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Adjunctive idalopirdine ineffective for Alzheimer’s disease

Study findings revealed that patients with mild-to-moderate Alzheimer’s disease who took idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, for 6 months as an adjunct to cholinesterase inhibitors did not experience improvement in cognition.

“Higher doses of cholinesterase inhibitors may be needed in patients with advanced Alzheimer’s disease, but this strategy is limited by increased adverse events due to peripheral nervous system cholinergic effects,” Alireza Atri, MD, PhD, from Ray Dolby Brain Health Center at California Pacific Medical Center, Brigham and Women’s Hospital and Harvard Medical School, and colleagues wrote in JAMA. “Amplifying central nervous system cholinergic function without inducing peripheral nervous system cholinergic symptoms may therefore provide greater clinical benefits.”

Atri and colleagues conducted three randomized, double-blind clinical trials including 2,525 patients aged 50 years or older with mild-to-moderate Alzheimer’s disease to analyze the efficacy of idalopirdine compared with placebo when added to a cholinesterase inhibitor. Patients received 10 mg, 30 mg or 60 mg of idalopirdine daily or placebo plus cholinesterase inhibitor therapy (donepezil in studies one and two; donepezil, rivastigmine or galantamine in study three). Researchers assessed change in cognition total score from baseline to 24 weeks. The studies took place between October 2013 and January 2017.

In total, 2,254 patients completed the studies. The results showed that there were no significant differences in the change in cognitive performance among participants receiving idalopirdine compared with placebo at week 24. In the first study, the average change in cognition 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). Mean change in cognition score between baseline and 24 weeks in the second study 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 (mean difference, 0.63 [95% CI, –0.38 to 1.65] for the 30-mg dose group). For the third study, the mean change in cognition score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (mean difference, –0.55; 95% CI, –1.45 to 0.36).

“In patients with mild-to-moderate Alzheimer’s disease, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment,” Atri and colleagues wrote. “These findings do not support the use of idalopirdine for the treatment of Alzheimer’s disease.”

In a related editorial, David A. Bennett, MD, from Rush Alzheimer’s Disease Center at Rush University Medical Center, commented that further research remains crucial to develop better symptomatic therapies, considering the prevalence of Alzheimer’s disease and dementia.

“This is a worldwide effort with many countries creating plans to counteract dementia and both governments and industry increasing research funding in this area,” Bennett wrote. “In addition, despite the complexity of the disease, the field is generating new knowledge at an unprecedented pace. It is just a matter of time before that knowledge is translated into effective strategies for the treatment and prevention of Alzheimer’s disease dementia.” – by Savannah Demko

Disclosures: Atri reports receiving honoraria for consulting, providing educational lectures, programs, and materials, or serving on advisory boards for Allergan, the Alzheimer’s Association, Axovant, Biogen, Grifols, Harvard Medical School Graduate Continuing Education, Lundbeck, Merck, Sunovion and Suven. He also reports receiving book royalties from Oxford University Press; and having institutional contracts or receiving investigational clinical trial–related funding from the American College of Radiology, AbbVie, Avid, Biogen, Lilly, Lundbeck, Merck and vTV. Please see the study for other authors’ relevant financial disclosures. Bennett reports serving on an adjudication committee funded by Takeda Pharmaceuticals and serving on a data and safety monitoring committee funded by AbbVie.