While promising data from Biogen and Eisai’s lecanemab breathed new life into the anti-amyloid approach last week, Alzheimer’s disease is complex enough that combination therapies will likely play a significant role in future symptomatic treatments.
A combination of medications has proven effective in treating multiple diseases, such as cancer and diabetes. Could the same be true for AD?
Sharon Rogers, Ph.D., chief executive officer of AmyriAD Therapeutics, believes treatments targeting the multiple symptoms of the disease will provide a benefit for patients receiving the standard-of-care treatment Aricept (donepezil).
Last week, AmyriAD hosted a virtual conference highlighting the need for combination therapies.
Rogers explained that for the past 15 years, the primary focus in AD has been on disease modification strategies. While this has expanded the understanding of the disease, Rogers said addressing the core symptoms of AD, such as cognition and core function, is a critical unmet need.
“We’re at the point now that we’re going to look at this with the complexity it deserves… addressing more than one target via combination therapy may provide more successful symptom management,” Rogers said during the panel. “We must do a better job of addressing symptom management, meaning introducing new treatments to improve patient cognition and function.”
Noted AD researcher Serge Gauthier, former director of the Alzheimer’s Disease and Related Disorders Research Unit of the McGill Center for Studies in Aging and Douglas Research Centre in Montreal, argued for this kind of approach.
“We should combine symptomatic drugs if there is a rationale and it’s safe… I will argue that combination therapy for symptom control is the way to go,” Gauthier said during the conference.
Noting the effectiveness in the aforementioned therapeutic areas, Gauthier said he believes a combination approach is also a potentially useful strategy in treating AD. Drugs such as donepezil can be paired with 5-HT receptor antagonists or MAO-B inhibitors and anticonvulsants to treat symptoms of the disease, he noted.
Beyond Anti-Amyloid
Gauthier pointed to the current emphasis on amyloid reduction using individual drugs such as monoclonal antibodies. He said that approach is showing little benefit. There was some hope sparked by Biogen’s Aduhelm, approved last year based on data that was considered controversial. The approval marked the first for AD in nearly two decades.
Despite the approval, Aduhelm ran into multiple issues, including safety concerns following reported deaths of some patients who were taking the medication. During clinical studies, Aduhelm was linked to cases of amyloid-related imaging abnormalities (ARIA-E), also known as cerebral edema. This was included on the drug’s warning label.
Those concerns though were enough for the Centers for Medicare and Medicaid Services to limit coverage of Aduhelm to patients who are participating in clinical trials. Earlier this year, the CMS extended that limitation to all monoclonal antibodies used to treat AD.
Lecanemab, a monoclonal antibody, showed the slowing of disease progression, including a slowing of loss of memory and thinking skills, Gauthier noted.
The companies called the data “highly statistically significant” and it could bolster potential approval. In July, the FDA accepted the Biologics License Application for lecanemab under the accelerated approval pathway and granted Priority Review.
Following the Sept. 28 announcement, Howard Fillit, M.D., co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, expressed excitement about the data but added there is still a need for next-generation approaches focused on other, non-amyloid Alzheimer’s targets.
At the AmyriAD conference, Fillit reiterated that statement.
“We’re seeing a little bit of success in the anti-amyloid group but we have to go beyond that,” Fillit said. He added that the successes seen with lecanemab seem incremental and modest when it comes to slowing the delay of disease-related decline.
“Lecanemab is showing hints of efficacy in the amyloid approach but we still need to treat the symptoms,” he said.
Fillit noted that aging is the leading risk factor for AD. With aging comes numerous risk factors that increase the risk of disease, including heart disease, diabetes, stroke, high blood pressure and high cholesterol, he said.
“To effectively conquer Alzheimer’s, we need to develop a unifying approach that targets a multifactorial disease,” Fillit said. “We need drugs that have multiple mechanisms of action and multiple combination therapy approaches. Inflammation has become a leading therapeutic strategy. We need to figure out how to slow down neuro-inflammation.”
For the first time, nearly three-quarters of the experimental treatments for AD are not targeting amyloid plaque nor tau tangles, Fillit noted. With lessons learned from the amyloid-targeted failures, he said researchers are shifting their targets toward these other related areas.
Repurposing Drugs
One way to speed up development of potential treatments is by repurposing older medications. If drugs share a pathway with approaches to the symptoms, repurposing a drug can be worthwhile, Fillit said. Because these older drugs are well-known, it could speed the clinical process and potentially bring a treatment to patients more quickly.
Fillit pointed to promising effects on cognitive decline and other disease hallmarks following treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 agonists are glucose-lowering medications typically used to treat type 2 diabetes, obesity and for cardiovascular risk reduction. There is speculation that AD is related to blood glucose levels.
Novo Nordisk initiated a Phase III trial in 2020 assessing its GLP-1 agonist Victoza (semaglutide) in AD. Data has shown the drug’s ability to lower neuroinflammation, which impacts cognition and memory function. The study is expected to be completed in 2024, according to Clinicaltrials.gov. Fillit said researchers will “learn a lot from this strategy.”
Combining with a Tried and True Approach
Donepezil, a cholinesterase inhibitor that has been a standard-of-care treatment for mild- to moderate AD patients for a quarter century, has the best evidence of providing a symptomatic benefit for Alzheimer’s patients – for a while, at least, Gauthier said. It is the type of drug that can benefit from add-on medications, he noted.
Rogers pointed to her company’s lead candidate AD101, an investigational, Phase III-ready therapeutic that demonstrated increased release of the neurotransmitter acetylcholine. The late-stage trial will investigate the potential of AD101 to demonstrate an improvement in cognition and global function through neuroselective T-type calcium channels.
While AD101 increases acetylcholine release, donepezil preserves acetylcholine from breaking down, Rogers said. If you can increase acetylcholine, there should be significant benefits, such as improved cognition.
For Fillit, it is an exciting time in Alzheimer’s research.
“We’re moving to a world of precision medicine like we have in cancer and other chronic diseases of aging,” he said. “I think our aging biology strategy will lead to a lot of benefit and I expect we’re going to have a whole host of drugs in combination therapy. We’re going to have to figure out how to do combination trials better because that’s the next frontier of clinical trials.”
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