FDA Advisory Committee Votes Unanimously to Confirm the Clinical
Benefit 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’s (FDA) Peripheral
and Central Nervous System Drugs Advisory Committee (PCNS) voted
unanimously that the data from Eisai’s Phase 3 Clarity AD clinical
trial confirms the clinical benefit of LEQEMBI® (lecanemab-irmb)
100 mg/mL injection for intravenous use for the treatment of
Alzheimer’s disease (AD). Additionally, the committee members
confirmed the overall benefit-risk profile of LEQEMBI, the clinical
meaningfulness of the data and discussed its use in specific
subgroups, including Apolipoprotein E (ApoE) ε4 homozygote
patients, patients requiring concomitant treatment with
anticoagulant agents, and patients with cerebral amyloid
angiopathy.
The unanimous decision by the panel of
independent experts was based on the supplementary Biologics
License Application (sBLA) which includes data from Eisai’s large
global confirmatory Phase 3 Clarity AD trial. The Clarity AD trial
met its prespecified primary endpoint, demonstrating a highly
statistically significant slowing of cognitive and functional
decline (27%, p=0.00005) compared to placebo over 18 months. Highly
statistically significant treatment effects were also observed for
all multiplicity-controlled secondary endpoints that examined
cognition and functional changes using other validated scales. The
most common adverse events (>10%) in the LEQEMBI group were
infusion reactions (LEQEMBI: 26.4%; placebo: 7.4%), ARIA-H
(combined cerebral microhemorrhages, cerebral macrohemorrhages, and
superficial siderosis: LEQEMBI: 17.3%; placebo: 9.0%), ARIA-E
(edema/effusion: LEQEMBI: 12.6%; placebo: 1.7%), headache (LEQEMBI:
11.1%; placebo: 8.1%), and fall (LEQEMBl: 10.4%; placebo: 9.6%).
Infusion reactions were largely mild-to-moderate (grade 1-2: 96%)
and occurred on the first dose (75%). The 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
[nejm.org].
LEQEMBI, a humanized immunoglobulin gamma 1
(IgG1) monoclonal antibody directed against aggregated soluble
(protofibril*) and insoluble forms of amyloid beta (Aβ), received
accelerated approval on January 6, 2023, 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.
Its continued approval may be contingent upon verification of
LEQEMBI’s clinical benefit in the confirmatory Clarity AD trial
(Study 301). The advisory committee agreed unanimously that Study
301 verified the clinical benefit. The Prescription Drug User Fee
Act (PDUFA) action date for the traditional approval is July 6,
2023.
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.
LEQEMBI has been approved under the FDA
accelerated approval pathway. Click here for the
Prescribing Information
[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 201, 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 [leqembi.com] in the United
States.
*Protofibrils are large Aβ aggregated soluble
species of 75-5000 Kd.1,2,3
Media Contacts:
Eisai Co., Ltd.Public Relations DepartmentTEL: +81
(0)3-3817-5120 |
Biogen Inc.Jack Cox+ 1 781 464
3260public.affairs@biogen.com |
|
|
Eisai Inc. (U.S.)Libby Holman+
1-201-753-1945Libby_Holman@eisai.com |
|
|
|
Eisai Europe, Ltd.(UK, Europe, Australia, New
Zealand and Russia) EMEA Communications Department+44 (0) 786 601
1272EMEA-comms@eisai.net |
|
|
|
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
LEQEMBITM
(lecanemab-irmb)Lecanemab (brand name in the U.S.:
LEQEMBI™) is the result of a strategic research alliance between
Eisai and BioArctic. Lecanemab 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 in the U.S. 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. On March 3, 2023, the FDA accepted Eisai’s sBLA based on the
Clarity AD clinical data, and the LEQEMBI application has been
granted Priority Review, with a Prescription Drug User Fee Act
(PDUFA) action date of July 6, 2023.
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 lecanemab subcutaneous
bioavailability study, and subcutaneous dosing is currently being
evaluated in the Clarity AD (Study 301) OLE. A maintenance dosing
regimen has been evaluated as part of Study 201 as well as the
Clarity AD (Study 301) OLE. Separate supplemental Biologics License
Applications for subcutaneous dosing and a maintenance dosing
regimen will be submitted to the FDA at the end of Eisai's fiscal
year.
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
www.eisai.com [eisai.com] (for global headquarters: Eisai Co.,
Ltd.), and connect with us on Twitter @Eisai_SDGs.
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, 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.
References
-
https://www.alzforum.org/news/conference-coverage/lecanemab-sweeps-toxic-av-protofibrils-catches-eyes-trialists
- Sehlin D, Englund H, Simu B,
Karlsson M, Ingelsson M, Nikolajeff F, Lannfelt L, Pettersson FE.
Large aggregates are the major soluble Aβ species in AD brain
fractionated with density gradient ultracentrifugation. PLoS One.
2012;7(2):e32014. doi: 10.1371/journal.pone.0032014. Epub 2012 Feb
15. PMID: 22355408; PMCID: PMC3280222.
- 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. 2023;20:195-206.
https://doi.org/10.1007/s13311-022-01308-6
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