Investigational Agent Stabilizes Cognition in Early Alzheimer's

May 31, 2007
Caroline Helwick

Internal Medicine World Report, April 2007, Volume 0, Issue 0

From the American Association of Geriatric PsychiatryNew Class Targets Cerebral Senile Plaques

NEW ORLEANS—Emerging agents for the treatment of Alzheimer’s disease (AD) are benefitting from new research and are therefore expected to be more effective than current medications. One of these, a drug aimed at reducing brain amyloid pathology, stabilized nearly 50% of the patients with mild disease in a study presented at the American Association of Geriatric Psychiatry annual meeting.

“Our study showed almost a flattening of the disease at 12 months in persons with the mildest disease,” said Suzanne Hendrix, PhD, of Myriad Pharmaceuticals. “The results are consistent with the mechanism of action of the drug and suggest there is a benefit in recognizing and treating early.”

The new drug—tarenflurbil (Flurizan)—is a member of a new class of agents called selective amyloid beta-42– lowering agents. The Aβ42 protein is the primary constituent of senile plaques and is thought to be the key initiator of AD, since it has the greatest tendency to aggregate, cause neuronal damage, and initiate amyloid deposits in the brain.

Aβ42 is produced by gamma-secretase during the processing of the amyloid precursor protein that is important to normal brain function. Tarenflurbil, a gamma-secretase modulator, is the drug that is farthest along in the development pipeline.

Dr Hendrix presented 24-month follow-up data from a phase 2 trial of tarenflurbil. The study included a 12-month placebo-controlled phase, followed by a 1-year double-blind trial in which original placebo recipients crossed over to tarenflurbil therapy.

Tarenflurbil, 400 or 800 mg twice daily, was compared with placebo in 207 patients with mild-to-moderate AD. Nearly all of them were taking acetylcholinesterase inhibitors at baseline and continued taking them throughout the study.

The primary outcome measures were the rate of change in activities of daily living based on caregiver responses, global function, and cognitive function, which were assessed using a variety of standardized measures. The placebo-crossover, or delayed-treatment group, served as controls for the 800-mg twice- daily group.

Cognitive Decline Stopped inMildest Patients

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At 12 months, as measured by Mini-Mental State Examination (MMSE) scores, participants with mild disease who received 800 mg twice daily showed a significant 67% reduction in cognitive decline compared with controls. Based on MMSE scores, 3 times as many patients receiving tarenflurbil improved or had no decline in cognition compared with controls (42% vs 14%, respectively). And 60% of those receiving the 800-mg dose were classified as responders on at least 1 primary outcome compared with 39% of those originally receiving placebo ( = .063).

At 24 months, disease stabilization (based on MMSE scores) was seen in 42% of treated patients compared with 10% of the controls. Of note, the control group did receive a shorter duration of treatment (12 months vs 24 months) and perhaps a lower dose of tarenflurbil, so actual differences between treatment and placebo might be even greater, Dr Hendrix noted.

Improvement or stabilization in all outcomes at 24 months was observed in 13% of those receiving tarenflurbil 800 mg twice daily versus 0% of controls.

“In patients with mild disease, there was almost a flattening of the disease curve after 12 months. The drug almost halted their decline,” Dr Hendrix said.

Tarenflurbil was well tolerated, with no dose-limiting adverse events. There were fewer dropouts in the 800-mg twice-daily arm than in the control arm.

Current Agents Show Modest Effects

A meta-analysis of trials evaluating available AD medications presented at the meeting suggested that current therapies provide only modest benefits.

Lon S. Schneider, MD, of the University of Southern California Keck School of Medicine, Los Angeles, used the Cochrane Trials and Specialized Dementia Register, meeting presentations, and other resources to find placebo-controlled, double-blind, randomized trials of cholinesterase inhibitors and memantine (Namenda). Five donepezil (Aricept) trials, 1 rivastigmine (Exelon) trial, and 6 memantine trials met the criteria.

The meta-analysis found modest statistical effects for donepezil and memantine on cognitive, global, and activities of daily living outcomes. Behavior was affected by memantine only; 4 of 5 donepezil trials found no effect.

“While there was a statistically greater cognitive effect for donepezil than for memantine, this was offset by little if any significant effect on behavior and by increased adverse events,” Dr Schneider observed. “Memantine was associated with modest cognitive, activities of daily living, and behavioral effects, with no increase in dropouts in the trials.”

Negative findings from 2 other studies of donepezil in patients with severe dementia were “suppressed or delayed,” he added, calling for full dissemination of all results from AD trials.