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 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 attack a protein involved in Alzheimer’s disease, and both can slow the progression of dementia by several months. Both also pose similar security risks. Leqembi, made by Eisai and Biogen, is administered every two weeks. Kisunla is given every month.
Kisunla has an important difference that may appeal to patients, doctors and insurers: Lilly says patients can stop the drug after it clears the protein, amyloid, that builds up in plaques in the brains of people with Alzheimer’s.
“Once you remove the target you’re after, then you can stop the dose,” said Anne White, Lilly’s executive vice president and president of its neuroscience division. He 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 who received 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 that slowdown will continue after the trial runs, said Dr. John Sims, medical director at Lilly.
The list price for Kisunla will be $32,000 for a one-year course of treatment. Leqembi costs $26,000 a year, but is not stopped after the amyloid is cleared. The The higher price, Ms White said, reflects the expectation that patients can stop Kisunla after their plaques are cleared.
Kisunla and Leqembi are seen as just an incremental step in the search for effective treatments for Alzheimer’s disease. Some experts say they may not slow the decline enough to be noticeable to patients or families.
The drugs belong to a new class of drugs 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 to receive approval was Aduhelm in 2021, but its maker, Biogen, discontinued it last year because there was insufficient evidence that it could benefit patients. So far, there are no treatments to stop or reverse memory loss or other cognitive problems.
Some Alzheimer’s experts are skeptical of anti-amyloid drugs and have said they believe the risks outweigh 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 that the more a drug reduces a patient’s viral load , better patient health and chance of survival.
But so far, Dr. Gracious said, “There is no correlation in any of their studies between the removal of amyloid plaques and clinical response in individual subjects.” That, he added, raised the question of “how does this drug work, if it works, and it’s kind of frustrating and painful for me as a clinician.”
Other experts said they see value in offering patients the drugs, even though the benefit may be modest.
Dr. B. Joy Snyder, a professor of neurology at the University of Washington School of Medicine who has participated in trials of the drugs and previously served as a consultant to both Eisai and Lilly, said the slowing of decline “wasn’t a huge difference. but it could make sense in people’s lives — for example, delaying the progression from mild forgetfulness to needing to be reminded about appointments.
“At least at the group level, amyloid clearance correlates with slowing disease progression,” he said. “It’s going to be hard to see these associations in an individual patient,” he said, because memory and thinking problems can fluctuate and because during the test “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 who received the drug declined 29 percent more slowly than the placebo group, a difference of seven-tenths of a point.
Almost 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 patients who received donanemab experienced swelling or bleeding in the brain. While most of the cases were mild or asymptomatic, about 2% were severe, and the side effects were linked to the death of three patients.
The donanemab trial had higher rates of edema 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 tiny brain bleeds and those with an Alzheimer’s-linked gene variant called APOE4 — especially if they have two copies of the variant.
Bev Krol, 69, of Phoenix participated in the donanemab study for nearly three years, receiving infusions at the 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 was on placebo during the 18-month baseline, she would have started the drug in the extension phase. If she had been on the drug during the 18-month baseline, chances are her amyloid would have cleared and you would have received a placebo at some point during the expansion phase.)
In an interview arranged by Lilly, her husband, Mark Krol, said that during the first 18 months, doctors said periodic scans sometimes found small bleeds in Mrs. Krol’s brain, but none serious enough to stop the infusions.
Mr. Kroll said that about six years ago, his wife, who had worked in sales and marketing for Coca-Cola and was very organized with a sharp memory, had become increasingly forgetful. Instead of baking several loaves of her signature cranberry-orange bread at once, baking even one became “a struggle,” she said. He said, “I’m not sure if I put the ingredients right,” he said.
He was diagnosed with mild cognitive impairment, a stage of pre-dementia. “From then to now, I went from being asked the same question twice in one day to being asked the same question twice in 10 seconds,” Mr Kroll said.
Ms Kroll said she did not feel she was experiencing cognitive decline. She said her main activity now was walking their greyhound, Bailey, twice a day, and that the reason she no longer regularly golfed with friends was “not that I can’t do it, I’m just so tired of doing things”.
Mr Kroll said the decline in her memory and attention continued gradually, but he hoped it had been slowed by the drug.
“It’s not a silver bullet,” he said. But, he added, “I think it’s important and I think it warrants FDA approval.”
Dr. Snyder said some patients decided not to start anti-amyloid drugs “as soon as they heard anything about brain swelling or swelling being a risk.” Others are so “terrified of losing their memory,” he said, that “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 after amyloid builds up and is more closely linked to memory and thinking problems.
Trial participants with intermediate tau levels tapered more slowly on donanemab than those with high levels, suggesting that treating patients earlier was more effective. This raised a question as to 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 many unknowns about stopping treatment after clearing plaques. At some point, “Do we need to restart them?” Dr. Snyder wondered. “Do we need to replace it with something else?”
Lilly scientists don’t have those answers yet. Dr. Sims estimated that it would take almost four years for amyloid levels to rise above the threshold, and possibly a decade for them to reach the amount the 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 could be better. “For the field in general, I think this is moving sideways and slowing progress,” said Dr. Greicius.
Dozens of other drugs are in clinical trials for Alzheimer’s disease, including drugs that attack important features such as tau tangles and neuroinflammation.
“Hopefully this is just the beginning,” said Dr. Snyder.
