Trigriluzole

The FDA told Biohaven its study using real-world data “would likely be inadequate to provide substantial evidence of effectiveness” when it was proposed, according to an agency rejection letter for the rare disease drug troriluzole. Earlier this week, the regulator rejected Biohaven’s drug, shutting down the company’s second attempt to get approval of a therapy for a neurodegenerative disease called spinocerebellar ataxia. In 2023, the FDA refused to even review Biohaven’s application for troriluzole after the drug failed a placebo-controlled trial. The letter was posted the same week Biohaven announced its drug was rejected, marking one of the quickest turnarounds for the agency to make a complete response letter public as part of its wider push to share why drugs were not approved. The letter lays out the concerns the FDA has with the use of real-world data, which rare disease drug developers have been trying to leverage as a way to move their treatments forward, as opposed to traditional clinical trials with a control arm. Biohaven’s real-world evidence study compared patients receiving troriluzole to those in a natural history study. But the agency said it wrote at the time of the study proposal that “the proposed natural history data source does not appear to be fit-for-purpose, and the externally controlled analyses will likely generate results that are difficult to interpret and subject to biases due to the baseline differences between the study subjects and external control subjects.” The FDA added that it reiterated its concerns after that as well. In the letter, the FDA laid out six reasons that Biohaven’s trial, known as Study 206-RWE, “cannot be considered an adequate and well-controlled investigation.” Those reasons included concerns that over half of the patients treated with troriluzole and in the natural history study were missing data for the primary endpoint, questions on whether trial subjects and external controls were comparable, and potential biases introduced by the choice of trial sites and the different time points used in the troriluzole trial compared to the natural history study. Based on the FDA’s letter, it appears the agency had concerns with the study before new leadership joined, including now-resigned CDER Director George Tidmarsh. That starkly contrasts with Biohaven CEO Vlad Coric’s comments to Endpoints News on Wednesday that the FDA made an “abrupt change” in its stance on the use of natural history data in Biohaven’s case, as well as in other rare disease cases, under new leadership at the agency. When asked about the difference in the FDA’s characterization of events and his own in a follow-up interview on Thursday, Coric said the contents of the letter are “consistent” with his earlier comments. He said the agency had always had concerns with the use of real-world evidence and pointed to a quote in Biohaven’s own release saying the FDA previously told the company “a large and robust treatment effect would be needed to overcome the biases” of such a trial. Several other rare disease drug developers, including uniQure and Replimune, have also faced regulatory hurdles or rejections. In Biohaven’s case, the agency had also scheduled and then canceled an advisory committee for troriluzole. Coric had strong words for how the agency handled its application amid turmoil at the FDA. “You have leadership that has been absent, and that’s a problem. There’s numerous issues going on, and it’s not just our company,” Coric said Wednesday. The FDA allowed Biohaven’s drug to be reviewed due to the “seriousness and rarity” of the disease, but a “comprehensive” review of the submission found that “substantial evidence of effectiveness has not been established,” the agency wrote in the rejection letter published Thursday. Troriluzole is another form of riluzole, a drug used to treat ALS. Biohaven is studying the treatment for spinocerebellar ataxia, which leads to progressive loss of muscle control and balance. “You will need to provide data from an adequate and well-controlled study that demonstrates an effect on a clinically meaningful endpoint in order to establish the effectiveness of troriluzole for the treatment of spinocerebellar ataxia,” the FDA wrote in its rejection letter. Biohaven said on Tuesday that it planned to meet with the FDA to determine next steps.

近日，Biohaven宣布收到FDA对其Troriluzole上市申请的完全回复函（CRL），拒绝批准其用于治疗脊髓小脑性共济失调（SCA）。 这是Troriluzole第二次遭拒。 事实上，就FDA对该审查期间所表露出的态度看来，Troriluzole被批准通过“颇具”悬念。 受此消息影响，Biohaven当日股价下跌40%。 这次被拒对公司的打击不止在股价上，由于CRL，Biohaven在新闻稿中表示，将会启动战略重组和成本优化措施，包括削减约60%的年研发支出，并优先推进三个高潜力后期临床项目。 第二次被拒 Troriluzole是第三代型谷氨酸调节剂，旨在调节体内一种至关重要的兴奋性神经递质—谷氨酸，其主要作用方式是降低突触谷氨酸水平，即旨在通过增强神经胶质细胞内兴奋性氨基酸转运蛋白的活性与表达，进而促进这些转运体对谷氨酸的有效地回收并再利用，最终减少神经突触间隙中过多的谷氨酸。 Troriluzole针对脊髓小脑性共济失调提交第一次上市申请被FDA拒是在2023年，当时的原因是Troriluzole在一项治疗SCA的Ⅲ期试验未达到主要终点。 2024年，Biohaven改用真实世界研究数据BHV4157-206-RWE向FDA再次提交了上市申请，这一申请也成功获得了FDA受理，并被授予了优先审评。 BHV4157-206-RWE中，相比外部对照组，Troriluzole将脊髓小脑性共济失调患者的疾病进展延缓50-70%，其预先指定的主要终点和和次要终点上均达到了统计学意义。 但FDA依旧对Troriluzole的批准存疑。 先是，今年5月FDA宣布推迟对Troriluzole的审批决定，之后，FDA又表示将召开咨询委员会会议来讨论该上市申请（在会议召开前几周又突然取消）。 最终，FDA还是发了CRL，就这封CRL看来，FDA拒绝批准主要是出于对“真实世界研究”本身所存在缺陷的质疑。 事实上，除了脊髓小脑性共济失调之外，围绕Troriluzole“降低突触谷氨酸水平”这一核心机制，Biohaven进行了多适应症开发尝试，包括阿尔茨海默症、广泛性焦虑障碍、强迫症，但这些适应症都经历临床失败，最终被放弃。 脊髓小脑性共济失调作为Troriluzole唯一还在开发推进的适应症，能否再次获得监管认可也决定了该药的未来。 与Troriluzole命运捆绑还有一笔投资。今年4月，Biohaven与Oberland Capital达成最高6亿美元的非稀释性融资，其中1.5亿美元与FDA是否批准Troriluzole直接挂钩。 原地拆分之后 现在的Biohaven是原Biohaven拆分而来。 Biohaven最早2013年成立了，是一家专注于神经以及精神疾病疗法开发的Biotech公司。2020年，其推出了全球首个治疗及预防偏头痛药物Nurtec ODT（口服CGRP受体拮抗剂）。 2022年5月，Biohaven被辉瑞116亿美元现金收购（所有CGRP管线），收购完成后，原Biohaven成为辉瑞的全资子公司，同时，基于剩下的非CGRP管线，其原地拆分出一家仍以Biohaven名称的新公司，仍作为一家独立的上市公司继续运营。 Troriluzole是自Biohaven拆分之后最为核心的管线，如果能顺利获批，也将是Biohaven被收购后所推出的的首款上市产品。 目前除了Troriluzole外，Biohaven还有10余条管线，其中BHV-7000（钾离子通道激活剂）、BHV-2000（肌生长抑制素阻断剂）、BHV-8000（TYK2/JAK1抑制剂）等管线也都推到了Ⅲ期，未来对资金的需求比较大，于Biohaven而言，去同步推进这些管线还是具有一定挑战性的。截至2025年6月30日，Biohaven的现金为4.082亿美元。 参考出处 https://endpoints.news/fda-rejects-biohavens-ataxia-drug-shutting-down-companys-second-attempt-to-win-approval/ https://www.biospace.com/business/biohaven-cuts-r-d-spending-by-60-after-fda-rejection-of-drug-for-rare-neurodegenerative-disease https://ir.biohaven.com/news-releases/news-release-details/fda-issues-complete-response-letter-biohavens-vyglxia https://ir.biohaven.com/news-releases/news-release-details/biohaven-reports-second-quarter-2025-financial-results-and · · · · · · ·