Mohs Richard, Bakker Arnold, Rosenzweig-Lipson Sharon, Rosenblum Michael, Barton Russell L, Albert Marilyn S, Cohen Sharon, Zeger Scott, Gallagher Michela
AgeneBio, Inc. Baltimore Maryland USA.
Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore Maryland USA.
Alzheimers Dement (N Y). 2024 Jan 24;10(1):e12446. doi: 10.1002/trc2.12446. eCollection 2024 Jan-Mar.
In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD.
One hundred and sixty-four participants were randomized to placebo ( = 83) or AGB101 ( = 81), an extended-release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint.
The mean change in CDR-SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is -0.10 (95% CI: -0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was -0.45 (95% CI: -1.43, 0.53) for ApoE-4 noncarriers and -0.10 (95% CI: -0.92, 0.72) for apolipoprotein E (ApoE)-4 carriers.
The possibility that ApoE-4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE-4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.
除淀粉样斑块和神经原纤维缠结的积累外，神经活动过度是阿尔茨海默病（AD）的病理标志，也是阿尔茨海默病所致轻度认知障碍（AD所致MCI）中AD病理进展及临床/认知恶化的预后指标。HOPE4MCI临床研究在一项为期78周的随机对照试验中，对一种已证明有能力使AD所致MCI患者海马体中增强的神经活动恢复正常的疗法的疗效进行了测试。
164名参与者被随机分为安慰剂组（n = 83）或AGB101组（n = 81），AGB101是低剂量（220毫克）左乙拉西坦的缓释制剂。主要终点是比较18个月随访时与基线时的临床痴呆评定量表总盒分（CDR-SB）的变化。主要疗效分析的目的是估计AGB101组和安慰剂组在主要终点平均变化方面的差异。
AGB101组CDR-SB的平均变化估计为1.12（95%置信区间[CI]：0.66，1.69），安慰剂组为1.22（95%CI：0.75，1.78）。两组之间的估计差异为-0.10（95%CI：-0.85，0.58），无统计学意义。在一项预先设定的分析中，对于载脂蛋白E（ApoE）-4非携带者，差异为-0.45（95%CI：-1.43，0.53），对于ApoE-4携带者，差异为-0.10（95%CI：-0.92，0.72）。
ApoE-4携带者和非携带者对治疗干预反应不同的可能性与最近生物制剂的报道结果一致，目前的结果表明，对ApoE-4等位基因非携带者的AD所致MCI患者进一步测试AGB101是有必要的。HOPE4MCI研究的结论主要由于样本量小而受到限制，结果只能作为未来研究的参考。
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