Lecanemab Wins Breakthrough Designation for Alzheimer Disease


The decision to grant breakthrough therapy designation was based off the proof-of-concept phase 2b study which explored the impact of lecanemab, formerly BAN2401, on reducing brain amyloid beta and clinical decline.

Jeffrey L. Cummings, MD, ScD

Jeffrey L. Cummings, MD, ScD

The FDA has granted breakthrough therapy designation for lecanemab (Eisai and Biogen), an investigational anti-amyloid beta (Aß) protofibril antibody formally known as BAN2401, for the treatment of Alzheimer disease (AD).1

The basis for the designation comes from the recently published Study 201 (NCT01767311), a phase 2b proof-of-concept trial that showed a reduction in brain amyloid with treatment of lecanemab in patients with mild cognitive impairment (MCI) due to AD or Alzheimer dementia. Additionally, the reduction was accompanied by a consistent reduction of decline across several clinical and biomarker end points.

Eisai and Biogen have multiple ongoing studies for lecanemab, including the Clarity AD phase 3 clinical trial (NCT03887455). That placebo-controlled, double-blind parallel-group, 18-month study with an open-label extension phase with confirm the safety and efficacy of lecanemab in individuals with early AD. In March, the companies completed enrollment for the study, with 1795 symptomatic patients included.

In July 2020, Eisai and Biogen launched their other study, AHEAD 3-45 (NCT04468659), in conjunction with the Alzheimer’s Clinical Trials Consortium (ACTCT). It aims to enroll 1400 participants with preclinical AD who will be treated with lecanemab for 216 weeks. A common screening period will be conducted, after with patients will be randomized to 1 of 2 trials: A3 and A45.

READ MORE: Data Collection Insights and the EFRONT Study in Frontotemporal Dementia

The aforementioned phase 2b Study 201 was a Bayesian-design clinical trial led by Jeffrey L. Cummings, MD, ScD, director emeritus, Lou Ruvo Center for Brain Health, Cleveland Clinic; and vice chair, Department of Brain Health, University of Nevada-Las Vegas, that randomized patients to lecanemab across a number of doses (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, 10 mg/kg biweekly) or placebo.2

Cummings and colleagues found that 10 mg/kg biweekly had a 76% probability in achieving 25% less decline on the primary end point, change on the Alzheimer’s Disease Composite Score (ADCOMS), than placebo. That dose regimen was identifed as the effective dose 90% (ED90), defined as the simplest dose that achieves greater than or equal to 90% of the maximum treatment effect at the 12-month Bayesian analysis.

Achievement of primary end point required 80% probability, though additional prespecified Bayesian analyses indicated a 97.6% and 97.7% probability of 10-mg/kg lecanemab being superior to placebo by any magnitude at both 12 and 18 months, respectively.

All dose-dependent reductions in amyloid positron emission tomography (PET) standardized uptake value ratio (SUVr) measures were observed using florbetapir as the imaging agent and whole cerebellum as reference region. At 18 months, the least squares (LS) mean changes from baseline to whole cerebellum mask were –0.306 for 10 mg/kg biweekly lecanemab.

Investigators also conducted conventional analyses of Study 201, which showed a dose-dependent reduction in change from baseline in ADCOMS over 18 months in the 10 mg/kg biweekly lecanemab group, with 30% (P = .034) less decline than placebo. A 26% less decline on Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) was observed in the same dosed group (P = .125), along with a 47% less decline on Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14).

1. Eisai and Biogen announces US FDA grants breakthrough therapy designation for lecanemab (BAN2401), an anti-amyloid beta protofibril antibody for the treatment of Alzheimer disease. News release. June 23, 2021. Accessed June 24, 2021. https://www.prnewswire.com/news-releases/eisai-and-biogen-inc-announce-us-fda-grants-breakthrough-therapy-designation-for-lecanemab-ban2401-an-anti-amyloid-beta-protofibril-antibody-for-the-treatment-of-alzheimers-disease-301318796.html
2. 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 24, 2021. 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
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