Eisai : Submits Supplemental Biologics License Application to FDA for Traditional Approval of LEQEMBI™ (lecanemab-irmb) for the Treatment of Alzheimer's Disease

(4523)   Report

Eisai Submits Supplemental Biologics License Application to FDA for Traditional Approval of LINK (lecanemab-irmb) for the Treatment of Alzheimer's Disease Submission for traditional approval follows FDA accelerated approval of LEQEMBI on the same day, and is based on data from the confirmatory Phase 3 Clarity AD clinical trial TOKYO and CAMBRIDGE, Mass., January 7, 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 Eisai has submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) supporting the conversion of the Accelerated Approval of LINK (lecanemab-irmb) 100 mg/mL injection for intravenous use to a traditional approval. This sBLA is subject to validation of whether the FDA accepts the application for review. LEQEMBI is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble ("protofibrils")* and insoluble forms of amyloid beta (Aβ), approved under Accelerated Approval Pathway by the FDA on January 6, 2023, for the treatment of Alzheimer's Disease (AD). 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. Accelerated Approval of LEQEMBI was based on Phase 2 data that demonstrated LEQEMBI reduced the accumulation of Aβ plaque in the brain, a defining feature of AD. Continued approval for this indication is contingent upon verification of LEQEMBI's clinical benefit in a confirmatory trial. The sBLA for LEQEMBI is based on the data from the Phase 3 confirmatory Clarity AD clinical trial. In Clarity AD, LEQEMBI met the primary endpoint and all key secondary endpoints with highly statistically significant results, and the profile of Amyloid-Related Imaging Abnormalities (ARIA) incidence was within expectations. In November 2022, the results of the Clarity AD study were presented at the 2022 Clinical Trials on Alzheimer's Disease (CTAD) conference, and simultaneously published in the New England Journal of Medicine, peer-reviewed medical journals. "We deeply appreciate the cooperation of people living with Alzheimer's disease and healthcare professionals who participated in LEQEMBI's Phase 3 Clarity AD clinical study, which enabled us to submit this sBLA. Alzheimer's disease causes significant impairment and burden to both the people living with this disease and their families, as well as having a profound impact on society," said Haruo Naito, Chief Executive Officer at Eisai. "The fact that Eisai was able to file LEQEMBI's supplemental Biologics License Application for traditional FDA approval on the same day we received accelerated approval demonstrates our commitment to the Alzheimer's disease community and is a major step forward in ensuring access for all those in the U.S living with this disease in need of this medicine. We will continue to actively cooperate with the FDA's review." Eisai has initiated submission of data for BLA to the National Medical Products Administration (NMPA) of China in December 2022. Eisai plans to file for marketing authorization applications of lecanemab in Japan and EU by the end of Eisai's FY2022, which ends March 31, 2023. "Today's filing is an important milestone for people living with Alzheimer's disease, demonstrating the resilience of the scientific and medical communities in their fight against this terrible disease despite the many setbacks and the challenges they've faced," said Christopher A. Viehbacher, President and Chief Executive Officer of Biogen. "We commend Eisai for their leadership on the development of lecanemab and for the speed in which they were able to complete this filing, which is based on important new data from the pivotal late-stage Clarity AD study." 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, 2 To learn more, visit URL. 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; 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 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-relatedreactions 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. Media Contacts: Eisai Co., Ltd. Biogen Inc. Public Relations Department Natacha Gassenbach TEL: +81 (0)3-3817-5120 + 1-857-777-6573 EMAIL Eisai Inc. (U.S.) Libby Holman + 1-201-753-1945 EMAIL Eisai Europe, Ltd. (Europe, Australia, New Zealand and Russia) EMEA Communications Department EMAIL +44 (0) 786 601 1272 Investor Contacts: Eisai Co., Ltd. Biogen Inc. Investor Relations Department Mike Hencke TEL: +81 (0) 3-3817-5122 + 1-781-464-2442 EMAIL Notes to Editors 1. About LEQEMBITM (lecanemab-irmb) LEQEMBITM (lecanemab-irmb) is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody that is directed against aggregated soluble ("protofibrils") and insoluble forms of amyloid-beta (Aβ). 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. LEQEMBI is the result of a strategic research alliance between Eisai and BioArctic. Eisai has been initiated submission of data for the BLA to the National Medical Products Administration (NMPA) of China in December 2022. Eisai plans to file for marketing authorization applications of lecanemab in Japan and EU by the end of Eisai's FY2022. 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, 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 S