在标准慢性（9 个月）毒理学研究中，在接受 Ritlecitinib 治疗的狗中观察到可逆性轴突肿胀和脑干听觉诱发电位 (BAEP) 变化，Ritlecitinib 是一种在肝细胞癌家族激酶抑制剂中表达的口服 Janus 激酶 3/酪氨酸激酶，暴露量高于批准的 50 毫克人体剂量。为了评估狗毒性发现的临床相关性，这项 2a 期双盲研究评估了接受 Ritlecitinib 治疗的成人斑秃患者的 BAEP 变化和表皮内神经纤维 (IENF) 组织学。患者被随机接受口服瑞特西替尼 50mg 每日一次（QD），为期 4 周的负荷剂量 200mg QD 或安慰剂，持续 9 个月（安慰剂对照阶段）；然后，他们进入积极治疗扩展阶段并接受 ritlecitinib 50 mg QD（对于从安慰剂转换的患者，4 周负荷剂量为 200 mg）。在 71 名患者中，第 9 个月时，在 Ritlecitinib 组或安慰剂组中，在刺激强度为 80dB nHL 时，BAEP 上的波 I-V 波间潜伏期（主要结果）或波 V 振幅与基线 (CFB) 的变化没有观察到显着的平均差异，组间波间潜伏期或 Wave V 幅度没有显着差异。第 9 个月时，各组之间的平均或中位 IENF 密度以及伴有轴突肿胀的 IENF 百分比的 CFB 很小且相似。 Ritlecitinib 治疗也与神经学和听力学不良事件的不平衡发生率无关。这些结果提供证据表明，狗身上发现的 BAEP 和轴突肿胀与人类没有临床相关性。© 2024 Pfizer Inc. 和作者。药理研究

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9-month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50-mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double-blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4-week loading dose of 200 mg QD or placebo for 9 months (placebo-controlled phase); they then entered the active-therapy extension and received ritlecitinib 50 mg QD (with a 4-week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I-V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.© 2024 Pfizer Inc. and The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.