Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Monoclonal Antibodies for Treatment of Alzheimer Disease [Aducanumab (e.g., Aduhelm) and Lecanemab (e.g., Leqembi)]

Description:

Aducanumab is an amyloid beta-directed antibody proposed as a treatment of Alzheimer’s disease based on reduction in amyloid beta plaques observed in individuals treated in clinical trials. This indication was given under an accelerated approval process with the proviso that continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

Alzheimer disease (AD) is a neurodegenerative disorder of uncertain cause and pathogenesis that primarily affects older adults and is the most common cause of dementia (~80%) and is invariably fatal. AD affects an estimated 6.2 million Americans ages 65 years and older and, with the aging population in the US, by 2050, the number of people living with AD is projected to more than double and is currently the 6th leading cause of death. The most essential and often earliest clinical manifestation of AD is selective memory impairment, although there are exceptions.

The disease characterized by the progressive accumulation of beta-amyloid protein plaques and neurofibrillary tangles of phosphorylated tau protein in the brain; these are hypothesized to damage neurons of many years and lead to the loss of cognition and physical functioning. Individuals are diagnosed with Alzheimer’s dementia when there is impairment of two cognitive domains and these deficits significantly interfere with the ability of the patient to function independently at work or at home.

Lecanemab is a monoclonal antibody consisting of the humanized version of a mouse antibody, mAb158, that recognizes protofibrils and prevents amyloid beta deposition in in animal models of Alzheimer’s disease. Lecanemab works by removing a sticky protein from the brain that is believed to cause Alzheimer’s disease to advance.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Effective May 17, 2023

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of aducanumab and lecanemab for the treatment of Alzheimer’s dementia, dementia of any other etiology, or any other condition does not meet member benefit certificate primary coverage criteria as present clinical trials have not found a consistent clinical benefit in net health outcomes and therefore present evidence is insufficient.

For members with contracts without primary coverage criteria, aducanumab and lecanemab are considered investigational.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective July 2021 to May 16, 2023

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of aducanumab for treatment of Alzheimer’s dementia, dementia of any other etiology, or any other condition does not meet member benefit certificate primary coverage criteria as present clinical trials have not found a consistent clinical benefit in net health outcomes and therefore present evidence is insufficient.

For members with contracts without primary coverage criteria, Aducanumab is considered investigational.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

In an initial dose-escalation study involving 165 patient with prodromal or mild AD, the use of aducanumab was associated with a substantial reduction of amyloid plaques (after 12 months of therapy, almost half of patients had no amyloid on PET imaging), but only small or inconsistent clinical improvement.

In two phase III, near-identical, mostly contemporaneous randomized clinical trials (RCTs), ENGAGE and EMERGE. The trials randomized patients with early AD (i.e., mild cognitive impairment [MCI] or mild dementia due to AD) to low- or high-dose aducanumab or placebo (exact dosing depended on presence or absence of a genetic marker of AD risk, apolipoprotein 𝜀𝜀4 [APOE 𝜀𝜀4]). In both trials and at all doses, aducanumab effectively removed beta-amyloid. The primary clinical outcome was change in mean score on the Clinical Dementia Rating Scale for which a minimal clinically important difference has not been clearly defined. Midway through the trials, the trial protocol was amended such that the high-dose group was titrated to 10 mg/kg, regardless of APOE 𝜀𝜀4 status.

In March 2019, ENGAGE and EMERGE were terminated following a prespecified interim analysis for futility. Subsequent analyses revealed a possible positive treatment effect from EMERGE. However, results from ENGAGE failed to detect any improvement in CDR-SB in the high-dose group compared with placebo. Analysis of secondary endpoints were consistent).

Pooled safety data from the two trials showed that almost 40% of patients on aducanumab experienced amyloid-related imaging abnormalities (ARIA), whose clinical effects can range from asymptomatic to severe. ARIA can take the form of edema (ARIA-E) and/or microhemorrhage (ARIA-H). MRI reveals fluid-attenuated inversion recovery (FLAIR) hyperintensity with or without microhemorrhage and/or superficial siderosis. Most patients (70 percent) with ARIA are asymptomatic, but others have headache, confusion, dizziness, falls, vision change, or nausea; these symptoms are not necessarily attributed to the imaging abnormality. ARIA can occur at any time during treatment but is most common within the first eight doses. In most patients (88 percent), it resolves over time; however, some patients experience a recurrence.

Although the majority of patients were asymptomatic or had symptoms such as headache, confusion, or dizziness that resolved with temporary stoppage of the drug, 6.2% of participants receiving the high dose of aducanumab discontinued the drug due to ARIA. Furthermore, some patients experienced bleeding into brain tissue; one death in the Phase Ib trial was attributed to this.

The post-hoc analyses: 1) does not account for the differences seen in high and low dose cohorts beyond the possibility of chance, 2) unclear whether the degree of “improvement: in the EMERGE is clinically meaningful, and 3) there are significant safety concerns given the occurrence of ARIA even in asymptomatic individuals.

In summary, as existing unpublished clinical trials have not found a consistent clinical benefit in net health outcomes, the drug had been denied approval by an FDA advisory committee of experts (November 2020 10-0-1 against approval), aducanumab has been rated as evidence insufficient by a panel of experts for the Institute for Clinical and Economic Review (draft May 2021), and the FDA process of approval is currently the subject of congressional investigation (June 2021), the data is insufficient at present.

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.

May 2023 Update

An 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).

A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.

Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Van Dyck CH, Swanson CJ, Aisen P, et al., 2023)

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

Budd Haeberlein S, O'Gorman J, Chiao P, Bussière T, von Rosenstiel P, Tian Y, Zhu Y, von Hehn C, Gheuens S, Skordos L, Chen T, Sandrock A.(2017) Clinical Development of Aducanumab, an Anti-Aß Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease. J Prev Alzheimers Dis. 2017;4(4):255-263. doi: 10.14283/jpad.2017.39. PMID: 29181491.

Sevigny J, Chiao P, Bussière T, et.al.(2016) The antibody aducanumab reduces Aß plaques in Alzheimer's disease. Nature. 2016 Sep 1;537(7618):50-6. doi: 10.1038/nature19323. Update in: Nature. 2017 Jun 21;546(7659):564. PMID: 27582220.

Van Dyck CH, Swanson CJ, Aisen P, et al.(2023) Lecanemab in Early Alzheimer’s Disease (Clarity AD). NEJM. 2023; 388:9-21. DOI: 10.1056/NEJMoa2212948. Available at https://www.nejm.org/doi/full/10.1056/NEJMoa2212948.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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