Updated Safety Results From Phase 3 Lecanemab Study in Early Alzheimer's Disease

Lawrence S. Honig, MD, PhD

The development of FDA-approved disease modifying therapies for Alzheimer's disease (AD) has been a major achievement in neurotherapeutics over the past few years. AD, which is a disease that affects cognition and memory, is caused by excessive beta-amyloid protein in the brain, which is deposited in the form of neuritic plaques, and is associated with the development of neurofibrillary degeneration and neurodegeneration including synaptic and ultimately neuronal cell losses. The clinical effects of AD, with disorientation, amnesia, language and visuospatial problems, and behavioral and functional impairments, places an enormous burden on the 7 million Americans, and others throughout the world, who are affected, and on their families, as well on healthcare systems. The development of therapies that slow the progression of disease has changed neurological care for persons with dementia. The most-used therapy is lecanemab, which is a monoclonal antibody that is administered intravenously and binds with high affinity to soluble beta-amyloid in the form of protofibrils, which are more toxic to neurons than monomeric beta-amyloid or insoluble polymeric forms of beta-amyloid. The drug lecanemab (also known as BAN-2401) is approved for use in the US, China, and Japan, after phase 2 and phase 3 studies proved that it decreased cerebral beta-amyloid levels, resulting in the marked clearance of beta-amyloid deposits known as senile neuritic plaques, and showed clear clinical benefits.

In the late 2010’s, an 18-month, phase 2, dose-finding study of lecanemab, using a Bayesian adaptive design was conducted in 856 participants with mild cognitive impairment (MCI) due to AD and mild dementia due to AD dementia (collectively termed “early AD”). This study showed removal of cerebral amyloid as measured by PET scans, favorable changes in a variety of fluid biomarkers, and evidence of dose-dependent clinical benefits. In the phase 2 study, as in prior studies of anti-amyloid antibodies, there were also side effects, most notably the dose-dependent development of brain edema and brain hemorrhages, called amyloid-related imaging abnormalities (ARIA). Following the phase 2 study, a phase 3, randomized, double-blind, placebo-controlled trial (called Clarity AD) with an open-label extension (OLE) was performed. This study confirmed lecanemab clinical efficacy, with slowing of cognitive and functional decline by a variety of neuropsychological and functional outcome measures, to the extent of 26% to 37% over the 18-month trial period, and resulted in the FDA-approval of the drug, and subsequent approval by regulatory authorities in Japan and China. While overall the drug was well tolerated in these trials, lecanemab treatment was again accompanied by not only some manageable infusion reactions (with greater incidence than in placebo), but also with ARIA-E (ARIA with edema or effusion) and ARIA-H (ARIA marked by microhemorrhages, superficial siderosis, or very rarely macrohemorrhages greater than 1 cm in diameter). ARIA-E and ARIA-H appear to be related to cerebral amyloid angiopathy (CAA), which in turn is significantly related to APOE-ε4 allele dosage.

Figure 1. Timing of ARIA-E events (A) overall and (B) by APOE4 genotype for lecanemab in Core + OLE and placebo in Core.

Now published in Alzheimer’s Research & Therapy, this publication presents detailed safety information from the double-blind Core phase and the OLE of the phase 3 Clarity AD study in early Alzheimer's disease. The data shows the serious adverse events and deaths which occurred during the study, and also more detailed and updated data on the cerebral side effects of ARIA-E and ARIA-H, complementing previously published trial data from the phase 2 and phase 3 Core studies. The phase 3 trial included 1795 participants in the Core phase and 1612 in the Core + OLE phases, with lecanemab showing good tolerability. During the Core phase there was no increase in deaths with lecanemab (0.7% deaths on lecanemab versus 0.8% deaths on placebo), but some increase in serious adverse events (14% on lecanemab vs 11% on placebo). Overall, frequent adverse events more common in the lecanemab group included infusion reactions (24.5%), ARIA-H (16.0%), and ARIA-E (13.6%). ARIA-E and ARIA-H events were predominantly mild-to-moderate in radiological severity; only about one in four ARIA-E events were symptomatic. Major findings are that ARIA-E occurs mostly in the first 3-6 months of therapy, and is much more common in ApoE ε4 homozygotes (33%), than in heterozygotes (11%), or non-carriers (5%); it is usually asymptomatic, and typically resolves over 90 days. ARIA-H microhemorrhages that are “isolated”, which is to say not occurring in the context of ARIA-E, are not clearly increased in incidence in those who received lecanemab treatment (8.7%) compared to those who received placebo (7.7%). Lecanemab treatment did seem to be associated with increase in isolated ARIA-H superficial siderosis, and likely in the rare macrohemorrhages that occurred in less than 0.5% of lecanemab-treated patients. ARIA-H is markedly related to ApoE genotype, with a monotonic increase in microhemorrhages over time, regardless of drug treatment, but occurring much more so in APOE e4 homozygotes, than heterozygotes or non-carriers.

The safety information on lecanemab is important for discussing risks and benefits in patients considering anti-amyloid therapy with lecanemab, and for understanding the FDA-mandated monitoring procedures, including three brain MRI studies in the first seven months of treatment with this drug. As increased numbers of patients receive anti-amyloid therapies, it is most important to have a thorough understanding of the potential risks, and the procedures to mitigate these risks through monitoring by healthcare providers, patients, and caregivers ensuring optimal patient management and care.

Lawrence S. Honig, MD, PhD
Professor of Neurology (in the Gertrude H. Sergievsky Center and the Taub Institute)
lh456@cumc.columbia.edu