23 May 2007. In a randomized, double-blind, placebo-controlled study conducted in Russia, the experimental Alzheimer drug Dimebon showed positive effects on all five clinical endpoints tested, according to recent presentations by Rachelle Doody of Baylor College of Medicine in Houston, Texas, a consultant to the drug’s maker and one of three U.S.-based consultants on the trial.
The trial enrolled 183 people with mild to moderate disease (MMSE 10-24), who received Dimebon as a monotherapy 20 mg three times a day or placebo for 24 weeks. The treatment resulted in statistically significant improvement over the placebo group (which declined on all scores during the study) and over baseline for five standard clinical tests of memory (ADAS-Cog), global function (CIBIC plus), cognition (MMSE), daily functioning (ADL), and behavior (NPI). The effects, which were apparent at week 12, were maintained at week 24. The difference with the placebo group grew larger over time for some measures, as the untreated patients continued to decline. Forty-four percent of patients improved on treatment, versus 19 percent on placebo.
Doody first presented the results at the 8th International Conference AD/PD in Salzburg, Austria, in March. On 3 May, at the American Academy of Neurology conference in Boston, she showed a subgroup analysis that separated patients with mild (MMSE greater than 18) or moderate (MMSE less than or equal to 18) disease. The study was not powered for subgroup analysis, but the difference in placebo and control was so significant in the whole group that some differences remained significant in the breakdown, Doody said. In particular, Dimebon produced statistically significant improvement over placebo in all five endpoints in moderate AD. In mild AD, the MMSE was significantly higher after treatment, with other measures showing increases that did not reach significance. The same proportion of patients, just over 40 percent, improved with treatment in both groups.
“This is the first trial, to my knowledge, to demonstrate such consistent positive effects,” Doody said. Given that the study was not powered for a subgroup analysis, Doody concluded that Dimebon “probably improved both mild and moderate patients in all five outcomes.”
The drug appeared safe and well tolerated. More than 80 percent of the participants completed the trial. Serious adverse events occurred in 2 percent of treated patients and 7 percent in the placebo group. Dry mouth was the major side effect, but the investigators also saw increases in depression and insomnia.
Dimebon was discovered in Russia and was marketed there in 1983 as an antihistamine. It was recently rediscovered in a screen for dual cholinesterase inhibitors/NMDA receptor antagonists at the Russian Academy of Sciences. Existing Alzheimer medicines target either acetylcholine-destroying cholinesterases or NMDA receptors. The rationale for a dual inhibitor was based on a trial that showed using both types of drugs gave additional benefit (see ARF related news story). Dimebon is reported to have additional actions to inhibit neuronal death, potentially by blocking the mitochondrial permeability pore transition, a key step in apoptosis (Bachurin et al., 2003).
The history of Dimebon partly explains the setting of the trial in Russia, Doody explained. The infrequent use of medications for dementia there was also a factor. In the U.S., it is difficult to recruit people who have no history of medication to establish the required placebo group, she said.
Dimebon has met with deep skepticism among U.S. and European Alzheimer researchers. Doody, Paul Aisen of Georgetown University in Washington, DC, and Mary Sano of Albert Einstein Medical School in New York, all worked as consultants to the drug’s maker, Medivation Inc. of San Francisco, California, on the design, data collection, and analysis of the Moscow trial. Doody said that she and Sano traveled to Moscow to train the investigators. “The study was rigorously conducted, designed, and carried out with the same high standards as a U.S. trial. I have confidence in the international sites, and confidence in the data.” Doody will be the first author on an upcoming publication of the data.
Development of the drug has begun in the U.S., as well. With an active IND registration, Medivation Inc. is planning to begin a phase 2 dose finding study this summer, according to Chief Medical Officer Lynn Seely, who spoke in a telephone conference after the AAN presentation. The drug is also in clinical trials in the U.S. for Huntington disease.
Doody could not answer the question of whether the drug effects are symptomatic, or might represent neuroprotective actions. “We can’t infer underlying mechanism by the shapes of curves," she said. “From preclinical work, it could be both, but we do not know if the compound has disease-modifying actions. The improvement over baseline is encouraging, as is the observation that at 24 weeks, the scores have not started coming back to baseline,” she said.
“Dimebon has a lot of interesting actions,” Doody said. “If all it does is work as a cholinesterase inhibitor and NMDA antagonist, then we would have one drug instead of two,” she said. “These results are encouraging, but let’s finish the work,” Doody concluded.
More data will be coming soon. Following the 6-month trial, the investigators continued with a blinded, placebo-controlled extension out to 1 year. The results of that phase will be presented on 12 June at the Alzheimer Association Conference in Washington, DC, according to David Hung, Medivation’s CEO.—Pat McCaffrey.