Leqembi (lecanemab-irmb) for Alzheimer’s disease

What is Leqembi for Alzheimer’s disease?

Leqembi (lecanemab) is an antibody-based therapy approved to treat people with Alzheimer’s disease who have mild cognitive impairment or mild dementia.

In Alzheimer’s, the protein beta-amyloid harmfully accumulates in the brain, clumping, and eventually forming large aggregates called plaques that further contribute to nerve cell dysfunction. People with Alzheimer’s experience gradually worsening cognitive problems that can progress to dementia, in which cognitive difficulties are severe enough to interfere with daily life.

Leqembi aims to slow cognitive decline in people with Alzheimer’s by helping clear beta-amyloid from the brain. It contains an antibody that binds to abnormal forms of beta-amyloid and tags them for clearance by the immune system. By targeting these forms of beta-amyloid, Leqembi helps reduce amyloid buildup and plaques in the brain.

By targeting beta-amyloid clumps in earlier disease stages — at the point of mild cognitive impairment or mild dementia — Leqembi may modestly slow disease progression.

Leqembi, given via intravenous (into-the-vein) infusions, was jointly developed by Biogen and Eisai. The companies also developed Leqembi Iqlik, an alternate formulation of the same active ingredient that can be given at home via subcutaneous (under-the-skin) injections after a healthcare provider determines that administration by the patient or caregiver is appropriate.

Therapy snapshot

Who can take Leqembi?

In the U.S., Leqembi is approved for the treatment of Alzheimer’s disease. It should be initiated in the mild cognitive impairment or mild dementia stages of the disease, as this is the group of patients for whom the medication was evaluated in clinical trials. The presence of amyloid-beta pathology should be confirmed before treatment is started.

Leqembi is contraindicated, or should not be used by people with a history of serious allergic reactions (hypersensitivity) to Leqembi or any of its ingredients.

The medication carries a boxed warning for amyloid-related imaging abnormalities (ARIA) — a group of brain-related side effects associated with beta-amyloid-targeted antibodies that can be seen on MRI scans. People with two copies of a genetic variant called APOE4 have a higher risk of ARIA, including serious ARIA, so patients should undergo testing for APOE4 before starting treatment. ARIA can be serious or life-threatening, so the potential benefits and risks should always be weighed when deciding if Leqembi is appropriate.

Leqembi is also approved in other regions, including the European Union (EU), where the medication is only indicated for adults with mild cognitive impairment or mild dementia due to Alzheimer’s disease who have confirmed amyloid pathology and zero or one copy of APOE4.

How is Leqembi administered?

Leqembi is administered by a healthcare provider via an intravenous infusion that lasts about an hour. Leqembi Iqlik is administered as under-the-skin (subcutaneous) injections using a prefilled autoinjector, which can be done at home by patients or caregivers after proper training.

The recommended starting dose of Leqembi infusions is 10 mg/kg once every two weeks, while Leqembi Iqlik is started at 500 mg once weekly, given as two consecutive 250 mg injections. After 18 months, doctors may recommend continuing the starting regimen or switching to a maintenance regimen of:

• 10 mg/kg once every four weeks, for Leqembi infusions
• 360 mg every week, for Leqembi Iqlik injections

Patients may be able to switch between Leqembi infusions and Leqembi Iqlik injections, depending on their treatment plan.

Before starting treatment, the presence of amyloid-beta pathology should be confirmed. Patients also need a recent baseline brain MRI before treatment.

Leqembi in clinical trials

Leqembi’s U.S. approval was supported by two clinical studies, both of which included adults ages 50 to 90 with mild cognitive impairment or mild dementia due to Alzheimer’s.

• A Phase 2b trial called Study 201 (NCT01767311) showed that intravenous Leqembi at its now-approved starting dose had a 64% probability of slowing decline on the Alzheimer’s Disease Composite Score — a measure of cognition and function — by a prespecified amount after a year compared with placebo, but this fell short of the trial’s prespecified 80% probability threshold. Scores on other measures, including the Clinical Dementia Rating – Sum of Boxes (CDR-SB) and Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog), showed slower decline with Leqembi at 18 months.
• A Phase 3 trial called Clarity AD (NCT03887455) showed that Leqembi at its approved starting dose significantly slowed decline on the CDR-SB and other cognitive and functional measures compared with placebo after 18 months, with continued benefit reported during the open-label extension.

Both studies also showed that Leqembi reduced brain beta-amyloid levels.

Other trials showed that subcutaneous lecanemab delivered by autoinjector provided exposure to the active ingredient similar to that achieved with intravenous administration, based on pharmacokinetic modeling. In a Clarity AD long-term extension substudy, both formulations showed beta-amyloid plaque reduction.

Leqembi side effects

The most common side effects associated with Leqembi include:

• infusion-related reactions with intravenous Leqembi
• ARIA, including swelling (edema) or small bleeds (microhemorrhages) in the brain
• headache

Infusion-related reactions with intravenous Leqembi may be managed by reducing the infusion rate, stopping the infusion, or using appropriate treatment as needed. Premedication with antihistamines, nonsteroidal anti-inflammatory drugs, or corticosteroids may be considered before future infusions.

The boxed warning for Leqembi notes that ARIA can include brain swelling (ARIA-E) and brain bleeding (ARIA-H). These complications usually occur early in treatment and are usually asymptomatic, but can still be severe or life-threatening. If symptoms do occur, they can include:

• headache
• confusion
• vision changes
• dizziness
• nausea
• difficulty walking or speaking
• seizures
• muscle weakness

To help detect ARIA early, patients should receive an MRI before starting Leqembi and after 1, 2, 3, and 6 months of treatment. If ARIA occurs, treatment may need to be paused, depending on its type and severity, and whether symptoms are present.