Merck’s Verubecestat Safely Lowers Amyloid in Alzheimer’s, But Cognitive Benefits Not Yet Proven

Merck’s Verubecestat Safely Lowers Amyloid in Alzheimer’s, But Cognitive Benefits Not Yet Proven
Merck’s amyloid-lowering drug, verubecestat, has proceeded to Phase 3 clinical trials after early studies showed it safely lowered the levels of amyloid-beta, the protein linked to neurodegeneration in the brains of Alzheimer's disease patients. Although the news may be reason for optimism, it remains to be seen if the treatment also can stymie or even improve cognitive symptoms in patients, which remains the main goal of ongoing trials. The study, "The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients," was published in the journal Science Translational Medicine. BACE1 is an enzyme cleaving the amyloid precursor protein (APP), which, together with the enzyme gamma-secretase, produces a range of amyloid-beta peptides. These protein parts easily aggregate into toxic forms that, according to the amyloid hypothesis of Alzheimer’s disease, is the key event triggering neurodegeneration. Earlier attempts to produce BACE1 blockers have resulted in compounds that cause unacceptable side effects, so the reported safety of verubecestat, the first BACE1-targeting drug, is welcome news. The newly released study reported data from both animal models and humans. In animals, including non-human primates, the drug lowered levels of the three investigated amyloid-beta types. Using doses that exposed rats and monkeys to 43- and 54-fold higher concentrations than what is used in the Phase 3 human trials, the research team could not detect any of the detrimental side effects seen in earlier studies of
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