The Food and Drug Administration on Tuesday approved a new drug for Alzheimer’s disease, the latest in a new class of treatments that has been greeted with hope, disappointment and skepticism.
The drug, donanemab, which will be sold under the brand name Kisunla, has been shown in studies to modestly slow the rate of cognitive decline in the early stages of the disease. It also had significant safety risks, including swelling and bleeding in the brain.
Kisunla, made by Eli Lilly, is similar to another drug, Leqembi, that was approved last year. Both are intravenous infusions that target a protein implicated in Alzheimer’s, and both can slow the development of dementia by several months. Both also carry similar safety concerns. Leqembi, made by Eisai and Biogen, is given every two weeks; Kisunla is given monthly.
Kisunla has one significant difference that could concern patients, doctors and insurers: Lilly says patients can stop taking the drug after it clears the amyloid protein, which builds up in plaques in the brains of people with Alzheimer’s.
“Once you remove the target you’re after, you can stop dosing,” said Anne White, Lilly’s executive vice president and president of its neuroscience division. She said that could reduce the overall cost and inconvenience of treatment, as well as the risk of side effects.
The company said 17 percent of patients who received donanemab in the 18-month clinical trial were able to stop the drug after six months, 47 percent stopped within a year, and 69 percent stopped within 18 months. Their cognitive decline continued to slow even after they stopped. The company is evaluating how long this slowing will continue beyond the duration of the trial, said Dr. John Sims, Lilly’s chief medical officer.
The list price for Kisunla will be $32,000 for a one-year course of therapy. Leqembi costs $26,000 per year, but is not stopped after the amyloid is cleared. The higher price, Ms. White said, reflects the expectation that patients will be able to stop treatment with Kisunla once the plaques have cleared.
Kisunla and Leqembi are considered just an incremental step in the search for effective treatments for Alzheimer's. Some experts say they may not slow the decline enough for patients or families to notice.
The drugs belong to 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 that class to receive approval was Aduhelm in 2021, but its maker, Biogen, discontinued it last year because there wasn’t enough evidence it could help patients. So far, there are no treatments that stop or reverse memory loss or other cognitive problems.
Some Alzheimer's experts are skeptical of anti-amyloid drugs, saying they believe the risks outweigh the potential small benefits.
Dr. Michael Greicius, a neurologist at Stanford University School of Medicine, said he did not prescribe Leqembi or offer Kisunla. He said that if the drugs were effective, data should show that individual patients who had more amyloid removed from their brains experienced slower rates of cognitive decline, just as HIV drugs have shown that the more a drug reduces a patient’s viral load, the better that patient’s health and chances of survival.
But so far, Dr. Greicius said, “There's no correlation in any of their studies between clearance of amyloid plaques and clinical response in individual subjects.” That, he added, has raised the question of “how does this drug work, if it works, and that's a little frustrating and distressing for me as a physician.”
Other experts said they think it is helpful to offer the drugs to patients, even if the benefit might be modest.
Dr. B. Joy Snider, a professor of neurology at Washington University School of Medicine who is involved in the drug trials and has previously advised both Eisai and Lilly, said that slowing the decline “isn’t a big difference” but could have a significant impact on people’s lives, such as delaying the progression from mild forgetfulness to needing to remember appointments.
“At least at the group level, amyloid clearance is correlated with slowing of disease progression,” he said. “It will be difficult to see these correlations in an individual patient,” he said, because memory and thinking problems can fluctuate and because during testing “you don’t know if you’re having a good day or a bad day.”
In a study of 1,736 early-stage patients, those with mild cognitive impairment or mild dementia, cognitive decline slowed by about 4½ to 7½ months over 18 months in those who received donanemab compared with those who received a placebo. On an 18-point cognitive scale, the overall group of patients who received the drug declined 29 percent more slowly than the placebo group, for a difference of seven-tenths of a point.
Nearly half of the patients given donanemab maintained the same cognitive level after a year of study, compared with 29 percent of those given the placebo.
About a quarter of those taking donanemab experienced swelling or bleeding in the brain. While most cases were mild or asymptomatic, about two percent were serious, and side effects have been linked to the deaths of three patients.
The donanemab study showed higher rates of swelling and bleeding than the Leqembi study, but comparisons are difficult because of differences in patients and other factors.
With both drugs, patients at highest risk are those who have had more than four microscopic bleeds in the brain and those who carry a genetic variant linked to Alzheimer’s called APOE4, especially if they have two copies of the variant.
Bev Krol, 69, of Phoenix has been in the donanemab study for nearly three years, receiving infusions at the Banner Alzheimer’s Institute, one of the trial sites. Neither she nor her doctors know when she received donanemab and when she received a placebo. (If she had received a placebo during the initial 18-month phase, she would have started taking the drug in the extension phase. If she had received the drug during the initial 18-month phase, it’s likely that her amyloid would have cleared up and she would have received a placebo at some point during the extension phase.)
In an interview arranged by Lilly, her husband, Mark Krol, said that during the first 18 months, doctors said periodic scans occasionally detected microbleeds in Mrs. Krol's brain, but none serious enough to stop the infusions.
Mr. Krol said that about six years ago, his wife, who had worked in sales and marketing at Coca-Cola and was highly organized and had a keen memory, had become increasingly forgetful. Instead of baking multiple loaves of her signature orange-cranberry walnut bread at once, baking just one loaf had become “a struggle,” he said. She would say, “‘I’m not sure I put the ingredients in right,’” he said.
She was diagnosed with mild cognitive impairment, a predementia stage. “Between then and now, he's gone from asking me the same question twice in one day to asking me the same question twice in 10 seconds,” Mr. Krol said.
Ms. Krol said she had not felt like she was experiencing cognitive decline. She said her main activity now was walking their beagle, Bailey, twice a day, and that the reason she no longer played golf regularly with friends was “not that I can't, I'm just so tired of doing stuff.”
Mr Krol said the decline in memory and attention continued gradually, but he hoped it had been slowed by the drug.
“It's not a miracle solution,” he said. But, he added, “I think it's significant and warrants FDA approval.”
Dr. Snider said some patients have decided not to start anti-amyloid drugs “as soon as they hear about brain swelling or edema as a risk.” Others are so “terrified of losing their memory,” she said, that “they don’t really care how much risk you tell them.”
An unusual feature of the donanemab trial 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.
Trial participants with intermediate tau levels declined more slowly on donanemab than those with high levels, suggesting that treating patients sooner was more effective. This raised the question of whether patients should have brain scans for tau before starting the drug, but neither Lilly nor the FDA recommended this because tau scans are not widely available.
Experts said there were several unknowns about stopping treatment after the plaques were removed. At one point, “Should we start it again?” Dr. Snider asked. “Should we replace it with something else?”
Lilly scientists don’t have those answers yet. Dr. Sims estimates it will take nearly four years for amyloid levels to rise above the threshold again and potentially a decade to reach the amount patients had before starting treatment.
Some experts worry that the emphasis on anti-amyloid drugs could discourage patients from participating in trials for treatments that might be better. “For the field overall, I think this is going sideways and slowing progress,” Dr. Greicius said.
Dozens of other drugs are in clinical trials for Alzheimer's, including drugs that target key hallmarks like tau tangles and neuroinflammation.
“I hope this is just the beginning,” Dr. Snider said.