Experimental Alzheimer’s drug lecanemab made it one of the first dementia drugs to show positive results last week when the companies testing it published trial results showing the drug met its goals.
In a randomized, placebo-controlled trial of nearly 1,800 people with early stages of memory loss, those who received lecanemab had about 27% less decline after 18 months than those who did not. The difference was about half a point on a commonly used scale called the Clinical Dementia Rating – Sum of the Boxes.. The difference was statistically significant, indicating that the improvement probably did not occur by chance.
The companies only gave a glimpse of the study in a news release, and experts said they would want to dig deeper into the details before fully understanding the results.
But if it succeeds, lecanemab will have left behind a long history of failure in the field.
By some estimates, lecanemab is the 16th drug developed to clear toxic amyloid plaques from the brain. Most of the others also worked as advertised; they removed the amyloid. The point is that almost none of them have shown any real benefit to patients, and many experts have concluded that the whole field is in left field.
They declared the amyloid hypothesis—the idea that amyloid plaques build up in the brain and are the cause of Alzheimer’s—false, and urged drugmakers to go back to the drawing board.
So why does lecanemab appear to have worked after this long string of failures? Is there anything in the medicine that makes it better? Or did the companies that tested it – Biogen and Eisai – finally conduct a smarter clinical trial that demonstrated the potential of such drugs?
Eisai’s Deputy Chief Clinical Officer for Alzheimer’s and Brain Health Dr.
Irizarry said that in planning the clinical trials, researchers were able to take advantage of advances in technology, such as new types of scans that confirm the presence of beta amyloid in the brain. Previously, doctors could only see amyloid in the brain during an autopsy.
They recruited people with earlier disease, at a point where agents like lecanemab could potentially do good.
“We’ve made sure we’re getting people into clinical trials who have a target and can respond to the drug,” Irizarry said.
They were also able to learn from missteps with previous treatments such as aducanumab by Biogen and Eisai. They enrolled about 1,800 people in the final phase of the clinical trial, enough to show a difference between the drug group and the placebo group.
Irizarry says the researchers also used Phase 2 trials to carefully select the dose, so all participants randomly assigned to therapy in Phase 3 received the same dose.
Ultimately, Irizarry says, all antibodies that target amyloid attach to it in slightly different places. Lecanemab binds to these protein fragments when they join together to form chains of amyloid fragments called protofibrils, but these chains join together to form plaques in the brain. Perhaps catching the amyloid earlier in the process also makes a difference.
Some independent experts doubt that this is much progress.
Johns Hopkins School of Medicine psychiatrist and professor Dr. “I don’t think we see a distinct clinical benefit from aducanumab,” said Constantine Lyketsos.
Aducanumab, sold under the name Aduhelm, was approved by the US Food and Drug Administration in June 2021 over objections from the agency’s outside advisory panel. Clinical trial results were mixed, with only one showing a small benefit for patients. Medicare agreed to cover the drug only under certain conditions, and this became a commercial challenge.
“The main difference is that lecanemab has a larger sample size,” Lyketsos said.
If you superimposed the results seen with lecanemab on top of those seen with aducanumab in the positive study, you would see roughly the same benefit.
“I think we’re seeing a successful strategic approach by the companies developing it to have a very large study that’s large enough to detect a small effect,” he said.
Lyketsos is also concerned about brain swelling called ARIA, short for amyloid-related imaging abnormalities. These side effects have been seen with other types of amyloid-clearing antibodies and occurred in about 1 in 5 participants receiving lecanemab.
He said the protofibrils the drug targets line the walls of blood vessels in the brain. When they are removed, the vessels can leak fluid or blood into the brain. If there is enough leakage, it shows up on an MRI.
Some people with ARIA have no symptoms. But sometimes they can be more serious, leading to hospitalization or permanent disability.
Lyketsos says experts don’t yet understand what happens when mild ARIAs come and go again and again, or how common a case of catastrophically bad brain swelling can be.
If lecanemab was given to only a few thousand people, it may not be a large enough sample to know if more severe brain swelling cases appear to be rare events.
“Maybe there is no such disaster. “We just don’t know,” he said. “So a lot of drugs like this, if they were to come to market, would have a big asterisk next to it that we don’t really know about long-term safety.”
Lyketsos says it would be really difficult to offer lecanemab to a patient.
“If it was a simple pill, if it wasn’t too expensive, I would do it,” he said. But given the drug’s likely cost — aducanumab, for example, now costs about $28,000 for a year’s treatment — and some slowing of the disease’s progression, it would be difficult.
The price of Lecanemab will only be announced if it is approved by the FDA.
He says he may change his mind if analysis of clinical trials shows that one group of people benefited more than others.
Eisai’s Irizarry says the company is currently analyzing trial results on this exact issue — whether people with a genetic risk for Alzheimer’s or people with complicating health conditions like diabetes or high blood pressure may respond differently to the treatment.
“It’s definitely an area we’re working on,” he said.
Other experts worry that the trials were skewed because ARIA events that occurred only in people receiving anti-amyloid antibodies revealed to doctors and patients that they were taking the drug, thus tainting the study.
The main measure used to evaluate the study participants was a questionnaire that ranked how well they were functioning in six areas of their lives, including memory, orientation and problem solving. This is largely based on the assessment of the person’s primary caregiver.
“It’s very prone to bias,” said Dr. Michael Greicius, a neuroscientist and professor at Stanford University.
“Obviously, everyone wants patients to do better—patients, caregivers, clinicians—and that’s why we rely so much on this double-blind concept so that no one knows whether you’re getting the active treatment or the placebo,” he said.
People receiving the treatment, which is given by intravenous infusion once every two weeks, may experience reactions such as chills, chills, and low-grade fever.
Greicius says no one has figured out how to mask research participants to these very prominent side effects, which would require participants to undergo additional brain scans and stop their treatment.
“I want to be sure that this actually moves the needle, but I need to see a little more evidence for that,” he said.
Another expert thinks lecanemab may work to some extent, but not for the reasons people assume.
In addition to removing beta amyloid from the brain, lecanemab increases levels of a normal version of the amyloid protein called AB42, says Dr. Alberto Espay, a neurologist at the University of Cincinnati.
He says that this version of the protein is integral to the structure and function of the brain, and his research has shown that its loss is most strongly associated with cognitive decline, not the accumulation of amyloid plaques. However, he acknowledges that this idea is not a leading theory in Alzheimer’s research.
Espay says he would never consider giving such drugs to his patients because the benefits are few and the costs can be staggering. If millions of people wear them, we’ll all pay the price, he says.
In November, Medicare announced it was increasing monthly premiums for the Part B plan, in part due to the expected cost of aducanumab.
In an emailed statement to CNN, Eisai said it has not yet priced lecanemab but is sensitive to concerns about the drug’s cost.
“In the US, Eisai’s pricing approach will be based on a modeling framework that takes into account the results of the Clarity AD trial, taking into account the sustainability of the health care system and the level of accessibility for people living with early AD,” the spokesperson said. Written by Christopher Vancheri.
These drugs “will disrupt the health care system,” Espay said. “If they were really good for patients, then yes, let’s hack the health care system because it will make a difference.
“Can’t make a difference.”