'Modest' Benefit for Lecanemab in Alzheimer's, Adverse Events Common

Randy Dotinga

November 29, 2022

UPDATED November 30, 2022 // Editor's note: This article has been updated with additional comments.

SAN FRANCISCO — Widely anticipated data from a phase 3 trial of the monoclonal antibody lecanemab suggest the drug "modestly" relieved cognitive impairment in patients with early Alzheimer's disease (AD) — but at a cost.

In the CLARITY AD trial, adverse events (AEs) were common compared with placebo, including amyloid-related edema and effusions; and a news report this week linked a second death to the drug.

Moving forward, "longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease," Christopher H. van Dyck, MD, Yale School of Medicine, New Haven, Connecticut, and colleagues write.

The full trial findings were presented here at the 15th Clinical Trials on Alzheimer's Disease (CTAD) Conference and were simultaneously published on November 29 in The New England Journal of Medicine.

Endpoints Met

The phase 3 trial of lecanemab has been closely watched in AD circles, especially considering positive early data released in September and reported by Medscape Medical News at that time.

The US Food and Drug Administration (FDA) is expected to make a decision about possible approval of the drug in January 2023. Only one other antiamyloid treatment, the highly controversial and expensive aducanumab (Aduhelm), is currently approved by the FDA.

For the new 18-month, randomized, double-blind CLARITY AD trial, researchers enrolled 1795 patients aged 50–90 years (average age, 71 years) with early AD. All were randomly assigned to receive either a placebo (n = 898) or intravenous lecanemab, a humanized immunoglobulin G1 monoclonal antibody that selectively targets amyloid beta (Aβ) protofibrils, at 10 mg/kg of body weight every 2 weeks (n = 897).

The study ran from 2019 to 2021. The participants (52% women, 20% non-White) were recruited in North America, Europe, and Asia. Safety data included all participants, and the modified intention-to-treat group included 1734 participants, with 859 receiving lecanemab and 875 receiving placebo.

The primary endpoint was the Clinical Dementia Rating–Sum of Boxes. Scores from 0.5 to 6 are signs of early AD, according to the study's authors. The mean baseline score for both groups was 3.2. The adjusted mean change at 18 months was 1.21 for lecanemab, vs 1.66 for placebo (difference, -0.45; 95% CI, -0.67 to -0.23; P < .001).

As van Dyck noted in a presentation at the CTAD meeting, this represents a 27% slowing of the decline in the lecanemab group.

The authors do not speculate about how this difference would affect the day-to-day life of participants who took the drug, although they do refer to "modestly less decline" of cognition/function in the lecanemab group.

Other measurements that suggest cognitive improvements in the lecanemab group in comparison with the placebo group include the Alzheimer's Disease Assessment Scale–Cognitive Subscale score (mean difference, -1.44; 95% CI, -2.27 to -0.61), the Alzheimer's Disease Composite Score (mean difference, -0.05; 95% CI, -0.074 to -0.027,), and the Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment score (mean difference, 2.0; 95% CI, 1.2 – 2.8; all, P < .001).

Overall, van Dyck said, "Lecanemab met the primary and secondary endpoints vs placebo at 18 month, with highly significant differences starting at 6 months."

In a substudy of 698 participants, results showed that amyloid burden fell at a higher rate in the lecanemab group than in the placebo group (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6).

"Lecanemab has high selectivity for soluble aggregated species of Aβ as compared with monomeric amyloid, with moderate selectivity for fibrillar amyloid; this profile is considered to target the most toxic pathologic amyloid species," the researchers write.

Concerning AE Data

With respect to AEs, deaths occurred in both groups (0.7% among those who took lecanemab and 0.8% among those who took the placebo). The researchers did not attribute any deaths to the drug. However, the journal Science reported November 27 that a 65-year-old woman who was taking the drug as part of a clinical trial "recently died from a massive brain hemorrhage that some researchers link to the drug."

The woman, the second person "whose death was linked to lecanemab," died after suffering a stroke. The author of the article in Science summarized a case report, saying that the drug "contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels."

Eisai, which sponsored the new trial, told Science that "all the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall or from any specific cause."

In a CTAD presentation, study co-author Marwan Sabbagh, MD, Barrow Neurological Institute, Phoenix, Arizona, said two hemorrhage-related deaths occurred in an open-label extension. One was in the context of a tissue plasminogen activator treatment for a stroke, which fits with the description of the case in the Science report. "Causality with lecanemab is a little difficult...," he said. "Patients on anticoagulation might need further consideration."

In the CLARITY AD trial, serious AEs occurred in 14% of the lecanemab group and led to discontinuation 6.9% of the time. AEs occurred in 11.3% of the placebo group and led to discontinuation 2.9% of the time, the investigators report.

They add that, in the lecanemab group, the most common AEs, defined as affecting more than 10% of participants, were infusion-related reactions (26.4% vs 7.4% for placebo); amyloid-related imaging abnormalities with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs 9%); amyloid-related imaging abnormalities with edema or effusions (12.6% vs 1.7%); headache (11.1% vs 8.1%); and falls (10.4% vs 9.6%).

In addition, macrohemorrhage was reported in 0.6% of the lecanemab group and in 0.1% of the placebo group.

Cautious Optimism

In separate interviews with Medscape Medical News, two Alzheimer's specialists who weren't involved in the study praised the trial and described the findings as "exciting." But they also highlighted its limitations.

Alvaro Pascual-Leone, MD, PhD, professor of neurology at Harvard Medical School and chief medical officer of Linus Health, said the study represents impressive progress after 60-plus trials examining anti-amyloid monoclonal antibodies. "This is the first trial that shows a clinical benefit that can be measured," he said.

However, it's unclear whether the changes "are really going to make a difference in people's lives," he said. The drug is likely to be expensive, owing to the large investment needed for research, he added, and patients will have to undergo costly testing, such as PET scans and spinal taps.

Still, "this could be a valuable adjunct to the armamentarium we have," which includes interventions such as lifestyle changes, he said.

Howard Fillit, MD, co-founder and chief science officer at the Alzheimer's Drug Discovery Foundation, noted that the trial reached its primary and secondary endpoints and that the drug had what he called a "modest" effect on cognition.

However, the drugmaker will need to explore the adverse effects, he said, especially among patients with atrial fibrillation who take anticoagulants. And, he said, medicine is still far from the ultimate goal ― fully reversing cognitive decline.

Michael Weiner, MD, president of the CTAD22 Scientific Committee, noted in a press release that there is "growing evidence" that some anti-amyloid therapies, "especially lecanemab and donanemab," have shown promising results.

"Unfortunately, these treatments are also associated with abnormal differences seen in imaging, including brain swelling and bleeding in the brain," said Weiner, who is professor of radiology, medicine, and neurology at the University of California, San Francisco.

"There is considerable controversy concerning the significance and impact of these findings, including whether or not governments and medical insurance will provide financial coverage for such treatments," he added.

Rave Reviews From the Alzheimer's Association

In a statement, the Alzheimer's Association raved about lecanemab and declared that the FDA should approve lecanemab on an accelerated basis. The study "confirms this treatment can meaningfully change the course of the disease for people in the earliest stages of Alzheimer's disease...," the association said, adding that "it could mean many months more of recognizing their spouse, children and grandchildren."

The association, which is also a staunch supporter of aducanumab, called on the Centers for Medicare & Medicaid Services to cover the drug if the FDA approves it. The association's statement did not address the drug's potential high cost, the adverse effects, or the two reported deaths.

15th Clinical Trials on Alzheimer's Disease (CTAD) Conference: Presented November 29, 2022.

N Engl J Med. Published online November 29, 2022. Abstract

The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. van Dyck reports having received research grants from Biogen, Eisai, Biohaven, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has also been a consultant to Cerevel, Eisai, Ono Pharmaceutical, and Roche. Relevant financial relationships for the other investigators are listed in the original article. Pascual-Leone reported scientific advisory board relationships with Neuroelectrics, Magstim Inc, TetraNeuron, Skin2Neuron, MedRhythms, and Hearts Radiant. He is also co-founder of TI Solutions, a neurotechnology company developing a noninvasive brain stimulation device; is co-founder and chief medical officer of Linus Health, a company developing digital biomarkers for screening of cognitive function; is listed as an inventor for several issued and pending patents related to brain stimulation; and is the principal investigator on an NIH-funded study into transcranial current stimulation. Fillit is a consultant for Alector.

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