In older adults with early symptomatic Alzheimer’s disease, does Kisunla (donanemab‑azbt) stop disease progression?

Does Kisunla Stop Progression of Alzheimer's Disease?

Kisunla (donanemab) does not stop Alzheimer's disease progression—it slows cognitive and functional decline by approximately 30-36% compared to placebo in patients with early symptomatic disease, but the disease continues to progress. 1, 2, 3

What Donanemab Actually Does

Disease-Modifying, Not Disease-Stopping

• Donanemab targets and removes amyloid-β plaques from the brain, achieving 60-85 Centiloid unit reductions in Phase III trials, but this plaque clearance translates to slowing—not halting—clinical decline. 2, 4

• In the TRAILBLAZER-ALZ 2 trial, donanemab slowed decline on the integrated Alzheimer's Disease Rating Scale (iADRS) by 35% and on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) by 36% at 76 weeks compared to placebo. 4, 3

• The Phase 2 TRAILBLAZER-ALZ trial showed a 3.20-point difference in iADRS scores favoring donanemab over placebo (P=0.04), but both groups still experienced decline from baseline—donanemab patients declined by 6.86 points while placebo patients declined by 10.06 points. 3

Who Benefits Most

Patient Selection Determines Outcomes

• Donanemab is FDA-approved only for adults with early symptomatic Alzheimer's disease—specifically those with mild cognitive impairment (MCI) or mild dementia stage with confirmed amyloid pathology. 1, 5

• Patients with low-to-medium tau burden show optimal clinical benefit, while those with high tau burden demonstrate reduced efficacy, making tau PET stratification crucial for treatment decisions. 2, 4

• The drug is explicitly inappropriate for cognitively unimpaired individuals, even with positive amyloid biomarkers, as they are in a preclinical stage where disease-modifying therapy is not indicated. 1, 2

Unique Treatment Feature

Potential for Treatment Cessation

• Unlike lecanemab which requires ongoing therapy, donanemab allows treatment cessation once amyloid clearance is achieved (below 24.1 Centiloids), with off-treatment amyloid increases of only 2.80 Centiloid units per year. 2

• This represents a practical advantage, though patients must undergo amyloid PET quantification to determine when clearance thresholds are met. 2

Critical Safety Considerations

Amyloid-Related Imaging Abnormalities (ARIA)

• ARIA—including cerebral edema (ARIA-E) and microhemorrhages (ARIA-H)—occurs in a substantial proportion of patients, with APOE ε4 carriers being approximately 4 times more likely to experience ARIA-E events by 24 weeks regardless of serum exposure levels. 2, 4

• Mandatory MRI monitoring is required before the 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) to detect ARIA, which may necessitate temporary or permanent treatment cessation and corticosteroid therapy. 1, 4

• Baseline brain MRI is essential before treatment initiation to screen for contraindications including macrohemorrhages, microhemorrhages, superficial siderosis, and significant white matter hyperintensities. 1, 2

Required Diagnostic Workup

Objective Cognitive Impairment Must Be Documented

• A Montreal Cognitive Assessment (MoCA) score ≤25 or comprehensive neuropsychological battery showing impairment in ≥1 cognitive domain is required to establish the objective cognitive impairment necessary for FDA-approved donanemab therapy. 1

• Clinical Dementia Rating (CDR) score of 0.5 (MCI) or 1.0 (mild dementia) must be documented to assess disease severity. 1

• Biomarker confirmation requires either amyloid PET showing >30 Centiloids, abnormal CSF Aβ42/40 ratio with elevated p-tau, or validated blood-based biomarkers such as plasma p-tau217 (which has 0.92-0.98 area-under-curve accuracy for predicting amyloid status). 6, 2

Implementation Requirements

Specialized Infrastructure Needed

• Treatment requires multidisciplinary teams with specialized training in ARIA detection and management, as safe administration cannot occur in standard primary care settings. 1, 2

• Enrollment in a CMS-approved registry is mandatory for Medicare reimbursement, adding administrative burden to treatment initiation. 1, 2

• Hub-and-spoke care models are being developed to address specialist shortages and expand access, but availability remains limited. 6, 2

Common Pitfall to Avoid

Biomarker Positivity ≠ Treatment Indication

• Positive plasma biomarkers (such as Aβ42/40 ratio or p-tau217) indicate increased risk of future cognitive decline and are appropriate for risk stratification, but do not alone justify treatment in the absence of documented objective cognitive impairment. 1

• Patients with subjective cognitive decline who lack objective impairment on formal testing should not receive donanemab, as they do not meet FDA-approved diagnostic criteria. 1, 2

Bottom Line on "Stopping" Progression

The term "stop" is misleading—donanemab slows the rate of cognitive and functional decline by roughly one-third compared to natural disease progression, but patients continue to worsen over time. 4, 3 The drug modifies the disease trajectory rather than arresting it, and benefits are most pronounced in carefully selected patients with early symptomatic disease and low-to-medium tau burden. 2, 4