The U.S. Food and Drug Administration on Tuesday approved a new drug for Alzheimer's disease, the latest in a series of new treatments that have been met with excitement, disappointment and skepticism.
The drug, donanemab, sold under the brand name Xanra, has been shown in studies to slightly slow the rate of cognitive decline early in the disease, but it also came with significant safety risks, including swelling and bleeding in the brain.
Xanla, made by Eli Lilly & Co., is similar to Rekembi, another drug approved last year. Both are infusions that attack a protein involved in Alzheimer's disease and can slow the progression of dementia by several months. Both have similar safety risks. Rekembi, made by Eisai and Biogen, is given every two weeks, while Xanla is given monthly.
Kisunra has one big difference that may be attractive to patients, doctors, and insurers: Lilly says that after Kisunra clears amyloid, the protein that builds up like plaque in the brains of Alzheimer's patients, they can stop taking the drug.
“If you remove the target, you can stop giving it,” said Anne White, Lilly's executive vice president and president of its neuroscience division. White said this could reduce the overall cost of treatment, as well as the inconvenience and risk of side effects.
The company said that 17% of patients who received donanemab in the 18-month clinical trial stopped taking the drug after six months, 47% stopped taking it within a year, and 69% stopped taking it within 18 months. Cognitive decline continued slowly after patients stopped taking the drug. The company is evaluating how long this slowing continues after the clinical trial period ends, said Dr. John Sims, Lilly's medical director.
Xanla has a list price of $32,000 for a one-year course of treatment. Rekembi costs $26,000 per year, but treatment does not stop after the amyloid is removed. White said the higher price reflects the expectation that patients will be able to stop taking Kisunra once the plaque disappears.
Kisunla and Lekuembi are considered only incremental steps in the search for an effective treatment for Alzheimer's, and some experts say they may not slow the progression of the condition enough to be noticeable to patients and their families.
These drugs are a new class of medications that address the underlying biology of Alzheimer's by attacking amyloid, which begins to build up in the brain years before symptoms appear. The first drug in this class was approved in 2021, Aduherm, but its manufacturer, Biogen, withdrew it last year, citing insufficient evidence that it would benefit patients. For now, there are no treatments that can halt or reverse memory loss or other cognitive impairment.
Some Alzheimer's experts are skeptical of anti-amyloid drugs, saying they believe the risks outweigh any small potential benefits.
Dr. Michael Greicius, a neurologist at Stanford University School of Medicine, said he has never prescribed Lukembi and wouldn't recommend Kisunla. He said that if these drugs were effective, the data should show that patients who clear more amyloid from the brain experience a slower rate of cognitive decline, just as HIV drugs have shown that the more a drug reduces a patient's viral load, the better they will do in health and have a better chance of survival.
But so far, “none of the studies have shown a correlation between the removal of amyloid plaques and clinical response in individual subjects,” Dr. Greicius said. That raises the question, he said, “is the drug working, and if so, how?” He added, “and that's frustrating and distressing for us as clinicians.”
Other experts said they believe it's worthwhile to offer the drug to patients, even if the effect may be small.
Dr. B. Joy Snyder, a professor of neurology at the University of Washington School of Medicine who worked on the drug's clinical trials and previously advised both Eisai and Lilly, said that while the slowing of decline is “not a huge difference,” it could have meaning in people's lives, for example by slowing the progression of mild forgetfulness to the need for appointment reminders.
“At least at the population level, amyloid removal correlates with slower disease progression,” she says. “Seeing that correlation in individual patients would be hard,” she says, because memory and thinking problems can fluctuate, and “you don't know if you're having a good day or a bad day” during a test.
In a study of 1,736 patients with mild cognitive impairment or the early stages of mild dementia, patients who received donanemab slowed their cognitive decline by about 4.5 to 7.5 months over 18 months compared with patients who received a placebo. On an 18-point cognitive scale, the overall group of patients who received the drug declined 29 percent slower than the placebo group, a difference of 0.7 points.
Nearly half of those who received donanemab maintained their cognitive levels one year after the study began, compared with 29 percent of those who received a placebo.
About a quarter of patients who took donanemab experienced brain swelling or bleeding. Most cases were mild or asymptomatic, but about 2% were severe, and the side effects were associated with the deaths of three patients.
Rates of swelling and bleeding were higher in the donanemab trial than in the Lukembi trial, but differences in patients and other factors make comparisons difficult.
Patients at high risk for either drug include those who have had four or more microbleeds in the brain and those who have the APOE4 gene variant linked to Alzheimer's disease, especially if they have two copies of the variant.
Bev Kroll, 69, of Phoenix, has been taking part in the donanemab trial for almost three years, receiving infusions at Banner Alzheimer's Institute, one of the trial sites. Neither Kroll nor her doctors know when she received donanemab or when she received a placebo. (If she'd received the placebo during the first 18-month phase, she would have started on the drug during the extension phase. If she'd received the drug during the first 18-month phase, her amyloid would probably have disappeared and she would have received a placebo at some point during the extension phase.)
In an interview arranged by Lilly, her husband, Mark Kroll, said that over the first 18 months, doctors told him that regular scans sometimes found microbleeds in her brain, but that they were never serious enough to stop her infusions.
Kroll said his wife, who worked in sales and marketing for Coca-Cola and was highly organized and had a sharp memory, began to forget things about six years ago. Instead of baking several loaves of their specialty cranberry-orange-nut bread at a time, she said, baking one loaf became “a struggle.” “She would say, 'I don't know if I put the ingredients in right,”'” he said.
She was diagnosed with mild cognitive impairment, a precursor to dementia. “From that point until now, I went from asking the same question twice a day to asking the same question twice in 10 seconds,” Kroll said.
Kroll says he doesn't feel his cognitive abilities are declining, his main activity now being walking his beagle, Bailey, twice a day, and he no longer plays golf regularly with friends “not because I can't do it, but because I'm just tired of doing it all.”
Kroll said her memory and attention problems have been declining gradually, but he hopes the medication will slow it.
“This is not a magic bullet,” he said, but added, “I think it's important and I think it deserves FDA approval.”
Some patients stop taking their anti-amyloid drugs “as soon as they hear there's a risk of brain swelling and edema,” Dr. Snyder said, and some are “so afraid of losing their memory” that “they don't really care when you tell them what their risk is.”
One unusual feature of donanemab's clinical trials was measuring levels of another protein, tau, which forms tangles in the brain after amyloid builds up and is more closely associated with memory and thinking problems.
Participants with moderate tau levels worsened more slowly with donanemab than those with high levels, suggesting that earlier treatment may be more effective. This raised the question of whether patients should have tau brain scans before starting the drug, but neither Lilly nor the FDA recommended it because tau scans are not widely available.
Experts said there were some unknowns about stopping treatment after the plaque has been removed. “Do we need to start the treatment again?” Dr. Snyder wondered at one point. “Do we need to replace it with something else?”
Lilly scientists don't yet have the answers. Dr. Sims estimates that it could take nearly four years for amyloid levels to rise back above that threshold, and up to 10 years for them to return to the levels a patient had before starting treatment.
Some experts worry that the focus on anti-amyloid drugs could lead to fewer patients being enrolled in clinical trials for better treatments. “I think this is a trend that's stagnating and slowing progress in the field in general,” Dr. Greicius said.
Dozens of drugs are in clinical trials to treat Alzheimer's, including those that attack key hallmarks such as tau protein tangles and neuroinflammation.
“Hopefully, this is just the beginning,” Dr. Snyder said.