Even as Biogen and Eisai’s Leqembi and Eli Lilly’s Kisunla slowly roll out onto the market, experts question the efficacy of these anti-amyloid antibodies and the amyloid hypothesis overall.
Despite the recent FDA approval of anti-amyloid antibodies for Alzheimer’s disease and new investment in the space, skepticism remains about the value of these first disease-modifying drugs and the validity of the amyloid hypothesis.
“These approaches have not worked,” George Perry, a neuroscientist at the University of Texas at San Antonio, told BioSpace, referring to Biogen and Eisai’s Aduhelm and Leqembi and Eli Lilly’s Kisunla. “The patients are not getting better.”
Christian Hölscher, co-founder and chief scientific officer at neuroscience-focused Kariya Pharmaceuticals, agreed, raising concerns in a November interview about the drugs’ safety and efficacy profiles. “The antibodies are too toxic, and the effect in patients is so small that it is unlikely that patients even notice a difference,” he told BioSpace.
Hölscher is not alone. In a recent Reuters survey, interviews with 20 neurologists and geriatricians revealed that many doctors still doubted the drug’s efficacy and safety, while others had “therapeutic nihilism,” or a belief that it is futile to treat Alzheimer’s disease.
One source of skepticism surrounding anti-amyloid antibodies is their scientific foundation. The amyloid hypothesis holds that the accumulation of amyloid-beta (Aβ) is responsible for Alzheimer’s disease. Proponents of this theory believe that when amyloid beta clumps together to form deposits in the brain, it triggers neurodegenerative processes that lead to the loss of memory and cognitive abilities that characterize the disorder.
Aβ was discovered to be a major component of senile plaques in 1984, Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, told BioSpace. “That was really what started the drug discovery and development process for trying to get rid of the plaques by removing the beta-amyloid from the plaques or by preventing the beta-amyloid accumulating in the plaques.” The FDA approved the first anti-amyloid antibody for Alzheimer’s, Aduhelm, in June 2021.
The following summer, allegations broke calling into question seminal research behind the amyloid hypothesis. While looking into claims of misconduct by Alzheimer’s drug developer Cassava Sciences, Vanderbilt neuroscientist and physician Matthew Schrag discovered that the pioneering research possibly contained tampered images of Western blots, a laboratory technique used to visualize proteins. These data, published in a 2006 paper, formed the backbone of the argument that Aβ*56—an oligomer of Aβ proteins—is responsible for the memory loss seen in Alzheimer’s.
But the hypothesis gained new life over the next two years, as the FDA approved two more anti-amyloid antibodies—Leqembi in January 2023 and Kisunla in July 2024. While Aduhelm was withdrawn from the market in January after it failed to gain traction, Leqembi and Kisunla are now slowly rolling out, with sales of Leqembi lower than expected but steadily climbing throughout 2024.
Companies are also continuing to invest in this approach. In October, AbbVie paid $1.4 billion in cash to acquire Aliada Therapeutics and its anti-amyloid antibody ALIA-1758. In an investor note at the time, Stifel analysts said the deal “seemingly offers a vote of confidence in amyloid, just as sentiment in the space is reaching an all-time low.”
The Role of Amyloid Beta in Alzheimer’s
While the exact role of Aβ in Alzheimer’s is up for debate, anti-amyloid antibodies without a doubt have some effect on the disease process. In the Phase III Clarity-AD study, Leqembi reduced clinical decline by 27% compared to placebo based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessment in patients with mild-to-moderate Alzheimer’s, while Kisunla reduced decline by 29% on the CDR-SB.
“Clearly, it is a validated mechanism of action,” Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace. “We have three approved anti-beta amyloid drugs. We have data that supports a view that if you’re able to lower beta-amyloid, that can lead to measurable improvement in patients.”
Fillit concurred, saying, “We have proof of concept that getting rid of the plaques is actually efficacious and has a reasonable benefit-to-risk ratio.”
But Perry contends that this efficacy is limited. “The effect is less than Aricept [an earlier Alzheimer’s drug], and yet they’re moving forward. If the theory was correct, if you remove the amyloid, some patients should get better.”
Perry argued that while amyloid is “important” to the Alzheimer’s disease process, it is not the driver. Rather, he said, amyloid accumulation is a response to neural damage, adding that antioxidant qualities found in amyloid-beta support this conclusion.
Suvannevejh agreed that amyloid-beta’s role in Alzheimer’s is “an outstanding question.”
“We don’t know what the trigger is for Alzheimer’s disease. We just know that a hallmark of Alzheimer’s disease is presence of beta-amyloid plaques in your brain.”
Improving on Leqembi and Kisunla
Ultimately, Suvannevejh said anti-amyloid antibodies are a “viable approach” to Alzheimer’s, but that Leqembi, Kisunla and Aduhelm are “probably not” the most optimal treatments. The challenge, he said, is getting them past the blood-brain barrier (BBB). “The body has been built wonderfully to protect the brain from outside insult, and a beta amyloid-directed antibody is viewed as that insult.”
With the currently approved anti-amyloid antibodies, “the amount of drug that gets into your brain is about 1%,” Suvannevejh said. “[That’s] not a very efficient way of treating Alzheimer’s disease.” Several companies—including Denali Therapeutics, Voyager Therapeutics and Aliada—are developing technologies to improve on that number.
Aliada’s Modular Delivery (MODEL) platform is “engineered for both efficient BBB (blood-brain barrier) transport and downstream therapeutic functionality,” according to the company’s website. Speculating on AbbVie’s interest in the company, Suvannevejh said, “It could easily be that Aliada has got the secret sauce” to solve the BBB challenge in Alzheimer’s.
Fillit agreed that efficiently crossing the BBB is key to treating Alzheimer’s and pointed to Roche’s anti-amyloid antibody trontinemab as an example of a therapy attempting to do that. Developed using the company’s proprietary Brainshuttle platform, trontinemab can cross the BBB and achieve higher levels of brain exposure and broader distribution across the central nervous system, according to Roche.
Safety is another challenge for antibodies targeting Aβ, in particular, amyloid-related imaging abnormalities (ARIA), which are characterized by brain swelling and can lead to death. Anti-amyloid antibodies are “putting patients at risk of death, or serious side effects,” Perry said.
However, Fillit pointed to the FDA advisory committee for Kisunla, which in June “voted 11-0 that the monoclonal antibody had a favorable benefit to risk ratio.”
‘Stuck in the Amyloid Trap’
Experts largely agree that anti-amyloid antibodies will be a part of the treatment landscape emerging for Alzheimer’s disease, but that they will only be a part of the arsenal.
“It’s pretty clear, I think, at this point, that Alzheimer’s will have to be treated with multiple drugs attacking multiple mechanisms that are related to the biology of aging,” Fillit said.
Some companies are exploring the potential of GLP-1s to treat Alzheimer’s disease. Kariya is developing KP405, a first-in-class, dual GLP-1/GIP receptor agonist, initially for Parkinson’s disease with plans for a study in Alzheimer’s, and several others are targeting tau and neuroinflammation.
Still, anti-amyloid remains the main focus, according to Hölscher. “The pharmaceutical industry is still stuck in the amyloid trap,” he said. Hölscher revealed that Kariya had spoken with AbbVie “and they were interested in what we’re doing.” Then AbbVie bought Aliada Therapeutics.
After 40 years, it would be difficult to give up on a theory that has produced the first three disease-modifying drugs for Alzheimer’s. But Hölscher argued it’s time for a new approach. “What is wrong with these people? Don’t they understand what failure is? [Don’t they] know when to stop?”
