Pemphigus is a rare but life-threatening autoimmune disease requiring long-term treatment that minimizes corticosteroid (CS) exposure while providing consistent disease control. The phase 2 pemphigus study of oral, reversible, covalent Bruton tyrosine kinase inhibitor rilzabrutinib demonstrated rapid and sustained efficacy with well-tolerated safety. Adults (aged 18–80 years) were randomized 1:1 to 400 mg rilzabrutinib (n = 65) or placebo (n = 66) twice daily (with CS ≤ 0.5 mg/kg/d) for 37 weeks in the phase 3 PEGASUS study in moderate-to-severe pemphigus vulgaris/pemphigus foliaceus. The primary endpoint of complete remission from week 29 to week 37 with the amended endpoint CS dose ≤10 mg/d was not significant for 13 of 54 (24%) rilzabrutinib versus 10 of 55 (18%) placebo patients with PV ( = .45). Secondary endpoints showed numerical but nonsignificant improvements with rilzabrutinib (vs placebo) in reduced CS use, prolonged complete remission duration, and faster time to first complete remission. Overall, rilzabrutinib was well-tolerated, with similar adverse events reported in both groups. Using minimal CS dose ≤10 mg/d and excluding remote observations, the primary efficacy endpoint was not met. However, results from a prespecified sensitivity analysis using CS dose ≤5 mg/d, considering all observations, and including all patients support Bruton tyrosine kinase inhibition as a viable therapeutic approach for pemphigus.

中文翻译：

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Rilzabrutinib 在天疱疮中的疗效和安全性：PEGASUS 3 期随机研究

天疱疮是一种罕见但危及生命的自身免疫性疾病，需要长期治疗，最大限度地减少皮质类固醇 (CS) 暴露，同时提供持续的疾病控制。口服、可逆、共价布鲁顿酪氨酸激酶抑制剂 rilzabrutinib 的 2 期天疱疮研究证明了快速、持续的疗效和良好的耐受性安全性。成人（18-80 岁）在 3 期 PEGASUS 试验中按 1:1 随机分配至 400 mg rilzabrutinib（n = 65）或安慰剂（n = 66），每天两次（CS ≤ 0.5 mg/kg/d），持续 37 周中度至重度寻常型天疱疮/落叶型天疱疮的研究。主要终点为从第 29 周到第 37 周的完全缓解，修正终点 CS 剂量≤10 mg/d，对于 54 名 rilzabrutinib 患者中的 13 名（24%）而言，与 55 名安慰剂患者中的 10 名（= . 45）。次要终点显示，利扎布替尼（与安慰剂相比）在减少 CS 使用、延长完全缓解持续时间和缩短首次完全缓解时间方面有数值但不显着的改善。总体而言，利扎布替尼耐受性良好，两组均报告了类似的不良事件。使用最小 CS 剂量≤10 mg/d 并排除远程观察，未达到主要疗效终点。然而，使用 CS 剂量≤5 mg/d 进行的预先设定的敏感性分析的结果，考虑到所有观察结果，并包括所有患者，支持布鲁顿酪氨酸激酶抑制作为天疱疮的可行治疗方法。