Elenbecestat is an oral therapy that Eisai and Biogen are developing to delay the start of early-stage Alzheimer’s, and perhaps stop its progression.

How elenbecestat works

Alzheimer’s results from a build-up of beta amyloid plaque in the brain, which damages nerve cells. The plaque is formed when the beta-amyloid cleaving enzyme, or BACE, cuts the parent protein of beta amyloid into pieces. The parent is known as amyloid precursor protein.

Elenbecestat is a BACE inhibitor. It is designed to reduce beta amyloid plaque by preventing the BACE enzyme from cutting up the parent protein.

Elenbecestat in clinical trials

Studies in animals showed that elenbecestat can lower beta amyloid levels in the brain, the cerebrospinal fluid that envelops the brain and spinal cord, and in the blood.

Eisai and Biogen have conducted nine Phase 1 clinical trials of elenbecestat, eight of which they  completed by March 2015. The first two trials showed that participants could tolerate doses of up to 200 mg, with dizziness and headaches the most common side effects.

The main objectives of a Phase 2 trial (NCT02322021) that began in November 2014 were to see if elenbecestat was safe and could slow the progression of Alzheimer’s in 700 patients with mild cognitive impairment or mild to moderate dementia.

Patients receive either a placebo or 5, 15 or 50 mg of elenbecestat in single daily doses over 18 months. The 50-mg dose was safe and generated the greatest reductions in beta amyloid levels, results showed. The trial is set to end in April 2018.

Eisai and Biogen started two Phase 3 trials in 2016. The main goal of the MISSION AD1 (NCT02956486) and MISSION AD2 (NCT03036280) studies was to further investigate the 50-mg dose’s effectiveness.

The plan was for 1,330 patients to receive 50 mg of elenbecestat daily for two years. One of the  effectiveness yardsticks is whether the drug can reduce the severity of patients’ dementia symptoms. Another is whether it can lower beta amyloid levels in the brain. Still another is whether it can prevent deterioration of the hippocampus, a brain structure that Alzheimer’s has a major effect on. An additional yardstick is whether it can improve several cerebrospinal fluid biomarkers of Alzheimer’s.

Both trials continue to recruit participants in the U.S. MISSION AD2 is also scheduled to be held in Japan. In addition, Eisai and Biogen have asked European regulators to approve trials there.

Further details

Eisai announced in 2016 that the U.S. Food and Drug Administration had granted fast-track status to elenbecestat. Fast track is aimed at accelerating the development and regulatory review of treatments for serious conditions.

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