An experimental drug from Biogen and its Japanese partner, Eisai, led to “moderately less” cognitive decline in patients with early symptoms of Alzheimer’s disease, but caused side effects in some recipients that required close monitoring, according to the full findings of a late-stage clinical trial.
The results, published Tuesday evening in the New England Journal of Medicine at the same time executives from Eisai began presenting them at a scientific conference on Alzheimer’s in San Francisco, likely will buoy proponents of the experimental drug and renew concerns among doubters.
In an 18-month study of nearly 1,800 patients with mild cognitive impairment or mild Alzheimer’s, lecanemab reduced cognitive decline by 27 percent in recipients compared with patients who received a placebo. That translated to 0.45 points on an 18-point scale, which experts said might not produce obvious benefits to patients but was statistically meaningful.
Patients who received the drug — which removes amyloid-beta, a protein that some researchers believe causes Alzheimer’s — were at increased risk for brain swelling and “microhemorrhages,” or small amounts of bleeding, in the brain. Most of the time those conditions caused little or no symptoms, but researchers said the side effects needed to be monitored to prevent serious problems.
A draft of the New England Journal article said the drug “resulted in modestly less decline on measures of cognition and function than placebo.” But in the final version of the article, “modestly less” was changed to “moderately less.”
Over the past four weeks, Eisai and Cambridge-based Biogen have been buffeted by news reports that two patients who participated in the late-stage clinical trial and received lecanemab died as a result of bleeding in the brain.
But Eisai said Tuesday that rates of cerebral macrohemorrhage were 0.1 percent in both the lecanemab group and the placebo group. The two deaths occurred in patients who received the drug after the 18-month study when all participants were offered the medicine, and both had “significant comorbidities and risk factors,” including use of blood thinners, the company said.
“Therefore, it is Eisai’s assessment that the deaths cannot be attributed to lecanemab,” it said. The company has taken the lead in developing the drug and applying for approval to the Food and Drug Administration.
Several Alzheimer’s experts said the full results confirmed the encouraging initial findings, which were reported on Sept. 27.
Although far from a cure for Alzheimer’s, lecanemab has given tentative hope to millions of Americans afflicted with the memory-robbing disease. It also could offer Biogen a second shot at opening a multibillion-dollar drug market to treat the disease after doctors, hospitals, and insurers rejected the firm’s first amyloid-busting drug, Aduhelm, even though the FDA approved it.
“After watching more than a dozen anti-amyloid drugs fail, this is the first one that’s unequivocally really done well,” Dr. Andrew E. Budson, chief of cognitive and behavioral neurology at the Veterans Affairs Boston Healthcare System, said after reading the full findings. “The drug truly seems to slow down the decline of Alzheimer’s disease.”
To be sure, he said, the amount was small, but he expected the effect would be greater the sooner people begin taking the drug.
Budson noted that there was no major difference in the rate of deaths during the trial between those who received lecanemab and the placebo. He said the side effects of lecanemab are tolerable, but he would discuss the risks of brain bleeding and swelling with patients. “I wouldn’t be prescribing it left and right without any thought, but I do think that somebody in the early stage of Alzheimer’s disease should seriously consider it,” Budson said.
Robert J. Vassar, director of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University Feinberg School of Medicine, said after reading the study results that lecanemab had a modest but “statistically significant” effect in slowing cognitive decline.
”You’re not going to bring function back that [patients have] lost,” he said. “But if you could stabilize them at a point where they’re less debilitated, and able to interact with the family and grandkids, I think that’s a huge win.”
Like Budson, Vassar hoped that taking the drug longer, or starting patients on it earlier, could lead to better results. “When these drugs are moved earlier in the disease process, there’s a real chance that they could actually prevent Alzheimer’s disease,” he said.
Biogen and Eisai are already testing that hypothesis in another clinical trial of people who aren’t yet experiencing symptoms of Alzheimer’s despite signs of amyloid accumulation in their brains. “I’m hopeful that going earlier is really going to make a big difference for prevention,” he said.
Still, several experts said it was crucial that scientists get to the bottom of what caused the deaths of two participants in the study.
In October, STAT reported that lecanemab may have contributed to the death in June of a man in his late 80s who experienced bleeding in the brain. That patient had been taking Eliquis, a popular blood thinner, for atrial fibrillation, a heart condition that increases the risk of heart attack and stroke.
On Tuesday, the journal Science reported the death of a second recipient of lecanemab, a 65-year-old woman who suffered a stroke. After the stroke was diagnosed at Northwestern University Medical Center in Chicago, she received a common blood-clot busting drug. Significant bleeding throughout her brain’s outer layer immediately followed, and she died a few days later.
Dr. Rudolph J. Castellani, a professor of pathology at Northwestern’s Feinberg School of Medicine, autopsied the woman’s body at her husband’s request. The neuropathologist was quoted in Science as saying her case was “very dramatic” and that her death unquestionably resulted from lecanemab infusions.
“There’s zero doubt in my mind that this is a treatment-caused illness and death,” said Castellani, who stressed to the Science reporter he was expressing a personal opinion, not Northwestern’s. “If the patient hadn’t been on lecanemab, she would be alive today.”
Vassar, who works at Northwestern but had no direct knowledge of the death, said it “really needs to be very carefully and thoroughly investigated to get to the bottom of what caused it.”
“It’s still really critically important to understand the relationship to blood thinners. There may need to be a very strict warning against the use of blood thinners in individuals that take these drugs,” he added.
Vassar said amyloid can accumulate around and damage blood vessels in the brain, especially in people with the APOE4 gene that increases their risk for Alzheimer’s. When amyloid-busting drugs like lecanemab remove amyloid, they could expose weakened or leaky vessels, possibly leading to ARIA, or amyloid-related imaging abnormalities. When those abnormalities show up on MRI scans, they can indicate swelling or tiny hemorrhages even if patients have no symptoms.
Dr. Sam Gandy, an Alzheimer’s expert and professor of neurology and psychiatry at the Mount Sinai Health System in New York, said lecanemab clearly had a statistically significant effect on patients, but “no one yet knows whether the benefit will be clinically meaningful. This may take years to determine, and the debate is likely to continue.”
He expected the FDA will approve the drug ― possibly on an accelerated basis in January ― but agreed that it was vital to get to the bottom of what caused two patients to die.