Controversy Surrounding Aduhelm's Approval Leads Researchers to Rethink Long Standing Hypothesis Driving Alzheimer's Research

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The following post was written and/or published as a collaboration between Benzinga’s in-house sponsored content team and a financial partner of Benzinga.

In a controversial move this past June, the FDA approved Aduhelm™ as a treatment for Alzheimer’s disease. The controversy stems from the questionable efficacy and potential side effects of the new drug but the debate it has sparked could reshape how we treat Alzheimer’s disease going forward. Here’s what the controversy is about and how it could change standards for treating neurodegenerative disease for the better.

Why Aduhelm’s Approval is so Controversial

The development of Aduhelm was driven by something called the amyloid hypothesis. This hypothesis suggests that plaque buildup in the brain is at least partially responsible for Alzheimer’s disease. Based on this hypothesis, Aduhelm works by targeting beta-amyloid, the tiny protein fragments that accumulate into plaque. 

However, early clinical trials of the drug were so inconclusive that Biogen halted research in March 2019 because it didn’t believe Aduhelm would meet the threshold for clinical effectiveness. In October 2019, it decided to resume clinical trials, citing “better but ultimately mixed results” in some patients.

By November 2020, the FDA’s advisory committee voted unanimously that the data on Aduhelm failed to demonstrate that the drug was effective. This would have been the end of the road for most drug candidates but in a surprise twist this past June, the FDA approved Aduhelm even though its own advisory committee had voted that it was not clinically effective just a few months prior.  The fallout from Aduhelm’s approval created an immediate firestorm - three advisory panel members resigned in protest, and the House of Representative Committee on Oversight and Reform launched an investigation into the drug approval and pricing.

This approval — in spite of the lack of evidence that the treatment works — was made even more controversial by the potential side effects of Aduhelm. The most concerning ones include brain swelling and brain bleeding. 

Moving the Amyloid Hypothesis to the Back Burner

For the past 30 years, this belief that targeting plaque was key to treating Alzheimer’s has informed the bulk of research on the neurodegenerative disease. As much as 90% of funding for Alzheimer’s research goes toward studies and drugs that are premised on this hypothesis. 

While it may well hold the key to treating the root causes of the disease, the recent controversy over Aduhelm suggests that drugs that can successfully treat Alzheimer’s disease by targeting plaque are still a long way off. 

In the meantime, researchers are starting to shift their focus toward developing drugs that can provide more meaningful immediate results and less harmful side effects. While patients wait for a more permanent cure, they urgently need more options for slowing the cognitive decline that comes with this progressively worsening disease.

The Shift Toward Symptomatic Treatments for Alzheimer’s Disease

One of the most promising alternative treatment paths researchers are exploring are symptomatic treatments. These drugs don’t target the root causes of Alzheimer’s disease — which are, so far, still unknown — but instead work to address its most troubling symptoms like memory loss, cognitive decline, and the increasing difficulty of basic self-care tasks.

Alpha Cognition ACOGF, a clinical stage biopharmaceutical company, for example, has seen promising early results in its clinical trials of Alpha-1062, a prodrug of galantamine designed to minimize side effects and maximize long term outcomes by addressing the symptoms of neurodegenerative disease.  ALPHA-1062 appears to work on multiple receptors in the brain, which have been shown to stimulate the cholinergic pathway and reduce inflammation.

Galantamine is a cholinesterase inhibitor that has been demonstrated to significantly reduce cognitive decline in Alzheimer’s and dementia patients as well as decrease the risk of death and the risk of developing severe dementia. While it doesn’t cure the disease, long-term use may prevent the progression of the disease enough to allow patients to enjoy a higher quality of life and potentially avoid the need to go into a full-time care facility. 

Before Alpha-1062, however, galantamine-based drugs have all come with unpleasant gastrointestinal (GI) side effects, including diarrhea and vomiting, which become more severe at the higher doses needed to see the best results. This has made long-term use and effective dosing of galantamine a challenge.

Alpha Cognition’s latest drug candidate, however, solves that problem using a unique formula that essentially allows the absorption of ALPHA-1062 inertly in the small intestine — bypassing active gut absorption to avoid GI distress. 

Alpha-1062 could be the first of these symptomatic treatments with a low side-effect profile that offers the demonstrated efficacy from galantamine.  Alpha-1062 is a leading example of the potential for breaking away from the amyloid hypothesis and shifting focus toward symptomatic treatments that can stop neurodegenerative diseases from becoming debilitating. 

The following post was written and/or published as a collaboration between Benzinga’s in-house sponsored content team and a financial partner of Benzinga.