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After many years of slow progress, drug companies searching for the next big treatment for Alzheimer's disease are finally starting to see the fruits of their labors.
A panel of brain and Alzheimer’s experts convened by the U.S. Food and Drug Administration (FDA) voted unanimously on June 10 that a new Alzheimer’s drug developed by Eli Lilly, called donanemab, is effective and that the benefits of the medication outweigh its risks. The agency will now take the committee’s advice under consideration as it decides whether to approve the drug.
The FDA postponed its original decision on donanemab, which was scheduled for late last year, because it wanted to see more safety data on the medication. After Lilly provided additional information from a late-stage trial, the agency convened its advisory committee in June to review that safety data, as well as some of the more unique aspects of the company’s latest study.
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First, Lilly used a relatively new way to identify patients whose disease is most likely to progress, relying on a PET (positron emission tomography) brain scan for a protein called tau. Many clinics still don't offer this type of brain scan, and some panel members noted that it requires some expertise to interpret the images properly. Not all hospitals have such experts available.
Second, the company allowed some patients in the trial to stop treatment after other brain scans showed they had cleared the buildup of amyloid plaques, which donanemab targets. It’s the first trial of an Alzheimer’s treatment that explores potentially stopping and starting treatment—similar to the way chemotherapy is used to treat cancer.
What does donanemab do?
Donanemab is the third so-called "disease-modifying treatment" for Alzheimer’s: a therapy that addresses the root causes of the neurodegenerative disease, rather than the symptoms. All three of these treatments are antibodies that bind to amyloid, the protein that builds up in the brains of patients and unleashes toxic effects on neurons, especially those related to memory and higher cognitive functions. In the two major studies that Lilly submitted for review by the FDA, researchers followed patients for just over three years and found that donanemab slowed progression of Alzheimer’s in people at the earliest stages of the disease by 22% compared to those receiving placebo. The study also reported a more than 80% drop in amyloid plaques in those receiving donanemab compared to placebo after three years.
A consequential side effect
The biggest risk associated with donanemab involves inflammation and bleeding in the brain, a side effect known as ARIA (short for amyloid-related imaging abnormalities). Both Lilly and FDA scientists agreed that ARIA is most likely the direct result of how the drug works to remove amyloid plaques from the brain, which can weaken blood vessels and make them prone to leaking. ARIA can be monitored with regular MRIs, which are part of the treatment protocol—especially for people at higher genetic risk of Alzheimer’s with the ApoE4 genotype, who are at higher risk of developing ARIA. In Lilly’s studies, the death rate from ARIA was about 2.3% in those receiving donanemab compared to 1.9% in the placebo group after three years.
What the committee found
After hearing presentations from both Lilly’s and FDA’s scientists, the committee members discussed the new questions that the latest trial raised: particularly how to identify patients who might benefit most from the treatment, as well as the potential of having patients cycle on and off the therapy. Regarding the right patients for the drug, which is given as an infusion over 30 minutes once a month, the committee members did not agree over whether people with a genetic predisposition for the disease—those with two copies of the risk gene ApoE4—would actually benefit from the drug. While they are at highest risk, they are also most vulnerable to the ARIA side effect, and it’s not clear from the small number of them in the trial whether the benefit for them outweighs the risk. But for the overall population, the committee members agreed that the potential benefits of donanemab were greater than the risk of ARIA.
They also agreed that the use of tau PET imaging was not necessary to qualify for the drug. Some members raised concerns that limited access to the test could potentially restrict who gets the drug, if the test were made a requirement. Lilly’s studies also showed that regardless of their tau levels, people responded to the drug and slowed progression of their disease. Kevin Krudys, a clinical efficacy reviewer at the FDA, said the agency determined that the drug's “effect on amyloid plaque reduction appears to be independent of baseline tau [levels].”
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Could patients possibly stop donanemab if their amyloid levels became so low as to be undetectable, then start again if the protein began accumulating? The company reported that as the 76-week study progressed, more people were able to clear amyloid enough so that the protein was no longer detectable on their brain scans. By the end of the study, 60% of people could consider stopping their monthly infusions, researchers determined.
But the FDA concluded that there were still too many unanswered questions about the data so far, including no clear guidance for doctors on which levels of amyloid would warrant restarting treatment, and what the long-term outlook of people who stopped and started would be. Lilly proposed testing people with an amyloid PET scan after one year on donanemab to determine if they could stop the therapy, but additional studies are needed to determine when and how often people should be tested, and when they should be restarted on therapy if their amyloid starts accumulating again.
What happens next
The committee voted that for most people with mild cognitive impairment or mild dementia due to Alzheimer’s disease, the data showed donanemab is effective in slowing their cognitive decline, and that the benefits outweighed the risks of the medication.
However, they concluded that more studies are needed in specific groups, such as those with higher genetic predisposition for the disease, as well as different racial and ethnic groups, to see if the benefits remain consistent for them.
Still, health experts and patient groups are excited by the encouraging data on donanemab and the prospect of having more treatment options, which could transform the way the disease is managed in coming years. "It's important to look at this milestone in the larger treatment landscape for Alzheimer's, which will entail a combination therapy and precision medicine approach," said Dr. Howard Fillit, chief science officer of the Alzheimer's Drug Discovery Foundation (who was not part of the committee) in a statement. Maria Carrillo, chief science officer of the Alzheimer's Association, noted that those options may also extend beyond just medications. "We look forward to more treatment options, and novel therapies that target other aspects of the disease, including lifestyle and behavioral-based interventions," she says.
