The neuropathologic hallmarks of Alzheimer’s disease (AD) include plaques containing amyloid beta and neurofibrillary tangles, along with synaptic and neuronal loss. These pathologic findings lead to hope that solanezumab, a monoclonal antibody that potentially clears amyloid beta from the brain, would help AD patients. Early studies with the drug in advanced AD patients were disappointing, but there was hope that intervention early in the disease may help. Based on this, researchers conducted a double-blind, placebo-controlled, Phase III trial involving patients who exhibited mild AD with amyloid deposition shown on PET scan or seen in spinal fluid analysis. Patients were randomized to solanezumab or placebo intravenously every four weeks for 76 weeks. The outcome was a standardized Alzheimer’s assessment score. At 80 weeks, there was no statistical mean difference in three baseline cognitive scores between the two groups (difference, -0.80; 95% confidence interval; -1.73 to 0.14; P = 0.10). No significant adverse effects were observed. The authors stated that solanezumab did not significantly affect cognitive decline in patients with mild AD (N Engl J Med 2018;378:321-330). This study is a huge disappointment for AD researchers, patients, and families who have been looking for a cure. Solanezumab joins a long list of failed drugs, and there is very little in the pipeline for those seeking a cure.
One of those failed drugs is idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, which was tested in patients with mild to moderate AD who were taking cholinesterase inhibitors.. Idalopirdine was studied in three randomized, clinical trials that included 2,525 patients. Each study lasted 24 weeks. The three studies used three different doses of the drug compared to placebo. None of the three doses improved cognition based on standardized cognitive testing. The authors concluded that these findings do not support the use of idalopirdine for the treatment of AD (JAMA 2018;319:130-142).