19 subunits that bind to the IL-23 receptor and signal through the JAK/STAT pathway. IL-23 has become a therapeutic target for both HS, psoriasis, and Crohn’s disease, three conditions with mechanistic as well as clinical overlap. Ustekinumab, an IL-12/23 inhibitor, has been FDA approved for the treatment of Crohn’s disease, while the data supporting its use in HS are less substantial. Ustekinumab has been shown to inhibit HS-related cytokine production in vitro. In addition to several case reports and case series suggesting benefit, moderate-to-marked improvements of the modified Sartorius score were seen in 82% of patients in a small open-label study of ustekinumab in 17 HS patients. More recent case series have suggested more frequent and higher doses of ustekinumab, with an initial intravenous infusion, may be of added benefit.

Recently, rizankizumab, a high-affinity monoclonal antibody to the p19 subunit of IL-23, demonstrated significantly increased rates of clinical remission of Crohn’s disease compared to placebo. They used doses of 600 mg intravenous infusion monthly, much higher than the FDA-approved dosing for psoriasis. Now there is increased interest in IL-23 specific antibodies for the treatment of HS. Currently, a phase II multicenter randomized double blinded placebo-controlled study is underway, evaluating the efficacy of rizankizumab at two dose levels for moderate to severe HS.

A similarly designed trial for HS is also starting for another IL23 p19 monoclonal antibody, guselkumab, at doses of 200 mg subcutaneously every 4 weeks, more than double the FDA-approved psoriasis dosing. One case report and a small case series of eight patients receiving guselkumab suggested benefit, with ~ 60% of patients demonstrating improvement over 2–4 months with typical psoriasis doses.

IL-1α/β

IL-1α and IL-1β contribute to the initiation of an immune response through a shared IL-1 receptor (IL-1R). IL-1R-associated kinase 4 (IRAK4) gets recruited to the internal domain of the IL1-R, resulting in downstream activation of pro-inflammatory transcription factors such as nuclear factor-kappa B (NF-κB). This results in the production of inflammatory mediators (i.e., IL-6), potent neutrophil chemoattractants (including G-CSF and IL-8), and MMPs. In addition, IL-1 receptor signaling results in increased production of both IL-1α and IL-1β, resulting in a positive feedback loop. IL-1α is constitutively expressed and actively secreted by many cells, most notably, myeloid cells, endothelial cells, and keratinocytes. Moreover, IL-1α can activate its receptor while membrane-bound or through apoptotic bodies released after cell damage or death. Release of IL-1β from macrophages and dendritic cells; on the other hand, is mediated by caspase-1, which, in its inactive form, is a component of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. In order to be activated, the IL-1β precursor must be cleaved by caspase-1. The IL-1 receptor signaling cross-talks with various inflammation pathways, including interactions with Th17 and type I interferon signaling. IL-1α and IL-1β act synergistically with IL-23 on T cells to produce IL-17. Type I interferons antagonize IL-1 signaling via suppression of IL-1α and IL-1β transcription, as well as several indirect mechanisms.

The role of IL-1—especially IL-1α—has become of increasing interest recently in the pathogenesis of HS. While some conflicting data exist, several studies have demonstrated overexpression of IL-1β in lesional and perilesional HS skin compared to controls. Similarly, elevated levels of IL-1α and IL-1β have been seen in pus from HS lesions. Increased serum levels of IL-1β in HS patients have also been reported.

Anakinra, a competitive antagonist of the shared IL-1 receptor, has demonstrated efficacy in case reports, case series, and a small randomized, placebo-controlled trial of 20 patients with severe HS. Retrospective analysis of this trial revealed 78% of anakinra patients versus 30% of placebo patients achieved HiSCR at 12 weeks. Currently, anakinra is recommended as third-line treatment consideration after failed response to TNF-α inhibitors. While anakinra has demonstrated some benefit in HS, canakinumab, a monoclonal antibody specifically targeting IL-1β, has had much more conflicting data.

Current clinical trials targeting IL-1 include bermekimab (previously known as MABp1), an anti-IL-1α monoclonal antibody which has shown promising results for HS. In a randomized placebo-controlled small study of 20 patients with moderate HS refractory to TNF-α inhibition, 60% of HS patients achieved HiSCR compared to only 10% in the placebo group. Similar responses were seen in a larger, multicenter, phase II open-label study of 42 patients with HS, with ~ 60 achieving HiSCR, with no difference between those that had failed TNF-α and those that were TNF-α inhibitor naïve. It has been proposed that its efficacy may be linked to its roles in both angiogenesis, as well as upregulation of human beta-defensin 2. A phase II clinical trial with bermekimab is currently ongoing.

PF-06650833, a small molecule inhibiting IL-1 receptor-associated kinase 4 (IRAK4), is also currently being investigated as a target for HS. Presently, a phase II, double-blind, randomized, placebo-controlled clinical trial is examining the efficacy and safety of PF-06650833 in moderate to severe HS alongside two other JAK family inhibitors.