Treating Alzheimer’s patients as early as possible — when symptoms and brain pathology are mild — gives a better chance of slowing cognitive decline, a large study of an experimental Alzheimer’s drug suggests. that was presented on Monday suggests.
The study of 1,736 patients reported that the drug, donanemab, made by Eli Lilly, may slightly slow the development of memory and cognitive problems in the early stages of Alzheimer’s, and that the slowing is greatest for early-stage patients when they have less a protein that creates tangles in the brain.
For people in the earlier stage, donanemab appeared to slow the decline in memory and thinking by about four and a half to seven and a half months over 18 months compared to those taking a placebo, according to the study. published in the journal JAMA. Among people with less of the protein, called tau, the slowing was most pronounced in those younger than 75 and in those who did not have Alzheimer’s but had a pre-Alzheimer’s condition called mild cognitive impairment, the data showed. on Monday at the Alzheimer’s Association International Conference in Amsterdam.
“The sooner you get in there, the more you can affect it before they decline and they’re on this rapid slope,” says Dr. Daniel Skovronsky, Eli Lilly’s chief medical and scientific officer, in an interview.
“No matter how you slice the data — earlier, younger, milder, less pathology — every time, it looks like early diagnosis and early intervention are the keys to managing this disease,” he added.
The findings and the recent approval of another drug that slightly slows the decline in the early stages of Alzheimer’s, Leqembi, signal a potentially promising turn in the long, rocky road to finding effective drugs for Alzheimer’s. , a brutal disease that afflicts more than six million Americans. Donanemab is currently under consideration for approval by the Food and Drug Administration.
Donanemab and Leqembi (also known by the scientific name lecanemab) have not been directly compared to each other in research studies. Individual trials of the two drugs differ in design and other aspects, so it is difficult to say which drug may be more effective.
Each drug poses significant safety risks, especially swelling and bleeding in the brain, which, although usually mild, can be serious in some cases. The donanemab trial had higher rates of inflammation and bleeding than the Leqembi trial, but comparisons are difficult because of differences in patients and other factors.
Neither drug reverses or repairs brain damage already caused by the disease. Many Alzheimer’s experts therefore consider them to be just a first step in a potentially fruitful direction.
“Whether the harms of these drugs are balanced by their modest clinical benefits will ultimately require more data,” the three geriatricians wrote in an editorial published Monday in JAMA.
Three deaths were linked to donanemab in its clinical trial, the study reported. Three participants in the Leqembi trials also died, after experiencing brain swelling and bleeding. But Eisai, the Japanese company that makes Leqembi along with Boston-based Biogen, said it was unclear whether the drug contributed to those deaths because the patients had complex medical issues. .
The two drugs attack another protein, called amyloid, that clumps in plaques in the brains of Alzheimer’s patients. Over the years of studies, other anti-amyloid drugs have failed to show that targeting amyloid can slow memory or cognitive problems. And the FDA’s decision in 2021 to grant a kind of conditional approval to the anti-amyloid drug Aduhelm while acknowledging uncertainty about whether it is beneficial has been generated by controversy, congressional investigations and reluctance to prescribe it.
Donanemab and Leqembi, infusions given intravenously, are the first drugs that attack amyloid with clear evidence of slowing cognitive decline early in the disease. But some Alzheimer’s experts say the slowdown is so modest that it’s unclear whether it will be noticeable to patients and families.
Leqembi patients, who received infusions every two weeks for 18 months, declined 27 percent more slowly than patients receiving placebo — a difference of less than half a point on an 18-point cognitive scale that assesses functions such as memory and problem solving. On the same scale in the donanemab trial, the overall group of patients receiving the drug, delivered in monthly infusions, declined 29 percent more slowly than the placebo group – or a difference of seven-tenths of a point.
Some Alzheimer’s experts say that for the slowing of decline to be significant or clinically noticeable, the difference between a drug and a placebo must be at least one point.
Other aspects of the donanemab trial are likely to be especially intriguing to Alzheimer’s experts. Patients stopped receiving donanemab and were switched to a placebo if their amyloid cleared below a certain threshold. About half reached the threshold within a year, and their decline continued to slow even after they stopped receiving donanemab.
Lilly scientists estimated it would take almost four years for amyloid levels to rise again over the threshold. It is uncertain whether the decline will continue as the amyloid begins to accumulate again.
The donanemab trial divided participants into patients with high tau levels and those with intermediate levels. Tau forms tangles after amyloid accumulates, and higher tau levels are more closely associated with memory and cognitive problems.
The test found that the intermediate group (which was larger) experienced a 36 percent slowing of decline, compared to 29 percent for the combined intermediate and high tau group and 21 percent in the high tau group alone. Another measure, which was the primary measurement tool of the test, showed the same pattern. Lilly calculated that decline for patients in the intermediate group would slow by 4.4 to 7.5 months over 18 months compared to people on placebo, while the combined population would see a slowdown of 2.5 to 5.4 months.
More people with intermediate tau stayed at the same cognitive level during their first year on the trial — 47 percent compared to 29 percent of people in the placebo group, the study estimated. In the combined tau groups, 36 percent of people on donanemab stayed at the same level compared to 23 percent of people on placebo.
In the intermediate tau group, donanemab patients with mild cognitive impairment slowed by 46 percent, while those who had advanced to early Alzheimer’s slowed by 38 percent, the company reported. Intermediate tau patients younger than 75 slowed by 45 percent, while older patients slowed by only 29 percent.
One criticism of the study is that, as in many Alzheimer’s drug trials, most patients were white, a concern highlighted by the authors of another editorial in JAMAwho noted that Black, Hispanic and other historically marginalized communities have a higher risk of Alzheimer’s.
The difficulty of predicting whether these drugs will be meaningful in everyday life is reflected in the experience of one patient in another donanemab trial.
About four years ago, Jim Sirois, 67, of Berlin, Conn., began having trouble finding words during conversations and forgetting which items to buy at the grocery store, his wife said. Sue Sirois in an interview arranged by Eli Lilly.
In November 2021, Mr. Sirois, a former power company electrician, began receiving monthly infusions of donanemab at A challenge comparing whether the drug removes more amyloid than the drug Aduhelm. Ms. Sirois, a former middle school math teacher, said donanemab cleared the plaques and treatment was stopped after about 13 months. But the couple said they did not know whether the drug slowed Mr.’s cognitive decline. Sirois.
Although her husband’s symptoms did not worsen, Ms. Sirois, “there are things he could do without a problem last summer that he’s struggling to do this summer.”
Mr. Sirois is no longer hooking up their pool vacuum or inserting a string into their weed whacker. “He just has a hard time with planning and anything with a lot of steps,” she said.
Even bowling, an activity he studied, was affected. His aim may be less on target now and, although he has recently had a perfect game, “his average is probably a good 20 pins lower than it was,” he said.
“I don’t know if the medicine helped him or not,” said Ms. Sirois. “I can not say.”
But, he added, “Anything we can do to slow progress or at least have the hope of slowing progress is what I want to do.”