Local doctors are spearheading a dramatic shift in the fight against Alzheimer's disease with a study that will use a promising experimental drug to try to halt a disease that some people are genetically destined to get.
The ambitious study will be conducted mainly on an extended Colombian family of 5,000 afflicted with a rare, inherited genetic mutation that makes it virtually certain that some will develop Alzheimer's symptoms, usually in their mid-40s.
The $100 million clinical trial by Banner Alzheimer's Institute in Phoenix, doctors in Colombia and a San Francisco-area biotechnology company will test the drug on the Colombians while they're healthy in an effort to help them avoid their genetic fate.
The potentially groundbreaking study, if successful, could lead to a method of attacking the memory-robbing disease with new treatments that delay or halt the disease among people who face the greatest genetic risk, local researchers say.
"We believe this is the first prevention trial in cognitively normal people who, based on their genetic background, are destined to develop Alzheimer's disease," said Dr. Eric Reiman, executive director of Banner Alzheimer's Institute. "This study has the potential to launch a new era of Alzheimer's prevention research."
Those involved in Banner's Alzheimer's Prevention Initiative say the study is unique because treatments will be administered to the Colombian family members before they show symptoms.
It also will allow scientists to scrutinize the theory that beta-amyloid plaques, proteins that accumulate in the brains of Alzheimer's patients, are a likely trigger of the disease. If the study shows that removing amyloid plaques from the brain halts the disease's progress, it would offer the most convincing evidence yet that the disease's attack on the brain is tied to amyloid plaques, according to the Banner scientists.
"This is the first time we are taking people who have 100 percent certainty and attempting to stave off the disease with treatment," said Dr. Pierre Tariot, director of Banner Alzheimer's Institute.
The Banner study comes as the Obama administration on Tuesday unveiled details of the National Alzheimer's Plan, which seeks to advance research on prevention and deliver effective treatments by 2025.
The plan stems from the National Alzheimer's Project Act passed by Congress and signed by President Barack Obama last year to address the human and economic toll of a disease that afflicts 5.4 million Americans, a number that is expected to reach 7.7 million by 2030.
The direct annual cost of providing care for Alzheimer's patients is expected to soar from $200 billion in 2012 to $1.1 trillion in 2050, with most costs likely absorbed by taxpayers through government-sponsored insurance programs such as Medicare and Medicaid.
With the daunting challenges of the disease, patient advocates and foundations say that a national project that emphasizes education, research and prevention is vital to improving the prospects for patients and their families.
"The field is looking for anything that will give us hope -- but, more important, give us a direction," said Eric J. Hall, president and CEO of the New York-based Alzheimer's Foundation of America. "The need for research is so vast. If this (Colombia) clan allows us to uncover or discover something vital, the project is necessary."
Phoenix-based Banner Alzheimer's Institute will conduct the study with a five-year, $16 million National Institutes of Health grant along with a $15 million donation from the Banner Alzheimer's Foundation. The balance of the funding will come from Genentech, a South San Francisco-based biotech company that will test its anti-amyloid drug, crenezumab, on patients. Genentech is owned by Swiss pharmaceutical giant Roche.
The pharmaceutical industry has struggled to develop a drug that has been safe and effective for Alzheimer's disease. It's been about a decade since the last new drug, Namenda, was approved to treat symptoms of the disease.
Several drug companies are testing drugs that seek to delay or prevent the disease by clearing the beta-amyloid plaques that accumulate in the brains of Alzheimer's patients. In 2010, Eli Lilly halted its study of an anti-amyloid drug, semagacestat, after finding it hurt patients' cognition and ability to perform daily functions.
Banner Alzheimer's Institute convened a panel of experts to evaluate more than 20 investigational drugs before selecting crenezumab as the one to test on the Colombians.
Genentech's crenezumab also is a drug that binds to and clears amyloid from the brain. It has been studied in healthy individuals and people with Alzheimer's disease. So far, it has shown no significant safety issues.
Some other drugs that clear amyloid from the brain also have shown a side effect called vasogenic edema, which is a buildup of fluid in the brain.
Genentech's crenezumab has shown no signs of vasogenic edema in animal studies, nor in a Phase 1 and an ongoing Phase 2 study on humans, according to Richard Scheller, executive vice president for Genentech research and early development.
Scheller said the trial offers the opportunity for a "definitive study" on the hypothesis that anti-amyloid drugs can halt progression of the disease.
A key to this trial is that the drug will be given to patients in sufficient doses to remove the plaques before the patients show symptoms, Scheller said. Other drugs that clear amyloid plaques have been tested on patients who already show memory or thinking problems, possibly too late to make a difference.
"The worry is the buildup of plaque and the degeneration of the nervous system has been taking place for several years by the time symptoms appear," Scheller said. "At that time, it might be difficult to stop the downward spiral of cognition."
The study will include 300 Colombians from an extended family of about 5,000 people in the Antioquia region of Colombia. The study also will enroll another 24 U.S. residents from families with a history of Alzheimer's disease.
Of the 300 Colombians who will participate in the study, 200 will be carriers of a mutated version of the presenilin gene tied to the early onset of the disease. Carriers of the gene, discovered by Dr. Francisco Lopera of the University of Antioquia, typically show symptoms of Alzheimer's disease at age 45.
Tariot of the Banner Alzheimer's Institute said half of those genetic carriers will get crenezumab, while another 100 will be given a placebo treatment. Another 100 Colombians who are non-carriers of the gene also will receive a placebo.
Carriers of the genetic mutation are not informed of their status, which is standard for medical care in Colombia.
The study will include Colombians in their 30s, with participants expected to receive the drug treatment beginning in 2013. It will measure the progress of the disease in participants through both physical and cognitive evaluations. Reiman said it will track and measure biomarkers associated with the disease, including MRI measurements to track brain shrinkage over time, spinal fluid measurements and PET images that track amyloid growth in the brain.
Study coordinators expect that the sophisticated biomarker and data measurements will give researchers clues about the progress of participants within two years of the start of the trial.
If the Colombian trial shows that the drug can slow the progress of Alzheimer's disease, it could open the possibility of performing a larger U.S.-based prevention trial for those who carry a higher risk of developing the disease.
Banner Alzheimer's Institute is contemplating a study of carriers of a gene, called APOE4, that is associated with a higher risk of developing the disease. An estimated 25 to 30 percent of the population has the APOE4 gene, but it is present in about 40 percent of people with late-onset Alzheimer's disease, according to the NIH's National Institute on Aging.
The Banner institute's Reiman said it has had discussions with pharmaceutical companies about the possibility of a large-scale prevention trial involving participants who carry the APOE4 gene.
Genentech's Scheller said favorable results from the Colombian trial would "certainly give us confidence to test this molecule on a broader, more general population."
Reiman sees the trial as the first of many to test anti-amyloid drugs through the Phoenix-based institute.
"We have a chance to test and to give people access to the most promising treatments," Reiman said. "We have an extraordinary need to advance the fight against Alzheimer's disease."
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