Lilly’s Donanemab Hit with Surprise Delay, Set to Face FDA Adcomm

Eli Lilly_iStock, jetcityimage

Pictured: Eli Lilly's headquarters in Indianapolis/iStock, jetcityimage

Eli Lilly on Friday announced that the FDA has decided to hold an advisory committee meeting to discuss its investigational Alzheimer’s disease antibody donanemab, pushing its target action date to beyond the first quarter of 2024.

The regulator will convene its Peripheral and Central Nervous System Drugs (PCNS) Advisory Committee to evaluate the safety and efficacy data supporting donanemab, as well as the “efficacy implications of the unique trial design of the TRAILBLAZER-ALZ 2 study,” according to Lilly’s announcement. The FDA has yet to set a date for the meeting.

The FDA wants more clarity regarding the study’s inclusion of patients based on tau levels and its dosing regimen, in which patients were allowed to stop treatment after amyloid plaques had been cleared from the brain.

Lilly called the FDA’s decision to hold an advisory committee meeting after the initial anticipated target action date “unusual,” while noting that such meetings were also held for the two other FDA-approved amyloid-targeting Alzheimer’s therapies.

“We are confident in donanemab’s potential to offer very meaningful benefits to people with early symptomatic Alzheimer’s disease,” Anne White, president of Lilly Neuroscience, said in a statement. “We look forward to the opportunity to further present the TRAILBLAZER-ALZ 2 results and put donanemab’s strong efficacy in the context of safety.”

Howard Fillit, co-founder and CSO of industry group Alzheimer’s Drug Discovery Foundation, in a statement agreed with the company that the PCNS meeting prior to approval “follows the regulatory process that was used for the other drugs in this class, including Leqembi.”

“Today’s FDA decision is not a setback, but another step forward in the drug approval process,” Fillit said. “The regulatory agency is doing its due diligence before the distribution of the drug to patients.”

Like Eisai and Biogen’s Leqembi (lecanemab)—which in June 2023 became the first anti-amyloid Alzheimer’s therapy to win full approval—donanemab is a monoclonal antibody that targets amyloid-beta aggregates and promotes their clearance from the brain.

Lilly is seeking approval for donanemab on the back of TRAILBLAZER-ALZ 2, a late-stage, double-blinded and placebo-controlled study that enrolled more than 1,700 participants who were selected through cognitive assessments and brain imaging techniques to quantify amyloid plaque and tau levels. All patients had early symptomatic Alzheimer’s disease.

TRAILBLAZER-ALZ 2 employed a unique treatment protocol that allowed patients to discontinue donanemab treatment after amyloid plaques in the brain had dropped past a specific pre-defined level. In January 2023, this “innovative” design—as described by Fillit—likely contributed to the FDA’s rejection of donanemab’s bid for accelerated approval.

In March 2023, Lilly posted more data from TRAILBLAZER-ALZ 2 demonstrating that donanemab met its primary efficacy endpoint and significantly slowed cognitive and functional decline in patients.

Despite its strong performance, however, several safety concerns remained. There were two deaths in TRAILBLAZER-ALZ 2, which were conclusively attributed to amyloid-related imaging abnormalities (ARIA). A third death was also observed but could not be linked to serious ARIA. Manifesting as microhemorrhages, ARIA were reported in 31.4% of donanemab-treated patients while ARIA indicative of brain swelling developed in 24%.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

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