Hope and Caution on Russian Antihistamine Drug for Alzheimer’s

by Jim Schnabel

October 16, 2008

An old Russian antihistamine drug known as Dimebon has arrested the cognitive and behavioral decline of people with Alzheimer’s as measured on standard tests, according to the results of a medium-sized clinical trial in Russia.

A larger clinical trial outside Russia is now under way, and the U.S. Food and Drug Administration (FDA) has indicated its willingness to accept minimal data from that trial to begin the review and approval process for marketing Dimebon in the United States to people with Alzheimer’s. But even if those data are positive, they are unlikely to resolve an important question: Does Dimebon stop the neuronal degeneration of Alzheimer’s or merely treat the symptoms temporarily, as existing approved drugs do?

At this point “one can only speculate as to how it might compare to the existing approved agents,” says Gary Kennedy, director of geriatric psychiatry at the Montefiore Medical Center in New York City. But based on the early results, “family members of my patients are already asking for Dimebon,” he says.

The Dimebon study

Over six months, in 11 hospitals in Russia, a total of 183 people diagnosed with Alzheimer’s ranging from mild to moderate received either Dimebon at a dose of 20 mg thrice daily, or a thrice-daily placebo. At the end of the study, those on Dimebon scored significantly higher, compared to their initial ratings, on two standard disease assessment tests, and slightly higher or about the same on three other tests. In a subset of patients whose initial scores indicated more advanced, “moderate” Alzheimer’s, relatively strong improvement was seen on all five tests. Meanwhile, those in the placebo group scored much worse on all tests; the gap in scores between treated and untreated patients—known as the “treatment effect”—was the largest ever seen in an Alzheimer’s clinical trial. Side effects of Dimebon, such as dry mouth, were relatively minor.

These results were reported in the July 19 issue of the Lancet. But the study continued beyond six months for 134 patients, and a poster with 12-month data from these patients was presented at the International Conference on Alzheimer’s Disease (ICAD) in Chicago in July. Even at 12 months the Dimebon-treated patients scored about as well as they had at the outset, while the scores of the untreated patients suggested a continuing deterioration. A further, open-label (less rigorous) study in some patients, running from month 12 to month 18, suggested that those who had been taking Dimebon remained more or less stable, while those who previously had been in the placebo group, and then switched to Dimebon, stabilized at a lower level.

Medivation, the San Francisco-based company that holds the U.S. rights to Dimebon, noted in an SEC filing in January that the FDA will consider approval of the drug based on only one more, confirmatory study in a different and at least partly U.S.-based patient population. “This signals to me that [the] FDA believes the Lancet study data,” says Sam Gandy, chairman of the medical and scientific advisory committee of the Alzheimer’s Association, which organized ICAD.

That confirmatory study, aiming to enroll 525 patients in all, has been under way since this past spring in more than a dozen European, North American and South American hospitals. If results from only six months of treatment in that study show a significant treatment effect, the FDA will accept the drug into its marketing approval process. That could happen as early as next year.

“Dimebon is now a few lengths ahead of anything else in contention to be the next Alzheimer’s treatment,” says Gandy.

Questions about methodology

The origins of Dimebon, the location of the recent clinical trial and the fact that no one really knows how it works have dampened the enthusiasm of some researchers. Even Gandy says he was skeptical when he heard an early report on the Russian trial at a scientific meeting last year: “Russian antihistamine? Trial done in Russia? My reaction was, ‘Gimme a break!’ ”

He has since become more optimistic about Dimebon, in part because of the 12-month data from the Russian trial. “There is improvement, followed by stabilization at the improved level,” he notes.

The Russian study also was designed and evaluated by three American Alzheimer’s researchers who trained the relevant Russian hospital staff. These researchers, Rachelle Doody of the Baylor College of Medicine, Paul Aisen of Georgetown University and Mary Sano at Mount Sinai School of Medicine, all have considerable experience in designing and managing Alzheimer’s clinical trials.

Nevertheless, the FDA’s insistence that the confirmatory trial include a significant number of U.S. patients suggests a lingering caution about the earlier trial results. Strong but temporary improvements on disease assessment tests due to the placebo effect have been seen in past open-label studies of Alzheimer’s drugs in which patients are not “blinded” to their treatment status and know that they are receiving an active drug. In the first 12 months of the Russian study, patients and caregivers were meant to be blinded; however a hypothetical “unblinding” due to a breakdown in the trial protocol would have made such an illusory effect possible.

Moreover, in the Russian trial, the placebo group did not take existing, approved Alzheimer’s drugs, as is normally allowed in European or American trials. Although these existing drugs do not stop the underlying disease process, they have positive effects on cognition and other standard diagnostic measures in the short term. Thus, the apparent “treatment effect” for the Russian study was higher than it would have been had the placebo group been allowed to take existing approved drugs. (In the confirmatory study, the placebo group again will not take existing approved drugs.)

Possibly relevant too is the fact that the Russian patients in the Dimebon study were also significantly younger, on average, than patients in Western-based Alzheimer’s trials. Gandy says he doubts that the difference explains Dimebon’s apparent effect, but it is conceivable that these younger patients responded better to Dimebon than the average Western Alzheimer’s patient would have.

How does Dimebon work?

Dimebon’s action as an antihistamine—for which it is no longer used, even in Russia—is considered irrelevant to its effect on Alzheimer’s patients. But how it does work remains to be established, at least in terms of published research.

Dimebon was “rediscovered” in the late 1990s as a possible Alzheimer’s drug because in Russian laboratory tests it appeared to combine the effects of the two kinds of existing Alzheimer’s drugs. These mildly and temporarily improve cognition either by boosting the brain systems that use the neurotransmitter acetylcholine or by blocking the systems that work via a brain-cell receptor known as the NMDA receptor. They are considered “symptom-modifying” drugs rather than “disease-modifying” drugs.

If Dimebon works in these ways, then its positive effect on Alzheimer’s patients is likely to wear off eventually. And Gary Kennedy of Moses Montefiore Medical Center notes that Dimebon’s published effect in boosting patients’ cognitive scores “is not an order of magnitude larger than what has been seen in studies with the existing agents.” Indeed, on one important Alzheimer’s-assessment test, which reflects a clinician’s impression of a patient’s overall functioning, about a third of patients in the study scored lower after the second six months of treatment.

Moreover, Medivation’s plan to go to the FDA with only six months of data from its confirmatory study suggests that it does intend, at least initially, to apply for approval of Dimebon only as a symptom-modifying drug. “Longer-term data will be necessary to demonstrate a disease-modifying as opposed to symptomatic benefit,” says Kennedy.

Whether that longer-term data will indeed show that Dimebon stops the underlying disease remains to be seen. But Medivation appears to believe that it does. It presented data at ICAD suggesting that the drug could protect brain cells not just via the acetylcholine and NMDA routes but also by preserving mitochondria within brain cells from the effects of a neurotoxin in lab tests. Also at ICAD, a group from the Karolinska Institute in Sweden presented data confirming these tests.

Mitochondria are small structures that float within cells and help to regulate some of their essential workings, from cellular division to the production of chemical energy. Some researchers have hypothesized that the degradation of mitochondria due to normal aging, environmental toxins and stresses related to genetic defects can lead to widespread cell death, particularly in the brain. Medivation is separately investigating Dimebon as a therapy for Huntington’s disease, which has been blamed in part on mitochondrial dysfunction.

The “mitochondrial hypothesis” for Alzheimer’s is a relatively recent one and hasn’t yet gained many adherents. But according to Gandy, it may end up connecting to the more mature “amyloid hypothesis” for the disease. “Mitochondrial dysfunction increases amyloid accumulation,” he says, citing a study in an Alzheimer’s mouse model that he co-authored and that is now in press at the journal Neurobiology of Disease. “So it stands to reason that if mitochondria are under stress in the brain of someone with Alzheimer’s, reducing the stress with Dimebon might mitigate that amyloid accumulation.”

Medivation and its academic consultants have generated additional data on how Dimebon works that they have not yet published, Gandy says. He has seen these data and cannot divulge the details, but at present, he says, “I would not exclude the possibility that Dimebon modifies amyloid metabolism and/or toxicity.”

In an earlier study of Dimebon, published in 2001, Russian researchers claimed that Dimebon blocked the toxicity of an amyloid fragment in laboratory cell cultures. However, the amyloid hypothesis itself has come under fire recently, as all drugs designed to clear or prevent amyloid accumulation have so far failed in large-scale clinical trials [See the Dana news story on Flurizan]. Dimebon’s actual mechanism against Alzheimer’s is therefore likely to be much debated in the months and years to come.

Even if that issue is not resolved, the drug could still become a standard Alzheimer’s therapy if it is clearly shown to help European and American patients in the ongoing confirmatory trial.

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