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Amyloid Hypothesis in the Hot Seat After Aduhelm Approved for Alzheimer’s

The FDA’s approval of Biogen’s new anti-amyloid drug Aduhelm was a landmark moment for Alzheimer’s — and it comes with no small amount of controversy. Some critics of the agency’s decision say Aduhelm’s approval, despite questions around the drugs effectiveness, gives undue credibility to an unfounded treatment approach.

June 7 was a momentous day for the Alzheimer’s community as the FDA approved the drug Aduhelm (generic name aducanumab), a treatment designed to target beta-amyloid plaques, hallmark proteins of Alzheimer’s. Biogen’s Aduhelm is now the first drug to be approved that targets Alzheimer’s pathology, and some believe it’ll be a boon for research and drug development.

But others have raised concerns about the accelerated approval. Among those concerns is that the FDA’s approval appears to be a default endorsement of the theory that reducing beta-amyloid plaques can ultimately improve cognitive function. Experts say there is currently not enough data to prove or disprove this idea, even though the amyloid hypothesis — the theory that Alzheimer’s is largely caused by these plaques — has dominated research for decades. Despite its longevity, the anti-amyloid approach has had a poor track record in clinical trials.

Dr. Jason Karlawish, co-director of the Penn Memory Center and previously an Aduhelm clinical trial site investigator, is among the scientists who say the agency has set a troubling precedent for research in the United States, writing on Twitter that the FDA’s approval is “vastly disturbing and disruptive [—] not simply to the [Alzheimer’s] field but to biomedical research in the U.S.”

By skirting the scientific process of “vigorous debate and progressive consensus to arrive at a truth,” he said the agency has effectively approved the drug by “decree,” failing to ask its advisers to consider whether the removal of amyloid plaques actually helps patients.

Dr. Halima Amjad, assistant professor of medicine at the Johns Hopkins University, wrote in the Twitter thread that the FDA has single-handedly “moved the field from debate over the amyloid hypothesis (appropriate debate given all prior studies) to accepting it as fact. Shameful.”

According to Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at USC and previously an Aduhelm clinical trial site investigator, there’s no doubt that the drug is effective at clearing amyloid plaques. Whether patients’ cognitive impairment will eventually improve as a result remains an open question, he explained, though the FDA believes it is “reasonably likely” to benefit patients.

“The FDA has essentially elevated that biomarker — the amyloid in general — to a premier place,” Schneider told Being Patient.

“We have a drug that’s approved to decrease that biomarker — those plaques — and we have a good amount of uncertainty about ultimate benefits,” he continued. “That comes back to the uncertainty of the approval indication.”

A new era for Alzheimer’s treatment

Proponents view Aduhelm’s approval as a first step toward managing a disease that was previously untreatable.

Some clinical trial participants told Being Patient they declined more slowly during the early stages of Alzheimer’s. One participant, Being Patient reporter Phil Gutis, said his PET scan revealed no more presence of amyloid in his brain. “The scan, taken about two years ago as part of the Aging Brain Cohort study at the Penn Memory Center, confirmed my growing inklings that aducanumab was indeed helping me,” Gutis, who was diagnosed with early-onset Alzheimer’s, wrote for Being Patient. “I began to feel like I was emerging from a constant mental fog … On the negative side, the memories that I’ve lost have not returned.”

Meanwhile, advocates believe the FDA’s move spells good news not only for promising anti-amyloid drugs in the pipeline, but also therapies with other targets such as tau tangles, another Alzheimer’s biomarker.

Alfred Sandrock, Biogen’s executive vice president for research and development, told the Wall Street Journal that the approval could catalyze innovation in Alzheimer’s research and attract investments into drug development. Researchers say further funding would enable more drugs to be tested, and in turn, additional Alzheimer’s treatments would ultimately be greenlit.

Dr. Stephen Salloway, a principal investigator of the Aduhelm clinical trial and the director of Butler Hospital’s Memory and Aging Program, told Being Patient he hopes the FDA approval “will open the door to a new treatment era for Alzheimer’s, where we have to do biomarker testing to confirm Alzheimer’s disease, and hopefully we have this treatment and others that will follow … that modify the underlying pathology and slow the course of the disease.”

The future of anti-amyloids

This hope has not been enough to quell distaste for the approval. Salloway, who has consulted for Biogen and other pharmaceutical companies, acknowledged that data from Aduhelm’s clinical trials is controversial and problematic. Skeptics say the benefits of Aduhelm are marginal at best. The drug also comes with a high price tag and the risk of side effects. In protest against the FDA’s move, three members of an independent advisory committee that advised the agency on the drug resigned.

Ronny Gal, a Bernstein pharmaceuticals analyst, worries the FDA’s decision will open the floodgates for anti-amyloid treatments in the pipeline. The FDA “made the unproven assertion that removing amyloid from the brain is enough to benefit Alzheimer’s patients, and with that understanding, other drugs that remove the plaque should be able to get approved,” Gal told the Wall Street Journal.

Others, like Jefferies biotech analyst Michael Yee, are more conservative: “Wall Street is very surprised and, I think, shocked by the approval, but they are not fully convinced just yet that the FDA is open to widely approving lots of Alzheimer’s drugs,” Yee told the Wall Street Journal. “This is the first step to moving the bar, but every company needs to have a large set of data to convince the FDA of clinical efficacy.”

In Biogen’s case, the FDA conditioned Aduhelm’s approval on a new clinical trial of the drug, and the company has until 2029 to finish the study. If the trail fails to verify the drug’s efficacy, the FDA could pull it from the market.

No magic bullet for Alzheimer’s

While it’s clear that amyloid plaques are a key element of the disease, a host of different factors are at play as well.

Before Aduhelm, many other drugs in the Alzheimer’s pipeline attempted the anti-amyloid approach and failed, costing researchers and drug developers billions of dollars and decades of precious time. Scientists were already starting to expand their horizons, looking toward a broader array of drug targets, like viruses, tau tangles and inflammation. Instead of a “magic bullet” drug, experts agree that a cocktail of drugs will likely be necessary to effectively treat Alzheimer’s.

“Amyloid plaques are a core component of Alzheimer’s disease — I don’t think there’s any debate about that — but Alzheimer’s is a complex disease,” Salloway said. “There are other proteins that build up … Connections between nerve cells break down … I think amyloid is definitely a good target, but it’s certainly not an isolated target. Alzheimer’s is going to require a combination treatment.”