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FDA Advisory Panel Unanimously Votes in Support of Eli Lilly's Alzheimer's Drug Donanemab

Eli Lilly biotechnology center in San Diego

NEW YORK – An advisory committee for the US Food and Drug Administration on Monday unanimously agreed that Eli Lilly's investigational Alzheimer's drug donanemab has proven efficacious in clinical trials, but they also said patients and doctors need significant education on how to manage the adverse events that may come with it.

If approved, donanemab will be the third drug in a growing class of monoclonal antibody Alzheimer's treatments to reach the market.

In an 11-to-0 vote, members of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee agreed that data provided by Lilly demonstrated that donanemab slows disease progression for patients with early Alzheimer's. In a separate vote, all committee members likewise agreed that the drug demonstrated a favorable benefit-risk profile. 

But in order to minimize the potential harms, donanemab should be delivered "with appropriate risk mitigation and surveillance," stressed committee member Tanya Simuni, professor of neurology at Northwestern University Feinberg School of Medicine.

The FDA convened the meeting to solicit feedback from an independent panel of experts on donanemab's activity based on data Lilly submitted in its biologics license application seeking market authorization. The FDA's advisory committees' recommendations are nonbinding, but the agency usually follows the advice of its experts. 

The agency, in 2021, controversially went against a panel's recommendation when it granted accelerated approval to Biogen and Eisai's Aduhelm (aducanumab), another drug in this class, but the sponsors have since discontinued selling it due to slow sales. An advisory panel last year unanimously backed a different monoclonal antibody for Alzheimer's, Biogen and Eisai's Leqembi (lecanemab), and in that case, the agency followed the committee's verdict that a confirmatory trial verified the clinical benefits needed to convert the drug's accelerated approval to a full approval. Leqembi remains on the market.

If the FDA takes this expert panel's advice and approves donanemab, Lilly will market it as a treatment for Alzheimer's patients with mild cognitive impairment or mild dementia who have confirmed amyloid pathology. Patients would take donanemab once every four weeks until their beta-amyloid reduces to a certain level, at which point they could stop treatment.

By contrast, patients must take Leqembi once every two weeks, and its sponsors are currently seeking FDA approval for it as an ongoing monthly maintenance therapy.

At the meeting Monday, advisory committee members overwhelmingly agreed that donanemab had proved effective in Lilly's pivotal, randomized-controlled Phase III trial, known as TRAILBLAZER-ALZ 2. In it, investigators observed slower disease progression from baseline to 76 weeks among donanemab-treated patients compared to those who received placebo. That included a 22 percent slowing of disease progression on the integrated Alzheimer's Disease Rating Scale (iADRS) and a 29 percent slowing of disease progression on the Clinical Dementia Rating-Sum of Boxes scale (CDR-SB).

In TRAILBLAZER-ALZ 2, Lilly only enrolled patients with elevated levels of tau, another protein biomarker that's typically seen in Alzheimer's patients after beta-amyloid accumulation. They used tau as a way to enrich the study population with patients who are slightly further along in their disease progression. However, the company doesn't want to limit the drug's indication based on tau pathology.

Advisory committee members agreed with this assessment and did not recommend using tau pathology as a way to determine who should get the drug, noting that donanemab's mechanism of action doesn't act on tau. 

While Lilly did not enroll patients with no or very low tau in the randomized-controlled portion of the Phase III study, they did collect biomarker information on 200 patients during an open-label safety addendum. Patients in this group experienced reductions in beta-amyloid and plasma phosphorylated-tau 217 that were similar to those with higher levels of tau.

Advisory committee members pointed to this promising biomarker data and noted that there is a lack of available and accessible methods to test for tau.

"From a very practical perspective, this would be not a wise thing to have as a barrier," said Kathleen Poston, a professor of neurology and neurological sciences at Stanford Medicine. "If there had been no biomarker data available in that group, I would have much more pause, but with the biomarker data there … I am comfortable with that."

The committee also agreed that Lilly's plan to have patients stop treatment after reaching a threshold of beta-amyloid clearance would be a positive for patients and caregivers, although uncertainties remain around what type of follow-up patients will need to monitor beta-amyloid levels after they cease therapy and whether they may need to restart treatment in the future.

Beyond the dosing regimen, advisory committee members highlighted a need to gather additional efficacy and safety data in specific subgroups, such as on the earlier-stage patients with no or very low levels of tau, minority populations, and in patients with Down syndrome, who are at an increased risk of developing dementia.

"It is everyone's duty to obtain that information going forward," said Nilüfer Ertekin-Taner, a professor of neuroscience and neurology at the Mayo Clinic in Jacksonville, Florida.

Should donanemab be approved, physicians will also need to be educated on the risk of various side effects with the drug and how to identify them.

For example, patients with two copies of the APOE4 allele have a higher risk of amyloid-related imaging abnormalities (ARIA), one of the most common adverse events seen in clinical trials of donanemab, which can present as temporary swelling or bleeding in the brain. While patients with ARIA are usually asymptomatic, when it does present issues, it can be difficult to diagnose since the symptoms are similar to those seen in stroke. Lilly has suggested that patients who receive donanemab carry a medical information card with information about the drug and risk of ARIA.

Additionally, Lilly has suggested that donanemab's label could potentially include a boxed warning about ARIA, a recommendation for APOE testing prior to treatment initiation, and a recommendation for MRI scans to monitor patients for ARIA events during early treatment. The FDA required such a boxed warning on ARIA and a recommendation for APOE testing when it approved Leqembi.

Lilly also proposed three post-marketing studies in which it would characterize safety risks associated with donanemab, including ARIA, intracerebral hemorrhage, and serious hypersensitivity reactions.

While the advisory committee members voted in favor of donanemab's benefit-risk profile, they emphasized the importance of those proposed steps to continue to study risks associated with donanemab and ensure that physicians and patients are aware of them. "The benefits outweigh the risks, as long as the risks are being monitored and educated upon appropriately," Poston said.