Washington, United States — Lecanemab (Lequembi®, Eisai), an anti-amyloid beta protofibril antibody, has been approved by the Food and Drug Administration (FDA) in the treatment of Alzheimer’s disease. This is the second antibody targeting amyloid β plaques to receive marketing authorization in this indication.
Like the controversial aducanumab (Aduhelm®, Biogen/Eisai), lecanemab was approved under an FDA Advance Clearance procedure, used to gain faster access to a drug with significant therapeutic benefit compared to others treatments available in the management of a serious or life-threatening illness.
However, unlike aducanumab, lecanemab has not been the subject of a formal meeting of the FDA advisory committee to obtain the opinion of experts before approval.
Indicated in the early stages of the disease
As a reminder, aducanumab received marketing authorization in the United States in 2021, but was refused a refusal for European territory by theEuropean Medicines Agency (EMA), due to results deemed insufficient.
“The big problems associated with these anti-amyloid products are that a statistically significant effect does not always mean a clinically significant effect”, underlined with Medscape French edition the Dr. Michel Dib (Pitié Salpêtrière hospital, AP-HP, Paris), during a previous interview.
“Alzheimer’s disease significantly handicaps the lives of patients who suffer from it and has devastating effects on their loved ones,” said Billy Dunndirector of the FDA Center for Drug Evaluation and Research Office of Neuroscience, in a press release.
“This treatment option is the latest to target and have an effect on the underlying disease process involved in Alzheimer’s disease, instead of just treating the symptoms of the disease,” added the official.
According to the FDA, “the package insert indicates that treatment with Lequembi® should be initiated in patients with mild cognitive impairment or at a mild stage of dementia – the population in which the drug has been evaluated in clinical trials”.
A slight benefit and side effects
The US agency approved the drug based on the results of the CLARITY AD trial, which showed a slight cognitive benefit with treatment in patients with early-onset Alzheimer’s disease, but at the cost increased risk of amyloid-related edema and effusions .
The trial included 1,795 adults with mild cognitive impairment or early-stage Alzheimer’s disease who were confirmed to have amyloid pathology. They were randomized to be treated either with lecanemab (10mg/kg intravenously twice a week) or with a placebo.
After 18 months of treatment, the results show a slowing of cognitive decline – determined by the CDR-SB scale (global cognitive and functional scale) – of 27% with lecanemab, compared to the placebo group, which corresponds to a difference in the change in scores of 0.45 points (progress in the CDR-SB score of 1.21 under lecanemab, versus 1.66 in the placebo group; p<0.001).
Although the results are presented as “good news”, this 0.45 point difference between the CDR-SB scores can be considered not clinically significant, the authors of a recent editorial pointed out. in The Lancet . Lecanemab could therefore be rejected by the EMA for a European MA, as was aducanumab.
The tolerance profile also remains worrying. Imaging abnormalities of amyloid origin with edema or effusions have been observed in one out of five patients treated with lecanemab. In addition, a report linked the drug to the death of an Alzheimer’s patient after multiple intracerebral hemorrhages. . He was also treated with tissue plasminogen activator (tPA) after an acute ischemic stroke.
This clinical case “suggests a risk of cerebral hemorrhage and necrotizing vasculopathy associated with tPA infusion in a patient with cerebrovascular amyloid disease treated with lecanemab”.
“An important step”
Nevertheless, anticipating an accelerated procedure to validate lecanemab, the American patient association Alzheimer’s Association filed a claim with the public insurance services Centers for Medicare and Medicaid Services (CMS) to ensure full, unrestricted coverage of FDA-approved Alzheimer’s disease treatments.
As reported by Medscape International Edition, the association asked, in a letter addressed to Chiquita Brooks-LaSurethe administrator of the CMS, to remove the criteria for “reimbursement according to the level of evidence” in its national reimbursement conditions for FDA-approved anti-amyloid monoclonal antibodies.
“Every day counts when it comes to slowing the progression of this disease,” said the Dr. Joanne Pikepresident of the Alzheimer’s Association, in a press release published last December.
“CMS’s current policy of severely limiting access to these treatments removes options for patients, promotes continued and irreversible disease progression and contributes to increasing health inequities. This is not acceptable,” said Dr. Pike.
In a new press release, the president welcomed the authorization of lecanemab by the FDA. “The Alzheimer’s Association welcomes the FDA’s decision. We now have a second approved treatment that significantly alters the course of Azheimer’s disease in the early stages of the disease.”
The scientific director of the Alzheimer’s Association, the Professor Maria Carrillo, for his part evoked the “crossing of an important stage”. According to her, “the progress observed in recent years, not only with this therapeutic class, but also in the diversification of treatments and therapeutic targets, is encouraging and gives real hope for those affected by this devastating disease”.
Support to adapt
Asked by Medscape International Editionthe Professor Alvar Pascual-Leone (Harvard Medical School, Boston, USA) was more reserved. The authorization of lecanemab by the FDA represents “an evolution and encouraging prospects, but certain criticisms are to be taken into consideration”, estimates the neurologist, also director of Linus Health, a company dedicated to mental health.
According to him, the health system is not currently ready to face the challenge and the demands inherent in treatment with lecanemab” and other therapeutic specialties to come. “First, we need a work plan to identify the patients who can benefit the most from the treatment,” says the Professor Pascual-Leone. Beyond the characterization of cognitive difficulties, it is necessary to determine the amyloid status.
“Currently, this requires expensive and invasive examinations”, for example using position emission tomography (PET) or lumbar punctures to analyze the cerebrospinal fluid (CSF). However, these examinations are not fully covered by insurance companies and it would be difficult to implement them on a large scale, he notes.
“In addition to the challenge of screening, health systems will have to address the challenge of administering lecanemab twice a month and the need to carefully assess potential side effects,” added Prof. Pascual-Leone. .
“Although lecanemab may represent the first widely available therapy with the ability to modify the course of Alzheimer’s disease at an early stage, the addition of other therapies in an approach combining pharmaceutical and non-pharmaceutical treatments seems more promising.
Pr Pascual-Leone has declared links of interest with Neuroelectrics, Magstim Inc, TetraNeuron, Skin2Neuron, MedRhythms and Hearts Radiant. He is also co-founder of TI Solutions and Linus Health.
This article originally appeared in the English edition of Medscape.com as FDA Approves Second Anti-Amyloid for Alzheimer’s Disease. Translated and adapted by Vincent Richeux.
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