A potential Alzheimer’s drug that had seemed to perform spectacularly well in a medium-scale clinical trial has now been shown in a larger and more conclusive trial to have no apparent effect on the disease.
The surprising failure of the drug, known as dimebon, is yet another disappointment for Alzheimer’s researchers as well as patients and their families. It also raises questions about the conduct and design of Alzheimer’s clinical trials, particularly in Russia where the initial dimebon trial took place.
“The prior doubts about the Russian trial appear to have been borne out,” says Sam Gandy, an Alzheimer’s researcher at Mount Sinai School of Medicine.
Dimebon (generic name latrepirdine) was originally developed and briefly used as an antihistamine in Russia in the 1980s. It began to be re-evaluated as a potential Alzheimer’s drug in the 1990s, after Russian researchers reported that it seemed to boost the levels of memory-related neurotransmitters in lab tests on brain cells.
A San Diego-based company, Medivation, Inc., eventually began clinical trials of dimebon in Russia, where the drug was already approved for use. In 2008, astounding results were reported in 183 Russian patients whose Alzheimer’s dementia was classified as “mild-to-moderate.” Half had received dimebon at a dose of 20 mg thrice daily, and half had received a thrice-daily placebo. After six months, the dimebon group scored much higher on standard tests of cognition and quality of life, and follow-up studies suggested that the progression of the disease had been stopped. The apparent “treatment effect” was the largest ever reported for an Alzheimer’s drug trial.
Some researchers expressed concern that such a powerful result was too good to be true, particularly since no one really knew how dimebon worked against Alzheimer’s. However, several well-known U.S. clinical trial experts had observed the Russian study and vouched for its validity. Other researchers soon reported evidence from laboratory studies that dimebon might be able to boost the general survival ability of neurons in a way that could make them resistant to other neurodegenerative diseases too (see “Hope and Caution on Russian Antihistamine Drug for Alzheimer’s”).
Unfortunately, dimebon seemed only weakly effective in a small-scale clinical trial in people with Huntington’s disease; its results were reported in February. And on March 3, dimebon’s candidacy as an Alzheimer’s drug was most likely terminated.
On that day, Medivation reported results from a large, apparently definitive trial of dimebon in 598 people with Alzheimer’s in North America, South America, and Europe. Those results suggest that dimebon, while safe, is completely ineffective against Alzheimer’s disease. The data failed to show even a hint of a consistent impact on patients’ cognition and quality of life, compared to a placebo.
In recent years, a number of Western drug companies have used Russian hospitals as a relatively inexpensive proving ground for early-stage drug development. However, in at least one other case, a positive result from a Russian trial has failed to translate to a larger, more rigorous Western trial.
Gandy says he wonders whether “something is systematically wrong over there.”
In the case of dimebon, not only the early clinical trial results but also a significant amount of laboratory work appears to be of questionable value. Over the past few years, researchers who were eager to find dimebon’s mechanism of action against dementia have reported, for example, that it blocks the toxicity of amyloid beta aggregates found in Alzheimers, or that it enhances the survival of mitochondria. If nothing else, the case underscores the weakness of such laboratory evidence in the absence of data in people that confirms it.
“At the moment I don’t think that any of these effects is clinically important,” said Gandy, whose own research group recently found that dimebon actually increases amyloid beta levels outside cells, in lab dish and animal experiments.
To some researchers, the dimebon failure, and the failure of many other Alzheimer’s drug candidates to date, points to a larger problem: The treatments are started too late in the course of the disease.
“What you want in such trials are people who are just starting to lose neurons, but typically by the time an Alzheimer’s patient goes to see a neurologist, his or her brain has already been severely damaged,” says Jeffery Kelly, an investigator at the Scripps Research Institute in La Jolla, California, whose work has focused on amyloid-associated conditions. “Considering the way the Alzheimer’s trials are being done now, I’m not sure that even a great drug could be discerned as such.”
Gandy agrees: “I think that our best chance for impact on this disease is presymptomatic intervention and prevention.”