Failed Verubecestat Trial May Call into Question Beta-amyloid Theory in Alzheimer’s, Study Suggests

Verubecestat (MK-8931) indeed failed to slow cognitive and functional decline in mild-to-moderate Alzheimer’s patients despite some reduction in beta-amyloid levels seen, final results of a Phase 2/3 study closed early by Merck for lack of efficacy confirmed.

The researchers behind this study suggested these findings may call into question whether the amyloid hypothesis of Alzheimer’s is “correct,” or whether it is relevant “once dementia is present.”

The findings were published in the New England Journal of Medicine, in a study titled “Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease.”

Verubecestat is an oral inhibitor of the BACE1 enzyme — the enzyme responsible for the cleavage of the amyloid precursor protein, which is the first step in the production of beta-amyloid molecules that accumulate and trigger Alzheimer’s disease.

Verubecestat had been shown to reduce beta-amyloid levels in the cerebrospinal fluid of healthy people and Alzheimer’s patients by more than 75%, suggesting that it could prevent further cognitive and functional decline in patients with the disease.

To evaluate the safety and effectiveness of two doses of verubecestat in patients with mild-to-moderate Alzheimer’s, Merck opened a Phase 2/3 study, called EPOCH (NCT01739348), that would have evaluated patients for up to five years.

Its primary goals were improvements in cognitive function as assessed using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and for everyday activities via Alzheimer’s Disease Cooperative Study—Activities of Daily Living Inventory (ADCS-ADL) scores after 78 weeks of treatment.

EPOCH enrolled 1,958 patients ages 55-85, who were randomized to receive either 12 mg of verubecestat (653 patients), 40 mg of verubecestat (652 patients), or a placebo (653 patients) every day for 78 weeks.

A total of 1,389 patients (70.2 to 72.1% of the patients in each group) completed its first safety part, and 1,042 patients (75.0%) continued in the extension phase.

In all three groups, the cognition (ADAS-cog) and daily-life function (ADCS-ADL) scores worsened over time, at at 78 weeks no significant differences were found between the declines in scores of verubecestat-treated patients and those given placebo.

However, the analysis of levels of several beta-amyloid forms in the cerebrospinal fluid of a patient subgroup showed verubecestat treatment was associated with reductions of 63% to 81%, compared to less than 10% reduction in a placebo group. Beta-amyloid levels seen in the brains of treated patients were also slightly lower than those seen in placebo patients.

Despite these benefits, however,  verubecestat treatment did not slow the clinical progression of mild-to-moderate Alzheimer’s disease.

“This suggests that once dementia is present, disease progression may be independent of Abeta [beta-amyloid] production or, alternatively, that the amyloid hypothesis of Alzheimer’s disease may not be correct,” the researchers wrote.

The team added that, since beta-amyloid deposition takes place years before the appearance of clinical symptoms, it has been proposed that this type of treatment targeting beta-amyloid production should be implemented before symptom onset.

Regarding safety, adverse and serious adverse events were more common with verubecestat treatment than with placebo, including falls and injuries, rash, sleep disturbances, diarrhea, weight loss, suicidal thoughts, and hair-color change.

In February 2017, five months before its schedule completion (part two), Merck decided to stop the trial based on an interim analysis of an independent data and safety monitoring committee that concluded there was “virtually no chance of finding a positive clinical effect.” The product’s safety was not at issue, according to the committee.

Merck also discontinued a Phase 3 study evaluating verubecestat in patients with prodromal Alzheimer’s disease, a stage when the very earliest symptoms appear, in February 2018 based on an independent risk-benefit analysis.