FDA Accepts LEQEMBI® (lecanemab-irmb) Biologics License Application for Subcutaneous Maintenance Dosing for the Treatment of Early Alzheimer's Disease

TOKYO and CAMBRIDGE, Mass., Jan. 13, 2025 (GLOBE NEWSWIRE) -- Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") and Biogen Inc. (NASDAQ:BIIB, Corporate headquarters: Cambridge, Massachusetts, CEO: Christopher A. Viehbacher, "Biogen")) announced today that the U.S. Food and Drug Administration (FDA) has accepted Eisai's Biologics License Application (BLA) for lecanemab-irmb (U.S. brand name: LEQEMBI^®) subcutaneous autoinjector (SC-AI) for weekly maintenance dosing. 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). A Prescription Drug User Fee Act (PDUFA) action date is set for August 31, 2025.

The BLA is based on data from the Clarity AD (Study 301) open-label extension (OLE) and modeling of observed data. If LEQEMBI subcutaneous maintenance dosing is approved by the FDA, LEQEMBI will be the only treatment for AD that can be administered subcutaneously at home using an autoinjector (AI). The injection process is expected to take, on average, 15 seconds. As part of the SC-AI 360 mg weekly maintenance regimen, patients who have completed the biweekly intravenous (IV) initiation phase, exact period under discussion with the FDA, would receive weekly doses that are expected to maintain the clinical and biomarker benefits.

AD is a progressive, relentless disease caused by a continuous underlying neurotoxic process that begins before and continues after plaque deposition.^1,2,3 Only LEQEMBI works to fight AD in two ways by continuously clearing protofibrils and rapidly clearing plaque. With continuous administration, LEQEMBI clears highly toxic protofibrils* which can continue to cause neuronal injury even after amyloid-beta (Aβ) plaque has been cleared from the brain. Long-term three-year LEQEMBI data presented at the Alzheimer's Association International Conference (AAIC) 2024 suggest that early and continuing treatment may prolong the benefit of therapy even after plaque is cleared from the brain.⁴

The SC-AI is expected to be simple and easy for patients and their care partners to use, and may reduce the need for hospital or infusion site visits and nursing care for IV administration, which will make it easier to continue maintenance administration and may contribute to further simplifying the treatment pathway for AD.

LEQEMBI is approved in the U.S., Japan, China, South Korea, Hong Kong, Israel, UAE, Great Britain, Mexico, and Macau. In November 2024, the treatment received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending approval. Eisai has submitted applications for approval of lecanemab in 17 countries and regions. The US FDA accepted Eisai's Supplemental Biologics License Application (sBLA) for monthly LEQEMBI IV maintenance dosing in June 2024 and set a PDUFA action date for January 25, 2025.

Eisai serves as the lead for lecanemab's development and regulatory submissions globally with Eisai and Biogen 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.⁵ 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.⁶ 

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.

IMPORTANT SAFETY INFORMATION

WARNING: AMYLOID-RELATED IMAGING ABNORMALITIES (ARIA) Monoclonal antibodies directed against aggregated forms of beta amyloid, including LEQEMBI, can cause ARIA, characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H). Incidence and timing of ARIA vary among treatments. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, rarely can occur. Serious intracerebral hemorrhages (ICH) >1 cm, some of which have been fatal, have been observed with this class of medications. Because ARIA-E can cause focal neurologic deficits that can mimic an ischemic stroke, consider whether such symptoms could be due to ARIA-E before giving thrombolytic therapy to a patient being treated with LEQEMBI. Apolipoprotein E ε4 (ApoE ε4) Homozygotes: Patients who are ApoE ε4 homozygotes (~15% of patients with AD) treated with this class of medications have a higher incidence of ARIA, including symptomatic, serious, and severe radiographic ARIA, compared to heterozygotes and noncarriers. Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed, they can still be treated with LEQEMBI; however, it cannot be determined if they are ApoE ε4 homozygotes and at higher risk for ARIA. Consider the benefit of LEQEMBI for the treatment of AD and the potential risk of serious ARIA events when deciding to initiate treatment with LEQEMBI.

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

Medications in this class, including LEQEMBI, can cause ARIA-E, which can be observed on MRI as brain edema or sulcal effusions, and ARIA-H, which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with AD, particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy (CAA), such as pretreatment microhemorrhage or superficial siderosis. ARIA-H generally occurs 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% and serious ARIA symptoms in 0.7% with LEQEMBI. Clinical ARIA symptoms resolved in 79% of patients during the period of observation. ARIA, including asymptomatic radiographic events, was observed: LEQEMBI, 21%; placebo, 9%. ARIA-E was observed: LEQEMBI, 13%; placebo, 2%. ARIA-H was observed: LEQEMBI, 17%; placebo, 9%. No increase in isolated ARIA-H was observed for LEQEMBI vs placebo.

Incidence of ICH

ICH >1 cm in diameter was reported in 0.7% with LEQEMBI vs 0.1% with placebo. Fatal events of ICH in patients taking LEQEMBI have been observed.

Risk Factors of ARIA and ICH

ApoE ε4 Carrier Status

Of the patients taking LEQEMBI, 16% were ApoE ε4 homozygotes, 53% were heterozygotes, and 31% were noncarriers. With LEQEMBI, 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.

Radiographic Findings of CAA

Neuroimaging findings that may indicate CAA include evidence of prior ICH, cerebral microhemorrhage, and cortical superficial siderosis. CAA has an increased risk for ICH. The presence of an ApoE ε4 allele is also associated with CAA.

The baseline presence of at least 2 microhemorrhages or the presence of at least 1 area of superficial siderosis on MRI, which may be suggestive of CAA, have been identified as risk factors for ARIA. Patients were excluded from Clarity AD for the presence of >4 microhemorrhages and additional findings suggestive of CAA (prior cerebral hemorrhage >1 cm in greatest diameter, superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that could potentially increase the risk of ICH.

Concomitant Antithrombotic or Thrombolytic Medication

In Clarity AD, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed if the patient was on a stable dose. Most exposures were to aspirin. Antithrombotic medications did not increase the risk of ARIA with LEQEMBI. The incidence of ICH: 0.9% in patients taking LEQEMBI with a concomitant antithrombotic medication vs 0.6% with no antithrombotic and 2.5% in patients taking LEQEMBI with an anticoagulant alone or with antiplatelet medication such as aspirin vs none in patients receiving placebo.

Fatal cerebral hemorrhage has occurred in 1 patient taking an anti-amyloid monoclonal antibody in the setting of focal neurologic symptoms of ARIA and the use of a thrombolytic agent.

Additional caution should be exercised when considering the administration of antithrombotics or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with LEQEMBI. Because ARIA-E can cause focal neurologic deficits that can mimic an ischemic stroke, treating clinicians should consider whether such symptoms could be due to ARIA-E before giving thrombolytic therapy in a patient being treated with LEQEMBI.

Caution should be exercised when considering the use of LEQEMBI in patients with factors that indicate an increased risk for ICH and, in particular, patients who need to be on anticoagulant therapy or patients with findings on MRI that are suggestive of CAA.

Radiographic Severity With LEQEMBI

Most 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%, moderate in 7%, and severe in 1% of patients. Resolution on MRI occurred in 52% of ARIA-E 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%, moderate in 2%, and severe in 3% of patients; superficial siderosis was mild in 4%, moderate in 1%, and severe in 0.4% of patients. With LEQEMBI, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes (5%) vs heterozygotes (0.4%) or noncarriers (0%). With LEQEMBI, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes (13.5%) vs heterozygotes (2.1%) or noncarriers (1.1%).

Monitoring and Dose Management Guidelines

Baseline brain MRI and periodic monitoring with MRI are recommended. Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment. Depending on ARIA-E and ARIA-H clinical symptoms and radiographic severity, use clinical judgment when considering whether to continue dosing or to temporarily or permanently discontinue LEQEMBI. If a patient experiences ARIA symptoms, clinical evaluation should be performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation should be performed prior to continuing treatment.

HYPERSENSITIVITY REACTIONS

Hypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred with LEQEMBI. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction and initiate appropriate therapy.

INFUSION-RELATED REACTIONS (IRRs)

IRRs were observed—LEQEMBI: 26%; placebo: 7%—and most cases with LEQEMBI (75%) occurred with the first infusion. IRRs were mostly mild (69%) or moderate (28%). Symptoms included fever and flu-like symptoms (chills, generalized aches, feeling shaky, and joint pain), nausea, vomiting, hypotension, hypertension, and oxygen desaturation.

In the event of an IRR, the infusion rate may be reduced or discontinued, and appropriate therapy initiated as clinically indicated. Consider prophylactic treatment prior to future infusions with antihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids.

ADVERSE REACTIONS

The most common adverse reactions reported in ≥5% with LEQEMBI and ≥2% higher than placebo were IRRs (LEQEMBI: 26%; placebo: 7%), ARIA-H (LEQEMBI: 14%; placebo: 8%), ARIA-E (LEQEMBI: 13%; placebo: 2%), headache (LEQEMBI: 11%; placebo: 8%), superficial siderosis of central nervous system (LEQEMBI: 6%; placebo: 3%), rash (LEQEMBI: 6%; placebo: 4%), and nausea/vomiting (LEQEMBI: 6%; placebo: 4%).

Please see full Prescribing Information for LEQEMBI, including Boxed WARNING.

MEDIA CONTACTS
Eisai Co., Ltd. Public Relations Department +81 (0)3-3817-5120 Eisai Inc. (U.S.) Julie Edelman +1-862-213-5915 [email protected] Eisai Europe, Ltd. EMEA Communications Department +44 (0) 797-487-9419 [email protected]	Biogen Inc. Jack Cox + 1-781-464-3260 [email protected]
INVESTOR CONTACTS
Eisai Co., Ltd. Investor Relations Department +81 (0)70-8688-9685	Biogen Inc. Tim Power +1-781-464-2442 [email protected]

Notes to Editors

1.   About lecanemab (LEQEMBI^®)

Lecanemab is the result of a strategic research alliance between Eisai and BioArctic. It is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibril) and insoluble forms of amyloid-beta (Aβ). Lecanemab is approved in the U.S.,⁷ Japan,⁸ China,⁹ South Korea,¹⁰ Hong Kong,¹¹ Israel,¹² the United Arab Emirates,¹³ Great Britain,¹⁴ Mexico,¹⁵ and Macau. In November 2024, the treatment received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommending approval. Eisai has submitted applications for approval of lecanemab in 17 countries and regions.

LEQEMBI's approvals in these countries was based on Phase 3 data from Eisai's, global Clarity AD clinical trial, in which it met its primary endpoint and all key secondary endpoints with statistically significant results. The primary endpoint was the global cognitive and functional scale, Clinical Dementia Rating Sum of Boxes (CDR-SB). In the Clarity AD clinical trial, treatment with lecanemab reduced clinical decline on CDR-SB by 27% at 18 months compared to placebo.^16,17 The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001). In addition, the secondary endpoint from the AD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), which measures information provided by people caring for patients with AD, noted a statistically significant benefit of 37% compared to placebo. The adjusted mean change from baseline at 18 months in the ADCS-MCI-ADL score was −3.5 in the lecanemab group and −5.5 in the placebo group (difference, 2.0; 95% CI, 1.2 to 2.8; P<0.001). The ADCS MCI-ADL assesses the ability of patients to function independently, including being able to dress, feed themselves and participate in community activities. The most common adverse events (>10%) in the lecanemab group were infusion reactions, ARIA-H (combined cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis), ARIA-E (edema/effusion), headache, and fall.

Since July 2020 the Phase 3 clinical study (AHEAD 3-45) for individuals with preclinical AD, meaning they are clinically normal and have intermediate or elevated levels of amyloid in their brains, is ongoing. AHEAD 3-45 is conducted as a public-private partnership between the Alzheimer's Clinical Trial Consortium that provides the infrastructure for academic clinical trials in AD and related dementias in the U.S, funded by the National Institute on Aging, part of the National Institutes of Health, Eisai and Biogen. Since January 2022, the Tau NexGen clinical study for Dominantly Inherited AD (DIAD), that is conducted by Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), led by Washington University School of Medicine in St. Louis, is ongoing and includes lecanemab as the backbone anti-amyloid therapy.

2.   About the Collaboration between Eisai and Biogen for AD

Eisai and Biogen have been collaborating on the joint development and commercialization of AD treatments since 2014. Eisai serves as the lead of lecanemab development and regulatory submissions globally with both companies co-commercializing and co-promoting the product and Eisai having final decision-making authority.

3.   About the Collaboration between Eisai and BioArctic for AD

Since 2005, Eisai and BioArctic have had a long-term collaboration regarding the development and commercialization of AD treatments. Eisai obtained the global rights to study, develop, manufacture and market lecanemab for the treatment of AD pursuant to an agreement with BioArctic in December 2007. The development and commercialization agreement on the antibody lecanemab back-up was signed in May 2015.

4.   About Eisai Co., Ltd.

Eisai's Corporate Concept is "to give first thought to patients and people in the daily living domain, and to increase the benefits that health care provides." Under this Concept (also known as human health care (hhc) Concept), we aim to effectively achieve social good in the form of relieving anxiety over health and reducing health disparities. With a global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to create and deliver innovative products to target diseases with high unmet medical needs, with a particular focus in our strategic areas of Neurology and Oncology.

In addition, we demonstrate our commitment to the elimination of neglected tropical diseases (NTDs), which is a target (3.3) of the United Nations Sustainable Development Goals (SDGs), by working on various activities together with global partners.

For more information about Eisai, please visit www.eisai.com (for global headquarters: Eisai Co., Ltd.), and connect with us on X, LinkedIn and Facebook.For audiences based in the UK and Europe, please visit www.eisai.eu and Eisai EMEA LinkedIn.

5.   About Biogen

Founded in 1978, Biogen is a leading biotechnology company that pioneers innovative science to deliver new medicines to transform patients' lives and to create value for shareholders and our communities. We apply deep understanding of human biology and leverage different modalities to advance first-in-class treatments or therapies that deliver superior outcomes. Our approach is to take bold risks, balanced with return on investment to deliver long-term growth.

The company routinely posts information that may be important to investors on its website at www.biogen.com. Follow Biogen on social media – Facebook, LinkedIn, X, YouTube.

Biogen Safe Harbor

This news release contains forward-looking statements, including about the potential clinical effects of lecanemab; the potential benefits, safety and efficacy of lecanemab; potential regulatory discussions, submissions and approvals and the timing thereof; the treatment of Alzheimer's disease; the anticipated benefits and potential of Biogen's collaboration arrangements with Eisai; the potential of Biogen's commercial business and pipeline programs, including lecanemab; and risks and uncertainties associated with drug development and commercialization. These statements may be identified by words such as "aim," "anticipate," "believe," "could," "estimate," "expect," "forecast," "intend," "may," "plan," "possible," "potential," "will," "would" and other words and terms of similar meaning. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage clinical studies may not be indicative of full results or results from later stage or larger scale clinical studies and do not ensure regulatory approval. You should not place undue reliance on these statements.

These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including without limitation unexpected concerns that may arise from additional data, analysis or results obtained during clinical studies; the occurrence of adverse safety events; risks of unexpected costs or delays; the risk of other unexpected hurdles; regulatory submissions may take longer or be more difficult to complete than expected; regulatory authorities may require additional information or further studies, or may fail or refuse to approve or may delay approval of Biogen's drug candidates, including lecanemab; actual timing and content of submissions to and decisions made by the regulatory authorities regarding lecanemab; uncertainty of success in the development and potential commercialization of lecanemab; failure to protect and enforce Biogen's data, intellectual property and other proprietary rights and uncertainties relating to intellectual property claims and challenges; product liability claims; and third party collaboration risks, results of operations and financial condition. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from Biogen's expectations in any forward-looking statement. Investors should consider this cautionary statement as well as the risk factors identified in Biogen's most recent annual or quarterly report and in other reports Biogen has filed with the U.S. Securities and Exchange Commission. These statements speak only as of the date of this news release. Biogen does not undertake any obligation to publicly update any forward-looking statements.

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