Monitoring for ARIA

Obtain a recent brain magnetic resonance imaging (MRI) prior to initiating treatment with ADUHELM. Obtain MRIs prior to the 5th infusion (first dose of 6 mg/kg), 7th infusion (first dose of 10 mg/kg), 9th infusion (third dose of 10 mg/kg), and 12th infusion (sixth dose of 10 mg/kg). 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

If dosing is resumed following a temporary suspension, dosing may resume at that same dose and titration schedule prior to the dosing suspension. The benefits of reaching and maintaining the 10 mg/kg dosage should be considered when evaluating a potential dose suspension.

Incidence of ARIA

Symptomatic ARIA occurred in 10% (110/1105) of patients treated with ADUHELM in Studies 1 and 2. Serious symptoms associated with ARIA were reported in 0.3% of patients treated with ADUHELM. Clinical symptoms associated with ARIA resolved in 88% of patients during the period of observation. Overall, recurrent episodes of ARIA-E were less frequently symptomatic (12%) compared with initial episodes of ARIA-E (25%).

Including asymptomatic radiographic events, ARIA was observed in 41% (454/1105) of patients treated with ADUHELM 10mg/kg compared to 10% (111/1087) of patients on placebo in Studies 1 and 2.

ARIA-E was observed in 35% (387/1105) of patients treated with ADUHELM 10 mg/kg compared with 3% (29/1087) of patients on placebo. ARIA-H was observed in 28% (312/1105) of patients treated with ADUHELM compared to 9% (94/1087) of patients on placebo. There was no increase in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) for ADUHELM compared to placebo.

The overall incidence of seizure, independent of ARIA, was 0.5% in the 10 mg/kg ADUHELM group and 0.8% in the placebo group in Studies 1 and 2. In patients with ARIA in the 10 mg/kg ADUHELM group, the incidence of seizure was 0.7%. Status epilepticus was reported in the placebo-controlled and long-term extension studies in patients treated with ADUHELM.

ApoE ε4 Carrier Status and Risk of ARIA

Approximately 15% of Alzheimer's disease patients are ApoE ε4 homozygotes. In Studies 1 and 2, among patients with a known ApoE ε4 genotype, 17% (182/1103) of patients in the ADUHELM group were ApoE ε4 homozygotes, 51% (564/1103) were heterozygotes, and 32% (357/1103) were noncarriers. The incidence of symptomatic ARIA was higher in ApoE ε4 homozygotes (16%) than in heterozygotes (11%) and noncarriers (5%) among patients treated with ADUHELM. However, the incidence of serious adverse reactions with ARIA-E, including risk of death, persistent or significant disability or incapacity, hospitalization, or other medically important event that may require intervention to prevent serious outcomes, was similar for ApoE ε4 carriers and noncarriers (2% in homozygotes, 1% in heterozygotes, 2% in noncarriers). The recommendations on management of ARIA do not differ between ApoE ε4 carriers and noncarriers [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 ADUHELM; 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 ADUHELM is not currently available. Currently available tests used to identify ApoE ε4 alleles may vary in accurary and design.

Radiographic Findings

The radiographic severity of ARIA associated with ADUHELM was classified by the criteria shown in Table 4.

The majority of ARIA-E radiographic events occurred early in treatment (within the first 8 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 ADUHELM was mild in 10% (115/1105) of patients, moderate in 20% (223/1105) of patients, and severe in 4% (49/1105) of patients. Resolution on MRI occurred in 68% of ARIA-E patients by 12 weeks, 91% by 20 weeks, and 98% overall after detection. The maximum radiographic severity of ARIA-H microhemorrhage in patients treated with ADUHELM was mild in 14% (154/1105) of patients, moderate in 3% (29/1105) of patients, and severe in 3% (29/1105) patients. The maximum radiographic severity of ARIA-H superficial siderosis in patients treated with ADUHELM was mild in 7% (79/1105) of patients, moderate in 4% (47/1105) of patients, and severe in 3% (36/1105) of patients. Among patients treated with ADUHELM, the incidence of severe radiographic ARIA-E was highest in ApoE ε4 homozygotes 11% (20/182), compared to heterozygotes 4% (21/564) or noncarriers 2% (8/357). Among patients treated with ADUHELM, the incidence of severe radiographic ARIA-H (microhemorrhage or superficial siderosis) was highest in ApoE ε4 homozygotes 20% (36/182), compared to heterozygotes 4% (21/564) or noncarriers 2% (6/357).

Intracerebral Hemorrhage

Intracerebral hemorrhage greater than 1 cm in diameter was reported in 0.5% (6/1105) of patients in Studies 1 and 2 after treatment with ADUHELM compared to 0.4% (4/1087) of patients on placebo. Fatal events of intracerebral hemorrhage in patients taking ADUHELM have been observed.

Concomitant Antithrombotic Medication

Patients were excluded from enrollment in Studies 1 and 2 for use of antiplatelet or anticoagulant medications other than 325 mg or less daily of aspirin. Although patients were allowed to receive aspirin in daily doses of 325 mg or less, some patients, because of intercurrent medical events that occurred after enrollment and required treatment, received aspirin in doses greater than 325 mg, other antiplatelet drugs, or anticoagulants during Studies 1 and 2. Patients who received ADUHELM and an antithrombotic medication (aspirin, other antiplatelets, or anticoagulants ) did not have an increased risk of ARIA-H or intracerebral hemorrhage compared to patients who received placebo and an antithrombotic medication. The majority of 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 greater than 1 cm in diameter have been observed in patients taking ADUHELM, additional caution should be exercised when considering the administration of anticoagulants or a thrombolytic agent (e.g., tissue plasminogen activator) to a patient already being treated with ADUHELM.

Other Risk Factors for Intracerebral Hemorrhage

Patients were excluded from enrollment in Studies 1 and 2 for findings on neuroimaging that indicated an increased risk for intracerebral hemorrhage. These included findings suggestive of cerebral amyloid angiopathy (prior intracerebral hemorrhage greater than 1 cm in diameter, more than 4 microhemorrhages, superficial siderosis, and history of diffuse white matter disease). Vasogenic edema could also be suggestive of cerebral amyloid angiopathy. These and other lesions (aneurysm, vascular malformation) could potentially increase the risk of intracerebral hemorrhage.

The presence of an ApoE ε4 allele is also associated with cerebral amyloid angiopathy which has an increased risk for intracerebral hemorrhage.

Caution should be exercised when considering the use of ADUHELM in patients with factors that indicate an increased risk for intracerebral hemorrhage and in particular for patients who need to be on anticoagulant therapy.

Monitoring and Dose Management Guidelines

Recommendations for dosing in patients with ARIA-E depend on clinical symptoms and radiographic severity [see Dosage and Administration (2.3)]. Recommendations for dosing in patients with ARIA-H depend on the type of ARIA-H and radiographic severity [see Dosage and Administration (2.3)]. Use clinical judgment in considering whether to continue dosing in patients with recurrent ARIA-E.

Baseline brain MRI and periodic monitoring with MRI are recommended [see Dosage and Administration (2.3)]. Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with ADUHELM, particularly during titration. 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 limited experience in patients who continued dosing through symptomatic ARIA-E or through asymptomatic moderate or severe ARIA-E. There are limited data in dosing patients who experienced recurrent ARIA-E.

The Alzheimer's Network for Treatment and Diagnostics (ALZ-NET) is a voluntary provider-enrolled patient registry that collects information on treatments for Alzheimer's disease, including ADUHELM. Providers may obtain information about the registry at www.alz-net.org or contact alz-net@acr.org.

Risk Summary

There are no adequate data on ADUHELM use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

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.

Data

Risk Summary

There are no data on the presence of aducanumab-avwa 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 ADUHELM and any potential adverse effects on the breastfed infant from ADUHELM or from the underlying maternal condition.

Effect of ADUHELM on Amyloid Beta Pathology

ADUHELM reduced amyloid beta plaque in a dose- and time-dependent manner in Study 1, Study 2, and Study 3, compared with placebo [see Dosage and Administration (2.2) and Clinical Studies (14)].

The effect of ADUHELM on amyloid beta plaque levels in the brain was evaluated using PET imaging (18F-florbetapir tracer). The PET signal was quantified using the Standard Uptake Value Ratio (SUVR) method to estimate brain levels of amyloid beta plaque in composites of brain areas expected to be widely affected by Alzheimer's disease pathology (frontal, parietal, lateral temporal, sensorimotor, and anterior and posterior cingulate cortices), compared to a brain region expected to be spared of such pathology (cerebellum). The SUVR was also expressed on the Centiloid scale.

In substudies of Study 1 and Study 2, ADUHELM reduced amyloid beta plaque levels in the brain, producing reductions at both ADUHELM low dose and high dose levels and at both Weeks 26 and 78 (p < 0.0001), compared to placebo. The magnitude of reduction was time- and dose-dependent. In the long-term extension of Study 1 and Study 2, a continued decrease in brain amyloid beta plaque levels was observed at Week 132 in patients initially randomized to ADUHELM.

In Study 3, ADUHELM reduced amyloid beta plaque levels in the brain, producing statistically significant dose- and time-dependent reductions compared to placebo in the 3 mg/kg, 6 mg/kg, and 10 mg/kg ADUHELM treatment groups at Week 26, and in all ADUHELM treatment groups at Week 54. Among those dosed with ADUHELM during the placebo-controlled period in Study 3, amyloid beta plaque levels in the brain continued to decline in a time- and dose-dependent manner in the long-term extension period through Week 222.

Effect of ADUHELM on Tau Pathophysiology

ADUHELM reduced markers of tau pathophysiology (CSF p-Tau 181, plasma p-Tau 181, and Tau PET) and neurodegeneration (CSF t-Tau) in Study 1 and Study 2 [see Clinical Studies (14)].

ADUHELM reduced CSF levels of p-Tau 181 in substudies conducted in Study 1 and Study 2. The adjusted mean change from baseline in CSF p-Tau 181 levels relative to placebo was in favor of the ADUHELM low (p<0.01) and high (p<0.001) dose groups at Week 78 in Study 1. Results in Study 2 numerically favored ADUHELM but were not statistically significant.

In Study 1 and Study 2, ADUHELM reduced plasma p-tau 181 levelscompared to placebo. In the long-term extension of Study 1 and Study 2, a continued decrease in plasma p-Tau 181 levels was observed at the high dose through Week 128 in patients initially randomized to ADUHELM.

ADUHELM reduced CSF levels of t-Tau in substudies conducted in Study 1 and Study 2. The adjusted mean change from baseline in CSF t-Tau levels relative to placebo was in favor of the ADUHELM low (p<0.05) and high (p<0.01) dose groups at Week 78 in Study 1. Results in Study 2 numerically favored ADUHELM but were not statistically significant.

Substudies were conducted in both Study 1 and Study 2 to evaluate the effect of ADUHELM on neurofibrillary tangles composed of tau protein using PET imaging (18F-MK6240 tracer). The PET signal was quantified using the SUVR method to estimate brain levels of tau in brain regions expected to be affected by Alzheimer's disease pathology (medial temporal, temporal, frontal, cingulate, parietal, and occipital cortices) in the study population compared to a brain region expected to be spared of such pathology (cerebellum). Data from the substudies were pooled, comprising 37 patients with longitudinal follow-up. The adjusted mean change from baseline in tau PET SUVR relative to placebo at follow-up was in favor of ADUHELM high dose in the medial temporal (p<0.001), temporal (p<0.05), and frontal (p<0.05) brain regions. No statistically significant differences were observed for the cingulate, parietal, or occipital cortices.

Exposure-Response Relationships

Model based exposure-response analyses for Studies 1 and 2 demonstrated that higher exposures to ADUHELM were associated with greater reduction in clinical decline on CDR-SB, ADAS-Cog13, and ADCS-ADL-MCI. In addition, higher exposures to ADUHELM were associated with greater reduction in amyloid beta plaque in Studies 1 and 2. An association between reduction in amyloid beta plaque and clinical decline on CDR-SB was also observed.

Higher exposures to ADUHELM were associated with greater reduction in plasma p-Tau 181.

An association between reduction in plasma p-Tau 181 and reduction in Amyloid PET SUVR was observed. An association between reduction in plasma p-Tau 181 and reduced clinical decline on CDR-SB, ADAS-Cog 13, and ADCS-ADL-MCI was also observed.

Distribution

The mean value (95% CI) for volume of distribution at steady state is 9.63 L (9.48, 9.79).

Elimination

ADUHELM is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. ADUHELM clearance (95% CI) is 0.0159 (0.0156, 0.0161) L/hr. The terminal half-life is 24.8 (14.8, 37.9) days.

Specific Populations

Body weight, age, sex, and race were found to impact exposure to ADUHELM. However, none of these covariates were found to be clinically significant.

Carcinogenesis

Carcinogenicity studies have not been conducted.

Mutagenesis

Genotoxicity studies have not been conducted.

Impairment of Fertility

Intravenous administration of aducanumab-avwa (0, 100, 300, or 1000 mg/kg/week) to male and female rats prior to and during mating and continuing in females to gestation day 7 resulted in no adverse effects on fertility or reproductive performance.

The relevance of these data to humans is limited because aggregated amyloid beta, the pharmacological target of aducanumab-avwa, is not present in rat.