San Francisco—Based on two phase II trials, hopes were raised that a selective 5-hydroxytryptamine-6 receptor antagonist, such as idalopirdine, could improve cognition in Alzheimer’s disease when combined with cholinesterase inhibitors.

Three new randomized clinical trials did not find that to be the case, however. The results were published recently in JAMA.

A study team led by researchers from California Pacific Medical Center, San Francisco, and Brigham and Women’s Hospital/Harvard Medical School in Boston report that idalopirdine administered for 6 months did not improve or reduce the loss of cognition for patients with mild-to-moderate Alzheimer’s disease. Idalopirdine (10, 30, or 60 mg/d) or placebo was added to cholinesterase inhibitor treatment—donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3.

The trials, conducted between October 2013 and January 2017, involved 2,525 patients aged 50 years or older with mild-to-moderate Alzheimer’s disease. Researchers looked for changes in measures of cognition from study entry to 24 weeks.

The researchers report:
• In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs. placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). 
• In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs. placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). 
• In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs. placebo, -0.55 [95% CI, -1.45 to 0.36]).

Adverse events related to treatment occurred in between 55.4% and 69.7% of participants in the idalopirdine groups and between 56.7% and 61.4% of participants in the placebo groups.

“In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment,” study authors conclude. “These findings do not support the use of idalopirdine for the treatment of AD.”

An accompanying editorial expressed disappointment over the continuing struggle to find effective treatments for Alzheimer’s disease.

“Over the past 15 years, more than 400 clinical trials of therapeutics for Alzheimer disease have been registered, with a failure rate of nearly 100% in those trials for which results have been reported,” writes commentator David A. Bennett, MD, of Rush University Medical Center in Chicago, adding that this report, “adds three more failed trials to this list. The lack of progress in the treatment and prevention of Alzheimer disease is frustrating for patients, families, physicians, researchers, industry, funders, and policy makers.”
« Click here to return to Weekly News Update.