Utter the word "Dimebon" to any neuroscientist studying Alzheimer's disease these days, and you'll likely hear a heavy sigh. "You mean 'Dimebomb'?" asks Robert Moir, assistant professor of neurology at Harvard Medical School. "What a disaster," says Sam Gandy, associate director of the Mount Sinai Alzheimer's Disease Research Center, in New York City.
Why the exasperation? Last month, the drug, which Pfizer and San Francisco-based Medivation have been developing, failed miserably in a Phase III trial involving patients with mild to moderate Alzheimer's disease. Hopes for success had been high: In a small Phase II trial conducted in Russia, the drug seemed to stop the disease in its tracks. Nothing had ever come close to such promising results; on the contrary, the graveyard for dead Alzheimer's compounds has grown increasingly crowded over the years.
Of course, any drug trial carries risk, but given the high hopes and the desperate need for treatments, the news of Dimebon's failure hit the Alzheimer's community hard. As for Medivation, its stock plummeted 67% to $13.25 per share on the day the data were released, and it has only drifted downward. The biotech firm has since laid off 23 people, or 20% of its workforce.
As researchers conduct several other trials testing Dimebon, others are questioning whether the drug has any life left. Medivation and Pfizer apparently believe it still has a chance, whereas investors and many neurologists seem to have written it off.
Dimebon was an unlikely candidate for such visions of therapeutic grandeur. The drug had been sold in Russia as an antihistamine more than two decades ago and otherwise mainly collected dust in compound libraries.
Medivation's chief executive officer, David T. Hung, discovered Dimebon through a circuitous route. After selling a medical device company, ProDuct Health, Hung spent two years scouring the globe for technology that could be the basis of another biotech firm. His violin teacher introduced him to a former postdoc student of Sergey Bachurin's. Bachurin is the Russian scientist who first showed that Dimebon had activity in animal models of Alzheimer's disease.
Bachurin is said to have tried dosing rats with Dimebon because he thought it might act in a way that combined the functions of Aricept and Namenda, the two currently marketed drugs that treat the symptoms of Alzheimer's. As Hung tells it, Bachurin noticed some unusual effects in his experiment with Dimebon: It improved the rats' memory and cognition, and surprisingly, it seemed to diminish some of the signs of aging, including cataract formation, balding, and graying.
"I'm a basic scientist, and there's really only one thing I see in the literature to make rats live longer: You starve them," Hung says. Caloric restriction means less energy for cells to operate, he explains. Bachurin's results led him to believe the drug was somehow reducing the activity of mitochondria, the energy center of the cell.
Hung bought the compound from Bachurin on the conviction that interrupting a disease such as Alzheimer's would require tapping into that energy cycle. "The brain is one of the most energy-dependent organs in the body," he says. "It only comprises 2% of body weight, but uses 25% of body oxygen and glucose."
The results of a Phase II trial of Dimebon, published in the Lancet, reinforced Hung's conviction. Although the trial was small, the results were significant: One year into treatment, patients on the drug did better on five of five key measurements—including cognitive skills and the ability to perform daily tasks—and, importantly, maintained the same general level of function as they had when the trial began.
"The Lancet paper was better than anyone has ever seen in Alzheimer's in improvement," Mount Sinai's Gandy says.
On the basis of the trial data, Pfizer made a hefty bet on the drug. Two months after publishing the results, Medivation was handed $225 million up front, promised hundreds of millions more in milestones, and still managed to retain a large share of rights to the drug. The companies launched multiple Phase III trials of Dimebon to treat both Alzheimer's disease and Huntington's disease.
After seeing the imprimatur of prominent Alzheimer's scientists on the Phase II data, Gandy, who was initially skeptical about Dimebon, started to become interested. "I sort of drank the Kool-Aid and started playing around with the drug in the lab," he says.
But what he saw gave him pause: The drug was actually causing levels of amyloid-β, the hallmark plaque in the brains of Alzheimer's patients, to rise. "We were trying to work out how that could be a good thing based on the notion that the clinical trial result was going to be replicable," he says.
Then came the dismal Phase III trial results. Dimebon not only failed to show any positive effect on any of the five measurements, or endpoints, but actually performed worse than a placebo on some of them. The setback has caused many Alzheimer's experts to question the integrity of the Phase II study, with some suspicious because the data were generated in Russia, not the U.S.
Howard Liang, a stock analyst with Leerink Swann, pointed out in a note to investors that Medivation specifically crafted its Dimebon partnership with Pfizer to hold on to as many rights to the drug as possible. The move suggests faith that the Russian trial was solid, Liang says. And indeed, before the Phase III study was unveiled, an independent panel of Alzheimer's consultants told Leerink that the Russian data seemed reliable.
Medivation's Hung is concerned with the unusual data set that came out of the Phase III trial. Some patients in the placebo arm actually improved with regard to one of the five endpoints. "Had both the drug arm and the placebo declined, it would have been a negative study," he says, but the actual results were perplexing.
Furthermore, he stresses that patients were given the drug for only six months; it's still possible that a yearlong trial will show an improvement. "It's only one study," Hung adds.
But most observers have written off the drug, suggesting the data from a small trial conducted in Russia were a fluke. "I'm very skeptical that anything is going to be salvageable there," Gandy says.
The Russian study results were, by all accounts, "too good to be true," Bernstein Research stock analyst Tim Anderson says. He questions whether Pfizer and Medivation will bother to continue with the other large Phase III trial that is under way.
Mene Pangalos, Pfizer's chief scientific officer for neuroscience, says the partners aren't jumping to conclusions before closely studying the results of the first trial. "The bottom line with Dimebon is we're still analyzing the data, and until we've really had a chance to look at them, it's too soon to tell," he says. Furthermore, although one hypothesis is that Dimebon modulates mitochondrial function or goes after a mixed set of receptors, "we're not really sure how it works, and we're now asking the question, 'Does it work?' " he adds.
The companies are now trying to identify the drug's molecular target, which might enable them to go after the next generation of compounds. "It probably has a rich pharmacology and uses a combination of mechanisms that may be enabling it to work," Pangalos says. "We have to look at the trial."