Abstract and Introduction
Background: Janus kinase (JAK)-mediated cytokine signalling contributes to local and systemic inflammation in hidradenitis suppurativa (HS).
Objectives: To describe the safety and efficacy results from two multicentre phase II trials of the JAK1 inhibitor INCB054707 in patients with moderate-to-severe HS.
Methods: Patients received open-label INCB054707 15 mg once daily (QD; Study 1) or were randomized to INCB054707 30, 60 or 90 mg QD or placebo (3 : 1 within each cohort; Study 2) for 8 weeks. Eligible patients were aged 18–75 years and had moderate-to-severe HS (Hurley stage II/III disease), lesions present in at least two anatomical locations, and a total abscess and inflammatory nodule count ≥ 3. The primary endpoint for both studies was safety and tolerability. Secondary endpoints included HS Clinical Response (HiSCR) and other efficacy measures.
Results: Ten patients were enrolled in Study 1 (15 mg INCB054707) and 35 in Study 2 (INCB054707: 30 mg, n = 9; 60 mg, n = 9; 90 mg, n = 8; placebo, n = 9). Overall, 70% of patients in Study 1 and 81% of patients receiving INCB054707 in Study 2 experienced at least one treatment-emergent adverse event; 30% and 42% of patients, respectively, had at least one treatment-related adverse event. Among the evaluable patients, three (43%) in Study 1 and 17 (65% overall: 30 mg, 56%; 60 mg, 56%; 90 mg, 88%) receiving INCB054707 vs. 4 patients (57%) receiving placebo in Study 2 achieved HiSCR at week 8.
Conclusions: INCB054707 was well tolerated, with responses observed in patients with moderate-to-severe HS. The safety and efficacy findings from these studies demonstrate proof of concept for JAK1 inhibition in HS. The studies are registered on ClinicalTrials.gov (NCT03569371 and NCT03607487).
Hidradenitis suppurativa (HS), or acne inversa, is a chronic, inflammatory condition characterized by painful, deep-seated nodules and abscesses of apocrine-gland-bearing skin.[1,2] In more severe disease, the development of pus-discharging tunnels, known as sinus tracts, results in irreversible tissue destruction and scarring. In European and US populations, the prevalence of HS is most likely between 0·7% and 1·2%. Women are predominantly affected in Western countries, whereas reports from Asia describe a male majority.[5–10] Increased prevalence among black and biracial vs. white individuals has been described in the USA.[8,11] Disease onset typically occurs in young adulthood, and the most commonly affected areas include the groin/genitals, axillae, buttocks and breasts.[12–16] Patients with HS may experience painful lesions, impaired work ability or productivity, reduced sexual health, and feelings of shame and stigmatization, all of which contribute to markedly reduced quality of life (QoL).[17–20] Furthermore, patients are often burdened by psychological comorbidities that worsen with increasing disease severity.[21–23]
Adalimumab [anti-tumour necrosis factor (TNF)-α] is the only agent approved by the US Food and Drug Administration and European Medicines Agency for the treatment of moderate-to-severe HS (Hurley stage II/III). In two phase III trials, adalimumab treatment resulted in disease improvement based on HS Clinical Response (HiSCR) criteria in a statistically significant but relatively small proportion of patients vs. placebo (PIONEER I, 42% vs. 26%; PIONEER II, 59% vs. 28%). Furthermore, response to adalimumab generally declines over time,[25,26] highlighting the need for additional therapeutic options.
The role of Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-mediated type I/II cytokine signalling in dermatological disease is becoming increasingly prominent.[27,28] Oral and topical JAK inhibitors have entered clinical testing in several inflammatory skin disorders, including alopecia areata, atopic dermatitis, psoriasis and vitiligo, with findings indicating reduced inflammation and improvement in disease severity and symptoms following treatment. Literature suggests that HS pathogenesis is driven by multiple JAK/STAT-mediated cytokines, including interleukin (IL)-1β, IL-17, IL-23 and IL-10 and, to a lesser extent, TNF-α.[1,29–37] Thus, inhibiting JAK-mediated pathways could address HS disease biology more broadly than agents targeting individual cytokines. A small case study of two patients with HS reported successful treatment with the pan-JAK inhibitor tofacitinib; however, clinical trials of JAK inhibitors in HS have not been previously published.
INCB054707 is an oral, small-molecule JAK1 inhibitor with approximately 52-fold greater selectivity for JAK1 vs. JAK2. Specifically targeting JAK1, a critical regulator of proinflammatory cytokine signalling implicated in several immune-related diseases, may reduce cytokine signalling involved in HS pathogenesis while limiting JAK2-mediated cytopenias. Here we describe the safety and efficacy of INCB054707 in two multicentre phase II trials in patients with moderate-to-severe HS: Study 1 (NCT03569371) and Study 2 (NCT03607487).
The British Journal of Dermatology. 2022;186(5):803-813. © 2022 Blackwell Publishing