Eisai Completes Submission of LEQEMBI® (lecanemab-irmb) Supplemental Biologics
License Application for IV Maintenance Dosing for the Treatment of
Early Alzheimer’s Disease to the U.S. FDA
TOKYO and CAMBRIDGE, Mass., April 1, 2024 – 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 Eisai submitted to the U.S. Food andDrug Administration (FDA) a Supplemental Biologics License Application (sBLA) for monthly
lecanemab-irmb (U.S. brand name: LEQEMBI®) intravenous (IV) maintenance dosing. LEQEMBI isindicated for the treatment of Alzheimer’s disease (AD) in patients with mild cognitive impairment or
mild dementia stage of disease (collectively referred to as early AD).
As part of the monthly IV maintenance regimen, the patients who have completed the biweekly IV
initiation phase, exact period under discussion with the FDA, would receive a monthly IV dose thatmaintains effective drug concentration to sustain the clearance of highly toxic protofibrils* which cancontinue to cause neuronal injury even after the amyloid-beta (Aβ) plaque has been cleared from thebrain. The sBLA is based on modeling of observed data from the Phase 2 study (Study 201) and its
open-label extension (OLE) as well as Clarity AD study (Study 301) and its OLE study.
Eisai had aimed to submit a Biologics License Application (BLA) for weekly maintenance therapy using
subcutaneous (SC) administration in March 2024. To respond to the FDA’s recent requirement ofadditional three-month immunogenicity data at the proposed maintenance dose of 360 mg weekly, Eisai
planned to initiate a rolling BLA for lecanemab SC maintenance in March 2024, under the existing Fast
Track and Breakthrough Therapy designations. However, Eisai was recently informed by the FDA thata Fast Track designation specific for the SC formulation is needed to receive rolling review. Following
the guidance, Eisai submitted a request for Fast Track designation for the SC formulation and will initiate
a rolling submission should the FDA grant this designation. The Fast Track designation will be
determined within 60 days from the March 2024 submission.
AD is an ongoing neurotoxic process that begins before and continues after plaque deposition. Thereis an urgency to treat early AD because early and ongoing treatment can slow the progression of AD
and continuing treatment may prolong the benefit even after plaque is cleared from the brain. The earlier
Mild Cognitive Impairment (MCI) due to AD and mild AD dementia are diagnosed and treated, thegreater the opportunity for the patient to benefit. Continued maintenance dosing is intended to maintainthe clinical and biomarker benefits with a dosing regimen that may be more convenient for somepatients and their care partners.
LEQEMBI is now approved in the U.S., Japan and China, and applications have been submitted forreview in the European Union, Australia, Brazil, Canada, Hong Kong, Great Britain, India, Israel, Russia,
Saudi Arabia, South Korea, Taiwan, Singapore, and Switzerland. Eisai serves as the lead forlecanemab’s development and regulatory submissions globally with both companies cocommercializing 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 Aβplaques 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.
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U.S. INDICATION AND IMPORTANT SAFETY INFORMATIONLEQEMBI (lecanemab-irmb) 100 mg/ml injection for intravenous (IV) use is indicated for the treatmentof Alzheimer’s disease. Treatment with LEQEMBI should be initiated in patients with mild cognitive
impairment or mild dementia stage of disease, the population in which treatment was initiated inclinical trials.
WARNING: AMYLOID RELATED IMAGING ABNORMALITIES (ARIA)• Monoclonal antibodies directed against aggregated forms of amyloid beta, including
LEQEMBI, can cause amyloid related imaging abnormalities (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 intreatment and is usually asymptomatic, although serious and life-threatening events
rarely can occur. Serious intracerebral hemorrhages >1 cm, some of which havebeen fatal, have been observed in patients treated with this class of medications.
• Apolipoprotein E ε4 (ApoE ε4) Homozygotes: Patients who are ApoE ε4homozygotes (approximately 15% of Alzheimer’s disease patients) treated with thisclass of medications, including LEQEMBI, have a higher incidence of ARIA,
including symptomatic, serious, and severe radiographic ARIA, compared toheterozygotes 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 theimplications 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 Alzheimer’s disease andpotential risk of serious adverse events associated with ARIA when deciding toinitiate treatment with LEQEMBICONTRAINDICATIONLEQEMBI is contraindicated in patients with serious hypersensitivity to lecanemab-irmb or toany of the excipients of LEQEMBI. Reactions have included angioedema and anaphylaxis.

WARNINGS AND PRECAUTIONSAMYLOID RELATED IMAGING ABNORMALITIES• LEQEMBI can cause ARIA-E and ARIA-H. ARIA-E can be observed on MRI as brain edema or sulcal
effusions, and ARIA-H as microhemorrhage and superficial siderosis. ARIA can occur spontaneously
in patients with Alzheimer’s disease. ARIA-H associated with monoclonal antibodies directed against
aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E.
ARIA-H and ARIA-E can occur together. ARIA usually occurs early in treatment and is usuallyasymptomatic, although serious and life-threatening events, including seizure and status epilepticus,
rarely can occur. Reported symptoms associated with ARIA may include headache, confusion, visualchanges, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms
associated with ARIA usually resolve over time.

ARIA Monitoring and Dose Management Guidelines• Obtain recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with
LEQEMBI. Obtain an MRI prior to the 5th, 7th and 14th infusions.
• Recommendations for dosing in patients with ARIA-E and ARIA-H depend on clinical symptoms andradiographic severity. Depending on ARIA severity, use clinical judgment in considering whether tocontinue dosing, temporarily discontinue treatment, or permanently discontinue LEQEMBI.

2• Enhanced clinical vigilance for ARIA is recommended during the first 14 weeks of treatment with
LEQEMBI. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be
performed, including MRI if indicated. If ARIA is observed on MRI, careful clinical evaluation shouldbe performed prior to continuing treatment.
• There is no experience in patients who continued dosing through symptomatic ARIA-E or throughasymptomatic, but radiographically severe, ARIA-E. There is limited experience in patients who
continued dosing through asymptomatic but radiographically mild to moderate ARIA-E. There arelimited data in dosing patients who experienced recurrent ARIA-E.
Incidence of ARIA
• In Study 2, symptomatic ARIA occurred in 3% (29/898) of LEQEMBI-treated patients. Serious
symptoms associated with ARIA were reported in 0.7% (6/898) of patients treated with LEQEMBI.
Clinical symptoms associated with ARIA resolved in 79% (23/29) of patients during the period of
observation.
• Including asymptomatic radiographic events, ARIA was observed in LEQEMBI: 21% (191/898);
placebo: 9% (84/897). ARIA-E was observed in LEQEMBI: 13% (113/898); placebo: 2% (15/897).
ARIA-H was observed in LEQEMBI: 17% (152/898); placebo: 9% (80/897). There was no increase
in isolated ARIA-H for LEQEMBI vs placebo.
ApoE ε4 Carrier Status and Risk of ARIA
• In Study 2, 16% (141/898) of patients in the LEQEMBI arm were ApoE ε4 homozygotes, 53%(479/898) were heterozygotes, and 31% (278/898) were noncarriers.
• The incidence of ARIA was higher in ApoE ε4 homozygotes (LEQEMBI: 45%; placebo: 22%) thanin heterozygotes (LEQEMBI: 19%; placebo: 9%) and noncarriers (LEQEMBI: 13%; placebo: 4%).
Among patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of ApoE ε4homozygotes compared with 2% of heterozygotes and 1% noncarriers. Serious events of ARIA
occurred in 3% of ApoE ε4 homozygotes, and approximately 1% of heterozygotes and noncarriers.
• The recommendations on management of ARIA do not differ between ApoE ε4 carriers andnoncarriers.
Radiographic Findings• The majority of ARIA-E radiographic events occurred early in treatment (within the first 7 doses),although ARIA can occur at any time and patients can have more than 1 episode. The maximum
radiographic severity of ARIA-E in patients treated with LEQEMBI was mild in 4% (37/898), moderate
in 7% (66/898), and severe in 1% (9/898). Resolution on MRI occurred in 52% of ARIA-E patientsby 12 weeks, 81% by 17 weeks, and 100% overall after detection. The maximum radiographic
severity of ARIA-H microhemorrhage in LEQEMBI-treated patients 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). Among LEQEMBI-treatedpatients, the rate of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 5% (7/141),
compared to heterozygotes 0.4% (2/479) or noncarriers 0% (0/278). Among LEQEMBI-treatedpatients, the rate of severe radiographic ARIA-H was highest in ApoE ε4 homozygotes 13.5%(19/141), compared to 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) of patients in Study 2 after
treatment with LEQEMBI compared to 0.1% (1/897) on placebo. Fatal events of intracerebral
hemorrhage in patients taking LEQEMBI have been reported.
Concomitant Antithrombotic Medication:• In Study 2, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants)
was allowed if the patient was on a stable dose. The majority of exposures to antithrombotic
medications were to aspirin. Antithrombotic medications did not increase the risk of ARIA with
LEQEMBI. The incidence of intracerebral hemorrhage was 0.9% (3/328 patients) in patients taking
LEQEMBI with a concomitant antithrombotic medication at the time of the event compared to 0.6%
(3/545 patients) in those who did not receive an antithrombotic. Patients taking LEQEMBI with an3•anticoagulant alone or combined with an antiplatelet medication or aspirin had an incidence of
intracerebral hemorrhage of 2.5% (2/79 patients) compared to none in patients who received
placebo.
Because intracerebral hemorrhages >1 cm in diameter have been observed in patients taking
LEQEMBI, additional caution should be exercised when considering the administration of
anticoagulants or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being
treated with LEQEMBI.

Other Risk Factors for Intracerebral Hemorrhage:• Patients were excluded from enrollment in Study 2 for findings on neuroimaging that indicated anincreased risk for intracerebral hemorrhage. These included findings suggestive of cerebral amyloid
angiopathy (prior cerebral hemorrhage >1 cm in greatest diameter, >4 microhemorrhages,
superficial siderosis, vasogenic edema) or other lesions (aneurysm, vascular malformation) that
could potentially increase the risk of intracerebral hemorrhage. The presence of an ApoE ε4 allele
is also associated with cerebral amyloid angiopathy, which has an increased risk for intracerebral
hemorrhage. Caution should be exercised when considering the use of LEQEMBI in patients withfactors that indicate an increased risk for intracerebral hemorrhage and in particular for patients
who need to be on anticoagulant therapy.
HYPERSENSITIVITY REACTIONSHypersensitivity reactions, including angioedema, bronchospasm, and anaphylaxis, have occurred in
LEQEMBI-treated patients. 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• In Study 2, infusion-related reactions were observed in LEQEMBI: 26% (237/898); placebo: 7%(66/897), and the majority of cases in LEQEMBI-treated patients (75%, 178/237) occurred with thefirst infusion. Infusion-related reactions were mostly mild (69%) or moderate (28%) in severity.
Infusion-related reactions resulted in discontinuations in 1% (12/898) of LEQEMBI-treated patients.
Symptoms of infusion-related reactions 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 infusion-related reaction, the infusion rate may be reduced, or the infusion may bediscontinued, and appropriate therapy initiated as clinically indicated. Prophylactic treatment withantihistamines, acetaminophen, nonsteroidal anti-inflammatory drugs, or corticosteroids prior to
future infusions may be considered.
ADVERSE REACTIONS• In Study 2, the most common adverse reactions leading to discontinuation of LEQEMBI was ARIAH microhemorrhages that led to discontinuation in 2% (15/898) of patients treated with LEQEMBI
compared to <1% (1/897) of patients on placebo.
• In Study 2, the most common adverse reactions reported in ≥5% of patients treated with LEQEMBI(N=898) and ≥2% higher than placebo (N=897) were infusion-related reactions (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
TEL: +81 (0)3-3817-5120

Biogen Inc.
Jack Cox+ 1-781-464-3260
public.affairs@biogen.com

4Eisai Inc. (U.S.)
Libby Holman+ 1-201-753-1945
Libby_Holman@eisai.com
Eisai Europe, Ltd.
EMEA Communications Department+44 (0) 786 601 1272
Emea-comms@eisai.net
INVESTOR CONTACTS
Eisai Co., Ltd.
Investor Relations Department
TEL: +81 (0) 3-3817-5122

Biogen Inc.
Chuck Triano+ 1-781-464-2442
IR@biogen.com

Notes to Editors
1. About lecanemab (Leqembi®)
Lecanemab is the result of a strategic research alliance between Eisai and BioArctic. It is ahumanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregatedsoluble (protofibril) and insoluble forms of amyloid-beta (Aβ).3 Lecanemab is approved in the U.S.,4
Japan,5 and China.6 In the U.S., Japan and China, the indications are as follows:• U.S.: For the treatment of Alzheimer’s disease (AD). It should be initiated in patients withmild cognitive impairment (MCI) or mild dementia stage of disease. 4• Japan: For slowing progression of MCI and mild dementia due to AD.5
• China: For the treatment of MCI due to AD and mild AD dementia.6
LEQEMBI’s FDA approval 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.7 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.7 The mean CDR-SB scoreat baseline was approximately 3.2 in both groups. The adjusted least-squares mean change frombaseline 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).7 In addition, the secondary endpoint from theAD Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCIADL), which measures information provided by people caring for patients with AD, noted astatistically significant benefit of 37% compared to placebo. 7 The adjusted mean change frombaseline 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).7 The ADCS MCI-ADL assesses
the ability of patients to function independently, including being able to dress, feed themselves andparticipate 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.7
Eisai has also submitted applications for approval of lecanemab in 14 countries and regions,
including the European Union (EU).
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 andEisai having final decision-making authority.

53. About the Collaboration between Eisai and BioArctic for AD
Since 2005, Eisai and BioArctic have had a long-term collaboration regarding the development andcommercialization 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 humanhealth 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), byworking 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. The website and social media channels
are intended for audiences outside of the UK and Europe. For audiences based in the UK andEurope, 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 todeliver new medicines to transform patient’s lives and to create value for shareholders and ourcommunities. We apply deep understanding of human biology and leverage different modalities toadvance first-in-class treatments or therapies that deliver superior outcomes. Our approach is totake 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, about the potential clinical effects oflecanemab; the potential benefits, safety and efficacy of LEQEMBI; potential regulatory discussions,submissions and approvals and the timing thereof; the treatment of Alzheimer's disease; theanticipated benefits and potential of Biogen's collaboration arrangements with Eisai; the potentialof Biogen's commercial business and pipeline programs, including LEQEMBI; and risks anduncertainties 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 inearly-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 relianceon these statements.
These statements involve risks and uncertainties that could cause actual results to differ materiallyfrom 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 ofadverse 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 ofsubmissions to and decisions made by the regulatory authorities regarding lecanemab; uncertainty
of success in the development and potential commercialization of lecanemab; failure to protect andenforce Biogen's data, intellectual property and other proprietary rights and uncertainties relating to6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 thefactors 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.
References
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ends and neurotoxic oligomers. Nat Commun. 2021;12:3451. doi:10.1038/s41467-021-23507z
2. Ono K, Tsuji M. Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying
Approach for Alzheimer's Disease. Int J Mol Sci. 2020;21(3):952. doi: 10.3390/ijms21030952.
PMID: 32023927; PMCID: PMC7037706.
3. LEQEMBI. Prescribing information. Eisai Inc. 2023.
4. US Food and Drug Administration. FDA Grants Accelerated Approval for Alzheimer’s Disease
Treatment. Available at: https://www.fda.gov/news-events/press-announcements/fda-grantsaccelerated-approval-alzheimers-disease-treatment. Last accessed: March 2024.
5. Eisai Global. 2023. “LEQEMBI® Intravenous Infusion” (Lecanemab) Approved for the Treatment
of
Alzheimer’s
DiseaseinJapan
Availableat:https://www.eisai.com/news/2023/news202359.html. Last accessed: March 2024.
6. Eisai Global. 2024. “LEQEMBI®” (Lecanemab) Approved for the Treatment of Alzheimer’s
Disease in China. Available at: https://www.eisai.com/news/2024/news202403.html. Last
accessed: March 2024.
7. van Dyck, H., et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine.
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