FDA Advisory Committee votes unanimously to confirm clinical benefit of LEQEMBI® (lecanemab-irmb) for the treatment of early Alzheimer’s disease

Stockholm, June 10, 2023 – BioArctic AB’s (publ) (Nasdaq Stockholm: BIOA B) partner Eisai 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 intravenous injection for the treatment of Alzheimer’s disease (AD). LEQEMBI received Accelerated approval from the FDA for the treatment of early Alzheimer’s disease on January 6, 2023. The PDUFA action date for traditional approval of LEQEMBI has been set for July 6, 2023, with designation of priority review.

Additionally, the committee members confirmed the overall risk-benefit 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 clinical 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: 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.

LEQEMBI, a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibril[1] 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 2b 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. The advisory committee agreed that Clarity AD 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 Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority. BioArctic has the right to commercialize lecanemab in the Nordic region and currently Eisai and BioArctic are preparing for a joint commercialization in the region.

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LEQEMBI has been approved under the FDA Accelerated Approval Pathway. Click here for the Prescribing Information.

INDICATION, DOSAGE AND ADMINISTRATION, AND IMPORTANT SAFETY INFORMATION IN THE U.S.

INDICATION

LEQEMBI 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 INFORMATION

WARNINGS 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 LEQEMBI US Prescribing Information.

This information is information that BioArctic AB (publ) is obliged to disclose pursuant to the EU Market Abuse Regulation. The information was released for public disclosure, through the agency of the contact person below, on June 10, 2023, at 01.00 a.m. CET.

For further information, please contact: 
Oskar Bosson, VP Communications and IR
E-mail:  oskar.bosson@bioarctic.se
Phone: +46 70 410 71 80 

About lecanemab
Lecanemab (Brand Name in the U.S.: LEQEMBI™) is the result of a strategic research alliance between BioArctic and Eisai. Lecanemab is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibril) and insoluble forms of amyloid-beta (Aβ). In the US, LEQEMBI was granted accelerated approval by the US 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 may be contingent upon verification of clinical benefit in a confirmatory trial. 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.

Please see full Prescribing Information in the United States.

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, which was 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 priority review was granted February 27, 2023. In Canada, Eisai submitted a New Drug Submission (NDS) to Health Canada on March 31, 2023, and was accepted on May 15 of the same year. In South Korea, Eisai submitted a marketing authorization application in June 2023.

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 the Phase 2b study (Study 201) OLE 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 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 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 and Eisai.

Since January 2022, the Tau NexGen clinical study for Dominantly Inherited AD (DIAD) is ongoing, where lecanemab is given as a background anti-amyloid treatment when exploring combination therapies with anti-tau treatments. The study is conducted by Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), led by Washington University School of Medicine in St. Louis.

About the collaboration between BioArctic and Eisai
Since 2005, BioArctic has a long-term collaboration with Eisai regarding the development and commercialization of drugs for the treatment of Alzheimer’s disease. The most important agreements are the Development and Commercialization Agreement for the lecanemab antibody, which was signed in December 2007, and the Development and Commercialization agreement for the antibody BAN2401 back-up for Alzheimer’s disease, which was signed in May 2015. In March 2014, Eisai and Biogen entered into a joint development and commercialization agreement for lecanemab. Eisai is responsible for the clinical development, application for market approval and commercialization of the products for Alzheimer’s disease. BioArctic has right to commercialize lecanemab in the Nordic under certain conditions and is currently preparing for commercialization in the Nordics together with Eisai. BioArctic has no development costs for lecanemab in Alzheimer’s disease and is entitled to payments in connection with regulatory approvals, and sales milestones as well as royalties on global sales.

About BioArctic AB
BioArctic AB (publ) is a Swedish research-based biopharma company focusing on disease-modifying treatments for neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and ALS. BioArctic focuses on innovative treatments in areas with high unmet medical needs. The company was founded in 2003 based on innovative research from Uppsala University, Sweden. Collaborations with universities are of great importance to the company together with its strategically important global partner Eisai in Alzheimer disease. The project portfolio is a combination of fully funded projects run in partnership with global pharmaceutical companies and innovative in-house projects with significant market and out-licensing potential. BioArctic’s Class B share is listed on Nasdaq Stockholm Large Cap (ticker: BIOA B). For more information about BioArctic, please visit www.bioarctic.com.

[1] Prototofibrils are large Aβ aggregated soluble species of 75-5000 Kd