Riluzole

撰文丨王聪编辑丨王多鱼排版丨水成文肌萎缩侧索硬化症（ALS，也叫做渐冻症）是一种罕见的自主运动系统疾病，与大脑和脊髓中的运动神经元丧失有关，会导致不可逆转的残疾和死亡，患者从出现症状到死亡，中位生存期仅为 2-3 年。FDA批准的渐冻症治疗药物利鲁唑（Riluzole）通常只能延长几个月的生存期，，因此，目前仍迫切需要更有效的渐冻症治疗方法。然而，由于对渐冻症相关靶点认识不足，以及渐冻症在临床和病理上的异质性，更有效的渐冻症治疗方法的确定一直受到阻碍。神经炎症被证明参与了广泛渐冻症表型，因此提供了一个有前景的治疗靶点，改变渐冻症发病机制中的炎症成分，可以提高生存率并减缓功能恶化。CD4+ FOXP3+ 调节性 T 细胞（Treg）是一种具有广泛免疫调节功能的 T 细胞亚群，其数量和功能的损伤与渐冻症的严重程度、进展和生存率有关。Treg 的生成、激活和存活都需要细胞因子白细胞介素-2（IL-2），这为增强免疫耐受和抑制神经炎症提供了一条可行且可测量的治疗途径。近日，国际顶尖医学期刊《柳叶刀》（The Lancet）发表了一篇题为：Efficacy and safety of low-dose IL-2 as an add-on therapy to riluzole (MIROCALS): a phase 2b, double-blind, randomised, placebo-controlled trial 的临床研究论文。这项临床试验结果提高了令人鼓舞的证据，表明了在标准疗法利鲁唑中添加低剂量 IL-2 治疗，可降低渐冻症患者死亡风险。这一发现提供了令人鼓舞的证据，表明了改变免疫系统可能是减缓渐冻症疾病进展的有效策略。提示了低剂量 IL-2 可被考虑作为一种安全且耐受性良好的渐冻症治疗方法，以增强利鲁唑治疗效果。渐冻症是一种危及生命的疾病，其特征是运动神经元进行性丧失，且治疗选择有限。在这项最新研究中，研究团队在临床试验中检验了低剂量 IL-2 作为利鲁唑附加疗法，在治疗渐冻症中的疗效和安全性。在这项随机、双盲、安慰剂对照的 2b 期临床试验中，18-76岁、症状持续时间 ≤24个月、慢肺活量 ≥70%、既往未接受过利鲁唑治疗的渐冻症患者，首先接受为期 12-18 周的利鲁唑单药导入期，随后以 1:1 比例随机分配至皮下注射 200 万国际单位低剂量 IL-2（IL-2LD）组或安慰剂组（每28天注射5天），持续治疗 18 个月。主要终点为 640 天（21个月）时的生存率。次要结局包括安全性、ALS 功能评定量表修订版（ALSFRS-R）评分及生物标志物检测（调节性T细胞、脑脊液磷酸化神经丝重链、血浆/脑脊液趋化因子CCL2）。主要终点分析采用未校正对数秩检验和基于预设预后协变量的 Cox 模型校正分析，以控制疾病和治疗反应异质性。在 2017 年 6 月 19 日至 2019 年 10 月 16 日期间，共筛查了 304 名渐冻症受试者，其中 220 名（72%）在完成 12-18 周利鲁唑单药导入期后符合所有随机分配标准。随机分配人群中，136名（62%）为男性，84名（38%）为女性。所有 220 名患者均记录为死亡（90例，占41%）或存活（130例，占59%），没有失访病例。主要终点未校正分析显示，IL-2LD 组死亡风险降低 19%，但无统计学意义，未能达到预设的死亡风险减半目标。基于随机分配时测量的预后协变量进行校正分析后，IL-2LD 组死亡风险显著降低68%，且脑脊液生物标志物（CSF-pNFH）水平与治疗效果存在显著交互作用。IL-2LD 安全性良好，各时间点均显著增加 Treg 细胞并降低血浆 CCL2 水平。根据基线 CSF-pNFH 分层分析显示：在 70% 低水平组（750-3700 pg/mL），IL-2LD 使死亡风险显著降低 48%，而 21% 高水平组（>3700 pg/mL）未见显著差异。尽管主要终点的未校正分析显示死亡风险降低 19%，但未达到统计学意义，预先计划的校正分析显示，IL-2LD 治疗显著降低死亡风险，且与 pNFH 水平存在显著交互作用。因此，这项 2b 期随机、双盲、平行组、安慰剂对照试验证实：作为利鲁唑的附加疗法，长期使用低剂量 IL-2 可安全改善渐冻症患者生存率并减缓功能衰退进程。论文链接：https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00262-4/fulltext设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群 微信加群 为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味

Biohaven has secured funding to support its potential drug launch and pipeline growth. Credit: Olena Malik via Getty Images. Biohaven has secured a funding deal worth up to $600m from Oberland Capital Management, providing the biotech with non-dilutive capital as it prepares for a potential US launch of troriluzole for spinocerebellar ataxia (SCA). The financing comes in the form of a note purchase agreement, allowing Oberland to acquire up to $600m of Biohaven’s senior secured notes in multiple tranches. The first tranche of $250m is scheduled to be funded by 30 April, according to the company statement issued on 28 April. The second tranche – worth $150m – is contingent on US Food and Drug Administration (FDA) approval of troriluzole and subject to additional unspecified conditions. A third tranche of $200m may be made available for strategic acquisitions and related expenses. Oberland Capital will be eligible for a regulatory approval milestone payment, payable quarterly through the end of 2030. Shares in Biohaven closed 9.6% higher at $21.74 on 28 April, compared to $19.84 at market open. The deal comes as Biohaven awaits a regulatory decision from the FDA on troriluzole. The candidate is a prodrug of riluzole, which is already approved for amyotrophic lateral sclerosis (ALS). Troriluzole is being evaluated for SCA , a rare neurodegenerative disorder with limited treatment options, characterised by a loss of coordination and balance. The FDA granted the application priority review in February 2025, with a final decision expected in Q3 2025. The company is positioning the new funding to accelerate commercial planning and advance its broader pipeline, which includes CNS-targeting therapies. GlobalData Strategic Intelligence US Tariffs are shifting - will you react or anticipate? Don’t let policy changes catch you off guard. Stay proactive with real-time data and expert analysis. By GlobalData Learn more about Strategic Intelligence Biohaven’s chief financial officer Matt Buten said: “This agreement with Oberland Capital provides us with the support and flexibility to continue advancing our pipeline as we make launch preparations in parallel, and we are excited to accelerate our planning efforts in earnest.” If it wins approval, troriluzole would represent Biohaven’s first greenlit product since it spun out from its migraine business following a $11.6bn acquisition from Pfizer back in 2022. However, Biohaven’s path to approval for troriluzole has not been straightforward. The drug failed to meet its primary endpoint in a Phase III trial (NCT03701399) conducted in 2022. Despite the setback, Biohaven shared subsequent analyses revealing benefits for patients with a certain subset of the disease and showed a slowed disease progression. The FDA initially refused to review the application but later accepted a revised submission following the release of this ad hoc data. Troriluzole’s prospects in Europe are more uncertain. Earlier in April, the European Medicines Agency (EMA) questioned whether the drug’s efficacy meaningfully differed from that of riluzole and challenged its classification as a new active substance. According to the EMA, Biohaven said it would generate additional data before submitting a new application. The new Biohaven entity was formed after the divestiture of its migraine assets to Pfizer in 2022. That deal included the commercial rights to Nurtec ODT (rimegepant), which generated $1.26bn in global sales in 2024, as per Pfizer’s financials. In January 2025, Pfizer agreed to pay $59.7m to settle allegations related to illegal payments made by the former Biohaven entity to healthcare providers before its acquisition. The US Department of Justice alleged that Biohaven paid kickbacks to physicians to boost prescriptions of Nurtec, resulting in false claims submitted to Medicare and other federal healthcare programmes between March 2020 and September 2022.