(Bloomberg) -- Shares of Eisai Co. and partner Biogen Inc. have soared since reporting that their drug lecanemab slowed Alzheimer’s, the first to unambiguously impede the progression of the disease in a final-stage trial. But many questions linger.
Doubts still remain over the magnitude of the benefits, side effects, and what kind of insurance coverage it will receive if approved. At the moment, all that’s known is the drug slowed early Alzheimer’s by 27% over 18 months when compared to a placebo in a giant trial. The companies said Tuesday that just over 21% of the people who received the drug in the trial experienced brain swelling or brain bleeding, a major side effect of antibodies that target amyloid, a toxic protein that clutters the brains of Alzheimer’s patients.
Beyond that, little is known, including which subsets of patients did best on the drug and which groups are most likely to suffer side effects. More details won’t be presented until a medical meeting on Nov. 29. The drugmakers also plan to publish the results in a medical journal.
From a statistical point of view, the results are strong, and likely enough to get full approval in the US, experts said, while cautioning the magnitude of benefits is hardly enormous.
“For the field of Alzheimer’s disease research, this is a sort of a triumph,” said Marsel Mesulam, a neurologist at Northwestern University’s Feinberg School of Medicine. “The not-so-good news is that this is very cumbersome, it has side effects, it is likely to be very expensive, and the clinical effect is very, very small.”
Antibodies such as lecanemab could be just a first step toward the development of convenient and more effective therapies for the disease that will ultimately target a variety of disease mechanisms, not just amyloid, said Howard Fillit, co-founder and Chief Science Officer at the Alzheimer’s Drug Discovery Foundation. Like cancer treatment, he said, treating Alzheimer’s may ultimately involve combination therapy targeting several different disease pathways.
Every Two Weeks
Eisai’s drug may not be particularly convenient for many patients. The current formulation must be infused every two weeks, meaning patients and their families will have to visit facilities that are set up to administer it. While Eisai is testing a more convenient, subcutaeous formulation that could be self-injected, it hasn’t revealed when that will be ready.
Over the years numerous companies have tried to treat the disease with drugs that target amyloid. One unanswered question is why Eisai’s trial succeeded when so many others have failed or produced mixed results. Among others, Biogen’s amyloid-lowering medicine Aduhelm produced contradictory results in two final-stage trials that were halted prematurely. While Aduhelm was ultimately approved by US regulators in 2021, the federal Medicare program refused to cover it broadly earlier this year, citing the unclear efficacy results.
One potential difference is that the Eisai drug targets a slightly different form of amyloid than previous antibodies that didn’t clearly work. Pioneered by researchers at BioArctic AB, it homes in on a form of amyloid known as protofibrils, that some researchers believe is more likely to be toxic than the larger amyloid plaques that have been the focus of much research.
But Eisai’s success might also be due to the fact it took its time to perform the clinical trials right. It conducted an unusually large phase-2 trial, involving more than 800 people, helping it select the most effective dose, which turned out to be the highest one. Then it ran a massive phase-3 trial involving almost 1,800 patients -- big enough to spot even small benefits from the drug. Eisai let the trial run to the end instead of halting it early, as Biogen did with Aduhelm.
How Meaningful?
The biggest question hovering over lecanemab is whether patients and their families will find the modest slowing of decline meaningful, and worth the hassles and potential side effects. Like many Alzheimer’s trials, Eisai’s evaluated patients using something called the clinical dementia rating scale, or CDR. It measures memory and cognition, and ability to perform basic daily functions, and combines that into one numerical score. In the trial, the difference between people who got the drug and those who got a placebo amounted to 0.45 points on the 18 point CDR scale.
CDR “is a highly technical outcome measure used only by Alzheimer’s experts,” Sam Gandy, a professor of neurology and psychiatry at Icahn School of Medicine at Mount Sinai, said in an email. “There is no way to know how this translates for any one individual.”
What to make of that 0.45 point difference “is now the big debate and there is no way to resolve it until the data are published,” Gandy said.
Some scientists said they were impressed with the efficacy results. The difference seen in the trial is “a very significant move in terms of slowing” the disease, said Maria Carrillo, chief science officer for the Alzheimer’s Association, in an interview. It could be the difference between a patient remaining in the earliest stages of mild cognitive impairment and progressing to mild dementia, she said.
Informed Decision
Feinberg School’s Mesulam said it would be difficult to explain the lecanemab trial results in a way that patients and their desperate families can understand in order to make an informed decision whether to try it or not.
In an individual patient, there’s no way to tell whether the drug is slowing the disease, or to decide when to stop treatment once twice-monthly infusions are started, he said. And, there’s no way to correlate the 0.45 point difference seen in the trial with a concrete benefit an individual might see, Mesulam said.
Some like Fillit, at the Alzheimer’s Drug Discovery Foundation, can’t wait for much more powerful treatments.
“It is not an earth shattering movement in terms of slowing the rate of decline. It is a very modest effect,” he said. “We would like to get to 100% slowing.”
Nonetheless, the statistically clear benefit may be big enough to gain broad coverage in the US. It could be a different story in other countries that more explicitly take cost effectiveness into account.
The benefit seen in the Eisai trial “is below what is generally considered clinically significant,” said Rob Howard, a professor of old age psychiatry at University College London. “This will be a problem” in places like the UK where cost effectiveness is a key determinant of coverage, he said.
©2022 Bloomberg L.P.
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