Experimental Alzheimer’s drug lecanemab made big news last week when the companies that tested it released trial results showing the drug met its goals, making it one of the first dementia drugs to return positive results.
In a randomized placebo-controlled study of nearly 1,800 people in the early stages of memory loss, those taking lecanemab had 27 percent less memory loss after 18 months than those not, the companies said. The difference was about half a point on what is commonly called a clinical dementia rating scale.. The difference was statistically significant, indicating that the improvement was probably not due to chance.
The companies released only a small portion of the research in a news release, and experts say they want to dig into the details before fully understanding the results.
But if successful, lecanemab will overcome a long history of failure in the field.
By some numbers, lecanemab is the 16th drug to be developed to clear toxic amyloid plaques from the brain. Many others have also worked as advertised; amyloid was removed. The point is that almost none have shown any real benefit to patients, and many experts concluded that the whole field was in left field.
The so-called amyloid hypothesis – that amyloid plaques build up in the brain and are the cause of Alzheimer’s disease – was declared wrong and drug developers were asked to go back to the drawing board.
So, after this long failure, why does lecanemab seem to have worked? Is there anything that makes the medicine better? Or did the testing companies – Biogen and Eisai – do a smarter clinical trial that finally showed the potential of these types of drugs?
“It’s actually a combination of the two,” said Dr. Michael Irizarry, chief clinical officer for Alzheimer’s and brain health at Eisai.
Irizarry said that in planning the clinical trial, researchers were able to take advantage of advances in technology, such as new types of scans that can confirm the presence of beta amyloid in the brain. Previously, doctors only saw amyloid in the brain during autopsies.
They recruited people who were earlier in the disease’s development, at a point when agents like lecanemab could benefit.
“We made sure we recruited people into the clinical trials who were on target and might be able to respond to the drug,” Irizarry said.
They were also able to learn from mistakes made in previous treatments, like aducanumab, which Biogen and Eisai also do. Nearly 1,800 people were included in the final phase of the clinical trial, enough to show a difference between the group that took the medication and the group that got the placebo.
Irizarry says the researchers also used the phase 2 trial to choose the dose carefully, so that in phase 3, all participants randomly assigned to the therapy received the same dose.
Finally, Irizarry says, all antibodies that target amyloid hit slightly different spots. Lecanemab binds to these protein fragments when they link together to form chains of amyloid pieces called protofibrils, but before those chains join together to form plaques in the brain. Catching the amyloid earlier in the process may also make a difference.
However, some independent experts doubt that this is much progress.
“I don’t think we’re seeing a clinical benefit that’s that different from aducanumab,” said Dr. Constantine Lyketsos, a psychiatrist and professor at the Johns Hopkins School of Medicine.
Aducanumab, sold as Aduhelm, was approved by the US Food and Drug Administration in June 2021 over objections from the agency’s external advisory panel. Clinical trial results were mixed, with only one showing a small benefit for patients. Medicare agreed to cover the drug only in certain circumstances, and it has become a commercial failure.
“The main difference is that lecanemab had a much larger sample size,” Lyketsos said.
If you superimpose the results seen with lecanemab on those seen with aducanumab, in the study that showed a positive result, you would see the same level of benefit.
“I think we’re seeing a successful strategic approach by the companies that develop 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 1 in 5 participants taking lecanemab.
The protofibrils targeted by the drug line the walls of blood vessels in the brain, he said. When they are removed, the vessels can leak fluid or blood into the brain. If enough leaks out, it shows up on an MRI.
Some people who take ARIA have no symptoms. But occasionally, they can become more serious, leading to hospitalization or permanent impairment.
Lyketsos says experts still don’t understand what happens when mild ARIAs go on repeatedly or how common a catastrophic case of brain swelling can be.
If lecanemab has been infused into only a few thousand people, this may not be a large enough sample to know whether cases of more severe brain swelling may appear as rare events.
“Maybe there is no such disaster. We don’t know,” he said. “So a lot of these drugs, if they were to come to market, would have this big asterisk next to them that says we don’t know about long-term safety.”
Lyketsos says it would be really challenging to offer lecanemab to a patient.
“If it was a simple pill, if it wasn’t very expensive, it might be,” he said. But given the safe cost of the drug – aducanumab, for example, now costs about $28,000 for a year’s treatment – and the modest rate of slowing disease progression, it would be difficult.
The price of Lecanemab will only be disclosed if approved by the FDA.
He says he may change his mind if clinical trial analysis shows that one group of people benefited more than others.
Eisai’s Irizarry says the company is analyzing test results for that specific problem right now; that people with a genetic risk of Alzheimer’s, or perhaps those with complicated health conditions such as diabetes or high blood pressure, may have responded differently to treatment.
“It’s definitely an area we’re working on,” he said.
Other experts worry that the trial was flawed because those ARIA events – which occur only in people receiving anti-amyloid antibodies – essentially revealed to doctors and patients that they were receiving the drug, so the study was disbanded.
The main measure used to assess the study participants was a survey that ranked how well they were functioning in six areas of their lives, including memory, orientation and problem solving. It is largely based on the assessment of the person’s primary caregiver.
“That’s a very biased trend,” said Dr. Michael Greicius, a neurologist and professor at Stanford University.
“Obviously, everyone wants their patients to do better — patients, caregivers, clinicians — and that’s why we rely so heavily on this notion of double-blind, where no one knows whether you’re getting the active treatment or the placebo,” he said.
People receiving the treatment – which is given by IV infusion every two weeks – may experience shivering, chills and a low-grade fever.
Greicius says no one has figured out how to mask these significant side effects in study participants, which requires participants to undergo additional brain scans and discontinue treatment.
“I want to be convinced that this is moving the needle, but I need to see a little more evidence of that,” he said.
Another expert believes that lecanemab may work to some extent, but not for the reasons people assume.
Dr. Alberto Espay, a neurologist at the University of Cincinnati, says that in addition to removing beta amyloid from the brain, lecanemab increases levels of a normal version of the amyloid protein, called AB42.
This version of the protein is involved in brain structure and function, he says, and his research has shown that its loss is more closely related to cognitive decline than to the accumulation of amyloid plaques. However, he admits that this idea is not a leading theory in Alzheimer’s research.
Espay says he would never consider giving these types of drugs to his patients, not only because their benefits are small, but because the costs can be prohibitive. If millions of people get involved, we will all pay the price, he says.
In November, Medicare announced it was raising its monthly Part B premiums, in part because of anticipated spending on aducanumab.
In an emailed statement to CNN, Eisai says he has not yet set a price for lecanemab, but is sensitive to concerns about the drug’s cost.
“In the US, Eisai’s pricing approach will be based on a model framework that takes into account the results of the Clarity AD trial, the sustainability of the health care system and the level of affordability for people with early AD,” the spokesperson said. Written by Christopher Vancheri.
These drugs “will break the health care system,” said Espay. “If they were very good for the patients, then yes, let’s break the health system because it will make a difference.
“He can’t make a difference.”