CHICAGO – An experimental drug designed to attack neurofibrillary tau tangles significantly improved some measures of memory among patients with mild cognitive impairment, although it failed to meet its primary cognitive end point.
Because of its significant effects on visual and verbal memory, AL-108 will continue on to a phase II trial in its target population, patients with mild to moderate Alzheimer's disease, Dr. Donald E. Schmechel said at a press conference during the International Conference on Alzheimer's Disease.
“Twelve weeks of AL-108 resulted in statistically significant, dose-dependent, and durable improvement on measures of short-term memory, including visual, verbal, and auditory working memory, which is a type of memory function that deteriorates throughout the progression of Alzheimer's,” according to Dr. Schmechel. “This makes AL-108 the first drug to validate in humans the importance of the tangle, or tau, pathway in the disease.”
Along with toxic plaques made up of amyloid beta, neurofibrillary tau tangles are a diagnostic hallmark of Alzheimer's disease. The tangles are composed of hyperphosphorylated tau, a protein that normally occurs in neurons. In its hyperphosphorylated state, tau forms tangled fibrils that interfere with neuronal function. AL-108, developed by Allon Therapeutics Inc. of Vancouver, is the first drug in development to exert action on those tangles.
Many more Alzheimer's drugs under investigation target the amyloid pathway of neurodegeneration. Dr. Schmechel, whose research was funded by Allon, said AL-108's success shows that tangles also can be a useful therapeutic target. “These new data suggest that 'tangles' may be as important–or perhaps more important–than 'plaques,'” he said.
The phase IIa study comprised 144 patients (mean age 69 years) with amnestic mild cognitive impairment. All patients had a Mini-Mental State Examination of at least 24.
The patients were divided into three groups: placebo, 5 mg AL-108 daily, and 15 mg AL-108 twice daily. The drug was administered for 12 weeks; cognition was tested at baseline and at weeks 4, 8, 12, and 16.
The drug was safe and well tolerated, Dr. Schmechel said at the meeting presented by the Alzheimer's Association. The dropout rate was 13% and not different between the active and placebo groups. Compliance was high (98%).
The study's primary end point was a composite of memory component scores from four standard cognitive tests. By 16 weeks, neither of the active groups scored significantly better than the placebo group on this measure.
However, those taking the higher dose showed a trend toward better performance than either the low-dose or placebo groups, noted Dr. Schmechel, professor of neurology at Duke University, Durham, N.C.
Significant differences emerged on some of the individual measures of memory. On the digit span forward test–a measure of verbal recall and short-term memory–the high-dose group performed significantly better than either the low-dose or placebo groups, with a 12% increase over baseline.