A Phase 3 pivotal trial of AGB101 to slow progression in MCI due to Alzheimer's Disease

AGB101 减缓阿尔茨海默病导致的 MCI 进展的 3 期关键试验

• 批准号: 9562247
• 负责人: RICHARD Charles MOHS
• 金额: $ 400万
• 依托单位: AGENEBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9562247
• 关键词: Address; Adverse effects; Affect; Alzheimer' s Disease; Amyloid; Atrophic; Blood; Brain; Caregivers; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical Trials Design; DNA; Data; Data Set; Dementia; Diagnosis; Disease; Disease Progression; Dose; Enrollment; Ensure; Epilepsy; Feasibility Studies; Formulation; Functional Magnetic Resonance Imaging; Funding; Guidelines; Healthcare Systems; Hippocampus (Brain); Human; Hyperactive behavior; Impaired cognition; Intervention; Levetiracetam; Magnetic Resonance Imaging; Measures; Memory; Nerve Degeneration; Neuronal Injury; Outcome Measure; Pathology; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Positron-Emission Tomography; Prevention trial; Program Development; Protocols documentation; Recording of previous events; Regulatory Pathway; Resolution; Resources; Rest; Risk; Safety; Schedule; Site; Sum; Testing; Therapeutic; Therapeutic Effect; Thick; Time; Toxic effect; amnestic mild cognitive impairment; amyloid imaging; biomarker development; clinical development; cognitive testing; cost; entorhinal cortex; experience; follow-up; high risk; improved; innovation; meetings; novel strategies; novel therapeutic intervention; patient population; phase 2 study; phase 3 study; pre-clinical; pre-clinical research; primary outcome; randomized placebo controlled trial; success; tau Proteins; therapeutic development; therapy development; trial design

A distinctive condition in the patient population with amnestic mild cognitive impairment (aMCI) is overactivity localized to the hippocampus by functional magnetic resonance imaging (fMRI), which longitudinally predicts subsequent cognitive decline/conversion to a dementia diagnosis (Sperling, 2007; Dickerson et al., 2008; Miller et al., 2008) and is significantly correlated with the extent of neuronal injury affecting the brain (Putcha et al, 2011). Such overactivity is most pronounced in MCI due to AD determined by PET amyloid imaging and persists over a three year follow up during which time greater worsening on Clinical Dementia Rating-sum of boxes (CDRsb) is evident in MCI due to AD relative to patients with amyloid negative PET scans (Huijbers et al., 2015). These data, together with preclinical research, provide strong evidence that hippocampal hyperactivity is a driver of neurodegeneration during the aMCI phase of disease, leading to subsequent cognitive decline. To determine whether an intervention to restore hippocampal activity to normal can have a positive therapeutic effect to slow disease progression, we are proposing a Phase 3 randomized placebo-controlled trial with AGB101, a once-a-day formulation of levetiracetam. In Phase 2 levetiracetam demonstrated target engagement by lowering hippocampal hyperactivity in a low dose range that concomitantly improved hippocampal function assessed in a memory task (Bakker et al., 2012; 2015). In a prior meeting (March 2014) the FDA agreed that there are no concerns on safety/toxicity in repurposing this medication given the large amount of safety data for levetiracetam at much higher doses in the treatment of epilepsy. Support under this application will ensure the timely initiation of a Phase 3 trial using a novel therapeutic approach with medication de-risked for adverse effects on patients. At the 2014 pre-IND meeting, the FDA also confirmed that an appropriate measure for efficacy in the pivotal trial would be the use of CDRsb as a sole primary endpoint and that no further preclinical or clinical data would be needed to support such a trial. The end of Phase 2 (EOP2) meeting with the FDA on the Phase 3 protocol is now scheduled for June 14, 2016 with a feasibility study for site selection currently underway. After the EOP2 meeting with the FDA, manufacturing of AGB101 for use in the Phase 3 trial and other activities will be completed prior to first patient enrollment expected in Q1 2017. In addition to the primary FDA regulatory objective of the Phase 3 trial to examine the efficacy of AGB101 on change in the CDRsb at 78 weeks from baseline, much additional data relevant to biomarker development (e.g. EC thickness/volume, hippocampal volume, DNA, resting fMRI, cognitive tests) will be collected under the Phase 3 protocol. Thus this proposal is aligned with the objectives under PAR-16-364 to advance late stage clinical development of therapies in AD. Funds under this application will specifically contribute to support of the costs for conducting the Phase 3 trial at sites in the U.S and partial support for a management team experienced in all Phases of translational and clinical development of therapeutics for AD.

遗忘型轻度认知障碍（aMCI）患者人群的一种独特状况是 通过功能性磁共振成像（fMRI）， 纵向预测随后的认知下降/转换为痴呆诊断（Sperling，2007; 迪克森等人，2008;米勒等人，2008），并且与神经元损伤的程度显著相关。 影响大脑（Putcha et al，2011）。这种过度活动在由AD引起的MCI中最明显， PET淀粉样蛋白成像，并持续超过3年的随访，在此期间，临床 相对于淀粉样蛋白阴性患者，AD所致MCI的痴呆评分总和（CDRsb）明显 PET扫描（Huijbers等人，2015年）。这些数据以及临床前研究提供了强有力的证据， 海马活动过度是疾病aMCI期神经退行性变的驱动因素，导致 随后的认知能力下降。为了确定是否干预恢复海马活动正常 可以有积极的治疗效果，以减缓疾病进展，我们提出了一个3期随机 AGB 101（一种每日一次的左乙拉西坦制剂）的安慰剂对照试验。II期左乙拉西坦 通过在低剂量范围内降低海马活动过度， 在记忆任务中评估的改善的海马体功能（Bakker等，2012; 2015）。在之前的会议上 （2014年3月）FDA同意重新使用这种药物没有安全性/毒性问题 左乙拉西坦在治疗癫痫时以高得多的剂量的大量安全性数据。支持 根据这项申请，将确保及时启动一项使用新的治疗方法的III期试验， 降低了药物对患者的不良反应风险。在2014年的IND前会议上，FDA还确认， 关键试验中疗效的适当指标是使用CDR b作为唯一的主要终点 并且不需要进一步的临床前或临床数据来支持这样的试验。第二阶段结束 （EOP 2）与FDA就III期方案举行的会议现定于2016年6月14日举行， 目前正在进行选址研究。在与FDA举行EOP 2会议后，AGB 101的生产 用于III期试验，其他活动将在第1季度预期首例患者入组前完成 2017.除了III期试验的主要FDA监管目标外， AGB 101在第78周时CDR b较基线的变化，与生物标志物相关的更多额外数据 发育（例如EC厚度/体积、海马体积、DNA、静息fMRI、认知测试）将被 根据第三阶段方案收集。因此，本提案与PAR-16-364的目标一致， 推进AD治疗的晚期临床开发。本申请项下的资金将具体 资助在美国研究中心进行III期试验的费用，并部分资助 管理团队在AD治疗药物的转化和临床开发的所有阶段都有丰富的经验。