ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?
ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?
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DOI：
10.3389/fnagi.2017.00068
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发表时间：
2017
影响因子：
4.8
通讯作者：
Hermine O
中科院分区：
文献类型：
--
作者：
Petrov D;Mansfield C;Moussy A;Hermine O
肌萎缩侧索硬化症（ALS）是一种毁灭性的疾病，全世界每年估计有30，000名患者死亡。报告的自发病以来的中位生存时间范围为24至48个月。阿曲唑是目前唯一获批的轻度有效治疗药物。阿曲唑于1995年在美国和1996年在欧洲获得上市许可。在随后的几年里，超过60种分子被研究作为ALS的可能治疗方法。尽管进行了大量的研究工作，但绝大多数人体临床试验（CT）未能证明临床疗效。在过去的一年中，口服马赛替尼和静脉注射依达拉奉已成为有前途的新疗法，声称对ALS患者的CT有效。鉴于其临床开发的高级阶段，人们可能会认为这些药物是ALS患者最有可能的近期治疗药物库的补充。在患者纳入方面，与唯一成功的依达拉奉CT相比，马赛替尼CT招募了更广泛、更具代表性、限制性更小的患者群体（依达拉奉合格标准仅代表马赛替尼研究患者的18%）。本手稿回顾了自利鲁唑首次获批以来的过去20年中进行的>50项CT。特别强调的是对现有证据的分析，以支持依达拉奉和马赛替尼的临床疗效和最终上市许可在治疗ALS的可能影响。
Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment. Riluzole received marketing authorization in 1995 in the USA and in 1996 in Europe. In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS. Despite significant research efforts, the overwhelming majority of human clinical trials (CTs) have failed to demonstrate clinical efficacy. In the past year, oral masitinib and intravenous edaravone have emerged as promising new therapeutics with claimed efficacy in CTs in ALS patients. Given their advanced phase of clinical development one may consider these drugs as the most likely near-term additions to the therapeutic arsenal available for patients with ALS. In terms of patient inclusion, CT with masitinib recruited a wider, more representative, less restrictive patient population in comparison to the only successful edaravone CT (edaravone eligibility criteria represents only 18% of masitinib study patients). The present manuscript reviews >50 CTs conducted in the last 20 years since riluzole was first approved. A special emphasis is put on the analysis of existing evidence in support of the clinical efficacy of edaravone and masitinib and the possible implications of an eventual marketing authorisation in the treatment of ALS.