Abstract
Hidradenitis suppurativa (HS) is an oftentimes debilitating condition that presents with painful nodules, abscesses, and sinus tracts. This condition is challenging to treat, in part because the pathogenesis of the condition is incompletely understood but also because there are limited therapeutic options. HS research is undergoing explosive growth with multiple new molecular pathways under study, which will hopefully lead to improved disease control for patients. Part I of this review will provide an overview of the emerging topical and systemic therapies under investigation for HS.
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Hidradenitis suppurativa (HS) has a devastating impact on patients’ lives, and existing treatment options are limited. |
The number of HS clinical trials has increased rapidly over the past few years. |
Topical treatments under investigation include a Janus kinase (JAK) inhibitor, an aryl hydrocarbon receptor inhibitor, a lytic peptidomimetic, gentian violet, and povodine-iodine. |
New systemic treatment pathways are also being studied such as interleukin (IL)-17 inhibition, IL-36 inhibition, Tyrosine kinase inhibition, complement blockade, leukotriene inhibition, glycan targeting, and heat shock protein inhibition. |
These therapies herald an exciting period in HS management as options for patients continue to increase, hopefully contributing to improved symptom control and quality of life. |
Introduction
Hidradenitis suppurativa (HS) is a chronic, autoinflammatory condition that causes a severe impact on patients’ quality of life. The cause of HS is still under investigation, but it is considered a disease of follicular occlusion with various factors contributing to pathogenesis, including immune dysregulation, hormonal and metabolic factors, dysbiosis, and genetics [1]. Additionally, physical triggers for HS, including friction, deodorant use, and shaving, have been reported [2,3,4]. Multiple inflammatory cytokines have been found to be elevated in both lesional HS skin and in the serum of HS patients, leading to investigation of targeted immunomodulators as HS treatments. Adalimumab is currently the only drug approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of HS; therefore, treatment options are limited for patients who fail to respond to the tumor necrosis factor (TNF)-alpha inhibitor. Further, delays in diagnosis, which are common in HS patients, may prevent timely initiation of adalimumab, which correlates with decreased response to treatment [5]. However, the number of clinical trials and treatments under investigation has been increasing precipitously over the past few years (Fig. 1), marking an inflection point in the management of this devastating condition that will hopefully allow clinicians to more effectively treat HS. This review will discuss emerging and investigational medical treatments for HS patients.
Number of hidradenitis suppurativa clinical trials posted on clinicaltrials.gov by year (source: clinicaltrials.gov)
Methods
For this narrative review, the term “hidradenitis suppurativa” was searched on clinicaltrials.gov on 8 January 2023. Emerging treatments with ongoing or recently completed trials were included; studies that were withdrawn or of unknown status were excluded. Other relevant articles were identified based on a search of each included drug’s name and “hidradenitis” as keywords on PubMed, and through review of reference lists of included articles. Publicly available key trial updates through March 2023 were also included. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Results
Topical Therapies
Janus Kinases
The Janus kinase (JAK) family contains four tyrosine kinases that are involved in various signaling cascades: JAK1, JAK2, JAK3, and tyrosine kinase (TYK)2. They participate in the JAK–signal transducer and activator of transcription (STAT) pathway, which regulates multiple inflammatory signals, including interleukin (IL)-1b, IL-6, IL-17, IL-23, interferons (IFNs), and tumor necrosis factor (TNF)-α [7, 8]. JAK3 gene transcripts as well as STAT1, STAT4, and STAT5 promoter binding sites are elevated in HS lesional skin [9, 10]. IFN-induced STAT1 activation was suppressed in vitro by JAK1-selective inhibition by upadacitinib [9].
Ruxolitinib is a JAK1/2 inhibitor that decreases TNF, IL-6, IL-8, IL-1β, and C-X-C motif chemokine ligand (CXCL)3 production by HS lesional keratinocytes by a factor of 2 compared with vehicle control [11]. Two phase 2 trials are investigating the use of topical ruxolitinib 1.5% cream in patients with HS: one compared with vehicle cream in 60 participants with HS (NCT05635838), and the other as an open-label single arm study in 24 participants (NCT04414514) (Table 1).
Aryl Hydrocarbon Receptor
The aryl hydrocarbon receptor (AHR) is a keratinocyte transcription factor activated by exposure to environmental toxins, including tryptophan derivatives produced by microorganisms, which mediates skin barrier function [12, 13]. It is involved in the differentiation of regulatory Treg (T) cells and Th17 cells [12]. Dysregulated tryptophan catabolism by bacterial skin flora in HS patients has been linked to decreased AHR activation [14]. Tapinarof, a topical AHR agonist, has been found to be effective in treatment of psoriasis and atopic dermatitis (AD) [13].
AT193 is a topical AHR agonist that is being studied in a phase 1b trial in 44 participants with HS (NCT04989517).
Lytic Peptidomimetic
LTX-109 is a peptide-mimic antimicrobial compound that exerts its bactericidal actions through membrane disruption and cell lysis [15]. Results are pending from a completed phase 1/2 study of LTX-109 3% gel, which enrolled 11 participants with HS (NCT04756336). LTX-109 has been studied in the treatment of nasal colonization of S. aureus, with serious adverse events (SAEs) of psychosis and post-operative bleeding [15]. Local side effects, upper respiratory infections (URIs), and headache also occurred.
Gentian Violet
Gentian violet is a dye and topical antiseptic that is effective against numerous microbes including methicillin-resistant S. aureus (MRSA) and Candida skin infections [16]. It also has anti-angiogenic properties and has been used for wound healing [16]. It will be investigated in a phase 2 study of 16 HS patients (NCT04388163).
Povidone-Iodine
A topical antimicrobial wash containing povidone-iodine acts against viral pathogens within 30 s and remains active for up to 9 h against bacterial and fungal pathogens on artificial skin [17]. It was evaluated in a prospective, blinded, randomized trial comparing it with benzoyl peroxide 10% wash in 25 participants with HS but results are not available (NCT01818167).
Systemic Therapies
TNF-α
TNF-α, a pro-inflammatory cytokine, is elevated in HS lesional skin as well as the serum of HS patients [7, 18, 19]. Inhibition of TNF-α decreases production of downstream cytokines, including interleukin (IL)-1ß, IL-6, IL-10, and IL-17A, revealing a complex interplay in the pathogenesis of HS, which remains incompletely understood [7, 20]. Several TNF-α inhibitors are effective in the treatment of HS, including adalimumab, which demonstrated efficacy in two phase 3 clinical trials [21], and infliximab, which was studied in a phase 2 trial [22].
TNF-α antagonist biosimilar medications are currently being studied. MSB11022 (an adalimumab biosimilar) has been studied in several phase 1 trials in the USA and the UK, demonstrating safety and bioequivalence compared with adalimumab [23, 24]. It has also demonstrated comparable efficacy in the treatment of psoriasis, but has not yet been studied in HS [25]. Remsima, an infliximab biosimilar, is currently in an active phase 1 trial in 16 patients with HS resistant to unspecified conventional treatments (NCT05663268) (Table 2).
The use of other TNF-α inhibitors, including certolizumab and golimumab, has been reported in small numbers of patients. Certolizumab is a pegylated TNF-α inhibitor that lacks a fragment crystallizable (Fc) region, preventing it from crossing the placenta during pregnancy. Therefore, it is often the first-line option when considering TNF-α inhibitors during pregnancy or in women who are trying to conceive. A total of 19 of 23 patients reported in case series demonstrated improvement, including 11 who met hidradenitis suppurativa clinical response (HiSCR) criteria [26,27,28,29,30,31,32,33,34,35]. Achievement of HiSCR requires a ≥ 50% reduction in total abscess and inflammatory nodule (AN) count, without increase in abscess or draining fistula count compared with baseline [6]. Seven patients were women of childbearing age, including two who were pregnant with no obstetric complications reported [29, 35].
Golimumab is a fully humanized monoclonal antibody [36]. Six of nine patients with relevant data available achieved HiSCR in a case series of patients who received golimumab [37]. Three out of four additional patients have improved [38,39,40].
The side effects of TNF-α inhibitors include injection or infusion reactions, nausea, headaches, increased risk of infections, and increased risk of malignancies, and they should be used with caution in patients with advanced heart failure, demyelinating diseases, history of malignancy, and active infections. Paradoxical HS and psoriasis have also been reported with the use of TNF inhibitors [41, 42].
IL-1
IL-1 is involved in the inflammatory cascade of HS through its interactions with TNF-α, creating a positive feedback cycle and leading to further downstream inflammation [43]. IL-1α is expressed in keratinocytes, and activation leads to recruitment of inflammatory cells and local auto-inflammation, while IL-1β is found in circulation and HS lesional skin [44]. It is also locally expressed in macrophages and dendritic cells in response to activation of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [44]. IL-1 receptor-associated kinases (IRAKs) mediate the interaction between IL-1 receptors and toll-like receptors (TLRs), resulting in downstream activation of NF-κB and MAPK [45, 46].
Bermekimab (MABp1) is a human monoclonal antibody that inhibits IL-1α. It has been evaluated in four phase 2 trials since 2017. One open label trial studied bermekimab in patients who had never tried or who had previously failed anti-TNF therapy, demonstrating 61% and 63% HiSCR achievement at week 12, respectively, [43]. A phase 2 trial evaluating efficacy of bermekimab demonstrated significantly improved HiSCR achievement of 60% compared with placebo [47]. Another trial investigating efficacy of bermekimab has been completed without available results (NCT04019041); however, an additional study was terminated prematurely after meeting prespecified futility criteria (NCT04988308).
Canakinumab is an IL-1β inhibitor that has been reported only in cases to date, comprising eight patients with mixed results [48,49,50,51,52,53]. Four patients had at least some response, including one remission, while three did not respond, and one patient’s HS worsened.
Lutikizumab (ABT-981) is an anti-IL-1 \(\alpha\)/β dual variable domain inhibitor, binding and inhibiting both IL-1α and IL-1β. A phase 2 study will assess lutikizumab in 160 patients who have failed anti-TNF therapy (NCT05139602).
Two compounds that act on IRAK4 are under investigation for their use in HS. PF06650833 is an IRAK4 inhibitor that has a completed phase 2 trial comparing multiple kinase inhibitors with placebo (NCT04092452). KT-474 is an oral heterobifunctional small molecular IRAK4 degrader; a phase 1 trial in 154 healthy volunteers, HS patients, and atopic dermatitis (AD) patients has been completed as of 2022 (NCT04772885).
A bispecific monoclonal antibody targeting both IL-1β and IL-18 is known as MAS-825. There is currently a phase 2 trial assessing efficacy and safety of MAS-825 compared with placebo (NCT03827798). This trial is also evaluating three additional compounds.
Side effects of IL-1 inhibitors include immunosuppression, increased risk of infections, diarrhea, nausea, headache, abdominal pain, and injection site reactions.
IL-4 and IL-13
HS appears to be a primarily Th1/Th17-driven condition, while IL-4 and IL-13 are Th2-associated cytokines that are elevated in AD. The level of IL-13 is inversely related to the level of Th1/Th17-associated cytokines in untreated HS lesional skin, and its role, if any, in the pathogenesis of HS is not fully understood [54]. However, patients with AD have 5.6 times the odds of being diagnosed with HS [55]. Possible links between these two conditions include dysregulated skin bacterial populations, antimicrobial peptide (AMP) production, or defects of sphingolipid metabolism [55,56,57].
Three cases of male patients with Hurley stage II or III HS and comorbid AD successfully treated with dupilumab have been reported [57,58,59].
Safety considerations with dupilumab include risk of conjunctivitis, increased reactivation of herpesvirus, increased susceptibility to parasitic infections, and injection site reactions.
IL-17
IL-17 comprises six proteins (IL-17A–F) with five receptors [IL-17 receptor (IL-17R) A–E], with IL-17A, IL-17C, and IL-17F elevated in HS lesional skin and IL-17A additionally elevated in serum of HS patients [1, 7]. The effects of activation of the IL-17 family in HS include downstream production of other inflammatory cytokines, including IL-19 and IL-36, and AMPs and recruitment of inflammatory cells [1, 7]. In terms of phase 3 trials for HS, both bimekizumab and secukinumab met their primary endpoints; however, only secukinumab is currently commercially available in the USA.
Bimekizumab is a humanized bispecific monoclonal antibody that inhibits IL-17A and IL-17F. A phase 2 trial studied bimekizumab compared with placebo and adalimumab, revealing a 57.3% HiSCR achievement rate at week 12 in the bimekizumab group [60]. A set of phase 3 trials (BE HEARD I and II) demonstrated efficacy of monthly and twice monthly dosing of bimekizumab compared with placebo, with HiSCR rates at week 16 for active arms ranging from 45.3% to 53.8%. In the observed case analysis for BE HEARD I and II, over 55% of patients achieved HiSCR 75 at week 48 [61].
Brodalumab inhibits IL-17RA, a component of the IL-17 receptor dimer, resulting in suppression of the effect of IL-17A, IL-17C, and IL-17F [1, 62]. Two early phase 1 trials of brodalumab with weekly or biweekly dosing in 20 participants (including seven who participated in both trials) demonstrated 100% achievement of HiSCR at weeks 2 or 4, maintained at week 24 [62, 63]. An additional early phase 1 open-label trial in four patients has been completed (NCT04979520). The use of brodalumab for HS has also been reported in five patients who improved on weekly (n = 1) or biweekly (n = 4) dosing [33, 64,65,66].
CJM112 is a fully human monoclonal antibody that inhibits IL-17A and the heterodimer IL-17A/F, targeting a different epitope than secukinumab [1, 67]. A phase 2 trial in 66 participants demonstrated that 32.3% of patients in the active group achieved the primary endpoint compared with 12.5% in the placebo group at week 16 (p = 0.03) [68].
Ixekizumab is a monoclonal antibody IL-17A inhibitor. There is no clinical trial data on ixekizumab in HS, but several cases and series have been reported, comprising nine positive results, including five patients who achieved HiSCR [28, 69,70,71,72,73]. Conversely, at least four patients have been reported to fail ixekizumab [28, 74, 75].
Izokibep is a selective inhibitor of IL-17A with small molecular size, which may afford it higher potency [76, 77]. In an on-going placebo-controlled phase 2b trial in 180 participants, early data showed that 71% achieved HiSCR and 33% achieved HiSCR100 at week 12 (NCT05355805) [77].
Secukinumab is a monoclonal antibody IL-17A inhibitor that has undergone two phase 3 trials (SUNSHINE and SUNRISE) that showed significantly improved HiSCR rates of 42% and 46% across two dosing regimens compared to placebo. Efficacy was shown to be durable over 52 weeks. [78] Across six studies (including retrospective series, retrospective cohort studies, and open-label trials), 83 out of 150 (55.3%) achieved HiSCR at weeks 16 or 24 [79,80,81,82,83,84]. All utilized psoriasis dosing except in two studies, one where 12 out of 47 patients were dosed bimonthly and one where 13 out of 23 patients had dose escalation to every 2 or 3 weeks depending on clinical response [82, 84]. Multiple case reports/small case series have also been published regarding secukinumab use in HS [85,86,87,88,89,90,91,92,93,94,95,96].
Sonelokimab is a trivalent camelid-derived nanobody specific to IL-17A, IL-17F, and human serum albumin administered subcutaneously [97]. Nanobodies are proprietary proteins based on antibody heavy chains. There is an ongoing phase 2 trial with sonelokimab that includes an active comparator adalimumab arm (NCT05322473).
Side effects of IL-17 inhibitors include injection site reactions, increased risk of infection, nasopharyngitis, candida infections, diarrhea, neutropenia, and nausea. IL-17 inhibition has been reported to contribute to the development or unmasking of inflammatory bowel disease, but a recent systematic review did not find a link [98]. The paradoxical development of HS has also been reported after treatment with secukinumab [34, 41]. Additionally, brodalumab carries a black box warning regarding the risk of suicidality.
IL-23
IL-23 is a member of the IL-12 family and is composed of the p40 subunit, shared with IL-12, and the p19 subunit. IL-23 induces differentiation of Th17 cells, activation of the JAK/STAT pathway, and subsequent expression of IL-17 [7, 46]. Macrophages from HS lesional skin express mRNA encoding IL-23p19 and IL-23 subunit proteins, and patients with elevated lesional levels of IL-23p19 were more likely to achieve HiSCR with IL-23 inhibition in one study of 26 patients [7, 99].
Guselkumab is a monoclonal antibody that inhibits IL-23p19. It has been studied in a phase 2b trial to evaluate the efficacy of two different dosing regimens of guselkumab compared with placebo followed by guselkumab starting at week 16 (NCT03628924). Of participants receiving guselkumab, 45% and 50.8% met HiSCR at week 16, which was not significantly higher than the placebo group (38.7%). Prior to the phase 2b trial, an open-label phase 2a trial studied guselkumab 200 mg SQ every 4 weeks in 22 patients [100]. A total of 13 out of 20 (65%) achieved HiSCR, while 7 out of 20 (35%) achieved HiSCR75 at week 16. Several cases and series have also reported the use of guselkumab for HS [49, 75, 101,102,103,104,105,106,107,108,109,110]. Across 34 patients, 25 experienced at least some improvement.
Risankizumab is a humanized monoclonal antibody that inhibits IL-23p19. A phase 2 trial in 243 participants evaluated two dosing regimens of risankizumab compared with placebo [111]. The study was terminated early, as the primary endpoint was not met: 46.8% of patients in the risankizumab 180 mg group, 43.4% of the risankizumab 360 mg group, and 41.5% of the placebo group achieved HiSCR at week 16. Prior to this trial, a prospective cohort study of 26 patients reported a HiSCR achievement rate of 69.2% (18 out of 26) at psoriasis dosing of risankizumab [99]. Additionally, there have been positive case series/reports on risankizumab use in HS. Of 11 patients treated with psoriasis dosing of risankizumab, 8 achieved HiSCR by month 6; 3 additional patients reported improvement [112,113,114,115,116].
Tildrakizumab is a humanized monoclonal antibody that inhibits IL-23p19. A series of nine patients treated with tildrakizumab had statistically significant decreases in mean abscess and nodule count at months 2, 5, and 15 [117]. One patient paused treatment due to pregnancy (no obstetric complications reported).
Side effects of IL-23 inhibitors include increased risk of infection, headaches, injection site reactions, rare hepatotoxicity, and arthralgias.
IL-36
The IL-36 family is a subset of the IL-1 family, which contains three agonists (IL-36α, IL-36β, and IL-36γ). These bind the receptor complex IL-36R and upregulate the NK-κB and MAPK pathways [44]. Downstream, this stimulates increased T-cell proliferation and production of inflammatory cytokines including additional interleukins, TNF-α, and members of the CXCL family [44]. The levels of all three agonist IL-36 proteins are elevated in lesional skin and serum of HS patients, while IL‐36β is elevated in perilesional skin, with higher levels of serum IL-36 proteins associated with up to 11 times increased risk of HS [44, 118,119,120].
Spesolimab is a humanized anti-IL-36R monoclonal antibody [121]. A phase 2a study evaluated spesolimab in 52 patients with moderate-to-severe HS [122]. At week 12, patients receiving the active arm experienced similar changes in total abscess and inflammatory nodule (AN) count compared with placebo arm (38.8% compared with 34.7%, respectively). However, a greater proportion of patients on spesolimab experienced a decrease in draining tunnel count at week 12 compared with the placebo arm (66.7% compared with 38.5%). There is an open-label extension trial (NCT04876391).
Imsidolimab (ANB019) is a humanized monoclonal antibody inhibiting IL-36 that was studied in a phase 2 trial in 149 participants with HS compared with placebo (NCT04856930) [44]. Results are pending.
Adverse events of IL-36 inhibitors observed in trials for HS and palmoplantar pustular psoriasis include headache, nausea, fatigue, injection site reactions, nasopharyngitis, and pyrexia (NCT03633396 and NCT03619902).
Complement 5a
Complement 5a (C5a) is an anaphylatoxin that is produced during complement activation, and plays an important role in immune stimulation including neutrophil chemotaxis, mast cell degranulation, and production of Th1/17 cytokines [1, 46]. Findings on complement levels in HS patients are conflicting [123,124,125,126].
Avacopan (CCX168) is an oral C5a receptor inhibitor. It underwent a phase 2 trial with 398 participants with HS (NCT03852472). A press release reported that the primary endpoint was not met in either active arm; however, more patients in the subgroup of Hurley stage III achieved HiSCR with higher dosing (42.6%) compared with placebo (22.2%) [46, 127].
Vilobelimab (IFX-1) is a monoclonal anti-C5a antibody. An open-label phase 2a trial of 12 participants who were not eligible for or had previously failed biologic therapy demonstrated 75% achievement of HiSCR at day 50 extending to 83.3% on day 134 [128]. However, a subsequent phase 2 trial comparing multiple dose regimens with placebo did not demonstrate superiority compared with placebo in HiSCR rates (NCT03487276) [124].
BDB-001 is a recombinant anti-C5a antibody developed from the same cell line as vilobelimab by Staidson (Beijing) BioPharmaceuticals (STS) [129]. It is being studied in two phase 2 trials each comprising 49 participants with HS (NCT05093855 and NCT05103423).
Serious adverse reactions reported for vilobelimab included infections and chronic obstructive pulmonary disease.
Cluster of Differentiation (CD)40
Cluster of differentiation (CD)40 is a cell surface receptor that is among the TNF receptor family [130]. It is increased in pyoderma gangrenosum (PG) lesional skin of patients with pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome [130].
Iscalimab (CFZ533) is a human monoclonal antibody that inhibits CD40. A phase 2 trial will study iscalimab compared with placebo in 200 participants with HS, along with three other compounds (NCT03827798).
Leukotriene A4 Hydrolase
Leukotrienes are pro-inflammatory lipid mediators that are synthesized from arachidonic acid after cleavage from membrane phospholipids [131]. Leukotriene A4 hydrolase (LTA4H) catalyzes the conversion of LTA4 into LTB4, which activates neutrophil and macrophage chemotaxis [131, 132]. The level of LTB4 has been demonstrated to be significantly elevated in HS lesions, and LTA4H gene expression is increased in HS lesional macrophages [132].
LYS006 is a small-molecule inhibitor of LTA4H that is currently being studied in a phase 2 trial with three other compounds (NCT03827798).
Janus Kinases
Povorcitinib (INCB054707) is a JAK1 inhibitor that has been studied in two completed phase 2 clinical trials [8]. In the first trial, an open-label single arm study, 3 out of 7 (43%) achieved HiSCR, while in the second randomized trial, 65% of patients in the active arm achieved HiSCR compared with 57% of patients receiving placebo. An additional placebo-controlled phase 2 trial in 209 participants demonstrated a statistically significant decrease in AN count in all three dosing regimens (15 mg, 45 mg, and 75 mg daily) of povorcitinib compared with placebo at week 16 (NCT04476043). Results from the open-label extension (OLE) of this phase 2 trial with all patients on 75 mg daily found that, at 52 weeks, HiSCR 100 was achieved by 22% and 29% of patients [133]. There are two ongoing paired phase trials totaling 1200 participants (NCT05620823 and NCT05620836).
Upadacitinib is an oral JAK1 inhibitor that was evaluated in a phase 2 trial of 68 participants (NCT04430855); 38.3% of participants in the active arm achieved HiSCR compared with 23.8% in the placebo arm (p = 0.018). A retrospective cohort study was also conducted with 20 HS patients treated with upadacitinib [134]. A total of 15 out of 20 (75%) achieved HiSCR at week 4, increasing to 100% at weeks 12 and 24; those who did not achieve HiSCR at week 4 were dose increased. Of the patients, 95% also met HiSCR75 at weeks 12 and 24.
Brepocitinib (PF06700841) is a JAK1/TYK2 inhibitor that was evaluated in a phase 2a trial of three different kinases (NCT04092452). Results have been submitted but are not yet available.
Ropsacitinib (PF06826647) is a TYK2 inhibitor that was also investigated in the same phase 2a trial as above (NCT04092452).
Tofacitinib is a partial and reversible inhibitor of all four JAKs, but preferentially binds receptor dimers containing JAK1 and JAK3 over JAK2 and TYK2 [135]. A phase 2 open-label study is studying tofacitinib in the treatment of multiple inflammatory conditions, including HS, in 47 participants with Down syndrome (NCT04246372). A case series of two patients with ulcerative Hurley stage III HS reported successful treatment with tofacitinib [136].
Adverse events of JAK inhibitors include cardiac events, blood clots, immunosuppression, increased risk of infections, gastrointestinal symptoms, and acne.
Other Tyrosine Kinase Inhibitors
Tyrosine kinases are transmembrane members of signal transduction cascades that respond to extracellular stimuli [137]. Several tyrosine kinases are involved in immunity, including Bruton tyrosine kinase (BTK), which is essential for B cell development, including plasma cells, and spleen tyrosine kinase (SYK), which participates in differentiating self from non-self antigens, plasma cell expansion, and antibody responses [137, 138]. BTK and SYK signaling is up-regulated in HS lesional skin, and several inhibitors of these pathways, including fosamatinib, demonstrated decreased B cell expression of downstream inflammatory mediators in vitro [137].
Remibrutinib (LOU064) is an oral highly selective BTK inhibitor [139]. It is being investigated as part of a phase 2 trial compared with placebo (NCT03827798).
Fostamatinib is an oral SYK inhibitor. An open-label single group phase 2 trial of fostamatinib in 20 participants with HS has been completed as of January 2023, but results have not yet been posted (NCT0504069).
Adverse events reported in non-HS trials of these compounds included headache, nasopharyngitis, diarrhea, hypertension, and nausea [140, 141].
Phosphodiesterase-4 Inhibitors
Phosphodiesterase-4 (PDE-4) is an enzyme that breaks down cyclic adenosine monophosphate (cAMP), which is used as a second messenger for multiple signaling pathways, including anti-inflammatory pathways. Inhibition of PDE-4 prevents degradation of cAMP, causing reduced production of downstream pro-inflammatory compounds [46].
Apremilast is an oral small-molecule inhibitor of PDE-4. An open-label single group phase 2 trial in 20 patients reported a 55% HiSCR rate at week 16, increasing to 60% at week 24 [142]. An additional phase 2 trial studied apremilast in 20 patients with an HS-PGA score of 3, and demonstrated a HiSCR response rate of 53.3% in 15 patients at week 16 compared with 0% in the placebo group [143]. Additionally, 22 patients have been reported in case series, with 12 out of 22 reported to have some degree of improvement on apremilast [49, 74, 144,145,146,147,148]. Side effects of apremilast include diarrhea, nausea, headache, weight loss, and depression/suicidal ideation.
Orismilast is an oral high-potency PDE4 inhibitor with selectivity for PDE4B and PDE4D subtypes in vitro [149]. An open-label phase 2 trial will study orismilast in 24 participants with HS (NCT04982432).
Glycan-Targeting Antibody
PTM-001 is a glycan-targeting antibody that has been shown to normalize the intestinal expression of glycans in a mouse model of inflammatory bowel disease (IBD) and is undergoing development as a novel therapeutic [150, 151]. There are murine (mPTM-001) and humanized (hPTM-001) variants of this compound, both of which have demonstrated improvement of mucosal wound healing in in vitro and in vivo models [152]. PTM-001 is undergoing a phase 2 randomized controlled trial to determine its immunomodulatory activity in 50 HS patients (NCT05020730).
C-X-C Motif Chemokines
Chemokines are a class of cytokines involved in chemotaxis, tumor growth, and angiogenesis [153]. C-X-C motif chemokines (CXC) are a subtype of chemokines, which are further subdivided into the ELR+ subgroup if they express a particular motif containing glutamic acid–leucine–arginine. The CXC receptor type 2 (CXCR2) binds ELR+ CXC ligands (CXCL), which activate various inflammatory cascades including neutrophil chemotaxis and the JAK2/STAT3 and MAPK pathways [153, 154]. Notably, CXCL1-3, CXCL8/IL-8, and CXCL16 were overexpressed in PG lesional skin of patients with PASH syndrome [130].
RIST4721 is an oral small-molecule inhibitor of CXCR2. It was being investigated in a phase 2 trial in patients with HS compared with placebo; however, this study was terminated as of 22 March 2023 due to safety findings in ongoing phase 2 trials (NCT05348681).
Eltrekibart (LY3041658) is a septa-specific monoclonal antibody that neutralizes all seven ELR+ CXC chemokines (CXCL1-3 and CXCL5-8), thereby limiting signaling through CXCR1 and CXCR2 [155]. A phase 2 trial studying the efficacy of eltrekibart in 67 participants demonstrated that 65.6% in the treatment group met HiSCR compared with 41.4% receiving placebo [154]. Side effects included COVID-19 infection, nasopharyngitis, constipation, nausea, arthralgia, and fatigue.
Mitogen-Activated Protein Kinase
The mitogen-activated protein kinase (MAPK) pathway is activated in monocytes, macrophages, and dendritic cells after stimulation of toll-like receptors (TLRs) by DAMPs produced by hair follicle rupture. IL-1b, TNF-a, and IL-23 are produced downstream of the MAPK pathway, resulting in Th17 cell polarization [156]. Notch signaling, which may be dysregulated in HS, activates MAPK phosphatase-1 (MKP-1) and deactivates MAPK [156].
Zunsemetinib (ATI-450) is an oral small-molecule MAPK-activated protein kinase 2 (MK2) inhibitor being investigated in a phase 2a trial in 90 participants compared with placebo (NCT05216224). According to a press release, as of 6 March 2023, zunsemetinib did not meet primary or secondary endpoints of change from baseline in AN or percentage of patients achieving HiSCR, respectively [157]. Adverse events in a phase 1 trial in 48 healthy adults included headache, dizziness, URI, and constipation [158].
Granulocyte Colony-Stimulating Factor
Granulocyte colony-stimulating factor (GCSF) activates neutrophils and promotes their survival. It is highly elevated in HS lesional skin samples compared with perilesional skin, skin from healthy controls, and skin from patients with other inflammatory diseases [159].
CSL324 is a human recombinant GCSF receptor antagonist monoclonal antibody. Administration of systemic CSL324 decreased expression of genes associated with neutrophil migration in peripheral blood cells after stimulation in healthy participants [160]. An open-label phase 1 trial in 39 patients with HS or palmoplantar pustulosis was completed in October 2022 (NCT03972280).
Heat Shock Protein
Heat shock proteins (HSPs) are chaperones that assist protein folding to maintain cell homeostasis and ensure proper functioning. HSP90 is involved in the folding of inflammatory proteins; therefore, inhibition of HSP90 may produce anti-inflammatory effects [161]. Topical RGRN-305 has been shown to reduce expression of chemically-upregulated pro-inflammatory genes in in vitro keratinocytes, including TNF, IL-1b, IL-17A, and genes encoding the MAPK and NF-κB pathways [161].
RGRN-305 is an oral inhibitor of HSP90 that has been studied in psoriasis [162]. It has also been studied in a phase 1 trial of 15 HS patients (NCT05286567). Side effects reported in the psoriasis trial included exanthematous drug eruption, abdominal pain, headache, and blurry vision [162].
Mammalian Target of Rapamycin
Mammalian target of rapamycin (mTOR) is part of a protein kinase family that forms multiprotein complexes called mechanistic target of rapamycin complex (mTORC)1 and mTORC2 [163]. These kinases are involved in differentiation of Th17 cells, and increases in mTORC1 have been observed in psoriasis, HS, and insulin resistance [163]. Ten patients treated with sirolimus in combination with TNF inhibitors for HS have been described, with eight patients responding, including two complete responses [164, 165]. Side effects of sirolimus include immunosuppression, increased risk of malignancy, hyperlipidemia, diarrhea, headache, nausea, and leukopenia.
Semisynthetic Glycopeptide Antibacterial
Dalbavancin (BI397) is a novel semisynthetic second-generation glycopeptide antibiotic [166]. The first generation of glycopeptides includes vancomycin, though dalbavancin has increased affinity for bacterial membranes and increased in vitro bactericidal activity against gram-positive organisms [166]. It has demonstrated in vitro activity against multiple types of staphylococci, Enterococcus, and Propionibacterium species, among others, and clinical efficacy against skin and soft tissue infections including MRSA [166]. Additionally, wounds treated with dalbavancin showed decreased matrix metaloproteinase levels compared with untreated wounds in a mouse infection model [167]. It may also be effective against biofilms based on evidence in vitro and some in vivo studies, which may portend utility in HS treatment [168].
Nine patients with Hurley stage II or III HS were treated with one dose of intravenous dalbavancin, and 7 out of 9 (78%) achieved HiSCR by week 12 [169, 170]. Side effects included pyrexia, headache, oral candidiasis, diarrhea, constipation, and nausea [166].
Conclusion
Many treatments are currently under investigation for their use in HS, including multiple that target new pathways. This is especially promising given that existing therapeutic modalities are limited in their efficacy and durability. Challenges that are seen with HS trials include lack of a standardized set of trial outcomes and high placebo rates with HiSCR, the main primary endpoint for most trials at this time. Furthermore, cost and access barriers often restrict treatment options for patients outside of clinical trials. However, an expanded therapeutic armamentarium for HS is on the horizon with the tremendous increase in HS research and clinical trials. With continued study into the pathogenesis of HS, we can hope to identify new options to improve patients’ quality of life, perhaps even aiming for complete disease remission.
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Acknowledgements
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Author Contributions
Natalie M. Fragoso: Concept and design, acquisition of data, and drafting of the manuscript. Rahul Masson: Checking data and drafting of the manuscript. T. Justin Gillenwater: Critical revision of the manuscript. Vivian Y. Shi: Critical revision of the manuscript. Jennifer L. Hsiao: Concept and design, critical revision of the manuscript, and supervision.
Prior Publication
This article is based on work that has been previously published in medical journals as medical literature or in the lay press as press releases; work that has been presented at medical conferences including the American Academy of Dermatology in New Orleans, LA, in March 2023; and ongoing and completed or terminated clinical trials available on ClinicalTrials.gov.
Disclosures
Natalie M. Fragoso is an investigator for Acelyrin. T. Justin Gillenwater is on advisory boards for Avita, Exsurco, and the Musculoskeletal Transplant Foundation. Vivian Y. Shi is on the board of directors for the Hidradenitis Suppurativa Foundation (HSF), is an advisor for the National Eczema Association, is a stock shareholder of Learn Health, and has served as an advisory board member, investigator, speaker, and/or received research funding from Sanofi Genzyme, Regeneron, AbbVie, Genentech, Eli Lilly, Novartis, SUN Pharma, LEO Pharma, Pfizer, Incyte, Boehringer Ingelheim, Alumis, Aristea Therapeutics, Menlo Therapeutics, Dermira, Burt’s Bees, Galderma, Kiniksa, UCB, Target-PharmaSolutions, Altus Lab/cQuell, MYOR, Polyfins Technology, GpSkin, and Skin Actives Scientific. Jennifer L. Hsiao is on the Board of Directors for the Hidradenitis Suppurativa Foundation; has served as a consultant for Aclaris, Boehringer Ingelheim, Novartis, and UCB; and has served as a consultant and speaker for AbbVie. Rahul Masson has nothing to disclose. There was no financial transaction for the preparation of this manuscript.
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Fragoso, N.M., Masson, R., Gillenwater, T.J. et al. Emerging Treatments and the Clinical Trial Landscape for Hidradenitis Suppurativa Part I: Topical and Systemic Medical Therapies. Dermatol Ther (Heidelb) 13, 1661–1697 (2023). https://doi.org/10.1007/s13555-023-00956-6
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DOI: https://doi.org/10.1007/s13555-023-00956-6