FDA Accepts Eisai’s Filing of a Supplemental Biologics License
Application and Grants Priority Review for Traditional Approval of
LEQEMBI™ (lecanemab-irmb) for the Treatment of Alzheimer’s
Disease
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 supplemental Biologics License Application (sBLA) for
LEQEMBI™ (lecanemab-irmb) 100 mg/mL injection for intravenous use,
supporting the conversion of the accelerated approval of LEQEMBI to
a traditional approval. The LEQEMBI application has been granted
Priority Review, with a Prescription Drug User Fee Act (PDUFA)
action date of July 6, 2023. The FDA is currently planning to hold
an Advisory Committee to discuss this application but has not yet
publicly announced the date of the meeting.
LEQEMBI is a humanized immunoglobulin gamma 1
(IgG1) monoclonal antibody directed against aggregated soluble
(protofibrils*) and insoluble forms of amyloid beta (Aβ), approved
under the Accelerated Approval Pathway for the treatment of
Alzheimer's Disease (AD) on January 6, 2023. Treatment with LEQEMBI
should only be initiated in patients with the mild cognitive
impairment or mild dementia stage of disease and confirmed presence
of Aβ pathology. On the same day that LEQEMBI received its
accelerated approval, Eisai submitted the sBLA to the FDA for
approval under the traditional pathway.
The sBLA is based on the findings from Eisai’s
recently published large, global confirmatory Phase 3 clinical
trial, Clarity AD. LEQEMBI met the primary endpoint and all key
secondary endpoints with highly 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.
LEQEMBI was approved under accelerated approval
in the U.S. and was launched in the U.S. on January 18, 2023. The
accelerated approval was based on Phase 2 data that demonstrated
that LEQEMBI reduced the accumulation of Aβ plaque in the brain, a
defining feature of AD, and its continued approval may be
contingent upon verification of LEQEMBI’s clinical benefit in a
confirmatory trial. The FDA has determined that the results of
Clarity AD can serve as the confirmatory study to verify the
clinical benefit of lecanemab.
Eisai serves as the lead of LEQEMBI development
and regulatory submissions globally with both Eisai and Biogen
co-commercializing and co-promoting the product and Eisai having
final decision-making authority.
* Protofibrils are large Aβ aggregated soluble
species of 75-500 Kd.1
To learn more, visit www.LEQEMBI.com.
INDICATION, DOSAGE AND ADMINISTRATION,
AND IMPORTANT SAFETY INFORMATION IN THE U.S.
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. There are no safety or
effectiveness data on initiating treatment at earlier or later
stages of the disease than were studied. This indication is
approved under accelerated approval based on reduction in amyloid
beta plaques observed in patients treated with LEQEMBI. Continued
approval for this indication may be contingent upon verification of
clinical benefit in a confirmatory trial.
IMPORTANT SAFETY
INFORMATIONWARNINGS AND PRECAUTIONS
Amyloid Related Imaging
Abnormalities
- LEQEMBI can cause amyloid related
imaging abnormalities-edema (ARIA-E) and -hemosiderin deposition
(ARIA-H). ARIA-E can be observed on MRI as brain edema or sulcal
effusions, and ARIA-H as microhemorrhage and superficial siderosis.
ARIA 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 (within one year)
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 1 (Study 201), symptomatic
ARIA occurred in 3% (5/161) of LEQEMBI-treated patients. Clinical
symptoms associated with ARIA resolved in 80% of patients during
the period of observation.
- Including asymptomatic cases, ARIA
was observed in LEQEMBI: 12% (20/161); placebo: 5% (13/245). ARIA-E
was observed in LEQEMBI: 10% (16/161); placebo: 1% (2/245). ARIA-H
was observed in LEQEMBI: 6% (10/161); placebo: 5% (12/245). There
was no increase in isolated ARIA-H for LEQEMBI compared to
placebo.
- Intracerebral hemorrhage >1 cm
in diameter was reported after one treatment in LEQEMBI: 1 patient;
placebo: zero patients. Events of intracerebral hemorrhage,
including fatal events, in patients taking LEQEMBI have also been
reported in other studies.
Apolipoprotein E ε4 (ApoE ε4) Carrier
Status and Risk of ARIA
- In Study 1, 6% (10/161) of patients
in the LEQEMBI group were ApoE ε4 homozygotes, 24% (39/161) were
heterozygotes, and 70% (112/161) were noncarriers.
- The incidence of ARIA was higher in
ApoE ε4 homozygotes than in heterozygotes and noncarriers among
patients treated with LEQEMBI. Of the 5 LEQEMBI-treated patients
who had symptomatic ARIA, 4 were ApoE ε4 homozygotes, 2 of whom
experienced severe symptoms. An increased incidence of symptomatic
and overall ARIA in ApoE ε4 homozygotes compared to heterozygotes
and noncarriers in LEQEMBI-treated patients has been reported in
other studies.
- The recommendations on management
of ARIA do not differ between ApoE ε4 carriers and
noncarriers.
- Consider testing for ApoE ε4 status
to inform the risk of developing ARIA when deciding to initiate
treatment with LEQEMBI.
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% (7/161) of patients, moderate
in 4% (7/161) of patients, and severe in 1% (2/161) of patients.
Resolution on MRI occurred in 62% of ARIA-E patients by 12 weeks,
81% by 21 weeks, and 94% overall after detection. The maximum
radiographic severity of ARIA-H microhemorrhage in patients treated
with LEQEMBI was mild in 4% (7/161) of patients and severe in 1%
(2/161) of patients; 1 of the 10 patients with ARIA-H had mild
superficial siderosis.
Concomitant Antithrombotic Medication
and Other Risk Factors for Intracerebral Hemorrhage
- Patients were excluded from
enrollment in Study 1 for baseline use of anticoagulant
medications. Antiplatelet medications such as aspirin and
clopidogrel were allowed. If anticoagulant medication was used
because of intercurrent medical events that required treatment for
≤4 weeks, treatment with LEQEMBI was to be temporarily
suspended.
- Most exposures to antithrombotic
medications were to aspirin; few patients were exposed to other
antiplatelet drugs or anticoagulants, limiting any meaningful
conclusions about the risk of ARIA or intracerebral hemorrhage in
patients taking other antiplatelet drugs or anticoagulants. Because
intracerebral hemorrhages >1 cm in diameter have been observed
in patients taking LEQEMBI, 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.
- Patients were excluded from
enrollment in Study 1 for the following risk factors for
intracerebral hemorrhage: prior cerebral hemorrhage >1 cm in
greatest diameter, more than 4 microhemorrhages, superficial
siderosis, evidence of vasogenic edema, evidence of cerebral
contusion, aneurysm, vascular malformation, infective lesions,
multiple lacunar infarcts or stroke involving a major vascular
territory, and severe small vessel or white matter disease. Caution
should be exercised when considering the use of LEQEMBI in patients
with these risk factors.
Infusion-Related Reactions
- Infusion-related reactions were
observed in LEQEMBI: 20% (32/161); placebo: 3% (8/245); and the
majority of cases in LEQEMBI-treated patients (88%, 28/32) occurred
with the first infusion. All infusion-related reactions were mild
(56%) or moderate (44%) in severity. Infusion-related reactions
resulted in discontinuations in 2% (4/161) of patients treated with
LEQEMBI. 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.
- After the first infusion, 38% of
LEQEMBI-treated patients had transient decreased lymphocyte counts
to <0.9 x109/L compared to 2% on placebo, and 22% of
LEQEMBI-treated patients had transient increased neutrophil counts
to >7.9 x109/L compared to 1% on placebo.
- 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 1, 15% of LEQEMBI-treated
patients, compared to 6% of placebo-treated patients, stopped study
treatment because of an adverse reaction. The most common adverse
reaction leading to discontinuation of LEQEMBI was infusion-related
reactions that led to discontinuation in 2% (4/161) of patients
treated with LEQEMBI compared to 1% (2/245) of patients on
placebo.
- The most common adverse reactions
reported in ≥5% of patients treated with LEQEMBI (N=161) and ≥2%
higher than placebo (N=245) in Study 1 were infusion-related
reactions (LEQEMBI: 20%; placebo: 3%), headache (LEQEMBI: 14%;
placebo: 10%), ARIA-E (LEQEMBI: 10%; placebo: 1%), cough (LEQEMBI:
9%; placebo: 5%), and diarrhea (LEQEMBI: 8%; placebo: 5%).
Please see full
Prescribing Information in the U.
S.
Contacts |
MEDIA CONTACT: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.netINVESTOR
CONTACT:Eisai Co., Ltd.Investor Relations DepartmentTEL: +81 (0)
3-3817-5122 |
MEDIA CONTACT:Biogen Inc.Natacha Gassenbach+
1-857-777-6573public.affairs@biogen.com INVESTOR CONTACT:Biogen
Inc.Mike Hencke+ 1-781-464-2442IR@biogen.com |
[Notes to editors]
1. About
LEQEMBITM
(lecanemab-irmb)
LEQEMBITM (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). In the U.S., LEQEMBI was granted
accelerated approval by the U.S. Food and Drug Administration (FDA)
on January 6, 2023. LEQEMBI is indicated for the treatment of
Alzheimer’s disease (AD) in the U.S. 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. There are no safety or effectiveness
data on initiating treatment at earlier or later stages of the
disease than were studied. This indication is approved under
accelerated approval based on reduction in Aβ plaques observed in
patients treated with LEQEMBI. Continued approval for this
indication may be contingent upon verification of clinical benefit
in a confirmatory trial.
In the U.S., Eisai submitted a supplemental
Biologics License Application (sBLA) to the FDA for approval under
the traditional pathway on January 6, 2023. The Clarity AD study of
lecanemab met its primary endpoint and all key secondary endpoints
with highly statistically significant results. Eisai submitted an
application for manufacturing and marketing approval to the
Pharmaceuticals and Medical Devices Agency (PMDA) on January 16,
2023, in Japan. The Priority Review was granted by the Ministry of
Health, Labour and Welfare (MHLW) on January 26, 2023. Eisai
utilized the prior assessment consultation system of PMDA, with the
aim of shortening the review period for lecanemab. In Europe, Eisai
submitted a marketing authorization application (MAA) to the
European Medicines Agency (EMA) on January 9, 2023, and accepted on
January 26, 2023. In China, Eisai initiated submission of data for
a BLA to the National Medical Products Administration (NMPA) of
China in December 2022, and the Priority Review was granted on
February 27, 2023.
Eisai has completed lecanemab subcutaneous
bioavailability study, and subcutaneous dosing is currently being
evaluated in the Clarity AD OLE.
Since July 2020, Eisai's 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 (ACTC) 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. 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, has been
ongoing since January 2022.
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 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 the 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 Twitter @Eisai_SDGs.
5. About
Biogen
Founded 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 Harbor
This news release contains forward-looking
statements, including statements made pursuant to the safe harbor
provisions of the Private Securities Litigation Reform Act of 1995,
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 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, including the Clarity
AD clinical trial and AHEAD 3-45 study; 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; 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 are based on Biogen's current
beliefs and expectations and speak only as of the date of this news
release. Biogen does not undertake any obligation to publicly
update any forward-looking statements, whether as a result of new
information, future developments or otherwise.
References1 Söderberg, L.,
Johannesson, M., Nygren, P. et al. Lecanemab, Aducanumab,
and Gantenerumab — Binding Profiles to Different Forms of
Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical
Trials for Alzheimer’s Disease. Neurotherapeutics (2022).
https://doi.org/10.1007/s13311-022-01308-6. Accessed February 9,
2023
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