The full potential for anti-amyloid therapies may still to be realized

medwireNews: Anti-amyloid treatments have transformed Alzheimer’s disease (AD) therapeutics, but perhaps more needs to be done before they are clinically useful for most patients with the disease, suggests a debate held at the 18th World Congress on Controversies in Neurology in London, UK. Many patients in the clinic are not eligible for anti-amyloid treatments Arguing that anti-amyloid drugs have only a limited effect and will not be clinically useful for most patients, Dorota Religa (Karolinska Institutet, Stockholm, Sweden) pointed out that patients expect a drug to stabilize or improve memory and functional ability, result in fewer behavioral problems, and enable them to remain living at home for longer. However, she highlighted that with all the anti-amyloid drugs – aducanumab, lecanemab, donanemab – most patients still experience deterioration just to a lesser degree than with placebo (0.45-point difference on the Clinical Dementia Rating–Sum of Boxes in the case of lecanemab in the CLARITY AD trial). “Even if we take away amyloid, the deterioration still progresses,” Religa said. She also touched on the lack of improvement in secondary outcomes such as functional and behavioral aspects and cognitive effects. Therefore “we are not sure how to judge in […] real life the benefit and risk for our patients,” she remarked. In terms of whether anti-amyloid medications will therefore be useful for the “majority” of patients, she made the argument that many of the patients included in the trials of anti-amyloids do not reflect those she sees in the clinic. She referred to a 2022 study in Sweden by Anna Rosenberg et al that came to the same conclusion, showing that in a typical memory clinic population most patients would not meet the recommended criteria for anti-amyloid treatments. For instance, the median age of participants in the CLARITY AD trial was 72 years, ranging from 50–89 years, but Religa said that she treats a lot of patients over 90 years old. Also, the study “did not include patients with moderate-to-severe AD or those who were cognitively normal with positive amyloid biomarkers,” she added. And patients whose body mass index was below 17 kg/m2 or over 35 kg/m2 were excluded, despite lecanemab being dosed by weight. Religa also referenced a large dementia registry in Sweden in which she is involved that includes more than 125,000 individuals. Most of the patients have mixed dementia – AD, vascular AD, Lewy body dementia, frontotemporal dementia – and comorbidities, including vascular and inflammatory changes, all of which would preclude them from anti-amyloid treatment, she explained. Also, as “around 50% live alone,” attending regular infusion sessions is difficult. Other issues she commented on were the known side effect of amyloid-related imaging abnormalities, the risk factors for which –anticoagulation therapy, cerebral amyloid angiopathy, and apolipoprotein EƐ4 homozygosity – also rule out patients, and the fact that the measurement scales used in CLARITY AD, for example, are not commonly used in the clinic. Religa concluded by recommending that other treatment strategies be considered, “some of which are in development,” adding that “Alzheimer’s is so complex a disorder, so it is not possible to be treated with one drug. It is too simple for a complex disorder.” Anti-amyloid treatments have paved the way Paul Edison (Imperial College, London), who presented the argument that anti-amyloids “will” be clinically useful for most patients, agreed that combination therapies based on anti-amyloid agents are likely to be the next step. He believes that “anti-amyloid treatments are transformative; they redefine the therapeutics of Alzheimer’s disease,” and by recognizing that these drugs work, we can “move the field forward.” High amyloid load is the earliest detectable change in the progression of AD, occurring decades before symptoms appear, and “more than 90% of AD patients have high amyloid,” Edison noted. By clearing amyloid from the brain, anti-amyloid therapies have shown that it is possible to modify Alzheimer’s disease, he pointed out. However, amyloid clearance alone is not enough, “it is the mechanism of how you clear the amyloid that is going to be the key,” he proposed. “By focusing on how amyloid is created and going after the drugs which can make a significant difference to the amyloid, we can understand how to make a better drug so that this can be used in a much wider population.” Earlier treatment in people with mild cognitive impairment (MCI), which was not the typical trial population, will also be essential, he highlighted. “We need to make sure that we treat the patients very early.” This is supported by a US Food and Drug Administration draft guidance for AD published this month that outlines to pharmaceutical companies “how they can make a drug and get fast-track approval,” said the presenter. This classifies AD into six stages, with stages 3 to 6 including patients with some functional and cognitive impairment. “But the reality is, they want us to actually treat patients who are in stage 1 and stage 2. That is well before people develop the symptoms and that is the key. You need to start the treatment when the pathological process happens,” Edison commented. He acknowledged that amyloid aggregation is not the only neurodegenerative process; there is tau deposition and neuroinflammation, for instance. He said there is reason to think that simultaneously targeting other processes in addition to amyloid to “produce a drug that has multiple effects,” may be the future. The benefits and risks of anti-amyloid treatment need to be weighed up by patients given the possible side effect of ARIA, but by better understanding why and how people are getting ARIA it might be possible to prevent it, perhaps by “changing the formulation of the drug” or the mechanism, Edison suggested. He concluded that “there is no doubt that [anti-amyloid therapies] will be a significant challenge to the healthcare systems,” but he believes that “one day we will be handed a [combination] treatment that will be based on anti-amyloid agents.” medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group This article was originally published on Journey to a New Era for Alzheimer’s Disease, an independent education program developed by Springer Healthcare IME. This program is supported by an educational grant from Lilly. This content is intended for healthcare professionals outside of the UK. CONy 2024; London, UK: March 21–23

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The full potential for anti-amyloid therapies may still to be realized

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