TOKYO and CAMBRIDGE,
Mass., March 31, 2024 /PRNewswire/ -- 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 and Drug Administration
(FDA) a Supplemental Biologics License Application (sBLA) for
monthly lecanemab-irmb (U.S. brand name: LEQEMBI®)
intravenous (IV) maintenance dosing. LEQEMBI is indicated 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 that
maintains effective drug concentration 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. 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 of additional 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 that a 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. There is 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, the greater the opportunity for the patient
to benefit. Continued maintenance dosing is intended to maintain
the clinical and biomarker benefits with a dosing regimen that may
be more convenient for some patients and their care
partners.
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 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
U.S. INDICATION AND IMPORTANT SAFETY
INFORMATION
LEQEMBI (lecanemab-irmb) 100 mg/ml injection for
intravenous (IV) use is indicated for the treatment of 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 in clinical
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 in treatment and is usually asymptomatic,
although serious and life-threatening events rarely can occur.
Serious intracerebral hemorrhages >1 cm, some of which have been
fatal, have been observed in patients treated with this class of
medications.
- Apolipoprotein E ε4 (ApoE ε4)
Homozygotes: Patients who are 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.
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 Alzheimer's disease and potential risk of serious
adverse events associated with ARIA 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
- 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 usually asymptomatic,
although serious and life-threatening events, including seizure and
status epilepticus, rarely can occur. Reported symptoms associated
with ARIA may include headache, confusion, visual changes,
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 and radiographic severity. Depending on
ARIA severity, use clinical judgment in considering whether to
continue dosing, temporarily discontinue treatment, or permanently
discontinue LEQEMBI.
- 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 should be performed prior to continuing
treatment.
- There is no experience in patients who continued dosing through
symptomatic ARIA-E or through asymptomatic, but radiographically
severe, ARIA-E. There is limited experience in patients who
continued dosing through asymptomatic but radiographically mild to
moderate ARIA-E. There are limited 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%) than in heterozygotes (LEQEMBI: 19%;
placebo: 9%) and noncarriers (LEQEMBI: 13%; placebo: 4%). Among
patients treated with LEQEMBI, symptomatic ARIA-E occurred in 9% of
ApoE ε4 homozygotes 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 and noncarriers.
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 patients by 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-treated patients, 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-treated patients, 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 an
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 an increased 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 with factors that indicate an increased risk
for intracerebral hemorrhage and in particular for patients who
need to be on anticoagulant therapy.
Hypersensitivity Reactions
Hypersensitivity 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 the
first 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 be discontinued, and
appropriate therapy initiated as clinically indicated. Prophylactic
treatment with antihistamines, 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 ARIA-H 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
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
|
Biogen
Inc.
Jack
Cox
+
1-781-464-3260
public.affairs@biogen.com
|
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 a humanized immunoglobulin gamma 1
(IgG1) monoclonal antibody directed against aggregated soluble
(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 with mild 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 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).7 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.7 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).7 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.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 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. The website and social media channels are
intended for audiences outside of the UK and Europe. 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
patient's 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, about the
potential clinical effects of lecanemab; the potential benefits,
safety and efficacy of LEQEMBI; 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
LEQEMBI; 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.
References
- Amin L, Harris DA. Aβ receptors specifically recognize
molecular features displayed by fibril ends and neurotoxic
oligomers. Nat Commun.
2021;12:3451. doi:10.1038/s41467-021-23507-z
- 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.
- LEQEMBI. Prescribing information. Eisai Inc. 2023.
- 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-grants-accelerated-approval-alzheimers-disease-treatment.
Last accessed: March 2024.
- Eisai Global. 2023. "LEQEMBI® Intravenous Infusion"
(Lecanemab) Approved for the Treatment of Alzheimer's Disease in
Japan Available at:
https://www.eisai.com/news/2023/news202359.html. Last accessed:
March 2024.
- 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.
- van Dyck, H., et al. Lecanemab in Early Alzheimer's
Disease. New England Journal of Medicine. 2023;388:9-21.
https://www.nejm.org/doi/full/10.1056/NEJMoa2212948.
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SOURCE Eisai Inc.