Crenezumab is an investigational therapy developed by AC Immune in partnership with Genentech, a subsidiary of Hoffmann-La Roche, to treat Alzheimer’s disease.

How crenezumab works

Crenezumab is a monoclonal antibody designed to bind to amyloid-beta proteins to prevent and break up their aggregation in existing plaques in Alzheimer’s disease.  The accumulation of amyloid-beta proteins in the brain is a hallmark of Alzheimer’s.

Crenezumab mediates the clearance of amyloid-beta from the brain by microglia, a process called phagocytosis. Microglia are the immune cells of the central nervous system derived from bone marrow. 

Crenezumab in clinical trials

Phase 1 clinical trials in healthy volunteers (NCT00997919) and people with Alzheimer’s disease (NCT00736775) showed crenezumab to be safe. This finding led to two Phase 2 trials called ABBY  (NCT01343966) and BLAZE (NCT01397578). These used higher doses and achieved higher brain exposure than the Phase 1 trials. Completed in 2014, the Phase 2 studies continued into an open-label extension study (NCT01723826) to assess the long-term safety profile of crenezumab in people with Alzheimer’s disease who had participated in former clinical trials.

The ABBY trial failed to meet its primary goals showing no difference between crenezumab and placebo in terms of thinking ability. However, it did show a difference between the two groups when a subgroup of patients who had only mild Alzheimer’s disease was evaluated.

The BLAZE trial also failed to show a difference between treatment and placebo in beta-amyloid deposits as measured by PET (positron emission tomography) imaging, but did show a difference in beta-amyloid levels in the cerebrospinal fluid (the fluid surrounding the brain and the spinal cord).

Following these results, crenezumab moved into Phase 3 clinical development in people with prodromal-to-mild (early stage) Alzheimer’s disease. The CREAD study (NCT02670083) evaluated the effectiveness and safety of an intravenous (into the bloodstream) infusion of crenezumab compared to placebo. Participants received the infusion every four weeks for 100 weeks, with the final assessment performed 52 weeks after the last dose. AC Immune’s partner, Genentech, also initiated a second Phase 3 study called CREAD2 (NCT03114657)

Roche announced in January 2019 that it would be discontinuing the CREAD and CREAD2 trials after interim analysis indicated they would be unlikely to meet their primary goals of change from baseline in clinical dementia rating sum of boxes (CDR-SOB) score. 

Another Phase 2 study (NCT01998841) is ongoing in pre-symptomatic participants from an extended Columbian family where 200 members carry a mutation known to cause early-onset Alzheimer’s disease.

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