NEW YORK – An advisory committee for the US Food and Drug Administration on Friday unanimously agreed that data submitted by Eisai and Biogen on the activity of their Alzheimer's disease drug Leqembi (lecanemab) confirms that it benefits patients.
The FDA granted accelerated approval to the monoclonal antibody in January based on its ability to clear amyloid, a hallmark sign of Alzheimer's that many say is the root cause of the brain degenerative disease. The same day as the accelerated approval, Eisai, the company leading development efforts for Leqembi, submitted a supplemental biologics license application seeking traditional approval for the drug based on results from a Phase III trial that it said confirmed the drug slows disease progression.
After reviewing the data, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee agreed in a 6-0 vote that the results of the CLARITY AD trial verified Leqembi's clinical benefit in Alzheimer's patients.
"The evidence for clinical benefit was very clear, very robust," Merit Cudkowicz, a neurology professor at Harvard Medical School and advisory committee member, said at the meeting. "For an illness like this where we really don't have very much, these are meaningful changes for people living with Alzheimer's."
Recommendations from the FDA's advisory committees are nonbinding. While the agency usually follows the advice of its independent expert panels, the agency controversially went against its advisory body's recommendation in granting accelerated approval to Aduhelm (aducanumab), another Alzheimer's drug developed by Biogen and Eisai, based on its impact on a surrogate endpoint — beta-amyloid plaque, the same biomarker targeted by Leqembi.
Leqembi is indicated for patients with cognitive impairment or mild dementia, who have evidence of amyloid pathology in their brains.
In the CLARITY AD study, investigators randomized about 1,700 participants with early Alzheimer's disease to receive either Leqembi or placebo and assessed memory and other changes using the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), an 18-point scale in which 0 represents no signs of clinical dementia.
After 18 months on treatment, patients on Leqembi averaged an increase of 1.21 points from baseline on the CDR-SB, while those on placebo averaged an increase of 1.66 points. That represented a statistically significant treatment effect, with Leqembi-treated patients experiencing a 27 percent slower rate of cognitive decline, according to the trial results presented by Eisai. In the Leqembi-treated cohort, the change from baseline in CDR-SB scores was statistically significantly smaller, compared to the placebo group, starting as early as six months after treatment, the company said.
However, during the public comment period at the advisory committee meeting, some physicians voiced concerns that there was only a 0.45 point difference between the average change in CDR-SB score in the two groups after 18 months. Other healthcare groups have voiced the same worries since Leqembi won accelerated approval earlier this year.
"Several of my colleagues and I have struggled to understand and translate to our patients what these small changes in cognitive score are in terms of cognitive and physical function, and whether or not they're meaningful," said Reshma Ramachandran, assistant professor at Yale School of Medicine. "FDA should not approve lecanemab and should require further studies to help us determine whether the drug is truly safe and effective for our patients."
Approving the drug based on current evidence would effectively, "unfairly shift the burden of uncertainty onto prescribing clinicians, patients, and their loved ones," she added.
Still, other physicians, Alzheimer's groups, and patients rallied around Leqembi. One patient with early-onset Alzheimer's and who participated in a Leqembi trial advocated for the drug's approval, describing her optimism for the future of Alzheimer’s treatments. "While the thought of a cure for Alzheimer's is certainly part of my optimism, I'd like you to know that, for me, more time is enough for now — and that is the promise of treatments like lecanemab," she said.
In remarks during the meeting, Teresa Buracchio, acting director of the FDA's office of neuroscience, also addressed concerns over the 0.45-point change on CDR-SB.
"I would like to clearly state that the agency considers the results of Study 301 to be clinically meaningful," she said. "A change on any individual domain on that scale represents a meaningful change in function for the patient."
Ahead of the advisory committee meeting, reviewers from the FDA released a briefing document, in which they said the treatment effect for Leqembi was "supported by the consistently favorable results" of the confirmatory trial. However, they asked the advisory committee to weigh the risks and benefits of the drug for three specific patient subgroups that experienced serious adverse events.
Overall, 14 percent of patients in the Leqembi-treated group and 11 percent of patients in the placebo group experienced at least one serious adverse event. These adverse events were generally consistent with what has been observed in previous trials, according to FDA reviewers. The most common serious adverse events in the Leqembi-treated group were infusion-related reactions, reported by 1.2 percent of patients, and edema, an amyloid-related imaging abnormality (ARIA), reported in 0.8 percent.
However, the risk of ARIA increased in patients who carried the APOE ε4 allele, which is associated with an increased risk for Alzheimer's. Forty-five percent of patients who were APOE ε4 homozygous reported ARIA, compared to 14 percent of non-carriers.
The second patient subgroup the FDA asked the advisory committee to consider were Leqembi-treated patients exposed to anticoagulants, who reviewers characterized as having a "slightly higher incidence of cerebral hemorrhage" than those who did not, 2.5 percent compared to 0.6 percent, respectively. FDA reviewers also said it's unclear whether the risk of serious outcomes from ARIA are higher for subjects with underlying cerebral amyloid angiopathy (CAA), representing the third patient subgroup.
While acknowledging safety concerns, committee members mostly agreed that there wasn't enough evidence to restrict access to Leqembi for any of the three patient subgroups at this time — noting small sample sizes of patients who suffered these adverse events. Cudkowicz, however, said she didn't think a patient taking anticoagulants should also receive Leqembi. "Until we have more safety data on the use of antithrombotics and this drug, … this is where I don't think the benefit outweighs the risk," she said, noting the serious nature of cerebral hemorrhage.
"This is where waiting for additional data from the open-label [extension] and from other studies might be helpful," she added.
However, most committee members said there was too much uncertainty to restrict the indication of the drug and would defer to the judgment of physicians, patients, and caregivers making decisions on the individual level. They recommended continued attention to these patient subgroups during the CLARITY AD study's open-label extension, which is ongoing.
"I know that we all as physicians try to protect our patients," said Michael Gold, chief medical officer at Neumora Therapeutics and advisory committee member. "Patients should be informed about the risk, and then it's their decision whether they want to take it or not. For some patients, there's a higher tolerance for risk than for other patients."
Leqembi's labeling already includes a warning about increased risk of ARIA in APOE ε4 homozygotes and a need to exercise caution when considering administering antithrombotic medications, including anticoagulants. Committee members suggested the FDA consider amending the label to require testing for APOE ε4, so that physicians can closely monitor those patients, and adding a warning about underlying CAA.
"We don't want to be too restrictive in our labeling," the FDA's Buracchio said. "We do want to allow for clinical flexibility. … We want prescribers to be aware of the risks, but we also really want to encourage good clinical judgment on an individual assessment level of a patient."
The US Centers for Medicare & Medicaid Services, which so far has restricted coverage for monoclonal antibody drugs that treat Alzheimer's by targeting amyloid, recently said it would cover such drugs if granted traditional approval from the FDA. The CMS said it would require the drug to be administered in clinical settings where providers agree to collect long-term outcomes data.
The FDA is expected to issue a decision on Leqembi by July 6.