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Although there were promising results in a phase 2 trial, patients with mild Alzheimer's disease who received the drug candidate tarenflurbil as part of a phase 3 trial did not have better outcomes on measures of cognitive decline or loss of activities of daily living compared to patients who received placebo.
This was the finding of a study that appears in the December 16 issue of the Journal of the American Medical Association.

A leading theory on the pathophysiology of Alzheimer's disease is the overproduction of amyloid-beta, a peptide of certain amino acids that appear to be the main constituent of amyloid plaques in the brains of patients with Alzheimer's, particularly 42 amino acid peptide Aβ42. "Tarenflurbil, a selective Aβ42-lowering agent, demonstrated encouraging results on cognitive and functional outcomes among mildly affected patients in an earlier phase 2 trial," the authors write.

Robert C. Green, M.D., M.P.H., of the Boston University Schools of Medicine and Public Health, and colleagues conducted a large, phase 3, randomized trial of tarenflurbil for patients with mild Alzheimer's disease to determine its efficacy, safety and tolerability. The study included 1,684 participants, of whom 1,649 were included in the analysis and 1,046 completed the 18-month trial. Patients were randomly selected to to receive 800 mg of tarenflurbil or placebo, administered twice a day.

The researchers found tarenflurbil had no beneficial effect on the primary outcomes of cognition and activities of daily living after 18 months. They found no significant differences on secondary outcomes, which included other Alzheimer's assessment measures, such as quality of life and caregiver burden.

Regarding adverse events, more participants taking tarenflurbil than those participants taking placebo experienced dizziness, upper respiratory tract infections and anemia.

"Our results are...a reminder that interventions affecting amyloid have not yet been shown to alter the course of [Alzheimer' diease]," the authors conclude.

Late-life Dementias: Does This Unyielding Global Challenge Require a Broader View?
In an accompanying editorial, Thomas J. Montine, M.D., Ph.D., of the University of Washington, and Eric B. Larson, M.D., M.P.H., of Seattle's Group Health Research Institute, comment on the findings of  two studies in this week's JAMA regarding dementia and Alzheimer's disease.

"The null outcome for the leading gamma-secretase modulator [tarenflurbil] in a phase 3 trial and the surprisingly strong association between plasma leptin and incident Alzheimer's disease underscore the need to broaden the current view of potential therapeutic approaches to cognitive impairment and dementia in older individuals. Research must seek a fuller understanding of the complex convergence of Alzheimer's disease with vascular disease and Lewy body disease [a type of dementia], the application of biomarkers and other surrogates to clinical trials to quantify specific pharmacologic effects and a multimodal approach to prevention and treatment. Doing so could have profound effects on the increasing numbers of older persons and on the societies confronting the global challenge of late-life dementias in decades to come."

Contact:
Jann Ingmire
312-464-2499
jann.ingmire@jama-archives.org