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 other BACE1 blockers, such as such as reduced nerve myelination (the envelopment of nerves with the protective myelin), neurodegeneration, glucose imbalance, and liver toxicity.

Since animal studies looked so promising, the team continued testing verubecestat in healthy, younger humans. Although the drug is intended for elderly patients, studies in younger people commonly are used to assess the safety of a treatment.

As in animals, verubecestat lowered the concentrations of amyloid-beta both in cerebrospinal fluid and in blood plasma, with higher doses suppressing amyloid-beta to a larger extent. As the treatment did not cause any extensive side effects, researchers continued to test the drug in a small group of patients.

Neither the effects of the drug or the body’s ability to metabolize it seemed to differ between patients and healthy people, who had similar reductions of amyloid beta as the volunteers.

Side effects were mostly mild or moderate, in fact, no severe side effects were reported, and adverse events occurred to a similar extent in placebo and verubecestat-treated groups.

After careful analysis, researchers decided to continue Phase 3 trials with a 40 mg dose of verubecestat, which lowered the levels of one amyloid-beta type with an average of 83.7% in 94.6% of patients.

Two Phase 3 trials of verubecestat are ongoing. A study (NCT01953601) focusing on people with mild memory impairment, is recruiting participants across numerous worldwide locations, while the other (NCT01739348) has enrolled patients with mild-to-moderate Alzheimer’s disease.