Cognition Enhancer Promising in Alzheimer's
by John Gever for MedPage Today:
A drug targeting the 5HT-6 serotonin receptor, when added to donepezil (Aricept) in patients with moderate Alzheimer's disease, significantly slowed cognitive decline compared with donepezil alone, a researcher reported here.
Patients receiving idalopirdine plus donepezil for 24 weeks in a phase II trial showed a 0.77-point improvement from baseline in ADAS-Cog scores, compared with a 1.38-point worsening in scores among patients taking donepezil plus placebo, reported Alireza Atri, MD, PhD, of California Pacific Medical Center in San Francisco.
A composite secondary endpoint combining ADAS-Cog and ADCS-Activities of Daily Living scores also showed a significant benefit for the idalopirdine add-on, Atri told attendees at the American academy of Neurology annual meeting.
Given that there will probably never be a "magic bullet" for patients with Alzheimer's disease, multidrug regimens are the most realistic prospect for relieving symptoms and improving quality of life, Atri told attendees at a plenary session.
Idalopirdine is not intended to be a disease-modifying agent, he explained. Preclinical evidence had suggested that the 5HT-6 receptor modulates a variety of neurotransmitter systems involved in cognition -- including glutamatergic and GABAergic pathways -- such that a selective antagonist could improve cognitive function with a different mechanism than current drugs such as memantine (Namenda) and acetylcholinesterase inhibitors.
As such, idalopirdine could serve as an add-on drug to current agents as well as future disease-modifying drugs, Atri said.
His group randomized 278 patients to double-blind treatment with donepezil plus either placebo (n=133) or idalopirdine (n=145). The latter drug was dosed at 30 mg three times daily.
Patients had mild to moderate Alzheimer's disease with mean Mini-Mental State Examination scores of 17 on a 30-point scale. Mean age was 75. All had previously been receiving donepezil at stable doses of 10 mg/day for a mean of 1.5 years.
In this short-term study, the idalopirdine-donepezil group showed a slight improvement in ADAS-Cog scores relative to baseline, whereas the control group had a mean 1.5-point decline from baseline at the end of 24 weeks.
The only safety signal of note, according to Atri, was what he characterized as "transient and mild" elevations in liver transaminases affecting about 10% of patients receiving idalopirdine.
Natalia Rost, MD, of Massachusetts General Hospital in Boston, who co-moderated the session, told MedPage Today that this would have to be watched carefully in future studies. She noted that many once-promising drugs for innumerable conditions had ultimately failed because of liver toxicity.
But otherwise, she said, the drug appeared promising and deserved a larger trial.
Such trials are now underway, Atri said -- three separate 24-week studies with a total of about 2,500 patients. He noted that lower doses of idalopirdine -- 10 to 60 mg/day -- would be tested in the trials. The reduction was decided on the basis of data suggesting that adequate receptor saturation could be achieved at doses lower than the 90 mg/day used in the phase II study.
Source: http://bit.ly/1SzJ0wR