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Approval of Eli Lilly’s experimental Alzheimer’s drug donanemab was delayed by the Food and Drug Administration. Cristina Arias/Cover/Getty Images
  • FDA approval of Eli Lilly’s experimental Alzheimer’s drug donanemab will be delayed beyond the end of March, the company said.
  • The FDA will call a meeting of its outside advisors to review the results of the drug’s clinical trial and evaluate safety and efficacy.
  • Donanemab targets plaques in the brain caused by beta-amyloid protein, the same mode of action as the FDA-approved lecanemab (Leqembi).

The approval of Eli Lilly’s experimental Alzheimer’s medication donanemab will be delayed beyond the end of the month, the drugmaker announced on March 8.

The Food and Drug Administration (FDA) reversed its fast-track approval of the drug and will call a meeting of outside advisors to review its safety and efficacy.

Eli Lilly said it had expected the FDA to approve the drug by the end of the first quarter of this year, which had already been pushed back from an expected earlier approval of sometime last year.

If approved, donanemab would become the second drug shown to slow the progression of Alzheimer’s disease (AD), a degenerative brain disease affecting more than 6 million Americans.

Last July, the FDA approved a similar drug, lecanemab (Leqembi), from Japanese drugmaker Eisai and Massachusetts-based drugmaker Biogen.

Both drugs are monoclonal antibodies, given as IV infusions, that target the buildup in the brain of plaques caused by the clumping together of the beta-amyloid protein.

Dr. Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, said in a statement that the FDA’s decision is not a “setback,” but is a sign that the FDA is “doing its due diligence” to ensure the safety and efficacy of donanemab.

“The decision to hold an advisory committee before granting approval follows the regulatory process that was used for the other drugs in this class, including Leqembi,” he said.

Lilly said the FDA advisory committee will discuss the results of its phase 3 clinical trial, published in JAMA in July 2023. The trial, called Trailblazer-Alz 2, tested the efficacy and safety of donanemab in people with early symptomatic Alzheimer’s.

As with the Leqembi trial, participants in the donanemab trial took cognitive assessments and underwent brain scans to measure the level of beta-amyloid plaques.

The FDA will also look at the donanemab study’s “unique trial design,” Lilly said. This includes allowing participants to stop treatment when scans showed that the beta-amyloid plaques had been cleared from the brain. In contrast, the clinical trial for Leqembi had no designated stopping point.

“A big question about this [aspect of the trial] is how it might be implemented in real-world practice. Do we stop medication in patients? Do we have to repeat PET scans?” said Dr. James Galvin, founding director of the Comprehensive Center for Brain Health and professor of both neurology and psychiatry and behavioral sciences at the University of Miami Miller School of Medicine in Florida.

Another unique aspect Lilly’s trial is that it measured the level in the brain of a protein called tau, which collects inside neurons in people with Alzheimer’s disease.

“Clinically, we have no good way of measuring this,” Galvin told Healthline. “So again, how might this be implemented in practice?”

The clinical trial for donanemab, which included more than 1,300 participants with early symptomatic Alzheimer’s disease, separated participants based on the level of tau.

Among participants with “low or medium” levels of tau, people who received donanemab had a 35% slower decline in the ability to think clearly and perform daily activities, compared to those receiving an inactive placebo.

When researchers also included people with high levels of tau — which suggests they are further along in the course of the disease — the benefit of donanemab compared to placebo was 22%.

In addition, 47% of people who received the drug showed no decline on a test of disease severity after one year, compared to 29% among people in the placebo group.

In addition, 47% of people in the “low or medium” tau group who received the drug showed no decline on a test of disease severity after one year, compared to 29% among people in the placebo group.

The main safety concerns of donanemab are brain swelling (edema) and micro-bleeding (hemorrhages), both known as amyloid-related imaging abnormalities, or ARIA.

In the clinical trial, among people receiving donanemab, micro-bleeding occurred in 31.4% and brain swelling in 24%.

ARIA usually does not cause symptoms, the company said in a release, but it can be serious and life-threatening. In the trial, three people died from a serious case of ARIA.

The rate of ARIA was lower in the clinical trial for Leqembi, but the drug has been linked to patient deaths as well.

“The seemingly higher rate of ARIA with donanemab compared to lecanemab is of concern and requires further scrutiny [by the FDA] that, in the long run, will serve to benefit current and future generations of patients with Alzheimer’s disease,” Dr. Seyed Sajjadi, a neurologist at UCI Health in California, told Healthline.

These side effects are serious enough to raise concerns among experts about whether these drugs are worth the risks.

“[Some] clinical neurologists continue to not use this family of medications, as they have not significantly improved patient’s memory loss in the drug trials, and have caused severe cerebral edema and intracranial bleeding,” Dr. Clifford Segil, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, told Healthline.

The date for the FDA advisory meeting has not been set, Lilly said in its news release. The FDA generally, but not always, follows the advice of its advisory committees.

“We are confident in donanemab’s potential to offer very meaningful benefits to people with early symptomatic Alzheimer’s disease,” Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience, said in the release.

“It was unexpected to learn the FDA will convene an advisory committee at this stage in the review process, but 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,” she said.

Galvin said the FDA’s decision to seek clarification from outside advisors before making its final decision is just a “bump in the road.”

“It is discouraging that patients will have to wait a few more months,” he said, “but we do have options available to treat patients right now.”

These other options include Leqembi and older medications such as:

“Patients can also participate in clinical trials, as over 150 agents are currently being tested,” said Galvin.

In addition, “a clinical trial is underway to assess the safety and efficacy of lecanemab for pre-symptomatic stages of Alzheimer’s disease, with results expected in the next few years,” Sajjadi said.

The clinical trial for donanemab and the earlier trial for Leqembi recruited people with early stages of Alzheimer’s disease, meaning they were already showing symptoms. Targeting beta-amyloid plaques before symptoms appear may help slow the course of the disease, although a clinical trial is needed to show whether this is true.

More info on Alzheimer’s research

For more information on Alzheimer’s clinical trials that are recruiting patients, see alzheimers.gov/clinical-trials.

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So far, drugs that target beta-amyloid plaques in people with Alzheimer’s disease have been slow to take off.

Before the approval of Leqembi, the FDA granted accelerated approval of Biogen’s Alzheimer’s drug aducanumab (Aduhelm) in 2021, despite the FDA’s advisory committee not supporting the drug moving forward.

The subsequent drug approval was met with criticism from the scientific community. Biogen discontinued Aduhelm last month.

Leqembi had a smoother route to FDA approval, but as of last month, only about 2,000 people were taking the drug, Biogen said Feb. 13 on its quarterly earnings call — far short of its goal of 10,000 by the end of this month.

This limited reach of Leqembi may be due to the number of brain scans and tests patients must undergo before starting treatment, or patient and physician concerns about the potential serious side effects.

It remains to be seen how the FDA’s advisory committee will handle donanemab. But Segil said he thinks the committee should not recommend the drug’s approval.

“Both [Leqembi and Aduhelm] are without any data showing they cause meaningful improvements in memory loss,” Segil noted, “and there is no post-market surveillance data to indicate they cause any noticeable improvements in patients using them.”

Drugmaker Eli Lilly announced that the approval of its experimental Alzheimer’s drug donanemab will be delayed, as the FDA calls a meeting of its outside advisors to review the safety and efficacy of the drug.

The drug targets the buildup of plaques in the brain caused by the clumping together of the beta-amyloid protein. It is the same mode of action as Leqembi, from Japanese drugmaker Eisai and Massachusetts-based drugmaker Biogen.

The main safety concerns seen with donanemab in clinical trials was swelling (edema) and micro-bleeding (hemorrhages), two types of amyloid-related imaging abnormalities, or ARIA.