The first report of long-term (three-year) stabilization of Alzheimer's disease symptoms with IVIG, including no decline on measures of cognition, memory, daily functioning and mood, was reported at the Alzheimer's Association International Conference 2012 (AAIC 2012) in Vancouver.
Updates also were given on three new presymptomatic Alzheimer's disease treatment trials that are beginning soon or in the planning stages.
Disappointing results from recent Alzheimer's clinical trials suggest researchers may be testing therapies too late in the process of the disease—that once dementia symptoms are evident, too much damage has been done to the brain for effective treatment.
"Fortunately, improving detection technologies and updated diagnostic guidelines are enabling the detection of early changes in the brain and subtle cognitive deficits that are consistent with what is now known as presymptomatic (or preclinical) Alzheimer's," said William Thies, Ph.D., Alzheimer's Association chief medical and scientific officer. "People in this stage of the disease are an ideal population for prevention trials to delay the onset or slow the progression of cognitive decline."
Well-organized and characterized study populations of people with younger-onset genetic Alzheimer's are making possible two of the innovative new studies. What is learned from studying this rare group of people with Alzheimer's—they comprise less than 2% of the total global Alzheimer's population—may provide strong guidance for attacking the much more common late onset sporadic Alzheimer's.
"These four studies are among the most exciting current and upcoming Alzheimer's therapy trials," Thies said.
Intravenous immunoglobulin (IVIG), a blood product administered intravenously, is being studied as an immunotherapy for Alzheimer's. Positive results of a placebo controlled phase II study in mild to moderate Alzheimer's were previously reported. The 24 participants in that study received six months of treatment followed by a 12-month, open-label extension in which all subjects received IVIG. Several doses were tested.
To evaluate the long-term effects, participants were offered additional IVIG treatment at a single standardized dose (0.4mg/kg every two weeks) for an additional 18 months. Sixteen of the originally enrolled subjects received treatment through month 36, including five originally given placebo and 11 treated with various doses of IVIG.
The researchers found that study participants treated with IVIG 0.4g/kg every two weeks for the full 36 months (n=4) had the best outcome, with no decline on several standard measures of cognition, memory, daily functioning and mood at the three-year endpoint. As a group, the 11 participants who received IVIG for the full 36 months had favorable outcomes in terms of their thinking abilities, behavior and daily function. The five participants who were initially treated with a placebo and then switched to IVIG declined while on placebo but experienced less rapid decline while receiving a uniform dose of IVIG.
A phase III trial is in progress.
The Alzheimer's Disease Cooperative Study (ADCS), formed in 1991 as a cooperative agreement between the National Institute on Aging and the University of California San Diego, has proposed a placebo-controlled, three-year trial in clinically normal older adults with biomarker evidence of Alzheimer's changes in their brains, to be known as the Anti-Amyloid Treatment of Asymptomatic Alzheimer's Disease (A4) trial. The funding application will be reviewed in early July 2012 at the National Institute on Aging, with the hope of starting participant enrollment in mid-2013.
Eligible participants will have normal memory and thinking abilities, age 70+, with evidence of amyloid buildup in their brain shown on a PET scan using an amyloid imaging dye. The primary outcome will be slowing the rate of cognitive decline on a test that probes episodic memory (times, places, associated emotions, and other related knowledge) and executive function (including functions such as planning, problem solving, verbal reasoning, inhibition, and initiation). The researchers are also developing a novel computerized test battery for an exploratory cognitive outcome. Multiple biomarkers, including structural and functional imaging, and spinal fluid assays, will be used as secondary outcomes.
The choice of an experimental treatment for the A4 trial has not yet been finalized. According to the scientists, it will likely be a monoclonal antibody against amyloid with clear evidence of target engagement and adequate safety data.
The Dominantly Inherited Alzheimer Network (DIAN)-Therapeutic Trials Unit is preparing to launch prevention trials in people with young-onset genetic Alzheimer's.
The DIAN Study itself is not designed to test any treatments or preventive strategies; rather, it is designed to collect information about the changes in the brain that precede the development of disease symptoms. However, because biochemical changes can be detected and measured many years before symptoms develop, it may be possible for researchers to develop treatments that halt or slow the biological processes that cause those biochemical changes, potentially arresting the disease process before brain function is impaired. The DIAN Therapeutic Trials Unit (DIAN-TTU) was developed to pursue this possibility.
The DIAN-TTU has developed a novel clinical trial design that may accelerate approval of the best therapeutic treatments for Alzheimer's. The proposed design is a two-stage study to delay, prevent or restore cognitive loss in people who carry an Alzheimer's gene mutation. The first stage will determine the biological engagement of the drug target and the impact of the drug on Alzheimer's biomarkers. The second stage will determine if there is a cognitive benefit. Three drugs will be tested initially. The trial is expected to start in late 2012 or early 2013.
"Prevention studies are likely to be most successful for those people with the highest risk of Alzheimer's," said study leader Randall Bateman, M.D., of Washington University School of Medicine, St. Louis.
Bateman said, the DIAN study already has confirmed the similarities between dominantly inherited Alzheimer's disease and sporadic Alzheimer's disease cases. Because of this similarity, the researchers believe the results of the DIAN project are likely to be applicable to a broader population affected by Alzheimer's disease.
The Alzheimer's Prevention Initiative (API) aims to conduct preclinical Alzheimer's treatment trials of amyloid-modifying treatments in cognitively normal people who, based on their age and genetic background, are at the highest imminent risk of Alzheimer's symptoms. It also aims to establish some of the tools and enrollment registries needed to test promising prevention therapies as quickly as possible. The primary study population is an unusually large kindred near Medellin, Colombia, affected by a genetically-caused form of younger-onset Alzheimer's.
The Banner Alzheimer's Institute of Phoenix, Ariz., chose crenezumab from Genentech, a humanized monoclonal antibody against beta amyloid, as the therapeutic agent for this trial. The API trial will test the drug on 300 individuals from the Columbian kindred, and about two dozen people in the U.S., who have younger-onset Alzheimer's-causing gene mutations but do not yet show symptoms of the disease.