Leqembi (lecanemab): BLA 761269

Substantial evidence of effectiveness is required on such an endpoint to support accelerated approval, just as it is required for an endpoint supporting standard approval.

In this BLA, the applicant is seeking accelerated approval based on reduction in amyloid plaque burden measured by PET imaging which is proposed to be reasonably likely to predict clinical benefit.

The clinical reviewer, Dr. Krudys, has concluded that the applicant has provided substantial evidence of effectiveness to support accelerated approval.

Dr. Massie further expresses uncertainty whether the treatment effect on amyloid is reasonably likely to predict change on the clinical outcome because, e.g., there is no apparent clinical endpoint treatment effect in ApoE ε4 non-carriers despite having amyloid reductions comparable to ApoE ε4 carriers.

The current data from lecanemab in Study 201 also support the use of the reduction of brain Aβ plaque on PET as a surrogate endpoint reasonably likely to predict clinical benefit.

Eisai Inc. (Applicant) submitted a Biologic Licensing Application (BLA) 761269 for lecanemab with the proposed indication for the treatment of Alzheimer's Disease (AD).5 This application is under review in the Division of Neurology 1 under the accelerated approval pathway.

Given the favorable results on clinical endpoints observed in Study 201 and the clinical benefit publicly reported in Study 301, Dr. Krudys questions the clinical relevance of the changes to whole brain volume and total ventricular volume.

Although not yet submitted to the Agency for review, it is also notable that the topline results of Study 301 that have been publicly reported appear to support the clinical benefit of Aβ plaque reduction; however, that study showed more robust results in ApoE ε4 non-carriers than in carriers.

The brain amyloid PET SUVr analysis showed a slight increase in amyloid load in the placebo group, reflective of the expected absolute percentage annual SUVr change of approximately 1% to 2% across all reference regions in a population with MCI due to AD and mild AD dementia (Landau et al, 2015).

In the double-blind, placebo-controlled period in Study 1, patients stopped study treatment because of an adverse reaction in 15% of patients treated with LEQEMBI, compared to 6% patients on placebo; in Study 2, patients stopped study treatment because of an adverse reaction in 7% of patients treated with LEQEMBI, compared to 3% patients on placebo.

In Study 1, 856 patients were randomized to receive one of 5 doses (161 of which were randomized to the recommended dosing regimen of 10 mg/kg every two weeks) of LEQEMBI or placebo (n=247).

Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.

The applicant did not submit a proposed REMS or risk management plan with this application.

DRM and the Division of Neurology 1 (DN1) have determined that a REMS is not needed to ensure the benefits of lecanemab outweigh its risks.

Since Leqembi was approved on January 6, 2023, we have become aware of clinical trial data showing an increased risk of symptomatic, serious, and severe radiographic amyloid related imaging abnormalities (ARIA) in ApoE ε4 homozygotes who are treated with Leqembi compared to heterozygotes and noncarriers.

Conduct adequate analytical validation testing to establish and support labeling of an FDA cleared or approved in vitro diagnostic device to accurately and reliably detect ApoE e4 alleles that is safe and effective for identifying patients at increased risk of ARIA if treated with Leqembi.

Patients treated with this class of medications, including LEQEMBI, who are ApoE ε4 homozygotes have a higher incidence of ARIA, including symptomatic and serious ARIA, compared to heterozygotes and noncarriers.

Patients who are apolipoprotein E ε4 (ApoE ε4) homozygotes (approximately 15% of Alzheimer's disease patients) treated with this class of medications, including LEQEMBI, have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers.

If required postmarketing clinical trials fail to verify clinical benefit or are not conducted with due diligence, we may withdraw this approval.

At the time of this review, final labeling, and post-marketing requirements (PMRs) were still under negotiation.

We have received your submission dated January 6, 2023, containing the final report for the following postmarketing requirement listed in the January 6, 2023, accelerated approval letter for BLA 761269.

Postmarketing requirements (4384-2 and 4384-3) were imposed with the January 6, 2023, accelerated approval, to improve the assay sensitivity and to use the improved and validated assay to assess the impact of antibody formation on pharmacokinetics, pharmacodynamics, safety, and efficacy of lecanemab in subjects enrolled in the confirmatory study.

The impact of immunogenicity on pharmacokinetics, pharmacodynamics, efficacy, and safety will be evaluated when data to support the postmarketing requirements (PMRs) are submitted.