The Food and Drug Administration (FDA) approved a new drug for Alzheimer’s disease on Tuesday, the latest in a new class of treatments that has been greeted with hope, disappointment and skepticism.
Studies have shown that the drug, donanemab, which will be marketed as Kisunla, slightly slowed the rate of cognitive decline in the early stages of the disease. It also posed 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 disease and both can slow the progression of dementia by months. Both also carry similar safety risks. Leqembi, made by Eisai and Biogen, is given every two weeks; Kisunla is given once a month.
Kisunla has one significant difference that could be of interest to patients, doctors and insurers: Lilly says patients can stop the drug after it clears the amyloid protein, which clumps together into plaques in the brains of people with Alzheimer’s disease.
“Once you eliminate the target drug, you can stop treatment,” 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 and the risk of side effects.
According to the company, 17% of patients who received donanemab in the 18-month clinical trial were able to stop the drug after six months, 47% stopped within a year and 69% stopped within 18 months. Their cognitive decline continued to slow even after stopping. The company is assessing how long that slowdown will continue beyond the trial, said Dr. John Sims, Lilly’s chief medical officer.
Kisunla’s list price will be $32,000 for a one-year course. Leqembi costs $26,000 per year, but is not stopped once the amyloid is cleared. The higher price, Ms. White said, reflects the hope that patients can stop Kisunla once their plaques are cleared.
Kisunla and Leqembi are seen as just another step in the search for effective treatments for Alzheimer’s. Some experts say they may not slow the disease’s decline enough for patients or families to notice.
These drugs belong to a new class of medications that address the underlying biology of Alzheimer’s disease 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, dropped it last year because there wasn’t enough evidence it could benefit patients. So far, there are no treatments that stop or reverse memory loss or other cognitive problems.
Some Alzheimer’s disease experts are skeptical of anti-amyloid drugs, saying 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 would not suggest Kisunla. He said if the drugs were effective, the data should show that individual patients who had amyloid removed from their brains experienced slower rates of cognitive decline, much as HIV drugs have shown that the more a drug reduces a patient’s viral load, the better the patient’s health and chances of survival.
But so far, Dr. Greicius said, “there’s no correlation in any of their studies between amyloid plaque clearance and clinical response in individual subjects.” That, he added, raises the question of “how this drug works, if it works at all, and that’s quite frustrating and distressing to me as a clinician.”
Other experts say it is useful to offer these drugs to patients, even if the benefits may be modest.
Dr. B. Joy Snider, a professor of neurology at the University of Washington School of Medicine who was involved in the drug trials and previously consulted for Eisai and Lilly, said the slowing of decline was “not a huge difference” but could be meaningful in people’s lives – for example, by delaying the progression from mild forgetfulness to needing to be reminded of appointments.
“At least at the group level, amyloid clearance is correlated with slowing disease progression,” she said. “It will be difficult to see these correlations in an individual patient,” she added, 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 patients with early-stage dementia (either mild cognitive impairment or mild dementia), cognitive decline slowed by about 4 1/2 to 7 1/2 months over 18 months in patients receiving donanemab compared with those receiving placebo. On an 18-point cognitive scale, the overall decline in the group of patients receiving the drug was 29% slower than in the placebo group, a difference of seven-tenths of a point.
Nearly half of those given donanemab remained at the same cognitive level one year after the study began, compared with 29% of those given the placebo.
About a quarter of people taking donanemab experienced brain swelling or bleeding. While most cases were mild or asymptomatic, about two percent were serious, and side effects were linked to the deaths of three patients.
The donanemab trial showed higher rates of swelling and bleeding than the Leqembi trial, but comparisons are difficult because of differences between patients and other factors.
With both drugs, patients at greatest risk are those who have had more than four microscopic bleeds in the brain and those who have a variant of the Alzheimer’s-related gene 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 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 received a placebo during the initial 18-month phase, she would have started taking the drug during the extension phase. If she received the drug during the initial 18-month phase, there’s a good chance her amyloid would have cleared 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 revealed microbleeds in Mrs. Krol’s brain, but none were serious enough to stop the infusions.
Mr. Krol said that about six years ago, his wife, who worked in sales and marketing for Coca-Cola and was highly organized and had a keen memory, became increasingly forgetful. Instead of baking several loaves of her cranberry-walnut bread at a time, baking just one became “a real challenge,” he said. She would say, “I’m not sure I put the ingredients in right,” he said.
He was diagnosed with mild cognitive impairment, a pre-dementia stage. “Since then, I’ve started asking the same question twice in one day, then asking it twice in 10 seconds,” Krol said.
Krol said she did not feel she was suffering from cognitive decline. She said her main activity now was walking her beagle, Bailey, twice a day, and that the reason she no longer played golf regularly with her friends was not “that I couldn’t do it, but that I was so tired of doing things.”
Mr Krol said the decline in his memory and attention had continued gradually, but he hoped it had been slowed by the medication.
“It’s not a silver bullet,” he said. But, he added, “I think it’s important and I think it warrants FDA approval.”
Some patients, Snider said, have decided not to start anti-amyloid drugs “as soon as they hear about the risk of brain swelling or edema.” Others are so “terrified of losing their memory,” she added, “that they don’t really care what level of risk you tell them.”
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 associated with 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 early was more effective. That raised the question of whether patients should have brain scans for tau before starting treatment, but neither Lilly nor the FDA has recommended this because tau scans are not widely available.
Experts said there are several unknowns about stopping treatment once the plaques are cleared. At some point, “should we start it again?” Dr. Snider wondered. “Should we replace it with something else?”
Lilly scientists don’t yet have answers to these questions. Dr. Sims estimates it would take about four years for amyloid levels to rise above the threshold and potentially a decade to reach the level patients had before treatment began.
Some experts worry that the focus on anti-amyloid drugs will discourage patients from participating in clinical trials of treatments that might be better. “For the field in general, I think it’s moving sideways and that’s slowing progress,” Dr. Greicius said.
Dozens of other drugs are in clinical trials for Alzheimer’s disease, including drugs that attack important features like tau tangles and neuroinflammation.
“I hope this is just the beginning,” Dr. Snider said.