What are the recommended dosing titration, MRI monitoring schedule, and discontinuation criteria for Kisunla (donanemab‑azbt) in adults with early‑symptomatic Alzheimer disease (mild cognitive impairment or mild dementia with amyloid‑positive PET or CSF)?

Kisunla (Donanemab-azbt) Dosing and Monitoring Protocol for Early Alzheimer's Disease

Kisunla should be administered at 700 mg IV every 4 weeks for the first three infusions, then escalated to 1400 mg IV every 4 weeks thereafter, with mandatory MRI surveillance before the 2nd, 3rd, 4th, and 7th infusions to monitor for amyloid-related imaging abnormalities (ARIA). 1, 2

Patient Eligibility Requirements

Before initiating Kisunla, confirm the following diagnostic criteria:

• Clinical stage: Mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease (Clinical Stages 3-4, MMSE 20-30) 2, 3
• Biomarker confirmation: Documented amyloid pathology via amyloid PET or CSF assay (Aβ42/40 ratio or elevated p-tau) 1, 2
• Functional status: CDR score of 0.5 (MCI) or 1.0 (mild dementia) with documented functional impairment 4, 2
• Objective cognitive impairment: MoCA score ≤25 or comprehensive neuropsychological testing showing impairment in ≥1 cognitive domain 4

Critical caveat: Kisunla is NOT indicated for cognitively unimpaired individuals with positive biomarkers alone, even if they have preclinical amyloid pathology 4

Dosing Titration Schedule

The FDA-approved dosing regimen follows a two-phase approach 1:

• Phase 1 (Infusions 1-3): 700 mg IV every 4 weeks
• Phase 2 (Infusion 4 onward): 1400 mg IV every 4 weeks
• Infusion duration: Approximately 30 minutes per infusion 1
• Missed dose management: Resume at the same dose as soon as possible, maintaining the 4-week interval 1

Pre-Treatment Safety Assessment

Mandatory Baseline Evaluation

• Baseline MRI: Obtain within 12 months prior to first infusion to assess for pre-existing ARIA and vascular pathology 1, 2
• APOE genotyping: Required to stratify ARIA risk (APOE ε4 carriers have higher risk) 2
• Exclusion criteria on MRI: >4 cerebral microbleeds, cortical superficial siderosis, or major vascular contribution to cognitive impairment 2

MRI Monitoring Schedule for ARIA Surveillance

Mandatory surveillance MRIs must be obtained at the following timepoints 1, 2:

1. Before 2nd infusion (approximately week 4)
2. Before 3rd infusion (approximately week 8)
3. Before 4th infusion (approximately week 12)
4. Before 7th infusion (approximately week 24)
5. Before 12th infusion in higher-risk individuals (APOE ε4 carriers) 2
6. Any time ARIA is clinically suspected (headache, confusion, visual disturbances, seizures) 1, 2

Common pitfall: Failure to obtain pre-infusion MRIs can result in undetected ARIA, which occurred in 24-30.5% of treated patients in clinical trials 5, 6

ARIA Management and Dosing Interruption Criteria

ARIA-E (Edema/Effusion) Management 1

Asymptomatic ARIA-E:

• Mild: May continue dosing at current schedule
• Moderate: Suspend dosing until radiographic resolution
• Severe: Suspend dosing until radiographic resolution

Symptomatic ARIA-E:

• Mild symptoms: May continue based on clinical judgment for mild ARIA-E; suspend for moderate/severe ARIA-E
• Moderate/severe symptoms: Suspend dosing regardless of ARIA-E severity

ARIA-H (Hemosiderin Deposition) Management 1

Asymptomatic ARIA-H:

• Mild: May continue dosing
• Moderate or severe: Suspend dosing until radiographic stabilization

Symptomatic ARIA-H:

• Any severity: Suspend dosing until radiographic stabilization

Intracerebral hemorrhage >1 cm: Suspend dosing until radiographic stabilization; use clinical judgment regarding resumption 1

Resumption Criteria

• Follow-up MRI: Obtain 2-4 months after initial ARIA identification to assess resolution or stabilization 1
• Clinical resolution: Symptoms must resolve before resuming treatment 1
• Permanent discontinuation: Consider if severe or recurrent ARIA occurs 1

Treatment Discontinuation Criteria

Amyloid Clearance-Based Discontinuation

Consider stopping Kisunla when amyloid plaques are reduced to minimal levels 1, 2:

• Timing: Typically assessed at 12-18 months after treatment initiation 2
• Confirmation method: Amyloid PET showing plaque level <24.1 centiloids 1
• Clinical trial data: In TRAILBLAZER-ALZ studies, patients achieving amyloid clearance were transitioned to placebo in a blinded manner 1, 6

This represents a unique feature of donanemab compared to other anti-amyloid therapies—treatment can be finite rather than indefinite once therapeutic goal is achieved 2, 7

Safety-Based Discontinuation

Permanently discontinue Kisunla for 1, 2:

• Severe or life-threatening ARIA that does not resolve
• Intracerebral hemorrhage >1 cm with clinical deterioration
• Recurrent symptomatic ARIA despite dose interruptions
• Treatment-related serious adverse events

Important safety note: Three deaths in clinical trials were considered treatment-related, primarily associated with ARIA complications 6

Additional Implementation Requirements

• Multidisciplinary team: Treatment requires specialized teams trained in ARIA recognition and management 8, 4
• CMS registry enrollment: Required for Medicare reimbursement 8, 4
• Shared decision-making: Discuss risks (24-30.5% ARIA rate), benefits (slowing of cognitive decline by 3.25 points on iADRS at 76 weeks), and treatment burden with patients and caregivers 2, 6

Practical consideration: The intensive monitoring schedule and ARIA management requirements necessitate close collaboration between primary care, neurology, radiology, and infusion services 8