On Monday, a panel of independent advisers to the US Food and Drug Administration voted to endorse Eli Lilly’s drug donanemab, a monoclonal antibody designed to slow the progression of early symptomatic Alzheimer’s disease, agreeing that it was safe and effective.
One in three older Americans dies with Alzheimer’s disease or another form of dementia, according to the Alzheimer’s Association, killing more people than prostate and breast cancer combined.
Donanemab works by helping the body remove amyloid plaque buildups in the brain that are a hallmark of Alzheimer’s disease. These plaques are harmful deposits that can form in the brain as people age. Removing the plaque seems to slow down the brain changes that seem to happen with Alzheimer’s.
As the drug enters the brain it binds to the amyloid plaques and its presence catches the attention of the immune system that facilitates the plaque removal.
There is no cure and there is still no drug to prevent the development of Alzheimer’s, but donanemab and Leqembi, another drug that is already on the market made by Eisai and Biogen, has been shown to slow the progression of the disease in its early stages.
Lilly told the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee that its data from late-stage clinical research showed “highly meaningful results” for patients who took donanemab, with a 37% lower risk of progression of the disease over a year and a half compared to patients who got the placebo.
Serious adverse events were “generally comparable” among all the groups in the trials, and were infrequent, Lilly told the committee, occurring in only 2% of patients. The patients on donanemab had a slightly higher mortality rate — 2%, compared with 1.7% in the placebo arm of the trial.
Three people died while taking the drug after developing ARIA, or micro-hemorrhages known as amyloid-related imaging abnormalities.
In trials of Leqembi, the drug that’s already on the market, some patients experienced ARIA, but it was at a lower rate than seen in the donanemab trial. Leqembi has also been tied to patient deaths.
Since most donanemab patients who experienced problems with ARIA did so in the first six weeks of the trial, Lilly told the committee that it added another MRI to the trial to look for the problem before giving the patient a second infusion. The aim would be to detect patients with asymptomatic ARIA. If it was detected, providers would pause treatment so it could resolve and not become more serious or symptomatic.
Looking at these results from the late-stage clinical trials, the FDA committee voted on two specific questions and discussed three other main topics.
The committee voted an unanimous “yes” to the questions of whether the data showed that the drug is effective for the treatment of Alzheimer’s disease and whether the benefits of the drug outweighed the risks in the treatment of Alzheimer’s in the population enrolled in the clinical trials.
The FDA will take the committee’s advice into consideration as it decides whether to greenlight the drug.
Committee member Dr. Dean Follmann, assistant director for Biostatistics at the National Institute of Allergy and Infectious Diseases, said he voted yes because the evidence “was strong and consistent across subgroups.”
In voting yes, Sarah Dolan, the acting consumer representative on the committee and a consultant with the Critical Path Institute in Tucson, Arizona, said she was pleased with the outcome of the research.
“There’s a huge unmet medical need here that hopefully can be addressed,” Dolan said.
Committee member Dr. Kathleen Poston, the director of Stanford Movement Disorders Center, said she voted yes believing there was a benefit to the drug, “as long as the risks are being monitored.”
The trials only included patients that had low-medium levels of tau, a protein that can become abnormal and contribute to the disease. Lilly excluded patients that had no or very low tau because the study wouldn’t follow the patients long enough to see if the drug made a difference. They also excluded people with high amounts of tau. The committee had some concern about extrapolating the results to a subset of patients with other levels of tau; they wanted to see more data.
The majority of the committee also wasn’t comfortable with the FDA requiring a tau PET test to determine if a patient was eligible to take the drug since the test is not widely available and would make it difficult for some people to get the drug.
The FDA also asked the committee to consider additional factors about ongoing research and factors related to the possible administration of the drug.
Lilly suggests patients may be able to stop the drug if they show enough progress on it. The committee suggested research would have to show what would be the appropriate criteria to stop or restart the drug if symptoms came back. The committee also noted that there was little diversity in the trial, most participants were White, and said future research will need to include more people of color to understand how the drug works in diverse populations. The committee also noted that if the drug is approved, doctors will have to educate their patients about the benefit versus the risk of taking this medication.
Initially, when the FDA said that it was going to hold this meeting, it came as a surprise announcement since many experts had thought the drug would have been approved by the FDA last year.
Before the votes, Dr. Reisa Sperling, a professor in neurology at Harvard Medical School told the committee that without treatments, the growing number of people with Alzheimer’s could become a serious threat to the country.
“We’re doing such a good job at keeping people alive longer, we are creating a public health emergency if we don’t find a way to stave off this disease,” Sperling said.
In the meantime, Lilly said it is working on additional Alzheimer’s treatments.
“Recognizing the enormous burden this disease carries, we take the responsibility of bringing a well characterized disease modifying therapy to patients very seriously,” Dr. David Hyman, chief medical officer with Eli Lilly and Company told the committee.
Lilly views donanemab as “an important but ultimately incremental” step in the treatment of Alzheimer’s disease. Ultimately, Hyman said Lilly would like to develop a drug that would treat the disease before someone even starts to show symptoms and are working on such a drug.
“Patients deserve more, and we continue to work on additional approaches to address this disease,” Hyman said.
After the meeting, Lilly said it was happy with the committee’s positive vote.
“We are pleased with the committee’s unanimous recognition of donanemab’s positive benefit-risk profile,” said Mark Mintun, Eli Lilly’s group vice president of neuroscience research and development in a news release. “We look forward to bringing this treatment option to patients.”
The Alzheimer’s Association had urged the committee to recommend approval of donanemab, welcomed the committee’s unanimous vote in favor of the drug.
“A future with more approved Alzheimer’s treatments is a tremendous advancement for people eligible for these drugs,” said Dr. Joanne Pike, Alzheimer’s Association President and CEO. “Progress with treatment is happening.”
USAgainstAlzheimer’s, a national nonprofit, that testified in favor of the drug during the public comment period in the meeting said that there is an urgency and a “massive unmet need” for Alzheimer’s treatments.
“If approved by the FDA, donanemab would be the second drug on the market to help people in the early stages of Alzheimer’s live a better quality of life for a longer period of time, while providing patients and their doctors with another option for their treatment plans,” said chair and co-founder George Vradenburg. “We are grateful to the advisory committee for its endorsement of this promising treatment.”
