Investigational Alzheimer’s Disease Drug Is Not Effective in Phase III Trials

LONDON—An investigational drug did not effectively treat symptoms of mild to moderate Alzheimer’s disease in phase III trials, according to results presented at the 2017 Alzheimer’s Association International Conference.

Investigators evaluated the efficacy and safety of idalopirdine, a selective 5-HT₆ receptor antagonist, as adjunctive therapy in patients taking acetylcholinesterase inhibitors. Researchers conducted three 24-week, double-blind, placebo-controlled trials that included more than 2,500 patients. Patients received 10, 30, or 60 mg/day of idalopirdine or placebo.

The drug had a good safety and tolerability profile, but did not effectively alleviate clinical symptoms, said Alireza Atri, MD, PhD, Ray Dolby Endowed Chair in Brain Health Research at California Pacific Medical Center in San Francisco and Lecturer in Neurology at Harvard Medical School in Boston.

Alireza Atri, MD, PhD

Serotonin 5-HT₆ receptor antagonists nevertheless may prove effective in other trials with different compounds and doses, he said. “We have to wait for the other clinical trials to see whether they are positive,” Dr. Atri said.

Proof-of-Concept Findings

In a phase II study in patients with moderate Alzheimer’s disease (defined as a Mini-Mental State Examination [MMSE] score from 12 to 19), idalopirdine (90 mg/day [30 mg tid]) added to stable donepezil treatment significantly improved cognitive performance, compared with donepezil monotherapy.

The phase III trials included patients age 50 or older with mild to moderate Alzheimer’s disease (defined as MMSE score from 12 to 22). The main primary end point was change from baseline to Week 24 in Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-cog) total score. Other co-primary end points were change from baseline to Week 24 in Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL23) and Clinical Global Impression of Change (ADCS-CGIC) scores. Significant benefit over placebo for the main primary end point and at least one co-primary end point were needed to establish efficacy.

The phase III trials had similar designs. STARSHINE enrolled patients taking donepezil who received placebo, idalopirdine (30 mg/day), or idalopirdine (60 mg/day). STARBEAM enrolled patients taking donepezil who received placebo, idalopirdine (10 mg/day), or idalopirdine (30 mg/day). STARBRIGHT enrolled patients taking any acetylcholinesterase inhibitor who received placebo or idalopirdine (60 mg/day).

About 4,000 patients were screened, and 2,525 patients were randomized across the three studies. Patients had a mean age of 74, baseline ADAS-cog score of 26, and baseline MMSE score of 17. Patients on average had been diagnosed with Alzheimer’s disease for 2.2 years and had been on cholinesterase therapy for 1.7 years. About 55% to 60% of patients were APOE positive, and 62% to 65% were female.

None of the doses of idalopirdine met the prespecified efficacy criteria. An analysis suggested some indication of potential efficacy for the 60-mg/day dose in patients with moderate Alzheimer’s disease (ie, an MMSE score between 12 and 18), but there was no consistent replication across all end points, Dr. Atri said.

High Rate of Study Completion

Serious adverse events occurred in about 5% of patients who received placebo and idalopirdine (10 mg/day), and in about 6% to 7% of patients who received idalopirdine (30 mg/day) or idalopirdine (60 mg/day).

The percentage of patients with treatment-emergent adverse events was similar between the idalopirdine and placebo groups. Transient, dose-dependent increases in liver enzymes and vomiting were infrequently observed (< 5%).

The high rate of study completion and enrollment in the extension study (about 90%) suggests unmet need for therapies to treat patients with mild to moderate Alzheimer’s disease, Dr. Atri said.

One limitation of the trials was that patients did not need to have evidence of Alzheimer’s disease biomarkers to participate. In addition, investigators excluded patients who were taking memantine.

Researchers plan to further analyze the data from the phase III trials, Dr. Atri said. Lundbeck, based in Valby, Denmark, developed idalopirdine. The company announced in February that the phase III results did not support seeking regulatory approval for the drug.

—Jake Remaly

Suggested Reading

Ferrero H, Solas M, Francis PT, Ramirez MJ. Serotonin 5-HT6 receptor antagonists in Alzheimer’s disease: Therapeutic rationale and current development status. CNS Drugs. 2017;31(1):19-32.

Wilkinson D, Windfeld K, Colding-Jørgensen E. Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer’s disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2014;13(11):1092-1099.