Alzheimer's disease drug-development pipeline: few candidates, frequent failures.
Alzheimer's disease drug-development pipeline: few candidates, frequent failures.
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DOI：
10.1186/alzrt269
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Zhong K
中科院分区：
文献类型：
--
作者：
Cummings JL;Morstorf T;Zhong K
随着全球人口老龄化，阿尔茨海默病（AD）的发病率正在增加。五种药物被批准用于治疗AD，包括四种胆碱酯酶抑制剂和一种N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。我们迫切需要找到新的治疗AD的方法。我们检查了Clinicaltrials.gov，这是一个记录正在进行的临床试验的公共网站。我们研究了2002年至2012年的十年，以更好地了解AD药物的发展。我们回顾了申办者、临床试验机构、药物作用机制、持续时间、所需患者数量以及从一个阶段进入下一个阶段的成功率。我们还审查了目前的AD治疗管道。在2002年至2012年的观察期内，进行了413项AD试验：124项I期试验，206项II期试验和83项III期试验。其中78%是由制药公司赞助的。美利坚合众国（U.S.）仍然是试验数量最多的单一世界地区;累积而言，非美国试验的数量多于美国试验。注册试验的最大数量涉及旨在改善认知的对症药物（36.6%），其次是疾病修饰小分子试验（35.1%）和疾病修饰免疫疗法试验（18%）。从第2阶段到第3阶段，试验的平均长度增加，并且在第2阶段和第3阶段之间，试验的参与者数量增加。疾病调节剂的试验比对症药物的试验规模更大，时间更长。发现了非常高的流失率，2002年至2012年期间的总体成功率为0.4%（99.6%失败）。Clinicaltrials.gov数据库表明，考虑到问题的严重性，对AD疗法进行的临床试验相对较少。从一个阶段进入另一个阶段的成功率很低，进入监管审查的化合物数量是任何治疗领域中发现的最低数量之一。AD药物开发生态系统需要支持。
Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD. We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline. During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure). The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.
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