Alzheimer’s Drug Decision Pushed: FDA Slows Down on Donanemab

The Food and Drug Administration has decided to postpone its decision on the approval of Eli Lilly’s candidate Alzheimer’s drug, donanemab. The delay has caught a number of Alzheimer’s experts, doctors, and patients off guard: The industry had expected the medication hit the market as soon as this month.

Instead, Eli Lilly has announced that the FDA will be convening an independent panel of experts to evaluate donanemab before a decision is made. The FDA cited the need for further understanding the drug’s safety (including its potential side effects) and efficacy and the drug’s trial design as factors that warrant a closer look.

Patients and advocates were especially eager for donanemab’s approval. After almost two decades of stagnation, two new drugs for Alzheimer’s have hit the market in the last three years. The approval of monoclonal antibody anti-amyloid drugs, Aduhelm and Leqembi, which fight Alzheimer’s by attacking deposits of beta-amyloid protein in the brain, bolstered the theory that clearing amyloid plaques could slow the disease. Both were created by drugmakers Biogen and Eisai. But then, the rollercoaster ride started: Sales and production of Aduhelm have been halted by the drugmakers, and the drug has been pulled off the market. Meanwhile, Leqembi secured full FDA approval — and patients who wish to take it are joining long waitlists. There are dozens more monoclonal antibodies for Alzheimer’s in the development pipeline behind these drugs, and donanemab is the furthest along.

Eli Lilly executives expressed their surprise over the FDA’s decision to assemble the committee and slow down the review process — especially since the agency usually calls upon independent advisory committees earlier in the review process.

“We were not expecting this,” Anne White, an executive vice president of Lilly and president of its neuroscience division, told the New York Times. While the F.D.A. often calls on such independent advisory committees to help evaluate drugs, she said, it’s unusual to do so “at the end of the review cycle and beyond the action date that the F.D.A. had given us.”

According to the Alzheimer’s Drug Discovery Foundation, the news doesn’t detract from the momentum this new generation of disease-modifying Alzheimer’s treatments have been building over the past couple years.

“Today’s FDA decision is not a setback, but another step forward in the drug approval process, with the regulatory agency doing its due diligence before the distribution of the drug to patients,” ADDF Co-Founder and Chief Science Officer Dr. Howard Fillit said in a statement. “The decision to hold an advisory committee before granting approval follows the regulatory process that was used for the other drugs in this class, including Leqembi.”

The FDA’s move will postpone any decision on donanemab’s approval until later in the year, with a few months expected before the advisory committee holds a hearing.

Does donanemab work for Alzheimer’s?

Overall, Phase 3 clinical trial results presented at the 2023 Alzheimer’s Association International Conference in July showed that the drug managed to slow cognitive decline by 22 to 29 percent (depending on the cognitive test used to measure), as compared to the placebo group.  In patients who had lower levels of tau in their brain, the drug managed to slow cognitive decline even more — 35 to 36 percent. (The percentages refer to the fraction-of-a-point differences in cognitive decline between the placebo and control groups.)

At the time of the July 2023 AAIC presentation, the presenters announced that they’ve submitted the data to the FDA and had expected to learn whether the drug will be approved by the end of 2023. Now, the company says, news of an FDA rejection or approval for donanemab could come as soon as soon as next month. Eli Lilly’s Chief Scientific Officer Dr. Daniel Skovronsky said in January that the drug was poised for a potential FDA approval in the first quarter of 2024, according to FiercePharma.

What do the 2023 Phase 3 trial results previewed at AAIC really say about what this new anti-amyloid drug could do for patients? A few notes on efficacy:

• The drug did not stop cognitive decline in the treatment nor placebo group. At best, the drug appears to slow down decline caused by the early stages of Alzheimer’s disease.
• However, the drug did lower the risk of progressing to the next stage of dementia. Over the course of a year, about one in six patients receiving donanemab progressed to the next stage of Alzheimer’s compared to about one in four patients in the placebo group. 
• About half of patients were able to go off the drug after a year, when amyloid plaques were cleared from the brain.
• The percentages refer to the fraction-of-a-point differences in cognitive decline between the placebo and control groups. While both groups progressed over the course of 18 months, the treatment group declined a little bit slower than people who thought they were taking the drug, but weren’t. In other words, the difference it makes may be relatively small.
• The earlier in their course of disease that the participants received the drug, the more improvement they experienced — a case for the need for better, more accessible diagnostics that can catch Alzheimer’s earlier.
• The Alzheimer’s risk gene ApoE4 did not affect how well the drug worked (though it did seem to influence a person’s vulnerability to side effects).

Based on the trial data, Eli Lilly estimates that this drug may delay progression on average of 7.5 months, as compared to the placebo.

How safe is donanemab for Alzheimer’s patients?

In the last few months, some researchers have raised concerns about the safety profile of anti-amyloid drugs like Aduhelm and Leqembi, which cause a condition called amyloid-related imaging abnormalities (ARIA). This which can lead to brain swelling (ARIA-E) and bleeding (ARIA-H). While it may be asymptomatic, the long-term consequences of ARIA are unknown. 

• Overall, almost two in five patients experienced some form of ARIA
• One in four patients taking the actual drug developed brain swelling (ARIA-E)   
• More than three in 10 patients taking the drug experience brain bleeding (ARIA-H)
• Rate of ARIA was higher in patients who carried the ApoE4 gene

Three out of 868 patients who took donanemab died during the course of the trial. Two deaths were linked directly to a drug side effect, ARIA, and the other one occurred following a severe case of ARIA.

Overall, almost two in five patients who received donanemab experienced some form of ARIA. One in four patients who received donanemab developed ARIA-E while more than three in 10 experienced ARIA-H. Around 1.5 percent of cases of ARIA were considered severe, and around 13 percent of the total patients taking donanemab dropped out of the trial because of side effects. 

Comparatively, in the Aduhelm trials leading up to Aduhelm’s FDA approval for Alzheimer’s treatment in the summer of 2021, ARIA occurred in more than one third of patients receiving the high dose of the drug. One in five people who received Leqembi experienced ARIA. Among these cases — only 3.5 percent were symptomatic.

Looking at anti-amyloids overall and their side effects, which can sometimes prove very serious and even fatal, not all researchers are convinced that the risks of these monoclonal antibody drugs for Alzheimer’s outweigh potential benefits. At the end of the day, experts say, people living with Alzheimer’s need access to more treatment options, and every patient and family needs to make an informed decision with their doctor about the cost-benefit analysis of taking an anti-amyloid. 

(Editor’s note: Lou Niles, a retired U.S. army officer who enrolled in the donanemab drug trial, told Being Patient in a Live Talk on his clinical trial experience that he personally didn’t experience any side effects from the drug — a completely anecdotal account, but interesting to read about his subjective experience with the drug, nonetheless.)

An Army Vet’s 23&Me Test Inspired Him to Join a Clinical Trial. There, He Learned He Had Early Signs of Alzheimer’s

How are drugmakers measuring donanemab’s efficacy?

Alzheimer’s drug trials measure the rate of cognitive decline over the course of 1.5 years using the 18-point Clinical Dementia Rating–Sum of Boxes (CDR-SB) scale and the 146-point The Integrated Alzheimer’s Disease Rating Scale (iADRS). The CDR-SB and iADRS are two validated measures of cognitive decline, where larger numbers indicate more impairment. Points are scored based on what patients can and can’t do (such as cooking food or their ability to finish a Sudoku). A loved one or caregiver is also involved in these interviews to make sure these scores are accurate.

In the Phase 3 trial, participants in the placebo group declined by approximately 13 points on the iADRS scale points while those receiving donanemab appeared to decline by approximately 10.08 points, over 18 months. If we’re talking percentages, that’s a 22+ percent improvement. On the CDR-SB scale, patients receiving the placebo declined approximately 2.4 points while those receiving donanemab only declined 1.7 points. This amounts to about 29+ percent slowing. Subgroups of patients who received the drugs earlier showed a slightly higher percentage of slowing compared to the placebo group.

Looking at the actual numbers, this appears to be a difference of 2.92 and 0.7 points respectively on these scales, which are both below the threshold that some clinicians believe to be noticeable to a patient. This is a larger positive difference for patients than in the Leqembi and Aduhelm trials, where data showed the drugs slowed decline by 0.45 points and 0.39 points respectively, compared to the new drug’s 0.7 on CDR-SB. Donanemab shows effectiveness similar to cholinesterase inhibitors like donepezil (Aricept). It is estimated that people taking the drug compared to a placebo group may slow their cognitive decline by 0.6 points over the course of 12 months. 

 “It is very complicated to compare efficacy and safety across trials,” Mark A. Mintun, vice president of neuroscience research and development at Eli Lilly, said in a press conference at AAIC 2023. He added that the patients recruited by Eli Lilly on average had higher levels of brain pathology like beta-amyloid and also showed more cognitive impairment in the trial. 

What’s next for donanemab?

Eli Lilly has filed for approval in the U.S. and expects to hear whether or not they’re approved in the coming months. If it is approved, it is likely that Medicare will opt to cover the drug as it did with Leqembi. 

Dr. Howard Fillit at the Alzheimer’s Drug Discovery Foundation said that while the July 2023 results marked “an important step in our journey to develop new and effective Alzheimer’s therapies,” the hard work isn’t done yet: “Recent success in anti-amyloid research spurs optimism and will serve as a catalyst for new investments in the pipeline and a stronger focus on the biology of aging. The results of the TRAILBLAZER-ALZ 2 trial accelerate recent momentum, bringing us one step closer to making Alzheimer’s a treatable, and eventually, a preventable disease.”

“These results demonstrate that diagnosing and treating people earlier in the course of Alzheimer’s disease may lead to greater clinical benefit,” Dr. Liana Apostolova at the Indiana University School of Medicine said. “The delay of disease progression over the course of the trial is significant and will give people more time to do such things that are meaningful to them.”

Maria C. Carillo, Alzheimer’s Association chief science officer added that the results provide convincing evidence that removing beta-amyloid slows disease progression: “These benefits are real and meaningful, giving people more time to participate in daily life, remain independent and make future health care decisions.”

The FDA has not make any public statements about the decision to slow down donanemab’s review process, but the assembly of the committee is expected to push an approval decision to later in 2024 at the soonest. Eli Lilly executives expect it will take months for the advisory committee to come together and hold a hearing.

“The FDA did commit to us to move quickly,” White at Eli Lilly told the New York Times, “so we would hope that they would then take action shortly after the advisory committee.”

UPDATED March 8, 11:30 A.M. – This article was updated with new information about the expected FDA approval timeline for donanemab.

UPDATED Feb. 22, 00:01 A.M. – This article was updated with new information about the expected FDA approval timeline for donanemab plus a patient perspective.