Reldesemtiv

本次直播免费参加，点击上方链接马上报名！2014年，一场由社交网络发起的冰桶挑战席卷全球，渐冻症患者开始进入公众视野。当年，肌萎缩侧索硬化症（简称ALS）协会将冰桶挑战筹得的220万美元投资于一款渐冻症新药的研发。8年后，这款由善款资助研发的药物Relyvrio获批上市，并迅速获得了商业化成功。尽管定价高达15.8万美元，ALS也属罕见病，但Relyviro仍创造了一个市场奇迹，2023年销售额达3.8亿美元，约合人民币27亿元。根据华尔街分析师预测，Relyvrio在巅峰时期有望为Amylyx创造超过10亿美元的年收入，妥妥的重磅炸弹。如今，这一切随着Relyvrio三期临床的失败，Amylyx决定将其撤出市场，戛然而止。可以说，Relyvrio的上市与退市，是患者迫切需求与科学严谨性博弈的结果，过程充满了期待与争议。它的上市，是在患者强烈呼声和未满足的临床需求推动下，FDA做出的一次妥协。然而，科学的严谨性不容忽视。Relyvrio在关键的三期临床试验中失败，主要终点、次要终点均未达成，亚组分析同样未能得到验证，最终导致了其退市的必然命运。尽管Relyvrio的故事似乎已经落幕，但它留给我们的启示却是深远的。在面对复杂疾病时，需要选择合适的主要终点和次要终点，需要更加重视患者个体差异，也需要对疾病机制进行更加深入的研究以寻求真正的突破。对于ALS这样的疾病，每一次药物研发的尝试都是对患者希望的承载，每一次失败都是对科学极限的探索。尽管道路漫长且充满挑战，但我们仍期待药企能够不断突破，为患者带来真正的希望。1渐冻症的市场奇迹渐冻症是一种不可逆的致死性运动神经元病，主要症状为四肢和躯干肌肉表现进行性加重的肌肉无力和萎缩，逐渐失去运动功能，就像被“冻住”一般。该病一般进展迅速，半数以上患者确诊后平均生存时间为3-5年，最后多死于呼吸肌无力导致的呼吸衰竭。据估计，ALS在全球范围内的发病率约为十万分之二。渐冻症与阿尔茨海默症一样，至今发病机制尚不明确。科学家普遍认为其病因是基因与环境共同作用的结果，还有专家曾试图用氨基酸毒性学说、人体免疫学说、神经微丝的新陈代谢异常学说等来解释渐冻症的发病原理，但均无统一定论。总而言之，这是一种致病机制十分复杂，没有明确靶点的疾病，这也导致ALS新药的研发失败率高，治疗药物十分有限。FDA分别于上世纪90年代和2017年批准两款ALS治疗药物利鲁唑和依达拉奉，但它们对患者生存和症状管理的影响不大。而Amylyx研发的Relyvrio，曾被不少人视为ALS患者的救星。这是一种由苯丁酸钠和牛磺酸二醇组成的专有口服固定剂量复方制剂，苯丁酸钠是一种小分子伴侣，旨在减少未折叠蛋白反应（UPR），防止因UPR导致的细胞死亡；牛磺酸二醇是一种Bax抑制剂，旨在通过凋亡减少细胞死亡。二者在固定剂量配方中联合使用，靶向ALS和其他神经退行性疾病中的内质网和线粒体依赖性神经元退行性变通路，减少神经元死亡和功能障碍。事实上，ALS不是Amylyx的最初目标，最初是阿尔茨海默氏症，而当得知该药也可能对ALS有效，且临床二期就可能获得FDA的批准，Amylyx决定优先转向ALS。随后，Relyvrio通过一个数据解读颇有争议的二期临床试验结果，与FDA反复周旋。起初，FDA外周和中枢神经系统药物咨询委员会并不打算批准这款药。在2期临床试验中，Relyvrio能减少与神经退行性疾病相关的标志物，如Tau和YKL-40。2期临床试验对比了Relyvrio与安慰剂的效果。结果显示，服药组肌肉功能和运动功能下降速度明显慢于安慰剂组，达到临床主要终点。2021年4月，FDA对Relyvrio的试验设计与操作提出质疑，提出需要等招募人数更多的三期试验结束才能接受申请。但是，在“生命倒计时”的渐冻症患者声讨中，FDA最终做出妥协，于同年9月允许Relyvrio以二期试验结果申请上市。而在上市专家委员会的讨论中，专家们再次表达了对Relyvrio现有数据说服力的怀疑——试验规模小、缺失数据、用于分析主要终点的统计方法的适当性以及随机化方案等问题。也就是说，专家们认为，二期结果虽具有统计学意义，但仍不足以确定Relyvrio可以改善疾病进展。2022年9月8日，FDA不顾专家委员会的反对，提前批准Relyvrio上市。由于Relyviro的研发、上市都获得了渐冻症患者组织的大力支持，这也使得该药上市前就在渐冻症患者群体中知名度很高，上市后也迅速获得市场青睐。此前，Relyvrio的定价为每年15.8万美元（约合人民币114万元）。财报显示，2023年，Relyviro销售额达3.8亿美元（约合人民币27亿元）。尽管定价高昂，ALS也属于罕见病，Relyviro仍创造了一个市场奇迹。而根据华尔街分析师预测，该药在巅峰时期有望创造超过10亿美元的年收入，妥妥的重磅炸弹。遗憾的是，上市仅一年半，Relyviro就从云端坠落。2走向退市尽管Relyvrio在早期研究中展现了一定潜力，但在更大规模、更长时间的试验中，其疗效并未得到充分验证。3月8日，Amylyx宣布Relyvrio在3期临床试验失败，公司股价暴跌82%，从近20美元/股跌至3.36美元/股，最新股价仅1.87美元/股，市值仅剩1.27亿美元。4月4日，Amylyx也宣布了一个被很多人认为是必然的动作，Relyvrio将退市。Relyvrio已获批上市还被要求做临床三期，这是因为其上市本身充满争议。当初，由于没有看到生物标记物差异无法以替代终点做加速审批，因此Relyviro已经获得了完全批准。两者的区别在于，加速批准建立在后期验证性临床试验成功，才能转为全面批准。FDA针对该药召开的专家听证会里，不少专家对Relyvrio全面获批后，其后续3期临床试验的意义和可行性表达了深切的担忧。而FDA则是基于强烈未满足的临床需求和患者呼声，决定批准其上市。当然，FDA也做好了药物无效时撤市的准备。为了消除监管顾虑，Amylyx在专家听证会上表态称，如果三期试验不成功，公司自愿将产品撤出市场。如今，Amylyx履行了当初的承诺。与此同时，Amylyx表示，若后续患者希望继续治疗，可通过医生联系过渡到免费药物计划。Relyviro退市背后，一个不容忽视的因素是，其试验结果过于失败。根据Amylyx在2024年美国神经学学会年会上提交的数据，在48周内，接受Relyvrio的患者在修订的肌萎缩侧索硬化功能评分量表（ALSFRS-R）中下降了14.98点。在后期试验中，安慰剂组患者的分数比基线下降了15.32点。由此产生的治疗效果为0.343，统计显著性的P值高达0.667，没有统计学意义，距离显著差异的距离更是过大。主要终点之外，次要终点也全部错过。甚至于，亚组分析同样没有发现显著功效的信号，也就是说，根据现有数据无法推断Relyviro在某些患者中可能的有效性。尽管已经决定从加拿大和美国退市，但Amylyx仍在试图找出Relyviro失败的原因。“可能有某些生物标志物，可能有某些生物差异，还是其他？还是只是统计问题？我认为所有这些都是可能的，也是我们想继续了解更多的事情。”Amylyx联席CEO表示。Relyviro的退市，对于Amylyx这家之前日入斗金的biotech来说，无疑是重大打击。在宣布退市的同时，公司也宣布了裁员70%的决定，以节约现金流，确保公司至少能够维持运作至2026年。3Relyvrio带来的启示创新药总是承载着无数患者的希望。但像Relyviro这样与患者深度“绑定”，甚至上市，也是在患者的强烈请愿下，才让FDA改变主意的并不多见。而Relyviro的失败，似乎也不会令人太意外。当初FDA专家一致反对其上市，认为二期临床数据不足以证明其有效性；到了2023年10月，欧洲药品管理局人用药品委员会也建议拒批Relyvrio在欧洲上市。如果从ALS新药研发层面出发，Relyvrio也只是众多失败者中的一员。仅在2023年，就有多个ALS新药研发遭遇失败。从Cytokinetics的reldesemtiv未能通过中期分析，到Apellis和Sobi宣布停止pegcetacoplan的开发，再到BrainStorm Cell Therapeutics撤回NurOwn的上市申请，这无不映射出ALS药物研发的艰难。到了今年，坏消息还在接踵而至。一个多月前，Denali Therapeutics透露，其与赛诺菲合作研发的药物DNL788治疗ALS的二期HIMALAYA研究未能达到ALSFRS-R评分的主要终点。而对于渐冻症患者来说，Relyviro的失败及退市，将使他们面对更有限的治疗选择，新的有效药物还需要漫长的等待与不确定性的煎熬。尽管失败在ALS领域似乎成了常态，但Relyviro的经历仍为我们带来了启示。首先，设计ALS临床试验时，选择合适的主要终点和次要终点颇为重要。为了确保试验的有效性，选择的临床终点应具有临床意义、可准确测量，并对药物的效应具有足够的敏感性。一般情况，主要终点通常包括延缓疾病进展、提高患者生存率或生活质量等，而次要终点可以是生物学指标，比如生物标志物的变化等。Relyviro提示着我们，如果能够发现和利用这些生物标志物，可以更早地诊断ALS、预测疾病进展并评估治疗效果，指导临床。其次，由于ALS患者表现出极高的临床异质性，包括症状的种类和程度、病情进展速度的不同，因此，同一种药物或许很难对所有患者都产生显著疗效。这种情况下，筛选对药物治疗敏感的患者亚群进行临床试验显得尤为重要。可惜的是，Relyviro的亚组分析同样没有发现显著功效的信号。或许，在设计神经退化性疾病药物临床试验方案时，需要特别重视患者个体差异的影响，通过加大样本量或是优化研究方法、反复评估，来提高研究的准确性和可靠性。同时，在临床阶段早期，就需要受试者的生物标志物、临床指标及其他相关的生理学和分子学数据，以便更好地识别出对治疗方法有积极反应的患者亚群，为后期的临床试验选择更合适的患者。当然，更重要的是，ALS发病机制复杂，其中遗传性ALS大约占10%，散发性则高达90%，因此，在早期药物研发阶段，明确药物的作用机理，理解其如何影响ALS的病理生理过程，并设定明确的治疗目标。这也是所有ALS新药需要为之努力的。尽管研发困难重重，但全球药企对于ALS的研发仍保持较高的热情。据医药魔方数据库的不完全统计，针对ALS适应症且处于III期临床阶段的药物近20个。面临相当的未满足临床需求，渐冻症患者迫切需要创新治疗药物。期待医学界能够早日找到攻克渐冻症的关键钥匙，为患者带来新生的希望。近期直播推荐:

PRESS RELEASE AB SCIENCE ANNOUNCES THAT HEALTH CANADA HAS GRANTED ELIGIBILITY FOR RECONSIDERATION REQUEST FOR MASITINIB IN AMYOTROPHIC LATERAL SCLEROSIS Paris, 3 April, 2024, 6pm CET AB Science SA (Euronext - FR0010557264 - AB) today announces that Health Canada has granted eligibility for reconsideration request for masitinib in amyotrophic lateral sclerosis (ALS). The reconsideration process will re-examine, with new assessors, the decision based on information that was included in the original submission. A Notice of Deficiency-Withdrawal (NOD/w) was issued on February 19, 2024 by Health Canada regarding the New Drug Submission (NDS) for masitinib in the treatment of ALS. The intention to submit a reconsideration request was based on the arguments summarized in the press release dated 26 February 2024. Health Canada and AB Science have held a meeting to discuss the reconsideration process. AB Science is working closely with the agency to facilitate the review of masitinib conditional approval in ALS. AB Science has 45 days to file the reconsideration request. The pivotal argument is on the treatment of missing data. Various sensitivity analyses show that study AB10015 was successful at week 48 when masitinib missing data are imputed as a placebo, which is recognized as a highly conservative methodology for missing data imputation (i.e., jump-to-reference). Rerandomization calculation, which ignores whether the data distribution is linear or not, was also successful. Furthermore, the Combined Assessment of Function and Survival (CAFS) analysis showed a p-value of 0.078, even though study AB10015 was not powered for this endpoint. A related time-to-event endpoint, Progression Free Survival (PFS), did show significant improvement in favor of masitinib. Additionally, in the subgroup of patients with ‘ALS prior to any loss of function’, a logically defined cohort based on masitinib’s mechanism of action, a long-term median overall survival (OS) benefit of +22 months (p=0.0192) was observed. Professor Albert Ludolph, MD, PhD, Medical Director of the Neurology Department of at the University of Ulm, and principal investor of masitinib confirmatory study in ALS commented that, “The recent failure of numerous phase 2 or 3 programs, including registered drugs such as AMX0035 (Amylyx) and oral edaravone (Ferrer), as well as investigational drugs such as TUDCA (the TUDCA-ALS consortium), reldesemtiv (Cytokinetics) and the RIPK1 inhibitor SAR443820 (Sanofi), have dashed the community's hopes of benefiting from new therapeutic advances and have effectively set us back with riluzole being the only treatment with a proven modest effect in the overall ALS population. We should learn from theses failures. First, that demonstration of efficacy over a 24-week period is not predictive of efficacy over a 48-week period, which is the adequate duration to demonstrate a disease modifying effect in ALS. Second, that a 48-week study inevitably generates a large number of missing data. This situation is not unique to masitinib. It is a real challenge in the evaluation of efficacy and we are at risk of overlooking promising compounds. Masitinib has published results over a 48-week period, positive when appropriate methodology to treat missing data is applied, and it deserves careful consideration”. About AB ScienceFounded in 2001, AB Science is a pharmaceutical company specializing in the research, development and commercialization of protein kinase inhibitors (PKIs), a class of targeted proteins whose action are key in signaling pathways within cells. Our programs target only diseases with high unmet medical needs, often lethal with short term survival or rare or refractory to previous line of treatment. AB Science has developed a proprietary portfolio of molecules and the Company’s lead compound, masitinib, has already been registered for veterinary medicine and is developed in human medicine in oncology, neurological diseases, inflammatory diseases and viral diseases. The company is headquartered in Paris, France, and listed on Euronext Paris (ticker: AB). Further information is available on AB Science’s website: www.ab-science.com. Forward-looking Statements - AB ScienceThis press release contains forward-looking statements. These statements are not historical facts. These statements include projections and estimates as well as the assumptions on which they are based, statements based on projects, objectives, intentions and expectations regarding financial results, events, operations, future services, product development and their potential or future performance. These forward-looking statements can often be identified by the words "expect", "anticipate", "believe", "intend", "estimate" or "plan" as well as other similar terms. While AB Science believes these forward-looking statements are reasonable, investors are cautioned that these forward-looking statements are subject to numerous risks and uncertainties that are difficult to predict and generally beyond the control of AB Science and which may imply that results and actual events significantly differ from those expressed, induced or anticipated in the forward-looking information and statements. These risks and uncertainties include the uncertainties related to product development of the Company which may not be successful or to the marketing authorizations granted by competent authorities or, more generally, any factors that may affect marketing capacity of the products developed by AB Science, as well as those developed or identified in the public documents published by AB Science. AB Science disclaims any obligation or undertaking to update the forward-looking information and statements, subject to the applicable regulations, in particular articles 223-1 et seq. of the AMF General Regulations. For additional information, please contact: AB ScienceFinancial Communication & Media Relations investors@ab-science.com Attachment CP Health Canada Reconsideration Eligibility VENG VF