High Confidence AD Drug Donanemab Will Get FDA Panel Nod

The Peripheral and Central Nervous System Drugs Advisory Committee of the US Food and Drug Administration (FDA) will meet on June 10 to discuss the biologics license application for donanemab for treatment of patients with early symptomatic Alzheimer’s disease (AD). 

The FDA delayed its decision on whether to approve the antiamyloid agent back in March, opting instead to hold a meeting of its outside experts to weigh the results of the phase 3 TRAILBLAZER-ALZ 2 trial. 

What is the evidence on donanemab? Why the FDA delay its decision, and what potential concerns might be raised by the advisory committee?

What Did TRAILBLAZER-ALZ 2 Find? 

Donanemab (Eli Lilly) is an investigational immunoglobulin G1 monoclonal antibody directed against an insoluble, modified, N-terminal, truncated form of beta-amyloid.

TRAILBLAZER-ALZ 2 evaluated the safety and efficacy of donanemab (vs placebo) in 1736 patients (mean age, 73 years) with early symptomatic AD (mild cognitive impairment or mild dementia) with evidence of amyloid and tau pathology on PET.

Donanemab was administered at a dose of 700 mg for the first three doses and 1400 mg thereafter. The drug was given once monthly for up to 72 weeks. Participants were stratified based on tau levels, a biomarker for AD progression, into a low/medium tau group and a combined tau group (low/medium and high tau).

As previously reported by Medscape Medical News, donanemab significantly reduced brain amyloid plaque burden and significantly slowed cognitive and functional decline, compared with placebo. 

The primary endpoint was change from baseline to 76 weeks on the integrated Alzheimer’s Disease Rating Scale (iADRS), which measures cognition and activities of daily living. 

The least-squares mean change in the iADRS score (range, 0-144; lower score indicates greater impairment) at 76 weeks was -6.02 in the donanemab group and -9.27 in the placebo group for the low/medium tau population and -10.19 in the donanemab group and -13.11 in the placebo group in the combined study population. Both results were statistically significant (P <.001>

Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24%; 52 symptomatic) in the donanemab group and 18 (2%; 0 symptomatic) in the placebo group. Infusion-related reactions occurred in 74 participants (8.7%) receiving donanemab and four participants (0.5%) receiving placebo. 

Three deaths in the donanemab group and one in the placebo group were considered treatment-related.

These results are “very exciting” and represent “the strongest data to date” for anti-amyloid monoclonal antibodies in AD,” Percy Griffin, PhD, director of scientific engagement, Alzheimer’s Association, told Medscape Medical News when the TRAILBLAZER-ALZ 2 results were released in July 2023.

Why the FDA Delay?

The FDA was expected to decide on donanemab in the first quarter of 2024, without a formal advisory committee meeting. 

The subsequent decision by the agency to convene a meeting of outside experts was “unexpected,” Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience, said in a statement at the time. 

J.K. Wall, senior director of neuroscience communications at Lilly, told Medscape Medical News that the FDA informed the company that it wants to “further understand topics related to evaluating the safety and efficacy of donanemab, including the safety results in donanemab-treated patients.”

“It also wants to discuss the efficacy implications of the unique trial design of the TRAILBLAZER-ALZ 2 study, including its limited-duration dosing regimen that allowed patients to complete treatment based on an assessment of amyloid plaque and the inclusion of participants based on tau levels,” said Wall.

Howard Fillit, MD, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, told Medscape Medical News the FDA decision to convene an advisory meeting on donanemab is “not a setback, but another step forward in the drug approval process, with the regulatory agency doing its due diligence before the distribution of the drug to patients.”

What Are the Potential Concerns?

Fillit doesn’t necessarily believe the FDA panel will have any major or unexpected concerns about donanemab but will want to discuss differences in the design of the TRAILBLAZER-ALZ 2 study of donanemab compared with the CLARITY-AD study of lecanemab (Leqembi; Eisai Inc).

“I think donanemab and lecanemab are about the same in terms of efficacy and safety. The difference was in the way the trials were conducted in terms of the dosing schedule, the stopping rules, and the use of tau imaging. Those are the three things the FDA wanted to discuss with their advisors,” said Fillit. 

“I think everyone in the field feels this [advisory committee] meeting is mostly informational, and I would hope that donanemab would be approved by the FDA in the not-too-distant future,” Fillit added.

Wall told Medscape Medical News that Eli Lilly has “full confidence in donanemab’s meaningful results, and we look forward to discussing them further with the FDA, medical experts, patients, and care partners at the advisory committee hearing.”

Wall said it is “premature” to talk about price or discuss label requirements for donanemab once approved. 

However, if it is approved, the drug will be the third antiamyloid monoclonal antibody okayed in the US, behind aducanumab and lecanemab. Aducanumab is no longer available, after Biogen announced earlier this year that it would discontinue a postapproval study and commercialization of the controversial drug.

Fillit is looking forward to having two available antiamyloid agents. “Competition in the field is always good. It gives more validity to the mechanism of action to this new class of drugs and when you have two in class, I think that’s a good thing,” he said.

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