Lilly's donanemab sails through FDA meeting with 2 unanimous votes in favor

Eli Lilly’s Alzheimer’s disease treatment sailed through an FDA advisory committee meeting Monday, with panelists praising the therapy as innovative—while also cautioning about a lack of data on specific subgroups.

The Peripheral and Central Nervous System Drugs Advisory Committee was tasked with two voting questions:

  • Do the available data show that donanemab is effective for the treatment of Alzheimer’s disease in the population enrolled in the clinical trials with mild cognitive impairment and mild dementia?
  • Do the benefits outweigh the risks of donanemab in the treatment of AD in the population enrolled in the clinical trials with mild cognitive impairment and mild dementia?

On both, the committee voted 11-0 in favor of donanemab, supporting approval of the medicine. The FDA is not bound by the committee’s recommendation but typically takes its advice.

“We are pleased with the committee’s unanimous recognition of donanemab’s positive benefit-risk profile,” said Mark Mintun, M.D., group vice president of neuroscience research and development at Lilly, in a statement provided to Fierce Biotech. He spoke earlier in the day on the clinical program for donanemab. “We look forward to bringing this treatment option to patients.”

Lilly is seeking approval for donanemab, which was tested in the 1,736-patient phase 3 TRAILBLAZER-ALZ 2 trial (also referred to as Study AACI), which measured a change in baseline on the integrated Alzheimer’s Disease Rating Scale (iADRS) at 76 weeks. This scale detects disease progression and treatment differences.


The committee was also asked to discuss whether the available data support the efficacy of donanemab across the tau PET imaging subgroups. Lilly used this type of imaging to determine which patients were likely to progress during the study.

But in briefing documents posted ahead of the meeting, the FDA seemed to wonder whether the exclusion of low-to-no-tau patients needed to be excluded because they were not specifically studied. Lilly did not request to have tau imaging included as part of the treatment paradigm post-approval.

Committee chairperson Thomas Montine, M.D., Ph.D., chair of the department of pathology at Stanford University School of Medicine, said the vast majority of the committee felt that imposing tau imaging is not necessary and would raise serious practical and access concerns.

The committee voted 11-0 that yes, the available data supported that donanemab is effective in the population enrolled in the clinical trials, which excluded patients with low to no tau burden.

The second major issue discussed at the meeting was that Lilly designed the trial to cease dosing once a patient achieved amyloid clearance. This would represent a change in Alzheimer’s care, but one the committee members called “innovative” on multiple occasions.

But, implementing such a change into clinical practice will cause growing pains. The committee members thought this was great for patients but wondered how clinicians in the real world would determine when to cease dosing.

“It’s very good for patients not to take medications more than they need to, but I do think it could be challenging for clinicians to decide when to redo the PET scan,” said Merit Cudkowicz, M.D., chair of the department of neurology at Harvard Medical School.

Getting some longer-term follow-up in Lilly’s ongoing open-label studies would be helpful to give more clear advice to doctors on stopping treatment and later restarting.

Again summarizing the discussion, Montine said there’s work to be done.

“Because it’s innovative, it raises a lot of questions,” he said, including, what is the duration of the benefit, how do you monitor patients between drug stoppage and restarting, what will happen with side effects in that interim or in restarting treatment?

“We just don’t know the answer to any of these things … but again, my feeling from listening to the comments is the committee feels that this is an innovative and positive outcome of the way the trial was designed,” Montine said.

Overall risk-benefit

The committee seemed very sure that the overall benefit of donanemab outweighed the risk of treatment. The major risk—and where much of the day’s discussion centered—was about amyloid-related imaging abnormalities (ARIA), which is the chief concern of this class of medicines. ARIA can suggest a risk of brain bleeds or swelling, and several deaths have occurred across the class due to this adverse event, including at least three from the donanemab group in Lilly’s Study AACI that was used to underpin the drug application.

But, many brought up a lack of data on patients within different subgroups. Of chief concern were patients who are ApoE ε4 homozygotes and who are at known increased risk of the side effects. Approved medicines in the class, including Biogen and Eisai’s Leqembi, already come with a boxed warning to test for ApoE ε4 status.

Nilüfer Ertekin-Taner, M.D., Ph.D., chair of the neuroscience department at the Mayo Clinic in Jacksonville, Florida, said the benefit-risk is certainly acceptable for those without this status. However, she recommended wording on the label to reflect the “less favorable” benefit-risk ratio for ApoE ε4 carriers.

Patient advocate Colette Johnston pointed out that risk means something different to someone with Alzheimer’s, a debilitating neurodegenerative disease that causes memory loss and behavior changes.

“When you get a diagnosis of Alzheimer’s, you don’t have anything but risk,” she said. “For those who are suffering now and those caregivers, you can’t imagine until you’ve walked in their shoes what they do, there is a benefit.”

Daniel Press, M.D., chief of the Cognitive Neurology Unit at Beth Israel Deaconess Medical Center, said that patients should have a right to take a therapy that has shown benefits even if it has a risk.

“But if there isn’t any benefit, then that’s a real concern,” he said. And so far, Lilly’s studies have not teased out whether there is any benefit in taking donanemab for this population. And there could, in fact, be none at all—just risk.

“I’m not saying that we shouldn’t offer it to them, but we should perhaps, even in the label, emphasize both the point that there’s a significantly higher safety concern and less evidence for efficacy,” he said.

At stake in all of this is, of course, the patients. The always emotional public hearing session heard some of those stories. Caregiver Maria Gates detailed her husband George’s early diagnosis at 57.

“Little by little his freedom is being stolen by dementia,” Gates said.

He has since been taking part in the TRAILBLAZER-ALZ studies, and his condition has improved. The caregiver described that he can now walk again with normal strides, his chronic sensitivity to cold is gone, he can now watch and enjoy TV while providing “animated funny commentary" and his activities of daily life have improved including showering and dressing on his own.

He's now 62, and will walk his youngest daughter down the aisle at her wedding this year.

“I feel distress for anyone who may be denied this drug,” Gates said. She added that the risk of not receiving donanemab is “100% catastrophic incapacitation leading to certain death.”

The committee seemed to agree that patients should have access now but urged Lilly to keep pushing for data in more specific populations.

“If there are some subgroups for which evidence is not available, that should not hold up making this drug available to the public,” said Costantino Iadecola, M.D., director and chair of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

One thing brought up by multiple committee members was the lack of diversity in Lilly’s trials. Ertekin-Taner urged further research on underserved patients, such as those with Down syndrome or autosomal dominance AD.

“It is everyone’s duty to obtain that information going forward,” she said.

Kathleen Poston, M.D., later echoed that push, with a request to include more African American patients.