Perlman Susan, Anheim Mathieu, Boesch Sylvia, Lewis James H, Lynch David R
Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Ave, Los Angeles, CA, 90095, USA.
Department of Neurology, University Hospital of Strasbourg, Strasbourg, France.
Neurol Ther. 2025 Jun 2. doi: 10.1007/s40120-025-00752-8.
Omaveloxolone is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥ 16 years and is under clinical development for pediatric patients. In the MOXIe study, alanine and aspartate aminotransferase (ALT and AST) elevations were among the most common treatment-emergent adverse events (TEAEs) in the omaveloxolone arm and were mild to moderate, generally asymptomatic, transient, and reversible; no patients who received omaveloxolone had laboratory abnormalities that met the Hy's law criteria. Omaveloxolone labels (US and EU) provide guidance for monitoring and managing these elevations. Here, practical use considerations, from experience-based opinions of four FA experts and a hepatologist via semi-structured interviews, are presented. Prior to omaveloxolone initiation, assessment of baseline ALT, AST, and total bilirubin is recommended per label. During treatment, ALT, AST, and total bilirubin should be monitored monthly for the first 3 months and periodically thereafter per label. Reduced frequency of patient monitoring after 3 months is suggested if aminotransferase levels remain normal. Per label, omaveloxolone should be temporarily discontinued if aminotransferases increase to > 5 × the upper limit of normal (ULN) or > 3 × ULN with other evidence of liver dysfunction. Stemming from real-world practical considerations wherein patients are followed up less frequently than in the trial setting, treatment interruption when aminotransferases increase to ≥ 3 × ULN without other signs of hepatic impairment may be considered. When aminotransferase elevations stabilize or resolve, omaveloxolone may be reinitiated with an appropriate increased frequency of monitoring of liver function per label. We propose patients who pause treatment may have testing repeated after 2 weeks, while those with resolving aminotransferase elevations may reinitiate omaveloxolone with stepwise dose titrations and testing every 2 weeks for ≈ 3 months. Use considerations herein may inform decisions on monitoring and managing ALT and AST elevations, which potentially help to encourage the treatment adherence needed to achieve the slowing of FA progression seen in MOXIe.Graphical abstract available for this article.
奥伐洛生已被批准用于治疗16岁及以上的弗里德赖希共济失调（FA）患者，目前正在针对儿科患者进行临床开发。在MOXIe研究中，丙氨酸和天冬氨酸转氨酶（ALT和AST）升高是奥伐洛生治疗组中最常见的治疗中出现的不良事件（TEAE），且为轻度至中度，通常无症状、短暂且可逆；接受奥伐洛生治疗的患者中，没有实验室异常符合Hy法则标准。奥伐洛生的标签（美国和欧盟）为监测和管理这些升高情况提供了指导。在此，我们介绍了来自四位FA专家和一位肝病专家基于经验的意见，通过半结构化访谈得出的实际使用注意事项。根据标签建议，在开始使用奥伐洛生前，应评估基线ALT、AST和总胆红素。治疗期间，前3个月应每月监测ALT、AST和总胆红素，此后根据标签定期监测。如果转氨酶水平保持正常，建议3个月后减少患者监测频率。根据标签，如果转氨酶升高至>正常上限（ULN）的5倍或>3倍ULN且伴有其他肝功能障碍证据，应暂时停用奥伐洛生。出于现实世界的实际考虑，即患者随访频率低于试验环境，当转氨酶升高至≥3倍ULN且无其他肝损伤迹象时，可考虑中断治疗。当转氨酶升高稳定或消退时，可根据标签适当增加肝功能监测频率后重新开始使用奥伐洛生。我们建议暂停治疗的患者可在2周后重复检测，而转氨酶升高消退的患者可逐步滴定剂量重新开始使用奥伐洛生，并每2周检测一次，持续约3个月。本文中的使用注意事项可能为监测和管理ALT和AST升高的决策提供参考，这可能有助于鼓励患者坚持治疗，以实现MOXIe研究中所见的减缓FA进展的效果。本文提供图形摘要。
