Emerging Treatments and the Clinical Trial Landscape for Hidradenitis Suppurativa Part I: Topical and Systemic Medical Therapies

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.

Key Summary Points

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 [2–4]. 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.

Fig. 1.

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).

Table 1.

Emerging topical treatments for HS

Drug name (MOA)	Author or clinical trial #	Study type	Study goal and primary endpoint(s)	Patients enrolled	(Anticipated) completion date	Results or recruitment status
Ruxolitinib 1.5% cream (JAK 1/2 inhibitor)	NCT05635838	Phase 2 randomized, double-blind vehicle-controlled	Evaluate efficacy in patients with mild to moderate HS Endpoint: change from baseline in AN count at week 16	60	March 2024	Recruiting
Ruxolitinib 1.5% cream (JAK 1/2 inhibitor)	NCT04414514	Phase 2 open label	Evaluate efficacy and effects on skin inflammation in patients with HS Endpoint: percentage of patients who achieve HiSCR at week 16	24	January 2025	Recruiting
AT193 (aryl hydrocarbon agonist)	NCT04989517	Phase 1 randomized, double-blind placebo-controlled	Evaluate safety and tolerability in patients with HS Endpoint: incidence of TEAEs up to week 10	44	February 2023	Active, not recruiting
LTX-109 3% gel (lytic peptidomimetic)	NCT04756336	Phase 2 proof of concept	Evaluate safety and efficacy in patients with HS Endpoints: investigator and patient assessed signs and symptoms, respectively, of local reactions to the product until week 6	11	July 2021	Completed
Gentian violet (antiseptic)	NCT04388163	Phase 2 open-label	Evaluate efficacy in patients with HS Endpoint: skin redness, drainage, and pain at baseline and 1 month post-treatment	16	December 2023	Not yet recruiting
Povidone-iodine cream (antimicrobial)	NCT01818167	Prospective multi-center blinded, randomized, controlled clinical trial	Compare efficacy of povidone-iodine topical cream to 10% benzoyl peroxide topical body wash for the treatment of early stage HS Endpoint: HS European Research Group scale up to 4 months	25	January 2015	Results submitted

AN abscesses and inflammatory nodules, HiSCR hidradenitis suppurativa clinical response, HS hidradenitis suppurativa, JAK Janus kinase, MOA mechanism of action, TEAEs treatment emergent adverse events

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).

Table 2.

Emerging systemic treatments for HS

Drug name (MOA)	Author or clinical trial #	Study type	Study goal and primary endpoint(s)	Patients enrolled	(Anticipated) Completion date	Results or recruitment status
MSB11022 (adalimumab biosimilar/TNF-α antagonist), SQ	Sabet et al. 2022 [23]	Phase 1 randomized, open-label, parallel-group	Evaluate PK, safety, and tolerability Endpoints: Cmax), AUC0–t, and AUC0–∞	216	March 2020	Delivery via AI or PFS was comparable in terms of PK
Remsima (infliximab biosimilar/TNF-α antagonist), SQ	NCT05663268	Phase 1 open-label	Assess efficacy and safety in patients with resistant HS Endpoints: HiSCR, HS-PGA, and DLQI after 14 weeks	16	September 2023	Active, not recruiting
Bermekimab (MABp1, IL-1α inhibitor), SQ	Gottlieb et al. 2020 [43]	Phase 2 open-label	Evaluate safety, tolerability, and efficacy in patients with moderate-to-severe HS who had either failed initial treatment with anti-TNF agents or never received anti-TNF treatment Endpoint: number with adverse events up to day 93	42	January 2019	61% and 63% of anti-TNF naïve and anti-TNF failure groups, respectively, achieved HiSCR after 12 weeks. No bermekimab-related adverse events except injection site reactions
Bermekimab (MABp1, IL-1α inhibitor), SQ	Kanni et al. 2018 [47]	Phase 2 double-blind, randomized placebo-controlled	Assess efficacy in patients with moderate-to-severe HS Endpoint: differences in achievement of HiSCR at week 12 between treatment and placebo group	20	February 2017	60% of patients in active arm achieved HiSCR compared with 10% in placebo arm
Bermekimab (MABp1, IL-1α inhibitor), SQ	NCT04988308	Phase 2 randomized, placebo- and active comparator-controlled, double-blind	Evaluate clinical efficacy in patients with moderate-to-severe HS Endpoint: percentage of patients achieving HiSCR	151	November 2022	Terminated
Bermekimab (MABp1, IL-1α inhibitor), SQ	NCT04019041	Phase 2 randomized, double-blind, placebo-controlled	Evaluate efficacy in patients with moderate-to-severe HS Endpoint: achievement of HiSCR at week 12	144	November 2020	Completed
Lutikizumab/ABT-981 (ABT-981, IL-1α/β dual variable domain), SQ	NCT05139602	Phase 2 multicenter, randomized, double-blind placebo-controlled	Compare lutikizumab (ABT-981) versus placebo for the treatment of adults with moderate-to-severe HS who have failed anti-TNF therapy Endpoint: achievement of HiSCR at week 16	160	December 2023	Recruiting
PF 06650833 (IRAK4 inhibitor), oral	NCT04092452	Phase 2 multicenter, randomized, double-blind placebo-controlled	Compare three kinase inhibitors (PF 06650833, PF 06700841, and PF 06826647) with placebo in moderate-to-severe HS Endpoint: achievement of HiSCR at week 16	194a	January 2022	Completed, results submitted
KT-474 (heterobifunctional small-molecule IRAK4 degrader), oral	NCT04772885	Phase 1 randomized, placebo-controlled	Assess safety, tolerability, and pharmacokinetics/pharmacodynamics in healthy volunteers and in patients with atopic dermatitis and HS Endpoints: incidence and severity of emergent adverse events up to 28 days, incidence and frequency of concomitant medications up to 28 days	154	October 2022	Completed
MAS-825 (IL-1β and IL-18 inhibitor), SQ	NCT03827798	Phase 2 randomized, double-blind, placebo-controlled	Assess safety and efficacy in patients with moderate-to-severe HS Endpoint: achievement of HiSCR at week 16	200b	May 2023	Recruiting
Bimekizumab (IL-17A/F inhibitor), SQ	NCT04901195	Phase 3 open-label, parallel group extension	Assess safety of long-term treatment in patients with moderate-to-severe HS Endpoint: percentage of patients with treatment-emergent adverse events from baseline until week 120	830	April 2025	Active, not recruiting
Bimekizumab (IL-17A/F inhibitor), SQ	Kimball et al. 2023 (BE HEARD II) [61]	Phase 3 randomized, double-blind, placebo-controlled	Assess safety and efficacy in patients with moderate-to-severe HS Endpoint: achievement of HiSCR at week 16	509	September 2022	53.8% of patients receiving monthly dosing and 52% of patients receiving twice monthly dosing achieved HiSCR at week 16, compared with 32.2% of placebo
Bimekizumab (IL-17A/F inhibitor), SQ	Kimball et al. 2023 (BE HEARD I) [61]	Phase 3 randomized, double-blind, placebo-controlled	Assess safety and efficacy in patients with moderate-to-severe HS Endpoint: achievement of HiSCR at week 16	505	March 2023	45.3% of patients receiving monthly dosing and 47.8% of patients receiving twice monthly dosing achieved HiSCR at week 16, compared with 28.7% of placebo
Bimekizumab (IL-17A/F inhibitor), SQ	Glatt et al. 2021 [60]	Phase 2 multicenter, investigator-blind, subject-blind, placebo-controlled	Assess efficacy, safety, and pharmacokinetics in patients with moderate-to-severe HS compared with adalimumab and placebo Endpoint: achievement of HiSCR at week 12	90	February 2019	Efficacious compared with placebo. 57.3% of 44 patients receiving bimekizumab achieved HiSCR at week 12 compared with 26.1% receiving placebo
Brodalumab (IL-17 inhibitor), SQ	Frew et al. 2020 [62]	Early phase 1	Identify biomarkers of disease activity and clinical response in patients with moderate-to-severe HS Endpoints: biomarkers at weeks 12/24 and TEAEs until week 24	10	June 2020	100% achieved HiSCR at weeks 4 and 24. No serious adverse events were reported
Brodalumab (IL-17 inhibitor), SQ	Frew et al. 2021 [63]	Early phase 1	Identify biomarkers of disease activity and clinical response in patients with moderate-to-severe HS Endpoints: biomarkers at weeks 12/24 and TEAEs from week 0 to week 24	10	September 2020	100% achieved HiSCR at weeks 4 and 24 No serious adverse events or thoughts of self-harm were reported during the study
Brodalumab (IL-17 inhibitor), SQ	NCT04979520	Early phase 1 open-label	Characterize molecular response to this treatment, identify blood and tissue markers reflecting disease severity, and better understand disease mechanisms Endpoint: IL-17A receptor saturation during brodalumab administration at week 12 versus baseline	4	July 2022	Completed, results not available
CJM112 (IL-17A inhibitor), SQ	Kimball et al. 2022 [68]	Phase 2 randomized, double-blind, placebo-controlled	To determine efficacy and safety of multiple doses in comparison to placebo Endpoint: Decrease in HS-PGA score by at least 2 points after 16 weeks	66	November 2016	Endpoint achieved in 32.3% (10/31) after 16 weeks compared with 12.5% (4/32) with placebo
Izokibep (IL-17A inhibitor), SQ	Acelyrin Inc. 2023	Phase 2b randomized, double-blind	Evaluate efficacy, safety, and immunogenicity in adults with moderate-to-severe HS Endpoint: Achievement of HiSCR after 16 weeks	180	February 2024	Part A data: 71% achieved HiSCR and 33% achieved HiSCR100 at week 12
Secukinumab (IL-17A inhibitor), SQ	Kimball et al. 2023 (SUNRISE) [78]	Phase 3 randomized, double-blind	Assess efficacy, safety, and tolerability of secukinumab at week 52 in subjects with moderate-to-severe HS Endpoint: Achievement of HiSCR after 16 weeks	544	July 2022	Significant HiSCR rates of 42% (every 2 weeks) and 46% (every 4 weeks) dosing compared with placebo at week 16
Secukinumab (IL-17A inhibitor), SQ	Kimball et al. 2023 (SUNSHINE) [78]	Phase 3 randomized, double-blind	Assess efficacy, safety, and tolerability of secukinumab at week 52 in subjects with moderate-to-severe HS Endpoint: achievement of HiSCR after 16 weeks	545	July 2022	Significant HiSCR rate of 45% (every-2-week dosing) compared with placebo at week 16
Secukinumab (IL-17A inhibitor), SQ	NCT04179175	Phase 3 randomized, triple-blind	Evaluate maintenance of HiSCR response at week 104 in either continuous or interrupted therapy, comparing every-2-week dosing to every-4-week dosing in HiSCR responders after 52 weeks, or switched to placebo. Endpoint: time to loss of response during 52 week treatment duration up to week 104	856	July 2026	Recruiting
Sonelokimab (IL-17A/F inhibitor), SQ	NCT05322473	Phase 2 randomized, parallel-group, double-blind, placebo-controlled	Demonstrate clinical efficacy and safety sonelokimab compared with placebo and adalimumab in the treatment of adult participants with moderate-to-severe HS Endpoint: percentage of participants achieving HiSCR75 after 12 weeks	210	November 2023	Active, not recruiting
Guselkumab (IL-23 inhibitor), SQ	NCT03628924	Phase 2 randomized, placebo-controlled, double-blind	Assess efficacy, safety, and tolerability of 2 doses of guselkumab compared with placebo in adults with moderate-to-severe HS Endpoint: achievement of HiSCR after 16 weeks	184	May 2020	HiSCR at week 16 (not significant): 50.8% of those on 200 mg SQ every 4 weeks, 45% of those on 1200 mg IV at weeks 0, 4, and 8 followed by 200 mg SQ at week 12 and thereafter, and 38.7% in placebo group
Guselkumab (IL-23 inhibitor), SQ	NCT04061395	Phase 2, open label	Investigate changes in inflammatory pathways induced by IL-23p19 blockade with guselkumab, in HS lesional skin Endpoint: changes in inflammatory pathways induced by IL-23p19 blockade with guselkumab	20	December 2020	Unknown
Risankizumab (IL-23 inhibitor), SQ	Kimball et al. 2023 [111]	Phase 2 randomized, placebo-controlled, double-blind	Assess safety and efficacy of risankizumab 180 mg and 360 mg versus placebo for moderate-to-severe HS in adults Endpoint: achievement of HiSCR after 16 weeks	243	August 2022	No significant difference in HiSCR achievement between treatment groups. Primary endpoint was not achieved
Spesolimab (IL-36 inhibitor), IV and SQ	Alavi et al. 2023 [122]	Phase 2 randomized, double-blind, placebo-controlled	Evaluate efficacy in patients with moderate-to-severe HS Endpoint: change from baseline in AN count at week 12	52	April 2022	38.8% decrease in AN count in treatment group compared with 34.7% decrease in placebo group
Spesolimab (IL-36 inhibitor), IV and SQ	NCT04876391	Phase 2 open-label, long-term extension trial	Evaluate long-term safety of spesolimab Endpoint: occurrence of TEAEs up to week 120	45	April 2024	Active, not recruiting
Imsidolimab/ANB019 (IL-36 inhibitor), IV and SQ	NCT04856930	Phase 2 randomized, double-blind, placebo-controlled	Evaluate efficacy in adults with HS and compare results with placebo Endpoint: change from baseline in AN count at week 16	149	December 2022	Completed
Avacopan/CCX168 (C5a receptor inhibitor), oral	ChemoCentryx 2020 [127]	Phase 2 randomized, double-blind, placebo-controlled, parallel group	Evaluate efficacy and safety in subjects with moderate-to-severe HS Endpoint: achievement of HiSCR after 12 weeks	435	March 2021	Primary endpoint not met. Subgroup analysis: 42.6% of Hurley stage III patients achieved HiSCR at higher dose compared with 22.2% of placebo (significant)
Vilobelimab/IFX-1 (anti-C5a antibody), IV	Giamarellos-Bourboulis et al. 2020 [128]	Phase 2 open-label trial	Evaluate safety and tolerability in patients with moderate-to-severe HS Endpoint: number of patients with TEAEs and anti-drug antibodies up to day 134	12	July 2017	75% achievement of HiSCR at day 50
Vilobelimab/IFX-1 (anti-C5a antibody), IV	Giamarellos-Bourboulis et al. 2020 [124]	Phase 2 randomized, double-blind, placebo-controlled	Evaluate the safety and tolerability of vilobelimab compared with placebo in patients with moderate-to-severe HS Endpoint: achievement of HiSCR after 16 weeks	179	January 2020	HiSCR achievement was not superior in treatment groups compared with placebo. IHS4 scores and draining fistulae count decreased with every other week dosing
BDB-001 (C5a inhibitor), IV	NCT05093855	Phase 2 open-label	Evaluate efficacy and safety in patients with moderate-to-severe HS Endpoint: change in IHS4 score from day 0 until week 8	49	December 2023	Recruiting
BDB-001 (C5a inhibitor), IV	NCT05103423	Phase 2 randomized, double-blind placebo-controlled	Evaluate efficacy and safety in adults with moderate-to-severe HS Endpoints: TEAEs, anti-BDB-001 antibody development, PK parameters	49	June 2023	Recruiting
Iscalimab/CFZ533 (CD40 inhibitor), SQ	NCT03827798	Phase 2 randomized, double-blind, placebo-controlled	Assess safety and efficacy in patients with moderate-to-severe HS Endpoint: achievement of HiSCR at week 16	200b	May 2023	Recruiting
LYS006 (leukotriene A4 hydrolase inhibitor), oral	NCT03827798	Phase 2 randomized, double-blind, placebo-controlled	Assess safety and efficacy in patients with moderate-to-severe HS Endpoint: achievement of HiSCR at week 16	200b	May 2023	Recruiting
Povorcitinib/INCB054707 (JAK-1 inhibitor), oral	NCT04476043	Phase 2 randomized, double-blind, placebo-controlled	Evaluate efficacy and safety of INCB054707 in participants with moderate-to-severe HS over a 16-week placebo-controlled period, followed by a 36-week extension period Endpoint: mean change from baseline in AN count at week 16	209	August 2023	Statistically significant difference in AN count across 3 doses compared with placebo at week 16
Povorcitinib/INCB054707 (JAK-1 inhibitor), oral	Alavi et al. 2022 [8]	Phase 2 placebo-controlled study	Evaluate the safety of INCB054707 over an 8-week treatment period in patients with moderate-to-severe HS Endpoint: number of TEAEs at week 12	35	August 2019	65% achieved HiSCR in treatment group vs. 57% in placebo after 8 weeks
Povorcitinib/INCB054707 (JAK-1 inhibitor), oral	Alavi et al. 2022 [8]	Phase 2 open-label, single-arm study	Evaluate the safety of INCB054707 in patients with moderate-to-severe HS Endpoint: number of TEAEs at week 12	10	April 2019	43% achieved HiSCR at week 8; 3 participants discontinued treatment
Povorcitinib/INCB054707 (JAK-1 inhibitor), oral	NCT05620823 (STOP-HS1)	Phase 3 randomized, double-blind, placebo-controlled	Evaluate the efficacy and safety of INCB054707 in participants with moderate-to-severe HS over a 12-week placebo-controlled period, followed by a 42-week extension period Endpoint: proportion of patients who achieve HiSCR at week 12	600	January 2026	Recruiting
Povorcitinib/INCB054707 (JAK-1 inhibitor), oral	NCT05620836 (STOP-HS2)	Phase 3 randomized, double-blind, placebo-controlled	Evaluate efficacy and safety of INCB054707 in participants with moderate-to-severe HS over a 12-week placebo-controlled period, followed by a 42-week extension period Endpoint: proportion of patients who achieve HiSCR at week 12	600	January 2026	Recruiting
Upadacitinib (JAK-1 inhibitor), oral	NCT04430855	Phase 2 randomized, double-blind, placebo-controlled	Evaluate efficacy and safety in participants with moderate-to-severe HS Endpoint: proportion of patients who achieve HiSCR at week 12	68	January 2022	38.3% achieved HiSCR in treatment group and 23.8% in placebo group
Brepocitinib/PF06700841 (TYK2/JAK1 inhibitor), oral	NCT04092452	Phase 2 randomized, double-blind, placebo-controlled	Compare 3 kinase inhibitors (PF 06650833, PF 06700841, and PF 06826647) with placebo in moderate-to-severe HS Endpoint: achievement of HiSCR at week 16	194a	January 2022	Completed, results submitted
Ropsacitinib/PF06826647 (tyrosine kinase 2 inhibitor), oral	NCT04092452	Phase 2 randomized, multicenter, double-blind, placebo-controlled	Compare efficacy of 3 kinase inhibitors (PF 06650833, PF 06700841, and PF 06826647) with placebo in patients with moderate-to-severe HS Endpoint: achievement of HiSCR at week 16	194a	January 2022	Results submitted
Tofacitinib (JAK inhibitor), oral	NCT04246372	Phase 2 open-label	Evaluate efficacy and safety of 5 mg twice daily in the treatment of multiple inflammatory conditions, including HS, in participants with Down syndrome Endpoint: number of TEAEs up to week 18 and change in interferon scores in the transcriptome of white blood cells	47	December 2024	Recruiting
Remibrutinib/LOU064 (BTK inhibitor), oral	NCT03827798	Phase 2 randomized, double-blind, placebo-controlled	Assess safety and efficacy in patients with moderate-to-severe HS Endpoint: achievement of HiSCR at week 16	200b	May 2023	Recruiting
Fostamatinib (spleen tyrosine kinase inhibitor), oral	NCT05040698	Phase 2 exploratory, proof-of-concept	A proof-of-concept study to evaluate efficacy Endpoint: Alterations in gene expression profiling, cell counts (CD3+, CD11c+, Neutrophil Elastase+, CD20+, CD138+) at weeks 4 and 12 compared with baseline	20	January 2023	Completed
Apremilast (PDE-4 inhibitor), oral	Kerdel et al. 2019 [142]	Phase 2 open-label	Evaluate efficacy and safety in patients with moderate HS Endpoint: proportion of patients who achieve HiSCR at week 16	20	August 2017	55% HiSCR rate at week 16
Apremilast (PDE-4 inhibitor), oral	Vossen et al. 2019 [143]	Phase 2 randomized, double-blind, placebo-controlled	Evaluate efficacy and short-term safety in patients with moderate HS Endpoint: proportion of patients who achieve HiSCR at week 16	20	June 2018	53.3% in treatment group met HiSCR and 0% in placebo met HiSCR
Orismilast (PDE-4 inhibitor), oral	NCT04982432	Phase 2 open-label	Evaluate efficacy and safety for the treatment of mild, moderate, or severe HS in adults Endpoint: change from baseline in AN count at week 16	24	December 2022	Not yet recruiting
PTM-001 (glycan-targeting antibody), oral	NCT05020730	Phase 2 randomized, double-blind, placebo-controlled	Evaluate immunomodulatory activity of PTM-001 in participants with HS Endpoint: effect of PTM-001 on IL-1β protein levels in lesional skin biopsies at week 12	50	June 2024	Recruiting
RIST 4721 (CXCR2 antagonist), oral	NCT05348681	Phase 2 randomized, double-blind, placebo-controlled	Evaluate efficacy and safety in patients with HS Endpoint: incidence of TEAEs and SAEs until week 12	25	February 2023	Terminated
Eltrekibart/LY3041658 (ELR and CXC chemokine neutralizer), IV	NCT04493502	Phase 2 randomized, double-blind, placebo-controlled	Evaluate efficacy in patients with moderate-to-severe HS Endpoint: percentage of patients who achieve HiSCR at week 16	67	October 2022	65.6% in treatment group met HiSCR compared with 41.4% in placebo group
Zunsemetinib/ATI-450 (small-molecule MK2 inhibitor), oral	Aclaris Therapeutics 2023 [157]	Phase 2 randomized, double-blind placebo-controlled	Evaluate efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of ATI-450 versus placebo in patients with moderate-to-severe HS Endpoint: change in AN count at week 12	95	January 2023	Did not meet primary or secondary endpoints
CSL324 (anti-GCSF receptor), IV	NCT03972280	Phase 1 open-label	Evaluate safety and PK of repeat doses in subjects with HS or palmoplantar pustulosis Endpoints: incidence of TEAEs and AESIs up to 24 weeks	39	October 2022	Completed
RGRN-305 (HSP90 inhibitor), oral	NCT05286567	Phase 1 randomized, double-blind, placebo-controlled	Evaluate efficacy in patients with moderate-to-severe HS Endpoint: percentage of patients who achieve HiSCR at week 16	15	August 2022	Completed

AI autoinjector, AN abscess and inflammatory nodule, AUC0–∞ area under the concentration–time curve from time 0 extrapolated to infinity, AUC0–t area under the concentration–time curve from time 0 to the last quantifiable concentration, BTK bruton tyrosine kinase, C5a complement component 5a, C_max maximum observed concentration, CXCR c-x-c chemokine receptor, DLQI Dermatology Life Quality Index, GCSF granulocyte colony-stimulating factor, HiSCR hidradenitis suppurativa clinical response, HS hidradenitis suppurativa, IHS4 International Hidradenitis Suppurativa Severity Score, IL interleukin, IRAK4 IL-1 receptor associated kinase 4, IV intravenous, JAK Janus kinase, MK2 mitogen-activated protein kinase (MAPK)-activated protein kinase-2, MOA mechanism of action, PDE phosphodiesterase, PFS pre-filled syringe, PGA Physician Global Assessment, PK pharmacokinetics, SQ subcutaneous, TEAEs treatment emergent adverse events, TNF tumor necrosis factor, TYK tyrosine kinase

^aIncluding patients on PF 06650833, PF 06700841, and PF 06826647

^bIncluding patients on MAS825, CFZ533, LYS006, and LOU064

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 [26–35]. 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 [38–40].

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 [48–53]. 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 [55–57].

Three cases of male patients with Hurley stage II or III HS and comorbid AD successfully treated with dupilumab have been reported [57–59].

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, 64–66].

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, 69–73]. 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 [79–84]. 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 [85–96].

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, 101–110]. 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 [112–116].

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, 118–120].

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 [123–126].

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, 144–148]. 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.