Study finds that treating Alzheimer’s disease very early offers the best hope of slowing regression

Treating Alzheimer’s patients as early as possible — when symptoms and brain disease are milder — offers a better chance of slowing cognitive decline, a large study released Monday found.

The study of 1,736 patients reported that the drug donanimab, made by Eli Lilly, could modestly slow the progression of memory and thinking problems in the early stages of Alzheimer’s disease, and that the slowing was greatest for patients in the early stage when they had less of a protein that creates tangles. in the brain.

For people at that early stage, dunanimab appeared to slow declines in memory and thinking by about four-and-a-half to seven-and-a-half months over the 18-month period compared to those taking a placebo, according to the study. Published in JAMA Magazine. Among people with less of a protein, called tau, the slowing was most pronounced in those younger than 75 and those who had not yet developed Alzheimer’s disease but had a pre-Alzheimer’s condition called mild cognitive impairment, according to data presented Monday in the Alzheimer’s Association. international. conference in Amsterdam.

“The earlier you can get there, the more you can impact them before they really refuse and they’re on that fast ramp,” Dr. Daniel Skovronsky, Eli Lilly’s chief medical officer and scientist, said in an interview.

He added, “No matter how you cut the data — earlier, younger, milder, less diseased — each time, early diagnosis and early intervention seem to be the key to managing this disease.”

The results and the recent approval of another drug that modestly slows the decline in the early stages of Alzheimer’s disease, Leqembi, point to a potentially promising turn in the long rocky path toward finding effective medications for Alzheimer’s, a brutal disease that afflicts more than six million Americans. . Donanemab is currently being considered 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, making it difficult to say which drug might be more effective.

Each drug poses significant safety risks, especially swelling and bleeding in the brain, which, while often mild, can be dangerous in some cases. The dunanimab trial had higher rates of swelling and bleeding than the Leqembi trial, but comparisons are difficult because of differences in patients and other factors.

None of the drugs reverse or repair brain damage already caused by the disease. So many Alzheimer’s experts consider it just a first step in a potentially fruitful direction.

Three geriatricians wrote in editorial Posted Monday in JAMA.

The study reported that three deaths were linked to withoutanimab in its clinical trial. Three participants in Leqembi’s experiments also died, after suffering brain swelling and bleeding. But Eisai, the Japanese company that makes Leqembi along with Boston-based Biogen, said it was unclear if the drug contributed to those deaths because these patients had complex medical problems.

The two drugs attack another protein called amyloid, which clumps into plaques in the brains of Alzheimer’s patients. Over years of study, other anti-amyloid drugs have failed to show that targeting amyloid can slow memory or thinking problems. And the FDA’s decision in 2021 to give some type of conditional approval to the anti-amyloid drug Aduhelm while acknowledging uncertainty about whether it would be helpful sparked controversy, congressional investigations, and an unwillingness to prescribe it.

Donanimab and ligambi, intravenously, are the first drugs to 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 injections every two weeks for 18 months, fell 27 percent more slowly than patients receiving a 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 total number of patients receiving the drug in monthly infusions fell 29 percent more slowly than the placebo group — or a difference of seven-tenths of a point.

Some Alzheimer’s experts say that for a slowing of decline to be clinically meaningful or noticeable, the difference between the drug and the placebo needs to be at least one point.

Other aspects of the dunanimab trial are likely to be of particular interest to Alzheimer’s experts. Patients stopped receiving donanimab and were switched to placebo if their amyloid clearance was below a certain threshold. About half of them reached the threshold within a year, and their decline continued to slow even after they stopped receiving donanemab.

Lilly’s scientists estimated that it would take Almost four years for amyloid levels to rise above the threshold again. It is uncertain whether the slowing of degradation will continue as amyloid buildup begins again.

The donanemab trial divided participants into patients with high tau levels and those with intermediate levels. Tau forms tangles after amyloid buildup, and elevated tau levels are closely associated with memory and thinking problems.

The trial found that the middle group (which was larger) experienced a 36 percent slower decline, compared with 29 percent for the middle and high tau groups combined and 21 percent in the high tau group alone. Another scale, which was the primary measurement tool for the experiment, showed the same pattern. Lilly calculated that for patients in the middle group, the decline would slow from 4.4 to 7.5 months over 18 months compared to people taking a placebo, while for the population combined, they would see a slowing from 2.5 to 5.4 months.

The study estimated that more people with intermediate tau remained at the same cognitive level in their first year in the trial — 47 percent, compared to 29 percent of people in the placebo group. In the combined tau groups, 36 percent of people on dunanimab remained at the same level compared to 23 percent of people on placebo.

In the intermediate tau group, dunanimab patients with mild cognitive impairment slowed down by 46 percent, while those who had already progressed to early-onset Alzheimer’s slowed down by 38 percent, the company reported. Intermediate tau patients under 75 years of age slowed down by 45 percent, while older patients only slowed by 29 percent.

One criticism of the study was that, as in many trials of Alzheimer’s drugs, the vast majority of patients were white, a concern highlighted by the authors of another JAMA editorial, who note that historically marginalized black, Latino, and other communities It has a higher risk of infection. Alzheimer’s disease.

The difficulty in predicting whether these drugs are meaningful in daily life in patient experience is reflected in another dunanimab trial.

About four years ago, Jim Serois, 67, of Berlin, Connecticut, began having trouble finding words during conversations and was forgetting items to buy at the grocery store, his wife, Sue Seruis, said in an interview arranged by Eli Lilly.

In November 2021, Mr. Sirwa, a former electrician with an electric company, began receiving monthly payments from Donanimap in trial Comparison of whether the drug removes more amyloid than Aduhelm. Ms. Serwa, a former middle school math teacher, said dunanmap cleared up the plaques and the treatment stopped after about 13 months. But the couple said they did not know if the drug slowed Mr. Serwa’s cognitive decline.

While her husband’s symptoms did not noticeably worsen, Ms. Sirwa said, “There were a few things he could do without problems last summer that he’s had a hard time doing this summer.”

Mr. Sirois is now unable to tie their pool broom or thread a string into their weeder. “He has a lot of difficulty planning and anything has multiple steps,” she said.

Even bowling, the activity in which he excels, has been affected. His aim can be less targeted now, and though he’s recently bowled a perfect game, “he’s probably averaging a good 20 pins less than he used to,” she says.

“I don’t know if the medication helped him or not,” said Ms. Serwa. “I can not say.”

But she added, “All we can do to slow the progression or at least have some hope of slowing the progression is what I want to do.”