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

健康正常受试者中 GSM 776890 的单次递增剂量/多次递增剂量 I 期研究

• 批准号: 10335246
• 负责人: DOUGLAS R GALASKO
• 金额: $ 252.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10335246
• 关键词: Abeta synthesis; Aducanumab; Adult; Adverse effects; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Area; Attenuated; Autopsy; Award; Biochemical; Biological Assay; Biological Markers; Brain; Brain region; Clinical; Clinical Trials; Cognition; Cognitive; Disease; Doctor of Philosophy; Dose; Drug Kinetics; Economic Burden; Enzyme-Linked Immunosorbent Assay; Enzymes; Evolution; FDA approved; Genetic; Health; Health Expenditures; Healthcare; Human; Immunoprecipitation; Immunotherapy; In Vitro; Inflammatory Response; Investigational Drugs; Late Onset Alzheimer Disease; Lead; Link; Mass Spectrum Analysis; Maximum Tolerated Dose; Measures; Membrane; Methods; Monitor; Mus; Mutation; Neurofibrillary Tangles; No-Observed-Adverse-Effect Level; Oral; Palliative Care; Pathogenesis; Pathologic; Peptides; Peripheral; Persons; Pharmacologic Substance; Phase; Phenotype; Placebos; Plasma; Prevention; Production; Property; Protein Isoforms; Proteolysis; Public Health; Rattus; Reporting; Reproducibility; Rodent; Role; Safety; Sampling; Senile Plaques; Site; Source; Specialist; Structure; Structure-Activity Relationship; Sweden; Therapeutic; Therapeutic Index; Time; Toxic effect; Toxicity Tests; Toxicology; Transgenic Mice; United States National Institutes of Health; Universities; Work; abeta accumulation; amyloid precursor protein processing; autosomal dominant Alzheimer' s disease; base; beta-site APP cleaving enzyme 1; cerebral amyloidosis; clinical development; design; early onset; exhaustion; gamma secretase; good laboratory practice; in vivo; inhibitor; innovation; instrument; lead optimization; male; multidisciplinary; nonhuman primate; notch protein; novel; phase 1 study; pre-clinical; presenilin; safety testing; scaffold; secretase; small molecule; social; socioeconomics

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.

科学抽象 AD目前是一个巨大的健康问题，造成了严重的社会和经济负担;在缺乏 一种有效的疾病治疗方法，预计将成为卫生保健的主要来源。 未来几十年的支出。不幸的是，现有的治疗是姑息性的， 暂时的症状性益处。通过NIH蓝图神经治疗学（BPN）网络和U 01 我们发现并开发了一种高效的γ -分泌酶调节剂（GSM），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γ-分泌酶活性（例如Notch蛋白水解），但变构增强APP加工 通过减少Aβ42和Aβ40的净产生，同时伴随着增加Aβ42和Aβ40的分泌， Aβ38和Aβ37的产生。化合物2（776890）在体外表现出优异的效力（IC 50 = 4.0 nM）以及体内（大鼠脑和CSF Aβ42水平降低约55%，血浆Aβ42水平降低约85% 和小鼠，剂量分别为5或10 mg/kg p.o.）。除了在体内显示出稳健的剂量依赖性外， 在两种不同啮齿动物种属中的有效性，大鼠和非大鼠中的7天剂量范围探索毒理学研究 人类灵长类动物（NHPs）的无明显不良作用水平（NOAEL）>50 在大鼠中确定了20 mg/kg的剂量，导致治疗指数（安全范围）>20。此外，继 3-化合物2（25 mg/kg）的重复每日（qd）口服给药数月未显示毒性迹象 根据全身尸检化合物2目前正在进行研究性新药（IND）启用， 通过NIH BPN在大鼠和NHP中进行的药物非临床研究质量管理规范（GLP）28天安全性和毒性试验 网络在这里，我们提出了一个单次递增剂量（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 利用特异性血浆生物标志物MSD V-plex ELISA测定的外周靶结合。另外我们 将进行一项为期14天的多次给药剂量递增（MAD）安全性和耐受性研究，详细描述以下PK 多次给药剂量递增（50 mg、100 mg和200 mg），并通过 使用来自48名受试者的新型创新IP-MS分析对血浆和CSF样本进行研究 在基线时和治疗剂量递增后均接受或安慰剂治疗。我们在瑞典的合作伙伴 (Dr Kaj Blennow，MD，PhD）开发了一种高度创新的免疫沉淀-质谱法 使用QExactive仪器的IP-MS方法，可以准确快速地监测所有主要的 人CSF中的Aβ亚型。Aβ38、Aβ40和Aβ42的血浆浓度将使用 特异性血浆生物标志物MSD V-plex ELISA测定。