FDA Advisors Unanimously Recommend New Drug for Alzheimer’s Disease

The risk-benefit ratio was deemed ‘acceptable’ even though more adverse events, including deaths, occurred in the drug treatment group.

The U.S. Food and Drug Administration (FDA) in White Oak, Md., on June 5, 2023. Madalina Vasiliu/The Epoch Times

The advisory committee to the U.S. Food and Drug Administration (FDA) unanimously voted on Monday to recommend the approval of donanemab to slow the progression of Alzheimer’s disease.

The Peripheral and Central Nervous System Drugs Advisory Committee was asked to consider whether donanemab is effective for treating Alzheimer’s in those with mild cognitive impairment and mild dementia in the clinical trial population and whether the drug’s benefits outweigh the risks.

Data presented at the meeting showed that donanemab did not improve cognition in those who took it, and 7 percent experienced a slight neurocognitive decline after being on the drug for a year and a half.

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However, brain imaging showed that 76.4 percent of patients achieved clearance of amyloid plaques.

Donanemab breaks down amyloid plaques in Alzheimer’s disease, an incurable neurodegenerative disease characterized by amyloid and tau protein deposits in the brain that are subsequently linked to neurocognitive decline. The drug is designed to slow the disease or improve cognitive decline in its early stages by breaking down amyloid and tau protein accumulation.

Dr. Costantino Iadecola, director and chair of the Feil Family Brain and Mind Research Institute, voted in favor of the drug because he said the benefits outweigh the risks. He added that if some subgroups require further analysis, it should not hold up donanemab’s availability to the public.

Dr. Nilufer Ertekin-Taner also voted in favor of recommending the drug but suggested more prolonged surveillance, especially for groups underrepresented in clinical trial data, such as African Americans, Latin Americans, and those with specific genetic variants that predispose them to a greater risk of Alzheimer’s.

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The FDA was expected to rule on the drug in March 2024 but deferred its decision on whether to approve donanemab until its advisory panel could discuss manufacturer Eli Lilly’s (also known as Lilly) unique trial design and results of its phase 3 TRAILBLAZER-ALZ 2 trial.

During the Monday meeting, the reviewers expressed concerns about who was included in the trial and racial and ethnic disparities. However, they liked the idea that a patient could stop the drug when amyloids no longer appeared on scans and said the drug provides patients with an innovative option. Although adverse events, including deaths, were more prevalent in patients treated with donanemab compared to placebo, experts felt the risk-benefit ratio was “acceptable.”

FDA Reviewers Raise Concerns Over Clinical Trial Data

In an FDA briefing document published ahead of Monday’s advisory committee meeting, the agency’s internal reviewers flagged several safety and efficacy concerns regarding Eli Lilly’s clinical trial data.

Lilly’s clinical trial for donanemab initially tested whether the drug improved cognition and memory. However, the endpoint was changed during the study to evaluate instead whether the drug reduced amyloid plaque.

Due to this change, donanemab’s metric for efficacy was also changed.

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At first, Lilly used a standardized test to evaluate cognition and memory. This was changed to an integrated Alzheimer Disease Rating Scale (iADRS) test, which measured amyloid reduction instead. This move was against FDA recommendations.

The FDA reviewers also questioned how Lilly excluded patients with no to very low levels of tau proteins from the study and only focused on those with low-to-medium levels. Additionally, they wondered if participants should be taken off the drug once their amyloid levels fell below a threshold (set by Lilly) since the number of plaques may increase once patients are off the drugs.

Finally, the agency noted an “imbalance in deaths” in the donanemab arm compared to placebo. The exact mortality numbers are uncertain because more than 20 percent of participants in both the donanemab and placebo groups discontinued the study.

Lilly said that the excess mortality is caused by the adverse events from the drug breaking up the amyloids in the brain. Still, the FDA reviewers said excess mortality could not be entirely explained by such adverse events or cerebral hemorrhage.

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Dr. Curtis Schreiber, a neurologist, dementia specialist, and principal investigator at one of Lilly’s clinical trial sites, advocated donanemab’s approval.

“I saw my own patients on donanemab having results that demonstrate the real-life clinical meaning of this treatment,” he said. “We need more tools in our fight against Alzheimer’s disease. Approve donanemab.”

3 Deaths in Clinical Trial Data

Lilly’s phase 3 TRAILBLAZER-ALZ 2 study, published in the Journal of the American Medical Association, evaluated the safety and efficacy of donanemab compared to a placebo in 1,736 patients with early symptomatic Alzheimer’s and evidence of amyloid and tau pathology in brain imaging.

The study found that monthly intravenous infusions of donanemab slowed Alzheimer’s progression over 76 weeks. However, the treatment group experienced more deaths compared to the placebo group, including three deaths directly linked to donanemab.

Additionally, 112 participants on donanemab discontinued the trial due to adverse events compared to 38 patients receiving a placebo.

Serious adverse events were reported in 17.4 percent of those given donanemab and 15.8 percent of those in the placebo group. Microhemorrhage events also more than doubled in the donanemab group.

“I remain concerned that donanemab is yet another drug in a class of medications that have not shown themselves to produce clinically meaningful results, have a dangerous side effect profile, and do not offer accessible or relevant solutions for communities who are disproportionately impacted by this disease,” Dr. Dona Kim Murphey, a neurologist and neuroscientist, wrote in a letter to the FDA. “The onus is on Lilly to prove that statistically significant differences between drug and placebo arms in their clinical trial translated to clinically meaningful results.”