Also, Special Session Previews the First Three Prevention Trials in Presymptomatic Alzheimer's
VANCOUVER, British Columbia, July 17, 2012 /PRNewswire-USNewswire/ -- The first report of long-term (three-year) stabilization of Alzheimer's disease symptoms with IVIG (Gammagard, Baxter), including no decline on measures of cognition, memory, daily functioning and mood, was reported today at the Alzheimer's Association International Conference® 2012 (AAIC® 2012) in Vancouver.
In addition, updates were given on three new presymptomatic Alzheimer's disease treatment trials that are beginning soon or in the planning stages. At an AAIC 2012 Featured Research Session titled "Collaboration for Alzheimer's Prevention: Common Issues Across Presymptomatic Treatment Trials," the principal investigators of the three trials described their current status, followed by a panel discussion.
Disappointing results from recent Alzheimer's clinical trials suggest that we 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, PhD, 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 we learn from studying this rare group of people with Alzheimer's – they comprise less than two percent 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.
First report of long-term stabilization of Alzheimer's in 3 year extension of Phase II IVIG trial
Intravenous immunoglobulin* (IVIG/Gammagard, Baxter) is being studied as an immunotherapy for Alzheimer's. Positive results of a placebo controlled Phase 2 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 where all subjects received IVIG. Several doses were tested.
To evaluate the long term effects of IVIG, participants were offered additional IVIG treatment at a single standardized dose (0.4mg/kg every 2 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 who were 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 (ADAS-Cog, CGIC, 3MS, ADCS-ADL, NPI, QOL) 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.
"Alzheimer's disease progresses over many years," said study leader Norman Relkin, MD, PhD, of Weill Cornell Medical College, New York City. "It is crucial that we find effective, long-term treatments."
"This is the first study to report long term stabilization of Alzheimer's symptoms with IVIG. While the small number of participants may limit the reliability of our findings, we are very enthusiastic about the results. A Phase 3 trial is in progress and, in less than one year, we'll have more definitive data on the efficacy of 18 months of IVIG treatment."
* IVIG is a blood product that is administered intravenously. Each dose contains pooled antibodies extracted from the plasma of more than 1,000 blood donors. IVIG is given to immune deficient patients who have decreased or absent antibody production capabilities to prevent infections. It is mainly used in immune deficiencies, autoimmune diseases, and acute infections.
Anti-Amyloid Treatment of Asymptomatic Alzheimer's Disease
The Alzheimer's Disease Cooperative Study (ADCS)** 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.
"This is the optimum time to launch this study because we now have the biomarker measuring tools and experimental drugs to test the hypothesis that reducing amyloid burden in the brain will slow the loss of nerve cells in Alzheimer's, and thereby delay or prevent cognitive decline." said A4 principal investigator Reisa Sperling, MD, of Harvard Medical School and Brigham & Women's Hospital, Boston.
"And, because we're planning to study cognitively normal older adults, the A4 trial will complement the Alzheimer's prevention initiatives conducted in younger-onset genetic Alzheimer's families."
** The ADCS was formed in 1991 as a cooperative agreement between the National Institute on Aging and the University of California San Diego. Led by Paul Aisen, MD, the ADCS is a major initiative for Alzheimer's disease clinical studies in the federal government to facilitate the discovery, development and testing of new drugs for Alzheimer's.
The Dominantly Inherited Alzheimer Network – Therapeutic Trials Unit
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 Alzheimer's Association is the lead funder of the project, accounting for 56% of its initial funding, with the DIAN Pharma Consortium, a pioneering consortium of 10 pharmaceutical companies providing the balance.
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, MD, of Washington University School of Medicine, St. Louis, Missouri.
"People with dominantly inherited Alzheimer's disease develop the same pathologic changes in the brain — amyloid plaques and neurofibrillary tangles — as people who have other forms of the disease, but those changes develop at a younger age. Scientists believe, therefore, that there is significant overlap of the causes and progression in people with dominantly inherited Alzheimer's and other forms of the disease."
According to Bateman, the DIAN study has already 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.
"Clinical studies in Alzheimer's that is caused by gene mutations are likely to pioneer the way to prevention trials for all forms of the disease," Bateman said.
The Alzheimer's Prevention Initiative
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.
"There is an urgent need to find effective preclinical Alzheimer's treatments to postpone the onset, reduce the risk of, or completely prevent Alzheimer's," said two of the lead investigators, Eric Reiman, MD, and Pierre Tariot, MD, of Banner Alzheimer's Institute, Phoenix, Arizona. "We believe this study group offers a unique opportunity because of its size, shared genetic background, and commitment to the fight against Alzheimer's."
As recently announced, study leaders from the Banner Alzheimer's Institute chose crenezumab (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.
According to Reiman, "The trial will determine whether crenezumab can reduce participants' chances of developing the disabling and irreversible symptoms of Alzheimer's, preserve memory and thinking abilities, and slow the progression of Alzheimer's biomarkers – including the best established brain imaging and cerebrospinal fluid measurements. It is based on the idea that certain treatments may need to be started before the onset of symptoms to have their greatest benefit."
"We feel that it is important to give persons at highest risk access to promising investigational treatments, and to conduct the study in a way that provides the greatest possible benefit to the field" Reiman said.
Similar to the DIAN-TTU, it is hoped that the findings will provide insights and lead to similar studies in people at risk for the more common form of the disease later in life.
The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
About the Alzheimer's Association
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. For more information, visit www.alz.org or call 800-272-3900.
SOURCE Alzheimer's Association