This year the Alzheimer's space has seen several drugs undergo phase 3 clinical trials.
This story is part of MD Magazine's Year-End Recap series.Click here for Part 1, a look into the success of ketamine as a multifaceted therapy.Click here for Part 3, a look into innovation in a type 1 diabetes device.
Throughout the last 30 years, researchers have made remarkable progress in understanding the Alzheimer’s Disease space, however, 2017 has proven an exciting time as several drugs in phase 3 clinical trials may hold great promise for the future.
A recent forecast calculated by the National Institutes of Health estimated that around 6 million American adults have Alzheimer’s disease or mild cognitive impairment — often times a precursor to Alzheimer’s — yet there are only a handful of drugs available to treat the symptoms, while none address the underlying disease processes or delay progression. Since 2003, no new drugs have been approved for treatment.
In 2017 alone, there have been several drugs that are now in phase 3 clinical trials. Early testing of these disease-modifying agents could potentially slow the development of structural and functional abnormalities in the central nervous system, providing sustainable functions which persist after drug withdrawal. The drugs show promise in reducing declines of memory and thinking skills in patients in the early stages of Alzheimer’s.
“There’s one study of an agent called aducanumab, that’s really the first amyloid therapy that’s been shown to not only decrease amyloid in the brain when you look at scans, but also improve cognitive function,” Richard Isaacson, MD, director, Alzheimer’s Prevention Clinic, New York Presbyterian/Weill Cornell Medicine, told MD Magazine. “In the past, drugs have reduced amyloid but cognitive function has not improved.”
The best known biological process, the main target of drug development so far, is the amyloid pathway which starts with amyloid precursor protein (APP). In patients with Alzheimer’s, the brain enzymes cut APP protein fragments into amyloid beta which accumulate into the sticky, insoluble amyloid plaques.
Researchers believe that beta-amyloid plaque plays a critical role in the development of the disease. Recent studies show that deposits of abnormal amyloid begin to build up in the brain 20—30 years before symptoms appear, followed later by the tau protein.
As evidence suggests brain changes in patients typically begin years prior to symptoms and a diagnosis, researchers believe that therapies may be most effective at the earliest stages before symptoms become evident and the amyloid is maxed out.
Isaacson suggests that while multiple phase 3 studies need to be conducted on aducanumab to prove its efficacy, we are almost at the point where we’re going to definitively know if the amyloid hypothesis is a valid hypothesis for drug development and if anti-amyloid drugs will work or not.
“Can we intervene against amyloid and will the patient improve? If not, we need to be taking other shots on goal, whether that’s working on glucose metabolism, insulin resistance, inflammation, infection, tau,” Isaacson added. “There’s so many other competing hypotheses, so maybe it’s not really a one size fits all disease. Maybe different things happen in different people, and different people need different therapies.”
A second disease process related to the amyloid pathway is the growth of tau tangles. The current drug in research that targets tau protein is AADvac1, which works to stimulate the body’s immune system to attack an abnormal form of tau. If successful, it has the potential to help stop the progression of the disease.
Beta-secretase (BACE) makes it possible for beta-amyloid to form, and JNJ-54861911, the current drug being researched, inhibits the ability of the BACE enzyme to make beta-amyloid. It’s being evaluated to determine if it slows cognitive decline in people without Alzheimer’s symptoms but have elevated levels of beta-amyloid in the brain.
Sargramostim, while approved by the US Food and Drug Administration (FDA) for bone marrow stimulation in patients with leukemia, stimulates the innate immune system. The inflammatory targeted drug is currently being tested for Alzheimer’s as it may stimulate immune processes that could protect neurons in the brain from toxic proteins.
Pimavanserin, the final drug currently in research, targets the 5-HT2a receptor and is being evaluated for its potential effect of reducing the symptoms of dementia-related psychosis.
Aside from the several drugs in current phase 3 clinical trials, Howard Fillit, MD, founding executive director and chief scientific officer, Alzheimer’s Drug Discovery Foundation, sat down with MD Magazine to discuss the need for repurposed drugs in the space.
While there is no current cure for the neurodegenerative condition, it’s important to focus on therapies that slow down the progression of the disease and cognitive impairment.
“It is actually a really exciting time to be in drug development and drug discovery for Alzheimer’s because there are so many targets that we know about now from biology that could be the focus of drugs — and we’re testing a lot of them, including 17 repurposing drugs,” Fillit said. “In other words, taking drugs that are on the market and testing them. They might be on the market for other neurodegenerative diseases, like ALS and Parkinson's, and are disease-modifying drugs, [and we are] repurposing them and testing them in Alzheimer's patients. A number of them will report out in the next year or 2.”
Fillit expects, based on the studies ongoing today, that a multi-modal approach will occur — so we won’t just have symptomatic therapies but hopefully disease-modifying therapies.
“The advantage of repurposing is that if these trials are positive and the drugs are shown to be safe, then the next day I can prescribe these drugs off-label for my patients,” Fillit noted. “I do not have to wait for FDA clearance. The big opportunity when you discover a repurposing drug that works is that then we can go back and do new chemistry, create new chemical entities, get new indications for unique drugs, and build the space because we have a proof-of-concept.”
The focus on prevention is a new approach to fighting this disease. By intervening years before Alzheimer’s manifests, researchers believe symptoms could be delayed, or even stopped before Alzheimer's begins.