A Single Ascending Dose / Multiple Ascending Dose Phase I study of the GSM 776890 in healthy normal subjects

《科学文摘》 AD目前是一个巨大的健康问题，造成严重的社会和经济负担；在缺乏 一种有效的治疗疾病的方法，预计它将成为医疗保健的主要来源 未来几十年的支出。不幸的是，现有的治疗方法只是治标不治本。 暂时缓解症状的好处。通过NIH蓝图神经治疗(BPN)网络和U01 获奖我们发现并开发了一种高效的γ-分泌酶调节剂776890(也 称为化合物2)。与Semagacestat和其他γ分泌酶抑制剂(GSI)不同，GSM不 抑制伽马分泌酶活性(例如Notch蛋白分解)，但通过变构增强APP加工 通过减少Aβ42的净产量，并在较小程度上减少β40的净产量，同时同时增加 Aβ38和Aβ37的制作。化合物2(776890)在体外表现出良好的药效(IC_(50)=4.0 NM)，以及在体内(~55%的大鼠脑和脑脊液Aβ42水平和~85%的血浆Aβ42水平降低 和小鼠分别以5 mg/kg和10 mg/kg剂量灌胃)。除了在体内表现出强烈的剂量依赖性之外 两种不同啮齿动物的疗效，大鼠和非大鼠的7天剂量范围毒理学研究 人类灵长类(NHP)已经完成，没有观察到的不良反应水平(NOAEL)为&gt；50 在大鼠中建立了mg/kg的治疗指数(安全边际)为20。此外， 每日重复口服化合物2(25 mg/kg)3个月，未发现毒性证据 基于全身尸检。化合物2目前正在进行研究新药(IND)使能， 良好实验室规范(GLP)通过NIH BPN对大鼠和NHP进行28天的安全性和毒性测试 网络。在这里，我们提出了一项单次递增剂量(SAD)的安全性和耐受性研究，以详细说明 递增剂量(12.5、50、100、200、400和600 mg)后的药代动力学(PK)并评估 利用特定的血浆生物标记物MSD V-plex ELISA法进行外周靶点结合。此外，我们 将进行为期14天的多次递增剂量(MAD)安全性和耐受性研究，详细说明以下PK 多个递增剂量(50 mg、100 mg和200 mg)和建立机构啮合通过 48例受试者血浆和脑脊液样本的IP-MS分析研究 在基线和递增剂量治疗后均使用或安慰剂治疗。我们在瑞典的合作者 (Kaj Blennow博士，医学博士，博士)开发了一种高度创新的免疫沉淀-质谱学 使用QExactive仪器的(IP-MS)方法，能够准确、快速地监控所有主要 人脑脊液中存在Aβ亚型。Aβ38、Aβ40和Aβ42的血浆浓度将使用 血浆特异性标志物MSD V-plex酶联免疫吸附试验检测。

Scientific Abstract AD is currently a huge health problem that imposes a severe social and economic burden; in the absence of an effective disease modifying treatment it is projected to become a dominant source of health care expenditures over the next several decades. Unfortunately, existing treatments are palliative providing only temporary symptomatic benefit. Through an NIH Blueprint Neurotherapeutics (BPN) Network and U01 award we have discovered and developed a highly potent γ -secretase modulator (GSM), 776890 (also referred to as compound 2). Unlike semagacestat and other γ -secretase inhibitors (GSIs), GSMs do not inhibit gamma-secretase activity (e.g. Notch proteolysis) but rather allosterically enhance APP processing by reducing the net production of Aβ42 and to a lesser extent Aβ40 while concomitantly augmenting the production of Aβ38 and Aβ37. Compound 2 (776890), demonstrates excellent potency in vitro (IC50 = 4.0 nM), as well as in vivo (~55% lowering of brain and CSF Aβ42 levels and ~ 85% plasma Aβ42 levels in rats and mice at doses of 5 or 10 mg/kg p.o, respectively). In addition to showing robust dose-dependent in vivo efficacy in two different rodent species, 7-day dose-range finding toxicology studies in both rats and non- human primates (NHPs) has been completed and a no observed-adverse-effect-level (NOAEL) of >50 mg/kg was established in rats, resulting in a therapeutic index (safety margin) of >20. In addition, following 3-months of repeated daily (qd) oral dosing of compound 2 (25 mg/kg) showed no evidence of toxicity based on full body necropsy. Compound 2 is currently undergoing investigational new drug (IND)-enabling, good laboratory practice (GLP) 28-day safety and toxicity testing in rats and NHPs through the NIH BPN Network. Here we propose a single ascending dose (SAD) safety and tolerability study, to detail the pharmacokinetics (PK) following ascending doses (12.5, 50, 100, 200, 400 and 600 mg) and assess peripheral target engagement utilizing specific plasma biomarker MSD V-plex ELISA assays. In addition, we will perform a 14-day multiple ascending dose (MAD) safety and tolerability study, detailing the PK following multiple ascending doses (50 mg, 100 mg and 200 mg) and establishing engagement of mechanism via studies with plasma and CSF samples using a novel and innovative IP-MS analysis from 48 subjects treated with or placebo both at baseline and after ascending doses of treatment. Our collaborator in Sweden (Dr Kaj Blennow, MD, PhD) has developed a highly innovative immunoprecipitation - mass spectrometry (IP-MS) method using a QExactive instrument that enables accurate and rapid monitoring of all of the major Aβ isoforms in human CSF. Plasma concentrations of Aβ38, Aβ40, and Aβ42 will be measured using specific plasma biomarker MSD V-plex ELISA assays.