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A Phase II Open-Label Study of Bermekimab in Patients with Hidradenitis Suppurativa Shows Resolution of Inflammatory Lesions and Pain

Open ArchivePublished:January 28, 2020DOI:https://doi.org/10.1016/j.jid.2019.10.024
      The objective of this study was to evaluate the safety and efficacy of bermekimab, an IL-1α inhibitor, in the treatment of hidradenitis suppurativa (HS). This study was a phase II, multicenter, open-label study of two dose cohorts of bermekimab in patients with moderate-to-severe HS who are naïve to or have failed prior anti-TNF therapy. Patients with HS (n = 42) were divided into groups A and B based on whether or not they had previously failed an anti-TNF therapy. In group A (n = 24), bermekimab was administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who had previously failed anti-TNF therapy; in group B (n = 18), bermekimab was administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who were anti-TNF naïve. Bermekimab, previously found to be effective in treating HS, was evaluated using a subcutaneous formulation in patients with HS naïve to or having failed anti-TNF therapy. There were no bermekimab-related adverse events with the exception of injection site reactions. Bermekimab was effective despite treatment history, with 61% and 63% of patients naïve to and having failed anti-TNF therapy, respectively, achieving HS clinical response after 12 weeks of treatment. A significant reduction in abscesses and inflammatory nodules of 60% (P < 0.004) and 46% (P < 0.001) was seen in anti-TNF naïve and anti-TNF failure groups, respectively. Clinically and statistically significant reduction was seen in patients experiencing pain, with the Visual Analogue Scale pain score reducing by 64% (P < 0.001) and 54% (P < 0.001) in the anti-TNF naïve and anti-TNF failure groups, respectively. IL-1α is emerging as an important clinical target for skin disease, and bermekimab may represent a new therapeutic option for treating moderate-to-severe HS.

      Abbreviations:

      AE (adverse event), HiSCR (hidradenitis suppurativa clinical response), HS (hidradenitis suppurativa), PGA (Physician’s Global Assessment), SAE (serious adverse event), VAS (Visual Analogue Scale)

      Introduction

      Hidradenitis suppurativa (HS) or acne inversa is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland–bearing areas of the body, most commonly the axillary, inguinal, and anogenital regions (
      • Kurayev A.
      • Ashkar H.
      • Saraiya A.
      • Gottlieb A.B.
      Hidradenitis suppurativa: review of the pathogenesis and treatment.
      ;
      • Zouboulis C.C.
      • Desai N.
      • Emtestam L.
      • Hunger R.E.
      • Ioannides D.
      • Juhász I.
      • et al.
      European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa.
      ). IL-1α has been implicated previously in this inflammatory cascade (
      • Folco E.J.
      • Mawson T.L.
      • Vromman A.
      • Bernardes-Souza B.
      • Franck G.
      • Persson O.
      • et al.
      Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1α and cathepsin G.
      ,
      • Kaplanski G.
      • Porat R.
      • Aiura K.
      • Erban J.K.
      • Gelfand J.A.
      • Dinarello C.A.
      Activated platelets induce endothelial secretion of interleukin-8 in vitro via an interleukin-1-mediated event.
      ), thus creating a theoretical role for agents that neutralize IL-1α in the treatment of HS.
      HS typically starts in adolescence. The clinical course is characterized by exacerbations and remissions of flare-ups. During these flare-ups, the follicular duct content expands and eventually ruptures with the subsequent discharge of purulent material. The mean duration of a single nodule is 7 to 15 days and may result in painful, deep dermal abscesses (
      • Esmann S.
      • Jemec G.B.
      Psychosocial impact of hidradenitis suppurativa: a qualitative study.
      ). Emotional stress is commonly associated with flare-ups, and flare-ups in women are more frequent before menses, suggesting a hormonal component to disease course (
      • Von der Werth J.M.
      • Williams H.C.
      The natural history of hidradenitis suppurativa.
      ). As the disease progresses, fistulas are formed under the dermis. These fistulas often suppurate continuously (
      • Révuz J.E.
      Hidradenitis suppurativa.
      ). This chronic inflammation and the accompanying pain account for the fact that HS is ranked among the top skin disorders in terms of adversely affecting quality of life (
      • Canoui-Poitrine F.
      • Revuz J.E.
      • Wolkenstein P.
      • Viallette C.
      • Gabison G.
      • Pouget F.
      • et al.
      Clinical characteristics of a series of 302 French patients with hidradenitis suppurativa, with an analysis of factors associated with disease severity.
      ). HS continues to emerge as a common disease. A large epidemiological survey in France has reported 1% disease prevalence (
      • Révuz J.E.
      • Canoui-Poitrine F.
      • Wolkenstein P.
      • Viallette C.
      • Gabison G.
      • Pouget F.
      • et al.
      Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies.
      ).
      Prior clinical trials also have evaluated the use of anti-TNF agents, such as adalimumab, for the treatment of HS (
      • Kimball A.B.
      • Jemec G.B.
      • Yang M.
      • Kageleiry A.
      • Signorovitch J.E.
      • Okun M.M.
      • et al.
      Assessing the validity, responsiveness and meaningfulness of the Hidradenitis Suppurativa Clinical Response (HiSCR) as the clinical endpoint for hidradenitis suppurativa treatment.
      ,
      • Kimball A.B.
      • Kerdel F.
      • Adams D.
      • Mrowietz U.
      • Gelfand J.M.
      • Gniadecki R.
      • et al.
      Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial.
      ). However, this treatment falls short for some patients with HS. Specifically, 41% to 58% of patients had primary response failures after 12 weeks of adalimumab treatment. Furthermore, among patients who did exhibit a clinical response at week 12, 48–55% relapsed by week 36. These data highlight the necessity of developing additional therapies, given that many patients will fail adalimumab (either primary or secondary failure).
      Some early promise was seen with anakinra, which blocks both IL-1β and IL-1α, in a recent small scale double-blind randomized clinical trial. Treatment with 100 mg anakinra for 12 weeks led to achieving HS clinical response (HiSCR) in seven of nine patients compared with three of ten patients treated with placebo (
      • Tzanetakou V.
      • Kanni T.
      • Giatrakou S.
      • Katoulis A.
      • Papadavid E.
      • Netea M.G.
      • et al.
      Safety and efficacy of anakinra in severe hidradenitis suppurativa: A randomized clinical trial.
      ). The hypothesis generated from this study is based on two factors. First, anakinra showed efficacy in treating patients with HS. Second, there were elevated concentrations of IL-1α in subjects’ HS lesions. Therefore, bermekimab may also be a promising new agent for patients with HS, including those who are not eligible for treatment with adalimumab. It also points to the possibility of achieving clinical efficacy with a targeted biologic, specifically against IL-1α.
      There are multiple cytokines involved in the HS phenotype and pathophysiology. However, the IL-1 pathway signals through the MYD88 cascade, linking IL-1α signaling to the IL-1 receptor associated kinases, TRAF, MAPK, and NF-κB to activate transcription of a host of inflammatory genes (
      • Acuner Ozbabacan S.E.
      • Gursoy A.
      • Nussinov R.
      • Keskin O.
      The structural pathway of interleukin 1 (IL-1) initiated signaling reveals mechanisms of oncogenic mutations and SNPs in inflammation and cancer.
      ). The downstream end of the IL-1 signaling pathway is in common with least eight other IL-1 receptor family members (i.e., toll-like receptors) in addition to the TNF receptor. The pathway therefore has been extensively characterized. The MYD88 pathway is known to induce IL-1β, IL-3, IL-6, IL-8, IL-17, TGFβ, IFN, major histocompatibility complex, VEGF, matrix metalloproteinases and other cytokines, and vascular endothelial adhesions (P-selectin, E-selectin, ICAM-1, and VCAM-1) that promote inflammation (
      • Chen C.J.
      • Shi Y.
      • Hearn A.
      • Fitzgerald K.
      • Golenbock D.
      • Reed G.
      • et al.
      MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals.
      ,
      • Garofalo R.
      • Mei F.
      • Espejo R.
      • Ye G.
      • Haeberle H.
      • Baron S.
      • et al.
      Respiratory syncytial virus infection of human respiratory epithelial cells up-regulates class I MHC expression through the induction of IFN-beta and IL-1 alpha.
      ,
      • Lima A.L.
      • Karl I.
      • Giner T.
      • Poppe H.
      • Schmidt M.
      • Presser D.
      • et al.
      Keratinocytes and neutrophils are important sources of proinflammatory molecules in hidradenitis suppurativa.
      ,
      • Sacre S.M.
      • Andreakos E.
      • Kiriakidis S.
      • Amjadi P.
      • Lundberg A.
      • Giddins G.
      • et al.
      The toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis.
      ).
      The IL-1 family includes both proinflammatory and anti-inflammatory cytokines, which when out of balance lead to disease states including HS. The proinflammatory members include IL-1α, IL-1β, IL-33, IL-18, IL-36α, IL-36β, and IL-36γ, which are opposed by the anti-inflammatory members including IL-1 receptor antagonist, IL-36 receptor antagonist, IL-37, and IL-38 (
      • Xie L.
      • Huang Z.
      • Li H.
      • Liu X.
      • Zheng S.
      • Su W.
      IL-38: A new player in inflammatory autoimmune disorders.
      ). In HS specifically, it was found that IL-36α, IL-36β, and IL-36γ were all upregulated (
      • Thomi R.
      • Kakeda M.
      • Yawalkar N.
      • Schlapbach C.
      • Hunger R.E.
      Increased expression of the interleukin-36 cytokines in lesions of hidradenitis suppurativa.
      ). This extensive composition of cytokines provides options for drug targets, both in terms of antagonism of a proinflammatory cytokine, as in the case of IL-1α, as well as agonism of an anti-inflammatory cytokine. There are myriad intricate communications between these cytokines, including the antagonist action of IL-38 on IL-36 (
      • Xie L.
      • Huang Z.
      • Li H.
      • Liu X.
      • Zheng S.
      • Su W.
      IL-38: A new player in inflammatory autoimmune disorders.
      ) and of the IL-1 receptor on IL-1β (
      • Witte-Händel E.
      • Wolk K.
      • Tsaousi A.
      • Irmer M.L.
      • Mößner R.
      • Shomroni O.
      • et al.
      The IL-1 Pathway Is Hyperactive in Hidradenitis suppurativa and Contributes to Skin Infiltration and Destruction.
      ). Moreover, TNF upregulates IL-1 expression, and IL-1 in turn upregulates production of TNF (
      • Ikejima T.
      • Okusawa S.
      • Ghezzi P.
      • van der Meer J.W.
      • Dinarello C.A.
      Interleukin-1 induces tumor necrosis factor (TNF) in human peripheral blood mononuclear cells in vitro and a circulating TNF-like activity in rabbits.
      ). Interrupting IL-1 signaling could help break the vicious cycle of inflammation that occurs with TNF–IL-1 crosstalk. Taken together, IL-1α may be viewed as high up in the cascade of cytokines that drives expansion of the inflammatory response. It is from this perspective that we consider IL-1α to be an important—but by no means exclusive—player in the overall pathophysiology of the dysregulated inflammatory response in HS.
      Bermekimab is a human monoclonal antibody that neutralizes IL-1α by binding the cytokine with high affinity and is therefore an effective blocker of IL-1α’s biological activity. IL-1α is a key mediator of sterile inflammatory responses and has been implicated in the pathology of advanced cancer, cardiovascular disease, and rheumatologic disease (
      • Kanni T.
      • Argyropoulou M.
      • Spyridopoulos T.
      • Pistiki A.
      • Stecher M.
      • Dinarello C.A.
      • et al.
      MABp1 targeting IL-1α for moderate to severe hidradenitis suppurativa not eligible for adalimumab: A randomized study.
      ). In addition, it has been implicated specifically in HS. Furthermore, IL-1β and IL-1α were present in increased amounts in the pus of lesions of all patients with Hurley III stage HS (
      • Kanni T.
      • Tzanetakou V.
      • Savva A.
      • Kersten B.
      • Pistiki A.
      • van de Veerdonk F.L.
      • et al.
      Compartmentalized cytokine responses in hidradenitis suppurativa.
      ). This unanimous presence provides evidence for the role of IL-1α in the inflammatory pathophysiology of HS. Specifically, IL-1α is released from intracellular storage when a cell is in a state of stress. It then is able to enact extracellular recruitment of hematopoietic cells, homing them to the damaged cell via a pathway of endothelial activation and vascular wall modifications (
      • Dinarello C.A.
      • Simon A.
      • Van der Meer J.W.
      Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.
      ,
      • Di Paolo N.C.
      • Shayakhmetov D.M.
      Interleukin 1α and the inflammatory process.
      ). In a double-blind, randomized, placebo-controlled study, 60% of patients with HS treated for 12 weeks with intravenous bermekimab (MABp1), which targeted IL-1α, achieved HiSCR, whereas 10% of patients in the placebo group achieved HiSCR at week 12 (
      • Kanni T.
      • Argyropoulou M.
      • Spyridopoulos T.
      • Pistiki A.
      • Stecher M.
      • Dinarello C.A.
      • et al.
      MABp1 targeting IL-1α for moderate to severe hidradenitis suppurativa not eligible for adalimumab: A randomized study.
      ).
      IL-6 levels have shown to be correlated with disease severity in HS and potentially have a greater reliability for predicting response to HS treatment than C-reactive protein levels (
      • Montaudié H.
      • Seitz-Polski B.
      • Cornille A.
      • Benzaken S.
      • Lacour J.P.
      • Passeron T.
      Interleukin 6 and high-sensitivity C-reactive protein are potential predictive markers of response to infliximab in hidradenitis suppurativa.
      ,
      • Xu H.
      • Xiao X.
      • He Y.
      • Zhang X.
      • Li C.
      • Mao Q.
      • et al.
      Increased serum interleukin-6 levels in patients with hidradenitis suppurativa.
      ). In previous clinical studies, decreased IL-6 levels have been demonstrated in patients receiving bermekimab therapy (
      • Hong D.S.
      • Hui D.
      • Bruera E.
      • Janku F.
      • Naing A.
      • Falchook G.S.
      • et al.
      MABp1, a first-in-class true human antibody targeting interleukin-1α in refractory cancers: an open-label, phase 1 dose-escalation and expansion study.
      ,
      • Kurzrock R.
      • Hickish T.
      • Wyrwicz L.
      • Saunders M.
      • Wu Q.
      • Stecher M.
      • et al.
      Inteleukin-1 receptor antagonist levels predict favorable outcome after bermekimab, a first-in-class true human interleukin-1α antibody, in a phase III randomized study of advanced colorectal cancer.
      ).
      The purpose of this clinical study was to evaluate the safety, tolerability, and efficacy of bermekimab in patients with moderate-to-severe HS who had either failed initial treatment with anti-TNF agents or never received anti-TNF treatment.

      Results

      Participant flow

      The study was conducted between July 2018 and January 2019. The trial ended at the end of follow-up for the last patient. In total, 42 subjects were enrolled into the study, 24 of whom had received and failed to respond to anti-TNF therapy (group A) and 18 of whom had not received any prior anti-TNF therapy (group B). Both groups were originally planned to receive 200 mg subcutaneous injections of bermekimab for 12 weeks; however, preliminary safety data from XBiotech’s PT044 atopic dermatitis study demonstrated good levels of safety and tolerability for 400 mg subcutaneous injections. A revised study design thus implemented 400 mg subcutaneous injections of bermekimab for 12 weeks. Baseline characteristics for enrolled patients in both groups are provided in Table 1.
      Table 1Anti-TNF Failures and Anti-TNF Naïve Baseline Characteristics
      Measure of disease severityGroup A (anti-TNF failed) (n = 24)Group B (anti-TNF naïve)

      (n = 18)
      Baseline mean ± SDBaseline mean ± SD
      Total number of abscesses and inflammatory nodules14.08 ± 9.856.39 ± 3.47
      PGA3.46 ± 0.723.72 ± 0.83
      VAS for disease8.12 ± 1.486.72 ± 2.19
      VAS for pain8.12 ± 1.427.28 ± 1.56
      DLQI16.29 ± 7.5017.89 ± 7.00
      Disease Activity Score109.58 ± 67.0490.75 ± 46.46
      HADS anxiety score7.96 ± 4.697.11 ± 4.73
      HADS depression score6.42 ± 3.924.83 ± 3.76
      HADS anxiety + depression14.38 ± 7.8611.94 ± 8.02
      Abbreviations: DLQI, Dermatology Life Quality Index; HADS, Hospital Anxiety and Depression Scale; PGA, Physician’s Global Assessment; VAS, Visual Analog Scale

      Primary study endpoint: Safety and tolerability

      The primary endpoints of this study were safety and tolerability. Bermekimab was well tolerated in all subjects throughout the study. Subcutaneous formulation of bermekimab 400 mg weekly for 13 consecutive weeks (week 0 to week 12; 13 doses) was studied in two cohorts in patients with moderate-to-severe HS, those who were naïve to an anti-TNF therapy and those who had previously failed an anti-TNF therapy.
      Safety was assessed by monitoring adverse events (AEs), vital signs, physical examinations, and clinical laboratory measurements. There were no discontinuations because of serious adverse events (SAEs). Overall, there were 58 non-SAEs reported, and most of them were grade I (59%) and grade II (36%). The most common AEs were injection site reactions (five grade II reactions in two subjects) and nausea (six grade II reactions in one subject). There were two SAEs in the study, (i) fall (grade III severity; not related to study drug; SAE criteria, hospitalization) and (ii) HS pain (grade III severity; not related to study drug; SAE criteria, hospitalization). All remaining AEs were mild to moderate in severity. A detailed summary of AEs for group A and group B are listed in Supplementary Table S1.
      All clinical laboratory abnormalities were either present at screening and did not progress over the course of the study, were reflective of known underlying comorbidities, or were the result of laboratory error. Similarly, abnormalities identified during vital signs assessment were all consistent with known comorbid pathology (most commonly primary essential hypertension) and none were clinically significant. Electrocardiogram findings were not clinically significant, and no consistent pattern of abnormalities emerged in association with bermekimab.

      Secondary study endpoint: Clinical efficacy

      Statistically significant improvement from baseline was seen for nearly all disease severity measures in both treatment groups. A summary of secondary endpoint descriptions can be found in Supplementary Table S2. The clinical efficacy of bermekimab was assessed through week 13 (or the subject’s final visit if he or she discontinued or was lost to follow-up).
      At that time point, subjects in group A (those that previously failed therapy with an anti-TNF agent) experienced an average reduction of 46% in inflammatory nodule and abscess count compared with baseline (P < 0.0001), and subjects in group B (those who were anti-TNF naïve) experienced an average reduction of 60% in inflammatory nodule and abscess count compared with baseline (P = 0.004) (Figure 1). HiSCR is used to assess disease activity in patients with HS. HiSCR is binary, in that it is either satisfied/met or not satisfied/met. To satisfy/meet HiSCR, a patient must have at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count compared with baseline. In this study, patients were evaluated for whether or not they satisfied/met HiSCR at week 12 relative to their week 1 baselines. In groups A and B, 63% and 61% of patients, respectively, achieved HiSCR when compared with their baseline visit (Figure 2).
      Figure thumbnail gr1
      Figure 1Mean percent change of subject inflammatory lesion count. This figure illustrates the statistically significant mean percent changes in inflammatory lesion count that patients in both groups A and B achieved relative to their baselines. Group A saw a 46% mean percent change from baseline (P < 0.0001) and group B saw a 60% mean percent change from baseline (P = 0.004).
      Figure thumbnail gr2
      Figure 2Achievement of HiSCR at weeks 2, 6, and 12. This figure illustrates the percentage of subjects in group A (n = 24) and group B (n = 18) who achieved HiSCR by weeks 2, 6, and 12. Error bars shown in the figure are mean ± SEM. Achievement of HiSCR is defined as at least a 50% decrease of the total inflammatory lesion count from the baseline before start of treatment and the absence of new abscess or fistula formation. By week 12, 63% of patients in group A and 61% of patients in group B achieved HiSCR. HiSCR, hidradenitis suppurativa clinical response.
      Assessment of subjects’ disease activity using both the Disease Activity Score (
      • Giamarellos-Bourboulis E.J.
      • Pelekanou E.
      • Antonopoulou A.
      • Petropoulou H.
      • Baziaka F.
      • Karagianni V.
      • et al.
      An open-label phase II study of the safety and efficacy of etanercept for the therapy of hidradenitis suppurativa.
      ) and Physician’s Global Assessment (PGA) (
      • Kimball A.B.
      • Kerdel F.
      • Adams D.
      • Mrowietz U.
      • Gelfand J.M.
      • Gniadecki R.
      • et al.
      Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial.
      ) showed significant improvements at week 12 relative to their baseline visit. Subjects in group A showed on average a 33% reduction in Disease Activity Score at week 12 (P = 0.02), whereas subjects in group B showed an average reduction of 66% at week 12 (P = 0.001). Subject PGA scores at week 12 in group A showed a 23% average reduction (P = 0.0018), whereas subjects in group B showed a 53% average reduction in PGA score (P < 0.0001).
      Treatment with bermekimab was also accompanied by better patient-reported outcomes. Improvements in the Visual Analogue Scale (VAS) for pain and disease were reported at week 12 relative to baseline in both groups. Group A showed an average improvement of 41% (P < 0.0001) and 54% (P < 0.0001) for pain and disease, respectively, whereas subjects in group B showed an average improvement of 50% (P < 0.0001) and 64% (P < 0.0001) for pain and disease, respectively.
      Subjects in both groups also reported improvements in the Dermatology Life Quality Index at week 12 relative to baseline. Subjects in group A achieved an average of 41% improvement (P < 0.0001), whereas subjects in group B achieved an average of 67% improvement (P < 0.0001).
      Subjects in group A also reported improvements from baseline at week 12 on the Hospital Anxiety and Depression Scale (
      • Zigmond A.S.
      • Snaith R.P.
      The Hospital anxiety and Depression Scale.
      ). Group A subjects achieved an average of 41% improvement in the anxiety score (P = 0.001), 25% average improvement in the depression score (P = 0.02), and 34% average improvement in the overall score (P = 0.002). Although group B subjects achieved, on average, improvement in all measures of the Hospital Anxiety and Depression Scale, none of these improvements was found to be statistically significant. Descriptive statistics summarizing patient endpoint outcomes can be seen in Table 2.
      Table 2Descriptive Statistics for Subjects Receiving Bermekimab: Change at Week 12
      Measure of DiseaseGroupnMeanSDStandard ErrorMedianRange95% CI for meanP-value
      Total number of abscesses and inflammatory nodulesA
      Anti-TNF failed group.
      246.465.471.127−10 to 144.15–8.77<0.0001
      B
      Anti-TNF naïve group.
      163.943.490.874−4 to 132.08–5.80.004
      PGAA
      Anti-TNF failed group.
      240.790.780.1610–30.46–1.120.0018
      B
      Anti-TNF naïve group.
      1621.590.420–51.15–2.85<0.0001
      VAS for diseaseA
      Anti-TNF failed group.
      243.332.840.583−1 to 82.13–4.53<0.0001
      B
      Anti-TNF naïve group.
      163.383.120.783.5−1 to 71.71–5.04<0.0001
      VAS for painA
      Anti-TNF failed group.
      244.383.40.694−3 to 92.94–5.81<0.0001
      B
      Anti-TNF naïve group.
      164.563.010.755.5−1 to 102.96–6.17<0.0001
      DLQIA
      Anti-TNF failed group.
      246.717.641.565.5−10 to 213.48–9.93<0.0001
      B
      Anti-TNF naïve group.
      16128.822.21101–277.30–16.70<0.0001
      DASA
      Anti-TNF failed group.
      2435.7582.7416.8948.5−222 to 1650.81–70.690.02
      B
      Anti-TNF naïve group.
      1663.5651.612.9054.5−35 to 19136.07–91.060.001
      HADS anxiety scoreA
      Anti-TNF failed group.
      243.255.431.115−13 to 110.96–5.540.001
      B
      Anti-TNF naïve group.
      161.132.870.721−6 to 7(-.41)–2.660.2
      HADS depression scoreA
      Anti-TNF failed group.
      241.583.240.661.5−6 to 100.21–2.950.02
      B
      Anti-TNF naïve group.
      160.252.490.620−4 to 6(-1.08)–1.580.4
      Abbreviations: CI, confidence interval; DAS, Disease Activity Score; DLQI, Dermatology Life Quality Index; HADS, Hospital Anxiety and Depression Scale; PGA, Physician’s Global Assessment; VAS, Visual Analogue Scale.
      1 Anti-TNF failed group.
      2 Anti-TNF naïve group.

      Discussion

      HS is a debilitating inflammatory skin condition with significant disease burden. Existing treatment options are not effective for all patients or may be contraindicated for some patients. There is therefore a significant unmet need for patients with HS. Bermekimab, through its mechanism of neutralizing IL-1α, functions to combat the inflammatory cascade that leads to the phenotype seen in moderate-to-severe HS. It is a novel therapeutic that shows significant promise for HS. In this study, we demonstrate the safety, tolerability, and clinical efficacy of bermekimab in treating moderate-to-severe HS. Patients in both treatment groups evaluated in this study showed statistically significant improvement in nearly every study endpoint at 12 weeks compared with baseline.
      This study importantly demonstrates the potential of bermekimab to treat patients with moderate-to-severe HS who are recalcitrant to adalimumab. Before this study, two phase III PIONEER studies allowed for adalimumab to be registered as an indicated treatment for moderate-to-severe HS. The investigators used the HiSCR score after 12 weeks as the primary efficacy outcome (
      • Kimball A.B.
      • Okun M.M.
      • Williams D.A.
      • Gottlieb A.B.
      • Papp K.A.
      • Zouboulis C.C.
      • et al.
      Two phase 3 trials of adalimumab for hidradenitis suppurativa.
      ). HiSCR achievement with adalimumab was reported in 41.8% of patients in the PIONEER I study and 58.9% of patients in the PIONEER II study (
      • Kimball A.B.
      • Okun M.M.
      • Williams D.A.
      • Gottlieb A.B.
      • Papp K.A.
      • Zouboulis C.C.
      • et al.
      Two phase 3 trials of adalimumab for hidradenitis suppurativa.
      ), which allowed antibiotic use. Adalimumab is an important advance for the treatment of HS. However, there is still a considerable unmet need for the subset of patients who failed or relapsed with adalimumab, including 41–58% of patients who have primary response failures after 12 weeks of adalimumab treatment and 30–50% of patients who have a positive initial response to treatment with adalimumab but relapse after 12 weeks of therapy. Treatment with bermekimab in patients who previously failed or relapsed after treatment with adalimumab led to HiSCR achievement by 61%. The ability of bermekimab to allow this cohort of patients to achieve such significant disease improvement is exciting and provides significant hope to many patients with HS who may feel hopeless with this debilitating disease. Bermekimab also provides hope for patients who may have contraindications to adalimumab, as evident by the significant improvements in study endpoints achieved by the cohort of patients who were naïve to anti-TNF therapy.

      Materials and Methods

      Study design

      This study was a phase II, multicenter, open-label study of two dose cohorts of bermekimab in patients with moderate-to-severe HS who are naïve to or have failed prior anti-TNF therapy. This trial was registered with clinicaltrials.gov (NCT03512275). The duration of subject participation was approximately 16 weeks, including a 3-week screening period and a 13-week treatment period. The study consisted of two groups: (i) group A (n = 24), bermekimab administered via subcutaneous injection weekly (13 doses) in patients who had previously failed anti-TNF therapy, and (ii) group B (n = 18), bermekimab administered via subcutaneous injection weekly (13 doses) in patients who were anti-TNF naïve. Because there was no prior clinical data for the 400 mg weekly dosing, a power calculation between groups was not possible, and sample size was thus exploratory. Both groups were originally administered 200 mg doses of bermekimab; however, preliminary safety data from XBiotech’s PT044 atopic dermatitis study demonstrated good levels of safety and tolerability for 400 mg injections of bermekimab. The dose was subsequently increased to 400 mg in both groups A and B. A summary of subject allocation is found in Figure 3. Patients were followed for 13 weeks to allow for assessment of safety and preliminary efficacy.
      Figure thumbnail gr3
      Figure 3Patient disposition flow chart. The study consisted of two groups. Group A (n = 24): bermekimab administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who had previously failed anti-TNF therapy. Group B (n = 18): bermekimab administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who were anti-TNF naïve. Patients were followed for 13 weeks to allow for assessment of safety and preliminary efficacy. PI, principal investigator.
      The limitations of the study design include a small sample size and uneven subject withdrawals between the two study groups. Because there was no prior clinical data for the 400 mg weekly dosing, a power calculation between groups was not possible, and sample size was thus exploratory. Because of this, although statistically significant differences were observed between the two study groups for nearly every study endpoint, these results are in the context of a limited sample size and may require additional testing with larger sample sizes in the future to confirm the efficacy of bermekimab in the population. It should be additionally mentioned that there were more withdrawals from group B (7) than group A (2). Although only one of the withdrawals was related to the drug (injection site redness), the larger difference between group numbers by the end of the study as compared with the start may have had an effect on the findings seen at study endpoint, despite the statistical significance found.

      Study ethics, inclusion criteria, and exclusion criteria

      Patients were enrolled after written informed consent. The protocol was approved by the institutional review board or ethics committee of the participating study sites. Further, the trial was conducted in compliance with the protocol, good clinical practice, and all applicable regulatory requirements.
      Patients 18 or older diagnosed with HS for at least 1 year before screening with at least two distinct anatomic areas affected, one of which had to be Hurley II or III stage HS, and with a total body count of no less than three inflamed nodules and abscesses were included in the study. For group A, patients must have received and failed at least one anti-TNF therapy previously. Group B subjects must not have received any prior treatment with any anti-TNF agent. Patients who received the 200 mg dose of bermekimab in this study were eligible to begin receiving the 400 mg dose beginning at the patient’s next scheduled visit for the remainder of his or her treatment plan. Female patients of childbearing potential willing to use one method of contraception of high efficacy during the entirety of the study were included. Female patients of nonchildbearing potential were considered with a medical history that indicated that pregnancy was not a reasonable risk.
      Main exclusion criteria included hepatic dysfunction, chronic infections by hepatitis B and C viruses and HIV, neutropenia, pregnancy or lactation, recent vaccination during the four weeks before screening, and history of treatment with bermekimab for any reason except patients previously treated with 200 mg in the previous versions of this study. Further, history of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies; intake of opioid analgesics within 14 days before screening; major surgery (requiring general anesthesia or respiratory assistance) within 28 days before day 0 of start of study drug; known or suspected history of immunosuppression; and Stage C Child-Pugh liver cirrhosis were included as exclusion criteria. Patients receiving oral antibiotic treatment or systematic therapies for HS within 28 days before screening were excluded from the study as well as patients receiving topical therapies 14 days before screening.
      If a patient was discontinued from the study, the reason for discontinuation was clearly documented in the source documentation and the electronic data capture. Study therapy was immediately discontinued for any the following reasons: (i) withdrawal of informed consent; (ii) any clinical AE, laboratory abnormality, intercurrent illness, or clinical progression of disease that indicates that the continued participation is not in the best interest of the subject; (iii) pregnancy; (iv) termination of the study by the sponsor; and (v) imprisonment or compulsory detention for medical treatment.

      Screening and treatment

      Once a patient was considered eligible for the study, the following was examined or performed at screening: (i) medical history and physical examination; (ii) height, weight, and body mass index; (iii) vital signs; (iv) serum creatinine and liver biochemistry; (v) complete blood count with differential and platelets; (vi) serum pregnancy test; (vii) serology for interferon-gamma release assay, HIV, hepatitis B virus, and hepatitis C virus; and (viii) inflammatory markers C-reactive protein and erythrocyte sedimentation rate. Treatment was provided at future visits. The study drug was provided by XBiotech (Austin, TX), who built the randomization sequence. This was an open-label study.

      Follow-up

      At weeks 0 (baseline), 2, 4, 6, 8, 10, and 12 before administration of drug, patients completed the Dermatology Life Quality Index, Hospital Anxiety and Depression Scale, and a physical examination and were self-assessed for impression of their HS and pain severity using the VAS, ranging from 0 (not at all severe disease or no pain) to 10 (extremely severe disease or worst imaginable pain); individual lesions were counted and HiSCR, PGA, and disease activity were scored; and patients’ vital signs were assessed. Patients were then injected with the proper amount of bermekimab through a subcutaneous injection. Patients were monitored for 1 hour, then vital signs were reassessed 1 hour after injection. Lastly, patients were asked for any AEs and SAEs. At weeks 0, 6, and 12, in addition to the procedures described, urinalysis and an electrocardiogram were performed to further assess the safety of bermekimab.
      At weeks 1, 3, 5, 7, 9, and 11, patients’ vital signs were assessed. Patients were then injected with the proper amount of bermekimab through a subcutaneous injection. Patients were monitored for 1 hour, then vital signs were reassessed 1 hour after injection. Patients were then asked for any AEs and SAEs.
      At every week except for the follow-up week 13, urine pregnancy tests were collected from female subjects.
      Week 13 included the following: (i) patients completed the Dermatology Life Quality Index, Hospital Anxiety and Depression Scale, and a physical examination; (ii) patients were self-assessed for HS and pain severity using the VAS from 0 (absent) to 10 (worst ever felt); (iii) individual lesions were counted and HiSCR, PGA, and disease activity were scored; and (iv) patients’ vital signs were assessed. Patients were then asked for any AEs and SAEs.
      Blood draws were performed at screening and at weeks 2, 4, 8, and 12 for serum creatinine and liver biochemistry, complete blood count with differential and platelets, and pharmacokinetics/biomarker analysis. An ELISA was developed to specifically measure bermekimab levels in human plasma. Blood was drawn into a single 6-ml collection tube at each pharmacokinetics collection time point (samples were collected before dosing at the investigative site per the study lab manual and immediately shipped to the sponsor for pharmacokinetics analysis).
      Any AE of grade II or higher was required to be entered into the electronic case report form within 24 hours of learning of the event. Any grade III or greater injection site reaction was to be reported to the sponsor within 24 hours of learning of the event. All SAEs were reported to the sponsor within 24 hours of knowledge of the event. These immediate reports were followed promptly by detailed, written reports. The subject was followed up with until stabilization of the reported SAE, either with full satisfactory resolution or resolution with sequelae or until death of the subject. Before declaring the subject was lost to follow-up, three unsuccessful attempts at contact were made and recorded on the SAE form. The immediate and follow-up reports identified subjects by unique code numbers assigned to the trial subjects rather than by the subjects’ names, personal identification numbers, and/or addresses. The investigators were obligated to submit SAEs to the institutional review board or ethics committee according to their institutional review board or ethics committee guidelines (ICH-GCP E6). Drug-related SAEs would have been reported to the Food and Drug Administration by XBiotech’s Medical Safety Officer according to 21 CFR 312.32.

      Study endpoints

      The primary study endpoint was the clinical safety and tolerability of bermekimab in moderate-to-severe HS. The secondary endpoints were change in the Hospital Anxiety and Depression Scale and HiSCR, assessment of pharmacokinetics, change in patient-reported outcomes (VAS for disease, VAS for pain, and Dermatology Life Quality Index), assessment of PGA and Disease Activity Score, and change in inflammatory lesion (abscesses and inflammatory modules) count from baseline to week 12.

      Statistical analysis

      All analyses were summarized using descriptive statistics and data was presented in tabular format for each treatment group. Changes in outcomes for all endpoints from baseline to week 12 for both treatment groups were summarized using the number of observations available (n), mean, SD, median, range, and 95% confidence interval of the mean change from baseline. Categorical data was summarized for each treatment group using counts and percentages. Any missing patient data was imputed using Last Observation Carried Forward.

      Data availability statement

      No datasets were generated or analyzed during this study.

      Conflict of Interest

      This study was executed and funded by XBiotech, Austin, Texas. AG holds stock and/or stock options for XBiotech. AG is a consultant to XBiotech and assisted in design of this study but has received no monetary compensation for her work. She is also a consultant for AbbVie as well as a consultant and investigator for Novartis’ secukinumab HS study, with all research compensation awarded to Mount Sinai. Nicola E. Natsis was hired as a consultant to aid in the creation of this manuscript. The remaining authors declare there is no conflict of interest regarding the publication of this article. Jessica Kaffenberger has served as principal investigator for AbbVie, AnaptysBio, Bristol-Myers, Cara Therapeutics, Celgene, Corrona, Eli Lilly, Janssen, Novartis, Pfizer, Regeneron, and XBiotech. John Simard is an employee of and holds stock and stock options for XBiotech. He holds patents related to anti–IL-1α therapy.

      Acknowledgments

      This study was executed and funded by XBiotech , Austin, Texas. Trial registration: ClinicalTrials.gov, NCT03512275.

      Supplementary Material

      Supplementary Table S1Number (Percentage) of Subject in Each System Organ Class/AE Preferred Term
      AE Preferred TermGroup A 400 mg (anti-TNF failure)

      (n = 24)
      Group B 400 mg (anti-TNF naïve)

      (n = 18)
      Grade IGrade IIGrade IIITotalGrade IGrade IIGrade IIITotal
      Eye disorders1 (4.2%)001 (4.2%)0000
       Ocular hyperemia1 (4.2%)3001 (4.2%)0000
      Gastrointestinal disorders2 (8.3%)002 (8.3%)2 (11.1%)2 (11.1%)04 (22.2%)
       Abdominal pain1 (4.2%)5001 (4.2%)0000
       Constipation1 (4.2%)2001 (4.2%)0000
       Diarrhea00001 (5.6%)44001 (5.6%)
       Nausea00001 (5.6%)41 (5.6%)202 (11.1%)
       Toothache000001 (5.6%)201 (5.6%)
      General disorders and administration site conditions3 (12.5%)003 (12.5%)1 (5.6%)2 (11.1%)03 (16.7%)
       Fatigue00001 (5.6%)2001 (5.6%)
       Injection site erythema1 (4.2%)5001 (4.2%)0000
       Injection site pruritus1 (4.2%)5001 (4.2%)0000
       Injection site reaction2 (8.3%)3,5002 (8.3%)02 (11.1%)4,502 (11.1%)
      General disorders and administration site conditions; skin and subcutaneous tissue disorders1 (4.2%)001 (4.2%)0000
       Injection site reaction; erythema1 (4.2%)3001 (4.2%)0000
      General disorders and administration site conditions; skin and subcutaneous tissue disorders; general disorders and administration site conditions1 (4.2%)001 (4.2%)0000
       Injection site reaction; erythema; injection site swelling1 (4.2%)5001 (4.2%)0000
      Infections and infestations4 (16.7%)004 (16.7%)1 (5.6%)1 (5.6%)02 (11.1%)
       Cellulitis000001 (5.6%)301 (5.6%)
       Influenza1 (4.2%)1001 (4.2%)0000
       Nasopharyngitis1 (4.2%)1001 (4.2%)0000
       Upper respiratory tract infection00001 (5.6%)1001 (5.6%)
       Urinary tract infection2 (8.3%)1,2002 (8.3%)0000
      Injury, poisoning and procedural complications001 (4.2%)1 (4.2%)0000
       Fall001 (4.2%)11 (4.2%)0000
      Metabolism and nutrition disorders01 (4.2%)01 (4.2%)0000
       Hypoglycemia01 (4.2%)201 (4.2%)0000
      Musculoskeletal and connective tissue disorders00001 (5.6%)1 (5.6%)02 (11.1%)
       Back pain000001 (5.6%)201 (5.6%)
       Muscle spasms00001 (5.6%)2001 (5.6%)
      Nervous system disorders3 (12.5%)1 (4.2%)04 (16.7%)0000
       Headache1 (4.2%)3001 (4.2%)0000
       Intracranial pressure increased01 (4.2%)201 (4.2%)0000
       Presyncope1 (4.2%)3001 (4.2%)0000
       Syncope1 (4.2%)1001 (4.2%)0000
      Reproductive system and breast disorders000001 (5.6%)1 (5.6%)2 (11.1%)
       Balanoposthitis0000001 (5.6%)21 (5.6%)
       Dysmenorrhea000001 (5.6%)101 (5.6%)
      Skin and subcutaneous tissue disorders2 (8.3%)01 (4.2%)3 (12.5%)02 (11.1%)02 (11.1%)
       Dry skin1 (4.2%)1001 (4.2%)0000
       Erythema000001 (5.6%)401 (5.6%)
       Hidradenitis001 (4.2%)11 (4.2%)01 (5.6%)201 (5.6%)
       Pruritus1 (4.2%)4001 (4.2%)01 (5.6%)401 (5.6%)
       Rash1 (4.2%)3001 (4.2%)0000
      Vascular disorders000001 (5.6%)01 (5.6%)
       Hypertension000001 (5.6%)301 (5.6%)
      Abbreviation: AE, adverse event.
      AEs are labeled as follows: 1not related; 2unlikely related; 3possibly related; 4probably related; 5definitely related.
      Supplementary Table S2Descriptive Explanations of Secondary Study Endpoints
      EndpointDescription
      DLQIDLQI is a 10-item validated questionnaire used in clinical practice and clinical trials to assess the impact of HS disease symptoms and treatment on QOL. The format is a simple response (0 to 3 where 0 is not at all and 3 is very much) to 10 questions, which assess QOL over the past week, with an overall scoring system of 0 to 30; a high score is indicative of a poor QOL.
      PGAPGA is an assessment scale used in clinical studies to determine severity of HS and clinical response to treatment based on a 5-point scale ranging from 0 (clear) to 5 (very severe). The definitions of the scores 0-5 are as follows: a) clear when the total number of abscesses is 0, the total number of draining fistulas is 0, the total number of inflammatory nodules is 0 and the total number of non-inflammatory nodules is 0; b) minimal when the total number of abscesses is 0, the total number of draining fistulas is 0, the total number of inflammatory nodules is 0 and there is presence of non-inflammatory nodules; c) mild when the total number of abscesses is 0, the total number of draining fistulas is 0, and the total number of inflammatory nodules is 1–4, or when there is presence of one abscess or draining fistula and absence of any inflammatory nodules; d) moderate when the total number of abscesses is 0, the total number of draining fistulas is 0 and the total number of inflammatory nodules is at least 5, or when there is presence of one abscess or draining fistula and at least one inflammatory nodule or when there are 2–5 abscesses or draining fistulas and fewer than 10 inflammatory nodules; e) severe when the total number of abscesses or draining fistulas is 2–5 and the total number of inflammatory nodules is at least 10; and f) very severe when there are more than 5 abscesses or draining fistulas.
      HADS anxiety scoreHADS is an instrument for screening anxiety and depression in nonpsychiatric populations; repeated administration also provides information about changes to a patient’s emotional state. HADS consists of 14 items, 7 each for anxiety and depression symptoms; possible scores range from 0 to 21 for each subscale. The following cut-off scores are recommended for both subscales: 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression.
      HADS depression scoreHADS is an instrument for screening anxiety and depression in nonpsychiatric populations; repeated administration also provides information about changes to a patient’s emotional state. HADS consists of 14 items, 7 each for anxiety and depression symptoms; possible scores range from 0 to 21 for each subscale. The following cut-off scores are recommended for both subscales: 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression.
      HiSCRHiSCR is used to assess disease activity in patients with HS. HiSCR is binary, in that it is either satisfied/met or not satisfied/met. To satisfy/meet HiSCR, a patient must have at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count compared with baseline. In this study, patients were evaluated for whether or not they satisfied/met HiSCR at week 13 relative to their week 1 baselines.
      VAS - Disease/PainVAS for disease and pain are horizontal graduated scales on which patients can report the impression they have of their disease and the severity of their pain ranging from 0 (not at all severe disease or no pain) to 10 (extremely severe disease or worst imaginable pain).
      DASDAS is defined as the sum of scores of all affected areas of each patient. Each area was evaluated by the following formula: (the number of lesions seen in the affected area multiplied by the degree of inflammation) + (the sum of the size in mm of the 2 largest lesions in the affected area).
      PharmacokineticsAn ELISA was developed to specifically measure bermekimab levels in human plasma. Blood was drawn into a single 6-ml collection tube at each pharmacokinetics collection time point (sample collection is pre-dose at visit 1, visit 3, visit 5, visit 9, and visit 13).
      Abbreviations: DAS, Disease Activity Score; DLQI, Dermatology Life Quality Index; HADS, Hospital Anxiety and Depression Scale; HiSCR, hidradenitis suppurativa clinical response; HS, hidradenitis suppurativa; PGA, Physician’s Global Assessment; VAS, Visual Analogue Scale.

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