Donanemab

KISUNLA TM is indicated for the treatment of Alzheimer's disease. Treatment with KISUNLA should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in the clinical trials. KISUNLA is an amyloid beta-directed antibody indicated for the treatment of Alzheimer's disease. Treatment with KISUNLA should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in the clinical trials. ( 1 )

Injection: 350 mg/20 mL (17.5 mg/mL) clear to opalescent, colorless to slightly yellow to slightly brown solution in a single-dose vial. Injection: 350 mg/20 mL (17.5 mg/mL) in a single-dose vial. ( 3 )

KISUNLA is contraindicated in patients with known serious hypersensitivity to donanemab-azbt or to any of the excipients. Reactions have included anaphylaxis [see Warnings and Precautions ( 5.2 )] . KISUNLA is contraindicated in patients with known serious hypersensitivity to donanemab-azbt or to any of the excipients. ( 4 , 5.2 )

Amyloid Related Imaging Abnormalities (ARIA): Enhanced clinical vigilance for ARIA is recommended during the first 24 weeks of treatment with KISUNLA. Risk of ARIA, including symptomatic ARIA, was increased in apolipoprotein E ε4 (ApoE ε4) homozygotes compared to heterozygotes and noncarriers. The risk of ARIA-E and ARIA-H is increased in KISUNLA-treated patients with pretreatment microhemorrhages and/or superficial siderosis. If a patient experiences symptoms suggestive of ARIA, clinical evaluation should be performed, including MRI scanning if indicated. ( 2.3 , 5.1 ) Infusion-Related Reactions: The infusion rate may be reduced, or the infusion may be discontinued, and appropriate therapy initiated as clinically indicated. Consider pre-treatment with antihistamines, acetaminophen, or corticosteroids prior to subsequent dosing. ( 5.3 )

5.1 Amyloid Related Imaging Abnormalities Monoclonal antibodies directed against aggregated forms of beta amyloid, including KISUNLA, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis. ARIA can occur spontaneously in patients with Alzheimer's disease, particularly in patients with MRI findings suggestive of cerebral amyloid angiopathy, such as pretreatment microhemorrhage or superficial siderosis. ARIA-H associated with monoclonal antibodies directed against aggregated forms of beta amyloid generally occurs in association with an occurrence of ARIA-E. ARIA-H of any cause and ARIA-E can occur together. ARIA usually occurs early in treatment and is usually asymptomatic, although serious and life-threatening events, including seizure and status epilepticus, can occur. ARIA can be fatal. When present, reported symptoms associated with ARIA may include, but are not limited to, headache, confusion, visual changes, dizziness, nausea, and gait difficulty. Focal neurologic deficits may also occur. Symptoms associated with ARIA usually resolve over time. In addition to ARIA, intracerebral hemorrhages greater than 1 cm in diameter have occurred in patients treated with KISUNLA. Consider the benefit of KISUNLA for the treatment of Alzheimer's disease and potential risk of serious adverse events associated with ARIA when deciding to initiate treatment with KISUNLA. Study 1 and Study 2 Overview [see Clinical Studies ( 14 )] In Study 1, safety was assessed in patients who received KISUNLA Dosing Regimen 1 (n = 853) compared to those who received placebo (n = 874). In Study 2, the effect of different dosing regimens of KISUNLA on ARIA was assessed, including in patients who received KISUNLA Dosing Regimen 2 (n=212), which is the recommended dosage and described below. Incidence of ARIA A lower incidence of ARIA was observed with Dosing Regimen 2 as compared to Dosing Regimen 1. Therefore, Dosing Regimen 2 is the recommended dosage for KISUNLA. In Study 1, symptomatic ARIA-E occurred in 6% of patients through 18 months of treatment with KISUNLA [see Adverse Reactions ( 6.1 )] . Clinical symptoms associated with ARIA-E resolved in approximately 85% of those patients. Including asymptomatic radiographic events, ARIA, ARIA-E, and ARIA-H were observed in 36%, 24%, and 31% of patients treated with KISUNLA, respectively, compared to 14%, 2%, and 13% of patients on placebo, respectively. There was no increase in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) for KISUNLA compared to placebo. In Study 2, symptomatic ARIA-E occurred in 3% of patients and symptomatic ARIA-H occurred in less than 1% of patients through 12 months of treatment with KISUNLA [ see Adverse Reactions ( 6.1 )] . Clinical symptoms associated with ARIA-E resolved in approximately 67% of patients at 12 months. Including asymptomatic radiographic events, ARIA, ARIA-E, and ARIA-H were observed in 29%, 16%, and 25% of patients treated with KISUNLA. Incidence of Intracerebral Hemorrhage Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% of patients treated with KISUNLA compared to 0.2% of patients on placebo in Study 1, and in 1% of patients treated with KISUNLA in Study 2. Fatal events of intracerebral hemorrhage in patients taking KISUNLA have been observed. Risk Factors for ARIA and Intracerebral Hemorrhage ApoE ε4 Carrier Status The risk of ARIA, including symptomatic and serious ARIA, is increased in apolipoprotein E ε4 (ApoE ε4) homozygotes, which include approximately 15% of Alzheimer's disease patients. In Study 1, of patients in the KISUNLA arm (n=850), 17% were ApoE ε4 homozygotes, 53% were heterozygotes, and 30% were noncarriers. The incidence of ARIA through 18 months was higher in ApoE ε4 homozygotes (55% on KISUNLA vs. 22% on placebo) than in heterozygotes (36% on KISUNLA vs. 13% on placebo) and noncarriers (25% on KISUNLA vs. 12% on placebo). Among patients treated with KISUNLA, symptomatic ARIA-E occurred in 8% of ApoE ε4 homozygotes compared with 7% of heterozygotes and 4% of noncarriers. Serious events of ARIA occurred in 3% of ApoE ε4 homozygotes, 2% of heterozygotes, and 1% of noncarriers. In Study 2, of patients treated with KISUNLA Dosing Regimen 2 (n=211), 10% were ApoE ε4 homozygotes, 55% were heterozygotes, and 36% were noncarriers. Symptomatic ARIA-E occurred in 0% of ApoE ε4 homozygotes compared with 4% of heterozygotes and 3% of noncarriers. The small number of events and limited exposure in the ApoE ε4 subgroups limit definitive conclusions about the risk of ARIA-E. The recommendations for management of ARIA do not differ based on ApoE ε4 carrier status [see Dosage and Administration ( 2.3 )] . Testing for ApoE ε4 status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes and the implications of genetic testing results. Prescribers should inform patients that if genotype testing is not performed, they can still be treated with KISUNLA; however, it cannot be determined if they are ApoE ε4 homozygotes and at a higher risk for ARIA. An FDA-authorized test for detection of ApoE ε4 alleles to identify patients at risk of ARIA if treated with KISUNLA is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accuracy and design. Radiographic Findings of Cerebral Amyloid Angiopathy (CAA) Neuroimaging findings that may indicate CAA include evidence of prior intracerebral hemorrhage, cerebral microhemorrhage, and cortical superficial siderosis. CAA has an increased risk for intracerebral hemorrhage. The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy. In Study 1, the baseline presence of at least 2 microhemorrhages or the presence of at least 1 area of superficial siderosis on MRI, which may be suggestive of CAA, were identified as risk factors for ARIA. Patients were excluded from enrollment in Study 1 for findings on neuroimaging of prior intracerebral hemorrhage greater than 1 cm in diameter, more than 4 microhemorrhages, more than 1 area of superficial siderosis, severe white matter disease, and vasogenic edema. Concomitant Antithrombotic or Thrombolytic Medication In Study 1, baseline use of antithrombotic medication (aspirin, other antiplatelets, or anticoagulants) was allowed. The majority of exposures to antithrombotic medications were to aspirin. The incidence of ARIA-H was 30% (106/349) in patients taking KISUNLA with a concomitant antithrombotic medication within 30 days compared to 29% (148/504) who did not receive an antithrombotic within 30 days of an ARIA-H event. […]

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 least 10% and higher incidence compared to placebo): ARIA-E, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) 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. Dosing Regimen and Safety A lower incidence of ARIA occurred with the dosing regimen administered in Study 2 (350 mg/700 mg/1,050 mg/1,400 mg; Dosing Regimen 2) as compared to the regimen administered in Study 1 (700 mg/700 mg/700 mg/1,400 mg; Dosing Regimen 1); therefore, Dosing Regimen 2 is recommended for administration of KISUNLA [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.2 ), Clinical Studies ( 14 )] . The safety of KISUNLA has been evaluated in 3727 patients with Alzheimer's disease who received at least one dose of KISUNLA intravenously. In the other clinical studies of KISUNLA, 1912 patients with Alzheimer's disease received KISUNLA once monthly for at least 6 months, 1057 patients for at least 12 months, and 432 patients for at least 18 months, at the Dosing Regimen 1. Study 1 In Study 1 (NCT04437511), a total of 853 patients with Alzheimer's disease received at least one dose of KISUNLA; patients were randomized to receive KISUNLA Dosing Regimen 1 or placebo. Thirteen percent of patients treated with KISUNLA compared to 4% of patients on placebo stopped study treatment because of an adverse reaction. The most common adverse reaction leading to discontinuation of KISUNLA was infusion-related reaction (4% of patients treated with KISUNLA compared to no patient on placebo). Table 7 shows adverse reactions that were reported in at least 5% of patients treated with KISUNLA and at least 2% more frequently than in patients on placebo in Study 1. Table 7: Adverse Reactions Reported in at Least 5% of Patients Treated With KISUNLA and at Least 2% Higher Than Placebo in Study 1 a Administered as a different titration regimen (700 mg/700 mg/700 mg/1,400 mg) than the currently recommended dosing regimen (350 mg/700 mg/1,050 mg/1,400 mg) b As assessed by MRI. A participant could have both microhemorrhage and superficial siderosis. Adverse Reaction KISUNLA a N = 853 % Placebo N = 874 % ARIA-H microhemorrhage b 25 11 ARIA-E 24 2 ARIA-H superficial siderosis b 15 3 Headache 13 10 Infusion-related reaction 9

0.5 Study 2 In Study 2 (NCT05738486), a total of 842 patients received at least one dose of KISUNLA; 212 patients were randomized to receive KISUNLA Dosing Regimen 2. In Study 2, compared to the rates reported with Dosing Regimen 1, higher rates of hypersensitivity reactions (8% of patients treated with Dosing Regimen 2) and infusion-related reactions (16% of patients treated with Dosing Regimen 2), and a lower rate of ARIA-E (16% of patients treated with Dosing Regimen 2) were observed [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14 )]. Less Common Adverse Reactions Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] Hypersensitivity reactions, including anaphylaxis, occurred in 3% of patients treated with KISUNLA compared to 0.7% of patients on placebo in Study 1 and in 8% of patients treated with KISUNLA Dosing Regimen 2 in Study 2. Intestinal Obstruction and Intestinal Perforation Serious adverse reactions of intestinal obstruction occurred in three patients (0.4%) treated with KISUNLA compared to no patients on placebo in Study 1 and one patient (0.5%) treated with KISUNLA Dosing Regimen 2 in Study 2. Serious adverse reactions of intestinal perforation occurred in two patients (0.2%) treated with KISUNLA compared to one patient (0.1%) on placebo in Study 1. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.6 )] Infusion-related reactions occurred more frequently in patients treated with KISUNLA who developed anti-drug antibodies (ADAs) compared to patients who did not develop ADAs (Study 1, Dosing Regimen 1: 10% compared to 2%; Study 2, Dosing Regimen 2: 20% compared to 8%).

8.1 Pregnancy Risk Summary There are no adequate data on KISUNLA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. No animal studies have been conducted to assess the potential reproductive or developmental toxicity of KISUNLA. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

8.2 Lactation Risk Summary There are no data on the presence of donanemab-azbt in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Published data from other monoclonal antibodies generally indicate low passage of monoclonal antibodies into human milk and limited systemic exposure in the breastfed infant. The effects of this limited exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KISUNLA and any potential adverse effects on the breastfed infant from KISUNLA or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use In Study 1, the age of patients exposed to KISUNLA ranged from 59 to 86 years, with a mean age of 73 years; 90% were 65 years and older, and 41% were 75 years and older. No overall differences in safety or effectiveness of KISUNLA have been observed between patients 65 years of age and older and younger adult patients. In Study 2, the range of patients exposed to KISUNLA ranged from 59 to 85 years, with mean age of 74 years; 93% were 65 years and older, 55% were 75 years and older. Study 2 did not include a sufficient number of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.

Donanemab-azbt is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer's disease. Donanemab-azbt reduces amyloid beta plaques, as evaluated in Study 1 [see Clinical Studies ( 14 )] .