Phase II trial of GM-CSF/sargramostim in Alzheimer's Disease

项目摘要 针对淀粉样β蛋白的阿尔茨海默病(AD)治疗显示出令人鼓舞的结果 转基因动物模型的结果，但在人体试验中不那么令人鼓舞的结果，这也受到了困扰 有严重不良事件(SAE)，包括淀粉样蛋白相关成像异常(ARIA)。我们的建议 创新的治疗方法是基于流行病学证据，患者患有炎症性疾病 疾病类风湿性关节炎(RA)患AD的风险降低，与使用非类固醇无关 抗炎药(NSAIDs)。我们鉴定了先天免疫系统刺激物粒细胞-巨噬细胞 集落刺激因子(GM-CSF)作为一种造血因子在RA中表达上调，我们发现其表达降低 转基因阿尔茨海默病小鼠的脑淀粉样变性和逆转认知障碍。其他研究表明，GM-CSF 在几种神经疾病和损伤模型中具有神经保护、抗细胞凋亡和神经源性作用。 我们还发现，重组人GM-CSF(沙氏/亮氨酸)治疗与认知能力有关 白血病患者骨髓化学消融和造血细胞移植治疗后的改善。 值得注意的是，沙格拉莫替丁是fda批准的一种药物，用于增加白血的产生和分化。 30多年来安全记录极佳的电池。最重要的是，我们最近完成了I/II阶段的安全 和疗效试验(NCT01409915)，在该试验中，轻至中度AD患者接受沙雷格斯汀治疗 (250微克/平方米/天SC)或安慰剂，每周五天，为期三周(每组20：20名参与者)， 神经心理学、神经成像和血液生物标记物评估。沙拉莫替丁治疗是安全的 (主要终点)，没有与毒品有关的SAE，也没有Arias。此外，简易精神状态检查(MMSE) 与基线相比，治疗结束(EOT)时，沙格拉司汀组的认知能力有所改善 (P=0.0074)，在EOT(p=0.037)和45天时，沙格拉司汀组与安慰剂组相比 电刺激后(p=0.0281)。其他评估显示没有治疗益处，但有一种负面趋势 MMSE和淀粉样蛋白-PET变化之间的相关性。我们现在建议进行一项随机的、双重的 对42名轻至中度AD参与者进行的盲法安慰剂对照试验，其中28人将接受沙格拉司汀(250 Mcg/m2/天SC)，其中14人将接受安慰剂治疗，每周5天，为期24周，并进行45天的随访。 我们已经获得了IND豁免(134291)和IRB批准(17-0215)，但将提交改进的 未来几个月的版本。我们的具体目标是：1)评估长期的安全性和耐受性 轻至中度AD患者中的沙格拉莫替丁(主要终点)。2)评估安非他明的效果 轻、中度阿尔茨海默病患者认知和日常生活能力的治疗 探索性端点)。3)评估与沙格拉司汀治疗相关的生物标志物的变化。 中度AD参与者(探索性终点)。

PROJECT ABSTRACT Alzheimer’s disease (AD) treatments designed to target the amyloid-beta peptide have shown encouraging results in transgenic animal models but less encouraging results in human trials, which have also been plagued with serious adverse events (SAEs), including amyloid-related imaging abnormalities (ARIAs). Our proposed innovative therapeutic approach is based on epidemiological evidence that patients with the inflammatory disease rheumatoid arthritis (RA) have a reduced risk of developing AD, unrelated to their use of non-steroidal anti-inflammatory drugs (NSAIDs). We identified the innate immune system stimulant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as a hematopoietic factor upregulated in RA, which we found reduced brain amyloidosis and reversed cognitive impairment in transgenic AD mice. Other studies have shown GM-CSF to be neuroprotective, anti-apoptotic, and neurogenic in several models of neurological diseases and injuries. We also found that recombinant human GM-CSF(sargramostim/Leukine) treatment is associated with cognitive improvements in leukemia patients after bone marrow chemo-ablation and hematopoietic cell transplant therapy. Notably, sargramostim is an FDA-approved drug for increasing the production and differentiation of white blood cells with an excellent safety record over 30 years. Most importantly, we recently completed a Phase I/II safety and efficacy trial (NCT01409915) in which mild-to-moderate AD participants were treated with sargramostim (250 mcg/m2/day SC) or placebo five days/week for three weeks (20:20 participants per group) with neurological, neuropsychological, neuroimaging, and blood biomarker assessments. Sargramostim treatment was safe (Primary Endpoint) with no drug-related SAEs and no ARIAs. Furthermore, the Mini-Mental State Exam (MMSE) showed cognitive improvement in the sargramostim group at the end of treatment (EOT) compared to baseline (p=0.0074) and in the sargramostim group compared to the placebo group at the EOT (p=0.037) and at 45 days after the EOT (p=0.0281). Other assessments showed no treatment benefits, but there was a trend negative correlation between changes in MMSE versus amyloid-PET. We now propose to carry out a randomized, double- blind, placebo-controlled trial in 42 mild-to-moderate AD participants, 28 of whom will receive sargramostim (250 mcg/m2/day SC) and 14 of whom will receive placebo, five days/week for 24 weeks with a 45-day follow-up visit. We have received both an IND exemption (134291) and IRB approval (17-0215) but will submit improved versions in the coming months. Our Specific Aims are: 1) Assess the long-term safety and tolerability of sargramostim in mild-to-moderate AD participants (Primary Endpoint). 2) Assess the effects of sargramostim treatment on cognition and activities of daily living in mild-to-moderate AD participants (Secondary and Exploratory Endpoints). 3) Assess changes in biomarkers associated with sargramostim treatment in mild-to- moderate AD participants (Exploratory Endpoints).