Eisai Presents New Phase 3 Analyses of ARIA and Quality of Life of Lecanemab-Treated Patients

Howard Fillit, MD

Recently, Eisai presented new analyses from the phase 3 Clarity AD study (NCT03887455) of lecanemab (Leqembi), that highlighted specific amyloid-related imaging abnormalities (ARIA) rates for patients on the medication, as well as improved health-related quality of life measures. Above all, these data provided additional evidence in the meaningful benefits of lecanemab for patients and caregivers.¹

ARIA risk showed to be slightly greater in the placebo group with antiplatelet (9.7%) or with anticoagulants (10.8%) compared with patients on placebo not on anticoagulants (8.7%). In addition, rates tended to be slightly lower in patients treated with lecanemab on antiplatelet or anticoagulation, compared with those treated on the therapy not with antiplatelet or with anticoagulation (no antiplatelet or anticoagulation, 21.8%; antiplatelet, 17.9%; anticoagulation, 13.3%).

Notably, the adjusted mean change from baseline in European Quality of Life–5 Dimensions (EQ-5D-5L) and Quality of Life in AD (QOL-AD) of patients on the medication showed declines of 49% and 56%, respectively, at month 18. At the same time, caregiver burden declined 38% and 23%, respectively, for the same measures.

Howard Fillit, MD, cofounder and chief science officer for the Alzheimer's Drug Discovery Foundation told NeurologyLive®, “There's a lot of interest in the biology of aging approach based on the recent monoclonal antibodies. There's roughly about a 30% slowing of the progression on decline of clinical symptoms and function. We want to get to 100% slowing of decline. We're going to need more therapies on more targets, combination therapy, and better biomarkers.”

The latest findings from Clarity AD were presented at the 2023 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held March 28-April 1, Gothenburg, Sweden. In the trial, ARIA did not occur more frequently in patients treated with lecanemab on antiplatelet or anticoagulant drugs relative to those who received the treatment that were not on either. Notably, the pattern of occurrence of isolated ARIA-H in lecanemab group was similar to that in placebo group.

“One of the highlights of the meeting is the advances in biomarkers that's being done, with blood tests in particular. It looks like the emerging winner on the blood test side is going to be what we call phosphorylated tau 181 and phosphorylated tau 217. In particular, phosphorylated tau 217, is predictive of amyloid in the brain, and seems to be a good diagnostic for Alzheimer's disease. We're just looking at all the various uses of these biomarkers and clinical care and clinical trials, it's just accelerating the field tremendously,” Fillit said.

The trial was a placebo-controlled, double-blind, parallel-group, randomized study in 1,795 patients with early AD who received 10 mg/kg bi-weekly IV of treatment or placebo (lecanemab group, n = 898; placebo group, n = 897). Previously reported, lecanemab met its primary endpoint and all key secondary endpoints in highly statistically significant fashion. Health-related quality-of-life (HRQoL) was measured using the EQ-5D-5L and QOL-AD scales at baseline and every 6 months post-baseline. QOL-AD was also assessed for the patient by the caregiver. Additionally, caregivers were administered the Zarit Burden Interview every 6 months for the assessment of caregiver burden in association with dementia.

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In the lecanemab group, the incidence rate of ARIA-edema (ARIA-E) was 13.1% and 1.5% in the placebo group when no antiplatelet or anticoagulant medication was used. When antiplatelet medication was used, incidence rates were 10.4% in the lecanemab group and 0.84% in the placebo group. Additionally, rates were 4.8% in the lecanemab group and 2.7% in the placebo group when anticoagulant medication was used. As for the incidence of ARIA-H, which included combined cerebral microhemorrhages, superficial siderosis, and intracerebral hemorrhages more than 1 cm in diameter, the lecanemab and placebo groups rates of 17.3% and 9.0%, respectively.

The rates of isolated ARIA-H in the lecanemab (8.9%) and placebo groups (7.8%) in Clarity AD were infrequent and occurred at a similar, steady rate over 18 months observed treatment.. In addition, the incidence of isolated ARIA-H escalated with number of apolipoprotein ε4 (APOE ε4) alleles in both placebo (noncarriers, 3.8%; heterozygotes, 7.3%; homozygotes, 18.0%), and lecanemab group (noncarriers, 8.3%; heterozygotes, 8.4%; homozygotes, 12.1%). Despite these observations, investigators concluded that carrier status did not impact timing on the overall occurrence of ARIA-H.

“There's a lot of optimism at this meeting beyond the amyloid story. There's just a lot in recognizing that aging is the leading risk factor for Alzheimer disease. We need to understand and apply the biology of aging to translate that basic knowledge into new drugs for Alzheimer disease. ” Fillit said. “There's a lot of interest in here and sessions on mitochondrial dysfunction with aging, metabolic disturbances, EPI, genetics, autophagy, and failure of misfolded protein management. There's a lot of alternate targets and biomarkers being developed, and I think that's where the next generation of the field is going.”

In November 2022, several in-depth analyses of the Clarity AD study were presented at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held November 29 to December 2, in San Francisco, California, including a talk on safety of the agent given by Marwan Sabbagh, MD, FAAN. The data showed that an occurrence rate of 12.5% for ARIA-E on lecanemab-treated patients compared with 1.7% of those on placebo, including symptomatic ARIA-E rates of 2.8% and 0.0% in the respective groups.²

REFERENCES
1. Eisai Presented New Analyses of ARIA and QOL on Lecanemab in Clarity AD at the AD/PD 2023 Annual meeting. News Release. Eisai. Published March 31, 2023. Accessed March 31, 2023. https://www.eisai.com/news/2023/news202325.html
2. Irizarry M, van Dyck C, Sabbagh M, Bateman R, Cohen S. Clarity AD: A phase 3 placebo-controlled, double-blind, parallel-group, 18-month study evaluating lecanemab in early Alzheimer disease. Presented at: CTAD Conference, November 29-Dec 2.