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 met with hope, disappointment and skepticism.
The drug, donanemabi, to be sold under the brand name Kisunla, was 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, approved last year. Both are intravenous infusions that attack a protein involved in Alzheimer’s, and both can slow the onset of dementia by several months. Both also carry similar security risks. The drug, made by Eisai and Biogen, is given every two weeks; Kisunla is given every month.
Kisunla has a significant difference that could appeal to patients, doctors and insurers: Lilly says patients can stop the drug after it cleans up the protein, amyloid, that builds up in plaques in the brains of people with Alzheimer’s.
“Once you’ve eliminated the target you’re going after, then you can stop the dose,” said Anne White, an executive vice president at Lilly and president of its neuroscience division. She said this could reduce the overall cost and inconvenience of treatment, as well as the risk of side effects.
The company said 17 percent of patients taking donanemab in the 18-month clinical trial were able to stop the drug at 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 slowdown will continue after the duration of the trial, said Dr. John Sims, a medical director at Lilly.
The list price for Kisunla will be $32,000 for a one-year course of therapy. The drug costs $26,000 a year, but it doesn’t stop after clearing the amyloid. of the higher price, Ms. White said, reflects the expectation that patients can stop Kisunla once their plaques are cleared.
Kisunla and Leqembi are considered just one step forward in the search for effective Alzheimer’s treatments. Some experts say they may not slow decline enough to be noticeable to patients or families.
The medications belong to a new class of drugs that address the underlying biology of Alzheimer’s by attacking amyloid, which begins to accumulate 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 was not enough evidence that it could benefit 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 and said they believed the risks outweighed the potential for a small benefit.
Dr. Michael Greicius, a neurologist at Stanford University School of Medicine, said he had not prescribed Leqembi and also would not offer Kisunla. He said that if the drugs were effective, the 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 how the more a drug reduces a patient’s viral load, the better the patient’s health and likelihood of survival.
But until now, Dr. Greicius said, “There is no correlation in any of their studies between amyloid plaque removal and clinical response in individual subjects.” That, he added, raises the question of “how this drug works, if it works at all, and it’s kind of frustrating and distressing for me as a clinician.”
Other experts said they considered it worthwhile to offer patients the drugs even though the benefit might be modest.
Dr. B. Joy Snider, a professor of neurology at the University of Washington School of Medicine who has been involved in drug trials and previously served as a consultant to Eisai and Lilly, said the slowing of the decline “was not a change big.” but it can be meaningful in people’s lives—for example, delaying the progression from easy forgetfulness to needing to remember about appointments.
“At least at the cohort level, amyloid clearance is associated with slowing disease progression,” she said. “It will be difficult to see these correlations in an individual patient,” she 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 trial of 1,736 early-stage patients — people with mild cognitive impairment or mild dementia — cognitive decline was 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 taking the drug declined 29 percent more slowly than the placebo group, a difference of seven-tenths of a point.
Nearly half of those who received donanemab remained at the same cognitive level a year after the study, compared with 29 percent who received a placebo.
About a quarter of those who received donanemab experienced swelling or bleeding in the brain. While most cases were mild or asymptomatic, about two percent were serious, and side effects were linked to the death of three patients.
The donanemab trial had higher rates of swelling and bleeding than the Leqembi trial, but comparisons are difficult because of patient differences and other factors.
With both drugs, patients at highest risk include those who have had more than four microscopic bleeds in the brain and those with an Alzheimer’s-related gene variant called APOE4 — especially if they have two copies of the variant.
Bev Krol, 69, of Phoenix has been a participant in the donanemab study for nearly three years, receiving infusions at Banner Alzheimer’s Institute, a trial site. Neither she nor the doctors know when she received donanemab and when she received a placebo. (If she took a placebo during the 18-month lead-in phase, she would have started taking the drug in the extension phase. If she had taken the drug during the 18-month lead-in phase, chances are her amyloid would have cleared and she will receive 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 sometimes found microbleeds in Mrs. Krol’s brain, but not serious enough to stop the infusions.
Mr. Krol said that about six years ago, his wife, who had worked in sales and marketing for Coca-Cola and was highly organized with a sharp memory, became increasingly forgetful. Instead of baking several pieces of her Cranberry-Orange Nut Bread at once, baking one became “a struggle,” he said. She would say, “‘I’m not sure if I put the ingredients right,'” he said.
She was diagnosed with mild cognitive impairment, a stage of predementia. “From then to now, it went from asking the same question twice in one day to asking the same question twice in 10 seconds,” said Mr. Krol.
Ms Krol said she did not feel 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 golfed regularly with friends was “not that I can’t do it, I’m just too tired to done things”.
Mr Krol said her decline in memory and attention had been gradual, but he hoped it had been slowed by the drugs.
“It’s not a silver bullet,” he said, but, he added, “I think it’s significant and I think it warrants FDA approval.”
Dr. Snider said some patients decided against starting anti-amyloid drugs “as soon as they heard anything that brain swelling or edema was a risk.” Others are so “terrified of memory loss,” she said, “they don’t really care how much risk you tell them they have.”
An unusual feature of the donanemab trial involved measuring levels of another protein, tau, which forms tangles in the brain as amyloid accumulates and is more closely linked to memory and thinking problems.
Trial participants with intermediate levels of tau declined more slowly on donanemab than those with high levels, suggesting that treating patients earlier was more effective. This raised a question about whether patients should have tau brain scans before starting the drug, but neither Lilly nor the FDA recommended this because tau scans are not widely available.
Experts said there were some unknowns about treatment discontinuation after plaque clearance. At one point, “Should we restart them?” Dr. Snider was surprised. “Should we replace it with something else?”
Lilly scientists don’t have those answers yet. Dr. Sims estimated that it would take nearly four years for amyloid levels to rise above the threshold and potentially a decade to reach the amount patients had before starting treatment.
Some experts worry that the emphasis on anti-amyloid drugs may discourage patients from participating in trials for treatments that might be better. “For the field in general, I think it’s moving sideways and slowing progress,” said Dr. Greicius.
Dozens of other drugs are in clinical trials for Alzheimer’s, including drugs that attack important features like tau tangles and neuroinflammation.
“Hopefully, this is just the beginning,” said Dr. Snider.