A phase 2 clinical trial of the investigational agent idalopirdine (Lu AE5854), a selective 5-HT6 receptor antagonist, as adjunctive treatment to the cholinesterase inhibitor donepezil has demonstrated improved cognition in patients with mild-to-moderate Alzheimer’s disease. The results also showed a trend toward ameliorating declines in function and global clinical status, researchers reported at the 2016 American Academy of Neurology annual meeting.
“Idalopirdine was generally safe and well-tolerated. Based on these promising phase 2 results, a large phase 3 program is currently enrolling to validate and extend these data,” said Alireza Atri, MD, PhD, MMSc, Ray Dolby Endowed Chair in Brain Health Research, California Pacific Medical Center, San Francisco.
Alzheimer’s disease is the most common form of dementia among older adults. Driven by the so-called silver tsunami, however, the prevalence and the costs of the disease are projected to triple in the next few decades, exhausting healthcare resources around the world.
The current pharmacologic treatment paradigm for Alzheimer’s disease involves monotherapy and combination treatment with “symptomatic” medications, such as cholinesterase inhibitors and memantine, but there is a “pressing need” for additional treatment options, said Dr Atri.
“The development of Alzheimer’s disease involves multiple pathophysiologic mechanisms, and its treatment may require a variety of strategies, including addressing putative underlying disease mechanisms and those moderating symptoms of the illness,” he observed.
This double-blind, placebo-controlled, parallel-group design, phase 2 study explored the efficacy and safety of idalopirdine 90 mg daily as an add-on therapy to donepezil background therapy in 278 patients with mild-to-moderate Alzheimer’s disease.
Using the Alzheimer’s Disease Assessment Scale-Cognitive subscale, Dr Atri and colleagues found significant cognitive benefits in patients who received idalopirdine therapy.
The secondary efficacy outcomes included global impression according to the Alzheimer’s Disease Cooperative Study (ADCS)-Clinical Global Impression of Change, activities of daily living according to the ADCS-Activities of Daily Living, and behavioral symptoms according to the Neuropsychiatric Inventory.
“Supportive data were also consistent with potential benefits on function and clinical global impression instruments,” said Dr Atri, adding that the overall behavioral effect was not significant. Transient elevations in liver enzymes were observed with idalopirdine, but these were “asymptomatic and normalized whether affected individuals continued with treatment or were withdrawn,” said Dr Atri.
Enrolling Patients for Phase 3 Study
Based on these results, a global phase 3 program is currently enrolling patients (aged ≥50 years) with mild-to-moderate Alzheimer’s disease who are receiving background cholinesterase inhibitor therapy, to study the benefits of idalopirdine therapy.
The program comprises three 24-week, double-blind, placebo-controlled clinical trials involving approximately 2500 patients worldwide, and a 6-month to 12-month, open-label extension study in approximately 1700 patients.
Although the current treatment for Alzheimer’s disease primarily involves symptomatic regimens, much headway has been made to recognize the underlying pathophysiology of this disease.
“Over the last 10 to 15 years, we’ve done a really good job of understanding the different biomarkers of this illness. In the future, we’re hoping that we use these biomarkers to detect Alzheimer’s in its earliest stages, many years before symptoms start to show, and give disease-modifying drugs,” said Dr Atri. “By the time people progress to clinical stages, we can provide symptomatic treatments on top of those,” he noted.
“In the next few years, we’re not going to have cures, but with drugs like idalopirdine, I think we’re going to see incremental improvements over time,” he concluded.