Unanimous: FDA Advisory Committee Backs Donanemab

Today the U.S. Food and Drug Administration’s advisory committee gave the nod to donanemab, clearing the way for its marketing approval. All 11 members voted that the antibody was effective for people with mild cognitive impairment or mild dementia due to AD, and that its risk-to-benefit ratio was favorable overall.

Members expressed concern about a worse risk-to-benefit for APOE4/4 homozygotes, as well as a lack of data on underrepresented groups and on people who have amyloid plaques and MCI but almost no tangles. Nonetheless, the committee refrained from recommending that these groups not be treated. Rather, they stressed the importance of communicating limitations and uncertainties in the product label.

“The committee recognized, correctly I think, that the data supported a modestly favorable benefit to risk ratio for donanemab,” David Knopman at the Mayo Clinic in Rochester, Minnesota, wrote to Alzforum. Michael Greicius at Stanford University, Palo Alto, California, remains skeptical about anti-amyloid antibodies as a class, and today’s meeting did nothing to persuade him. “Fundamental questions about the efficacy of donanemab and lecanemab remain. It is remarkable that we have not seen a scatterplot showing the association between amyloid reduction and cognitive outcomes in the donanemab or lecanemab studies,” he wrote to Alzforum (comments below).

In good news for drug sponsor Eli Lilly, the committee argued against requiring tau PET scans before prescribing donanemab. The Phase 3 trial had selected patients by tau PET, enrolling only those above a cutoff of 1.10 SUVR. Those below this threshold were invited to join an open-label addendum trial that administered donanemab and tracked effects on biomarkers and safety, but did not measure cognitive/clinical outcomes. Despite the lack of this data, committee members nevertheless noted that this “no-tau” group notched similar biomarker benefits as did people in the Phase 3 trial. The committee believed requiring tau PET would impose too great a burden on patients and healthcare systems, strangling access to the drug.

In the donanemab trial, providers stopped treatment once plaque was gone. The AdComs liked this approach, saying it could motivate patients to complete treatment, and would free up infusion center chairs and provider time for a greater number of patients. However, the committee noted the dearth of data on what happens to cognitive status after stopping, and no data on when to restart treatment if a patient worsens. They felt these decisions should be left up to individual providers and patients.

During the meeting’s open forum, 18 people spoke in favor of donanemab, three against. The supporters comprised 10 patients or caregivers, three providers, and five representatives of advocacy or research groups.

If approved, donanemab will join lecanemab as the second anti-amyloid antibody currently on the market, after the earlier withdrawal of aducanumab. A more detailed story will appear in this space later this week.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Donanemab
  2. Leqembi
  3. Aduhelm

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