What clinical evidence supports the use of lecanemab for Alzheimer disease?

Introduction
On January 6, 2023, lecanemab (Leqembi) was granted accelerated approval by the United States Food and Drug Administration (FDA) for the treatment of early Alzheimer disease (AD).¹ The second in its class, lecanemab is preceded by the controversial amyloid beta-directed monoclonal antibody, aducanumab (Aduhelm). Like aducanumab, lecanemab is indicated for use in patients with mild cognitive impairment or mild dementia.²

Per the prescribing information, lecanemab is administered as a 1-hour intravenous (IV) infusion once every 2 weeks at a recommended dose of 10 mg/kg.² Similar to aducanumab, lecanemab is associated with amyloid-related imaging abnormalities (ARIA), which can manifest as edema (ARIA-E) and/or hemosiderin deposition (ARIA-H) and are identifiable via magnetic resonance imaging (MRI). Consequently, an MRI is required within 1 year prior to treatment initiation, and before the 5th, 7th, and 14th infusions. Other common adverse events (AEs) observed at a frequency of 10% or greater relative to placebo include infusion-related reactions and headache.^2,3

Clinical trials
Accelerated approval for lecanemab was granted on the basis of results from a phase 2, double-blind, placebo-controlled, dose-finding study, specifically the observed reductions in amyloid beta, a surrogate marker of AD.^1,4 The study’s objective was to establish the most effective dose of lecanemab using a primary endpoint of change from baseline in the Alzheimer’s Disease Composite Score (ADCOMS) at 12 months.³ To meet this endpoint, lecanemab had to demonstrate an 80% probability of achieving a ≥25% reduction in clinical decline relative to placebo. Secondary endpoints included change from baseline at 18 months in brain amyloid pathophysiology (as assessed by positron emission tomography [PET]), ADCOMS, Clinical Dementia Rating Sum-of-Boxes (CDR-SB) score, and the Alzheimer Disease Assessment Scale-Cognitive Subscale with 14 Tasks (ADAS-Cog14). Brain amyloid pathophysiology was assessed as part of a PET substudy for which participation was optional.

In total, 856 patients were randomized to either placebo (n=247) or 1 of 5 lecanemab IV treatment arms (2.5 mg/kg biweekly [n=52], 5 mg/kg monthly [n=51], 5 mg/kg biweekly [n=92], 10 mg/kg monthly [n=253], or 10 mg/kg biweekly [n=161]).³ All study participants were confirmed to have amyloid beta pathology with either mild cognitive impairment due to AD or mild dementia stage of AD. Ultimately, while the 10 mg/kg biweekly dosing regimen was identified as most effective, it demonstrated only a 64% probability of being superior to placebo by ≥25% at 12 months, thereby missing the 80% probability threshold required to meet the primary endpoint. Despite not meeting its primary endpoint, lecanemab demonstrated dose-dependent reductions in brain amyloid at 18 months, along with reductions in clinical decline per ADCOMS, ADAS-Cog14, and CDR-SB (Table 1).

Infusion-related reactions and ARIA-E were the most common treatment-emergent AEs.³ Of the 161 patients receiving lecanemab 10 mg/kg biweekly, 9.9% experienced ARIA-E compared with 0.8% of those in the placebo group. Most cases of ARIA-E were mild-to-moderate in severity. Overall study discontinuation was 36% across all lecanemab treatment arms and 23.7% in the placebo arm. Study discontinuation due to an AE occurred in 14.9% of those receiving lecanemab 10 mg/kg biweekly versus 6.1% of placebo-treated patients.

After the accelerated approval, the manufacturer of lecanemab submitted a supplemental application for FDA review via the traditional approval pathway.⁵ The application includes data from the recently published confirmatory phase 3 Clarity AD trial, which enrolled 1795 patients to either placebo or lecanemab 10 mg/kg IV biweekly.⁶ The primary endpoint in Clarity AD was change from baseline in the CDR-SB score at 18 months, with amyloid burden at 18 months as a secondary endpoint. Other secondary endpoints assessed at the 18-month mark were changes from baseline in ADAS-cog14, ADCOMS, and Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL). The trial met its primary endpoint, with change from baseline in CDR-SB being significantly less with lecanemab (1.21) than with placebo (1.66), suggesting a positive effect on clinical decline (difference, -0.45; 95% CI, -0.67 to -0.23; p<0.001) (Table 2). Additionally, lecanemab met all secondary endpoints and demonstrated significant reductions in brain amyloid at 18 months, lending support to the brain amyloid findings of the phase 2 study.

Safety results from Clarity AD include higher rates of infusion-related reactions (26.4% vs. 7.4%), ARIA-E (12.6% vs. 1.7%), and ARIA-H (17.3% vs. 9.0%) with lecanemab and placebo, respectively.⁶ Mortality during the 18-month follow-up was similar between groups (0.7% vs. 0.8%). Limitations of the Clarity AD trial include a 17.2% dropout rate and potential subjectivity of scales used for the primary and secondary endpoints, and the possibility of unblinding due to the occurrence of ARIA.^6,7

How does lecanemab compare with aducanumab?
The controversy surrounding the accelerated approval of aducanumab is well known and has been discussed previously.⁸ Aside from the approval process itself, much of the aducanumab debate has centered on the use of an unvalidated surrogate marker – amyloid beta – as the basis for the drug’s approval.^9,10 It remains uncertain whether declines in amyloid beta correlate with cognitive benefit, which calls into question the clinical efficacy of aducanumab. Nonetheless, the FDA used this surrogate endpoint as the basis of lecanemab’s approval as well.

Unlike aducanumab, however, lecanemab has less uncertainty regarding its Phase 3 trial data. Aducanumab’s EMERGE and ENGAGE trials were halted based on results of a futility analysis, which was later determined to be invalid.¹¹ Once data collection resumed, however, only the EMERGE trial met its primary endpoint of CDR-SB at 18 months. That one trial met its primary endpoint while the other failed to, raising concerns that the data were not sufficient to support the efficacy of aducanumab.^10,12 For lecanemab, however, Phase 3 trial data demonstrated statistical significance for the primary clinical endpoint and for all secondary endpoints (Table 2).⁶

Positive Phase 3 findings for lecanemab notwithstanding, the clinical significance of these findings has been called into question.^7,13-15 The difference between lecanemab and placebo  for the primary endpoint in the Clarity AD trial (-0.45 points) is likely less than the clinically important difference.^7,15 Consequently, the statistically significant results observed with lecanemab may not prove to be clinically significant with real-world use, and real-world use will be limited by payer reluctance to cover therapies without definitive clinical benefit.¹⁶

Conclusion
Besides its effects on amyloid beta, lecanemab has been shown to result in less decline on several measures of cognition and function in patients with early AD. Phase 3 primary endpoint data have demonstrated that treatment with lecanemab results in significantly less change from baseline in the CDR-SB score when compared with placebo; similar reductions in decline were seen with ADAS-cog14, ADCOMS, and ADCS-MCI-ADL. While the data for lecanemab are statistically significant, whether these differences translate into clinically significant and meaningful outcomes is still unknown. Ongoing clinical trials with lecanemab, aducanumab, and donanemab (an anti-amyloid monoclonal antibody still in development) will continue to bring clarity about optimal strategies to prevent progression in early AD.^6,17,18

References

1. FDA approves LEQEMBI™ (lecanemab-irmb) under the accelerated approval pathway for the treatment of Alzheimer’s disease as the first and only Alzheimer’s disease treatment to address a defining pathology of the disease. Eisai. January 6, 2023. Accessed March 20, 2023. https://media-us.eisai.com/2023-01-06-FDA-Approves-LEQEMBI-TM-lecanemab-irmb-Under-the-Accelerated-Approval-Pathway-for-the-Treatment-of-Alzheimers-Disease
2. Leqembi [package insert]. Nutley, NJ: Eisai Inc.; 2023.
3. 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. Alzheimers Res Ther. 2021;13(1):80. doi:10.1186/s13195-021-00813-8
4. FDA grants accelerated approval for Alzheimer’s disease treatment. U.S. Food and Drug Administration. January 6, 2023. Accessed March 20, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
5. Eisai submits supplemental biologics license application to FDA for traditional approval of LEQEMBI™ (lecanemab-irmb) for the treatment of Alzheimer’s disease. Eisai. January 6, 2023. Accessed March 20, 2023. https://media-us.eisai.com/2023-01-06-Eisai-Submits-Supplemental-Biologics-License-Application-to-FDA-for-Traditional-Approval-of-LEQEMBI-TM-lecanemab-irmb-for-the-Treatment-of-Alzheimers-Disease
6. 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
7. Thambisetty M, Howard R. Lecanemab trial in AD brings hope but requires greater clarity. Nat Rev Neurol. 2023;19(3):132-133. doi:10.1038/s41582-022-00768-w
8. What is the clinical evidence supporting, and controversy surrounding, the use of aducanumab (Aduhelm) for Alzheimer disease? University of Illinois Chicago Drug Information Group. October 2021. Accessed March 20, 2023. https://dig.pharmacy.uic.edu/faqs/2021-2/october-2021-faqs/what-is-the-clinical-evidence-supporting-and-controversy-surrounding-the-use-of-aducanumab-aduhelm-tm-for-alzheimer-disease/
9. FDA grants accelerated approval for Alzheimer’s drug. U.S. Food and Drug Administration. June 7, 2021. Accessed March 20, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
10. Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement. 2021;17(4):696-701. doi:10.1002/alz.12213
11. Haeberlein SB, von Hehn C, Tian Y, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. Presented at: Clinical Trials on Alzheimer’s Disease (CTAD) 2019; December 5, 2019; San Diego, CA. Accessed March 20, 2023. https://investors.biogen.com/static-files/ddd45672-9c7e-4c99-8a06-3b557697c06f
12. Hollmann P, Lundebjerg NE. Food and Drug Administration’s review of Biogen’s drug aducanumab for Alzheimer’s disease. Letter. The American Geriatrics Society. June 2, 2021. Accessed March 20, 2023. https://www.americangeriatrics.org/sites/default/files/inline-files/American%20Geriatrics%20Society_Letter%20to%20FDA%20Biogen%20Drug%20for%20Alzheimer%27s%20%28June%202021%29%20FINAL%20%281%29.pdf
13. Mahase E. Lecanemab trial finds slight slowing of cognitive decline, but clinical benefits are uncertain. BMJ. 2022;379:o2912. Published 2022 Dec 1. doi:10.1136/bmj.o2912
14. Walsh S, Merrick R, Richard E, Nurock S, Brayne C. Lecanemab for Alzheimer’s disease. BMJ. 2022;379:o3010. Published 2022 Dec 19. doi:10.1136/bmj.o3010
15. The Lancet. Lecanemab for Alzheimer’s disease: tempering hype and hope. Lancet. 2022;400(10367):1899. doi:10.1016/S0140-6736(22)02480-1
16. CMS Statement: Response to Alzheimer’s Association’s Request to Reconsider the Final National Coverage Determination. Centers for Medicare & Medicaid Services. February 22, 2023. Accessed March 20, 2023. https://www.cms.gov/newsroom/press-releases/cms-statement-response-alzheimers-associations-request-reconsider-final-national-coverage
17. Lilly Shares Positive Donanemab Data in First Active Comparator Study in Early Symptomatic Alzheimer’s Disease. Lilly. November 30, 2022. Accessed March 20, 2023. https://investor.lilly.com/news-releases/news-release-details/lilly-shares-positive-donanemab-data-first-active-comparator
18. Mead S, Fox NC. Lecanemab slows Alzheimer’s disease: hope and challenges. Lancet Neurol. 2023;22(2):106-108. doi:10.1016/S1474-4422(22)00529-4

Prepared by:
Rosa Macrito
PharmD Candidate Class of 2023

Heather Ipema, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2023

The information presented is current as of March 20, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.