FDA Panel Votes in Favor of Eisai’s Lecanemab for Early Alzheimer Disease

The FDA’s Peripheral and Central Drugs Advisory Committee has voted unanimously that the current data on lecanemab (Leqembi, Eisai), an antiamyloid therapy for early Alzheimer disease, is sufficient enough to warrant traditional approval by the agency. The therapy has already been conditionally approved under the accelerated approval pathway, with a PDUFA date of July 6, 2023, for traditional approval.¹

Following the discussion topics, the panel was asked to vote on whether the results of the Clarity AD trial (NCT03887455) verified the clinical benefit of lecanemab for the treatment of AD. The panel voted 6–0 (6 Yes; 0 No; 0 Abstain) in favor of the agent.

The FDA's advisory committee answered questions related to 2 main discussion topics. The first question discussed the results from the Clarity AD trial and whether the data provide evidence of the clinical benefit of lecanemab for the treatment of AD. The second question discussed the overall benefit and risk assessment of lecanemab. Additionally, the discussion considered the following subgroups in the assessment of the treatment, including APOE homozygotes, patients who required concomitant treatment with anticoagulant agents, and patients with cerebral amyloid angiopathy.

Throughout the hearing, the agency brought up several concerns, including the mortality rates associated with cerebral amyloid angiopathy and inflammatory vasculitis in patients from the Clarity AD trial. The FDA also brought up safety concerns such as amyloid-related imaging abnormalities (ARIA), cerebral hemorrhage, infusion-related reactions, and hypersensitivity, which they noted are the main safety signals associated with lecanemab.

“We are encouraged by the FDA Advisory Committee’s decision to endorse Leqembi, but we recognize that the mission to develop effective treatments for all patients with Alzheimer disease is far from over,” said Howard Fillit, MD, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF), in a statement. “While this is an exciting step forward, our understanding of the biology of aging tells us we will need multiple therapies that target novel pathways and can be used in combination with other drugs, like anti-amyloids, for a precision medicine approach.”

Lecanemab is only the second early AD treatment that has received FDA approval in the past 20 years following the contentious approval of aducanumab (Aduhelm; Eisai/Biogen) in 2021, which remains under conditional approval.

Despite approval of aducanumab, access to the drug has been severely limited due to coverage restrictions placed by the Centers for Medicare & Medicaid Services (CMS). However, the agency announced last week that it would indeed provide coverage of antiamyloid therapies intended to slow the progression of AD that recieve traditional approval by the FDA.

Under CMS proposed policy, if the FDA grants traditional approval to other drugs in this class, they would be eligible for broader coverage. To get Medicare coverage, individuals will need to be enrolled in Medicare Part B, have a diagnosis of mild cognitive impairment or early dementia caused by AD, and have a qualified physician participating in a registry with an appropriate clinical team and follow up care.

Formerly known as BAN2401, it is a humanized monoclonal antibody that eliminates toxic amyloid-ß protofibrils. It was conditonally approved in January 2023 under the accelerated approval pathway, with the supplemental biologics license application (sBLA) for traditional approval accepted on March 6, 2023.² The sBLA was supported by positive data from the phase 3 confirmatory Clarity AD study, an 18-month study that further demonstrated lecanemab’s effect in early AD. Clarity AD included 1795 patients with early AD randomly assigned 1:1 to treatment of 10 mg/kg biweekly of lecanemab or placebo. An estimated 25% of the total enrollment in the US included Hispanic and African American individuals with early AD, and the overall cohort demographics were generally comparable to the Medicare population.³

Lecanemab also met secondary end points in Clarity AD, including change in amyloid PET centiloids (difference in least-squares [LS], –50.12; P <.0001) and Alzheimer’s Disease Assessment Scale-Cognitive 14 (LS difference, –1.442; P = .00005) relative to placebo over the 18-month period. Additionally, it outperformed placebo on the Alzheimer's Disease Composite Scale (ADCOMS; LS difference, –0.00; P = .00002), and Alzheimer’s Disease Cooperative Study-Activities of Daily Living (LS difference, 2.016; P <.00001). Specifically, it slowed disease progression on ADCOMS by 24% and disease progression on ADCS MCI-ADL by 37% at the same time point.

Using mixed model regression modeling, the treatment difference at 18 months was –0.394 on Clinical Dementia Rating Scale-Sum of Boxes when repeated to evaluate the impact of the COVID-19 pandemic, which was similar to the overall treatment difference of –0.45 between groups. When censoring assessments after the occurrence of ARIA-edema/effusion (ARIA-E), the treatment difference was –0.500, a 30% slowing of disease progression.

As for safety, the incidence of ARIA-E was within expectations. ARIA-E occurred in 12.5% of the lecanemab group and 1.7% in the placebo group. Symptomatic ARIA-E occurred at a rate of 2.8% in the lecanemab group and 0.0% in the placebo group. The rate of ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis (ARIA-H) was 17.3% for lecanemab compared with 9.0% for placebo, while symptomatic ARIA-H occurred at a rate of 1.4% in the lecanemab group and 0.2% in the placebo group.

Overall, there were no significant trends in changes over time for any of the laboratory, ECG, or vital sign parameters. Infusion-related reactions, which occurred in 26.4% of those on lecanemab, were largely mild to moderate and occurred on the first dose (75%). Notably, most subjects (65%) only had 1 infusion-related reaction.

ARIA-E events were largely mild to moderate radiographically (91%) and asymptomatic (78%). In the 2.8% of subjects with symptomatic ARIA-E, commonly reported symptoms were headache, visual disturbance, and confusion. Most individuals with mild radiographic ARIA-E did not worsen and could continue dosing without drug interruption. Overall, the ARIA-E and ARIA-H were less common in APOE e4 noncarriers vs carriers, with higher frequency in APOE e4 homozygous carriers vs APOE e4 heterozygous carriers.

On biomarker analyses, cerebrospinal fluid (CSF) and plasma phosphorylated tau181 (p-tau181) continued to increase in the placebo group while those on lecanemab showed levels that returned to normal at all time points measured. This indicated that lecanemab’s removal of amyloid improves downstream tau phosphorylation at amyloid responsive 181 site. There was no difference in change of CSF neurofilament light (NfL) between the groups; however, with larger sample size, trends began to show significance for those on lecanemab (P = .06) at 18 months. Notably, CSF total tau increased for those on placebo while decreasing for those on active drug.

Recent analyses from Clarity AD study were presented at the International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD), held March 28 to April 1, 2023, in Gothenburg, Sweden.⁴ The results 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.

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.

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.

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.

Designed as a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody, lecanemab was originally greenlit on data from the phase 2 Study 201 (NCT01767311), which demonstrated the drug’s significant effect on reducing amyloid-ß in the brain.⁵ In Study 201, investigators conducted a Bayesian design clinical trial randomizing 856 patients with early AD with a confirmed presence of amyloid pathology to lecanemab (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, 10 mg/kg biweekly) or placebo, identifying 10 mg/kg biweekly as the effective dose 90%.²

At the end of the 18-month treatment period, 10 mg/kg biweekly lecanemab reduced brain amyloid by a mean of 0.306 standardized uptake value ratio (SUVr) units from a baseline mean of 1.37. Additionally, this treated group had a 76% probability of achieving 25% less decline on the primary end point, the change on the ADCOMS, than placebo. Developed by Eisai, ADCOMS combines items from the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog), Clinical Dementia Rating (CDR), and the Mini-Mental State Examination (MMSE) scales to enable a sensitive detection of changes in clinical functions of early AD symptoms and changes in memory.

In conventional analyses, treatment with lecanemab 10 mg/kg biweekly resulted in a dose-dependent reduction in change from baseline in ADCOMS over 18 months, with 30% (P = .034) less decline than placebo. Additionally, a 26% less decline on CDR-sub of boxes was observed in the same dosed group (P = .125), along with a 47% less decline on ADAS-Cog scales as well. Amyloid-related imaging abnormalities-edema/effusion, a concern for patients with AD, was found in 9.9% of patients on 10 mg/kg biweekly dosing in Study 201.

REFERENCES
1. FDA Peripheral and Central Nervous System Drugs Advisory Committee Meeting. June 9, 2023. Accessed June 9, 2023.
2. FDA Accepets Eisai’s filing of a supplemental biologics license application and grants priority review for traditional approval of Leqembi (lecanemab-irmb) for the treatment of Alzheimer’s disease. News release. Eisai. March 5, 2023. Accessed June 9, 2023. https://www.prnewswire.com/news-releases/fda-accepts-eisais-filing-of-a-supplemental-biologics-license-application-and-grants-priority-review-for-traditional-approval-of-leqembi-lecanemab-irmb-for-the-treatment-of-alzheimers-disease-301762846.html
3. 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.
4. 18-month, pre-specified analysis showing consistent reduction in clinical outcome measures from a lecanemab (BAN2401) phase 2b clinical trial in early Alzheimer disease published in peer-reviewed journal, Alzheimer’s Research and Therapy. News release. Eisai. Biogen. April 19, 2021. Accessed June 9, 2023. https://www.prnewswire.com/news-releases/18-month-pre-specified-analysis-showing-consistent-reduction-in-clinical-outcome-measures-from-a-lecanemab-ban2401-phase-2b-clinical-trial-in-early-alzheimers-disease-published-in-peer-reviewed-journal-alzheimers-research-an-301271976.html
5. 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 June 8, 2023. https://www.eisai.com/news/2023/news202325.html