Eisai Presents Latest Analysis of Lecanemab’s Effect on Biomarker
Changes and Subcutaneous Dosing at The Alzheimer’s Association
International Conference (AAIC) 2023
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 results of a detailed analysis of the Phase 3
Clarity AD study demonstrated that lecanemab-irmb (generic name,
U.S. brand name: LEQEMBI®) treatment showed reductions in
amyloid-beta (Aβ) pathology and downstream biomarker changes. This
analysis, and the latest findings on the lecanemab subcutaneous
(SC) formulation currently under development, were presented at the
Alzheimer's Association International Conference (AAIC) 2023. The
U.S. Food and Drug Administration (FDA) granted traditional
approval for LEQEMBI for the treatment of Alzheimer’s disease (AD)
on July 6, 2023.
Clarity AD was a global confirmatory Phase 3
placebo-controlled, double-blind, parallel-group, randomized study
in 1,795 people with early AD (lecanemab group: 10 mg/kg bi-weekly
IV treatment: 898, placebo group: 897). Lecanemab met the primary
endpoint (change from baseline at 18 months on the global cognitive
and functional scale, Clinical Dementia Rating-Sum of Boxes
[CDR-SB]) and all key secondary endpoints with statistically
significant results. In November 2022, results of the Clarity AD
study were presented at the Clinical Trials on Alzheimer's Disease
(CTAD) conference and simultaneously published in the peer-reviewed
medical journal, The New England Journal of Medicine.
Lecanemab: Amyloid Reduction and
Evidence of Downstream Biomarker ModificationIn addition
to the key secondary endpoint of lecanemab's effect on amyloid
accumulation in the brain as measured by amyloid positron emission
tomography (PET), the Clarity AD study also measured multiple
A/T/N+ (amyloid, tau, neurodegeneration) biomarkers involved in the
pathophysiology of AD, such as amyloid (Aβ1-42 in CSF, Aβ42/40
ratio in plasma), tau (p-Tau181 in cerebral spinal fluid [CSF] and
plasma), neurodegeneration (total tau [t-tau] in CSF and
neurofilament light [NfL] in CSF and plasma), astrocyte activation
(plasma GFAP: glial fibrillary acidic protein) and synaptic
dysfunction (neurogranin in CSF).
An increase in plasma Aβ42/40 ratio was observed
with lecanemab compared to placebo (adjusted mean change from
baseline of lecanemab: 0.008, placebo: 0.001, p<0.0001). A
reduction in plasma p-Tau181 was observed with lecanemab compared
to placebo (adjusted mean change from baseline of lecanemab: -0.575
pg/mL, placebo: 0.201 pg/mL, p<0.0001). The other biomarkers
also improved after treatment with lecanemab. These outcomes
suggested lecanemab impacts A/T/N+ biomarkers involved in the AD
pathophysiology and exerts biological effects that demonstrate
slowing of disease progression.
Baseline characteristics and initial results
were presented from the tau PET substudy of Clarity AD. Lecanemab
administration slowed the accumulation of tau pathology in the
temporal lobe. Additionally, lecanemab administration showed a
clinical effect in the overall population of the tau PET substudy,
and a large effect size was observed in the low tau population*
defined in this presentation, which represents the early phase of
AD.
Subcutaneous (SC) Lecanemab is Predicted
to Achieve Comparable Efficacy and Improved Safety Compared to
Lecanemab IV in Early ADIn an exposure/bioavailability and
modeling study comparing intravenous (IV) and subcutaneous (SC)
dosing of lecanemab, the bioavailability of SC dosing of lecanemab
was shown to be approximately 50% of that of IV dosing. Further
analysis using the PK/PD model showed that a fixed lecanemab SC
dose of 720 mg administered weekly may potentially result in
comparable exposure (area under the curve [AUC]) and efficacy as
measured by reduction in amyloid PET SUVr to 10 mg/kg IV dose
administered bi-weekly. Models developed with data following IV
administration show that amyloid-related imaging abnormalities with
edema/effusion (ARIA-E) are related to concentrations of lecanemab
in the blood, with maximum blood concentrations being the best
predictor of ARIA-E. Because SC dosing will have lower maximum
blood concentrations than IV dosing, SC dosing is predicted to have
a lower incidence of ARIA-E, if the relationship is the same for SC
dosing.
The presentation materials of this release will
be posted on the investors section of the Eisai Co., Ltd. website
at 19:30 on July 20 in the U.S EDT (8:30 on July 21 in Japan
time).
Eisai serves as the lead of lecanemab
development and regulatory submissions globally with both Eisai and
Biogen co-commercializing and co-promoting the product and Eisai
having final decision-making authority.
* Using the MK6240 tau PET probe, tau
accumulation in the brain was defined as low tau accumulation group
(MK6240 cutoff value <1.06, 141 subjects), intermediate
accumulation group (MK6240 cutoff value between 1.06 and 2.91, 191
subjects), and high accumulation group (MK6240 cutoff value
>2.91, 10 subjects).
INDICATIONLEQEMBI 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.
IMPORTANT SAFETY INFORMATION
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 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 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 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 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 DepartmentTEL: +81
(0) 3-3817-5120Eisai Inc. (U.S.)Libby Holman+
1-201-753-1945Libby_Holman@eisai.comEisai Europe,
Ltd.(UK, Europe, Australia, New Zealand and Russia) EMEA
Communications Department+44 (0)
786-601-1272EMEA-comms@eisai.net |
Biogen Inc.Jack Cox+
1-781-464-3260public.affairs@biogen.com |
|
Investor Contacts: |
Eisai Co.,
Ltd.Investor Relations DepartmentTEL: +81 (0)
3-3817-5122 |
Biogen Inc.Chuck
Triano+ 1-781-464-2442IR@biogen.com |
Notes to Editors
1. About
LEQEMBI®
(lecanemab-irmb)LEQEMBI® (lecanemab-irmb) is the
result of a strategic research alliance between Eisai and
BioArctic. LEQEMBI is a humanized immunoglobulin gamma 1 (IgG1)
monoclonal antibody directed against aggregated soluble
(protofibril) and insoluble forms of amyloid-beta (Aβ). LEQEMBI is
an amyloid beta-directed antibody indicated as a disease-modifying
treatment for Alzheimer’s disease (AD) in the U.S. The U.S. Food
and Drug Administration (FDA) granted LEQEMBI accelerated approval
on January 6, 2023, and Traditional Approval on July 6, 2023.
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.
Eisai has also submitted applications for
approval of lecanemab in Japan, EU, China, Canada, Great Britain
and South Korea. In Japan and China, the applications have been
designated for priority review, and in Great Britain, lecanemab has
been designated for the Innovative Licensing and Access Pathway
(ILAP), which aims to reduce the time to market for innovative
medicines.
Eisai has completed a lecanemab subcutaneous
bioavailability study, and subcutaneous dosing is currently being
evaluated in the Clarity AD (Study 301) open-label extension (OLE).
A maintenance dosing regimen has been evaluated as part of Study
201 OLE.
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.
2. About the
Collaboration between Eisai and Biogen for ADEisai and
Biogen have been collaborating on the joint development and
commercialization of AD treatments since 2014. Eisai serves as the
lead of LEQEMBI 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 ADSince
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 LEQEMBI for the treatment of AD pursuant to an agreement
with BioArctic in December 2007. The development and
commercialization agreement on the antibody LEQEMBI 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
http://www.eisai.com/ (for global headquarters: Eisai Co., Ltd.),
and connect with us on Twitter, LinkedIn and Facebook.
5. About
BiogenFounded in 1978, Biogen is a leading global
biotechnology company that has pioneered multiple breakthrough
innovations including a broad portfolio of medicines to treat
multiple sclerosis, the first approved treatment for spinal
muscular atrophy, and two co-developed treatments to address a
defining pathology of Alzheimer’s disease. Biogen is advancing a
pipeline of potential novel therapies across neurology,
neuropsychiatry, specialized immunology and rare diseases and
remains acutely focused on its purpose of serving humanity through
science while advancing a healthier, more sustainable and equitable
world.
The company routinely posts information that may
be important to investors on its website at www.biogen.com.
Follow Biogen on social media – Twitter, LinkedIn, Facebook,
YouTube.
Biogen Safe HarborThis news
release contains forward-looking statements about 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 or the scientific data
presented.
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 LEQEMBI; actual timing and content of
submissions to and decisions made by the regulatory authorities
regarding LEQEMBI; uncertainty of success in the development and
potential commercialization of LEQEMBI; 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; third party collaboration
risks; and the direct and indirect impacts of the ongoing COVID-19
pandemic on Biogen's business, 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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