A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease.
A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease.
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IB期在阿尔茨海默氏病中的AZD0530（Saracatinib）的安全性，耐受性和中枢神经系统可用性的多次升级剂量研究。
DOI：
10.1186/s13195-015-0119-0
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
van Dyck CH
中科院分区：
文献类型：
--
作者：
Nygaard HB;Wagner AF;Bowen GS;Good SP;MacAvoy MG;Strittmatter KA;Kaufman AC;Rosenberg BJ;Sekine-Konno T;Varma P;Chen K;Koleske AJ;Reiman EM;Strittmatter SM;van Dyck CH
尽管取得了重大进展，但尚未开发出阿尔茨海默病（AD）的疾病修饰疗法。最近的研究结果表明可溶性寡聚淀粉样蛋白β是AD发病机制中最相关的蛋白质构象。我们最近描述了一个信号级联反应，其中寡聚淀粉样蛋白β结合到神经元细胞表面的细胞朊蛋白，激活细胞内Fyn激酶介导突触毒性。Fyn激酶在体外模型和人类受试者中均与AD病理生理学有关，并且是AD的有希望的新治疗靶点。在此，我们提出了一项Ib期试验的重新用途的研究药物AZD 0530，Src家族激酶抑制剂特异性Fyn和Src激酶，用于治疗轻中度AD患者。该研究是一项为期4周的Ib期、多次给药剂量递增、随机化、双盲、安慰剂对照试验，在简易精神状态检查（MMSE）评分范围为16 - 26的AD患者中评估AZD 0530。共招募了24名受试者，分为三个连续组，每组随机接受每日50 mg、100 mg、125 mg或安慰剂口服AZD 0530，持续4周。药物：安慰剂比例为3：1。主要终点为AZD 0530的安全性、耐受性和脑脊液（CSF）渗透。次要终点包括临床疗效指标的变化（阿尔茨海默病评估量表-认知子量表、MMSE、阿尔茨海默病合作研究-日常生活活动量表、神经精神量表和临床痴呆评定量表-方框总和）和通过氟脱氧葡萄糖正电子发射断层扫描测量的局部脑葡萄糖代谢。AZD 0530在不同剂量下通常安全且耐受性良好。1例接受125 mg AZD 0530治疗的受试者因发生充血性心力衰竭和非典型肺炎而中止研究，认为这些事件可能与研究药物相关。AZD 0530的血浆/CSF比值为0.4。100 mg和125 mg剂量达到的CSF药物水平与转基因小鼠模型中挽救记忆缺陷的脑水平相对应。AZD 0530治疗1个月对临床疗效指标或局部脑葡萄糖代谢无显著影响。AZD 0530在轻度至中度AD患者中具有合理的安全性和良好的耐受性，口服剂量为100-125 mg时可实现显著的中枢神经系统渗透。靶向Fyn激酶可能是AD的一种有前途的治疗方法，最近启动了AZD 0530治疗AD患者的更大规模IIa期临床试验。ClinicalTrials.gov：NCT01864655。2014年6月12日注册。
Despite significant progress, a disease-modifying therapy for Alzheimer’s disease (AD) has not yet been developed. Recent findings implicate soluble oligomeric amyloid beta as the most relevant protein conformation in AD pathogenesis. We recently described a signaling cascade whereby oligomeric amyloid beta binds to cellular prion protein on the neuronal cell surface, activating intracellular Fyn kinase to mediate synaptotoxicity. Fyn kinase has been implicated in AD pathophysiology both in in vitro models and in human subjects, and is a promising new therapeutic target for AD. Herein, we present a Phase Ib trial of the repurposed investigational drug AZD0530, a Src family kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients with mild-to-moderate AD. The study was a 4-week Phase Ib multiple ascending dose, randomized, double-blind, placebo-controlled trial of AZD0530 in AD patients with Mini-Mental State Examination (MMSE) scores ranging from 16 to 26. A total of 24 subjects were recruited in three sequential groups, with each randomized to receive oral AZD0530 at doses of 50 mg, 100 mg, 125 mg, or placebo daily for 4 weeks. The drug:placebo ratio was 3:1. Primary endpoints were safety, tolerability, and cerebrospinal fluid (CSF) penetration of AZD0530. Secondary endpoints included changes in clinical efficacy measures (Alzheimer’s Disease Assessment Scale – cognitive subscale, MMSE, Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Clinical Dementia Rating Scale – Sum of Boxes) and regional cerebral glucose metabolism measured by fluorodeoxyglucose positron emission tomography. AZD0530 was generally safe and well tolerated across doses. One subject receiving 125 mg of AZD0530 was discontinued from the study due to the development of congestive heart failure and atypical pneumonia, which were considered possibly related to the study drug. Plasma/CSF ratio of AZD0530 was 0.4. The 100 mg and 125 mg doses achieved CSF drug levels corresponding to brain levels that rescued memory deficits in transgenic mouse models. One-month treatment with AZD0530 had no significant effect on clinical efficacy measures or regional cerebral glucose metabolism. AZD0530 is reasonably safe and well tolerated in patients with mild-to-moderate AD, achieving substantial central nervous system penetration with oral dosing at 100–125 mg. Targeting Fyn kinase may be a promising therapeutic approach in AD, and a larger Phase IIa clinical trial of AZD0530 for the treatment of patients with AD has recently launched. ClinicalTrials.gov: NCT01864655. Registered 12 June 2014.
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影响因子：
11.2
作者：
Kaufman, Adam C.;Salazar, Santiago V.;Haas, Laura T.;Yang, Jinhee;Kostylev, Mikhail A.;Jeng, Amanda T.;Robinson, Sophie A.;Gunther, Erik C.;van Dyck, Christopher H.;Nygaard, Haakon B.;Strittmatter, Stephen M.
通讯作者：
Strittmatter, Stephen M.
影响因子：
5.7
作者：
Chen, Kewei;Langbaum, Jessica B. S.;Fleisher, Adam S.;Ayutyanont, Napatkamon;Reschke, Cole;Lee, Wendy;Liu, Xiaofen;Bandy, Dan;Alexander, Gene E.;Thompson, Paul M.;Foster, Norman L.;Harvey, Danielle J.;de Leon, Mony J.;Koeppe, Robert A.;Jagust, William J.;Weiner, Michael W.;Reiman, Eric M.
通讯作者：
Reiman, Eric M.
DOI：
10.1016/j.jalz.2011.03.005
发表时间：
2011-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
McKhann GM;Knopman DS;Chertkow H;Hyman BT;Jack CR Jr;Kawas CH;Klunk WE;Koroshetz WJ;Manly JJ;Mayeux R;Mohs RC;Morris JC;Rossor MN;Scheltens P;Carrillo MC;Thies B;Weintraub S;Phelps CH
通讯作者：
Phelps CH
影响因子：
16.6
作者：
Freir, Darragh B.;Nicoll, Andrew J.;Klyubin, Igor;Panico, Silvia;Mc Donald, Jessica M.;Risse, Emmanuel;Asante, Emmanuel A.;Farrow, Mark A.;Sessions, Richard B.;Saibil, Helen R.;Clarke, Anthony R.;Rowan, Michael J.;Walsh, Dominic M.;Collinge, John
通讯作者：
Collinge, John
影响因子：
9.9
作者：
Cummings, JL
通讯作者：
Cummings, JL