Three Phase 3 clinical studies have failed to reproduce previously reported benefits of adding investigational idalopirdine to a background therapy of cholinesterase inhibitors. The three randomized trials detected no improvements in cognition among mild to moderate Alzheimer’s disease patients treated this way.
To date, the U.S. Food and Drug Administration (FDA) has approved only two classes of medications for Alzheimer’s: cholinesterase inhibitors such as Aricept (donepezil), Exelon (rivastigmine) and Razadyne (galantamine), and the NMDA receptor antagonist Namenda (memantine).
The brains of Alzheimer’s patients have lower levels of a neurotransmitter called acetylcholine. Cholinesterase inhibitors prevent an enzyme, called acetylcholinesterase, from breaking down acetylcholine. That increases acetylcholine levels and maintains communications between nerve cells.
Patients with advanced Alzheimer’s may require higher doses of cholinesterase inhibitors, but this causes side effects such as nausea, vomiting and diarrhea. This means researchers must find ways of increasing acetylcholine without unwanted consequences.
Previous Phase 2 studies suggested that idalopirdine — an antagonist of the serotonin 6 (5-HT6) receptor — added to cholinesterase inhibitor therapy could improve cognition in Alzheimer’s patients. In one of these studies, 90 mg/d of idalopirdine added to a stable dose of donepezil boosted cognitive performance relative to donepezil monotherapy in patients with moderate Alzheimer’s dementia.
To further test the efficacy of idalopirdine combined with a cholinesterase inhibitor in mild to moderate Alzheimer’s patients, researchers conducted three Phase 3 randomized clinical trials in 34 countries: STARSHINE (NCT01955161), STARBEAM (NCT02006641) and STARBRIGHT (NCT02006654).
The trials studied 2,525 patients aged 50 or older. In each Phase 3 trial, patients were randomly selected to receive either a placebo combined with donepezil or another cholinesterase inhibitor group, or idalopirdine plus a cholinesterase inhibitor therapy. Idalopirdine as an adjuvant therapy was tested at different doses including 10 mg, 30 and 60 mg.
Patients received daily doses of the therapy, and outcomes were measured after 24 weeks. The primary endpoint was change in cognition total score measured by the 11-item ADAS-Cog (Alzheimer’s Disease Assessment Scale-cognitive subscale). Secondary endpoints included changes in daily living activities and overall clinical response.
From the initial pool of patients, 2,254 (or 89 percent) completed the studies. Combining idalopirdine with a cholinesterase inhibitor did not improve cognition or mitigate symptoms over the 24-week treatment period, in contrast to the Phase 2 study that supported its potential efficacy.
However, researchers noted that the Phase 3 program tested a lower daily dose of idalopirdine — three doses of 10, 30 and 60 mg — and a different treatment schedule — daily single dose — than the Phase 2 study, in which patients received 90 mg of idalopirdine daily administered as 30 mg doses three times a day.