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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 (Discontinued)
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 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. In March 2014, Eisai signed an agreement with Biogen to collaborate in its clinical development.

Elenbecestat is reported to bind BACE 1 with 3.53-fold higher affinity than BACE 2 (see elenbecestat section in May 2019 AD/PD news). According to Eisai, no depigmentation due to BACE 2 inhibition was seen in either animal studies or clinical trials so far.


By March 2015, eight Phase 1 trials had been completed to evaluate 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 Phase 2 dose-finding study in what was to be 700 symptomatic people whose amyloid PET scans were positive. This seven-arm trial was designed to compare an 18-month course of three different doses to placebo in people whose dementia had been classified as being at the MCI/prodromal stage, and two doses to placebo in people whose dementia had 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.

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 elenbecestat per day, reporting that the drug was safe and that the high dose reduced CSF Aβ1-x by 70 percent. 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 conducted at 271 sites in the Americas, Asia and Europe. It was to compare a two-year, 50 mg once-a-day course of E2609 to placebo in 1,330 patients age 50 to 85 with biomarker-confirmed MCI due to AD/prodromal AD. Change from baseline on the CDR-SB at the two-year time point was to serve as the primary outcome; secondary outcomes included time to worsening and rate of change on the CDR-SB, also other cognitive and functional measures. The trial was to assesses exploratory outcomes such as change on amyloid PET, hippocampal volume and functional connectivity MRI, and CSF biomarkers, and was set to read out in 2021.

In December 2016, MISSION AD2 started; it is identical to AD1 but ran at 297 different sites across the Americas, South Africa, Australia, Israel, as well as numerous countries in Europe and Asia.

In June 2018, Eisai issued a press release on its 70-person Phase 2 trial, stating that after 18 months of treatment, elenbecestat continued to be safe and tolerable, reduced brain amyloid, and showed a possible cognitive signal (Jun 2018 news). Data from this trial were presented at AAIC and CTAD, reporting a 25 centiloid drop on amyloid PET, a cognitive benefit in the 50 mg elenbecestat group, but also nightmares as a notable side effect (Nov 2018 conference newsLynch et al., 2018).

In May 2019, Eisai announced that the Alzheimer’s Clinical Trials Consortium (Dec 2017 news) chose elenbecestat and the anti-amyloid protofibril antibody BAN2401 for primary and secondary prevention trials starting up in early 2020 (company press release).

On September 13, 2019, Biogen/Eisai announced they would end both MISSION trials, following a finding of unfavorable risk/benefit by its data safety monitoring board (Sept 2019 news). A remaining Phase 2 long-term extension trial was also scrapped.

Interim data presented at CTAD 2019 indicated no negative effect on cognition at early timepoints, in contrast to the BACE inhibitors verubecestat, atabecestat, and umibecestat. However, there was no significant improvement in cognitive scores after two years of treatment in the small number of people who received the full course. People taking drug lost more weight, and had more skin rashes and neuropsychiatric adverse events than those on placebo (Dec 2019 conference news). Full trial results presented at AD/PD 2021 noted a decline in some cognitive tests at six months, which disappeared by 12 months and did not recur. Elenbecestat treatment resulted in a small, statistically significant reduction of brain amyloid by 8 centiloids over two years. Like other BACE inhibitors, the drug caused a loss of brain volume. Additional adverse events included a transient drop in white blood cells, and elevation of liver enzymes in some people (Apr 2021 conference news).

For all clinical trials of elenbecestat, see

Clinical Trial Timeline

  • Phase 2
  • Phase 3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034
Eisai Co., Ltd. NCT02322021
Eisai Co., Ltd. NCT02956486
Eisai Co., Ltd. NCT03036280

Last Updated: 07 May 2021


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News Citations

  1. Anti-Amyloid Drug Pipeline Shows No Sign of Drying Up
  2. Hanging in There: Another BACE Inhibitor Still Safe in Phase 2
  3. Bump in the Road or Disaster? BACE Inhibitors Worsen Cognition
  4. Clinical Trials Consortium Succeeds ADCS, Focuses on Prevention
  5. End of the BACE Inhibitors? Elenbecestat Trials Halted Amid Safety Concerns
  6. Picking Through the Rubble, Field Tries to Salvage BACE Inhibitors
  7. Drop of Hope? No Cognitive Worsening on BACE Inhibitor
  8. Wave of New BACE Inhibitors Heading to Phase 2
  9. BACE Inhibitors: Postmortem on One, Live Updates on Two

Therapeutics Citations

  1. Verubecestat
  2. Atabecestat
  3. Umibecestat

Paper Citations

  1. . Elenbecestat, E2609, a Bace Inhibitor: Results From a Phase-2 Study in Subjects With Mild Cognitive Impairment and Mild-to-Moderate Dementia Due to Alzheimer's Disease. Alzheimer's & Dementia, July 2018

Other Citations

  1. BAN2401

External Citations

  1. Oct 2014 CAMD meeting
  2. company press release

Further Reading


  1. . The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med. 2016 Nov 2;8(363):363ra150. PubMed.
  2. . Systematic in silico analysis of clinically tested drugs for reducing amyloid-beta plaque accumulation in Alzheimer's disease. Alzheimers Dement. 2021 Sep;17(9):1487-1498. Epub 2021 May 2 PubMed.
  3. . Investigational BACE inhibitors for the treatment of Alzheimer's disease. Expert Opin Investig Drugs. 2019 Nov;28(11):967-975. Epub 2019 Oct 29 PubMed.