Phase 1 clinical studies with the gamma-secretase modulator, NGP 555 to establish safety, pharmacokinetics, and biomarker efficacy

使用 γ 分泌酶调节剂 NGP 555 进行 1 期临床研究，以确定安全性、药代动力学和生物标志物功效

• 批准号: 8859242
• 负责人: William T Comer
• 金额: $ 137.98万
• 依托单位: NEUROGENETIC PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8859242
• 关键词: Adverse effects; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Applications Grants; Award; Behavioral; Biological Markers; Cerebrospinal Fluid; Clinical; Clinical Research; Cognitive; Confusion; Data; Dementia; Development; Dose; Drug Kinetics; Effectiveness; Elderly; Electronics; Elements; Failure; Goals; Health; Impaired cognition; Maximum Tolerated Dose; Measurement; Measures; Memory Loss; Monitor; Multienzyme Complexes; Nerve Degeneration; Neurons; Oral; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Plasma; Production; Risk; Safety; Senile Plaques; Skin; Small Business Innovation Research Grant; Societies; Staging; Toxic effect; base; bioimaging; cellular development; clinical efficacy; cost; gamma secretase; gastrointestinal; healthy volunteer; inhibitor/antagonist; innovation; neurogenetics; neuron loss; notch protein; novel; patient population; phase 1 study; pre-clinical; secretase; tau Proteins; volunteer

DESCRIPTION (provided by applicant): Currently, there is no cure for AD; however, it is widely accepted that inhibiting amyloid plaque formation would be beneficial for the prevention of Alzheimer's disease. Although there are many mechanistic approaches for the treatment of AD, one novel and innovative approach is to modulate the activity of the key enzyme complex involved in Aß42 production (a primary component of amyloid plaques), γ-secretase. Because of the potential for serious side-effects associated with inhibition of γ-secretase, modulation of its activity was targeted in order to avoid non-specific effects. The failure of γ-secretase inhibitors has mostly been attributed to side-effects caused by other γ-secretase substrates such as Notch, an essential element for normal cellular development, and the buildup of the amyloid precursor protein carboxyl-terminal fragments (APP-CTFs), toxic fragments which likely cause loss of neuronal function. Our scientific approach resulted in the discovery and preclinical development of the clinical candidate, NGP 555, which is mechanistically devoid of these non-specific activities. Under NeuroGenetic Pharmaceuticals' (NGP) current SBIR-fast track award with NINDs we have completed the final nonclinical studies necessary to file an IND and have prepared our IND for electronic filing, expected July, 2014. In our application to NIA (PAR 14-089), we propose to initiate Phase 1 clinical trials and accomplish single ascending dose (SAD) and multiple ascending dose (MAD) trials with safety and pharmacokinetic (PK)/pharmacodynamic (PD) readouts in normal healthy/elderly volunteers and in mild AD patients. In addition to the standard safety determinations, including showing NGP 555 is devoid of gastrointestinal and skin toxicity, we expect to determine drug effectiveness with Aß biomarker measurements in plasma and cerebrospinal fluid (CSF) along with neuronal health measurements of tau in the CSF. These data should be compelling enough to mitigate risks for entering into longer term trials with additional safety, bio-imaging, and cognitive endpoints of clinical efficacy for Ph 2a and 2b trials.

描述（由申请人提供）：目前，没有治愈AD的方法;然而，人们普遍认为抑制淀粉样蛋白斑块形成将有利于预防阿尔茨海默病。尽管有许多治疗AD的机制方法，但一种新颖的创新方法是调节参与A β 42产生的关键酶复合物（淀粉样蛋白斑块的主要组分）γ-分泌酶的活性。由于与抑制γ-分泌酶相关的严重副作用的可能性，靶向调节其活性以避免非特异性作用。γ-分泌酶抑制剂的失败主要归因于由其他γ-分泌酶底物引起的副作用，例如Notch，正常细胞发育的必需元素，以及淀粉样前体蛋白羧基末端片段（APP-CTF）的积累，其是可能导致神经元功能丧失的毒性片段。我们的科学方法导致了临床候选药物NGP 555的发现和临床前开发，该药物在机制上没有这些非特异性活性。根据NeuroGenetic Pharmaceuticals（NGP）目前的SBIR-快速通道NIND奖，我们已经完成了提交IND所需的最终非临床研究，并准备了我们的IND电子备案，预计2014年7月。在我们的NIA申请（PAR 14-089）中，我们建议在正常健康/老年志愿者和轻度AD患者中启动I期临床试验，并完成单次给药剂量递增（SAD）和多次给药剂量递增（MAD）试验，以及安全性和药代动力学（PK）/药效学（PD）读数。除了标准的安全性测定，包括显示NGP 555没有胃肠道和皮肤毒性，我们期望用血浆和脑脊液（CSF）中的Ablast生物标志物测量沿着CSF中tau的神经元健康测量来确定药物有效性。这些数据应具有足够的说服力，以降低进入2a期和2b期试验的更长期试验的风险，这些试验具有额外的安全性、生物成像和临床疗效的认知终点。