Upon reexamination, the European Medicines Agency has made a U-turn on Eisai and Biogen’s Alzheimer’s disease drug Leqembi.
After a rejection in July, drug reviewers at the EMA have now recommended an approval for Leqembi to treat mild cognitive impairment or mild dementia due to Alzheimer’s disease, but only in patients who have one or no copy of the ApoE4 gene, the agency said Thursday.
The EMA recommendation excluded patients with two copies of ApoE4 because they are at a higher risk of experiencing the side effect of brain swelling or bleeding, known as amyloid-related imaging abnormalities (ARIA), than other patients when taking Leqembi.
The EMA’s human medicines committee concluded that, in this restricted population, “the benefits of Leqembi in slowing down progression of symptoms of the disease are greater than its risks.”
The U.K.’s Medicines and Healthcare products Regulatory Agency previously adopted the same limitation by ApoE4 count in its approval for Leqembi, shortly after the EMA spurned the anti-amyloid antibody in a larger population. Even though the FDA has given Leqembi a broad indication regardless of ApoE4 status, many U.S. doctors have voluntarily decided not to give the drug to patients with two copies of the gene given the risk of ARIA.
In the EMA’s reexamination performed at the request of Eisai, the agency considered subgroup analyses showing that 8.9% and 12.9% of patients in the restricted population experienced ARIA brain swelling or bleeding, respectively, versus 12.6% and 16.9% in the overall population, which included those with two ApoE4 copies.
In the subgroup, patients treated with Leqembi had a slower worsening cognitive and functional symptoms compared with placebo after 18 months as measured by a rating scale known as CDR-SB. The increase on CDR-SB score was 1.22 for Leqembi and 1.75 for a dummy drug, where higher numbers indicate greater impairment.
Besides the additional subgroup analyses, the EMA said it “also considered submissions from patients, carers, clinicians and organizations, who shared their perspectives on the unmet needs of patients with Alzheimer’s disease and the data on cognitive decline and risks.”
Along with the thumbs-up, the EMA is also asking that Leqembi be available through a controlled access program to ensure that the restriction is followed. Same as the FDA, the European regulator is requiring MRI scans to monitor for ARIA before initiating Leqembi and before the fifth, seventh and 14th doses.
Eisai is also on the hook to conduct a post-marketing safety study to further characterize ARIA and to assess whether some risk countermeasures work, according to the EMA. An EU-wide registry will be set up to include real-world patients treated with Leqembi. This registry study will collect information on side effects and Alzheimer’s progression.
The positive EMA opinion will be sent to the European Commission to make a final marketing authorization decision.
An EU nod could add some fuel to the languid engine that is Leqembi’s launch. In the third quarter, the drug brought in sales of about $67 million globally, including $39 million from the U.S., a year after the FDA’s conversion of a previous accelerated approval into a full nod.
Eisai, Biogen and analysts are counting on the potential introduction of a subcutaneous formulation as an inflection point for Leqembi, which currently is administered via intravenous infusion.