From the Alzheimer's Drug Discovery Foundation (L.G.F., N.M., Y.H., M.O., A.T., H.M.F.), New York; Chambers-Grundy Center for Transformative Neuroscience (J.L.C.), Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas; ADM Diagnostics (D.C.M.), Inc. Northbrook, IL; Servier Pharmaceuticals (J.Z.), Boston, MA; Global Alzheimer's Platform Foundation (R.C.M.), Washington, DC; AgeneBio (R.C.M.), Inc. Baltimore, MD; AbbVie Inc. (D.W.), North Chicago, IL; Pentara Corporation (S.B.H., S.P.D.), Salt Lake City, UT; Berry Consultants (M.Q.), Austin TX; Keck School of Medicine of the University of Southern California (L.S.S.), Los Angeles; Global R&D Partners (M.G.), LLC, University of California, San Diego, La Jolla; Department of Neurosciences (H.H.F.), University of California, San Diego, La Jolla; Albert Einstein College of Medicine (J.J.), Bronx, NY; CognitionMetrics (J.J.), LLC; Department of Clinical Neurological Sciences and Robarts Research Institute (E.C.F.), Schulich School of Medicine and Dentistry, University of Western Ontario; Parkwood Institute (E.C.F.), Lawson Health Research Institute, St. Josephs Health Care, London, Ontario, Canada; Rodin Therapeutics (J.M.R.), Boston, MA; Association for Frontotemporal Degeneration (D.N., S.L.-J.D.), Radnor, PA; and Modus Outcomes LLP (J.T.M.), Cambridge, MA.
Neurology. 2021 May 18;96(20):944-954. doi: 10.1212/WNL.0000000000011774. Epub 2021 Mar 5.
Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.
阿尔茨海默病和其他神经退行性痴呆症（包括额颞叶痴呆）的药物研发经历了漫长的 2 期和 3 期临床试验阶段，但这些临床试验都未能显示出研究药物的疗效。尽管这些疾病在临床和行为特征上存在差异，但它们具有共同的病理学特征，在设计能够预测后期成功的早期试验时面临着共同的挑战。在这里，我们讨论神经退行性痴呆症的探索性临床试验。这些试验通常是 1b 期或 2a 期试验，旨在评估药物的药理作用，并依赖于生物标志物结果，与传统的 2 期研究相比，这些试验的治疗持续时间更短，患者人数更少。探索性试验可以确定是继续还是停止药物研发，可以为概念验证和剂量选择提供依据，并终止那些未能显示出与合适的暴露量和可接受的安全性相关的目标结合的药物。早期失败可以节省宝贵的资源，包括机会成本。这对于学术界和小型生物技术公司的项目尤其重要，但也可以应用于大型制药公司的高风险项目，以比传统方法更快、更低的成本实现概念验证。在分期临床开发计划中的探索性研究可能会提供有前景的数据，从而证明需要大量资源来推进化合物进入后期开发。为了优化探索性试验的设计和应用，阿尔茨海默病药物发现基金会和额颞叶痴呆协会召集了一个顾问小组，就这些类型的研究和研究设计的结果测量和统计考虑因素提供建议，以提高临床开发的效率。
