Eli Lilly submits donanemab to FDA as it shares full PhIII results at medical meeting

Eli Lilly said Monday morning that it has submitted an application for its experimental Alzheimer’s drug donanemab to the FDA, and expects a decision by the end of the year.

If full approval is granted, donanemab would be the second Alzheimer’s drug in 20 years to reach that milestone, following Biogen and Eisai’s Leqembi. The FDA approved Leqembi earlier in July, opening the doors to coverage for millions of Medicare recipients.

An approval would also set the stage for a showdown between the two Alzheimer’s drugs, as providers will have to weigh which option to give their patients. Both drugs work by uprooting clumps of proteins known as amyloid plaques which are a hallmark of Alzheimer’s disease.

Lilly announced its FDA submission alongside its presentation of full data from the Phase III trial, TRAILBLAZER-ALZ 2, at the Alzheimer’s Association International Conference in Amsterdam, which was published simultaneously in JAMA.

Dawn Brooks

“Everyone is saying there’s a buzz,” Dawn Brooks, Lilly’s head of global brand development for donanemab, said of the conference. “It sets the stage for doctors working with patients to have important conversations and offer hope, where in the past, you could do a diagnosis, but maybe there wasn’t really much to say next.”

But the new drugs also come with significant side effects, including tiny brain hemorrhages and brain swelling that have led to death in a few cases. And on Monday, a third patient death in the trial was linked to donanemab.

In May, Lilly unveiled topline data showing that donanemab slowed decline on a cognitive and functional scale by 35% over an 18-month period in certain patients with early Alzheimer’s. Leqembi is dosed biweekly and donanemab is dosed once every four weeks.

“As with lecanemab, donanemab showed an impressive ability to remove amyloid from the brain, leading to what will eventually either be categorized as an extraordinary feat of science or a statistically significant but minimally clinically relevant result,” Eric Widera of the University of California, San Francisco, Sharon Brangman of SUNY Upstate, and Nathaniel Chin of the University of Wisconsin wrote in an accompanying editorial published in JAMA.

New data on safety, and another confirmed death

Three patients in the donanemab Phase III trial died following a treatment-related side effect known as ARIA, which can manifest into brain swelling or small hemorrhages. Previously, Lilly had confirmed that two of these deaths were linked to ARIA, and they suspected a third was linked as well.

Two of the three were carriers of one copy of a genetic marker called APOE ε4, which is associated with an increased risk of Alzheimer’s and earlier disease onset. The third was a noncarrier.

Notably, the study investigators noted that none were prescribed an anticoagulant or antiplatelet medicine — the simultaneous use of these treatments with Leqembi was implicated in the deaths of two patients.

Overall, patients who were ​​APOE ε4 carriers had a heightened risk of ARIA-E, which can lead to brain swelling. Those who carried two copies of the allele had the highest rate, at 40.6%. Just under a quarter — 22.8% — of those who had one copy of the allele had ARIA-E, while 15% of noncarriers did.

And 13.1% of patients on donanemab in the trial discontinued treatment due to adverse safety events, including injection reactions and ARIA-E. While cross-trial comparisons are far from perfect due to different patient enrollment criteria, by comparison, 6.9% in Leqembi’s Phase III trial discontinued from adverse events.

Trial lacks diversity, affecting analysis

Notably, the trial enrolled few patients of color — to the point that results in racial and ethnic subgroups outside white people were not statistically significant.

Mark Mintun

“We have very small numbers of people in these groups and the confidence intervals are very broad,” Eli Lilly VP of neuroscience Mark Mintun said during a press briefing. “It’s very, very hard to interpret and make conclusions from these type of data at this point.”

Of 1,251 trial participants from the US, only two were American Indian or Alaska Natives, 11 were Asian, 34 were Black and 71 were Hispanic.

“This donanemab trial does not provide sufficient evidence of safety or efficacy among people racialized as American Indian or Alaska Native, Asian, Black, or Hispanic,” Jennifer Manly, a professor of neuropsychology at Columbia, and Kacie Deters, a professor at UCLA, wrote in an editorial. With the “disproportionate burden of cognitive impairment and dementia due to Alzheimer’s disease in many of these groups, it is critical that clinicians, patients, and families understand the limits of what is known,” they wrote.

Mintun said for upcoming trials with donanemab — including one for safety and a prevention study for those at risk of Alzheimer’s disease — Lilly has “doubled down” on recruitment efforts to increase racial and ethnic diversity.

The study also capped the age of participants at 85, but doctors noted that the drug may be used in adults that are older than that in the real world.

“Debates about safety and efficacy aside, 2023 will see amyloid antibodies moving from the tightly controlled world of clinical trials to the real world,” Widera and colleagues wrote. “What matters now is taking data, however imperfect, and implementing in a population that may look very different than the population studied.”

Editor’s note: This story has been updated throughout with additional details from the trial and the medical conference. This story has also been updated to correct that 34, not 24 participants were Black.

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