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FDA delays decision on donanemab

The FDA today announced that it will convene an advisory panel to review the data submitted to support potential approval of donanemab, a monoclonal antibody against the beta amyloid protein that demonstrated efficacy in early Alzheimer’s disease in a recent Phase 3 clinical trial. A positive decision to approve donanemab had been expected before the end of this month.

Though data for donanemab’s ability to lower brain amyloid levels are convincing, the FDA had opted not to grant accelerated approval to the drug, citing limited safety data. This contrasted the agency’s decisions for two other amyloid-lowering drugs, aducanumab and lecanemab and means that, for now, donanemab will not be available for clinical use. 

FDADr. John Sims, medical director at Eli Lilly and first author of the paper describing the recent trial results, told the New York Times that the FDA’s decision could stem from the uniqueness of Lilly’s trial designs to test donanemab. In contrast to other trials, studies of donanemab employed two novel approaches. First, the criteria for enrollment included staging disease based on neurofibrillary tangle burden using tau PET. A Phase 2 trial limited inclusion to those with “enough” tau burden, but not “too much.” The Phase 3 trial included patients with higher tau burden, but limited the primary evaluation of efficacy compared to placebo to those patients with “low” or “medium” tau. 

The second unique aspect of the donanemab trials was how the drug was used, or more specifically how it was stopped. In both Phase 2 and Phase 3, the company chose to test donanemab through a treatment approach that halted therapy once patients had their amyloid lowered to “not elevated” levels. In the trials, patients were switched to placebo once their amyloid had been lowered; in clinical practice, patients would presumably simply stop treatment. In the low/medium tau group treated with donanemab in the Phase 3 trial, 80% of patients had their amyloid successfully lowered. 

The data for donanemab remain convincing, but the FDA advisory panel will be highly anticipated. The FDA’s reluctance to grant accelerated approval would seem to foreshadow discussions about the adequacy of safety data, but questions about whether the drug label will include information about tau PET levels loom. For now, it appears we’ll all need to stay tuned and wait for more information, including a date for the advisory panel meeting.