Treating Alzheimer’s patients as early as possible — when symptoms and brain pathology are mildest — offers a better chance of slowing cognitive decline, suggests a large study of an experimental Alzheimer’s drug presented Monday.
A study of 1,736 patients showed that donanumab, a drug made by Eli Lilly, could slow the progression of memory and thinking problems in the early stages of Alzheimer’s, and that the slowing was greatest for early-stage patients when They had less of a protein that causes tangles in the brain.
For people in that early phase, donunumab showed a slower decline in memory and thinking over an 18-month period, about four and a half to seven and a half months, compared to people who took a placebo, according to the study. published in the journal JAMA, Among people with low levels of a protein called tau, the slowing was most pronounced in people younger than 75 and in people who haven’t yet had Alzheimer’s but are developing Alzheimer’s, according to data presented Monday at the Alzheimer’s Association International. Had a condition before, called mild cognitive impairment. Conference in Amsterdam.
Dr. Daniel Skowronsky, Eli Lilly’s chief medical and scientific officer, said in an interview, “The sooner you can get there, the more impact you can have on that, before they’ve already declined and they’re going to be able to do this.” Go downhill fast.”
“No matter how you slice the data — earlier, younger, milder, less deformity — each time, it appears that early diagnosis and early intervention are the keys to managing this disease,” he said.
Lekembi’s findings and the recent approval of another drug that modestly slows decline in early-stage Alzheimer’s signal a potentially promising turn in the long, rocky road toward finding effective drugs for Alzheimer’s, a cruel disease. disease that afflicts more than six million Americans. , Donanumab is currently being considered for approval by the Food and Drug Administration.
Donanumab and Lekembi (also known by the scientific name lecanumab) have not been directly compared to each other in research studies. The individual trials of the two drugs differ in design and other aspects, making it difficult to say which drug may be more effective.
Each drug poses significant safety risks, particularly swelling and bleeding in the brain, which, while often mild, can be severe in some cases. The donemumab trial had higher rates of inflammation and bleeding than the Lecambi trial, but comparisons are difficult because of differences in patients and other factors.
No drug will cure or reverse brain damage already caused by the disease. That’s why many Alzheimer’s experts see it as only the 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,” wrote the three geriatricians. an editorial Published Monday in JAMA.
The study reports that three deaths were linked to donamumab in its clinical trials. Three participants in Lekembi’s trials also died after experiencing swelling and bleeding in the brain. But Japanese company Eisai, which makes Lekembi along with Boston-based company Biogen, has said it is unclear whether the drug contributed to those deaths because those patients had complex medical problems.
Both drugs attack another protein called amyloid, which sticks to plaques in the brains of Alzheimer’s patients. In years of study, other anti-amyloid drugs failed to show that targeting amyloid could slow memory or thinking problems. And the FDA’s decision to grant a type of conditional approval to the anti-amyloid drug EduHelm in 2021 generated controversy, congressional scrutiny and a reluctance to prescribe it, while acknowledging uncertainty about whether it was beneficial.
Donanumab and Lecambi, infusions that are administered intravenously, are the first amyloid-attacking drugs with clear evidence of slowing cognitive decline early in the disease. But some Alzheimer’s experts say the slowing is so slight that it’s unclear whether it will be visible to patients and families.
Lekembi patients who received injections every two weeks for 18 months declined 27 percent more slowly than patients who received a placebo — a difference of less than half that on an 18-point cognitive scale, which measures memory and problems. – Assesses tasks such as solutions. On the same scale in the donanumab trial, the overall group of patients receiving the drug, delivered in a monthly infusion, 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 clinically meaningful or noticeable, there must be at least a one-point difference between the drug and the placebo.
Other aspects of the donanumab trial are likely to be of particular interest to Alzheimer’s specialists. If patients’ amyloid cleared below a certain threshold, they were stopped from donanumab and given a placebo. About half of the people reached the limit within a year, and their decline continued to slow even after they stopped taking donanemab.
Lilly scientists estimate it will take time about four years Amyloid levels to go above the threshold again. It is uncertain whether the rate of decline will continue to slow as amyloid will begin to re-deposit.
The donanumab trial divided participants into patients with high levels of tau and those with intermediate levels. Tau tangles form after amyloid is deposited, and higher tau levels are more closely linked to problems with memory and thinking.
The trial found that the intermediate group (which was larger) saw a 36 percent reduction in decline, compared with 29 percent for the combined intermediate and high tau groups and 21 percent in the high tau group alone. Another scale, which was the primary measurement tool of the test, also showed the same pattern. Lilly calculated that the decline of patients in the intermediate group would be 4.4 to 7.5 months slower over 18 months than those taking the placebo, while the combined population would see a slower rate of 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 taking donanumab remained at the same level compared to 23 percent of people taking a placebo.
The company reported that in the intermediate tau group, donanumab patients with mild cognitive impairment slowed 46 percent, while those who had already progressed to early Alzheimer’s slowed 38 percent. Intermediate tau patients who were under the age of 75 slowed by 45 percent, while older patients only slowed by 29 percent.
One criticism of the study was that, like many Alzheimer’s drug trials, the majority of patients were white, a concern highlighted by the authors. Another editorial in JAMAwho noted that the risk of Alzheimer’s is higher in black, Hispanic and other historically marginalized communities.
The difficulty of predicting whether these drugs will be meaningful in daily life is reflected in the experience of a patient in another donanumab trial.
About four years ago, in Berlin, Conn. Jim Sirois, 67, began having trouble finding words during conversations and forgetting what items to buy at the grocery store, his wife, Sue Sirois, said in an interview conducted by Eli Lilly.
In November 2021, Mr. Sirois, a former electrician for the power company, began receiving monthly donanemab infusions. a test To compare whether the drug cleared more amyloid than the drug EduHelm. 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 had slowed Sirois’ cognitive decline.
While her husband’s symptoms haven’t gotten much worse, Ms. Sirois said, “There were things he could do last summer without problems, but he’s having a hard time doing them this summer.”
Mr. Sirois is no longer able to hook up his pool vacuum or string his weed whisker. “They have a lot of difficulty with planning and with anything that has multiple phases,” he said.
Even the bowling, in which he excels, has been affected. His hitting may be less targeted now and, although he has thrown a perfect game recently, “his average is probably 20 pins lower than before,” he said.
“I don’t know if the medication helped him,” Ms. Sirois said. “I can’t tell.”
But, she added, “Anything we can do to slow progress or at least have some hope of slowing progress, that’s what I would like to do.”
