Harvard Medical School and Beth Israel Deaconess Medical Center, Boston.
Pfizer Inc, Collegeville, PA.
NEJM Evid. 2024 Mar;3(3):EVIDoa2300155. doi: 10.1056/EVIDoa2300155. Epub 2024 Feb 9.
Hidradenitis suppurativa (HS) is a debilitating, inflammatory skin disease with limited treatment options and partially understood pathophysiology. Using an umbrella trial design, three kinase inhibitor immunomodulators with different mechanisms of action were evaluated. METHODS: This phase 2a, double-blind, parallel-group trial enrolled adults with moderate to severe HS who were then randomly assigned (1:1:1:1) to once-daily brepocitinib 45 mg (a JAK1/TYK2 inhibitor), zimlovisertib 400 mg (an IRAK4 inhibitor), ropsacitinib 400 mg (a TYK2 inhibitor), or matching placebo for 16 weeks. The primary end point was the percentage of participants achieving HS clinical response (HiSCR) at week 16. Safety, including treatment-emergent adverse events (TEAEs), was monitored throughout. RESULTS: Totals of 52, 47, 47, and 48 participants were assigned to brepocitinib, zimlovisertib, ropsacitinib, and placebo, respectively. At week 16, 28% were lost to follow-up and assumed to be nonresponders; HiSCR occurred in 33.3% (16/48) of participants receiving placebo and in 51.9% (27/52), 34.0% (16/47), and 37.0% (17/46) of those receiving brepocitinib, zimlovisertib, and ropsacitinib (difference in percentage points vs. placebo [90% confidence interval], 18.7 [2.7 to 34.6], 0.7 [−15.2 to 16.7], and 3.5 [−12.6 to 19.6]), respectively. TEAEs occurred more frequently with active treatment (brepocitinib, 30 [57.7%]; zimlovisertib, 26 [55.3%]; ropsacitinib, 29 [61.7%]; placebo, 23 [47.9%]). Most TEAEs (infections, skin disorders, and gastrointestinal symptoms) were mild; there were no deaths. CONCLUSIONS: Participants with moderate to severe HS treated with brepocitinib experienced greater clinical response, whereas those on zimlovisertib and ropsacitinib did not, compared with placebo. These results favor the JAK/STAT pathway as an immunologic target in HS and did not confirm a role for selective IRAK4 or TYK2 inhibition. These results should be confirmed in larger studies with longer follow-up. (Funded by Pfizer; ClinicalTrials.gov registration number, NCT04092452.)
化脓性汗腺炎（HS）是一种使人衰弱的炎症性皮肤病，其治疗选择有限，发病机制部分尚不清楚。本研究采用伞式试验设计，评估了三种具有不同作用机制的激酶抑制剂免疫调节剂。
这是一项 2a 期、双盲、平行分组试验，招募了中重度 HS 成年患者，然后将其随机分为（1:1:1:1）四组，分别接受每日一次的 brepocitinib（JAK1/TYK2 抑制剂）45mg、zimlovisertib（IRAK4 抑制剂）400mg、ropsacitinib（TYK2 抑制剂）400mg 或匹配安慰剂治疗 16 周。主要终点是第 16 周时达到 HS 临床反应（HiSCR）的参与者比例。安全性，包括治疗后出现的不良事件（TEAEs），在整个试验过程中进行监测。
分别有 52、47、47 和 48 名参与者被分配至 brepocitinib、zimlovisertib、ropsacitinib 和安慰剂组。第 16 周时，28%的患者失访并被假定为无应答者；接受安慰剂的患者中有 33.3%（16/48）达到 HiSCR，而接受 brepocitinib、zimlovisertib 和 ropsacitinib 的患者分别有 51.9%（27/52）、34.0%（16/47）和 37.0%（17/46）达到 HiSCR（与安慰剂相比，差异百分比[90%置信区间]为 18.7[2.7 至 34.6]、0.7[-15.2 至 16.7]和 3.5[-12.6 至 19.6]）。与安慰剂组相比，活性治疗组（brepocitinib 组 30[57.7%]、zimlovisertib 组 26[55.3%]、ropsacitinib 组 29[61.7%]）发生治疗相关不良事件（TEAEs）的频率更高。大多数 TEAEs（感染、皮肤疾病和胃肠道症状）为轻度；无死亡病例。
与安慰剂相比，接受 brepocitinib 治疗的中重度 HS 患者的临床反应更大，而接受 zimlovisertib 和 ropsacitinib 治疗的患者则没有。这些结果支持 JAK/STAT 通路作为 HS 的免疫治疗靶点，并未证实选择性 IRAK4 或 TYK2 抑制有作用。这些结果应在随访时间更长的更大规模研究中得到证实。
（由辉瑞公司资助；临床试验.gov 注册号：NCT04092452。）
