An FDA advisory committee gave its strong backing to Eli Lilly’s Alzheimer’s drug donanemab, giving further support for the agency’s expected approval after a surprise delay earlier this year.
The committee of outside experts voted 11-0 that donanemab’s benefits outweigh its risks. It also voted 11-0 that the data presented by Indianapolis-based Lilly showed the drug was effective.
While the FDA doesn’t have to follow the committee’s recommendations, it often does, and a rejection of the treatment would be a surprise despite a decision by the agency in March to delay an approval decision. At that time, Lilly said the FDA had asked for more data on safety as well as its plans to let patients stop treatment once a key biomarker fell significantly.
During Monday’s debate on the drug, many of the panel’s experts noted that while donanemab came with risks, they thought those could be managed and should not stop the agency from making it available to patients.
“It seems like there are some very clear parameters we can put in place,” said Cynthia Carlsson, an adcomm member and professor of medicine at the University of Wisconsin. “We all know that our patients have different values they attach to different benefits”
If approved by the agency, potentially in the coming weeks, Lilly’s drug would go head-to-head with Eisai and Biogen’s Leqembi. While hailed as the first drug to conclusively show it can slow the symptoms of Alzheimer’s, Leqembi’s sales have gotten off to a slow start.
Safety considerations
During its presentation on Monday, the FDA outlined several lingering questions about donanemab’s safety. But it appears most likely to take the path of emphasizing the drug’s risks in a label rather than throwing up a meaningful roadblock.
“Safety is a significant concern for these therapies,” Teresa Buracchio, director of the office of neuroscience at the FDA’s Center for Drug Evaluation and Research, said in opening remarks.
A major focus is a symptom called ARIA, which can be a sign of brain bleeds or swelling. In its presentation, the FDA noted that ARIA symptoms can mimic a stroke, which can set the stage for a dangerous scenario.
One 70-year-old patient in Lilly’s study who developed stroke-like symptoms and was treated with the clot-busting drug tenecteplase died four days later. The case echoed a similar anecdote about death following the use of blood thinners in a patient who had a stroke that was taking Leqembi, which works in a similar way.
Natalie Branagan, a clinical safety reviewer at the FDA, said that if donanemab is approved, patients should carry a medical information card to indicate that they are being treated with donanemab. But she said the agency would be unlikely to bar patients from receiving blood thinners, and would leave that tough decision to caregivers and doctors.
“You are between a rock and a hard place,” Branagan said. “You are going to have a difficult time as that prescriber figuring out the right thing to do for that patient.”
The committee asked the FDA how it would handle known risk factors for ARIA, such as the number of microhemorrhages revealed on a patient’s brain scan before starting treatment. Branagan said that some patients did well on the treatment even as they developed new microhemorrhages during Lilly’s study, so the agency would “have a hard time saying this would be an absolute contraindication.”
Two delays
The FDA’s decision on the drug has already been delayed twice. Although the adcomm’s vote is nonbinding, it’s a pivotal moment in Lilly’s thirty-year effort to develop a drug that slows dementia.
Near the beginning of the meeting, Lilly chief medical officer David Hyman said that the company believes there is “significant alignment” with the FDA on interpreting donanemab’s data.
One question the FDA will have to decide is whether treatment with Lilly’s drug can stop once its shown an effect. In Lilly’s trial, patients stopped receiving donanemab once amyloid plaques, thought by some to cause the disease, were largely cleared from their brains. Biogen and Eisai, in contrast, suggest that their amyloid-busting drug Leqembi be given indefinitely.
But Kevin Krudys, a clinical efficacy reviewer at the FDA, said there is “considerable uncertainty” about how much amyloid needs to be reduced for benefit. Although Lilly said that amyloid was slow to reaccumulate when patients stopped taking donanemab, Krudys noted that data from a short period of the company’s study, and that Lilly did not include an appropriate comparison group.
Removing amyloid early in the course of the disease appears to modestly slow cognitive decline, but it can also cause signs of brain bleeding and swelling known as amyloid-related imaging abnormalities, or ARIA. Reisa Sperling, a neurologist and clinical investigator at Massachusetts General Hospital, said that ARIA seems to be a side effect inherent to the entire drug class.
“It’s unlikely that we’re going to be able to completely avoid ARIA and still achieve the amyloid reduction that appears to be necessary for clinical benefit,” Sperling said.
Staging patients
Lilly also compared the efficacy of its drug in patients with slightly earlier or more advanced disease, determined by how much of the protein tau had built up in their brain. It was more effective in patients with less tau and less advanced disease. One of Lilly’s greatest concerns is that the drug would be restricted to patients with low-to-medium tau, and the company argued that donanemab benefited both groups.
Buracchio, the FDA’s neuroscience director, said that the agency doesn’t expect the differences in the tau subgroups would change its decision to approve or reject the drug, but it could factor into the wording on the drug’s labeling.
Rather than focusing on the lower efficacy seen in patients with high tau levels, some adcomm members expressed concern about extrapolating to patients with no-to-low tau, a group that was excluded from Lilly’ study, even though the company and some scientists expect these patients may receive even greater benefit because they are in an even earlier stages of disease.
“It could be that it’s better to wait a while to get the biggest benefit of the drug as opposed to starting it as early as you can,” said Dean Follmann, an adcomm member and biostatistician at the National Institutes of Health. “Further study of this to understand can we keep giving it or is there an optimal time will be important to do.”
There was also debate about how to address patients with the APOE4 gene, which increases the odds of developing Alzheimer’s. Having the gene also dramatically raises the risk of ARIA, especially if patients have two copies of the gene. Branagan said the FDA would strongly recommend getting tested for the gene, but wouldn’t require it, partly due to the many uneasy questions it can raise for a patient and their relatives.