For the past two months, doctors have debated the significance of surprisingly positive clinical trial results for a closely watched Alzheimer’s disease drug.
But they have had little to go on, knowing only the barest outline of how beneficial treatment with the drug, called lecanemab, actually was for the study participants who received it. A late September press release from lecanemab’s developers, Eisai and Biogen, revealed it slowed patients’ mental and physical decline by 27% versus a placebo, but shared few other data points.
On Tuesday evening, the researchers who ran that study pulled back the curtain, publishing full results in The New England Journal of Medicine and presenting their findings at the annual Clinical Trials on Alzheimer’s Disease conference in San Francisco.
The new data corroborate the companies’ September declaration, validating lecanemab as the first drug of its kind to clearly succeed in late-stage testing. Yet, there are still questions about lecanemab’s side effects, and whether they're worth the modest benefits seen so far.
How these data are viewed by Alzheimer’s doctors and specialists could go a long way to determining whether lecanemab ultimately gets used, should the Food and Drug Administration approve it early next year as is currently expected.
Three years ago at CTAD, Biogen failed to erase doctors’ many doubts about its earlier Alzheimer’s drug aducanumab, leading to tepid interest in prescribing it when the FDA controversially approved it as Aduhelm in June 2021. Biogen has since abandoned efforts to sell the drug in the U.S.
“I was so discouraged and skeptical at the [CTAD] meeting in 2019 with aducanumab,” said Mary Sano, director of the Alzheimer’s Disease Research Center at Mount Sinai School of Medicine. “I do want people to understand that, while [lecanemab] is not a panacea, it is dramatically different.”
Eisai, which also worked with Biogen on Aduhelm, sees in lecanemab an effective treatment for the many people with early Alzheimer’s and a would-be blockbuster product. The CTAD presentation and NEJM publication are the main evidence that will support the company’s case to the medical community. Here’s what to make of them:
What new information is now available?
Eisai and Biogen’s September press release described what are known as topline results, indicating that the trial met its main and secondary goals and summarizing reported side effects.
That information was enough to frame lecanemab as the most promising Alzheimer’s drug to emerge from clinical testing in decades, and added billions of dollars to Eisai’s and Biogen’s respective market values.
The NEJM paper lays out the full results that the FDA will pore over to make its approval decision and that doctors will need to prescribe the drug. They show that study participants given lecanemab experienced significantly slower decline on four rating scales investigators used to gauge patients’ cognitive and functional ability. Notably, the statistical method used to calculate the difference between groups strongly favored lecanemab on each measure.
The data also suggest that, on the study’s main measure, an 18-point rating scale known as the Clinical Dementia Rating – Sum of Boxes, or CDR-SB, the difference between patients on Eisai and Biogen’s drug and those on placebo widened over time. As lecanemab is meant to be taken chronically, a growing benefit could indicate potential for more substantive changes in the disease’s course beyond the trial’s 18 months of follow-up.
Moreover, analyses used to gauge how sensitive the data are to other variables were generally consistent with the main findings on the primary endpoint, the study authors wrote. Further subgroup data consistently favored lecanemab across criteria used to randomize participants between the drug and placebo, such as by use of other Alzheimer’s medicines, genetic risk factors and where they were located.
The publication of study results in NEJM concurrent with the CTAD presentation contrasts with Biogen’s handling of its data for Aduhelm, which was not published in a peer-reviewed medical journal until March 2022 — after the drug’s approval and more than two years after the data’s first presentation at CTAD.
At this year’s conference, study authors are presenting their findings in a series of five presentations Tuesday evening.
Primary and secondary endpoint results from Eisai, Biogen Phase 3 study of lecanemab
| Study endpoint* | Adjusted mean difference vs. placebo | P value vs. placebo |
|---|---|---|
| Change in CDR-SB score | -0.45 (favoring lecanemab) | <0.001 |
| Change in amyloid burden | -59.12 (favoring lecanemab) | <0.001 |
| Change in ADAS-cog14 score | -1.44 (favoring lecanemab) | <0.001 |
| Change in ADCOMS score | -0.05 (favoring lecanemab) | <0.001 |
| Change in ADCS-MCI-ADL score | 2.0 (favoring lecanemab) | <0.001 |
*From baseline to 18 months SOURCE: The New England Journal of Medicine
Was lecanemab’s benefit supported by biomarker data?
Like Aduhelm and many other experimental Alzheimer's drugs, lecanemab is designed to bind to a protein known as amyloid beta. Research indicates these proteins normally provide helpful functions in the brain. But sometimes they misfold, which, over time, causes them to clump together and form a kind of sticky, toxic plaque that has long been thought to play a central role in the development of Alzheimer's.
Biogen and Eisai have noted that lecanemab appears to have a specific affinity for one form, called “soluble protofibrils,” that amyloid beta takes. This form is thought by some to be more toxic to neurons than others.
Lecanemab was already viewed as a potent clearer of amyloid beta and the full data disclosed Tuesday help confirm that. Results from a subgroup of nearly 700 study participants showed those treated with the drug over the 18-month study period ended up having, on average, amyloid beta levels that were below the threshold which determines whether they're "positive" for the protein.
Study authors also wrote that the lecanemab-treated group experienced greater reductions in other markers of neural cell degradation and inflammation.
In the case of Aduhelm, the FDA granted a so-called accelerated approval based on the drug's ability to clear amyloid beta plaques in the brain, an effect which the agency argues is "reasonably likely to predict a clinical benefit to patients."
How meaningful is the benefit actually?
When Eisai and Biogen first released their results for lecanemab, experts were torn about whether they represented a meaningful effect on Alzheimer’s progression. That debate could continue even after doctors see the full results.
In the trial, the CDR-SB scores of patients who received lecanemab declined by about half a point less, on average, than those who received a placebo after 18 months. Clinicians use the CDR-SB to evaluate brain and physical function.
To some, that’s a significant benefit, especially considering the trial allowed participation from patients who were on other Alzheimer’s medications like Aricept.
“It is a small effect size. But I would argue that it’s more than we’ve seen, and it’s on top of giving it all we have,” said Sano.
“So it’s incremental, but it’s robust. I think that’s a very big deal,” added Sano, who has consulted for Eisai, Biogen, and other Alzheimer’s drug developers. She reviewed the trial results on BioPharma Dive’s request, on condition she not share the data.
But Constantine Lyketsos, director of the Memory and Alzheimer’s Treatment Center at Johns Hopkins Medicine, notes that many Alzheimer’s experts believe a drug would need to offer at least a 1- to 2-point effect on that scale to be considered clinically meaningful.
“I think the field has spoken,” said Lyketsos, who has consulted for Eisai and other drug companies and also reviewed the data on condition he not share it. “It ultimately comes down to, do we have a minimally clinically important difference or not? And the answer is I still don’t think we do [with lecanemab].”
In their paper, the NEJM authors struck a somewhat cautious note, writing “longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.”
What risks are there to treatment?
The primary concern surrounding lecanemab, and other amyloid-targeting drugs like it, is a side effect known as amyloid-related imaging abnormality, or ARIA. It’s a well-known consequence of taking drugs designed to eliminate amyloid beta in the brain, and has cropped up in other Alzheimer’s studies.
In Eisai’s trial, about 22% of participants on lecanemab experienced ARIA associated with brain swelling or bleeding, compared to just under 10% of those in the placebo group. In most, the side effect was asymptomatic, while the few who did have symptoms commonly experienced headaches, visual disturbances and confusion.
Of the 17% of lecanemab-treated patients who had ARIA with hemorrhages, only six had symptoms.
Six patients on lecanemab died in the study, compared to seven on placebo. Recent reports by Stat and Science described two deaths in lecanemab’s Phase 3 trial that were considered possibly related to the drug. Both involved brain bleeding, although there were other factors, such as the use of blood thinners, that could have played a role.
“Blood on the brain is not good,” said Lyketsos. “When we're talking about a drug that, if FDA approves, will potentially be given to hundreds of thousands, if not millions, of people. Then the risks, the numbers of people who will have these hemorrhages become very large.”
Sano, of Mount Sinai, agreed the microhemorrhages reported in the study are concerning. Still, she added that lecanemab’s risk should be weighed against its reported benefit.
“There aren't a lot of drugs for a lot of serious diseases that don't have high risk,” Sano said. “Are the cognitive benefits important enough for you to take some of that risk?”
What’s next?
Eisai has already filed for accelerated U.S. approval of lecanemab based on earlier study data. The company anticipates a verdict on its application by Jan. 6. and, based on the new late-stage trial results, plans to ask for full approval later next year.
On Wall Street, the expectation is that regulatory clearance is highly likely. Brian Abrahams, an analyst at the investment firm RBC Capital Markets, pegged the approval odds at 95% in a mid-November note to clients. The analyst teams at RBC and Raymond James have estimated peak annual sales from the drug could eventually surpass $9 billion.
There were similarly sky-high forecasts when Aduhelm gained approval in June 2021. But pushback from insurance companies, as well as deep doubts among doctors about the drug’s effectiveness, led to anemic sales during its first year on the market.
Should lecanemab come to market, Eisai and Biogen will have a second chance at a blockbuster drug for Alzheimer’s.
Yet the companies may face a more difficult challenge from following Aduhelm. Medicare, for instance, imposed a restrictive coverage policy on anti-amyloid Alzheimer’s drugs earlier this year, which would also cover lecanemab. Analysts expect Eisai’s positive late-stage results will help unlock broader reimbursement, but that will take additional time.
