Lecanemab-irmb Approved for Alzheimer Disease

In January 2023, the FDA granted accelerated approval for lecanemab-irmb (Leqembi) for the treatment of patients with mild cognitive impairment or mild dementia stage of Alzheimer disease.¹ Lecanemab-irmb is a humanized monoclonal antibody that specifically targets both aggregated soluble and insoluble forms of amyloid-β.² By doing so, lecanemab-irmb effectively reduces the accumulation of amyloid-β plaques, which are recognized as a defining pathophysiological feature of Alzheimer disease.

'Alzheimer' spelled in wooden blocks / LIGHTFIELD STUDIOS - stock.adobe.com

The FDA granted accelerated approval for this indication based on observed reductions in amyloid-β plaques in patients who were treated with lecanemab-irmb. The FDA granted full approval on July 6, 2023, based on the results of a confirmatory trial. It is important to note that lecanemab-irmb carries a boxed warning due to the potential risk of amyloidrelated imaging abnormalities (ARIA).

Efficacy

Lecanemab-irmb was evaluated in a double-blind, placebo-controlled trial (NCT01767311) consisting of a 79-week, double-blind phase and a 260-week, open-label extension. The study enrolled 856 participants: A total of 161 received the advised dosing of 10 mg/kg biweekly; 71.4% of participants were ApoE ε4 carriers who were later excluded.

The primary outcome was change from baseline to week 53 using a composite score from the Clinical Dementia Rating Score-Sum of Boxes (CDR-SB), Mini-Mental State Examination, and Alzheimer’s Disease Assessment ScaleCognitive Subscale 14 item (ADAS-Cog 14). Lecanemab-irmb demonstrated a 64% probability of slowing progression by 25% or more vs placebo, which did not meet the prespecifed success criterion of 80%.

Secondary outcomes included changes in amyloid PET with standardized uptake value ratio composite at week 79 and alterations in both CDR-SB and ADAS-Cog14 scores at the same time point. Patients receiving lecanemab-irmb displayed less variation in these scores relative to the placebo. Lecanemab-irmb demonstrated some efficacy in decelerating Alzheimer progression despite not meeting the primary end point and showed notable potential in secondary outcomes.

Results of another phase 3 trial, Clarity AD (NCT03887455)—a parallel-group, randomized study—revealed that lecanemab reduced clinical decline on the CDR-SB, with a 27% slowing of decline vs placebo over 18 months. Significant changes were noted as early as 6 months and increased over time. Lecanemab-irmb signifcantly reduced amyloid plaque burden and slowed cognitive function decline by 26%, disease progression by 24%, and daily living activities decline by 37%

Safety

In the first study, lecanemab-irmb caused infusion-related adverse reactions in 20% of patients, the majority of which (88%) occurred during the first infusion. These reactions were mild (56%) to moderate (44%) and led to discontinuation in 2% of patients. Post infusion, 38% of patients experienced transient lymphocyte counts below 0.9 x 109, while 22% had a transient increase in neutrophil counts above 7.9 x 109, vs 2% and 1% in placebo, respectively.

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The safety profile includes other common adverse reactions, with higher incidence rates vs placebo: headache, ARIA-E, cough, and diarrhea. Intracerebral hemorrhage (> 1 cm) was reported in 1 patient after a single treatment with lecanemab-irmb. Caution is warranted when considering the use of antithrombotics or thrombolytic agents in patients already receiving lecanemab-irmb. In Clarity AD, similar common adverse events were noted, including infusion-related reactions and ARIA.

Dosing and Administration

Lecanemab-irmb is administered biweekly as an intravenous infusion at a recommended dose of 10 mg/kg. Before initiation, it is essential to confirm the presence of amyloid β pathology and obtain a recent (within 1 year) brain MRI to assess preexisting ARIA. During the initial 14 weeks of treatment, enhanced clinical vigilance for ARIA is recommended. Further MRIs should be conducted before the 5th, 7th, and 14th infusions; treatment adjustments may be required based on the type, severity, or presence of symptoms related to ARIA. If an infusion is missed, the next dose should be administered as soon as possible.

No specific studies have evaluated pharmacokinetics in patients with renal or hepatic impairment. The active ingredient in lecanemab-irmb is degraded by proteolytic enzymes and is not expected to undergo renal elimination or hepatic metabolism, suggesting no dose adjustment is necessary for these patient populations.

Egla Hasimllari, PharmD, is a PGY1 pharmacy resident at UConn John Dempsey Hospital in Farmington, Connecticut. Kevin Chamberlin, PharmD, FASCP, is associate vice president and chief pharmacy ofcer at UConn Health in Farmington, Connecticut.

READ MORE: Neurology Resource Center

References

1. Leqembi. Prescribing information. Biogen Inc; 2023.https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269s000lbl.pdf

2. 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