Leqembi Vs. Kisunla: An Alzheimer’s Drug Point-by-Point Comparison

With the 2024 FDA approval of Eli Lilly’s Kisunla for early-stage Alzheimer’s disease, there are now two fairly similar anti-amyloid on the market in the United States. Kisunla and Biogen and Eisai’s Leqembi are both designed to target the pathology underlying the disease to help slow down cognitive decline at least slightly. 

With two options now available, doctors and patients must look across a number of factors to evaluate their potential as a treatment option — and decide between the two. To do this, they need to consider how they work, how safe they are, how they’re administered, how much they cost, and more.

Comparing the two isn’t so straightforward: Experts told Being Patient that the drugs’ respective clinical trial data can’t easily be compared head to head because of differences across the trials and how the results are reported.

But Dr. Sharon Cohen, neurologist and director of the Toronto Memory Program, told Being Patient that the participants in the Leqembi trial were earlier along in the Alzheimer’s disease process. Additionally, many participants in the Kisunla trial stopped treatment after six months or a year based on amyloid clearance, whereas in the Leqembi trial, patients received the drug for a full 18 months. 

Meanwhile, Dr. David Weisman, a neurologist at Abington Neurological Associates, told Being Patient that Kisunla might be a fit for patients who live farther away and may have trouble traveling for frequent infusions. Since there are higher rates of ARIA with Kisunla, he added that it is probably a better fit for patients without APOE4, which tacks on an extra risk of ARIA. 

Another consideration, Cohen said, is the way that companies determine the dosage of the drugs.  “Leqembi doses are based on a person’s body weight while Kisunla is given as a fixed dose,” she said. “This may lead to under or overdosing individuals with very high or very low weights, respectively.”

Beyond these points, there are a number of other considerations, including the differences in what types of biomarkers each drug treats best, the comparative risk of potentially serious side effects and more. 

How do Leqembi and Kisunla slow down Alzheimer’s?

Leqembi and Kisunla are part of a class of drugs called monoclonal antibodies. These drugs are proteins engineered to stick to something specific in the body. In this case, both drugs are anti-amyloids, meaning they stick to beta-amyloid. The antibody acts like a giant neon sign for the brain’s immune cells, microglia, to eat and destroy whatever it is attached to — in this case, beta-amyloid.

While both drugs stick to beta-amyloid, a key biomarker associated with Alzheimer’s disease, they target different forms of the misfolded protein.

Leqembi targets small chains of linked-up beta-amyloid proteins called protofibrils. By preventing these protofibrils from merging, the drug prevents amyloid plaques from forming. In addition, it also targets amyloid plaques. Meanwhile, Kisunla only targets the beta-amyloid plaques.

Do Kisunla and Leqembi work?

Neither drug stops the progression of Alzheimer’s disease. In clinical trials, the drugs each appeared to slow down the progression of the disease down a little bit. How meaningful is the change? 

Doctors say that ultimately, that the drug slows clinical progression by about six months, keeping patients at milder stages of the disease longer. But that progress isn’t always noticeable.

In fact, it may be so subtle, that according to scientific scales that measure “meaningful” clinical differences, neither of the drugs actually meets standards for clinical meaningfulness. 

So, while doctors see an improvement, if you ask the scientists who oversee these scales, the drugs don’t make “noticeable” changes to cognitive function. Leqmebi scored 0.48 less than the benchmark for clinical meaningfulness on a certain scale, while Kinsula scored 0.3 less.

In fact, the European Medicines Agency recently declined to approve Leqembi’s drug application because the regulators did not think that the small cognitive benefits provided by the drug outweighed the risks of brain bleeds and swelling. The EMA is currently reviewing Kisunla.

And then, there’s the patient perspective: Sandra Carlino, who spoke on behalf of her husband George, at a recent FDA advisory committee meeting for Kisunla said that the drug slowed down her husband’s cognitive decline “to the point of a casual observer or acquaintance they would not know he has this condition.”

The question of tau

One small difference between the two drugs is how they treat people who have a certain Alzheimer’s protein biomarker called tau in their brains. Kisunla might be a little less effective than Leqembi specifically for people who have a lot of tau in their brains or a very small amount, according to data presented to the FDA advisory committee. So it’s helpful for patients to know, when comparing the two drugs, where on that spectrum they fall. But, the FDA does not require a tau PET scan before treatment. This kind of PET scan isn’t covered by Medicare and it’s only available in a few medical centers across the U.S. Some doctors say this makes it a bit harder for them to know which of the two drugs is best for their patient.

“As the treating neurologist, there are certainly cases where knowing tau PET stage would inform my recommendations, in conjunction with other clinical data,” Dr. Gil Rabinovici, a neurologist and professor at the University of California San Francisco, wrote on AlzForum, adding that it isn’t currently feasible to require tau PET scans. “That said, my hope is that, rather than accepting a ‘lowest common denominator’ approach to care, we strive as a field to elevate care. This should include efforts to enhance access, affordability and coverage for amyloid and tau PET.”

How safe are Kisunla and Leqembi? How do the risks measure up to the benefits?

These drugs have side effects, including brain swelling and brain bleeds (called  amyloid-related imaging abnormalities, ARIA), and brain shrinkage. These risks tend to be higher for people with the genetic biomarker of Alzheimer’s, APOE4. There can also be higher risk if someone is on anticoagulant drugs.

As these drugs are administered by infusion, this is also the risk of infusions-related reactions, as well as allergic reactions in general.

Alzheimer’s anti-amyloids and ARIA side effects

In the Leqembi trial, 20 percent of patients developed ARIA, 15 percent developed brain bleeds (ARIA-H), and 11 percent developed brain swelling (ARIA-E). In the Kisunla trial, rates of ARIA were higher: double as many people developed ARIA, double as many developed brain bleeds (ARIA-H), and more than twice as many people (around 25 percent) had ARIA-E. Across the two drugs, between three and six percent of people had asymptomatic ARIA.

“From a safety perspective, Leqembi has a substantially lower rate of ARIA and therefore is the safer drug,” said Cohen.

“While with appropriate selection, monitoring and management, ARIA usually does not produce symptoms and clears within two to four months, in a small percentage of persons ARIA can lead to serious symptoms and disability and, rarely, even death,” Atri said.

During the 2024 Clinical Trials on Alzheimer’s Disease conference, researchers presented data that Kisunla could be administered at a lower dose, reducing the frequency of ARIA, while still clearing out amyloid plaques effectively. 

Weisman said that his clinic will use the new dosing but added that it will not change the way he thinks about the risks of the drug. “If we can prevent one case of ARIA, then it is worthwhile,” he added. “Our consent language is the same, as this reflects the reality of the trial, even if we try to make it less risky [with the different dose].”

Dr. Suzanne Schindler, a neurologist and researcher at the Washington University School of Medicine in St. Louis said their clinic also plans on instituting the new dose regimen for Kisunla. “I really see no disadvantage of doing this, and if it makes treatment with these therapies safer, that it’s an obvious thing to do,” she told Being Patient.

Some clinicians are still skeptical that the benefits of either drug outweigh the risks. Others believe that the slight slowing of cognitive decline is worth it. 

Dr. Marwan Sabbagh at Barrow Neurological Institute’s Alzheimer’s and Memory Disorders Program, regularly tests patients in his practice to help understand their ARIA risk on anti-amyloids.  

“We went from not talking about [genetic testing] at all to now using it for risk stratification,” Sabbagh said, “because we know that if you’re an ApoE4 double copy, your risk of having complications with the monoclonal [antibody treatments for Alzheimer’s] is quite high.”

In the Leqembi trial, people with no copies of ApoE4 had a 5.4 percent risk of ARIA-E and 11.9 percent risk of ARIA-H, heterozygotes (one copy of the gene) had a 10.9 percent risk ARIA-E and 14 percent risk of ARIA-H, while homozygotes (two copies) had a 32.6 percent risk of ARIA-E and 39 percent risk of ARIA-H. In the Kisunla trial, overall ARIA rates for people with ApoE4 were higher: 15.7 percent risk of ARIA for people with no copies, 22.8 percent for heterozygotes, and 40.6 percent for homozygotes. The published trial results did not provide separate data for rates ARIA-E and ARIA-H for ApoE4 carriers. 

Brain shrinkage

These anti-amyloid drugs also cause brain shrinkage, though it isn’t clear what this means long-term for patients. While patients taking Leqembi or Kisunla seemed to have a slowing cognitive decline in clinical trials, accelerated brain shrinkage is usually associated with Alzheimer’s disease progression.

Dr. Madhav Thambisetty, neurologist and senior clinical investigator at the National Institute on Aging wrote for Stat News that the shrinkage is a “cause for concern” and there is “uncertainty about the long term effects” it may have on patients.

At the 2024 Alzheimer’s Association International Conference, professor Nick Fox of the U.K. Dementia Research Institute presented data from a new study suggesting that the brain shrinkage wasn’t healthy tissue dying off but attributed it to beta-amyloid plaque clearance. The research he presented hasn’t been published yet.

Infusion-related reactions

Some patients experience infusion-related reactions. When these reactions and symptoms are mild, they go away on their own. Symptoms of these reactions include: 

• Fever and flu-like symptoms
• Nausea or vomiting
• Dizziness or lightheadedness
• Changes in heart rate and blood pressure
• Difficulty breathing or shortness of breath

One in four patients in the Leqembi trial experienced an infusion-related reaction, with 28 percent being moderate or severe. Infusion related reactions were about three times rarer in the Kisunla trial but were more likely to be cause for concern: Nine percent of patients developed a reaction, 43 percent of the time it was moderate or severe. 

Allergy

Some patients experience allergic reactions, which, in rare cases, can cause swelling of the face, lips, mouth, and tongue, hives, or difficulty breathing. The frequency of these reactions was not reported in the published results for the Leqembi trial, and in the Kisunla trial, 0.4 percent of participants developed serious allergic reactions.

Drug interactions

There is some controversy over whether people taking anticoagulant medications such as Coumadin (generic name: warfarin) are at a higher risk of developing brain bleeds. 

In the Leqembi trial, for example, people taking anticoagulants did not have a higher risk of developing brain bleeds. Though the FDA label doesn’t prohibit prescribing Leqembi drugs for patients on anticoagulants, prescribing guidelines outlined by neurologists recommend against it. 

“This has widely influenced prescribers such that many are unwilling to proceed if a patient is on an anticoagulant,” Cohen said. She expects the recommendations for Kisunla to take a similar stance.

Why the concern? Up to 80 percent of people with Alzheimer’s have a condition called cerebral amyloid angiopathy (CAA). In CAA, amyloid plaques crowd the brain’s blood vessels, replacing the muscles that normally surround them. Lecanemab (Leqembi) and other anti-amyloid antibodies weaken the blood vessels by getting rid of these plaques, making them weak and susceptible to hemorrhage.

People taking anticoagulants will have a harder time clotting blood, putting them at a higher risk of developing brain bleeds. According to third-party experts who reviewed cases of lecanemab deaths during the open-label trial extension in 2022, anticoagulant use may have contributed to the worsening of ARIA in two of three reported deaths.

Atri added that there are also concerns around the use of clot-busting drugs in patients on Leqembi or Kisunla who are experiencing stroke-like symptoms of brain bleeds. In a few case studies, these medications are also linked to worsening brain bleeds and death.

How long do patients stay on these drugs?

In the Kisunla clinical trial, half the patients stopped taking the drug after a year after their brains had cleared amyloid plaques. It isn’t clear why some people cleared plaques faster than others. 

Dr. David Weisman, a neurologist at Abington Neurological Associates, told Being Patient that it will take time to figure out how to do this in the clinic. He pointed out that the trial participants underwent an amyloid PET scan every six months to measure amyloid. “In clinical care, we don’t do this,” he said. “Nor do we check back in five years.”  

Atri said that many specialists will likely order an amyloid PET scan 12 to 18 months after a patient starts taking Leqembi or Kisunla and then use the information from the scan to guide further treatment.

In the clinical trial, 22 percent of patients remained positive after 1.5 years. “I’d keep treating them personally if they are tolerating it well,” Weisman said.

Infusion and administration

Both drugs require intravenous infusions at a specialized clinic. Leqembi requires biweekly infusions, while Kisunla requires monthly infusions. While a Leqembi infusion takes about an hour, a Kisunla infusion only takes 30 minutes.

Kisunla comes with stoppage instructions. When beta-amyloid is cleared below a minimal level, the doctor can take the patient off the drug. Patients will need to get additional amyloid PET scans while they’re taking the drug to assess when they’re ready to go off treatment. 

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

Cost and insurance coverage

Leqembi costs $26,500 for a person weighing the approximate average adult human weight of 165 pounds. It’s now covered by Medicare, Many insurers don’t think the drug’s benefits are worth it and aren’t covering it.  It isn’t clear yet how changes in dosing will affect the price of Kisunla.

Kisunla is notably more expensive by Leqembi year over year ($32,000 compared to $26,500), but the total cost to a patient and/or their insurer will depend on how long patients stay on it. Unlike Leqembi, treatment stops once amyloid plaques are reduced to a certain level. Cost could be as little as $12,522 for six months, and as much as $48,896 for a year and a half.  Medicare covers Kisunla, and it is too early to tell whether private insurers will cover it.