Symptomatic AD treatment fails in first phase III

Lundbeck's and Otsuka Pharmaceutical's idalopirdine failed in a first phase III trial in patients with mild to moderate Alzheimer disease, further lowering expectations for a novel class of drugs that aim to offer symptomatic treatment for the neurodegenerative disease.

Idalopirdine is an antagonist of the 5-hydroxytryptamine receptor 5-HT₆, a receptor that is primarily expressed in areas of the brain that are involved in cognition and is thought to be involved in learning and memory (Alzheimers Res. Ther. 5, 15; 2013). Despite a surge of interest in this target more than 10 years ago, the trial of idalopirdine is one of the first pivotal trials of a 5HT₆-specific antagonist in Alzheimer disease. The partners have yet to release detailed data, but said the drug failed to meet the primary end point, a reduction in the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) total score when treatment was added to acetylcholinesterase inhibitor donepezil.

Two more pivotal trials of the drug are ongoing, with data expected early next year.

Other companies who have also worked on this target include Pfizer and GlaxoSmithKline (GSK). Pfizer has discontinued two phase II candidates, in 2012 and then in 2015, due to lack of efficacy. GSK advanced its GSK742457 into phase II trials in 2005, but progress subsequently stalled. The biotech Axovant Sciences licensed and resurrected GSK's drug last year, renaming it RVT-101 and pushing it into phase III development.

Axovant has remained optimistic in the face of the recent failure, arguing that Lundbeck made changes between phase II and phase III trials — such as lowering the dosing of the drug — that could account for the lack of efficacy. Data from Axovant's phase III trial are expected next year.

Pfizer and Medivation's Dimebon (latrepirdine), once a highly hyped Alzheimer disease drug candidate, also has activity against the 5-HT₆ receptor, as well as against other targets including cholinesterase and N-methyl-D-aspartate (NMDA) receptors. The drug failed in phase III trials in 2011.