Last night, Merck announced that it is stopping a clinical trial of a pill it is developing to treat Alzheimer's because there is "virtually no chance of finding a positive clinical effect." Investors were not surprised, given the track record of other such medicines.
The drug, verubecestat, is the latest in a long string of medicines to fail to have an effect on the disease. Over the past decade, experimental Alzheimer's drugs have repeatedly failed to slow the memory-destroying disease. Late last year, an antibody drug infused into patients' bodies, made by Eli Lilly, didn't have a significant effect on the disease. A medicine from Pfizer, Johnson & Johnson and Elan Pharmaceuticals, which was similar to the Lilly drug, had also previously also failed.
Given the failures, it's fair to ask if the basic idea behind all these drugs is wrong. All target a protein called beta amyloid, which builds up in clumps in the brains of Alzheimer's patients and is thought to be a cause of the disease, an idea scientists call "the amyloid hypothesis." But Roger Perlmutter, Merck's head of research and development, says this study does not mean that amyloid is not a key player in the disease.
"Obviously if the study had been robustly positive then you would have said, 'Aha! The hypothesis is confirmed,'" Perlmutter says. But while genetic studies indicate amyloid is important, he argues that it may have been too late to help these patients.
"Because Alzheimer’s progresses over a period of decades, it’s understandable that it might be necessary to get in really quite early," Perlmutter says. "This study was done in 2,200 patients who had mild-to-moderate cognitive impairment, so they already had suffered significant neuronal loss. Even under the best of circumstances it might not have been possible to see an effect in this patient population."
It will take Merck several months to analyze the data from the stopped study. There could be several clues as to whether the amyloid hypothesis holds up. One analysis would be to look at people depending on whether they have a mutation in a gene called APOE4, which increases Alzheimer's risk. Another would be to look at a sub-study that used imaging tests to look for the presence of amyloid in patients' brains.
A second study of verubecestat in patients with a much earlier stage of Alzheimer's is expected to finish in February 2019. According to Timothy Anderson at Bernstein Research, two studies of a similar Alzheimer's pill from Eli Lilly and AstraZeneca will read out that August; studies of another drug from Eisai and Biogen will follow a year after that, with a study of an experimental medicine from Johnson & Johnson and Shionogi expected in 2023. All those drugs are pills that block the beta-amyloid converting enzyme (BACE), which creates beta amyloid.
Studies of aducanumab, a new antibody drug from Biogen that showed promise in small, preliminary studies, are expected no sooner than 2019.
