May 18, 2012 — An ambitious National Alzheimer’s Plan announced this week by the Department of Health and Human Services to address the growing threat of Alzheimer’s disease (AD) in the United States includes funding for the first prevention trial in people genetically predisposed to develop early symptoms.
The double-blind, placebo-controlled study will test the drug crenezumab, an antibody that targets beta-amyloid, in a large extended family in Colombia, many of whom carry genetic risk mutations. Typically, cognitive impairment begins at around age 45 in affected individuals.
This trial is an important step in testing the amyloid hypothesis of the disease and could have wide-reaching implications, said Ronald Petersen, MD, PhD, director, Alzheimer’s Disease Research Center, Mayo Clinic, Rochester, Minnesota. Dr. Petersen chaired the Advisory Council on Alzheimer’s Research, Care and Services that was charged with developing the National Alzheimer’s Project Act (NAPA) signed into law by President Barack Obama in 2011. The National Alzheimer’s Plan was called for in NAPA.
“It’s going to be relatively pure test of the amyloid hypothesis,” said Dr. Petersen, because the drug targets amyloid. “This is something that needs to be done, but whether it’s going to be applicable to the general population of patients with AD is another question.”
The government will also contribute to a $7.9-million effort to investigate an insulin nasal spray as a treatment for AD. A recent small study showed memory improvements in adults with amnestic mild cognitive impairment or AD who used the spray.
The funding for both trials is included in the $50 million in research support announced for fiscal 2012 as part of the Alzheimer’s Plan. Another $80 million was announced for fiscal 2013. The plan has a stated aim of finding an effective AD treatment or preventive strategy by the year 2025.
The plan, said Dr. Petersen, signals a real commitment to the cause.
“The fact that the president, the congress, everybody, has mobilized around this at least makes us think that people at the federal government level are starting to pay attention, and realizing that we have got to do something about this; we just can’t continue with the niceties and give lip service to it,” he told Medscape Medical News.
Families at Risk
Autosomal dominant AD is caused by a mutation in 1 of 3 genes — amyloid-beta precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) — and accounts for about 1% of all AD cases. “Statistically, children of an affected parent have a 50/50 chance of inheriting that mutation, across all generations,” said Dr. Petersen. Carriers have a 100% risk of developing the disease at roughly the same age as their parent, but offspring who don’t carry the mutation have the same risk as anyone else.
The government’s plan includes National Institutes of Health funding on the order of $16 million toward the $100 million cost of the study in Colombia. The trial will enroll 300 participants 30 years of age or older, 100 in each of 3 groups: participants with the mutation who will take crenezumab, those with the mutation who will take placebo, and noncarrier relatives who will receive placebo. It will also include “a handful” of Americans, perhaps 20 or 30, said Dr. Petersen.
Participants will receive placebo or the treatment drug, being developed by Genentech in collaboration with Swiss biotech company AC Immune SA, for up to 5 years. Using advanced imaging techniques, cerebrospinal fluid tests, biomarkers, and sensitive cognitive measures, researchers will assess whether the treatment reduces accumulation of amyloid and maintains brain size, and whether it preserves cognitive function.
Recruitment for the trial, set to begin early next year, should be “relatively straightforward” compared to a regular drug trial, partly because of what’s known already about the affected families and also because “these people are eager” to find a cure, said Dr. Petersen.
Investigators will work with Francisco Lopera, MD, from Grupo de Neurociencias de Antioquia at the University of Antioquia in Colombia, who first identified the family’s illness nearly 3 decades ago and helped determine its cause: a presenilin mutation. The trial will be led by Eric M. Reiman, MD, executive director, Banner Alzheimer’s Institute (BAI), in close cooperation with Dr. Lopera and Genentech’s research and clinical team.
“We are grateful for the chance to evaluate such a promising prevention treatment,” Dr. Reiman said in a statement. “We have tried to design the study in a way that might bring the field closer to ending Alzheimer’s before another generation is lost.”
In addition to government funding of the trial, BAI is committing $15 million, with Genentech contributing the remaining cost, in addition to providing the study drug and clinical and operational expertise.
Preclinical studies showed that crenezumab binds to amyloid proteins and clears them from the brain. It has been studied in both healthy individuals and people with AD and is being evaluated in a phase 2 clinical study in patients with mild to moderate symptoms. To date, no significant safety issues have been detected.
A panel of experts chose the Genentech drug among several other candidate agents for the prevention trial because it has fewer side effects. For example, it does not cause vasogenic edema.
Other similar antiamyloid drugs include bapineuzumab, being tested by Pfizer Inc and Johnson & Johnson, and solanezumab, under investigation by Eli Lilly and Co.
Experts, including Dr. Petersen, believe that this trial, which involves taking a treatment when still cognitively normal, could provide the best evidence yet on the involvement of amyloid in AD. It’s possible that previous trials of other antiamyloid drugs didn’t show an effect because patients were too far along in the disease
Results of earlier trials give experts reason to believe they’re on the right track in starting a treatment well in advance of symptoms. The first results from the Dominant Inherited Alzheimer’s Disease (DIAN) study, a multicenter international study of autosomal dominant AD, reported last summer during the Alzheimer’s Association International Conference, showed that measurable biochemical and imaging markers can be detected up to 20 years before symptoms appear.
Baseline data for that study showed that cognitively normal individuals who are mutation carriers and therefore destined to develop AD in their 40s, 30s, and sometime even their 20s have lower levels of beta-amyloid 42 (Aβ-42) and elevated levels of tau and phosphorylated tau (p-tau) compared with their non–mutation-carrying siblings, as determined by imaging and cerebrospinal fluid and blood testing.
As well, DIAN investigators were able to detect cognitive changes on clinical testing among mutation carriers who were asymptomatic at baseline.
If the new study shows that crenezumab can prevent AD in people certain to develop it, other trials could be designed to test it and other antiamyloid drugs in larger populations, according to a Banner statement. If the treatment’s effects on biological measurements of the disease are shown to predict its clinical benefit, the study could establish a much faster way to test future therapies.
Experts predict that without an effective treatment, the number of Americans with Alzheimer’s will double by 2050 to more than 10 million, and related healthcare costs could soar to over $1 trillion a year. This is in addition to the caregiver burden, which can take a serious toll on the physical, mental, and financial well-being of family members.
Also included in next year’s $100 million effort to combat Alzheimer’s disease is $4 million earmarked for the development of high-quality, up-to-date training for doctors, nurses, and other providers. The plan will also allocate $4.2 million to improved public awareness that will include a television advertisement and a new Web site (www.alzheimers.gov), $10.5 million to caregiver support, and $1.3 million toward improved data collection.
The federal plan “is going in the right direction” but is still just a step, commented Dr. Petersen. “To make the giant leaps, we really need the major changes in funding, but I think more news is good news.”
However, it’s still encouraging, particularly in light of the current belt-tightening environment, he said.
“In the grand scheme of things, when you look at what’s happening at the federal government level, everybody is gearing up for a downturn, a reduction of up to 10%,” said Dr. Petersen. “They are battening down the hatches at NIH (National Institutes of Health), and there may be even more draconian cuts coming down the road. Here’s a little glimpse of something going in a positive direction, and that’s good.”
The Alzheimer’s Association applauded the plan. “This is a strong plan that promises important progress when implemented,” Harry Johns, president and CEO of the Alzheimer’s Association, said in a statement. “For all Americans, not just the more than 5 million living with Alzheimer’s and their 15 million caregivers today — this plan is an historic achievement.”