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Scientists have made significant advances in treating Alzheimer’s, with monoclonal antibodies emerging as a major stride to stop progression and address symptoms.
Alzheimer’s disease is caused by the buildup of abnormally high levels of proteins called amyloid and tau that form plaques. These tangled structures damage the nerve cells over time, particularly the cells in the brain that control memory.
Nearly 7 million people in the U.S. have Alzheimer’s disease, according to the Alzheimer’s Association. While 73% of people with Alzheimer’s disease are aged 75 and older, there is a growing younger population of adults who are at a high risk of developing the disease. This is due to rare genetic mutations – sometimes passed down through generations. A new trial led by Washington University School of Medicine (WashU Medicine) in the U.S. is investigating a monoclonal antibody that could potentially halt Alzheimer’s decades before it begins to progress.
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Can monoclonal antibody remternetug prevent Alzheimer’s disease?
A monoclonal antibody is a protein that binds to specific targets in the body. In the case of Alzheimer’s disease, these would be amyloid-beta protein aggregates in the brain. Typically, when they bind to these aggregates, it triggers the immune cells in the brain called microglia to get rid of these harmful proteins and slow cognitive decline.
The monoclonal antibody, remternetug, is being evaluated by WashU Medicine in close partnership with pharma giant Lilly to prevent Alzheimer’s disease. It is designed to eliminate amyloid-beta from the brain and even block them from accumulating in the first place. By clearing out low levels of amyloid-beta plaques or preventing them from accumulating during the early phase of the disease when people don’t experience the symptoms yet, the researchers hope to interrupt the development of the disease at the earliest stage and spare people from ever developing symptoms.
“We have seen tremendous progress in the treatment of Alzheimer’s disease in the past few years,” said Eric McDade, a professor of neurology and the trial’s principal investigator, in a press release last week. “Two amyloid-targeting drugs were shown to slow symptoms of the disease and have now been approved by the Food and Drug Administration (FDA) as treatments for people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. This provides strong support for our hypothesis that intervening when amyloid-beta plaques are at the very earliest stage, long before symptoms arise, could prevent symptoms from emerging in the first place.”
The study is enrolling people aged between 18 and 25, who have little to no Alzheimer’s-related changes in protein levels in the brain – before the expected onset of dementia symptoms. Currently, the trial is limited to people with genetic mutations, putting them at risk of developing Alzheimer’s, but the researchers expect the outcome of the study to help plan future therapeutic efforts for all forms of Alzheimer’s disease.
More than $130 million has been devoted to the trial, including grants from the National Institutes of Health’s (NIH’s) National Institute on Aging (NIA), the Alzheimer’s Association, and the GHR Foundation.
“This a groundbreaking approach,” said GHR Foundation’s Chief Operating Officer Fred Miller. “For the first time, we’re working to prevent the buildup of Alzheimer’s pathology before it starts. The research will provide insight on how we prevent Alzheimer’s disease for these families, as well as the nearly 13 million Americans projected to have Alzheimer’s disease by 2050 and countless others around the world.”
Monoclonal antibodies: approved for Alzheimer’s disease but not without concerns
While remternetug’s progress is a major breakthrough, monoclonal antibodies have come a long way in addressing Alzheimer’s disease. The first monoclonal antibody that was tested in humans for treating Alzheimer’s disease was bapineuzumab, a humanized variant of anti-amyloid-beta antibodies found in a mouse. High doses of the drug were delivered intravenously to combat the issue of not being able to pass the blood-brain barrier (BBB), but this led to the breakdown of the BBB instead and the buildup of fluid – called vasogenic edema – resulting in the drug’s failure in 2012.
This didn’t stop other monoclonal antibodies from being pursued in the clinic. Still, setbacks continued as these drugs did not succeed in slowing cognitive decline in patients even if they were effective in reducing amyloid plaques.
Even the approval of the first monoclonal antibody for Alzheimer’s disease was mired in controversy. The FDA cleared aducanumab, known by its brand name Aduhelm, in 2021, only for the Biogen-owned drug to be discontinued last year. This was following reports stating that the drug’s approval was “rife with irregularities,” especially since it was greenlit based on a single study. Moreover, safety risks, such as brain swelling and bleeding, were of grave concern, and its initial price tag of $56,000 wasn’t justified by insurers and patients alike.
So, Biogen and its collaborator, Japanese pharmaceutical Eisai, decided to refocus its resources on Leqembi, another monoclonal antibody, which snagged the FDA stamp of approval in 2023. LEQEMBI is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody that targets amyloid-beta to clear them out of the brain.
Its approval was based on phase 3 data where Leqembi met its primary endpoint and all key secondary endpoints. Treatment with the drug reduced cognitive decline by 27% at 18 months compared to placebo. Plus, the secondary endpoint of Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL) – a tool used to measure the ability of patients to function independently – as measured by people caring for patients with Alzheimer’s disease, was a statistically significant benefit of 37%.
Besides Biogen’s drugs, pharma giant Lilly’s Kisunla (donanemab) received the FDA nod in July last year. This was after it slowed cognitive decline by up to 35% compared to placebo at 18 months – slightly higher than Leqembi – and reduced the risk of patients’ disease progressing by up to 39%. Like Leqembi, it is an IgG1 monoclonal antibody and works by eradicating amyloid-beta plaques in the brain.
Monoclonal antibodies in the clinic to address Alzheimer’s disease
Biotechs think that they can beat these results. Roche’s clinical candidate trontinemab, although it is a monoclonal antibody, works a bit differently from Leqembi and Kinsunla. It has a slight edge over approved Alzheimer’s monoclonal antibodies, as it is engineered to move past the BBB more easily, meaning that a lower dosage would suffice. It has been developed with the help of the Swiss pharma’s Brain Shuttle technology. The technology involves attaching a Fab fragment – a part of an antibody that contains an antigen-binding site – that binds the human transferrin receptor that is attached to the effector domain of the IgG1 antibody.
Fewer cases of brain swelling and bleeding have been detected in patients, making it potentially more equipped to mitigate side effects and treat Alzheimer’s. The latest trial showed that treatment with the candidate led to rapid and robust amyloid plaque clearances in the two higher dose groups – 1.8 mg/kg and 3.6 mg/kg – after 12 to 28 weeks. However, a patient death triggered a protocol change. The 78-year-old patient died after experiencing a brain bleed. Now, participants with superficial siderosis, a rare condition that results in brain bleeding, have been excluded from the trial.
“Using active transport mechanisms to get these drugs across the blood-brain barrier will dramatically accelerate the levels of amyloid removal, and equally importantly, really reduce those rates of amyloid-related imaging abnormalities (ARIA),” said Catherine Mummery, a consultant neurologist, at the Clinical Trial on Alzheimer’s Disease conference held in Spain in November. Mummery added that trontinemab’s progress was “fantastically exciting.”
Meanwhile, U.S.-based Acumen Pharmaceuticals’ sabirnetug is in a phase 2 trial, which is enrolling patients at present. It is the first humanized monoclonal antibody to clinically demonstrate targeting amyloid-beta oligomers, which are toxic clusters of amyloid-beta.
The drug candidate managed to lower levels of cerebrospinal fluid (CSF) biomarkers in the brain. CSF biomarkers help diagnose Alzheimer’s disease by detecting changes in levels of proteins present in the fluid.
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Overcoming safety issues
While the ongoing trial aims to build on the monoclonal antibody’s efficacy, it will also be crucial to improve the drug’s safety profile. As mentioned previously, this class of drugs has come under fire for the health hazards they pose. An analysis by the American Academy of Family Physicians suggested that the risks of monoclonal antibody treatments for people with Alzheimer’s disease might outweigh the benefits, the most serious risk being ARIA. A number of bleeding conditions, such as cerebral microhemorrhages and hemosiderosis, have been observed in trials, and one way to improve the safety of these drugs is to optimize the dosage.
Currently, the recommended dosage for Leqembi is 10 mg/kg, but maybe newer monoclonal antibodies like trontinemab that have an easier time passing through the BBB could bring about a change in dosing patients to minimize side effects.
Another factor to be wary of is other existing conditions that patients have. So, carefully selecting patients based on risk factors is important. For instance, the exclusion of participants with superficial siderosis in the trontinemab trial can help avoid complications for patients who are more prone to bleeding.
But this has left only a small percentage of people with early-stage disease eligible to be treated with monoclonal antibody drugs, according to a study published in Neurology.
“There is hope that these new therapies for Alzheimer’s may slow progression of the disease for many people, although the fact remains that the drugs have only been studied in people with the earliest forms of the disease,” said study author Maria Vassilaki, a member of the American Academy of Neurology, in a press release in 2023. “The inclusion and exclusion criteria of the clinical trials that led to FDA accelerated approval of these therapies form the basis of how people should be invited or discouraged from receiving one of these drugs. Our study estimates that only a small percentage of older people with early cognitive impairment due to Alzheimer’s may be eligible to be treated with monoclonal antibodies for amyloid-beta in the brain.”
Perhaps that’s where a drug candidate like trontinemab could possibly shift things, as it has proven to pass through the BBB fairly easier, and so, the lower dosages could allow more patient cohorts to be involved in drug trials. Moreover, if it is possible to nip the disease in the bud, with the help of a drug like remternetug, there could be a decline in the number of people affected by Alzheimer’s disease in the future, and treatments could be developed to focus more on treating late-stage Alzheimer’s – which remains an area devoid of much therapeutic progress.
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