Any last hopes for serotonin receptor 6-targeted cognitive enhancers ran into cold reality this week, with the publication of results from three failed Phase 3 trials of the 5-HT6 antagonist idalopirdine. In the January 8 JAMA, Alireza Atri of California Pacific Medical Center in San Francisco and colleagues present the wholly negative findings of the STARSHINE, STARBEAM, and STARBRIGHT trials.
- Data are formally published from three large Phase 3 trials of a serotonin receptor 6 antagonist in Alzheimer’s.
- The drug did not benefit cognition.
- The trials follow on failures of similar drugs, diminishing hopes for this class of drug.
The program, involving 2,525 people with mild to moderate Alzheimer’s disease in hundreds of centers in 34 countries, came to naught when idalopirdine at any dose failed to produce improvement in cognitive symptoms over placebo.
The results are no surprise: The drug manufacturer, Lundbeck, previously released topline results of the STARSHINE study (Sep 2016 news), while Atri reported on the STARBEAM and STARBRIGHT outcomes at the Alzheimer’s Association International Conference last summer (Aug 2017 conference news). Lundbeck announced in its February 2017 annual report that the results “did not demonstrate efficacy to support a regulatory submission.”
In all three studies, people with mild to moderate AD took idalopirdine (10, 30, or 60 mg per day) or placebo, along with a cholinesterase inhibitor for 24 weeks. To succeed, the drug had to show a significant benefit over placebo on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) and one or more secondary endpoints measured from baseline.
Blockade of the 5-HT6 receptor enhances cholinergic and glutamatergic neurotransmission, and is hypothesized to improve cognition, learning, and memory. Several antagonists have now been tested, with similarly negative outcomes. In 2017, Axovant’s intepirdine also failed in Phase 3 and was discontinued (Sep 2017 news). Pfizer dropped its candidate, PF-05212377, after it bombed in Phase 2, though SUVEN Life Sciences is trialing its 5-HT6 antagonist SUVN-502.
Idalopirdine initially showed promise in Phase 2, where a dose of 90 mg per day, added to the cholinesterase inhibitor donepezil, improved cognitive performance (Oct 2014 news). The decision to lower the dose for Phase 3 could have contributed to the failure, wrote David Bennett, Rush University Medical Center, Chicago, in an accompanying editorial. Nevertheless, Bennett wrote, the recent release of data from the failed randomized trial of intepirdine “will likely end efforts with [idalopirdine] for the treatment of AD.”—Pat McCaffrey
No Available Further Reading
- Atri A, Frölich L, Ballard C, Tariot PN, Molinuevo JL, Boneva N, Windfeld K, Raket LL, Cummings JL. Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease: Three Randomized Clinical Trials. JAMA. 2018 Jan 9;319(2):130-142. PubMed.
- Bennett DA. Lack of Benefit With Idalopirdine for Alzheimer Disease: Another Therapeutic Failure in a Complex Disease Process. JAMA. 2018 Jan 9;319(2):123-125. PubMed.