A Food and Drug Administration advisory committee today recommended traditional approval of Eisai’s anti-amyloid antibody lecanemab. On the sole voting question before it, the six-member committee unanimously agreed that lecanemab’s Phase 3 Clarity study verified the treatment’s clinical benefit. This clears the way for lecanemab, currently available under an accelerated approval, to receive traditional approval as well as broader coverage from the Centers for Medicare and Medicaid Services (Jan 2023 news; Jun 2023 news).
Unlike the contentious AdComm for Biogen’s Aduhelm three years ago, this time there were no fireworks (Nov 2020 news). The FDA’s in-house clinical and statistical presentations presented a unified picture. Statistician Tristan Massie, who had previously pointed to problems with Aduhelm’s mixed Phase 3 results, expressed no reservations about the Clarity data. He said sensitivity analyses showed the findings were robust.
Alzheimer’s researchers agreed that lecanemab has proved itself. “This time is different,” David Knopman at the Mayo Clinic in Rochester, Minnesota, wrote in a comment to the FDA. He had been critical of aducanumab’s approval. “With prospective and ongoing care, a balance between benefit and risk seems sufficiently favorable to justify offering lecanemab to appropriate patients,” Knopman wrote.
The AdComm consisted of five scientists—chairman Robert Alexander at Banner Alzheimer’s Institute; ALS researcher Merit Cudkowicz at Massachusetts General Hospital, Boston; biostatistician Dean Follmann at the National Institute of Allergy and Infectious Diseases; neuroscientist Klaus Romero at the Critical Path Institute; and Parkinson’s researcher Tanya Simuni at Northwestern University, Chicago—as well as patient advocate Collette Johnston. Michael Gold at Neumora Therapeutics participated in the discussion, but did not vote.
ost of their discussion centered around safety. While the committee deemed the overall benefit/risk ratio favorable, members were concerned about the higher risk for subgroups of patients. Presentations from Eisai and the FDA highlighted a sixfold higher risk of ARIA-E in APOE4 homozygotes than noncarriers, 33 percent versus 5 percent, and 11 percent for heterozygous carriers. Though usually asymptomatic, ARIA can have serious health consequences. The most severe outcome, intracerebral hemorrhage, occurred in 0.7 percent of people on lecanemab, versus 0.2 percent on placebo. Three deaths in the Clarity open-label extension were associated with brain bleeds (Jan 2023 news).
FDA analyst Deniz Erten-Lyons presented additional information on these deaths, noting that in two of the cases, the person had severe cerebral amyloid angiopathy with inflamed blood vessels in the brain, a condition known as CAA-ri. Both these people were APOE4 homozygotes, and developed headaches after starting lecanemab. The third case involved a person taking anticoagulants due to a history of atrial fibrillation. Eisai trial data also flagged anticoagulant use as a potential risk factor for intracerebral hemorrhage, with two people on lecanemab in the placebo-controlled portion of the trial developing it, and none on placebo. Curiously, participants taking anticoagulants did not have higher rates of ARIA overall.
The FDA asked the committee for guidance on how the label might reflect the increased risk for these groups. Currently, the label recommends APOE genotyping, and suggests caution when prescribing to people on anticoagulants or with vascular risk factors. The committee concluded there were too many uncertainties in the data to make definitive policies at this time. They supported strongly recommending or requiring APOE genotyping, but stopped short of excluding any groups from treatment, noting that the benefit/risk ratio varies among individuals even in high-risk categories.
“At this point, I would leave this to clinical judgment,” Romero said. Johnston agreed. “As a caregiver, I want the option to have the information and make the decision,” Johnston said.
On the much-discussed question of clinical meaningfulness, researchers were less conflicted. The FDA’s Teresa Buracchio noted that the primary outcome measure, the CDR-SB, measures skills that are inherently meaningful to patients. “The FDA considers the results clinically meaningful,” she said. Committee members largely agreed with this assessment. Simuni noted that although the CDR-SB difference between the treatment and placebo groups was small, that has to be considered in the context of the overall slow rates of decline at this early stage of AD. The committee was particularly impressed by patient-reported outcomes on maintained quality of life, and the five-month delay in disease progression seen in Clarity (Apr 2023 conference news). “Delayed progression is absolutely meaningful,” Gold said.
Lecanemab’s AdComm attracted less attention from the public than did aducanumab’s. There were only 25 comments submitted to the FDA before the meeting, nearly all recommending approval. During the meeting’s public forum, 21 people spoke, with 16 of them supporting approval and five against. Supporters comprised three neurologists, seven advocacy groups, and six patients or caregivers. Some of the patients had participated in Clarity and are currently in the open-label extension, and believe the drug has helped them. One caregiver noted that her husband became more talkative and helped around the house more after starting the drug. Another said his wife was better able to follow TV shows and remember conversations. A patient who had forgotten how to use her computer said she is now using it again. “This gives me hope I can maintain my independent life,” said another early stage patient.
Those opposed included two neurologists affiliated with the advocacy group Doctors for America, which promotes affordable care, as well as three representatives of health research organizations. All said the treatment’s risks outweighed its benefits.
The most controversial moment for this AdComm came before the meeting started, when one member was asked to recuse himself due to a conflict of interest. David Weisman at Abington Neurological Associates has consulted for Eisai and Biogen, and last year signed an Alzheimer’s Association letter supporting lecanemab approval, presumably precluding an open mind about the question today (Dec 2022 conference news). Weisman has commented on Alzforum, which has a voluntary policy on disclosing conflicts of interest.
On June 9th, the FDA issued a briefing document on the matter; the agency will render its decision by July 6.—Madolyn Bowman Rogers
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