Lecanemab (Leqembi; Eisai), formerly known as BAN2401f, is a humanized monoclonal antibody that removes toxic amyloid-ß protofibrils. In recent news, the therapy has become the second FDA-approved early Alzheimer disease (AD) treatment in the past 20 years following the contentious approval of aducanumab (Aduhelm; Eisai/Biogen) in 2021—and the first to be approved via the traditional pathway.1 The decision was supported by the results of the phase 3 Clarity AD trial (NCT03887455), a confirmatory study, which verified the clinical benefit of lecanemab for the treatment of AD.2
Clarity AD enrolled 1795 patients with evidence of amyloid on PET or cerebrospinal fluid who were followed for an 18-month treatment period. Published in the New England Journal of Medicine, findings from the analysis showed that lecanemab met its primary end point of change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, with treated patients demonstrating a statistically significant 27% reduction.3
Following the approval of lecanemab, Howard Fillit, MD, the cofounder and chief science officer of the Alzheimer's Drug Discovery Foundation, sat down in an interview with Patient Care® partner site NeurologyLive® to share his reactions. He talked about lecanemab's mechanism of action in reducing cognitive and functional decline in patients with AD. He also spoke about the potential changes that can be expected in care and diagnosis with the availability of lecanemab. Additionally, he discussed how the success of lecanemab paves the way for future AD therapies and the alternative pathways are currently being explored in research.
NeurologyLive: Could you give a brief overview of lecanemab, including the mechanism of action in how it works?
Howard Fillit, MD: Lecanemab as humanized monoclonal antibody against ß-amyloid, but it's particularly against forms of ß-amyloid that are deposited in the plaques. Essentially, these plaques can be monitored in patients using the PET scan. In this case, it was the amyloid PET scan. For the purposes of enrollment into the trial, everyone had to have at least a positive PET scan or spinal tap that showed that the patients had AD. A positive PET scan was then used as a target engagement biomarker to show that the drug was working over the course of time. By 18 months, the majority of patients had cleared their plaques from the brain. The pharmacology of the drug clearly worked. Then, there were clinical measures over time to show that look at the rate of reduction in cognitive and functional decline, which turned out to be statistically significant. So, it showed that in association with removing the plaques, there was a slowing of the rate in decline. That alternative time course of a trial, of 18 months, that was a savings of about 5 months, in progression, which was considered clinically significant.
In addition, some important biomarkers like phospho-tau also improved as the levels in the blood decreased. It was interesting that blood tests were also used in the trial monitoring agents. Also, there were significant safety measures in the trial. These were the amyloid-related imaging abnormalities-edema (ARIA-E) and ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis (ARIA-H), which were monitored by serial MRI from outset.
Over the course of the first 3 months or so, people had to have serial MRIs to look for these signs of cerebral hemorrhage in a small percentage of patients. There were serious symptomatic effects associated with the administration of the antibody, particularly in people that had APOE ε4 homozygote. So, a majority of patients got it in a week before testing but as it turns out, patients with APOE ε4 homozygotes had more tendency to have some of these 50 outcomes in terms of ARIA-E and ARIA-H. They also found that people that were on anticoagulants were at risk for hemorrhage. On the FDA indication there is some language about being careful about enrolling people that have our own anticoagulation for various reasons and informing them of the relative risks and benefits of the drug in that context.
How does this therapy benefit patients with AD in changing the landscape of care and what does this teach us about treating the disease?
FIllit: I personally think it'll have a pretty big impact on care because it'll encourage not only the setup of infusion centers, but memory care infusion centers that in general, [will] have patients come to the centers in a holistic way to get their care if they're concerned about their memory to get a quality evaluation, so that they can be considered for infusion with lecanemab and probably with donanemab in the coming months. I think it's going to have a big impact on what we call memory care in general and AD care.
I think there'll be somewhat of a shift from where the majority of patients are cared for now—not necessarily diagnosed—but cared for now in primary care. I think there'll be a shift towards neurology care in memory centers with the availability of infusion capacity. I think that'll overall be an improvement for patients and their loved ones in terms of early diagnosis, and ultimately, care. That's my hope. This drug is indicated for mild AD, mild cognitive impairment, and mild dementia, but now over time it remains to be seen in how people with moderate to severe dementia will continue to be cared for patients who are progressing into the more advanced stages of the disease.
Do you think the approved therapy will open more doors in the future for other effective therapies to treat AD or be used in combination with others?
Fillit: Well, I think there's 2 things to that. One is that the success of these trials and the FDA approval tell the world, industry, and drug developers that it's not futile to try to develop drugs for Alzheimer, that we have a pathway. I think we've enabled the pathways with the new technologies that we have, with PET brain scans and blood tests and biomarkers like phospho-tau. I think the advances in technology and biomarkers, and then our ability to really run efficient and rigorous clinical trials will encourage investors to come into the area.
The other point is that since we only have about a 30% slowing of the disease. We have a big gap in getting to, let's say, 100% slowing of the disease and even prevention. I think that has opened the door to many other pathways being investigated, such as neuroinflammation and metabolic disturbances that now comprise 75% of the drug development portfolio for Alzheimer, where 5 or 10 years ago, 75% of the drug development portfolio were predominantly antiamyloid strategies, so there's been a big shift.
I think a third thing is that we will see new formulations of these monoclonal antibodies in terms of subcutaneous administration, and even at home injections, the way we do with insulin, for example, now. I think that'll reduce the costs in that second generation of administration, assuming it works, it'll reduce the cost and the burden of getting these monoclonal antibodies. I think that's going to be another next step. Then potentially down the road, there's possibility and there's a couple of programs out there that will use small molecules or orally available pills to address this amyloid pathway. Those are in roughly phase 2, development at this point, late-stage phase 2. If those work, I think there'll be another advance in the field along the pathway of amyloid. But again, we're going to need combination therapy with precision medicine using biomarkers to identify the pathways involved in various patients and treating them with more than 1 drug.
Transcript edited for clarity.