FDA Approves New Alzheimer’s Drug Kisunla (Donanemab)

UPDATED JULY 3: The Food and Drug Administration has approved Kisunla (generic name donanemab), a new Alzheimer’s drug developed by Eli Lilly. The published data from donanemab’s Phase 3 clinical trial showed that the drug cleared out beta-amyloid plaques from the brain — a process associated with a small improvement in cognition. The announcement came on July 2, a couple weeks after a committee of independent advisors to the FDA unanimously recommended the drug’s regulatory approval.

Anti-amyloid monoclonal antibodies like Kisunla are thought to modify the course of the disease by targeting amyloid plaques, which build up in the brains of people with Alzheimer’s. These drugs are significant because they are designed to modify the disease itself, slowing or stopping Alzheimer’s progression. Meanwhile, every other Alzheimer’s drug currently available to patients only serve as a band-aid for the symptoms of Alzheimer’s, like memory problems, confusion, agitation.

The first drug of this kind, Aduhelm, was conditionally approved in 2021 while drug trials continued, but it was discontinued by the drugmaker earlier this year. The second such drug, Leqembi, received its full FDA approval in late 2023. With Kisunla’s arrival, early-stage Alzheimer’s patients and their doctors now have two anti-amyloid drug options to choose from (though access to Leqembi has proven a challenge for some patients).

Does Kisunla work?

Kisunla (donanemab) might help slow the progression of Alzheimer’s disease but it is not a cure. The Phase 3 trial stratified patients based on the levels of tau in their brain. Patients with higher levels of tau are typically further along in the disease process. Here are the key findings from the Phase 3 clinical trial.

• The drug did not stop cognitive decline, but appeared to slow the progress of the disease in the early stages. 
• The drug lowered the risk of progressing to the next stage of Alzheimer’s. Over the course of a year, one in six patients who received the drug progressed to the next stage of the disease compared to one in four in the placebo group.
• The percentages referred to by other publications highlight 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.
• Patients with medium levels of tau in their brain benefited most while patients with high levels of tau did not seem to benefit as much.
• 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).

Half the patients went off the drug after a year after amyloid plaques were cleared from their brain.

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.

In an advisory committee hearing about Kisunla in June, Sandra Carlino spoke on behalf of her husband George who participated in the Kisunla (donanemab) trial: “Our experience in this trial has been life-changing,” she said. “We understand that his disease may never be cured but his progression has slowed down immensely that to the point of a casual observer or acquaintance they would not know he has this condition.”

“Kisunla demonstrated very meaningful results for people with early symptomatic Alzheimer’s disease, who urgently need effective treatment options. We know these medicines have the greatest potential benefit when people are treated earlier in their disease, and we are working hard in partnership with others to improve detection and diagnosis,” Anne White, executive vice president and president of Lilly Neuroscience, Eli Lilly and Company said in a statement. “Our deepest thanks to the patients and their loved ones for participating in our clinical programs and to Lilly scientists and collaborators persevering over decades of research. Each year, more and more people are at risk for this disease, and we are determined to make life better for them.”

Alzheimer’s Drug Discovery Foundation cofounder and Chief Science Officer Dr. Howard Fillit echoed the sentiments of many drug development experts when he noted the pressing need to develop multiple new disease-modifying drugs targeting different Alzheimer’s biomarkers. With two anti-amyloid drugs now on the market, and 75% of drugs in the development pipeline focused on targets other than amyloid and tau, a “combination therapy approach” looms on the horizon. In order for that to be effective, pathways to early and accurate diagnosis are a must.

“We are no longer asking whether or not we can diagnose Alzheimer’s, but, rather, how early can we detect the disease?” Fillit said in a statement. “With the validation of new biomarkers, especially blood tests, we can now diagnose the disease with ease and intervene earlier than ever, including in the preclinical phase, opening the door prevention. We can finally deliver the right drugs to the right patients at the right time.”

How is the Kisunla different from Leqembi and Aduhelm, the other two-disease modifying drugs that have previously been approved (or in Aduhelm’s case, conditionally approved) by the FDA?

Currently, the monoclonal anti-amyloid drugs are all infused intravenously and all work to prevent the buildup of beta-amyloid plaques in the brain. Leqembi attaches to beta-amyloid before it forms plaques, while Aduhelm (no longer available) and donanemab attach to beta-amyloid once it has formed the plaque.

The other difference: When beta-amyloid is fully cleared from the brain as measured by an amyloid PET scan, the patients can go off the drug.

How effective is Kisunla (donanemab)?

To measure the effectiveness of Kisunla (donanemab), researchers measured the rate of cognitive decline over the course of 1.5 years using two standardized scales — the 18-point Clinical Dementia Rating–Sum of Boxes (CDR-SB) scale and the 146-point The Integrated Alzheimer’s Disease Rating Scale (iADRS). 

A higher score on either of these scales indicates more impairment. The 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.

Participants in the placebo group declined by 13.11 points on the iARDS scales while those on donanemab declined approximately 10.19 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. Some patients who received the drug earlier in the course of their disease showed a little more slowing of the disease process.

When the researchers looked specifically at the subset of participants with low-to-medium levels of tau, participants in the placebo group declined by 9.27 points while those on donanemab declined 6.02 points, a +35 percent improvement. On the CDR-SB scale, patients receiving placebo declined by 1.88 points while those on donanemab declined by 1.2 points, a +36 percent improvement.  

Is Kisunla (donanemab) more effective than Aduhelm and Leqembi?

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. 

But comparing these drugs head-to-head is tricky.

“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.

Does Kisunla have side effects?

Anti-amyloid monoclonal antibody drugs like Donanemab and Leqembi cause brain swelling and brain bleeding — a condition called amyloid-related imaging abnormalities (ARIA). While most cases 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.

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. 

In the Aduhelm trials, 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.

Do the risks of Kisunla outweigh the benefits?

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. 

People who carry one or two copies of the Alzheimer’s APOE4 gene are also at a higher risk of these side effects.

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.

Who is eligible to receive Kisunla?

Patients who have mild cognitive impairment or early Alzheimer’s disease are eligible to receive this treatment. Treatment involves a monthly 30-minute infusion and is stopped once the drug clears out the majority of amyloid plaques as measured by an amyloid PET scan. 

The drug label mentions that people are at a higher risk of developing brain bleeds if they’re taking blood clot medications such as Coumadin (generic name: warfarin). It also mentions that people who have the Alzheimer’s risk gene APOE4 are at a higher risk of developing ARIA, but it does not require patients to get tested before getting prescribed.

There are currently waitlists to access Leqembi at many infusion clinics, so patients might face similar issues trying to access donanemab.  

Where can I get Kisunla?

This drug will be available at hospitals and infusion centers. However, it may be difficult to access for people who live far from major metropolitan areas or hospitals where there are fewer specialty infusion centers.

Will Kisunla be covered by insurance?

According to Lilly’s press release, the total cost of Kisunla depends on when patients complete treatment as the drug is stopped once amyloid plaques are removed to minimal levels based on an amyloid PET scan. Six months of treatment costs $12,522, 12 months costs $32,000 while 18 months costs $48,896. Medicare and Medicaid will cover the cost of the drug, in line with its coverage policy announced in June 2023.

Eli Lilly has set up a website and hotline (1-800-LillyRx (1-800-545-5979) for patients with questions about drug coverage and care coordination.

About Kisunla, from Lilly: Kisunla™ (donanemab-azbt) (pronounced kih-SUHN-lah) is an amyloid-targeting treatment for people with mild cognitive impairment (MCI) as well as people with mild dementia stage of early symptomatic Alzheimer’s disease, with confirmed amyloid pathology. Kisunla can cause serious side effects, including amyloid-related imaging abnormalities, or ARIA, and infusion-related reactions. Kisunla is a prescription medicine administered intravenously every four weeks, 700 mg for the first three doses and 1400 mg thereafter.

UPDATE 3 July 2024, 11:34 A.M. – This article was updated to include a statement from the ADDF.