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, with simultaneous publication November 29 in the New England Journal of Medicine.
Complications in the Field
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 (IgG1) 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 (CDR-SB). Scores from 0.5 to 6 are signs of early AD, according to the study. 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).
The published findings do not speculate about how this difference would affect day-to-day life of participants who took the drug, although it does refer to “modestly less decline” of cognition/function in the lecanemab group.
Other measurements that suggest cognitive improvements in the lecanemab group vs. placebo 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, −.074 to −.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).
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% in those who took lecanemab and 0.8% in those who took the placebo). The researchers did not attribute any deaths to the drug. However, the journal Science reported Nov. 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. Science summarized a case report as saying that the drug “contributed to her brain hemorrhage after biweekly infusions of lecanemab inflamed and weakened the blood vessels.”
Esai, 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 the CLARITY AD Trial, serious AEs occurred in 14% of the lecanemab group, leading to discontinuation 6.9% of the time, and 11.3% of the placebo group, leading 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 (ARIA) with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (17.3% vs 9%, respectively); 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 0.1% of the placebo group.
Michael Weiner, MD, president of the CTAD 22 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 also professor of radiology, medicine and neurology at UCSF.
“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.
The New England Journal of Medicine. Published Nov. 29, 2022. Abstract
15th Clinical Trials on Alzheimer’s Disease (CTAD) conference, presented November 29, 2022.
The trial was supported by Eisai (regulatory sponsor) with partial funding from Biogen. van Dyck reports having received research grants from Biogen, Eisai, Biohaven Pharmaceuticals, Cerevel Therapeutics, Eli Lilly, Genentech, Janssen, Novartis, and UCB. He has also been a consultant to Cerevel, Eisai, Ono Pharmaceuticals, and Roche Products. Relevant financial relationships for the other investigators are fully listed in the original paper.
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