Global pharmaceutical company Merck announced its plans to halt the Phase III trial of experimental drug verubecestat on Tuesday, after an independent study concluded it was ineffective. Developed to treat mild-to-moderate Alzheimer’s disease, the drug was deemed to have “virtually no chance of having a positive clinical effect” according to the independent data analysis committee.
This continues the latest trend of failures in the clinical trials of experimental drugs intending to treat Alzheimer’s. Just three months earlier, pharmaceutical company Eli Lilly announced its drug, solanezumab, failed to combat dementia. Over 99% of all Alzheimer’s drugs have failed clinical trials attempting to demonstrate alleviation of symptoms.
The drug was administered to patients with later-stage Alzheimer’s, which is suspected to have caused its inefficacy. Highly anticipated by the pharmaceutical and medical communities, verubecestat is one of many experimental drugs classified as a BACE (beta-secretase 1) inhibitor. BACE inhibitors target protein fragments in the brain before they solidify into plaque, which is believed to be the cause of Alzheimer’s.
Among those disappointed was neurology professor David Knopman of Mayo Clinic. Because the drug was tested on patients in whom plaque had already developed, he believes the tardy approach is futile in treating the disease, equating it with “closing the barn door after the cows have left.” He suggests the drug could be potent if introduced earlier in the progression of the disease, or in larger doses.
Previous studies suggest the drug’s efficacy in reducing plaque levels if introduced early enough. Merck will pursue this finding by continuing a separate Phase III clinical trial of verubecestat; this trial will involve administering the drug to early-stage Alzheimer’s patients in hopes of preventing plaque buildup. Dr. Roger Perlmutter, President of Merck Research Lab, stated, “While we are disappointed that a benefit was not observed in this study, our work continues studying verubecestat in people with less advanced disease.” Echoing Knopman’s optimistic sentiment, director of Alzheimer’s Association James Hendrix points out the only way to combat the disease is to intervene at its earliest stage. The trial is expected to conclude in February 2019.
In this upcoming trial, Merck will face the same problem that many pharmaceutical companies are grappling with: identifying patients who truly are diseased in the first place. Eli Lilly’s November trial had to be redone after PET scans revealed that 1/3 of the patients being studied did not have Alzheimer’s. As the pursuit of an effective drug continues, several pharmaceutical companies continue their late-stage clinical trials of BACE inhibitors similar to Merck’s. However, some doubt the veracity of this amyloid hypothesis that pharmaceutical companies are subscribing to.
Axovant, a smaller biotech company targeting the cognitive deficits of patients, is up next in reporting its trial data. The results are expected in the third quarter of this year.
Dr. Amit Roy of Foveal says that all BACE inhibitors “fail for the same reason”: a failure to understand the true cause of the disease and the testing of factors merely associated with the disease. Nonetheless, over a dozen companies — most notably Biogen and Genentech — remain hopeful that the key to fighting the disease is preventing amyloid protein production. Biogen will not have results from its Phase III trial of its drug, aducanumab, until 2018; Genentech is expected to conclude its trial of crenezumab in 2021.
Robert Vassar. BACE1 Inhibitor Drugs in Clinical Trials for Alzheimer’s Disease. PubMed. 2014
Merck. APECS Study in People with Prodromal Alzheimer’s Disease to Continue. Merck. 2017.