Investigational Drug Slows Functional Decline in Early Alzheimer's

By John Gever
OXFORD, England, 30 april 2008-- The investigational anti-amyloid drug tarenflurbil (Flurizan) significantly slowed declines in the overall ability to function among mild Alzheimer's disease patients, researchers here said.
"This phase II study provides preliminary evidence of a possible therapeutic effect of tarenflurbil, the first selective [amyloid] lowering agent to complete a phase II evaluation," wrote Gordon K. Wilcock, D.M., of the University of Oxford, and colleagues online in Lancet Neurology.
Highlights of the data were presented two weeks ago at the American Academy of Neurology meeting in Chicago (See: AAN: Investigational Amyloid Inhibitor Slows Early Alzheimer's Progression).
Tarenflurbil inhibits the gamma-secretase enzyme that cleaves beta-amyloid protein from a larger precursor molecule. In particular, it blocks production of the Ab42 species of beta-amyloid that forms fibrillary plaques in the brains of Alzheimer's patients.
Expectations are that the drug will prevent additional deposits of amyloid plaques in the brain, but it is unlikely to eliminate existing plaques.
The agent is a chemical sibling (specifically, the R-enantiomer) of the nonsteroidal anti-inflammatory drug flurbiprofen (Ansaid).
Dr. Wilcock and colleagues tested two doses of tarenflurbil (800 and 400 mg twice daily) against placebo in 210 patients with mild to moderate Alzheimer's disease, as defined by scores of 15 to 26 on the Mini-Mental State Exam.
The placebo-controlled study, conducted in Britain and Canada, lasted one year. Canadian patients could then participate in a one-year extension trial in which those previously assigned to tarenflurbil continued at the same doses, and 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)
Dr. Wilcock and colleagues found that neither dose of tarenflurbil had a significant effect in patients with moderate Alzheimer's disease, defined by scores of 15 to 19 on the Mini-Mental State Exam.
However, during the first year of treatment, global function and daily activities scores showed lower decline in patients receiving 800 mg of tarenflurbil twice daily versus those taking placebo.
When Activities of Daily Living scores were graphed, Dr. Wilcock and colleagues found a difference in slope of 3.98 (95% CI 0.33 to 7.72) points per year between high-dose tarenflurbil and placebo. This difference translated into a reduction of 46.4% from the decline rate with placebo (Cohen's d 0.45, P=0.033).
Similarly, the difference in slope for global function scores was -0.80 points per year (95% CI -1.57 to -0.03), translating into an effect size of 35.7% (d 0.42, P=0.042).
Cognitive subscale also suggested a benefit with high-dose tarenflurbil, with an effect size of 33.7%, but it was not significant (d 0.20, P=0.327).
But cognitive decline was significantly slowed according to results in the extension trial, comparing 22 patients receiving 24 months of high-dose tarenflurbil with 11 patients initially on placebo and then switched to high-dose tarenflurbil in the extension.
Mean change in cognition scores was 2.9 points (SD 1.7) among patients continuously taking high-dose tarenflurbil for two years, versus 11.5 points (SD 2.4) among those initially in the placebo group (P=0.005).
Patients also showed significantly better scores on the other two primary outcome measures at the end of the extension.
The lower dose showed no significant benefit on any outcome measure.
Few significant differences in adverse effects were seen among groups receiving either of the tarenflurbil doses or placebo. At the higher drug dose, significantly more patients had eosinophilia compared with the placebo group.
On the other hand, patients in the placebo group had higher rates of urinary incontinence.
About 85% to 90% of patients in all groups had some type of adverse event. Among patients in the high-dose tarenflurbil group, the most common were diarrhea and nausea, each seen in 10% of patients. These were not significantly less common in the placebo group (seen in 8% and 6% of patients, respectively).
In an accompanying commentary, Paul S. Aisen, M.D., of the University of California San Diego, noted that the drug failed to meet the original primary endpoint in the study, significant slowing in cognitive and functional decline in patients with moderate as well as mild Alzheimer's disease.
He chalked up the failure to the difficulties of proving benefit in a phase II trial with this type of drug.
"Disease-modifying interventions are expected to slow the progressive decline of cognitive and clinical measures without any short-term effect," he pointed out. "Proof of efficacy, or even proof of mechanism, might be impossible in a phase II study."
Indeed, the phase II results with tarenflurbil are "hardly conclusive," Dr. Aisen wrote.
Nevertheless, he said it was good that the drug's sponsor, Myriad Pharmaceuticals, has gone ahead with phase III testing.
Two phase III trials are now underway. 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 is scheduled to end in October.
Wrote Dr. Aisen, "With the need so enormous, and the potential benefit suggested (although not proven) by these phase II results, the effort is indeed justified despite the substantial uncertainty. In a few months, we will learn whether tarenflurbil will be the first anti-amyloid intervention to be efficacious in a pivotal trial."
The phase II study was funded by Myriad Pharmaceuticals.
Study co-authors reported relationships with Myriad.
Dr. Aisen reported that he was a site investigator on a phase III trial of tarenflurbil but has not had a consultant relationship with Myriad.
Primary source: Lancet NeurologySource reference:Wilcock G, et al "Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: A randomised phase II trial" Lancet Neurology 2008; DOI: 10.1016/S1474-4422(08)70090-5 Additional source: Lancet NeurologySource reference: Aisen P, "Tarenflurbil: A shot on goal," Lancet Neurology 2008; DOI: 10.1016/S1474-4422(08)70091-7