By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the second human recombinant immunoglobulin gamma (IgG1 anti-amyloid beta) monoclonal antibody, after aducanumab, to treat Alzheimer’s disease (AD). It received priority review, an accelerated approval, and a breakthrough therapy designation.1 The accelerated approval was based on the reduction of amyloid beta plaque. Continued approval may be contingent upon verification of clinical benefit in a confirmatory trial.2
INDICATIONS
Lecanemab can be prescribed to treat AD.2 Initiate this treatment in patients with mild cognitive impairment or mild dementia stage of disease, with confirmation of amyloid beta pathology. Perform PET scanning or cerebrospinal fluid measurements for surrogate markers before treatment to establish the presence of brain amyloid positivity.
DOSAGE
Administer 10 mg/kg as an intravenous infusion over approximately one hour, every two weeks.2 Perform MRI within one year before initiating treatment to evaluate pre-existing amyloid-related imaging abnormalities (ARIA).2 Also perform MRI scans before infusion 5, 7, and 14 to assess for treatment-related ARIA and possible dosing interruption, depending on the severity of the ARIA.2
POTENTIAL ADVANTAGES
Lecanemab has demonstrated favorable binding to the more toxic profibrils compared to aducanumab, and was more efficient during in vitro immunodepletion studies.3 Lecanemab is effective in alleviating brain beta-amyloid burden.2,4,5,6 At 18 months, 81% of patients achieved amyloid negativity vs. 22% of placebo-treated patients.6
POTENTIAL DISADVANTAGES
Infusion-related reactions (mild to moderate in severity) occurred in 26% of lecanemab-treated subjects vs. 7.4% of placebo-treated subjects.4 Rates for ARIA, such as edema (ARIA-E), were of lecanemab-treated subjects 13% vs. 2% of placebo-treated subjects. Microhemorrhage and superficial siderosis rates were 17% in lecanemab-treated subjects vs. 9% in placebo-treated subjects. The incidence of ARIA-E was highest in those homozygous for APOE compared to heterozygous and noncarriers (33% vs. 11% vs. 5%, respectively) and occurred within the first three months of initiating treatment.4,5 The benefit of lecanemab in patients with moderate or severe AD is unknown, as is how well the clinical studies generalize to the broad AD population.
COMMENTS
The accelerated approval was evaluated in a proof-of-concept, Phase IIb, double-blind, placebo-controlled, parallel-group, dose-finding study.2,5,6 Subjects had AD with confirmed amyloid pathology and mild cognitive (64%) or mild dementia stage of disease (36%) consistent with stage 3 and 4 AD. Originally, 856 subjects were randomized to one of five doses (placebo, 2.5 mg/kg biweekly; lecanemab, 5 mg/kg monthly; lecanemab, 5 mg/kg biweekly; lecanemab, 10 mg/kg monthly; or lecanemab, 10 mg/kg biweekly). In a subgroup enrolled in the amyloid PET substudy, lecanemab 10 mg/kg biweekly (n = 44) significantly reduced brain amyloid beta plaque levels from baseline vs. placebo (n = 98) when assessed at weeks 53 and 79. Plasma biomarkers levels (amyloid beta 42/40 ratio, p-tau181) also were significantly lower.
The authors of a confirmation Phase III, 18-month study compared lecanemab 10 mg/kg biweekly to placebo. (This was a modified intention-to-treat population; n = 859 on lecanemab, n = 875 on placebo.)5 The primary endpoint was the change in the score on the Clinical Dementia Rating Sum of Boxes (CDR-SB) from baseline to 18 months. The rating assesses six domains: memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care. Each domain ranges from 0 to 3 points. Key secondary endpoints included amyloid burden on PET, 14-item cognitive subscale of the Alzheimer Disease Assessment Scale, and Alzheimer’s Disease Composite Score. Lecanemab showed a modest, but statistically significant, benefit over placebo on the primary endpoint 0.45-point improvement for 27%; the CDR-SB score at baseline was approximately 3.2 in both groups; mean worsening from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo). Non-carriers of APOE were more likely to benefit compared to carriers. All secondary outcome measures also statistically favored lecanemab.
CLINICAL IMPLICATIONS
AD is a neurodegenerative disease that is believed to affect 6.2 million Americans age 65 years or older.5 Currently approved treatments include cholinesterase inhibitors, such as donepezil, rivastigmine, and galantamine, and the N-methyl-D-aspartate receptor agonist memantine, all of which offer limited benefit. Approval of the first anti-amyloid beta-directed monoclonal antibody, aducanumab, was controversial because studies showed inconsistent clinical benefit, and the approval was based on a surrogate marker. The results of lecanemab in the Phase III trial showed a modest slowing of decline in measures of cognitive function vs. placebo in patients with early AD. It is uncertain how meaningful an absolute difference of 0.45 points on CDR-SB is between the lecanemab and placebo groups, as some have suggested that a 1-2-point change is the minimal clinically important difference.7 These data have been submitted to the FDA for a traditional approval.
The estimated cost of lecanemab is $26,500 annually. The Institute for Clinical and Economic Review suggested an annual cost of $15,700 to achieve $150,000 per quality-adjusted life year and $21,400 at the $200,000 threshold from a modified societal perspective.8
REFERENCES
1. U.S. Food & Drug Administration. FDA grants accelerated approval for Alzheimer’s disease treatment. Jan. 6, 2023.
2. Eisai. Leqembi prescribing information. January 2023.
3. Söderberg L, Johannesson M, Nygren P, et al. Lecanemab, aducanumab, and gantenerumab - Binding profiles to different forms of amyloid-beta might explain efficacy and side effects in clinical trials for Alzheimer’s disease. Neurotherapeutics 2022; Oct 17. doi: 10.1007/s13311-022-01308-6.
4. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med 2023;388:9-21.
5. Center for Drug Evaluation and Research. Summary review. Leqembi.
6. 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-Abeta protofibril antibody. Alzheimers Res Ther 2021;13:80.
7. Andrews JS, Desai U, Kirson NY, et al. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials. Alzheimers Dement (N Y) 2019;5:354-363.
8. Institute for Clinical and Economic Review. Beta-amyloid antibodies for early Alzheimer’s disease. Draft evidence report.
Lecanemab can be prescribed to treat Alzheimer's disease. Initiate this treatment in patients with mild cognitive impairment or mild dementia stage of disease, with confirmation of amyloid beta pathology.
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