When an Alzheimer’s drug recently gained a second chance from European regulators after an initial rejection, the decision bucked the agency’s norm.
Leqembi became the first fully FDA-approved drug among the emerging class of anti-amyloid Alzheimer’s treatments in 2023. Developed by Biogen and Eisai, Leqembi was originally granted an accelerated approval by the FDA before scoring a full nod later in the year.
The situation was different across the Atlantic.
A European Medicines Agency committee decided not to recommend Leqembi for approval in July 2024. Biogen and Eisai appealed the decision, and the agency, which doesn’t typically reverse such decisions, agreed to give it another look. Now, with a positive recommendation secured, they may have a better shot.
Leqembi’s only anti-amyloid rival, Kisunla, which was developed by Eli Lilly and approved by the FDA last summer, is also facing difficulties getting the go-ahead in Europe. After the EMA rejected it late last month, Lilly said it would ask for the agency’s Committee for Medicinal Products for Human Use to reconsider.
In both cases, European regulators expressed concerns over the risk of a brain swelling side effect called amyloid-related imaging abnormalities associated with the treatments. The committees ultimately concluded that the benefits don’t outweigh the safety risks.
And the challenging path the companies have faced getting their Alzheimer’s treatments onto both the U.S. and European markets showcases an emerging regulatory trend: The FDA provides more flexibility for novel drugs compared to the EMA, according to a recent study in Health Affairs. Their approvals in the U.S. also underscore how regulators are balancing the need for innovation with uncertainties in clinical results.
FDA’s flexibility
The FDA approved more first-in-class drugs compared to its European counterpart between 2013 and 2023, the Harvard researchers found. Out of 186 drugs approved by the FDA in the review period, only 121 were scored a nod from both regulators.
The FDA has also been more willing to give first-in-class drugs a speedier path through the approval process — 81% were designated for expedited programs by the FDA compared to 30% in Europe
Even with more flexibility in the U.S., drugmakers still face challenges with novel therapies.
“The substantial regulatory flexibility applied to first-in-class drug approvals can help ensure that such drugs reach the market as quickly as possible, but it also raises the stakes for post-approval oversight of the drugs to ensure that they continue to have the expected effectiveness and safety in routine clinical use,” the study authors wrote.
Lilly and Eisai have firsthand experience from their first go at Alzheimer’s.
The partners’ treatment Aduhelm, which became the first amyloid plaque-clearing drug to hit the U.S. market, received accelerated approval by the FDA in 2021, but was pulled from shelves in early 2024 amid controversy around safety, efficacy and price. The companies canceled a post-approval study for Aduhelm and instead focused on Leqembi, which has seen better uptake and sales.
But Leqembi’s launch was slower than originally expected due to caution among healthcare providers and limited coverage. It’s a common experience for first-in-class drugmakers, according to the study authors, as payers may not want to shell out for expensive drugs they deem experimental.
“In the U.S., payers may choose not to cover some first-in-class drugs because of uncertain evidence of safety and effectiveness,” they wrote.
The same is true in other countries, including the U.K., Canada and Australia, where more than 25% of FDA-approved drugs received negative reimbursement decisions “because of uncertain benefits and high prices,” the authors said, citing previous studies.
While the FDA might be more welcoming of experimental treatments, the approach has stirred concerns at times. The Harvard researchers noted that other studies suggest the FDA’s expedited programs can lead to approvals for drugs that don’t offer “substantial added clinical benefits” and may have higher safety risks.
That particular issue was raised when a teenage patient died in March after taking Sarepta Therapeutics’ Elevidys, an adeno-associated virus-based gene therapy that received accelerated approval as a first-in-class drug for Duchenne muscular disease in 2023. Peter Marks, formerly the director of the FDA’s the Center for Biologics Evaluation and Research, went against reviewers to grant an approval to Sarepta twice –– first on an accelerated basis and then for an expansion. While reviewers flagged insufficient and conflicting data, Marks pushed the approval through, citing the agency’s need for flexibility when reviewing drugs targeting rare diseases.
Going forward, the researchers suggested the FDA review and set standards to ensure expedited programs are only used for safe and effective drugs. They also noted that future studies should examine the post-market performance of first-in-class drugs and track patient outcomes.
Overall, the study authors urged that consistency will be key. An accumulation of controversial approvals like Aduhelm has the potential to erode trust from doctors and patients, as well as drive uncertainty about the tolerance for evidence gaps in pharma.
