BACKGROUND Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aβ), was developed for oral treatment for Alzheimer's disease (AD). The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed. METHODS In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85 years were randomized (1:1:1) to placebo or atabecestat 10 or 50 mg once daily (later reduced to 5 and 25 mg) for 6 months. Participants entered ALZ2004, a 12-month treatment extension with placebo or atabecestat 10 or 25 mg, followed by an open-label phase. Safety, changes in CSF biomarker levels, brain volume, and effects on cognitive performance were assessed. RESULTS Of 114 participants randomized in ALZ2002, 99 (87%) completed, 90 entered the ALZ2004 double-blind phase, and 77 progressed to the open-label phase. CSF Aβ fragments and sAPPβ were reduced dose-proportionately. Decreases in whole brain and hippocampal volumes were greater in participants with mild cognitive impairment (MCI) due to AD than in preclinical AD, but were not affected by treatment. In ALZ2004, change from baseline in RBANS trended toward worse scores for atabecestat versus placebo. Elevated liver enzyme adverse events reported in 12 participants on atabecestat resulted in dosage modification and increased frequency of safety monitoring. Treatment discontinuation normalized ALT or AST in all except one with pretreatment elevation, which remained mildly elevated. No case met ALT/AST > 3× ULN and total bilirubin > 2× ULN (Hy's law). CONCLUSION Atabecestat was associated with trend toward declines in cognition, and elevation of liver enzymes. TRIAL REGISTRATION ALZ2002: ClinicalTrials.gov, NCT02260674, registered October 9, 2014; ALZ2004: ClinicalTrials.gov, NCT02406027, registered April 1, 2015.

中文翻译：

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口服BACE1抑制剂atabecestat（JNJ-54861911）在阿尔茨海默氏病早期患者中的长期安全性和耐受性：一项随机，双盲，安慰剂对照研究和一个为期两期的扩展研究。

背景技术Atabecestat是一种有效的脑可穿透的BACE1活性抑制剂，可降低CSF淀粉样蛋白β（Aβ），用于口服治疗阿尔茨海默氏病（AD）。两项两项2期研究评估了atabecestat对痴呆前期AD参与者认知能力的长期安全性和影响。方法在安慰剂对照的双盲父母ALZ2002研究中，将年龄50至85岁的参与者随机（1：1：1）随机接受安慰剂或atabecestat 10或50 mg每天一次（后来减少至5和25 mg），持续6个月。参与者进入ALZ2004，使用安慰剂或atabecestat 10或25 mg进行为期12个月的治疗扩展，然后进入开放标签阶段。评估安全性，CSF生物标志物水平的变化，脑容量以及对认知能力的影响。结果ALZ2002中随机分配了114名参与者，完成了99项（占87％），有90项进入了ALZ2004双盲阶段，有77项进入了开放标签阶段。脑脊液Aβ片段和sAPPβ呈剂量比例减少。与AD相比，患有AD的轻度认知障碍（MCI）参与者的全脑和海马体积减少幅度更大，但不受治疗影响。在ALZ2004中，atabecestat与安慰剂相比，RBANS从基线的变化趋向于评分较差。atabecestat上12名参与者报告的肝酶不良事件升高，导致剂量调整和安全监测频率增加。停药可使所有患者的ALT或AST均正常化，但治疗前升高的患者仍保持轻度升高。没有病例符合ALT / AST> 3倍ULN和总胆红素> 2倍ULN（Hy定律）。结论Atabecestat与认知能力下降和肝酶升高的趋势有关。试用注册ALZ2002：ClinicalTrials.gov，NCT02260674，2014年10月9日注册；ALZ2004：ClinicalTrials.gov，NCT02406027，2015年4月1日注册。