Three Key Takeaways
1. FDA Approval Pathways for Alzheimer's Medications: Lecanemab-irmb (Leqembi) received accelerated FDA approval for Alzheimer disease due to demonstrated clinical efficacy in reducing amyloid beta plaques, highlighting the potential of accelerated approval for addressing unmet medical needs.
2. Lecanemab Mechanism and Adverse Effects: Lecanemab, a monoclonal antibody targeting amyloid beta, effectively reduces amyloid plaques but may cause infusion site reactions and amyloid-related imaging abnormalities.
3. Clinical Benefits and Financial Considerations: Lecanemab's traditional approval has implications for insurance coverage and reduced financial burden for patients, making it a promising treatment option for Alzheimer disease.
In January, the FDA granted accelerated approval to lecanemab-irmb (Leqembi) for the treatment of Alzheimer disease (AD). This type of approval is utilized for medications that may address otherwise unmet medical needs of patients after showing evidence indicating clinical efficacy.1
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In this case, lecanemab showed a reduction of amyloid beta plaque in patients with AD. In July 2023, the FDA shifted the accelerated approval to a traditional approval after the clinical benefit was proven.2 Another monoclonal antibody that was created in an attempt to treat AD, aducanumab-avwa (Aduhelm), was approved via the accelerated pathway in 2021.3
AD is a progressive disorder in which the primary clinical symptom presents as dementia or cognitive decline. More diagnostic evidence, such as imaging and cerebral spinal fluid, are used to diagnose AD as compared to other forms of dementia.
Although the true cause of AD is still debated, the amyloid cascade hypothesis is used for guiding newer treatments of the disease. This hypothesis indicates that the accumulation of amyloid beta plaques is the earliest sign of AD, sometimes appearing 20 years prior to symptom onset.4
Lecanemab Mechanism of Action
This medication is a monoclonal antibody that is targeted for amyloid beta and has been shown to reduce amyloid beta plaques.5 The standard dose of lecanemab is 10mg/kg, which is administered via intravenous infusion diluted with normal saline over 1 hour every 2 weeks. It requires periodic MRIs for monitoring of amyloid-related imaging abnormalities (ARIA).5
Adverse Effects (AEs) of Lecanemab
There are 2 categories of serious AEs that may occur when using lecanemab: infusion site reactions and amyloid-related imaging abnormalities (ARIA). The infusion site reactions were considered mild or moderate with some of the symptoms, including fever, flu-like symptoms, nausea, vomiting, oxygen desaturation, and blood pressure abnormalties.4
Most of these reactions occurred with the first infusion and prophylactic treatment using antihistamines or other medications may be used for subsequent infusions.5
ARIA AEs can be further categorized as ARIA with edema and ARIA with hemosiderin deposition. ARIA with edema can manifest as brain edema, whereas ARIA with hemosiderin deposition can manifest as microhemorrhage.5
Both types of ARIA may occur together and can rarely lead to seizures, including status epilepticus. Other signs and symptoms of ARIA can include confusion, gait difficulty, headache, and dizziness, which typically resolve without intervention. Dosing of lecanemab should be suspended if a patient has ARIA, apart from patients who are asymptomatic and have mild severity.5
Confirmatory Trial for Lecanemab
The clinical benefit of lecanemab was shown through the CLARITY AD trial. The international, double-blind, placebo-controlled trial was completed over 18 months with more than 1500 participants. There was a noted benefit both in cognition of the patient (quantified using the Clinical Dementia Rating–Sum of Boxes) and amyloid burden shown in a PET scan.
There was no portion that would indicate that Leqembi was equal or inferior to placebo. Based on the study, the average level of amyloid was 22.99 centiloids, which is considered below the level required to be classified as elevated brain amyloid levels (30 centiloids).6
Potential Controversy With Lecanemab
Lecanemab has shown great potential for the treatment of AD through the reduction of amyloid beta plaques within the brain. However, concerns linger that there will be similar issues with this medication as with aducanumab in the recent past. The manufacturer of aducanumab, Biogen, had further trials cancelled in 2019 because there was evidence to suggest that aducanumab would not slow impairment caused by AD.7
However, Biogen and the FDA continued with a group to examine the data from previous trials to gain approval for the drug to go to market. According to an investigation conducted by the US House of Representatives Committee on Oversight and Reform and Committee on Energy and Commerce, concerns from experts in the Center for Drug Evaluation and Research Office of Biostatistics were ignored prior to the approval of aducanumab.7
As of the time of writing, the author has been unable to find any evidence of lecanemab sharing a similar approval process to aducanumab. As discussed above, lecanemab had completed a successful phase 3 trial and was granted traditional approval.
Aducanumab led the way for insurance payers to determine the coverage of monoclonal antibodies for the treatment of AD. The Centers for Medicare and Medicaid Services had reached a coverage decision in which this class of medication would be covered if the drug was approved by the FDA via the traditional pathway, not accelerated.8 Based on the recent traditional approval of lecanemab, it is now covered by both Medicare and Medicaid.
Although Medicare has announced the coverage of lecanemab with conditions, with an annual out-of-pocket cost of more than $26,000, many patients will still face financial burden after insurance, in which 20% of the cost will still need to be covered by the patient. Also, a condition of the coverage includes the provider to enter certain patient information, such as AEs and the use of blood thinning medication, into a registry.9
Based on the above information presented, lecanemab has evolved past aducanumab in multiple facets, including financial burden and AEs. Lecanemab is more cost effective than its predecessor (with a overall annual cost of $26,000 compared to $56,000) and has less reports of serious AEs from trials.3,5,10
Namely, ARIA with edema occurred in 35% of patients within the aducanumab trial compared with only 10% of patients in the lecanemab trial.3,5 As more patients who qualify for the medication begin treatment, aftermarket data will be collected to further manage the use of the medication.
Lecanemab provides a ray of hope for patients and caregivers looking for a treatment where others have failed and has trial evidence that supports its use for patients with AD.
About the Author
Laura Borgerding is a PharmD candidate at the USF Taneja College of Pharmacy, anticipated to graduate in spring 2024. She completed this article during a virtual Advanced Pharmacy Practice rotation at STACK. For more information about conducting an APPE at STACK, visit www.managewithstack.com.
- FDA grants accelerated approval for Alzheimer’s disease treatment. FDA. January 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
- FDA converts novel Alzheimer’s disease treatment to traditional approval. FDA. July 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
- Aduhelm (aducanumab-avwa) package insert. FDA. Revised June 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s000lbl.pdf
- Weller J, Budson A. Current understanding of Alzheimer's disease diagnosis and treatment. F1000Res. 2018;7:F1000 Faculty Rev-1161. Published 2018 Jul 31. doi:10.12688/f1000research.14506.1
- Leqembi (lecanemab-irmb) package insert. FDA. Revised January 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269s000lbl.pdf
- 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
- The high price of Aduhelm’s approval: an investigation into FDA’s atypical review process and Biogen’s aggressive launch plans. Committee on Oversight and Reform and Committee on Energy and Commerce. U.S. House of Representatives. December 2022. https://democrats-energycommerce.house.gov/sites/democrats.energycommerce.house.gov/files/documents/Final%20Aduhelm%20Report_12.29.22.pdf
- CMS finalizes Medicare coverage policy for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease. CMS. April 7, 2022. https://www.cms.gov/newsroom/press-releases/cms-finalizes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment
- Kimball, S. “Medicare will pay for Alzheimer’s drug Leqembi. What patients and doctors should know.” CNBC. July 8, 2023. https://www.cnbc.com/2023/07/08/leqembi-and-medicare-what-patients-and-doctors-should-know.html
- Wolf, Z. B. The hard math on the new $56,000 Alzheimer’s drug. CNN. July 20, 2021. https://www.cnn.com/2021/07/20/politics/aduhelm-alzheimers-drug-cost-what-matters/index.html