Eli Lilly headquarters in Indianapolis, Indiana, US, Wednesday, May 3, 2023. Eli Lilly shares rose at the open on Wednesday after an experimental Alzheimer’s drug slowed the progression of the disease in a late-stage trial, paving the way for the company to file for U.S. approval.
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An independent advisory committee for the Food and Drug Administration said Monday Eli LillyThe company has filed for regulatory approval of its Alzheimer’s disease treatment donanemab, paving the way for the treatment to receive full approval in the United States later this year.
The FDA typically follows the advisory committee’s recommendations but is not required to do so. If approved for use, Lilly’s donanemab would be the second Alzheimer’s treatment to hit the U.S. market, joining another treatment called Lukembi from Biogen and its Japanese partner Eisai.
If approved, the treatment would expand currently limited treatment options for the more than six million Americans who suffer from Alzheimer’s disease, the fifth leading cause of death among adults over 65.
In an initial vote, the 11-member committee unanimously said available data on the drug shows it is effective in treating Alzheimer’s patients in the early stages of the debilitating disease, but several advisers noted that more data on donanemab in other groups, such as black and Hispanic patients, is needed.
In a second vote, the advisers unanimously said the benefits of Eli Lilly’s donanemab outweigh the risks.
“There’s a huge amount of unmet medical need here, and I hope we can get it addressed,” ad hoc committee member Sarah Dolan said at Monday’s meeting. Dolan is a consultant for the Critical Path Institute, a nonprofit that aims to improve the drug development process.
Mark Mintan, vice president of Eli Lilly’s neuroscience research and development group, said in a statement that the company was “pleased” with the committee’s recommendation and looked forward to offering the treatment to patients.
The recommendation comes in response to obstacles Eli Lilly and Co. faced in bringing the treatment to market.
In March, just weeks before a deadline to make a decision on the treatment, the FDA convened a last-minute meeting of an advisory committee to further review the safety and effectiveness of the Eli Lilly & Co. drug in late-stage clinical trials.
The move was another blow to Eli Lilly, which had initially expected donanameb to be approved late last year after the FDA rejected the drug in January, saying there was insufficient data for approval.
Requenvi and donanemab represent a breakthrough in the treatment of Alzheimer’s disease after three decades of failed efforts to develop drugs that could fight the deadly disease.
Both drugs are monoclonal antibodies that target the amyloid plaques in the brain that characterize Alzheimer’s disease, slowing the progression of the disease in patients in the early stages.
However, neither treatment leads to a cure.
Drugs that target and remove amyloid plaques can cause patients to suffer from brain swelling and bleeding, which can be severe and even fatal in some cases. Three patients who took the Eli Lilly drug in late-stage clinical trials have died from severe cases of a side effect called amyloid-related imaging abnormalities (ARIA).
A number of hurdles have slowed the rollout of Lukembi since its July approval, including the steps required to diagnose Alzheimer’s and monitor and manage the weekly infusions needed to administer the drug. Biogen and Eisai signaled in April that adoption was accelerating.
Leerink Partners analyst David Rising said in a note Sunday that he expects commercial adoption of donanemab to be more limited than Lukembi because the Eli Lilly drug has “more safety concerns” and is less convenient because it is given once a month via vein, a method known as intravenous infusion.
Reisinger noted that Rekembi is currently given as a twice-monthly infusion, but Biogen plans to launch an injectable version next year. He expects donanemab to achieve $500 million in sales in 10 years.
How effective is Eli Lilly’s Alzheimer’s drug?
A Phase 3 trial conducted by Eli Lilly and Co. in more than 1,700 patients found that donanemab slowed the progression of Alzheimer’s disease by 29% compared with a placebo after about 18 months, based on traditional ways of measuring the severity of dementia.
These results are comparable to those observed in Leqembi.
Patients enrolled in Lilly’s Phase 3 clinical trial had to show positive PET scans for amyloid plaques and another protein in the brain called tau, which is considered a marker of Alzheimer’s disease severity. People with no or very low levels of tau were not included in the trial’s primary analysis because researchers thought they were unlikely to experience disease progression over the course of the study.
Lilly’s trial focused primarily on patients with low to moderate tau levels, who appear to benefit more from the treatment than those with higher tau levels.
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Eli Lilly argued that patients need to be tested for amyloid plaques to receive the drug, but not for tau. The company said it tested for tau in its trial to enroll patients whose condition was expected to worsen, which increased the chances that the study would be able to “clearly determine” the drug’s effectiveness.
Most advisers agreed that tau testing should not be required to access donanemab, because doing so would likely limit the people who could benefit from the drug.
“From a very practical standpoint, I don’t think it’s wise to have this as a barrier,” Dr. Kathleen Poston, a professor of neurology, neuroscience and neurosurgery at Stanford University and a member of the ad hoc committee, said at Monday’s meeting.
Patients who took Lilly’s drug in the trial were eligible to switch to a placebo if their brain amyloid levels fell below a certain threshold. By the end of the trial, 60% of participants taking donanemab were able to stop treatment.
Dolan said allowing patients to stop taking the medication once enough amyloid has been removed could be a “motivating factor” for them to comply with infusions and regular checkups.
Brain swelling and risk of bleeding
About 24% of study participants who took donanemab experienced brain swelling, and 31% experienced brain hemorrhage.
The majority of ARIA cases were mild to moderate, with 6% of participants with brain swelling and 1% of participants with brain hemorrhage experiencing symptoms. Symptoms included headache, confusion, dizziness, nausea and, rarely, seizures.
Severe cases occurred in 1.5% of patients with brain swelling and in less than 1% of patients with cerebral hemorrhage.
FDA staff said that if donanemab is approved, they expect to see strong “boxed” warnings on the drug’s package insert about the risk of brain swelling and bleeding, especially in people who have two copies of a gene called ApoE4, and they also expect to recommend MRIs to monitor patients for these side effects, among other strategies.
This is consistent with Leqembi’s approval label.
A final analysis of the data by FDA staff found that 19 deaths occurred among participants who took donanemab over the 18-month trial, three of which were attributable to the Eli Lilly drug, compared with 16 deaths among patients who took a placebo, reflecting a smaller imbalance in deaths between those who took donanemab and those who did not.
