CHICAGO—Growing evidence suggests that the accumulation of amyloid beta (Abeta) in the brain is a consequence of Alzheimer disease (AD) rather than the cause, but getting rid of it remains the primary strategy of several new treatments for the disease. Unfortunately, these treatments, when they work at all, produce only marginal changes in memory, cognition, and other measures of mental status.
Most of these treatments employ the body's own defenses against the toxic Abeta, which apparently stresses neurons and aggregates into brain plaques, one of the two hallmarks of AD.
The other hallmark — tau tangles within neurons — correlates better with the severity of dementia, but so far only one drug that seems to dissolve tau tangles is in development, and it was discovered largely by accident.
ARTICLE IN BRIEF
Investigators presented new data on anti-amyloid and other approaches to preventing and slowing Alzheimer disease.
TAU AGGREGATION INHIBITORS
TauRx Therapeutics of Singapore is testing methylthioninium chloride, or MTC, under the trade name Rember. In the days before antibiotics, MTC was sold under the name Urolene Blue to treat urinary tract infections, but a clinical trial with 321 mild-to-moderate AD patients in the UK and Singapore demonstrated that the compound slowed their rate of decline by 81 percent compared to placebo after only 24 weeks. The drug also reduced tangle density in the hippocampus and prevented loss of brain volume, while those on placebo lost 7 percent.
“MTC is the first tau aggregation inhibitor,” said Claude M. Wischik, MBChB, chairman of TauRx and a professor of psychiatric gerontology at the University of Aberdeen, Scotland, at a news briefing held during the Alzheimer's Association International Conference on Alzheimer's Disease (ICAD) here in July.
Dr. Wischik said, “The data suggest that tau aggregation inhibition therapy with MTC could prevent progression from Braak stage 2,” when tau tangles are much more extensive in the transitional entorhinal region, causing cell death. The Braak stages measure the number and location of tau tangles in the brain. [See “The Braak Scoring System: Assessing Alzheimer Disease Pathology.”]
A phase 3 trial of Rember is scheduled to begin in 2009.
RESULTS ON BAPINEUZUMAB
Virtually all other notable clinical trials, however, are aimed at reducing levels of toxic Abeta. The most eagerly awaited is an 18-month phase 2 clinical trial of a monoclonal antibody known as bapineuzumab, a fully humanized antibody derived from a mouse antibody and transformed biochemically into a human version that attacks the N-terminus of Abeta. Developed by Elan and Wyeth, bapineuzumab was designed to avoid a major complication of AN1792, the vaccine that triggered meningoencephalitis when Elan tested it on humans in 2000.
In the placebo-controlled study of 234 patients, the only serious side-effect attributed to bapineuzumab was vasogenic edema, which may have been related to the dose, according to Sid Gilman, MD, professor of neurology and director of the Alzheimer's Disease Research Center at the University of Michigan, who served as head of the independent safety monitoring committee for the clinical trial.
There were 12 cases of vasogenic edema among carriers of the ApoE4 (apolipoprotein E4) allele — the strongest genetic risk factor for AD — but only two among non-carriers, and both of those were receiving the highest dose. Of the 12 cases, six had no symptoms and six had very mild symptoms, although one patient received steroids. The vasogenic edema was found during routine MRI scans. Three deaths occurred during the trial, although they were not related to treatment, according to the researchers.
The study failed to attain statistical significance on the pre-specified efficacy endpoints, but closer analysis revealed meaningful but somewhat perplexing results.
Patients who did not carry the gene for ApoE4 showed improvement on cognitive tests: the AD Assessment Scale-cognitive subscale of 5.0 (p=0.026), an improvement on the Neuropsychological Test Battery of 0.35 (p=0.006), and the Clinical Dementia Rating-sum of boxes of 1.5 (p=0.04). A favorable change for Disability Assessment of Dementia of 6.9 (p>0.10) also was observed. Researchers conducted multiple tests to detect changes in cognitive status as well as more subjective behaviors linked to dementia.
Most of the trials involved both a global scale and a cognitive scale,” Dr. Gilman told Neurology Today. “Both have to be significant for drug approval.”
Non-carriers of ApoE4 also showed less brain atrophy and better performance on the battery of tests compared to the placebo group. ApoE4 carriers, in contrast, showed no significant differences in brain atrophy, and scored lower than the placebo group.
“Perhaps there is a biological difference between carriers and non-carriers (of the gene),” Dr. Gilman suggested while presenting the results here. “Or perhaps carriers have more Abeta.”
WHEN ABETA IS REMOVED
This is just one of several examples showing that the removal of Abeta from the brain does not always produce major improvement.
After an 18-month study involving 1,684 patients — the largest Alzheimer disease treatment study ever conducted — Myriad Genetics announced it was suspending development of tarenflurbil (Flurizan), a gamma-secretase modulator that significantly reduced Abeta 42. Those taking the drug, however, showed no improvement over the placebo group on several cognitive and memory tests.
“There was no efficacy of the compound in this trial,” said principal investigator Robert C. Green, MD, of Boston University School of Medicine, as he announced Myriad's abandonment of the drug after an investment of about $200 million.
Similar results emerged from a follow-up study of the 80 participants in Elan's suspended clinical trial of AN1792. The vaccine significantly reduced levels of Abeta 42, but did not prevent progressive degeneration.
“These results suggest that plaque removal is not enough to halt progressive neurodegeneration in Alzheimer disease and prompts challenges to the amyloid hypothesis,” said Clive Holmes, MD, lead author of the 2008 analysis in Lancet.
Eli Lilly announced that a phase 2 trial of LY2062430, another anti-amyloid monoclonal antibody, increased levels of two forms of Abeta in the CSF — a sign that the drug was successfully removing toxic protein from the brain. However, no change in brain levels of Abeta was found using SPECT, and no change was observed in cognitive scores, although no change was expected in a clinical trial for only 12 weeks. Lilly plans to move ahead with a phase 3 trial of the antibody.
Norman Relkin, MD, PhD, director of the Memory Disorder Program at Weill Cornell Medical College, is developing another approach that involves intravenous immunoglobulin, or IVIg, which contains anti-amyloid antibodies that occur naturally in human blood. Instead of recognizing the chemical makeup of these proteins, the antibodies recognize their misfolded, aggregated shape, which guarantees that the antibodies will not attack normal proteins.
The antibodies, obtained by cold ethanol extraction from the plasma of thousands of healthy donors, “may be part of an innate defense against disorders such as AD,” Dr. Relkin said. “Although titers vary across individuals and age groups, most people have measurable amounts of anti-amyloid antibodies in their blood.” Some research suggests that Alzheimer patients have fewer anti-amyloid antibodies than people without the disease, he added.
Dr. Relkin presented interim results of the phase 2 clinical trial of IVIg — which showed a significant reduction in Abeta 40 and Abeta 42 in the CSF of patients and stabilization of their cognitive status — at the 2008 AAN annual meeting and the ICAD conference here, but has not yet published a final report on the data. A 360-patient phase 3 study by Baxter and the NIH is under way.
Dimebolin hydrochloride (Dimebon) sold for more than two decades in Russia as an antihistamine, is being tested for its ability to slow AD, apparently by stimulating mitochondria in neurons. Results of a clinical trial on 104 patients showed that patients who took the drug stabilized across several measures of cognitive functioning, according to Jeffrey L. Cummings, MD, professor of neurology and psychiatry at the David Geffen School of Medicine at the University of California-Los Angeles. Dr. Cummings described the results here at the ICAD meeting.
After taking dimebolin 18 patients scored 19 on the Mini-Mental State Examination while those on placebo scored 17; they declined 2.4 points on the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale, compared with a 4.3-point decline in those on placebo; they declined by 0.68 points on the Neuropsychiatric Inventory compared with 3.2 points for those on placebo. Also, on the Clinician's Interview-Based Impression of change plus Caregiver Input, 57.4 percent of dimebolin patients improved or showed no change, compared with 39.1 percent of those on placebo.
“People initially treated with placebo who then crossed over to dimebolin did not show the same level of benefit as those people who took dimebon for the full 18 months,” Dr. Cummings said. “This emphasizes the benefit of earlier treatment.”
In one of the final presentations at ICAD, James Nicoll, MD, of the University of Southampton in the UK, suggested that removing amyloid plaques may not be sufficient to halt AD. “Even when plaque removal is effective, patients move toward dementia,” he said. “This is a challenge to the amyloid hypothesis. Plaque may be necessary to initiate but not to maintain neurodegeneration.”
This was echoed in a July 19 commentary in The Lancet by veteran AD researchers Peter H. St. George-Hyslop, MD, of the University of Toronto, and John C. Morris, MD, of the Washington University School of Medicine, who wondered if the past two decades of anti-amyloid research “were spent barking up the wrong tree.” They concluded that preventing the accumulation of Abeta might make far more sense than attempting to remove it.
“Perhaps the correct use of anti-amyloid monotherapies will be effective as a prophylactic given long before the onset of symptoms in people at risk for the disease,” they wrote.
But that will require reliable biomarkers of early stages in the disease, which another vigorous arm of AD research is seeking. •
THE BRAAK SCORING SYSTEM: ASSESSING ALZHEIMER DISEASE PATHOLOGY
The Braak staging system asserts that the neurofibrillary pathology of Alzheimer disease evolves in a predictable sequence across the medial temporal lobe structures, subcortical nuclei, and neocortical areas of the brain in six stages, with a seventh stage (stage 0) representing the absence of cortical neurofibrillary changes.