Eli Lilly and Company have unveiled the full clinical results for its Alzheimer’s drug candidate, a monoclonal antibody called donanemab. The data, published in the Journal of the American Medical Association and also presented on July 17 at the Alzheimer’s Association International Conference in the Netherlands, show that donanemab staves off disease progression among people with early-stage Alzheimer’s (DOI: 10.1001/jama.2023.13239). Lilly first announced in May that donanemab met its primary and secondary endpoints during Phase 3 clinical trials.
In the 1,736-person, 18-month study, donanemab slowed cognitive decline by 29% compared to the placebo. For some patients, the investigational drug delayed cognitive worsening by as much as 7.5 months. Participants who took the drug saw amyloid plaque in their brains decrease by an average of 84%. This plaque, insoluble deposits of amyloid-β protein, is hypothesized to be a driver of the disease.
However, like other amyloid-busting monoclonal antibodies, donanemab also caused swelling and bleeding in the brain. These side effects, called amyloid-related imaging abnormalities (ARIA), can be fatal. ARIA occurred in 37% of participants on donanemab. The study also reported three treatment-related deaths among those who took the experimental drug.
Overall, donanemab’s performance was comparable to Eisai and Biogen’s lecanemab, marketed as Leqembi, the only other disease-modifying monoclonal antibody for Alzheimer’s . “The prospects for donanemab are incredibly positive, and the drug presents as a strong competitor for Leqembi,” says Pamela Spicer, a principal analyst at Citeline. Earlier this month, the US Food and Drug Administration granted lecanemab traditional approval, making it the first amyloid-eliminating antibody to gain full authorization. Donanemab is also advancing toward the regulatory finish line, with an FDA decision slated for the end of the year.
“We really had no surprises with respect to the basic questions about the efficacy, the safety, and the biomarker outcomes,” David Knopman, a Mayo Clinic neurologist, says of the new report. However, he notes that donanemab did not appear to reduce the amount of neurotoxic tau protein in the brain. Tau is a hallmark of neurodegeneration, whereas amyloid-β’s impact on the brain is less clear. “If the outcomes from lecanemab and donanemab are the best we can do, it certainly suggests that the amyloid hypothesis by itself is incomplete,” he says.
Whether donanemab’s statistics translate to real-world benefit for patients is still an open question, Knopman says, and can only be answered by more data collection for longer than 18 months.
As a physician, he is on the fence about which monoclonal antibody he would hypothetically prescribe, Eisai-Biogen’s or Lilly’s. Donanemab is administered once a month, twice less frequently than lecanemab’s dosing schedule. Donanemab dosing can also be halted as soon as 6 months, once brain plaque clears, so it’s not an indefinite obligation, unlike lecanemab. But its safety risk for ARIA is double its competitor’s. “I would leave it to families to decide whether they think that the convenience outweighs the risks,” Knopman says.
Lastly, there’s the issue of pricing that could tilt patients’ decisions one way or another. Biologics like lecanemab do not come cheap, with oversize sticker prices that can soar upward of $50,000. “[Donanemab’s] price hasn’t been announced yet, so that could change everything,” Knopman adds.
This story was updated on July 21, 2023, to correct a quote by David Knopman. He said “I would leave it to families to decide whether they think that the convenience outweighs the risks,” not “convenience and outweighs the risks.”