Alzheimer’s drug idalopirdine fails to show benefit in phase III trial programme
Idalopirdine, a drug designed for treatment of Alzheimer’s Disease (AD), fails to show benefit in three phase III trials.
The three studies, namely STARSHINE (n=933), STARBEAM (n=858) and STARBRIGHT (n=734), were under a phase III development programme and included a total of 2,525 patients with mild to moderate AD. The patients were randomized to receive 24 weeks of idalopirdine 10 mg, 30 mg or 60 mg, or matching placebo, in addition to background cholinesterase inhibitor therapy. [JAMA 2018;319:130-142]
The study’s primary endpoint was a significant improvement in the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score (range, 0–70).
However, none of the studies met the primary endpoint. In STARSHINE, the placebo-adjusted mean change in ADAS-Cog total score was 0.05 in the idalopirdine 60 mg group and 0.33 in the idalopirdine 30 mg group. In STARBEAM, the placebo-adjusted mean change in ADAS-Cog total score was 0.63 in the idalopirdine 30 mg group and -0.09 in the idalopirdine 10 mg group. In STARBRIGHT, the placebo-adjusted mean change in ADAS-Cog total score was -0.55 in the idalopirdine 60 mg group.
“Our studies showed that 24 weeks of idalopirdine treatment added to background therapy failed to improve cognition or mitigate the decline in AD symptoms,” the authors reported. “This is in contrast to results of a phase II study that supported the potential efficacy of adding idalopirdine to a cholinesterase inhibitor.” [Lancet Neurol 2014;13:1092-1099]
Idalopirdine is a 5-hydroxytryptamine-6 (5-HT6) antagonist. 5-HT6 receptors affect learning and memory, and 5-HT6 receptor blockade was shown to be linked to improved cognitive performance in animal models. [Neurotherapeutics 2008;5:458-469; Alzheimers Res Ther 2013;5:15]
“In a broader context, results of our studies suggest a lack of efficacy with 5-HT6 antagonism adjunctive to cholinesterase inhibitor for treatment of AD,” the authors added.
“Medications approved for the treatment of AD provide little symptomatic benefit, and the most recent approval by the US FDA occurred in 2003,” wrote Dr David Bennett of the Rush University Medical Center, Chicago, Illinois, US, in an accompanying editorial. “Over the past 15 years, more than 400 clinical trials of therapeutics for AD have been registered, with a failure rate of nearly 100 percent.” [JAMA 2018;319:123-124]
“A recent analysis using a clinical trial simulator concluded that clinical studies of an AD drug might need 5–10 years to detect an effect,” he continued. “However, most of these studies have been limited to about 1.5–3 years.” [Lancet 2017;390:2327-2329]
“Perhaps the most important issue that remains to be confronted is the complexity of the disease,” stressed Bennett. “Clinically evident AD dementia is a function of multiple pathological abnormalities adding to and interacting with multiple resilience factors. Thus, treatments that alter a single pathology are unlikely to have a major effect.”