• 15 May 2024
• Admin
• News Article

Eisai Initiates Rolling Biologics License Application to US FDA for LEQEMBI

Eisai Initiates Rolling Biologics License Application to US FDA for LEQEMBI® (lecanemab-irmb) for Subcutaneous Maintenance Dosing for the Treatment of Early Alzheimer’s Disease Under the Fast Track Status

Overview

Eisai Inc. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Biogen Inc. (Nasdaq: BIIB, Corporate headquarters: Cambridge, Massachusetts, CEO: Christopher A. Viehbacher, “Biogen”) announced today that Eisai has initiated the rolling submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for lecanemab-irmb (U.S. brand name: LEQEMBI®) subcutaneous autoinjector for weekly maintenance dosing after it was granted Fast Track designation by the FDA. LEQEMBI is indicated for the treatment of Alzheimer’s disease (AD) in patients with Mild Cognitive Impairment (MCI) or mild dementia stage of disease (collectively referred to as early AD).

 Study 301 Behind BLA

• The BLA is based on data from the Clarity AD (Study 301) open-label extension (OLE) and modeling of observed data. 
• If approved by the FDA, the LEQEMBI autoinjector could be used to administer LEQEMBI at home or at medical facilities. 
• The injection process requires less time than the IV formulation. 
• As part of the subcutaneous autoinjector 360 mg weekly maintenance regimen under review, patients who have completed the biweekly IV initiation phase would receive weekly doses that maintain effective drug concentrations to sustain the clearance of highly toxic protofibrils* which can continue to cause neuronal injury even after the amyloid-beta (Aβ) plaque has been cleared from the brain.

AD: a Neurotoxic Process

• AD is an ongoing neurotoxic process that begins before and continues after plaque deposition. 
• Data suggest that early and continuing treatment may prolong the benefit even after plaque is cleared from the brain. 
• This SC autoinjector is easier for patients and their care partners to use, and may reduce the need for hospital visits and nursing care compared to intravenous (IV) administration. 
• In addition to potentially maintaining the clinical and biomarker benefits, subcutaneous maintenance dosing may be more convenient for patients and their care partners to continue the treatment.

LEQEMBI

• LEQEMBI is now approved in the U.S., Japan and China, and applications have been submitted for review in the European Union, Australia, Brazil, Canada, Hong Kong, Great Britain, India, Israel, Russia, Saudi Arabia, South Korea, Taiwan, Singapore and Switzerland. 
• Eisai submitted to the FDA a Supplemental Biologics License Application (sBLA) for monthly LEQEMBI intravenous (IV) maintenance dosing in March 2024.

Eisai serves as the lead for lecanemab’s development and regulatory submissions globally with both companies co-commercializing and co-promoting the product and Eisai having final decision-making authority.

* Protofibrils are believed to contribute to the brain injury that occurs with AD and are considered to be the most toxic form of Aβ, having a primary role in the cognitive decline associated with this progressive, debilitating condition.1 Protofibrils cause injury to neurons in the brain, which in turn, can negatively impact cognitive function via multiple mechanisms, not only increasing the development of insoluble Aβ plaques but also increasing direct damage to brain cell membranes and the connections that transmit signals between nerve cells or nerve cells and other cells. It is believed the reduction of protofibrils may prevent the progression of AD by reducing damage to neurons in the brain and cognitive dysfunction.2  

INDICATION

• LEQEMBI® [(lecanemab-irmb) 100 mg/mL injection for intravenous use] is indicated for the treatment of Alzheimer’s disease (AD). 
• Treatment with LEQEMBI should be initiated in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.CONTRAINDICATION

Contraindication- LEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or to any of the excipients of LEQEMBI. Reactions have included angioedema and anaphylaxis.

WARNINGS AND PRECAUTIONS

Amyloid-Related Imaging Abnormalities

• LEQEMBI can cause ARIA-E and ARIA-H, which can occur together. ARIA-E can be observed on magnetic resonance imaging (MRI) as brain edema or sulcal effusions and ARIA-H as microhemorrhage and superficial siderosis. 
• ARIA can occur spontaneously in patients with AD. With this class of medications, ARIA-H generally occurs in association with ARIA-E. 
• Reported ARIA symptoms may include headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms usually resolve over time.

Incidence of ARIA

• Symptomatic ARIA occurred in 3% (29/898) and serious ARIA symptoms in 0.7% (6/898) with LEQEMBI. 
• Clinical ARIA symptoms resolved in 79% (23/29) of patients during the period of observation. 
• ARIA, including asymptomatic radiographic events, was observed: LEQEMBI, 21% (191/898); placebo, 9% (84/897). ARIA-E was observed: LEQEMBI, 13% (113/898); placebo, 2% (15/897). 
• ARIA-H was observed: LEQEMBI, 17% (152/898); placebo, 9% (80/897). No increase in isolated ARIA-H was observed for LEQEMBI vs placebo.

ApoEε4 Carrier Status and Risk of ARIA

• Of the patients taking LEQEMBI, 16% (141/898) were ApoE ε4 homozygotes, 53% (479/898) were heterozygotes, and 31% (278/898) were noncarriers. With LEQEMBI, the incidence of ARIA was higher in ApoE ε4 homozygotes (LEQEMBI: 45%; placebo: 22%) than in heterozygotes (LEQEMBI: 19%; placebo: 9%) and noncarriers (LEQEMBI: 13%; placebo: 4%). Symptomatic ARIA-E occurred in 9% of ApoE ε4 homozygotes vs 2% of heterozygotes and 1% of noncarriers. 
• Serious ARIA events occurred in 3% of ApoE ε4 homozygotes and in ~1% of heterozygotes and noncarriers. 
• The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers.

Radio Graphic Findings

• The majority of ARIA-E radiographic events occurred within the first 7 doses, although ARIA can occur at any time, and patients can have >1 episode. 
• Maximum radiographic severity of ARIA-E with LEQEMBI was mild in 4% (37/898), moderate in 7% (66/898), and severe in 1% (9/898) of patients. Resolution of ARIA-E on MRI occurred in 52% of patients by 12 weeks, 81% by 17 weeks, and 100% overall after detection. 
• Maximum radiographic severity of ARIA-H microhemorrhage with LEQEMBI was mild in 9% (79/898), moderate in 2% (19/898), and severe in 3% (28/898) of patients; superficial siderosis was mild in 4% (38/898), moderate in 1% (8/898), and severe in 0.4% (4/898) of patients. With LEQEMBI, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes (5%; 7/141) vs heterozygotes (0.4%; 2/479) or noncarriers (0%; 0/278). With LEQEMBI, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes (13.5%; 19/141) vs heterozygotes (2.1%; 10/479) or noncarriers (1.1%; 3/278).

Intracerebral Hemorrhage

• Intracerebral hemorrhage >1 cm in diameter was reported in 0.7% (6/898) with LEQEMBI vs 0.1% (1/897) with placebo. 
• Fatal events of intracerebral hemorrhage in patients taking LEQEMBI have been reported.