Clinical Overview: Lecanemab Offers Hope for Patients With Alzheimer Disease

Commentary
Article

Lecanemab is a humanized immunoglobulin gamma 1 monoclonal antibody that targets amyloid plaques, which are thought to play a role in the development and progression of Alzheimer disease.

Alzheimer disease (AD) is a disorder that causes progressive cognitive deterioration and affects behavior and functional status. AD is characterized by amyloid plaques and neurofibrillary tangles in the cerebral cortex.1

Image credit: Александр Марченко | stock.adobe.com

Image credit: Александр Марченко | stock.adobe.com

Oral pharmacological therapies include cholinesterase inhibitors (e.g., donepezil) and the n-methyl-d-aspartate (NMDA) receptor antagonist memantine, all of which do not treat the underlying cause of AD or halt disease progression, driving the need for additional pharmacotherapy.1 In January 2023, the FDA approved Eisai’s lecanemab (lecanemab-irmb; Leqembi) under the accelerated approval pathway for the treatment of AD associated with mild cognitive impairment or mild dementia stage disease. Full approval was granted via the traditional pathway in July 2023.2,3

Lecanemab is a humanized immunoglobulin gamma 1 monoclonal antibody that targets amyloid plaques, which are thought to play a role in the development and progression of AD.4 Lecanemab is the second anti-amyloid monoclonal antibody to be approved following the FDA’s controversial accelerated approval of aducanumab (Aduhelm) in 2021.5 These agents have the potential to be disease-modifying.6

Clinical Studies

The accelerated FDA approval of lecanemab was based on the results of an 18-month, phase 2b, multinational, double-blind, randomized, placebo-controlled study that aimed to identify the target dose of lecanemab, while assessing efficacy and safety.7 In the trial, 856 patients with mild cognitive impairment due to AD or mild AD-dementia and confirmed amyloid beta plaques were randomized to 1 of 5 experimental groups: intravenous lecanemab 2.5 mg/kg biweekly (every 2 weeks), 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly) or placebo.

The primary endpoint was change from baseline at 12 months on the Alzheimer’s Disease Composite Score (ADCOMS), a sensitive measure of cognition changes in early stages of AD.8 Secondary endpoints included change from baseline at 18 months in the presence of brain amyloid plaques, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) score, and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) score.7

The 10 mg/kg biweekly dose was identified as the target dose. The primary endpoint was met if this dose had an 80% probability of achieving at least 25% less clinical decline on the ADCOMS as compared with placebo. This threshold was not met; the 10 mg/kg biweekly dose had a 64% likelihood of 25% or greater slowing of progression on the primary endpoint.

Regardless, lecanemab was approved based on the positive clinical benefits noted in key secondary endpoints. The adverse events (AEs) reported in at least 5% of patients treated with lecanemab 10 mg/kg biweekly (n=161) and at least 2% higher than placebo were infusion-related reactions (20% vs. 3%), headache (14% vs. 10%), amyloid-related imaging abnormality with edema/effusion (ARIA-E; 10% vs. 1%), cough (9% vs. 5%), and diarrhea (8% vs. 5%).4

ARIA with hemosiderin deposition (ARIA-H)—including microhemorrhage and superficial siderosis and can spontaneously occur in patients with AD—was reported in 7% of patients treated with lecanemab 10 mg/kg biweekly versus 5% in placebo-treated patients.4 There was an increased incidence of ARIA reported in apolipoprotein E ε4 (ApoE ε4) homozygotes compared with heterozygotes and noncarriers.7

The efficacy and safety of lecanemab were further evaluated in the CLARITY AD global confirmatory phase 3, double-blind study involving 1795 patients with early AD, the results of which led to the drug’s full approval.9 Patients were randomized to receive intravenous lecanemab 10 mg/kg biweekly or placebo for 18 months.

The primary endpoint was a change from baseline at 18 months in the CDR-SB total score, a validated measure assessing cognition and function. The total score ranges from 0-18 and is obtained by interviewing patients and their care partners.10

Key secondary endpoints included the 18-month change in amyloid burden on positron emission tomography and the scores on the ADAS-Cog14, ADCOMS, and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment. The change from baseline in the CDR-SB score was significantly less in those treated with lecanemab than with placebo (1.21 vs. 1.66, respectively, P<0.001).

Results for the secondary endpoints were all statistically significant as well, favoring lecanemab.9 Notably, a clinically meaningful change on the CDR-SB has not been established; still, lecanemab slowed clinical decline by 27% at 18 months.11

Although generally well-tolerated, the most frequently (>10%) reported AEs in the lecanemab-treated group versus the placebo-treated group were infusion-related reactions (26% vs. 7%), ARIA-H (14% vs. 8%), ARIA-E (13% vs. 2%), and headache (11 % vs. 8%). ARIA events were more common among ApoE ε4 carriers compared with noncarriers.9

Safety

Given the clinical study data, the lecanemab prescribing information includes a black box warning related to ARIA and warnings/precautions related to infusion-related reactions and hypersensitivity reactions.4 Prior to initiating therapy with lecanemab, a baseline brain magnetic resonance imaging (MRI) is required to evaluate for pre-existing ARIA and to weigh the risks versus benefits of treatment.

Testing for ApoE ε4 carrier status should be performed.4 Enhanced clinical vigilance for ARIA symptoms is needed during the first 14 weeks of treatment.

Though usually asymptomatic, patients with ARIA may present with headache, confusion, visual changes, dizziness, nausea, gait difficulty, and focal neurologic deficits. Serious and life-threatening events, such as seizure and status epilepticus, have rarely occurred.

Generally, symptoms associated with ARIA resolve over time.4 Additional MRIs are recommended prior to the fifth, seventh, and fourteenthinfusions, and if a patient experiences symptoms of ARIA.4

Serious intracerebral hemorrhages (>1 cm in diameter) have also occurred in those treated with lecanemab. Caution should thus be exercised in patients who are currently taking antithrombotics or thrombolytic therapy, and in those with other risk factors for intracerebral hemorrhage.4

If injection-related reactions occur, the rate of infusion may be reduced or therapy discontinued, and appropriate treatment initiated as clinically indicated before reinitiating subsequent dosing. Pre-medication with antihistamines, non-steroidal anti-inflammatory drugs, or corticosteroids may be considered for future infusions.4

Prompt discontinuation of the infusion is necessary upon the first observation of any signs or symptoms of a hypersensitivity reaction. Angioedema and anaphylaxis have been reported and as such, lecanemab is contraindicated in patients with a history of serious hypersensitivity to the drug or any of the excipients.4

Dosage and Administration

Lecanemab treatment is limited to patients with mild cognitive impairment or mild dementia stage of AD. Prior to initiating therapy, the presence of amyloid plaques in the brain must be confirmed.4

The recommended dosage of lecanemab is 10 mg/kg, infused over approximately 1 hour once every 2 weeks under medical supervision at a participating infusion center. Dosing may need to be interrupted based on radiographically observed ARIA and the severity of ARIA symptoms. Product labeling should be consulted for precise recommendations.4

Conclusion

Although lecanemab appears promising for the treatment of AD, its use may be limited given the restricted indication, safety risks, and limited patient access. The medication is priced at $26,500 per year, not including additional costs for drug administration and monitoring.12

It will be covered by Medicare only if the prescriber participates in a registry designed to gather information on the drug’s safety and efficacy.13 Nonetheless, the development of targeted therapies, such as lecanemab, highlights the ongoing efforts to address the unmet medical needs in the treatment of AD and provides hope for improved management of this debilitating condition.

About the Authors

Daniel Ryabo, PharmD candidate 2025; Ifra Khan, PharmD candidate 2025; Aslan Amirov, PharmD candidate 2025; Mahmoud Shahin, PharmD candidate 2025; Tina Zerilli, PharmD, associate professor of Pharmacy Practice, LIU Pharmacy | Arnold & Marie Schwartz College of Pharmacy and Health Sciences.

References

  1. Crouse EL, Zimmerman KM, Peron EP, Sargent LJ, Hobgood SE. Alzheimer Disease. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12e. McGraw Hill; 2023. Accessed June 1, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3097&sectionid=267240515
  2. Eisai Inc. FDA Approves LEQEMBI (lecanemab-irmb) Under the Accelerated Approval Pathway for the Treatment of Alzheimer’s Disease. Updated January 6, 2023. Accessed September 27, 2023. https://investors.biogen.com/news-releases/news-release-details/fda-approves-leqembitm-lecanemab-irmb-under-accelerated-approval
  3. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. FDA. Updated July 6, 2023. Accessed September 27, 2023. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
  4. Lecanemab. Prescribing Information. Eisai Inc; 2023. Accessed September 27, 2023. https://www.leqembi.com/-/media/Files/Leqembi/Prescribing-Information.pdf?hash=77aa4a86-b786-457a-b894-01de37199024
  5. Aducanumab. Prescribing Information. Biogen Inc; 2021. September 27, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=41706573-546f-6774-6872-5374726f6e67
  6. Lakhan S. Alzheimer Disease Treatment & Management. Medscape. Updated April 17, 2023. September 27, 2023. https://emedicine.medscape.com/article/1134817-treatment#d10
  7. Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody [published correction appears in Alzheimers Res Ther. 2022 May 21;14(1):70]. Alzheimers Res Ther. 2021;13(1):80. Published 2021 Apr 17. doi:10.1186/s13195-021-00813-8
  8. Tahami Monfared AA, Houghton K, Zhang Q, Mauskopf J; Alzheimer’s Disease Neuroimaging Initiative. Staging Disease Severity Using the Alzheimer's Disease Composite Score (ADCOMS): A Retrospective Data Analysis [published correction appears in Neurol Ther. 2022 Jun;11(2):915-927]. Neurol Ther. 2022;11(1):413-434. doi:10.1007/s40120-022-00326-y
  9. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948
  10. Tzeng RC, Yang YW, Hsu KC, Chang HT, Chiu PY. Sum of boxes of the clinical dementia rating scale highly predicts conversion or reversion in predementia stages. Front Aging Neurosci. 2022;14:1021792. Published 2022 Sep 23. doi:10.3389/fnagi.2022.1021792
  11. Pelc C. Lecanemab: Why a new Alzheimer's drug has drawn praise and some concern. Medical News Today. January 6, 2023. Accessed September 27, 2023. https://www.medicalnewstoday.com/articles/lecanemab-why-a-new-alzheimers-drug-has-drawn-praise-and-some-concern
  12. Eisai Inc. Eisai’s Approach to U.S. Pricing for Leqembi (lecanemab), a Treatment for Early Alzheimer’s Disease, Sets Forth our Concept of “Societal Value of Medicine” in Relation to “Price of Medicine ''. Updated January 7, 2023. Accessed September 27, 2023. https://www.eisai.com/news/2023/news202302.html
  13. CMS Announces New Details of Plan to Cover New Alzheimer’s Drugs. CMS. Updated June 22, 2023. Accessed September 27, 2023. www.cms.gov/newsroom/fact-sheets/cms-announces-new-details-plan-cover-new-alzheimers-drugs.
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