ICAD: Investigational Alzheimer's Drug Found Beneficial in Extension Trial

By Todd Neale
CHICAGO, 01 aug 2008 -- For patients with mild to moderate Alzheimer's disease, the investigational drug dimebon continued to show benefits and safety in a six-month, open-label extension of a placebo-controlled trial, researchers reported here. Earlier this month, Rachelle Doody, M.D., of Baylor College of Medicine in Houston, and colleagues reported in The Lancet that after one year, Alzheimer's patients who received dimebon had significantly improved cognitive function, memory, activities of daily living, and behavior compared with those on placebo, who progressively worsened. Participants in both groups were then eligible to enroll in the six-month open-label extension and 104 patients -- 54 who had been taking dimebon and 50 who had received placebo -- entered the study.
As expected, those who had originally been taking dimebon began to decline to below baseline values on the various measures through the extension phase, but the declines were delayed compared with the estimated drop in function with placebo.
"We did not arrest the disease permanently," said co-author Jeffrey Cummings, M.D., of the University of California Los Angeles, at the International Conference on Alzheimer's Disease. "Eventually the mechanisms of the disease, whatever they are, overwhelm the benefits of dimebon."
Patients who had been on placebo stabilized when they crossed over to treatment with dimebon for the extension phase, but at a lower level of function than those who were originally taking the active treatment.
"This emphasizes the benefit of earlier treatment, and suggests the possibility that dimebon may slow the progression of Alzheimer's," Dr. Cummings said.
"However," he added, "open-label extensions are not the same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution."
The researchers are currently enrolling patients for a phase III clinical trial to be conducted in multiple countries, including the U.S.
According to Dr. Cummings, the FDA has said that the trial will provide enough evidence to move forward with a new drug application. He said that dimebon could be on the market by 2011.
Dimebon works by repairing mitochondrial function at sites of cellular stress, such as beta-amyloid plaques. The repair might help prevent cell death and increase signaling between neurons, according to Dr. Cummings.
In the six-month extension phase, the 104 participants were all given 20 mg of dimebon three times a day; 92 (88.5%) completed treatment.
The mean age of the participants at the beginning of the extension phase was 69. Those who had been taking dimebon in the one-year study had a higher mean score on the Mini-Mental State Examination compared with those who had been taking placebo (19 versus 17).
The projected decline on various assessments if a patient was to take placebo was estimated using a linear regression analysis of data from the one-year study.
Those who received dimebon in the one-year study preserved function close to baseline values after 18 months and continued to show an advantage over the predicted decline with placebo.
On the Alzheimer's Disease Assessment Scale -- cognitive subscale (ADAS-cog), patients who had received dimebon for 18 months had a significantly smaller decline than those who had crossed over from placebo (P<0.05).
On the Alzheimer's Disease Cooperative Study -- Activities of Daily Living (ADCS-ADL) scale, patients who were on dimebon dropped 2.40 points through 18 months, compared with a 4.3-point decline in those who had been taking placebo.
On the Neuropsychiatric Inventory (NPI), patients who were taking dimebon declined by 0.68 points at 18 months, compared with 3.2 points in those who were taking placebo.
On the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), 57.4% of patients on dimebon improved or showed no change at 18 months, compared with 39.1% of placebo patients.
Dr. Cummings said that dimebon was well tolerated, although dry mouth, sweating, and depressed mood and sadness were more common in patients taking active treatment compared with placebo.
He said that the rates of depression with active treatment (about 15%) were not high enough to halt the phase III trial that is being planned.
The study was funded by Medivation, maker of dimebon.
Dr. Cummings and three of his co-authors reported serving as consultants for Medivation. Two of his co-authors are employees, shareholders, and board members of Medivation.
Primary source: International Conference on Alzheimer's DiseaseSource reference:Cummings J, et al "18-month data from an open-label extension of a one-year controlled trial of dimebon in patients with mild-to-moderate Alzheimer's disease" ICAD 2008; Abstract P4-334.