Researchers at the Princeton Medical Institute, as well as at other institutions, are investigating a novel drug to fight Alzheimer’s disease in a phase-II clinical trial called the NOBLE study.
Alzheimer’s is a neurodegenerative illness that affects more than five million adults in the United States. The last drug to have entered the market, memantine, was introduced more than a decade ago.
The study explores the potential of T-817MA, a compound that may prevent neuron loss in the brain and even promote the regeneration of neurites. The study is ongoing across 51 research sites in the United States and currently recruits qualifying patients with mild to moderate cases of Alzheimer’s.
There are currently only four FDA-approved drugs for Alzheimer’s treatment, Jeffrey Apter, the principal investigator for the clinical site in Princeton, said.
“There are drugs on the market currently for Alzheimer’s, but they don’t prevent progression of the disease — purely symptomatic,” Apter said. “We’re trying to determine how safe and efficient [T-817MA] is in delaying or altering the decline in memory in patients with Alzheimer’s disease.”
If successful, T-817MA holds the potential to open up new avenues in Alzheimer’s treatment, Apter said.
“It inhibits neuron cell death and promotes neurite outgrowth, so we call it the neurotrophic agent,” Apter said. “That’s different from anything else that is currently available for Alzheimer’s disease.”
According to Dean Hartley, director of Science Initiatives at the national advocacy group Alzheimer’s Association, there are five other major studies beside the NOBLE study currently looking at the anti-amyloid hypothesis, which is the idea that drugs targeting beta-amyloid waste between brain cells may help delay the progression of Alzheimer’s. Hartley was not directly affiliated with the NOBLE study.
While the field has been increasingly committed to the anti-amyloid approach, there are still issues, Stefano Sensi, head of the Molecular Neurology Unit at the Center for Excellence on Aging at University G.d Annunzio, Italy, said.
“Unfortunately, there is not a very strong correlation between the amount of amyloid in the brain and the level of cognitive deficit or disease,” Sensi said. “And more disturbing, 30 percent or so of cognitive-intact people have strong amyloid deposition, so that questions the causative role of amyloid in the disease.”
Another type of naturally occurring proteins associated with Alzheimer’s isthe tau proteins. Though the tau proteins are harder to access due to their location in the brain, rapid advancements in imaging technology are enabling researchers to study their relationship to Alzheimer’s development. Sensi’s own clinical model is looking into tau protein buildup in addition to amyloid deposition.
“[Tau protein-related pathology] is probably more promising as a potential way to interpret the disease,” Sensi said. “This model is packing it all together and seems a very comprehensive model for starving the disease.”
However, studies involving the tau proteins are even newer than the investigations targeting amyloid, and their potential remains to be seen. According to Piero Antuono, professor of neurology and biophysics at the Medical College of Wisconsin, researchers are still trying to determine which target is critical and how exactly to approach it.
“There is some skepticism that the anti-amyloid approach is the solution to the disease,” Antuono said. “Another target under study is called tau protein, [whose] presence in the brain is always associated with dementia ... Maybe tau is the target that’s going to make a difference.”
Nonetheless, matters remain more complicated than simply picking and choosing the correct target protein, Antuono said.
“Generally the first change we see in people who have Alzheimer’s is this amyloid change,” Antuono explained. “Chronologically, it’s the first thing we see. Then, eventually tau protein appears. At this point, I would say that the field is still open.”
Antuono said that if the targeting of amyloid is the most promising way to proceed, the NOBLE Study’s T-817MA is truly a novel compound in light of other anti-amyloid studies.
“This drug is different [from] the way that most anti-amyloid approaches, or neuroprotective approaches, are using antibodies against [amyloid],” Antuono said. “This medication is aiming to prevent the accumulation of the protein. In other words, rather than removing the protein which has accumulated in the brain, it aims to prevent the deposition of this protein in the part of the brain that regulates memory."
Researchers’ commitment to investigating causes of the disease has already brought about major accomplishments, Sanjay Asthana, director of the Wisconsin Alzheimer’s Disease Research Center, said. Asthana is also a principal investigator for the NOBLE Study, overseeing its clinical site in Madison.
“The field of Alzheimer’s research has come very, very far in the last 25 years,” Asthana said. “We’ve really substantially improved our understanding of how the brain works and also how Alzheimer’s disease and its pathology works.”
However, both Hartley and Asthana said there is a need for more government funding toward Alzheimer’s research. While Congress has directed its largest funding initiatives in the last few years to the frontlines of cardiovascular and cancer research, Alzheimer’s disease has received far less in comparison.
“We are very underfunded — somewhere around $586 million in patient research [for Alzheimer’s] versus the $2 to 6 billion for cancer and heart disease,” Hartley said. “Funding is the most critical piece to moving this. It’s not a matter of if we find the treatment, it’s a matter of when, and that depends on resources.”
The economic costs of Alzheimer’s and its overall burden on the healthcare system are staggering, Hartley said, adding that at present, the direct cost to the federal government is $226 billion. Compounded by the rise of an aging baby boomer generation, the population of Alzheimer’s patients in America is projected to reach nearly 14 million by 2050.
“The fact that it’s such a costly disease, both to the U.S. government in terms of Medicaid and Medicare, as well as out-of-pocket expenses for family, [makes] this is a burden for generations to come,” Hartley said.
Pursuits like the NOBLE study are the key to faster drug discovery, more effective patient care and the alleviation of an otherwise massive burden for families in America, Hartley said.
Asthana said he hopes for positive results from the NOBLE study.
“If that is the case, this will be a very important treatment for Alzheimer’s disease … for patients, scientists and, basically, the human race,” Asthana said.
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