AAN: Investigational Amyloid Inhibitor Slows Early Alzheimer's Progression

By John Gever
CHICAGO, 18 April 2008 -- Progression of early Alzheimer's disease was significantly delayed with an investigational pill that blocks rogue beta-amyloid protein, a researcher said here.For patients with mild Alzheimer's, a year of tarenflurbil (Flurizan) led to slower declines in global function and in the ability to engage in normal daily activities compared with placebo, reported Sandra E. Black, M.D., of the University of Toronto at the American Academy of Neurology's annual meeting.However, patients in the phase II trial with more advanced disease had "absolutely no beneficial effect" from the drug, Dr. Black said. "For this to be an effective therapy, it's going to have to be started earlier in the disease," she said.
The drug inhibits the gamma-secretase enzyme that produces beta-amyloid protein from a larger precursor molecule. In particular, it blocks production of the AB42 species of beta-amyloid that is prone to form fibrillary plaques in the brains of Alzheimer's patients.
Consequently, the drug is expected to prevent additional deposits of amyloid plaques in the brain, but is unlikely to eliminate existing plaques.
It's a chemical sibling (specifically, the R-enantiomer) of the nonsteroidal anti-inflammatory drug flurbiprofen (Ansaid).
The 24-month phase II trial was conducted in Canada and Britain and had two components. The first was a double-blind, randomized, placebo-controlled study lasting one year, in which 207 patients with mild or moderate Alzheimer's received placebo or 400 or 800 mg of tarenflurbil twice daily.
The lower dose was included for exploratory purposes, Dr. Black said. The 800-mg dose was the study's main focus for efficacy and safety analysis.
Most patients were on cholinesterase inhibitor therapy at enrollment and were allowed to remain on it through the trial.
In the second year, 86 of 106 eligible Canadian participants either continued on their previous drug doses, or, in the case of those taking placebo, were re-randomized to one of the two doses of active drug. The double-blind was maintained.
Primary outcomes were rates of decline in three standardized measures used to assess Alzheimer's disease:
Alzheimer's Disease Assessment Scale, cognitive subscale
Alzheimer's Disease Cooperative Study Group Activities of Daily Living
Clinical Dementia Rating-Sum of Boxes (assesses global function)
Patients with mild disease (scores of 20 to 26 on the Mini-Mental State Exam) who received the higher dose of tarenflurbil had statistically significant benefits at the one-year evaluation, in terms of slower decline in activities of daily living scores (Cohen's d=0.44, P=0.033) and global function scores (d=0.42, P=0.042).
Dr. Black said there was a positive but statistically insignificant trend toward better cognitive performance in patients receiving the drug compared with placebo.
Both groups continued to show worsening function on the three measures relative to baseline. But the rates of decline were slower in those receiving the active drug, Dr. Black said.
Dr. Black and colleagues also conducted a responder analysis, counting patients who showed no decline or actually improved on at least one outcome measure.
They found that 60% of patients on the 800-mg dose were responders at the one-year evaluation, compared with 39% of placebo patients (P=0.063).
In the Canadian patients continuing in the trial to 24 months on 800 mg twice daily, the difference became significant at the two-year evaluation.
At that point, 42% of patients on the high tarenflurbil dose were classed as responders versus 10% of the placebo group (P=0.02).
The two-year evaluation also showed the treatment effect size in daily living activities had increased to d=0.87 (P<0.001).
Dr. Black reported a similar finding for global function at 24 months (effect size d=0.69, P<0.001).
Also, a significant benefit for the 800-mg dose in cognition scores emerged during the extension (effect size d=1.14, P<0.001).
The 400-mg dose was less effective than the higher dose, she reported.
Another finding was that patients who had been on placebo during the first year appeared to show little benefit from the drug during the extension phase.
They showed the same or accelerated rates of decline in all three outcome measures, according to Dr. Black.
She characterized the drug as well tolerated. Transient eosinophilia, mild anemia, blood pressure elevations, lower respiratory infections, and rash were the notable adverse effects associated with tarenflurbil, she said. None were serious.
Two adverse effects were less common with tarenflurbil, Dr. Black added. Eighteen patients on placebo had a psychiatric event, compared with seven on the higher dose of tarenflurbil (P=0.02).
Also, fewer active-treated patients had urinary incontinence, she said.
Two phase III trials are now underway, according to Dr. Black. Data from a U.S.-based trial of 1,684 patients are now being analyzed and are expected to be reported later this year. An international study involving 840 patients will end in October, she said.
The study was supported by Myriad Pharmaceuticals.
Dr. Black reported relationships with Eisai-Pfizer, Novartis, Myriad, Janssen-Ortho, Epix, GlaxoSmithKline, Boehringer Ingelheim, sanofi-aventis, and Pfizer. Co-authors on the study included employees of Myriad. Text for disclosure
Primary source: NeurologySource reference:Black S, et al "Efficacy and safety of tarenflurbil, a selective amyloid beta42-lowering agent, in Alzheimers disease (AD): A phase 2 trial of up to 24 months of treatment" Neurology 2008; 70: A392-A393.