Doctors and scientists want the US Food and Drug Administration (FDA) to convene an expert panel to review safety concerns around an Alzheimer’s drug that won fast-track approval in January.
Some health experts are saying the agency is not doing enough to address questions about Eisai’s lecanemab – including three patient deaths during clinical trials that scientists connected to the drug.
It’s the latest concern over whether the FDA is cutting corners evaluating Alzheimer’s drugs, prompted by its controversial 2021 approval of Biogen’s Aduhelm, which was despite the objections of an advisory panel and without evidence the drug actually slowed the decline of memory and brain function.
Additionally, reports Axios, in the case of lecanemab, the FDA did not follow its customary process and convene an advisory panel before green-lighting the accelerated approval. Accelerated approvals are based on variables suggesting a drug probably works, instead of real-world clinical results.
Late last year, Congress gave the FDA more authority over confirmatory trials that are supposed to prove the drugs work. At a recent National Academies of Sciences, Engineering and Medicine workshop, FDA officials were told they should be more transparent about the rationale for using the fast-track process in new areas beyond cancer drugs and infectious diseases.
Several specialists suggest the agency should convene a public discussion on Eisai’s drug, before deciding whether it should get a full approval based on its actual clinical benefit.
The experts point to a congressional probe into the Aduhelm case that found that the FDA did not follow its own guidance and practices during that approval process. As was pointed out during the Aduhelm controversy, the underlying concern is that the FDA’s decisions could undermine medical standards and give millions of patients false hope, because green-lighting more drugs just because they might work could unleash perverse incentives.
In January, the FDA granted accelerated approval to Eisai’s lecanemab – marketed at Leqembi – which had shown in large clinical trial results published in the New England Journal of Medicine that it can slow the progression of the disease by 27%, as well as slow the rate of cognitive decline over 18 months.
The study showed that patients who took lecanemab presented more adverse effects than those given a placebo.
Eisai reported 13 deaths out of the nearly 1 800 participants in the trial. However, the company has not released any details on the deaths, so scientists have been unable to independently determine whether lecanemab had anything to do with them.
“Critical questions remain as to whether the benefits outweigh the risks reported of brain swelling, brain bleeding and death among patients who received this drug,” the independent advocacy group Doctors for America said in a statement.
Eisai researchers have suggested that Alzheimer’s patients are willing to take a drug with health risks if it could slow the progression of the condition: “They are willing to risk a brain haemorrhage,” Sharon Cohen, one of the principal investigators, said in November.
A report in Nature Reviews Neurology found that while the lecanemab trial represents “an important milestone”, there's still a need for “a thorough appraisal of the data” to indicate whether the results are clinically meaningful.
Lecanemab targets amyloid plaques, proteins in the brain that are believed to contribute to the development of Alzheimer’s.
The accelerated approval was not based on the NEJM study but on a phase II trial that looked at patients’ cognitive scores as the primary clinical endpoint. The drug actually failed to meet the required scores on the primary endpoint and the approval was granted instead based on a surrogate endpoint, or variable, that indicated the reduction of amyloid plaques.
The presence of amyloids is measured through PET scans. However, there is no conclusive evidence that PET amyloid-beta scans are “reasonable and necessary” for the diagnosis or treatment of Alzheimer’s, per the Centres for Medicare and Medicaid Services.
An independent panel needs to meet to discuss the use of beta amyloid PET scans to support a drug’s accelerated approval, which is of “tremendous public health urgency”, said Jason Karlawish, a professor at the University of Pennsylvania Perelman School of Medicine.
Lecanemab is the third drug that FDA has used beta amyloid PET scans “to decide whether they're going to grant accelerated approval, and yet we've never had a public discussion of the data to support the use of that endpoint”, Karlawish added.
The FDA has so far evaluated three Alzheimer’s drugs based on the amyloid hypothesis and are measured by the beta amyloid PET scans: Aduhelm, lecanemab and Eli Lily’s donanemab, the last of which did not receive FDA accelerated approval.
Axios article – Health experts want FDA safety review of fast-tracked Alzheimer's drug (Open access)
See more from MedicalBrief archives:
FDA denies accelerated approval for Alzheimer’s drug
Concern over FDA’s fast-track approval of Alzheimer's drugs
Scientists hail Alzheimer’s breakthrough despite two trial candidates’ deaths
Alzheimer’s drug slows cognitive decline in trial – breakthrough or another false dawn?