Failed Trial Results of Verubecestat in Alzheimer's Published

Megan Brooks

May 03, 2018

Final results of the discontinued phase 3 trial of verubecestat (Merck & Co) for the treatment of mild to moderate Alzheimer's disease (AD) were published online May 3 in the New England Journal of Medicine.

The final results confirm early results reported last year at the Clinical Trials in Alzheimer's Disease conference. Those results showed that verubecestat, a small molecule inhibitor of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), did not reduce the decline in cognitive function or in overall function as compared with placebo.

The trial involved 1958 patients who had received a clinical diagnosis of mild to moderate AD: 653 patients were randomly assigned to receive verubecestat 12 mg/day, 652 patients received verubecestat 40 mg/day, and 653 patients received matching placebo.

Clear Lack of Benefit

The trial was terminated early for futility 50 months after the start. Results showed that the patients who took the BACE1 inhibitor declined at a similar rate as the patients who received placebo on the primary outcome measures — scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL).

The estimated mean change from baseline to week 78 in ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (for the comparison between the 12-mg group and the placebo group, P = .63; for the comparison between the 40-mg group and the placebo group, P = .46).

The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (for the comparison between the 12-mg group and the placebo group, P = .49; for the comparison between the 40-mg group and the placebo group, P = .32).

There was also no difference between treatment and placebo groups in the secondary measures of Mini–Mental State Examination and Neuropsychiatric Inventory scores. The lack of treatment benefit with verubecestat was seen in both carriers and noncarriers of APOE4.

Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and change in hair color, were more common in the patients who received verubecestat than in the patients who received placebo. Verubecestat was not found to be associated with the amyloid-related imaging abnormalities that have been observed with some other antiamyloid therapies, the authors note.

More Questions

In their article, Michael Egan, MD, of Merck Research Laboratories, and colleagues note that despite a "near-maximal" reduction in amyloid-beta (Aβ) in cerebrospinal fluid and a "modest" reduction in brain amyloid load after 78 weeks of treatment with verubecestat, the drug was not effective in slowing the clinical progression of mild to moderate AD.

"This suggests that once dementia is present, disease progression may be independent of Aβ production or, alternatively, that the amyloid hypothesis of Alzheimer's disease may not be correct," they offer.

"Because Aβ deposition takes place years before clinical symptoms become apparent, it has been proposed that treatments targeting amyloid should be implemented early in the disease process, before the onset of clinical symptoms," Egan and colleagues say.

Commenting on the findings for Medscape Medical News, Gayatri Devi, MD, a neurologist at Lenox Hill Hospital in New York City who specializes in memory disorders, said, "We learn to conceptualize Alzheimer's disease as a spectrum disorder, with multiple different subtypes with varying progression and varying responses to treatment.

"In my opinion, it will be hard to find a one-drug-cures-all Alzheimer's medication. In clumping all Alzheimer's patients together under one umbrella, it is harder to tease out subgroups that may be responsive to treatment. More finesse in diagnosing subtypes and earlier diagnosis is necessary," Devi added.

The study was supported by Merck. Several authors are employees of the company. The original article contains a list of the authors' relevant financial relationships. Dr Devi is the author of The Spectrum of Hope: An Optimistic and New Approach to Alzheimer's Disease and other Dementias.

N Engl J Med. Published online May 3, 2018. Abstract

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