Leqembi Okayed for Subset of Early Alzheimer’s Patients

The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Leqembi (lecanemab) to treat mild cognitive impairment and early Alzheimer’s disease, following a re-examination of the clinical data. The recommendation is only for patients who have one or no copies of the apolipoprotein E4 (APOE4) gene variant. 

The announcement overturns a negative opinion from their initial examination in July 2024 concerning a broader patient population. 

Symptoms of mild cognitive impairment and early Alzheimer’s overlap. They include memory loss, difficulties in solving problems or planning, and higher distractibility. Around 52 million people in Europe are estimated to have preclinical Alzheimer’s disease, while 6.9 million have Alzheimer’s disease dementia and 15 million have prodromal Alzheimer’s disease. The estimations mean that 25% of Europeans aged 50 years or older are affected by the condition. 

Leqembi’s active substance, lecanemab, is a monoclonal antibody that binds to aggregated soluble and insoluble forms of amyloid beta, preventing them from depositing and removing existing plaques. 

The CHMP decision comes after re-examining results from a phase 3 trial with 1795 participants, which found that lecanemab reduced amyloid markers in early Alzheimer’s disease and resulted in moderately less cognitive decline and function. 

The study, however, also reported a significant safety concern: heightened incidence of amyloid-related imaging abnormalities (ARIA), which involves edema or fluid accumulation in the brain, known as ARIA-E, or potential hemorrhage, known as ARIA-H. 

While ARIA can occur in all patients with Alzheimer’s disease, antibody drugs targeting amyloid beta, like lecanemab, increase its risk. Patients with two copies of the APOE4 gene are at the highest risk for ARIA. 

For the re-examination, the CHMP examined a subgroup analysis of data from the main study including 1521 patients who had one or no APOE4 gene copies. The primary outcome was a change in cognitive and functional symptoms after 18 months, as assessed via the CDR-SB dementia rating scale.

After 18 months, patients treated with lecanemab experienced a 1.22-point increase in their CDR-SB score, while those receiving a placebo experienced a 1.75 increase. The findings indicate that cognitive decline was slower among those taking lecanemab. 

Of note, the re-examination also reported that, whereas 12.6% and 16.9% of patients with two copies of APOE4 experienced ARIA-E and ARIA-H, the same was true for 8.9% and 12.9% of the restricted population. Among restricted patients treated with a placebo, 1.3% and 6.8% experienced ARIA-E and ARIA-H. 

The CHMP noted that the benefits of Leqembi outweigh the risks in the restricted population, provided minimization measures are in place to reduce the risk for severe and symptomatic ARIA, and that these patients undergo long-term monitoring. 

Leqembi will be available as a 100 mg/mL concentrate solution for infusion. Patients should undergo MRI scans to check for ARIA before treatment and before the fifth, seventh, and 14th dose. Additional MRI scans may be required should patients develop symptoms of ARIA such as headache, confusion, and difficulty walking. 

Eisai GmbH, the drug’s manufacturer, will provide an alert card for patients as well as a guide, checklist, and training programs on ARIA for healthcare professionals to increase awareness and ensure early detection and treatment. The company has also been instructed to carry out a postauthorization safety study to further characterize ARIA-E and ARIA-H and assess the effectiveness of risk-minimization efforts. 

Leqembi is now awaiting a decision from the European Commission. Detailed recommendations on how to use the drug will be made available in the summary of product characteristics, which will be published in all European Union languages upon granting of marketing authorization.

Annie Lennon is a medical journalist. Her writing appears on Medscape, Medical News Today, and Psych Central, among other outlets.