Yet another Alzheimer’s drug being tested in clinical trials has failed, resulting in the trial being stopped. Merck, the pharmaceutical company that is testing the drug verubecestat, announced recently that the trials, which were in Phase 2/3, were halted because the drug was not showing any results in patients.
Approximately 44 million people worldwide are afflicted with Alzheimer’s disease (AD) and that number is expected to rise in the coming decade. While no one knows for sure what the exact cause of Alzheimer’s disease is and how it develops, it is known that amyloid plaques in the brain are involved. Amyloids are proteins that collect in deposits on the brain, but they are abnormal and can result in cell death and memory loss. Multiple studies on AD have shown that patients who develop these plaques usually have some form of dementia, most often AD. The mechanism seems to be that neurons in the brain somehow attract clumps of the protein. Since neurons are essentially the communication highway in the brain, these clumps of abnormal proteins diminish communications between cells in the brain resulting in the cognitive impairment seen so often with AD. When enough of the proteins accumulate, it moves beyond impaired communication and on to cell death. No treatment exists to reduce or remove these plaques.
In November Eli Lilly, the pharmaceutical company developing another possible Alzheimer’s drug, Solanezumab, announced that a round of clinical trials of their drug did not show any progress in slowing or halting cognitive decline in test subjects. The Lily clinical trials included 2,100 patients, half of whom were given Solanezumab, and half of whom were given a placebo. When testing the patients for memory, cognition and mental decline, those who received the drug were no better off, at least not to a statistical significance.
The Merck drug, MK-8931, or verubecestat is a small-molecule inhibitor of BACE1 and BACE2. Researchers study BACE inhibition because it’s believed that it can interfere with the production of amyloid beta production in the brain. The trial that was stopped was begun in November 2012. Dubbed EPOCH, it was an 18-month Phase 2/3 trial comparing 12, 40, or 60 mg/day of MK-8931 given as once-daily tablets to placebo in people with mild to moderate AD. EPOCH started out treating 200 people in Phase 2 and, after an interim safety analysis, expanded to Phase 3 with a total of 2,221 participants. This trial included conventional cognitive and functional primary outcomes, as well as substudies for biomarker outcomes indicating changes in brain amyloid, CSF tau levels, and brain volume.
In a press release, Merck stated they were stopping the trials based on an interim analysis conducted by the external Data Monitoring Committee (eDMC), which assessed overall benefit/risk. The finding of the eDMC was that there was “virtually no chance of finding a positive clinical effect.” The EPOCH trial was in patients who were in the later stages of Alzheimer’s. Merck will continue testing verubecestat in a second group of trials involving patients who are in the earlier stages of the disease. Those patients, who are in the prodromal stages of the disease, have objective cognitive decline, but still can function independently in their daily lives. The patients in the EPOCH trial had more severe impairments that significantly reduced their level of daily functioning. The video below explains more about this disappointing news.