How Does Lilly's Alzheimer's Drug Compare to Aduhelm and Leqembi?

Fact checked by Nick Blackmer

• Eli Lilly shared phase 3 clinical trial data showing that a new monoclonal antibody treatment can slow the progression of Alzheimer’s disease by 35% over a year and a half.

• The once-monthly infusion, called donanemab, stopped the progression of disease in half the participants.

• The company also reported some safety risks of the drug. Three people died during the clinical trial.

Eli Lilly said its new Alzheimer’s drug, called donanemab, can slow the progression of the most common form of dementia, prolonging some patients’ ability to live independently and do daily tasks. The company announced the findings from its phase 3 clinical trial in a press release Wednesday.

In people with early symptomatic Alzheimer’s disease, the monthly antibody infusion slowed their loss of cognition.

“It’s not a cure. It’s not going to bring back what you lost, but it could slow things down significantly for people, and it’s a big step forward in terms of what we have,” Erik Musiek, MD, PhD, neurologist and associate professor of neurology at the Washington University School of Medicine.

Donanemab follows Aduhelm (aducanumab-avwa) and Leqembi (lecanemab-irmb) as the third monoclonal antibody therapy with late-stage data showing benefit for people with Alzheimer’s. These three drugs work by removing beta amyloid plaques from the brain. Both Aduhelm and Leqembi are already conditionally approved for use.

But as with its predecessors, Lilly’s monthly antibody infusion comes with significant safety risks. Donanemab can cause brain swelling and bleeding that can, in rare cases, be severe or even fatal.

“Similar to the other [drugs], the cognitive benefit is modest, but the risks are high, and I’m not sure the cost-benefit ratio is there to make this seem like a huge breakthrough,” Matthew Schrag, MD, PhD, assistant professor of neurology and Director of the Cerebral Amyloid Angiopathy Clinic at Vanderbilt University.

Lilly plans to file for FDA approval as soon as June. The full study results will be presented at the Alzheimer’s Association conference in July and submitted for publication in a journal.

“We always wait for the full data to make big conclusions because a lot of times the details actually matter quite a lot in how you interpret something like this,” Schrag said.

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The study included 1,736 people ages 60 to 85 years with early symptomatic Alzheimer’s. This includes people with mild cognitive impairment and those in the mild dementia stage of the disease.

One of the primary goals of the study was to keep patients at their current cognitive state without progressing. Donanemab achieved that in 47% of participants over 18 months, compared to 29% in the placebo group.

Researchers also evaluated cognition among patients as they went about daily activities like managing finances, driving, hobbies, conversing about current events. Patients undergoing treatment declined 40% less when it came to performing these daily activities.

“You may have a patient who is going to go from being able to drive a car and pay their own bills and live independently to not being able to do those things over the course of five years. If you could lengthen that by 30% or 40% and get seven to eight more years of doing those things, I think that would be meaningful to people,” Musiek said.

Related:Is Lecanemab a Game-Changing Alzheimer's Drug? It May Depend On the Stage of Dementia

The study included people with intermediate levels of the protein tau, which can be toxic to neurons when it builds up in the brain. When the researchers included people with high levels of tau, they found the drug was less effective at slowing decline. This was expected, Lilly said, as people who are further along in their Alzheimer’s progression tend to be less responsive to therapy.

There aren’t any studies directly comparing the anti-amyloid drugs, but donanemab and Leqembi appear work about as well. While Aduhelm showed efficacy in some clinical trials, it’s little used due to controversy over its price and safety risks. Musiek said it’s reassuring that multiple different drugs that target amyloid have shown to be beneficial to cognition.

However, scientists disagree over amyloid plaques are the central driver of Alzheimer’s. While scientists have long known amyloid plays a key role, Schrag is less convinced than Musiek that Lilly’s data proves that clearing amyloid treats the disease, rather than just the symptoms.

A key way to test dementia patients’ cognition is to use a tool called the CDR Sum of Boxes, in which patients are scored on an 18-point scale. Schrag said the donanemab efficacy numbers look appealing, but in reality, the patients who respond to the treatment are only likely to move about half a point on the scale. That, he said, is not enough for patients or their loved ones to see a noticeable difference in their cognitive abilities.

“We’re still talking about something that’s a very modest clinical benefit,” he said.

Side Effects May Be Severe

In the class of antibody therapies designed to clear amyloid plaque, serious side effects are called amyloid-related imaging abnormalities (ARIA). These include brain swelling and bleeding, including microhemorrhages.

Brain swelling occurred in 24% of people taking donanemab, with about 6% of those being symptomatic. About a third of treated participants experienced brain bleeding. Most of these cases were mild or moderate and were resolved, Lilly said.

ARIA was severe in 1.6% of participants. Two people died due to ARIA and the company did not verify whether a third death was related to ARIA.

“We are encouraged by the potential clinical benefits that donanemab may provide, although, like many effective treatments for debilitating and fatal diseases, there are associated risks that may be serious and life-threatening,” Mark Mintun, MD, group vice president of Neuroscience Research & Development at Lilly and president of Avid Radiopharmaceuticals, said in the statement.

Still, a clinical setting probably represents the best-case scenario for safety, Schrag said. When the drug is used in the real world, there’s likely to be less consistency in pre-screening patients, safety monitoring, and drug administration.

“These kinds of numbers definitely get my attention. That fear is a very nontrivial risk,” Schrag said. “I think that’s the major challenge with this—a minor cognitive effect could be a very nice result, but I think it’s getting washed out by these very significant risks.”

Musiek compared donanemab to chemotherapy. Just as a harsh treatment is needed to tackle deadly cancers, so too are they required to slow Alzheimer’s.

“It’s a difficult drug. All these drugs are all difficult,” Musiek said. “They require infusions, they require MRIs, and there are significant side effect risks that have to be considered. It’s a serious treatment for a serious disease.”

Related:What Is a Monoclonal Antibody?

This Treatment May Require Less Commitment

The patients taking donanemab were considered finished with the treatment once a certain amount of amyloid plaque was cleared. About half the patients were able to stop the treatment within a year. Another 20% completed it within 18 months.

Leqembi requires patients to get infusions twice a month, likely for the rest of their lives. Donanemab, on the other hand, only requires infusion once a month. Most patients may be able to stop the treatment after 12 to 18 months.

“That means that patients aren’t necessarily committed to taking the drug long term,” Schrag said. “With a very expensive treatment and a treatment that’s difficult to administer, that’s a much better scenario in terms of how it’s going to impact patients.”

However, the study only followed patients for 18 months. It’s not yet clear whether those patients will reaccumulate plaque or need more treatment after their plaques are cleared the first time.

It’s important to remember, Schrag said, that this treatment isn’t a cure. It doesn’t help patients to regain lost memory, but rather slows how quickly they lose it.

The Price Is Not Yet Determined

The FDA will consider the data submitted by Lilly to gauge whether to approve it for use. Schrag said he will be looking to see how different subgroups performed on donanemab, and to see how well certain minority populations are represented in the trial.

If the FDA approves the drug for use, it will be up to the company to set the price. Leqembi costs $26,500 per year and Aduhelm costs $28,200 annually.

Related:CMS: Alzheimer's Patients Must Be Enrolled in Clinical Trial to Take Aduhelm

The Centers for Medicare and Medicaid Services (CMS) said it won’t cover the cost of any amyloid-clearing therapies until the FDA reviews full clinical data. That means that insurers won’t cover the hefty price tag for Leqembi and Aduhelm.

Lilly said it believes its data meets the standard of evidence required for CMS to cover an Alzheimer’s therapy, though it’s up to the agency to make that decision.

Donanemab is not a cure for Alzheimer’s. While it can slow how quickly someone loses their cognition and ability to function independently, it will not restore memories. Talk to a trusted medical provider about how to weigh the pros and cons of taking a monoclonal antibody treatment for Alzheimer’s.