Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial.
Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial.
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DOI：
10.3233/jad-230868
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发表时间：
2023
影响因子：
4
通讯作者：
Thompson, Richard E.
中科院分区：
文献类型：
--
作者：
Alkon, Daniel L.;Sun, Miao-Kun;Tuchman, Alan J.;Thompson, Richard E.
在临床前研究中，苔藓虫素分子量为904，具有突触生成、抗凋亡、抗淀粉样蛋白和抗tau缠结的功效。在一项慢性苔藓虫素治疗试验中，确定与安慰剂相比，AD患者表现出显著的认知益处。在这项为期6个月的122例AD患者苔藓虫素试验中，有两个队列：中度队列（MMSE, Mini-Mental Status Exam: 15-18）和中度重度队列（MMSE 10-14）作为预先指定的次要终点。根据基线SIB对患者进行随机分组，以确保治疗组之间基线认知能力的平衡。在数据安全和监测委员会没有注意到安全事件的情况下，中度严重（MMSE 10-14）苔藓虫素治疗的患者在第13周至第42周期间比安慰剂患者有显著改善。在26周的时间内，7次静脉注射苔藓虫素两个周期后，每2周测量一次10-14队列严重损伤电池（SIB），使用混合模型重复测量模型（MMRM，双尾，p < 0.05），在第13周至第42周，甚至在第26周给药完成后16周，显示出显著的益处。安慰剂10-14患者没有任何益处，到第42周下降到负12.8点。趋势分析证实了该队列的MMRM数据，安慰剂组有显著的下降斜率（相当于认知能力下降），p < 0.001，双尾，但苔藓虫素治疗组没有显著下降（p = 0.409， NS），治疗与安慰剂相比p < 0.007。中等队列患者没有明显的获益。苔藓虫素治疗的MMSE 10-14患者在整个10个月的试验中没有出现明显的认知能力下降，而安慰剂患者的认知能力下降了-12.8 SIB点。
In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p = 0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit. The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients’ decline of -12.8 SIB points.