2018年6月6日,卫材（Eisai）与合作伙伴百健（Biogen）近日公布了口服BACE抑制剂elenbecestat（研发代码：E2609）治疗阿尔茨海默氏症（AD）II期临床研究Study 202（NCT02322021）的数据。
  该研究是一项多中心、司机、双盲、安慰剂对照、平行组、18个月研究，在由AD引起的轻度认知损害（MCI）或因AD引起的轻度至中度痴呆的患者中开展，这些患者经PET筛查证实存在淀粉样病变。研究中，70例患者随机分成4个治疗组，分别接受每日一次elenbecestat（5mg，15mg，50mg）或安慰剂治疗。在研究期间，elenbecestat 5mg和15mg治疗组中有超过一半的患者转向50mg治疗组治疗3个月或更长时间。50mg治疗组加上切换至50mg治疗的患者被称为“50mg总组（38例）”，接受elenbecestat 50mg治疗的中位持续时间约11个月。

  数据显示，经过18个月的治疗，elenbecestat表现出可接受的安全性和耐受性。在50mg总组，观察到的6种最常见不良事件为接触性皮炎、上呼吸道感染、头痛、腹泻、跌倒和皮炎。该研究中未观察到提示为肝毒性的严重不良反应。

  除了安全性目标之外，该研究在治疗第18个月时还采用淀粉样体PET评估了患者大脑中β-淀粉样蛋白（Aβ）的水平以及临床症状方面的功效。数据显示，与安慰剂组相比，50mg总组在大脑Aβ水平表现出了统计学上的显著差异。这是首次在轻度认知损害（MCI）至中度AD痴呆患者临床研究中证实一种BACE抑制剂可对大脑Aβ水平产生显著的影响。

  CDR-SB（临床痴呆评分总和）是一个探索性终点，旨在评估临床症状方面的疗效。该研究显示，与安慰剂相比，elenbecestat 50mg总组在CDR-SB方面表现出数值上的小幅度下降，具有潜在的临床上重要差异，但无统计学意义。此外，在卫材最新开发的评估量表ADCOMS方面的一项时候分析中，elenbecestat 50mg总组与安慰剂组观察到了相似的幅度和方向的下降。不过，该研究的目的并不是证实elenbecestat相对于安慰剂在临床症状的统计学差异。

  卫材已计划在未来召开的医学会议上公布该研究的详细结果。
  elenbecestat由Eisai公司研发，目前处于III期临床试验，治疗由AD所导致的轻度认知损害和轻至中度痴呆症。2014年，Eisai和Biogen签署协议，联合开发Elenbecestat。BACE是Aβ肽产生过程中的关键酶，通过靶向抑制BACE， elenbecestat可降低Aβ的产生，这被认为能够减少大脑中因毒性寡聚体和原纤维聚集导致的淀粉样斑块形成。在美国，之前FDA已授予elenbecestat快速通道地位。

  原文出处：PHASE II CLINICAL STUDY OF ELENBECESTAT DEMONSTRATES SAFETY AND TOLERABILITY IN MCI AND MILD TO MODERATE ALZHEIMER’S DISEASE AT 18-MONTHS

Name: Elenbecestat
Synonyms: E2609, BACE inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Biogen, Eisai Co., Ltd.

Elenbecestat is a small-molecule inhibitor of BACE, aka the β-secretase enzyme. It was developed with the rationale of interfering with the amyloid cascade upstream of Aβ peptide generation. BACE inhibition is sometimes envisioned as long-term maintenance therapy to limit Aβ production after an initial round of immunotherapy to remove existing amyloid deposits. 

At the 2012 AAIC conference in Vancouver, Canada, Eisai presented data to suggest that elenbecestat lowers Aβ concentration in the brain, CSF, and plasma of rats and guinea pigs, and that it lowers CSF and plasma Aβ in non-human primates (Jul 2012 conference news). Eisai developed this compound preclinically, and in March 2014 signed an agreement with Biogen to collaborate in its clinical development.

As of March 2015, eight Phase 1 trials had been completed. They evaluated the safety and pharmacology of elenbecestat in nearly 500 healthy volunteers and people with early Alzheimer's disease. Eisai presented results from the first two studies at the 2012 AAIC conference. A single oral ascending-dose study of 5 to 800 mg elenbecestat showed a reduction of plasma Aβ levels; a 14-day ascending-dose study of 25 to 400 mg showed a dose-dependent reduction of up to 80 percent in CSF Aβ levels. 

According to Eisai, elenbecestat showed acceptable tolerability across all doses, with headache and dizziness the most common adverse events. A press release stated that no clinically significant safety concerns were observed following repeated oral dosing of up to 200 mg. Several cases of orolabial herpes relapse were observed in the 200 mg cohort, and safety findings in the 400 mg group were not disclosed.

Another trial tested seven different single oral doses in 65 people with mild cognitive impairment who had biomarker evidence of amyloid pathology, and measured CSF Aβ levels as a primary outcome measure. This trial was completed in October 2013 but no data have been disclosed. One study compared safety and pharmacology of E2609 in Japanese and Caucasian people, and one tested whether the inhibitor affects the function of the heart. One trial evaluated interactions with drugs commonly prescribed to the elderly, another one focused on bioavailability with food. 

In December 2014, Eisai listed a large phase 2 dose-finding study in what was to be 700 people with MCI due to AD or prodromal AD whose amyloid PET scan was positive. This seven-arm trial was designed to compare an 18-month course of three different doses to placebo in people whose dementia has been classified as being at the MCI/prodromal stage, and two doses to placebo in people whose dementia has been staged at mild AD. The lower doses were intended to increase during the trial based on interim analyses. The primary outcome was change from baseline in the prodromal group on a new cognitive/clinical measure developed for predementia/prodromal called Alzheimer's Disease Composite Score (ADCOMS) (see Oct 2014 CAMD meeting). Secondary outcomes included hippocampal atrophy, CSF biomarkers, and change on ADCOMS in the mild AD group.

However, only the smaller phase 2a safety/tolerability part of this was trial was run. At the 2017 AD/PD conference, Eisai presented results of the phase 2a trial of 5, 15, or 50 mg of elebecestat per day, reporting that the drug was safe and that the high dose reduced CSF Aβ1-x by 70% . Based on these results, Eisai decided to scrap the 2b efficacy part of this trial and instead go directly into phase 3 (May 2017 conference news). 

In August 2016, a ninth phase 1 trial was added to compare the pharmacokinetics and metabolism of the inhibitor in people with normal versus impaired liver function and in spring of 2017, a 10th phase 1 trial evaluated a 50 mg dose in 16 healthy Japanese volunteers.

On October 31, 2016, Eisai announced that it had begun enrolling people into the first study of its Phase 3 program of elenbecestat, called MISSION AD. MISSION AD1, aka study 301, is a global trial to be conducted at 288 sites in the Americas, as well as countries in Asia and Europe. It will compare a two-year, 50 mg once-a-day course of E2609 to placebo in 1,330 patients age 50 to 85 who have biomarker-confirmed MCI due to AD/prodromal AD. Change from baseline on the CDR-SB at the 2-year time point serves as the primary outcome; secondary outcomes include time to worsening and rate of change on the CDR-SB, also other  cognitive and functional measures. The trial also assesses exploratory outcomes such as change on amyloid PET, hippocampal volume and functional connectivity MRI, and CSF biomarkers. This trial is set to run through 2020.

In December 2016, MISSION AD2 started; it is identical to AD1 but being conducted at 289 different sites across the Americas, South Africa, Australia, Israel, as well as numerous countries in Europe and Asia.

As of May 2018, no study results had been posted on clintrials.gov, or published in peer-reviewed journals yet.