As Eisai and Biogen work to cement the clinical profile of their amyloid-busting antibody lecanemab—now sporting an accelerated approval as Leqembi—the companies have plunged headfirst into one of the drug’s most familiar side effects.
The clutch of new analyses, which debuted at the 2023 annual meeting of the International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD), offers more context around the tough conversations patients and caregivers may need to have with their doctors before going on treatment. Plus, the new data will inform Eisai’s bid to translate its speedy green light into a full, traditional FDA approval, which will be necessary to achieve the company's goal of broad and simple Medicare coverage.
Still, the results may "not provide the certainty investors were hoping for" when it comes to a trio of trial deaths blamed in part on the use of blood thinners with Leqembi, analysts at BMO Capital Markets wrote Monday.
Of ARIA and aspirin
Eisai’s new analyses of its phase 3 trial for Leqembi, Clarity AD, homed in on three major points: First, cases of amyloid-related imaging abnormalities (ARIA) didn't appear to occur more frequently in Leqembi patients who were also taking antiplatelet drugs like aspirin—as well as anticoagulant medications—versus those on Leqembi alone.
Second, rates of isolated ARIA-H, which Eisai says are "infrequently associated with symptoms," were similar across the study drug and control cohort patients in Clarity AD.
ARIA-H is defined by small hemorrhages on the brain, which are often joined by the iron overload disorder hemosiderosis. Another type of the side effect, called ARIA-E, refers to cerebral edema, or the gathering of excess fluid in the intra- or extracellular spaces of the brain.
For the third analysis, Eisai says the phase 3 study garnered additional evidence that the drug may help patients and caregivers see “meaningful benefits of lecanemab treatment," the company said in a Friday press release.
“Overall, for all these forms of ARIA, the rate is higher in lecanemab than in placebo,” Michael Irizarry, M.D., Eisai’s senior vice president of clinical research and deputy chief clinical officer of Alzheimer’s disease and brain health, said in an interview. The same is generally true of all antibody drugs targeting amyloid in the brain.
While ARIA rates were higher for Leqembi patients, the analyses may provide doctors with more information about who could be vulnerable to the side effect—and when it might occur during the course of their treatment.
Risks with other popular medicines
Meanwhile, the results of the antithrombotic (antiplatelet and anticoagulant) analysis were “quite interesting,” Irizarry explained.
Within the placebo group, being on antiplatelet or anticoagulant agents seemed to increase the risk of ARIA. In the Leqembi group, however, “the rates of these events on people that were on both lecanemab and antithrombotics was not higher than people that were on lecanemab alone,” Irizarry said.
It’s important to note the number of cases seen was “very small,” Eisai pointed out in its AD/PD presentation. Therefore, it may be tough to draw a strong conclusion one way or the other.
As for what those safety signals mean for the talks caregivers and patients will need to have with their doctors, “I still think the discussion really needs to be focused on what’s on the label,” Irizarry stressed.
Lecanemab’s current label already highlights the fact that concurrent use of such medications with Leqembi "may increase the risk of bleeding in the brain." This “should be included as part of the benefit/risk discussion" for patients who consider Leqembi, Irizarry said.
ARIA-H without the 'E'
Looking at isolated cases of ARIA-H, meaning those that didn't occur in conjunction with the riskier ARIA-E, Eisai found the "infrequently" symptomatic side effect occurred "randomly in both the placebo and treatment groups at almost the same rate," the company explained in an emailed statement.
Further, unlike ARIA-E, which most often cropped up early among Leqembi patients in Eisai's phase 3 trial, isolated ARIA-H surfaced "without any relationship to initiation or duration of therapy," the company explained in a slideshow presentation.
The data seem to suggest ARIA-H by itself is less of a concern. They also appear to flag the first six months of Leqembi treatment as the most dangerous, as that's when ARIA-E and ARIA-H are more likely to occur simultaneously.
"We believe that this allows a better understanding of ARIA and the key components of assessing risk in relation to ARIA," an Eisai spokesperson explained over email.
Buying quality time
Eisai further investigated Clarity AD with a view to showing Leqembi can help chart a “relative” preservation of health-related quality of life and caregiver burden, as reported by patients and care partners themselves.
To track quality of life (QOL) changes, Eisai leveraged three measures of disease burden. Those were: the European Quality of Life-5 Dimension (EQ-5D-5L) and Quality of Life in AD (QOL-AD) scales, plus the Zarit Burden Interview to weigh care partner burden associated with dementia.
At the 18-month mark, patients on Leqembi experienced 49% and 56% lower mean declines on the EQ-5D-5L and QOL-AD scales than those on placebo, respectively.
On the Zarit Burden Interview and QOL-AD scale for caregivers, meanwhile, Leqembi helped reduce declines at 18 months by 38% and 23%, respectively.
Carving a commercial path
Eisai is currently working to convert its accelerated nod for Leqembi into a full approval. At present, the Centers for Medicare & Medicaid Services (CMS) has restricted access to the drug and others like it under what’s known as the “coverage with evidence development” pathway. This effectively cuts the class off from most Medicare patients. The CMS made its original determination on the anti-amyloid drug class in response to Aduhelm's controversial launch in 2021 and 2022.
Overall, Eisai is “not so nervous” about Leqembi’s long-term access prospects, the company’s U.S. CEO Ivan Cheung said during a recent interview.
According to analysts with GlobalData Healthcare, Eisai and its commercial partner Biogen are poised to realize $12.9 billion in revenue from Leqembi through 2028. The projection assumes that Leqembi will gain full approval from the FDA, clearing the way for wider access.