What's the mechanism of action for Leqembi (lecanemab-irmb)?

Leqembi is an anti-Aβ (amyloid-beta) protofibril antibody and has been shown to reduce brain amyloid and modestly slow cognitive decline in adult patients with early Alzheimer disease. It is thought to slow down the progression of Alzheimer’s by neutralizing and eliminating the toxic amyloid-beta aggregates found in the brain.

The accumulation of amyloid plaques in the brain is a defining feature of Alzheimer disease.

Timeline for Leqembi approval

In July 2023, the FDA granted traditional approval of Leqembi (lecanemab-irmb) from Eisai / Biogen. It is the second intravenous (IV) amyloid beta-directed monoclonal antibody to treat patients with Alzheimer disease with mild cognitive impairment (MCI) or mild dementia.

• It was first FDA-approved on Jan. 6, 2023 on an "accelerated" basis, which means in clinical studies people responded to it, but further studies were needed before it could be fully approved. It became available to patients on Jan 18, 2023.
• On March 5, 2023 the FDA accepted the Confirmatory Phase 3 Clarity AD data (Study 301) as a priority review to determine whether to convert accelerated approval of Leqembi to a traditional approval.
• On June 9, 2023 the FDA Peripheral and Central Nervous System Drugs Advisory Committee voted unanimously that the data and the overall benefit-risk profile from Eisai’s Phase 3 Clarity AD clinical trial confirmed the clinical benefit of Leqembi use for the treatment of Alzheimer’s disease (AD).
• On July 6, 2023, the FDA granted a full (traditional) approval to Leqembi based on the Phase 3 CLARITY AD results and Advisory Committee recommendations.

Aduhelm (aducanumab), approved in June 2021, was the first approved IV amyloid-beta directed monoclonal antibody.

Does Leqembi work? Studies for Leqembi

Studies have shown that Leqembi reduces brain amyloid plaques and slows disease progression in early Alzheimer disease.

• In a Phase 2 study, patients who received Leqembi 10 mg/kg every two weeks demonstrated a statistically significant reduction in brain amyloid plaques at both Weeks 53 and 79 (p<0.001) and showed a slowing of disease progression measured by The Alzheimer Disease Composite Score (ADCOMS) at 18 months (P<0.05).
• ADCOMS has been shown to be a more sensitive measure of cognitive change in early AD (i.e., mild cognitive impairment and mild Alzheimer dementia) than other commonly used measures.
• Accelerated approval was based on the surrogate endpoint of reduction in amyloid beta plaques in the brain in a Phase 2 dose-finding study. A surrogate endpoint is an indicator or sign used in place of another to tell if a treatment works.

CLARITY AD study (Study 301)

The Phase 3, global, placebo-controlled confirmatory CLARITY AD study (Study 301) included 1,795 participants with mild cognitive impairment or mild dementia stage of disease and confirmed presence of amyloid beta pathology. Patients received placebo or Leqembi at a dose of 10 milligrams (mg)/kilograms (kg), once every two weeks.

Treatment of patients with Leqembi met the primary endpoint, which was reduction from baseline in cognition and function as measured by the Clinical Dementia Rating–Sum of Boxes (CDR-SB) by 27% compared with placebo (1.21 with lecanemab and 1.66 with placebo [difference, -0.45; 95% CI -0.67 to -0.23; P<0.001) at 18 months. Results started as early as 6 months. CDR-SB is a numeric scale used to quantify the various severity of symptoms of dementia.

A subgroup analysis also showed significant reductions in brain amyloid at 18 months vs. placebo. Other key secondary endpoints, like the Alzheimer’s Disease Assessment Scale Cognitive Subscale 14, and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment were also met.

How is Leqembi given?

Leqembi is given into your vein through a needle placed into your arm by a healthcare provider (IV infusion). Before starting treatment with Leqembi, your healthcare provider will confirm the presence of brain amyloid.

• A recent (within one year) brain MRI is obtained prior to initiating treatment to evaluate for pre-existing Amyloid Related Imaging Abnormalities (ARIA).
• An MRI is also required prior to the 5th, 7th, and 14th infusions.

The recommended dose is 10 mg/kg given once every two weeks as a one-hour intravenous (IV) infusion. It is given every 2 weeks and each infusion will last about 1 hour. You will need to spend additional time at the infusion clinic.

Your doctor may give you medicine (antihistamines, steroids) before your Leqembi infusion to help prevent infusion-related side effects. Infusion-related side effects can include: fever, nausea, vomiting, chills, dizziness, lightheadedness, changes in your heart rate, or shortness of breath.

What is ARIA with Leqembi?

Leqembi has an important warning for Amyloid Related Imaging Abnormalities (ARIA). ARIA is a side effect that does not usually cause any symptoms, but serious symptoms may occur. Your healthcare provider will check you for ARIA before and during treatment with a magnetic resonance imaging (MRI) scan.

• ARIA-E (Edema) is a temporary swelling in the brain and ARIA-H (Hemosiderin) leads to small areas of bleeding and iron deposits in the brain. It is most commonly seen as small spots of swelling or bleeding in the brain from an MRI image, but larger areas can occur too.
• Side effects seen with MRI are usually asymptomatic and resolve with time, but can be serious in some patients.
• If you get symptoms such as: a headache, confusion, dizziness, vision changes, nausea, difficulty walking, or seizures, contact your healthcare provider or contact emergency medical treatment (call 911) right away.
• A Boxed Warning is included in the Leqembi prescribing information to warn patients and caregivers to the potential risks associated with ARIA.

Some people may have a genetic risk factor (homozygous apolipoprotein E gene carriers) that can increase the risk for ARIA. Talk to your healthcare provider about testing for this risk factor.

How often does ARIA occur with Leqembi?

Phase 2 Study

In the Phase 2 accelerated approval studies, the most common side effects (at least 10% incidence) included:

• infusion-related reactions (20% vs. 3% placebo)
• headache (14% vs. 10% placebo)
• ARIA-E (10% vs. 1% placebo)

ARIA is swelling in areas of the brain, with or without small spots of bleeding in or on the surface of the brain (ARIA). ARIA-E resolved in 94% of patients. Most ARIA-E side effects seen on an MRI occurred within the first 7 doses, but ARIA can occur at any time and frequency.

The risk of ARIA was greater in patients who are ApoE4 homozygotes compared to heterozygotes and noncarriers. Your doctor may test you for ApoE4 status prior to starting treatment.

Phase 3 Study

In the Phase 3 study CLARITY AD, symptomatic ARIA-E occurred at 2.8% of patients receiving Leqembi vs. 0% of patients on placebo. The total incidence of ARIA (ARIA-E and/or ARIA-H) was 21.3% in the Leqembi group and 9.3% in the placebo group.

In initial studies, 15% of patients treated with Leqembi vs. 6% of patients on placebo stopped treatment because of a side effect (most commonly infusion reactions, 2% vs. 1% placebo). For infusion reactions, premedication may be needed.

Be sure to tell your healthcare provider if you take medicines to reduce blood clots from forming (antithrombotic medicines, including drugs like warfarin or aspirin). Ask your healthcare provider for a list of these medicines if you are not sure.

How much does Leqembi cost?

The price of Leqembi is $26,500 per year, slightly below the $28,200 annual cost of Aduhelm. Leqembi became commercially available from Eisai on January 18th, 2023.

Eisai offers a Patient Support Program and Copay Assistance Program that can help you determine and navigate your insurance coverage and answer any questions you or your doctor may have. To learn about the Eisai Patient Support Program for patients prescribed Leqembi, you can call 1-833-4-LEQEMBI (1-833-453-7362) or access the information online.

This is not all the information you need to know about Leqembi (lecanemab-irmb) for safe and effective use and does not take the place of your doctor’s directions. Review the full Leqembi information and discuss this information and any questions you have with your doctor or other health care provider.