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.
In June 2018, Eisai issued a press release on the 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 (June 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, and nightmares as a notable side effect (Oct 2018 conference news, Lynch et al., 2018).
For all clinical trials of elenbecestat, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Phase 3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
- Anti-Amyloid Drug Pipeline Shows No Sign of Drying Up
- Hanging in There: Another BACE Inhibitor Still Safe in Phase 2
- Bump in the Road or Disaster? BACE Inhibitors Worsen Cognition
- Wave of New BACE Inhibitors Heading to Phase 2
- Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, Egan M, Ereshefsky L, Hodgson RA, Hyde LA, Jhee S, Kleijn HJ, Kuvelkar R, Li W, Mattson BA, Mei H, Palcza J, Scott JD, Tanen M, Troyer MD, Tseng JL, Stone JA, Parker EM, Forman MS. 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.