lecanemab

Proportion of Community-Dwelling Individuals Older Than 70 Years Eligible for Lecanemab Initiation

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Abstract

Objectives

To determine the prevalence of individuals with Alzheimer disease (AD) eligible for treatment with the recently FDA-approved lecanemab based on data from a population-based sample of 70-year-olds and extrapolate an estimation of individuals eligible in Europe and the United States.

Methods

Participants from the Gothenburg H70 Birth Cohort Study with clinical data, CSF-amyloid beta 42, and brain MRI analysis were evaluated for eligibility to receive lecanemab treatment according to FDA-approved recommendations, noting factors requiring special consideration. Results were used to extrapolate the number of eligible individuals in Europe and the United States using public demographic data.

Results

Thirty (10.3%) of 290 participants met the indication for treatment of whom 18 (6.2%) were eligible and did not present factors requiring special consideration. Our estimate that 6.2% of all 70-year-olds in the full cohort are eligible for treatment extrapolates to an approximation that around 5.9 million Europeans and 2.2 million US residents could be eligible.

Discussion

Information on proportion of individuals eligible for AD treatment with lecanemab in the general public is limited. We provide information on 70-year-olds in Sweden and extrapolate these data to Europe and the United States. This study opens for larger studies on this proportion and implementation of lecanemab treatment.

Introduction

Alzheimer dementia (AD) is the leading cause of dementia, proposedly caused by the cerebral deposition of amyloid beta (Aβ)-plaques leading to neurodegeneration.1 Lecanemab is an antibody directed against aggregated forms of Aβ, approved by The Food and Drug Administration (FDA) for the treatment of AD.2

The treatment has been associated with increased risk of amyloid-related imaging abnormalities (ARIA) on MRI and serious intracerebral hemorrhage.3 Therefore, factors associated with increased risk should be considered when using lecanemab.2 These factors are detailed as findings on brain MRI indicating an increased risk of intracerebral hemorrhage, concurrent antithrombotic medication, and APOE ε4 homozygosity. In addition, in the clinical trials leading to approval, patients with more severe vascular lesions on MRI were excluded. Information on the proportion of individuals who are eligible for treatment with lecanemab, according to FDAs criteria in the general public is limited. The objective of this study was to examine eligibility in a population-based sample of 70-year-olds and extrapolate our results to estimate the magnitude of individuals eligible in the United States and EU, based on public data and the FDA-approved prescribing information for lecanemab (LEQEMBI).2

Methods

We determined the proportion of individuals meeting indication for lecanemab in a population-based cohort of the Gothenburg H70 Birth Cohort Study (H70-BCS), born 1944. First, identifying individuals meeting indication, and second identifying individuals presenting factors requiring special consideration, which may exclude them from treatment (factors presented in Table 1).Table 1 Prevalence of Factors Which May Require Consideration in Lecanemab Treatment Among the 30 Eligible Participants From the Population-Based Gothenburg H70 Birth Cohort Study of 1944

 n (%)
Stroke in medical history2 (7)
Any anticoagulant medication2 (7)
Homozygote for APOEε44 (13)
Superficial siderosis0 (0)
Microbleeds >41 (3)
Lacunes5 (17)
Fazekas score = 34 (13)
Signs of intracerebral hemorrhage1 (3)

EXPAND TABLE

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LEQEMBI is indicated for treatment of AD with mild cognitive impairment (MCI) or mild dementia, without any further definition. Here, we define MCI and mild dementia as a clinical dementia rating (CDR) of 0.5–1. AD was defined as amyloid positivity, through CSF-Aβ42 < 530 pg/mL, based on a previous study.4

All citizens of Gothenburg born on specific birth dates in 1944 were invited, with no exclusion criteria.5 Nurses with psychiatric training examined participants, including medical background, blood sampling, and cognitive testing. All participants without contraindications were invited to undergo a brain MRI and lumbar puncture (LP).5,6 Anticoagulants were defined as any medication with an ATC code under B01. Participants were genotyped for APOE ε4, and Aβ42 concentration in CSF was measured using INNOTEST Aβ1-42.7,8

Standard Protocol Approvals, Registrations, and Patient Consents

This study was conducted according to the Helsinki Declaration approved by the Regional Ethical Review Board in Gothenburg. All the participants and/or their close relatives gave written consent before any study-related procedures were performed.

Data Availability

Anonymized data can be obtained by reasonable request from any qualified investigator.

Results

H70 Birth Cohort Proportion on Individuals Who Are Eligible for Lecanemab Treatment

Twelve-hundred three (response rate 72.2%) accepted participation of whom 290 had complete data on relevant variables (Figure).5 Thirty of the 290 were amyloid-positive and had MCI or mild dementia. Twelve of the 30 eligible participants presented 1 or several items requiring special consideration before treatment (Table 1). Taken together, in the H70-BCS, 18 of the 290 study participants (6.2%) were eligible for lecanemab treatment without any factor indicating risk of adverse events (Figure).

Figure Study Flowchart Detailing How Many Participants of the Gothenburg H70 Birth Cohort Study of 1944 Who Had Complete Data Sets on Clinical, MRI, and CSF Variables; How Many Who Met the Indication for Lecanemab Treatment; and How Many Who Did Not Present Any Factor Which Required Special Consideration for the Treatment

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Clinical characteristics of the sample (n = 290) were compared with the 913 individuals from the full birth cohort to assess representativity of the sample (Table 2). The sample had a small overrepresentation of men (52% vs 45%). Owing to a contraindication of some anticoagulant medications to perform LP, individuals with anticoagulant treatment or a medical history of cerebral stroke were overrepresented among those with missing data. No difference was seen on other characteristics, including CDR or APOE ε4 homozygosity.Table 2 Clinical Characteristics of Individuals in the Gothenburg H70 Birth Cohort Study of 1944 (n = 1203) With Complete Data Sets or Missing Data on Any Variable

 Missing data on any variable (n = 913)No missing data on any variable (n = 290)
Male sex, n (%)409 (45)150 (52)a
Education, years in school13 (10–16)12 (10–15)
Household monthly income, SEK34000 (24000–50000)33200 (22000–50000)
CDR 0.5–1, n (%)176 (20)60 (21)
MMSE score29 (29–30)29 (28–30)
10-word immediate recall test5 (4–7)5 (4–7)
Body mass index, kg/m225.5 (23.1–28.8)24.9 (22.9–27.9)
Systolic blood pressure, mm Hg140 (126–150)140 (125–150)
Diastolic blood pressure, mm Hg80 (70–85)80 (70–85)
Dementia diagnose, n (%)26 (3)4 (1)
Previous cerebral stroke, n (%)69 (8)8 (3)a
Hypertension, n (%)633 (70)210 (72)
Diabetes, n (%)152 (17)35 (12)
Any anticoagulant medication, n (%)229 (25)46 (16)a
APOEε4 heterozygosity, n (%)240 (27)97 (33)
APOEε4 homozygosity, n (%)30 (3)11 (4)

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Categorical variables presented as n (%) and continuous variables as median (IQR).

Statistical tests used were χ2, Fisher exact test, and Mann-Whitney U test.

Missing data on Household monthly income (n = 296), CDR (n = 11), MMSE (n = 25), 10-word immediate recall test (n = 37), body mass index (n = 36), blood pressure (n = 7), any anticoagulant medication (n = 3), and APOEε4 homozygosity (n = 38).

a

Statistical difference between groups with p < 0.05.

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Estimating Proportion in Similar Populations Through Extrapolation and Public Data

Based on the proportion of individuals in the H70-BCS eligible for lecanemab treatment, without factors requiring special consideration, an estimate of magnitude was extrapolated in Europe and the United States based on the following assumptions (details in eAppendix 1): (1) The sample with complete data in this study is representative of the full H70-BCS. (2) Participants in the H70-BCS are representative of 70-year-olds in Sweden. (3) Swedish residents are equally affected by AD as other residents in Europe and the United States.9 (4) Proportion of individuals who are eligible is similar in 70-year-olds and older individuals because factors requiring special considerations regarding risk of adverse events increase with age to a similar magnitude as the prevalence of AD. This can be motivated because prevalence of factors such as stroke and anticoagulant treatment due to atrial fibrillation increase drastically with age.10

According to public data from “Our world in data,” EU currently has 95 million citizens between 70 and 89 years and the United States has 35 million.11 Based on this, the total number of individuals eligible for lecanemab treatment in the EU and the United States would account for approximately 5.9 million and 2.2 million individuals, respectively.

Discussion

We determined the proportion of 70-year-olds eligible for lecanemab treatment in the H70-BCS through examinations, including cognitive function, medical history, genotyping, CSF analysis, and brain imaging, and found that 6.2% met the indication without any factor requiring special consideration.2 Assuming a similar proportion, and a similar ratio of individuals with AD without complicating factors in other parts of Europe and the United States, this could indicate that approximately 5.9 million Europeans and 2.2 million US residents may be eligible for treatment.

Studies on the absolute proportion of individuals in Europe and the United States who are eligible for treatment are few. A population-based study from the United States recently found that a limited proportion of older adults met the strict clinical trial criteria for lecanemab treatment.12 Our assessment of eligibility using the FDA-approved prescribing information resulted in higher proportion eligible for treatment. On a larger scale, it was recently estimated that 5.4 million Europeans are eligible for lecanemab treatment, based on public data, and an assumption that one-third of individuals with AD and MCI would qualify for treatment.13 Our estimate of 5.9 million Europeans aligns well with this, although extrapolated from a population-based sample with individual clinical and MRI data. Together, these independent estimations support each other and indicate that our extrapolation holds some validity on the larger scale. Furthermore, our extrapolation suggests that 2.2 of the 6.7 million Americans with Alzheimer dementia may be candidates for treatment.14

The presented estimates of eligibility in EU and the United States are crude and should not be used for future policy making or direction of funds for future care. However, our study contributes to data based on the current FDA-approved prescribing information. Furthermore, we analyzed Aβ42 in CSF, which can be influenced by other diseases in the CNS, and may differ slightly from using PET.15 As our extrapolations are based on 70-year-olds, this may result in an underestimation of eligibility. Conversely, the proportion of individuals with stroke and anticoagulant treatment was lower than in the full H70-BCS, which could lead to a slight overestimation of eligibility. Thus, these 2 concerns could mitigate each other. Our sample with full data was comparatively small (290 of 1,203) and not ethnically diverse, and risk factors for AD may also differ from country to country and influence generalizability. However, there were no other differences between participants with complete or missing data, and previous estimates on the proportion eligible in Europe have presented similar numbers through other methods.

In conclusion, we found that 6.2% of the 70-year-olds in the H70 Birth Cohort Study born 1944 are eligible for lecanemab treatment. Other large population-based studies should determine the proportion in other settings to provide further information regarding the magnitude of individuals who may benefit from lecanemab treatment.

Lecanemab: Investigating Another Amyloid Medication for Early Alzheimer Disease

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Jennifer Rose V. Molano, MD, reviewing van Dyck CH et al. N Engl J Med 2023 Jan 5 Reish NJ et al. N Engl J Med 2023 Jan 4 Sabbagh M and van Dyck CH. N Engl J Med 2023 Jan 4

Patients with early Alzheimer disease taking an anti-amyloid monoclonal antibody showed improvements in cognitive, functional, and biomarker outcomes compared with placebo; monitoring for potential adverse effects is needed.

In this phase 3, industry-sponsored, multicenter, double-blind trial, researchers studied if lecanemab, a humanized immunoglobulin G1 monoclonal antibody targeting soluble amyloid-beta protofibrils, was safe and effective in treating early Alzheimer disease (AD). Participants met criteria for mild cognitive impairment (MCI) or mild dementia due to AD and had evidence of amyloid deposition on cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) imaging.

The 1795 participants (mean age, 71; about half female; about 75% white) were randomized 1:1 to 10 mg/kg of lecanemab or placebo every 2 weeks for 18 months. Approximately 80% of participants completed the study. The primary outcome was a change in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, which assesses cognition and function as observed by patients and caregivers. Secondary outcomes included change in amyloid burden on PET imaging and additional cognitive and functional assessments.

The mean CDR-SB score at baseline was 3.2. Significantly less cognitive and functional decline was seen with lecanemab versus placebo (adjusted mean difference, –0.45; 95% confidence interval, –0.67 to –0.23; P<0.001). The amyloid burden was significantly lower with the lecanemab group than with placebo. Other secondary outcomes were also significantly better with lecanemab. Adverse effects included infusion-related reactions, amyloid-related imaging abnormalities (ARIA), headache, and falls. Serious adverse effects were seen in 14% of lecanemab recipients versus 11% of placebo recipients. Most cases of ARIA were asymptomatic (78%), occurred during the first 3 months of treatment, and resolved within 4 months. Death occurred in 0.7% of the lecanemab group (vs. 0.8% of the placebo group), which was not attributed to treatment.

A subsequent correspondence presented a patient who had received at least three doses of lecanemab in the trial, developed multiple cerebral hemorrhages after receiving intravenous tissue plasminogen activator for acute ischemic stroke, and subsequently died, with autopsy results showing multifocal intracerebral hemorrhages, cerebral amyloid angiopathy, AD changes, and vasculitis. In response, study authors noted that the patient was homozygous for apolipoprotein-E ℇ4, which, in addition to systolic blood pressure >200 mm Hg, may have contributed to the patient’s clinical progression. They also noted that vasculitis has not been reported previously with lecanemab.

Comment

A clear benefit from targeting amyloid to treat AD has been elusive. The results of this study showed promising results on outcomes in early AD, although consideration of safety issues in those homozygous for apolipoprotein-E ℇ4 is needed. Close monitoring for potential adverse effects is needed. The FDA recently approved lecanemab for mild cognitive impairment or mild dementia due to AD. An ongoing open-label study will provide additional data on whether lecanemab is a viable treatment option for AD.

Scattered Brain Bleeds, Vasculitis in Alzheimer’s Trial Death

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Case report is published days ahead of FDA lecanemab decision

A computer rendering of a person’s transparent head with a cerebral hemorrhage highlighted

A fatal bleeding event in an Alzheimer’s clinical trial participant may have been linked with the investigational anti-amyloid agent lecanemab, a case report suggested.

However, drug trialists are not willing to assign blame yet, especially as lecanemab’s fate hangs in a potential FDA approval for early Alzheimer’s disease later this week.

Information about the case initially surfacedopens in a new tab or window just days before the November report of the randomized CLARITY AD trialopens in a new tab or window: a 65-year-old lecanemab user with cerebral amyloid angiopathy (CAA) died after being given tissue plasminogen activator (tPA) for an acute ischemic stroke that happened during the open-label phase of the trial.

In separate letters published in the New England Journal of Medicine, the Northwestern team who treated the stroke patient shed light on the numerous, unusual acute intracerebral bleedsopens in a new tab or window observed, while the CLARITY study investigators stressed the potential role of the patient’s underlying conditionopens in a new tab or window, not lecanemab.

The trial participant was homozygous for the APOE4 allele and had a last lecanemab infusion 4 days before the stroke occurred. A head MRI performed 81 days before the stroke showed mild small-vessel disease, with no microhemorrhages, edema, or amyloid-related imaging abnormalities (ARIA); CT performed just before tPA administration showed no hemorrhage, either, according to neurocritical care specialist Sherry Chou, MD, and colleagues of Northwestern University Feinberg School of Medicine in Chicago.

The patient received IV tPA, as there were no contraindications to thrombolysis. Problems emerged 50 minutes into the infusion, when hypertension suddenly developed and forced tPA infusion to be stopped. CT showed extensive, multifocal intraparenchymal hemorrhages without systemic bleeding.

Chou and colleagues administered cryoprecipitate and tranexamic acid. They also gave multiple antiseizure medications for the frequent, nonconvulsive seizures seen on electroencephalography. Three days later, the patient underwent endotracheal intubation, and imaging showed acute right thalamocapsular infarction and innumerable multifocal cortical and subcortical hemorrhages with surrounding edema.

At the request of the family, the patient received comfort measures before dying. Autopsy showed extensive multifocal intraparenchymal hemorrhages, cerebral amyloid angiopathy, Alzheimer’s disease neuropathologic changes, and diffuse histiocytic vasculitis with necrotizing vasculopathy involving amyloid deposition within blood vessel walls.

“The extensive number and variation in sizes of the cerebral hemorrhages in this patient would be unusual as a complication of tPA solely related to cerebrovascular amyloid. The findings raise the possibility of cerebral hemorrhages and necrotizing vasculopathy associated with tPA infusion in a patient with cerebrovascular amyloid who had received lecanemab,” Chou’s group wrote.

In a written response, CLARITY AD investigators Marwan Sabbagh, MD, of Barrow Neurological Institute in Phoenix, Arizona, and Christopher van Dyck, MD, of Yale School of Medicine, clarified that autopsy findings may have been affected by several intervening events since the time of the patient’s hemorrhage.

The duo also highlighted the known risk of intracerebral hemorrhage — and uncommon cases of vasculitis — in persons with CAA not on anti-amyloid therapy.

“We agree that this case raises important management issues for patients with Alzheimer’s disease, particularly patients who are homozygous for the APOE4 allele,” Sabbagh and van Dyck said.

Having occurred during CLARITY AD’s extension phase, the death was not counted among the 13 deaths (six in the lecanemab arm and seven in placebo) in the trial report of nearly 1,800 people.

Also not included was a 79-year-old woman’s deathopens in a new tab or window — also during the extension phase of CLARITY AD — that occurred more recently after the patient experienced extensive brain swelling and bleeding and seizures. Previously, a man in his late 80s died of a brain hemorrhage after using lecanemab and apixaban (Eliquis) for atrial fibrillation, though lecanemab developer Eisai argued that the death was unrelated to the drug.

During the randomized phase of CLARITY, no deaths had been judged to be related to lecanemab or occurred with ARIA. ARIA with edema or effusions occurred in 12.6% of people who received lecanemab. Combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis occurred in 17.3%, study authors reported.

CLARITY’s main finding was that lecanemab was associated with a statistically significant albeit modest reduction in clinical decline after 18 months in people with early Alzheimer’s disease.

The FDA is expected to announce in the upcoming days whether to grant lecanemab accelerated approval for early Alzheimer’s disease. Some have suggested the agency requires a risk evaluation and mitigation strategy in face of fears of the drug’s ARIA risks.

Lecanemab May Reverse Alzheimer’s Disease, But 3 Deaths Raise Questions

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FDA granted Leqembi as the seventh drug for the treatment of Alzheimer's disease.

FDA granted Leqembi as the seventh drug for the treatment of Alzheimer’s disease.

The U.S. Food and Drug Administration (FDA) granted Leqembi accelerated approval on Jan. 6, 2023. It is the seventh drug the FDA has approved for the treatment of Alzheimer’s disease.

The generic name of the drug is Lecanemab. It has been developed by the Japanese company Eisai in partnership with the U.S. company Biogen. These are the same companies that developed the sixth drug for the treatment of Alzheimer’s disease, Aduhelm (generic name aducanumab).

Lecanemab Is the First FDA-Granted Anti-amyloid Drug to Improve Cognitive Function

The first five FDA-approved drugs are donepezil, rivastigmine, galantamine, memantine, and memantine combined with donepezil. These drugs can temporarily relieve symptoms. Patients may have some amelioration in cognitive function, but the underlying brain pathologies of Alzheimer’s disease cannot be reduced or stopped, and the course of the disease cannot be altered.

By contrast, Lecanemab and aducanumab are human IgG1 anti-amyloid monoclonal antibodies and can decrease the expression of pathological biomarker Aβ aggregation in early Alzheimer’s disease.

The difference between the two is that aducanumab does not result in cognitive improvement, while Lecanemab can moderately ameliorate cognitive decline in Alzheimer’s disease cases.

When the FDA approved aducanumab in 2021, the decision prompted many disagreements in the medical field. Some medical professionals claimed that the decision was made on the ability to remove Aβ plaques without supportive evidence of improving cognitive function. Others claimed there was insufficient data to approve the drug’s efficacy.

Lecanemab, on the other hand, had solid data to approve its effectiveness in reducing the rate of cognitive decline by 27 percent after an 18-month clinical investigation on 898 patients in the early stages of Alzheimer’s disease during the double-blind phase 3 clinical trial.

Lecanemab can both improve cognitive function and reverse the course of Alzheimer’s pathology.

This sounds promising, but a significant problem remains: whether Aβ aggregation is the cause of Alzheimer’s disease has been the subject of debate in the medical field.

At the same time, the side effects of Lecanemab are causing concerns.

Safety Concerns, Including Three Deaths

Though the first five Alzheimer’s drugs that the FDA approved could not fundamentally reduce the pathological changes of Alzheimer’s disease, they have relatively mild side effects, such as headache and nausea.

However, aducanumab is associated with a 40 percent increased risk of a serious condition called amyloid-related imaging abnormalities (ARIA), an indicator of brain swelling. Individuals receiving aducanumab should be monitored closely, so ARIA is quickly identified and safely managed.

In a study of Lecanemab, 20 percent of participants experienced an adverse event, such as swelling or bleeding in the brain, with symptoms of headaches, visual disturbances, and confusion.

So far, the treatment with Lecanemab during clinical trials has also been linked to three deaths.

One individual suffered a stroke before the treatment and received a blood thinner before receiving Lecanemab. A second death occurred when a woman suffered stroke symptoms after starting Lecanemab treatment, followed by a series of seizures; she died a few days later, and her doctor found massive bleeding in her brain.

On Jan. 4, two days before the FDA approved the drug, the third death was reported in the New England Journal of Medicine—a patient receiving Lecanemab was treated for acute ischemic stroke with tissue plasminogen activator and subsequently died from multiple cerebral hemorrhages.

The three deaths were all related to strokes, and the patients took blood thinner before or after Lecanemab treatment.

Though these cases are still under investigation, they suggest fatal brain hemorrhage could occur during treatment with Lecanemab.

For safety reasons, FDA approved that Leqembi should be initiated in patients with mild cognitive impairment or mild dementia, which is the same with the population in the clinical trials. The labeling on the drug also states no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.

In the future, the FDA should address the balance of efficacy and safety of Lecanemab and keep an eye on adverse events. Longer trials are needed to explore the contraindications and side effects.

Antihypertensives and Dementia; Peripheral Neuropathy Marker; Who Can Get Lecanemab?

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News and commentary from the world of neurology and neuroscience

Neuro Break over a computer rendering of neurons.

New use of antihypertensive medicationsopens in a new tab or window that stimulated rather than inhibited type 2 and 4 angiotensin II receptors was linked with lower dementia risk. (JAMA Network Open)

Full data about an implanted endovascular brain-computer interfaceopens in a new tab or window for paralyzed people were reported in JAMA Neurology. Findings were first presentedopens in a new tab or window at the 2022 American Academy of Neurology meeting.

A newly discovered meningeal layeropens in a new tab or window appears to line the brain. (Science)

Blood-based measures of neurofilament light chain were associated with neuronal injury in peripheral neuropathyopens in a new tab or window, a meta-analysis showed. (JAMA Network Open)

People with incident Parkinson’s disease had cognitive and functional decline before diagnosisopens in a new tab or window that exceeded rates associated with normal aging. (Neurology)

Jet Medical agreed to pay $200,000 to resolve criminal allegations relating to a migraine treatmentopens in a new tab or window, while Jet and two related companies agreed to pay another $545,000 in a civil settlement involving the same device, the Department of Justice said.

Remote observational researchopens in a new tab or window provided a “reasonable evaluation” of disability trajectory over time in a multiple sclerosis study during the pandemic. (Neurology: Neuroimmunology and Neuroinflammation)

As soon as lecanemab (Leqembi) received the green light through the FDA’s accelerated approval pathway, Eisai submitted an application for traditional approvalopens in a new tab or window of the drug.

Based on its accelerated approval status, who can get lecanemabopens in a new tab or window? (NBC News)

A novel vaccine appeared to protect miceopens in a new tab or window against SARS-CoV-2 brain infection. (Nature Neuroscience)

Researchers identified a unifying functional framework for multiple dimensions of consciousnessopens in a new tab or window.

FDA grants accelerated approval for Alzheimer’s treatment

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The FDA has granted accelerated approval for Leqembi for the treatment of Alzheimer’s disease, making it the second approved Alzheimer’s treatment, the agency announced in a press release.

The approval comes after review of phase 3 data, which was published in The New England Journal of Medicine in November 2022. The results showed that Leqembi (lecanemab-irmb, Eisai) reduced markers of amyloid in early AD and resulted in less decline in cognition and function.

Source: Adobe Stock.
The FDA granted accelerated approval for Leqembi for the treatment of Alzheimer’s disease.Source: Adobe Stock

“This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease,” Billy Dunn, MD,director of the office of neuroscience at the FDA’s Center for Drug Evaluation and Research, said in the release.

Leqembi was approved under the accelerated approval pathway, which the FDA uses to approve drugs for serious conditions when there is an unmet medical need. The agency stated that Alzheimer’s disease affects more than 6.5 million Americans.

“This is encouraging news, but the approval of lecanemab is just the first step,” Howard Fillit, MD, chief science officer at the Alzheimer’s Drug Discovery Foundation, said in a foundation press release. “Alzheimer’s therapies will only be beneficial to patients if the right drug is given to the right patient at the right time based on their unique disease pathology, and for that we need new and novel diagnostic biomarkers.”

Prescribing information for Leqembi includes a warning for amyloid-related imaging abnormalities (ARIA), which are known to occur with antibodies of the class, the FDA release states. ARIA usually does not have symptoms, although serious and life-threatening events rarely occur.

An additional warning includes risk for infusion-related reactions, with symptoms such as flu-like symptoms, nausea, vomiting and changes in blood pressure.

The Leqembi label states that it is indicated for treatment of AD and should be initiated for those with mild cognitive impairment or mild dementia. In addition, the label states that there are no safety or efficacy data on initiating treatment at earlier or later stages of disease.

“By slowing progression of the disease when taken in the early stages of Alzheimer’s, individuals will have more time to participate in daily life and live independently,” Alzheimer’s Association President and CEO Joanne Pike, DrPH, said in a release from the association. “This could mean more months of recognizing their spouse, children and grandchildren. This could also mean more time for a person to drive safely [and] accurately and promptly take care of family finances and participate fully in hobbies and interests.”

New Alzheimer’s Drug Shows ‘Modest’ Success, And Risks

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photo of medical research

Widely anticipated data from a phase 3 trial of a new Alzheimer’s disease treatment suggests the drug “modestly” relieved cognitive problems in patients early into the disease — but at a cost.

In the trial, adverse events among patients taking the drug, lecanemab, were common compared with placebo, including leaking blood vessels ; and a news report this week linked a second death to the drug.

Moving forward, “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease,” Christopher H. van Dyck, MD, of the Yale School of Medicine in New Haven, CT, and colleagues write.

The full trial findings were presented at the 15th Clinical Trials on Alzheimer’s Disease conference, and were also published  Nov. 29 in the New England Journal of Medicine.

Endpoints Met 

The phase 3 trial of lecanemab has been closely watched in Alzheimer’s circles, especially considering positive early data released in September, reported by Medscape Medical News at that time.

The FDA is expected to decide whether to approve the drug in January. The agency has approved only one other similar treatment, the highly controversial and expensive aducanumab (Aduhelm).

For the new 18-month, randomized, double-blind trial, researchers enrolled 1,795 patients ages 50 to 90 with early Alzheimer’s.. All were randomly assigned to receive either a placebo or intravenous lecanemab.

The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. 

Those on the experimental drug scored 27% better on a Alzheimer’s rating scale compared to those on the placebo. 

The study authors did not speculate about how this difference would affect the day-to-day life of patients who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.

Concerning Adverse Event Data

With respect to adverse events, deaths occurred in both groups (0.7% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, the journal Science reported Nov. 27 that a 65-year-old woman who was taking the drug as part of a clinical trial “recently died from a massive brain hemorrhage that some researchers link to the drug.”

The woman, the second person “whose death was linked to lecanemab,” died after suffering a stroke. Science summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”

Eisai, which sponsored the new trial, told Science that “all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause.”

Cautious Optimism

In separate interviews with Medscape Medical News, two Alzheimer’s specialists who weren’t involved in the study praised the trial and described the findings as “exciting.” But they also highlighted its limitations.

Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School
and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining what are known as anti-amyloid monoclonal antibodies. “This is the first trial that shows a clinical benefit that can be measured,” he said. 

However, it’s unclear whether the changes “are really going to make a difference in people’s lives,” he said. The drug is likely to be expensive due to the large investment needed for research, he added, and patients will have to undergo costly testing such as PET scans and spinal taps. 

Howard Fillit, MD, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and had what he called a “modest” effect on cognition.

However, the drugmaker will need to explore the adverse effects, he said, especially in patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal — fully reversing cognitive decline. 

Rave Reviews from the Alzheimer’s Association

In a statement, the Alzheimer’s Association raved about lecanemab and declared the FDA should approve lecanemab on an accelerated basis. The study “confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease…,” the association said, adding that “it could mean many months more of recognizing their spouse, children and grandchildren.”

The association, which is also a staunch supporter of aducanumab, called on the Centers for Medicare and Medicaid Services to cover the drug if the FDA approves it. The association’s statement did not address the drug’s potential high cost, the adverse effects, or the 2 reported deaths. 

Source: WebMD