Last Review Date: 08/08/2023

Date of Origin: 02/02/2023

Dates Reviewed: 02/2023, 06/2023, 08/2023

1. Description of Procedure or Service ¹

Leqembi™ (lecanemab-irmb) is a recombinant human immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta which is potentially a disease-modifying treatment.

2. Policy

Leqembi™ (lecanemab-irmb) is considered not medically necessary for all indications including treatment of Alzheimer’s Disease (AD).

Note: There is insufficient clinical evidence for demonstrated efficacy

3. Key Points ^1,5,6,9

Alzheimer’s disease is a fatal neurodegenerative brain disease with progressive accumulation of plaques in the brain that contain beta-amyloid protein and neurofibrillary tangles of phosphorylated tau protein.  Current treatment options for AD focus on supportive management and includes the treatment of dementia with medications that are not disease-modifying (e.g., donepezil, rivastigmine, galantamine, memantine, etc.). Lecanemab promotes the clearance of beta-amyloid plaques from the brain, however, the role of beta-amyloid protein in disease is not well understood. At this time, lecanemab is not addressed in any clinical guidelines by U.S. or non-U.S. based organizations. The Institute for Clinical And Economic Review (ICER) did assess the effectiveness and value of the first amyloid beta-directed antibody (aducanumab) for Alzheimer’s disease in a draft evidence report in May 2021 and they concluded that the current available evidence is insufficient to determine the net health benefit of aducanumab.⁹ The Centers for Medicare & Medicaid Services (CMS) has noted that monoclonal antibodies directed against amyloid for the treatment of AD provided outside of an FDA-approved randomized controlled trial, CMS-approved studies, or studies supported by the NIH, are nationally non-covered.¹¹

4. Clinical Trials and FDA Review ^1,5,6,9

Eisai completed a rolling submission to the FDA of a BLA under the accelerated approval pathway based on data from the proof-of-concept Phase 2b Study 201 Core (NCT0176711).⁵ Data from this trial, as well as the open-label extension (Study 201 OLE), and safety data from the confirmatory Clarity AD Phase 3 were used to garner the initial approval based on treatment effect on amyloid beta plaque. Amyloid beta plaque was quantified using PET-imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology.

Eisai has submitted a supplemental BLA to the FDA to support conversion of the accelerated approval to traditional approval based upon data from its ongoing confirmatory trial Clarity AD (NCT03887455; published) which was a randomized, double-blind, phase 3 clinical trial evaluating the safety and efficacy of lecanemab in patients with early AD. A total of 1795 patients were randomized 1:1 to lecanemab (10 mg/kg; n=898) or placebo (n=897), given intravenously every 2 weeks. The primary efficacy endpoint was the change in CDR-SB after 18 months of treatment. Key secondary endpoints included the change from baseline to 18 months in the following measures: amyloid burden on positron emission tomography (PET); score on ADAS-cog14; score on ADCOMS; and score on ADCS-MCI-ADL. ¹

• Inclusion criteria: Age 50-90 years old; either MCI due to AD or mild AD-related dementia (based on the National Institute on Aging-Alzheimer's Association criteria); evidence of amyloid positivity on PET or CSF measurement; objective impairment of episodic memory as indicated by 1 standard deviation below the age-adjusted mean in the Weschler Memory Scale IV-Logical Memory II. ¹
• Baseline demographics: Median age, 71; 52% female; 77% White, 3% Black, 17% Asian, 4% other or missing race; 12% Hispanic/Latino; 38% had mild dementia due to AD and 62% had MCI; mean CDR-SB score at baseline, 3.2 (scores between 0.5-6 indicate early AD). ApoE status: Noncarrier: 31%; carrier (homozygous): 15%; carrier (heterozygous): 53%. (1)
• Primary and secondary endpoint information is outlined in Table 5 below. ¹

Discussion: Results of the primary endpoint favored lecanemab, along with those observed for the secondary endpoints. Baseline amyloid levels were 77.92 and 75.03 centiloids in the lecanemab and placebo arms, respectively. After 18 months of treatment, the mean amyloid level in the lecanemab arm was 22.99 centiloids, below the threshold for amyloid positivity (30 centiloids) which is associated with elevated amyloid levels in the brain. A definition of clinically meaningful effects for the primary endpoint (CDR-SB) has not been formally defined, but this trial exceeded its predefined target. Limitations of the trial included the limited duration of follow-up (18 months) and use of a modified intent-to-treat analysis without imputation of missing values. Finally, the occurrence of ARIA events may have affected blinding to a certain degree.

5. Billing Code/Availability Information

HCPCS Code:

• J3590 – Unclassified biologicals (Discontinue on 07/06/2023)
• C9399 – Unclassified drugs or biologicals (Hospital Outpatient Use Only) (Discontinue on 07/06/2023)
• J0174 – Injection, lecanemab-irmb, 1mg; 1 billable unit = 1 mg (Effective 07/06/2023)

NDC:

• Leqembi 200 mg/2 mL (100 mg/mL) solution in a single-dose vial: 62856-0212-xx
• Leqembi 500 mg/5 mL (100 mg/mL) solution in a single-dose vial: 62856-0215-xx

6. References

1. Leqembi [package insert]. Nutley, NJ; Esai, Inc; January 2023. Accessed May 2023.
2. McKhann GM, Knopman DS, Chertklow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.  Alzheimers Dement. 2011;7(3):263. Epub 2011 Apr 21. 
3. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):280. Epub 2011 Apr 21.
4. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med 2022 November 29. DOI: 10.1056/NEJMoa2212948.
5. 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. Alzheimer's Research and Therapy 2021;13:80. DOI: 10.1186/s13195-021-00813-8.
6. Reish NJ, Jamshidi P, Stamm B, et al. Multiple Cerebral Hemorrhages in a Patient Receiving Lecanemab and Treated with t-PA for Stroke. N Engl J Med 2023 January 4. DOI: 10.1056/NEJMc2215148.
7. O'Bryant SE, Lacritz LH, Hall J, et al. Validation of the new interpretive guidelines for the clinical dementia rating scale sum of boxes score in the national Alzheimer's coordinating center. Arch Neurol. 2010 Jun;67(6):746-9. doi: 10.1001/archneurol.2010.115.
8. Skinner J, Carvalho, JO, Potter GG, et al. The Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus): an expansion of the ADAS-Cog to improve responsiveness in MCI. Brain Imaging Behav. 2012 Dec;6(4):489-501. doi: 10.1007/s11682-012-9166-3.
9. Lin GA, Whittington MD, Synnott PG, et al. Aducanumab for Alzheimer’s Disease: Effectiveness and Value; Final Evidence Report and Meeting Summary. Institute for Clinical and Economic Review, August 5, 2021. https://icer.org/assessment/alzheimers-disease-2021/.
10. Lin GA, Whittington MD, Wright A, et al. Beta-Amyloid Antibodies for Early Alzheimer’s Disease: Effectiveness and Value; Draft Evidence Report. Institute for Clinical and Economic Review, December 22, 2022. https://icer.org/assessment/alzheimers-disease-2022/#timeline.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determination (NCD), Local Coverage Articles (LCAs), and Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. They can be found at: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications may be covered at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCA/LCD): N/A