Lecanemab

12.1 Mechanism of Action Lecanemab-irmb is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease. LEQEMBI reduces amyloid beta plaques, as evaluated in Study 1 and Study 2 [see Clinical Studies ( 14 )] .

1 INDICATIONS AND USAGE 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. LEQEMBI is an amyloid beta-directed antibody 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. ( 1 )

2 DOSAGE AND ADMINISTRATION Confirm the presence of amyloid beta pathology prior to initiating treatment. ( 2.1 ) Obtain a recent baseline brain MRI prior to initiating treatment. ( 2.4 , 5.1 ) Obtain an MRI within approximately one week prior to the 3 rd , 5 th , 7 th , and 14 th infusions. If radiographically observed ARIA occurs, treatment recommendations are based on type, severity, and presence of symptoms. ( 2.4 , 5.1 ) Recommended starting dosage: 10 mg/kg once every 2 weeks administered after dilution as an intravenous infusion over approximately one hour. ( 2.2 ) After 18 months, continue treatment once every 2 weeks or transition to an intravenous or subcutaneous maintenance dosage. ( 2.2 ) Recommended maintenance dosage: Intravenous infusion: 10 mg/kg once every 4 weeks ( 2.2 , 2.5 ) Subcutaneous injection: 360 mg administered once a week using the LEQEMBI IQLIK autoinjector ( 2.2 , 2.6 ). See Full Prescribing Information for preparation and administration instructions. ( 2.5 , 2.6 ) 2.1 Patient Selection Confirm the presence of amyloid beta pathology prior to initiating treatment [see Clinical Pharmacology ( 12.1 )] . 2.2 Recommended Dosage Initiate LEQEMBI as an intravenous infusion using the starting dosage (see Table 1). After 18 months, the starting dosage may be continued or a transition to maintenance dosage regimen may be considered, which can be administered by either intravenous infusion or subcutaneous injection (see Table 1). If transitioning from starting dosage to a maintenance dosage regimen, administer the first maintenance dose two weeks after the last starting dose. Table 1: Starting and Maintenance Dosage Regimens Route of Administration Dose Frequency Infusion Rate (if Intravenous) Starting Dosage Intravenous Only (LEQEMBI) 10 mg/kg Once every 2 weeks Over approximately one hour Maintenance Dosage Intravenous (LEQEMBI) 10 mg/kg Once every 4 weeks Over approximately one hour Subcutaneous (LEQEMBI IQLIK) 360 mg Once every week ------------------------ For intravenous infusion, use LEQEMBI vials. LEQEMBI vials must be diluted before administration [see Dosage and Administration ( 2.5 )]. For subcutaneous administration, use LEQEMBI IQLIK [see Dosage and Administration ( 2.6 )]. 2.3 Switching Between Maintenance Dosage Regimens During maintenance dosage regimen, patients may switch the route of administration (intravenous LEQEMBI or subcutaneous LEQEMBI IQLIK). This transition should be initiated at 1 week following the last maintenance dose of either the intravenous or subcutaneous dosing regimen. Thereafter, follow the dosing schedule for the newly assigned maintenance dosage regimen. 2.4 Monitoring and Dosing Interruption for Amyloid Related Imaging Abnormalities LEQEMBI can cause amyloid related imaging abnormalities -edema (ARIA-E) and -hemosiderin deposition (ARIA-H) [ see Warnings and Precautions ( 5.1 )] . Monitoring for ARIA Obtain a recent baseline brain magnetic resonance imaging (MRI) prior to initiating treatment with LEQEMBI. Obtain an MRI prior to the 3 rd , 5 th , 7 th , and 14 th infusions. In general, the MRI should be performed within approximately one week before the scheduled infusion of LEQEMBI and reviewed prior to proceeding with the infusion. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including an MRI if indicated. Recommendations for Dosing Interruptions in Patients with ARIA ARIA-E The recommendations for dosing interruptions for patients with ARIA-E are provided in Table 2. Table 2: Dosing Recommendations for Patients with ARIA-E Clinical Symptom Severity 1 ARIA-E Severity on MRI 2 Mild Moderate Severe Asymptomatic May continue dosing Suspend dosing 3 Suspend dosing 3 Mild May continue dosing based on clinical judgment Suspend dosing 3 Moderate or Severe Suspend dosing 3 1 Clinical Symptom Severity Categories: Mild: discomfort noticed, but no disruption of normal daily activity. Moderate: discomfort sufficient to reduce or affect normal daily activity. Severe: incapacitating, with inability to work or to perform normal daily activity. 2 See Table 4 for MRI radiographic severity [Warnings and Precautions ( 5.1 )] . 3 Suspend until MRI demonstrates radiographic resolution and symptoms, if present, resolve; consider a follow-up MRI to assess for resolution 2 to 4 months after initial identification. Resumption of dosing should be guided by clinical judgment. ARIA-H The recommendations for dosing interruptions for patients with ARIA-H are provided in Table 3. Table 3: Dosing Recommendations for Patients with ARIA-H Clinical Symptom Severity ARIA-H Severity on MRI 1 Mild Moderate Severe Asymptomatic May continue dosing Suspend dosing 2 Suspend dosing 3 Symptomatic Suspend dosing 2 Suspend dosing 2 1 See Table 4 for MRI radiographic severity [Warnings and Precautions ( 5.1 )] . 2 Suspend until MRI demonstrates radiographic stabilization and symptoms, if present, resolve; resumption of dosing should be guided

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Amyloid Related Imaging Abnormalities [see Warnings and Precautions ( 5.1 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] Infusion-Related Reactions [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (at approximately 10% and higher incidence compared to placebo): infusion-related reactions, amyloid related imaging abnormality-microhemorrhages, amyloid related imaging abnormality-edema/effusion, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials with Intravenous Administration The safety of LEQEMBI has been evaluated in 2090 patients who received at least one dose of LEQEMBI by intravenous infusion. In Studies 1 and 2 in patients with Alzheimer’s disease, 1059 patients received LEQEMBI 10 mg/kg every two weeks by intravenous infusion [see Clinical Studies ( 14 )] . Of these 1059 patients, 50% were female, 79% were White, 15% were Asian, 12% were of Hispanic or Latino ethnicity, and 2% were Black. The mean age at study entry was 72 years (range from 50 to 90 years). In the combined double-blind, placebo-controlled period and long-term extension period of Studies 1 and 2, 1604 patients received LEQEMBI for at least 6 months, 1261 patients for at least 12 months, and 965 patients for 18 months. In the double-blind, placebo-controlled period in Study 1, patients stopped study treatment because of an adverse reaction in 15% of patients treated with LEQEMBI, compared to 6% patients on placebo; in Study 2, patients stopped study treatment because of an adverse reaction in 7% of patients treated with LEQEMBI, compared to 3% patients on placebo. In Study 1, 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. In Study 2, the most common adverse reaction 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. Table 5 shows adverse reactions that were reported in at least 5% of patients treated with LEQEMBI and at least 2% more frequently than in patients on placebo in Study 1. Table 5: Adverse Reactions Reported in at Least 5% of Patients Treated with LEQEMBI 10 mg/kg Every Two Weeks and at least 2% Higher than Placebo in Study 1 Adverse Reaction LEQEMBI 10 mg/kg Every Two Weeks N= 161 % Placebo N= 245 % Infusion-related reactions 20 3 Headache 14 10 ARIA-E 10 1 Cough 9 5 Diarrhea 8 5 Table 6 shows adverse reactions that were reported in at least 5% of patients treated with LEQEMBI and at least 2% more frequently than in patients on placebo in Study 2. Table 6: Adverse Reactions Reported in at Least 5% of Patients Treated with LEQEMBI 10 mg/kg Every Two Weeks and at least 2% Higher than Placebo in Study 2 Adverse Reaction LEQEMBI 10 mg/kg Every Two Weeks N= 898 % Placebo N= 897 % Infusion-related reactions 26 7 ARIA-H 14 8 ARIA-E 13 2 Headache 11 8 Superficial siderosis of central nervous system 6 3 Rash 1 6 4 Nausea/Vomiting 6 4 1 Rash includes acne, erythema, infusion site rash, injection site rash, rash, rash erythematous, rash pruritic, skin reactions, and urticaria. Less Common Adverse Reactions Atrial fibrillation occurred in 3% of patients treated with LEQEMBI, compared to 2% in patients on placebo. In Study 1, lymphopenia or decreased lymphocyte count was reported in 4% of patients treated with LEQEMBI after the first dose, compared to less than 1% of patients on placebo [see Warnings and Precautions ( 5.3 )]; lymphocytes were not measured after the first dose in Study 2. Clinical Trials with Subcutaneous Administration The safety of LEQEMBI IQLIK for maintenance treatment was evaluated in an open-label study, which included 49 patients who received LEQEMBI IQLIK 360 mg by subcutaneous administration once every week. The overall safety profile in these patients was similar to what was observed in patients who received LEQEMBI by intravenous infusion in Study 1 and Study 2. Patients who received LEQEMBI IQLIK experienced localized and systemic injection-related reactions. Localized injection-related reactions included erythema, induration, swelling, heat, pain, pruritis, rash, ecchymosis, and hematoma. Systemic injection-related reactions were observed less frequently, with symptoms of headache, fever, and fatigue. Injection-related reactions in patients re