Eisai’s efforts to bring its FDA-approved Alzheimer’s disease drug to patients in Europe have hit a setback. A European Medicines Agency committee has recommended against the granting of marketing authorization for the product, Leqembi, stating that the therapy’s benefits do not outweigh its risks.
The Thursday opinion issued by the EMA’s Committee for Medicinal Products for Human Use (CHMP) specifically cited the risk of amyloid-related imaging abnormalities (ARIA), which is swelling and bleeding in the brain. Commission rules permit drug companies to seek a re-examination of a negative CHMP opinion. Eisai said Friday that it plans to do so.
The formation of plaques of toxic amyloid protein is a hallmark feature of Alzheimer’s progression. Leqembi, administered as an intravenous infusion every two weeks, binds to amyloid and reduces the buildup of this protein in the brain. The drug was developed under a multi-drug neuroscience alliance between Eisai and Biogen. Tokyo-based Eisai led the development of Leqembi.
The main goal of the clinical trial used to support Leqembi’s regulatory submissions was to measure at 18 months the score according CDR-SB, a scale used to assess cognitive impairment in Alzheimer’s patients. The higher the score, the greater the impairment. Results showed the average score in the treatment group was 1.21. In the placebo arm, the average score was 1.66. While these results were sufficient to support the full FDA approval awarded to Leqembi last year, the CHMP’s review of the same clinical trial data left that advisory body unpersuaded.
“Although most cases of ARIA in the main study were not serious and did not involve symptoms, some patients had serious events, including large bleeds in the brain which required hospitalization,” the opinion said. “The seriousness of this side effect should be considered in the context of the small effect seen with the medicine.”
The CHMP was also concerned by the higher complication risk in certain patients. Carrying the ApoE4 gene is a known risk factor for developing Alzheimer’s. The CHMP noted that the ARIA risk is more pronounced in people who have a certain form of this gene and is highest in those with two copies of the gene. The committee said its opinion was also informed by input from a scientific advisory group comprised of neurologists and Alzheimer’s patients.
ARIA is a known risk factor for the class of anti-amyloid antibody drugs. This complication was flagged in a black box warning on the label of Aduhelm, an Alzheimer’s drug from the Eisai/Biogen alliance whose development was led by Biogen. Commercial struggles led Biogen to discontinue Aduhelm earlier this year. The ARIA and ApoE4 risks also appear on the labels of Leqembi and Kisunla, the Eli Lilly Alzheimer’s drug approved by the FDA in early July.
In a note sent to investors on Friday, William Blair analyst Myles Minter wrote that the negative opinion puts at risk the firm’s projection of $1.33 billion in European Union peak sales for Leqembi in 2035. The U.S. remains the larger market opportunity for the product with William Blair projecting $4.6 billion in sales by 2035.
Acknowledging Eisai’s plan to seek a re-examination of the negative CHMP opinion, Minter noted that published research shows re-examinations are successful in leading to an approved product only 25% of the time. He added that the CHMP’s focus on ARIA risk has negative readthrough to Lilly’s new Alzheimer’s drug, which showed higher rates of the complication in its clinical trials. Nevertheless, Minter still sees a path forward for these drugs in Europe.
“While we view this news as a setback for Biogen and Eisai, along with the beta-amyloid antibody field, we believe Biogen and Eisai’s argument to the EMA, which will be strengthened by continued use in the global market as well as current trials to reduce dosing frequency, will continue to get stronger and will ultimately lead to EMA approval,” Minter said. “Moreover, we believe a potential similar setback to Lilly’s Kisunla will not alter the competitive landscape in the EU.”
In addition to its FDA approval, Leqembi also has regulatory nods in Japan, China, South Korea, Hong Kong, and Israel.
Photo: Yuriko Nakao/Bloomberg, via Getty Images
