BOSTON – An investigational nicotinic receptor agonist demonstrated cognitive benefits similar to those seen with donepezil in a phase II trial of patients with mild to moderate Alzheimer’s disease.
Based on positive results of the study, research on the drug, ABT-126, will continue, Dr. Laura Gault said at the Alzheimer’s Association International Conference 2013.
"ABT-126 showed evidence of a treatment effect on cognition, in a dose- and exposure-response fashion," said Dr. Gault of AbbVie Pharmaceuticals, Abbott’s newly created pharmaceuticals research and development arm.
ABT-126 potentiates the action of the alpha-7 nicotinic receptor, which is expressed both pre- and postsynaptically. The hippocampus and prefrontal cortex are especially rich in nicotinic receptors, which influence the release of acetylcholine, dopamine, and glutamate.
Dr. Laura Gault
Researchers have postulated that nicotinic receptor agonists could have similar benefits to acetylcholinesterase inhibitors, but with a better side effect profile.
In animal models of Alzheimer’s, ABT-126 boosted cognition and memory. It has also demonstrated safety and good tolerability in several phase I studies totaling 249 subjects; the groups included Alzheimer’s and schizophrenia patients, as well as healthy elderly controls.
The 12-week, phase II study randomized 274 subjects to either placebo, 10 mg donepezil, or 5 or 10 mg ABT-126. The 5-mg dose was chosen to match plasma levels obtained in Alzheimer’s model studies, Dr. Gault said. The 10-mg dose was the highest dose supported by the extant safety and tolerability data. Since then, she said, additional studies on ABT-126 have supported a larger dose, which is currently being investigated.
The primary endpoint was the total change from baseline on an 11-item version of the Alzheimer’s Disease Assessment Scale-Cognition domain (ADAS-Cog 11). The study was powered to detect a 30% change on this measure over that which has been demonstrated with donepezil.
Secondary endpoints included the change from baseline on a 13-item version of the ADAS-Cog, the Mini Mental State Examination, the Clinician’s Interview-Based Impression of Change, the Neuropsychiatric Inventory, and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL).
The patients were a mean of 74 years old; 51% tested positive for the apolipoprotein E epsilon-4 allele. Half had been on prior pharmacologic treatment, but since the study was a monotherapy trial, no additional drugs were allowed for its duration. The mean baseline score on the ADAS-Cog was 26 and the mean MMSE was 19.
On the ADAS-Cog 11 total score, donepezil performed the best, with a statistically significant 1.4-point increase. The 10-mg ABT-126 group also improved over baseline, with a statistically significant 1.2-point change. The 5-mg dose did not separate from placebo.
On the memory subscale of the ADAS-Cog 11, both the 10-mg dose of ABT-126 and donepezil showed significant improvements. Scores on the praxis subscale were significantly higher for patients who took donepezil, compared with those who took ABT-126. Neither drug significantly affected scores in the language subscale.
Both the 10-mg dose of ABT-126 and donepezil significantly improved total scores on the ADAS-Cog 13.
A linear model showed a relationship between exposure to the study drug and cognitive improvement, with no plateau over 12 weeks. "This suggests that a higher dose might lead to improved efficacy," Dr. Gault said.
There were 17 dropouts in the study. The rates were highest in the 10-mg ABT-126 and donepezil groups (6 each). Nine were due to adverse events, including five with donepezil, two with placebo, one with 10-mg ABT-126 and one with 5-mg ABT-126.
The most common adverse events were nausea, diarrhea, and vomiting, all of which were most frequent in the donepezil group.
AbbVie’s next steps with the drug are two 24-week, placebo-controlled phase II trials, both of which are expected to enroll about 400 patients with mild-moderate disease. One will test the drug as monotherapy, and the other as an add-on to rivastigmine and donepezil.
The company is also investigating the drug’s possible effect on cognition in patients with schizophrenia.
AbbVie sponsored the trial.
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