Omaveloxolone

Global Phase 3 BRAVE study will evaluate the efficacy and safety of omaveloxolone in children 2 to <16 years old with Friedreich ataxia, a rare neurodegenerative disorder BRAVE study will explore the potential of omaveloxolone to address the critical unmet need of the pediatric FA population Omaveloxolone is currently marketed under the brand name SKYCLARYS® for the treatment of adults and adolescents aged 16 years and older affected by Friedreich ataxia CAMBRIDGE, Mass., June 18, 2025 (GLOBE NEWSWIRE) -- Biogen Inc. (Nasdaq: BIIB) announced the initiation of dosing in the BRAVE study, a global Phase 3 clinical trial. The BRAVE study will evaluate the efficacy and safety of omaveloxolone in children with Friedreich ataxia (FA) between the ages of 2 to <16. Both non-ambulatory and ambulatory participants may qualify for the study. Participants will be randomized 2:1 to receive omaveloxolone or placebo once a day for 52 weeks before having the opportunity to move into the open-label extension (OLE). Currently, omaveloxolone is commercialized under the brand name SKYCLARYS® in over 40 countries, including in the U.S. and the European Union, and is the only approved product for FA in adults and adolescents aged 16 years and older. “Recognizing the symptoms of Friedreich ataxia typically begin in childhood, and earlier onset of symptoms is associated with faster disease progression, there is tremendous unmet need in the pediatric community. Building on the work of Reata we have been urgently advancing the pediatric development plan for omaveloxolone and are thrilled that the Phase 3 BRAVE study has now begun,” said Stephanie Fradette, Pharm.D., Head of the Neuromuscular Development Unit at Biogen. “We are immensely grateful for the input from the entire FA community that has helped shape the design of this important study.” The BRAVE study will evaluate the efficacy, safety, pharmacokinetics and pharmacodynamics of omaveloxolone in approximately 255 children living with FA. Part 1 is a 52 week, randomized, double-blind, placebo-controlled study, designed to evaluate efficacy of omaveloxolone compared to placebo. The primary outcome measure for Part 1 is change from baseline in Upright Stability Score (USS), a subscale that is recognized by the FA community as the most sensitive means of measuring disease progression in children living with FA. USS is part of the validated modified FA rating scale (mFARS). Part 2 will be an open-label extension (up to week 104) where all participants will receive omaveloxolone to further our understanding of the long-term effects of the drug. “Early onset patients often have the most aggressive and fast progressive form of Friedreich ataxia and through the BRAVE study we aim to determine the potential safety and efficacy of omaveloxolone for children living with the disease. This vulnerable population faces significant unmet need, with no approved treatments currently available,” said Susan Perlman, M.D., Professor of Neurology and Director of the Ataxia Center, David Geffen School of Medicine at UCLA. The design of this Phase 3 study has been informed by previous studies and input from investigators, global medical experts and the FA community. Enrollment has initiated in the United States and we plan to open BRAVE study sites around the world pending final alignment with local regulators and ethics committees. Individuals interested in participating in this study should speak with their healthcare provider. They can also email Biogen at clinicaltrials@biogen.com. Individuals located in the U.S. can also call the Biogen Clinical Trials Center at 866-633-4636. Both clinicaltrials.gov (NCT06953583) and Biogen Trial Link (Biogen Trial Link) will be updated as more information about the BRAVE study becomes available. About SKYCLARYS® (omaveloxolone)SKYCLARYS® (omaveloxolone) is an oral, once-daily medication indicated for the treatment of Friedreich’s ataxia (FA) in adults and adolescents aged 16 years and older in over 40 countries, including the U.S. and European Union. SKYCLARYS received Orphan Drug, Fast Track, and Rare Pediatric Disease Designations from the U.S. Food and Drug Administration. The European Commission granted Orphan Drug designation in Europe to SKYCLARYS for the treatment of FA. Please click here for Important Safety Information and full Prescribing Information for SKYCLARYS® (omaveloxolone) in the U.S. or visit your respective country’s product website. About Friedreich AtaxiaFriedreich ataxia (FA) is a rare, genetic, life-shortening, debilitating, and degenerative neuromuscular disorder. It is the most common inherited ataxia.1,2,3 Early symptoms of FA, such as progressive loss of coordination, muscle weakness and fatigue, typically appear in childhood and can overlap with other diseases.4 Most people living with FA will need to use a wheelchair within 10-20 years of their first symptoms.2 The reported average age of death for FA patients is just 37 years old, although with appropriate and targeted care, individuals may live many years after confinement to a wheelchair.5-7 About BiogenFounded in 1978, Biogen is a leading biotechnology company that pioneers innovative science to deliver new medicines to transform patients’ lives and to create value for shareholders and our communities. We apply deep understanding of human biology and leverage different modalities to advance first-in-class treatments or therapies that deliver superior outcomes. Our approach is to take bold risks, balanced with return on investment to deliver long-term growth.We routinely post information that may be important to investors on our website at www.biogen.com. Follow us on social media - Facebook, LinkedIn, X, YouTube. Biogen Safe Harbor This news release contains forward-looking statements including relating to the potential benefits, safety and efficacy of SKYCLARYS; potential regulatory discussions, submissions and approvals and the timing thereof; the treatment of Friedreich’s ataxia; the potential of Biogen’s commercial business and pipeline programs, including Friedreich’s ataxia; and risks and uncertainties associated with drug development and commercialization. These statements may be identified by words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “intend,” “may,” “plan,” “possible,” “potential,” “will,” “would” and other words and terms of similar meaning. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical studies may not be indicative of full results or results from later stage or larger scale clinical studies and do not ensure regulatory approval. You should not place undue reliance on these statements. Given their forward-looking nature, these statements involve substantial risks and uncertainties that may be based on inaccurate assumptions and could cause actual results to differ materially from those reflected in such statements. These forward-looking statements are based on management's current beliefs and assumptions and on information currently available to management. Given their nature, we cannot assure that any outcome expressed in these forward looking statements will be realized in whole or in part. 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溶出数据显示，拟定的omaveloxolone胶囊，50毫克，在拟定溶出介质（即50 mol磷酸钠缓冲液中，pH值6.8，%1的SLS）中45min实现完全溶解。2）溶出方法区分力a）原料药粒径分布（PSD）的变化 申请人通过有意生产具有不同PSD原料药批次的制剂，研究了溶出方法对原料药粒度改变的区分力，如表6所示。溶出结果如图4所示，表明拟定溶出方法无区分PSD变化的能力。表6: 无定型原料药变异PSD溶出区分力研究图4 Omaveloxolone胶囊的平均溶出曲线（N=18），50mg，无定型原料药粒度变化，在%1SLS的pH 6.8磷酸盐缓冲盐，100rpm转速FDA审评：Omaveloxolone是一种BCS IV类药物，具有中/高生物药剂学风险。FDA期望拟定溶出方法对关键物料属性（CMAs）和关键工艺参数（CPPs）具有一定的区分能力。期望该方法能够区分原料药PSD变化。然而，在上述研究中，拟定溶出方法并没有区分原料药粒径分布（PSD）变化。原因可能是三批次原料药之间的PSD差异不显著。在生物药剂学问询中，FDA进一步要求企业研究拟定溶出方法是否能区分原料药PSD的更大差异。企业在回复FDA问询时阐述到，实际生产中，很难得到有巨大差异PSD的原料药，同时企业也同意修改原料药PSD接受标准，对D90限度进行修改，从NMT XXum 修改至NMT XXum。c）处方变化企业通过改变辅料的比例来特意生产以下批次，如表7. 对于这些批次，拟定的溶出方法没有展示出区分力，数据如图5.表7:改变处方组成图5: Omaveloxolone 胶囊50mg规格平均溶解曲线（N=12），处方比例变化， 在1% SLS磷酸盐缓冲液pH 6.8，100 rpm转速FDA审评意见：由于原料药生产过程限制，企业无法得到在PSD上差异很大的不同批次制剂，以进一步研究拟定溶出方法的区分力。然而，拟定溶出方法的区分力（b）（4）当溶出接受标准为Q"= XX% XXmin" 修订为 Q"= XX% 45 min时，带有（b）（4）的批次将被拒绝，这将进一步减轻生物药剂学风险。总体而言，拟定溶出方法被认为是可以接受的。2.溶出数据和接受标准a）溶出数据 企业提供了10个临床批次和3个注册批次的详细信息和完整的溶出曲线数据（表8和表9）。发现几乎所有溶出数据为6粒/批，而不是FDA要求的12粒/批的溶出数据。而且，不同批次有不同的取样时间点（比如，批170114的取样时间点：10，15，20，30，45，60min；批318136R的取样时间点：15，30，45，60min），这样的数据导致很难对比批间的溶出差异。企业对于生物药剂学IR1的回复，提供的数据见表10.表8:所有临床批次和注册批次表9:所有注册批次表10:关键临床批次和注册批次平均溶出曲线数据（n=12）【解读】对于具有BCS IV类特征的化合物，其具有中高生物药剂学风险，即溶出是否可以识别出那些不合格的批次样品。这些不合格的样品可能是不同工艺，或者不同CQA原料药生产得到的。FDA挑战了方法对原料药粒度的区分能力，但可惜的是，通过生产不同粒度原料药得到的制剂，溶出曲线没有表现出差异，即溶出方法对原料药粒度变化没有区分力。企业通过变化处方中不同辅料比例得到的批次，拟定的溶出方法测试数据与不同粒度原料药一样，没有显示方法的区分力。FDA的审评意见中，可以看出溶出方法对某一参数或因素的变化，可以表现出区分力，通过修订Q值时间，区分出这些参数/因素变化的批次。即使是BCS IV类化合物，拟定的溶出方法没有在原料药粒度或处方组成上表现出区分力，FDA在审评过程中提出了一些问询，但没有否定该溶出方法，而是希望企业提供更多的研究数据说明，以及体内的PK数据说明，拟定方法可以用于批次质量放行。FDA指出企业提供的不同批次溶出数据有一些瑕疵，即取样时间点各有不同，无法进行批次之间的溶出曲线对比，这些批次中有用于确证性临床的，其溶出数据的对比对于溶出方法的拟定和接受标准拟定非常关键。推荐文章：1. AI智能体发布大家都在用的“智能体小程序”作者精彩原创集锦1、创新药研发中原料药工艺与沟通交流常见难点2、创新药研发中「制剂工」常见难点3、创新药研发中「变更」相关难点4、创新药研发中「质量分析控制」相关难点（1）5、创新药研发中「质量分析控制」相关难点（2）6、创新药研发难点分析与CMC研究策略探讨7、《已上市化学药品药学变更研究技术指导原则（试行）原料药变更的问答》浅析8、FDA：原料药中亚硝胺风险评估的最新观点9、亚硝胺「传奇」：5年来监管和制药界的反思10、【学习笔记】2023年度CDE审评报告11、FDA审评：吡托布鲁替尼的药学变更桥接(完)12、CDE：ICH指南在国内的实施概况13、「解读」FDA审评：repotrectinib胶囊5次CMC会议内容14、FDA：IND阶段CMC关注点15、药品注册检验难点与建议16、最新 FDA 人用药物亚硝胺杂质指南更新的「底层」参考17、不同国家地区注册检验差异对比曾文亮 博士  近20年药物研发经验，擅长新药研发与注册申报，近5年积累了近十个小分子新药中美IND申报成功和两个1类抗肿瘤新药上市申报成功经验。先后任职于某大型CRO医药研发公司、USP大中华区研发中心和港资原料药厂等，主导过MNC质量研究项目、USP各论更新和药厂QC实验室通过国家GMP检查和WHO审计。  受中国医药保健品进出口商会邀请在二十二届世界制药原料药中国展（CPHI）主导策划了“小分子创新药质量研究和注册策略”沙龙并发表主题演讲；同时受专业药学论坛邀请发表了《创新药质量研究要点和案例分析》、《中美新药申报沟通交流常见问题和案例分析》、《亚硝胺杂质的FDA和EMA控制策略》、《分析方法开发，验证和转移的统计学评价》和《FDA483中清洁验证的典型案例分析》等十余次主题演讲。  更多精彩内容可关注：▲ 关注文亮频道，探索未知世界声明：  根据《中华人民共和国广告法》和《互联网药品信息服务管理办法》相关规定，本平台内容不属于药品广告范畴。所涉药品信息仅作客观陈述，不具备商业推广属性。  本平台发布内容仅代表作者基于专业认知的学术观点，仅代表作者个人观点，不代表任何组织及本公众号立场，如有不当之处，敬请指正。如需转载，请注明作者及来源：蒲公英Ouryao