Drug Update · Neurology

FDA Approves donanemab for Alzheimer: iADRS Benefit 2.92 Points

July 10, 2026

iADRS benefit (Study 1)

2.92-point smaller decline versus placebo at Week 76 [12]

CDR‑SB difference

-0.70 (29% slowing of decline) versus placebo at Week 76 [12]

ARIA‑E frequency (placebo-controlled)

24.4% with donanemab vs 1.9% with placebo [1]

ARIA‑H frequency (placebo-controlled)

31.3% with donanemab vs 13.0% with placebo [1]

Approval date

2024-07-02 (FDA) [12]

Approved dosing (intravenous)

Infusion 1: 350 mg; Infusion 2: 700 mg; Infusion 3: 1,050 mg; Infusion 4+: 1,400 mg every 4 weeks [5][12]

Clinical Perspective

Neurologists, geriatricians, and other clinicians treating patients with early symptomatic Alzheimer's disease should consider KISUNLA for patients with confirmed amyloid beta pathology who are in the mild cognitive impairment or mild dementia stage, consistent with the trial population and FDA indication ^[2]^[4]. The FDA label supports MRI monitoring prior to initiation and at specified infusions, and notes increased ARIA risk in ApoE ε4 homozygotes and in patients with baseline microhemorrhages or superficial siderosis ^[2]^[4]. Because dosing can be stopped based on amyloid PET thresholds, clinicians will need access to amyloid PET imaging and a plan for serial imaging and MRI monitoring when using KISUNLA ^[2]^[4].

Dr. Aditi Kulkarni, MBBS, MD (General Medicine), DM (Neurology) · Neurology

The FDA approved donanemab (KISUNLA) for the treatment of Alzheimer's disease on 2024-07-02 based on Study 1 (NCT04437511) showing a 2.92-point smaller decline on the integrated Alzheimer's Disease Rating Scale (iADRS) versus placebo at Week 76 ^[4]. The approval specifies initiation in patients with mild cognitive impairment or mild dementia stage of disease, consistent with the trial population ^[2]^[4].

Clinical Context

Donanemab-azbt (KISUNLA) is an amyloid beta-directed monoclonal antibody developed by Eli Lilly and Company that targets insoluble N-truncated pyroglutamate amyloid beta and reduces amyloid beta plaques in the brain ^[4]. The FDA label indicates treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of Alzheimer's disease and requires confirmation of amyloid pathology before starting therapy ^[2]^[4]. Dosing is by intravenous infusion every 4 weeks with a recommended titration schedule; MRI monitoring for amyloid-related imaging abnormalities (ARIA) is specified in the label ^[2]^[4]. Clinicians should consult current prescribing information for full dosing guidance. Study 2 evaluated alternative titration regimens and aimed to compare effects on amyloid plaque reduction and ARIA incidence versus the original dosing regimen ^[4].

Key Findings

The pivotal Study 1 (NCT04437511) showed that KISUNLA (donanemab-azbt) reduced decline on the integrated Alzheimer's Disease Rating Scale (iADRS) by 2.92 points versus placebo at Week 76 in the combined trial population (statistical significance p<0.0001) ^[4].
In Study 1 the Clinical Dementia Rating Scale–Sum of Boxes (CDR‑SB) adjusted mean change from baseline was 1.72 with KISUNLA versus 2.42 with placebo, a difference of -0.70 representing a 29% slowing of decline versus placebo (p<0.0001) ^[4].
Secondary cognitive and functional measures (ADAS‑Cog 13 and ADCS‑iADL) also favored KISUNLA at Week 76 (ADAS‑Cog 13 adjusted mean difference -1.33, 20% slowing; ADCS‑iADL adjusted mean difference 1.70, 28% slowing) ^[4].
Amyloid imaging informed treatment duration: in Study 1 the percentages of patients eligible to stop dosing based on amyloid PET thresholds were 17% at Week 24, 47% at Week 52, and 69% at Week 76, reflecting substantial plaque reduction by PET ^[4]. Study 2 evaluated dosing regimens with comparable pharmacodynamic effects on amyloid plaque reduction and reduced ARIA-related events versus the original regimen ^[4].

Safety & Tolerability

In the placebo-controlled trials, frequencies of ARIA‑E (ARIA with edema/effusion) and ARIA‑H (ARIA with microhemorrhages and hemosiderin deposition) were higher with donanemab: ARIA‑E 24.4% and ARIA‑H 31.3% versus placebo ARIA‑E 1.9% and ARIA‑H 13.0% ^[1].
In the open‑label addendum, ARIA‑E was 19.8% and ARIA‑H 27.2% with donanemab ^[1].
Serious ARIA‑E occurred in 1.5% and symptomatic ARIA‑E in 5.8% of donanemab‑treated participants in the placebo‑controlled trials; the symptoms most frequently reported with ARIA‑E were headache and confusional state ^[1].
The label highlights ARIA (both ARIA‑E and ARIA‑H), infusion‑related reactions, and hypersensitivity including anaphylaxis as important warnings and precautions; the most common adverse reactions (≥10% and greater than placebo) listed include ARIA‑E, ARIA‑H microhemorrhage, ARIA‑H superficial siderosis, and headache ^[2]^[3].

Study Design

Study 1 (NCT04437511) was a double‑blind, placebo‑controlled, parallel‑group randomized trial in patients with early symptomatic Alzheimer's disease (MMSE ≥20 and ≤28) who had confirmed amyloid pathology and met tau PET criteria; 1,736 patients were randomized 1:1 to donanemab Dosing Regimen 1 (N = 860) or placebo (N = 876) for up to 72 weeks ^[4]. The primary efficacy endpoint was change in the integrated Alzheimer's Disease Rating Scale (iADRS) from baseline to Week 76 ^[4]. Study 2 investigated alternative titration regimens and their effects on ARIA and amyloid plaque reduction ^[4]. Additional prespecified imaging‑guided rules allowed stopping dosing when amyloid PET Centiloid thresholds were reached ^[4].

FAQ

Q1 What is donanemab (KISUNLA) approved for?

Donanemab‑azbt (KISUNLA) is indicated for the treatment of Alzheimer's disease and treatment should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population enrolled in the pivotal trials. Confirmatory amyloid testing is required prior to initiating treatment. Clinicians should consult current prescribing information for full dosing guidance.

Q2 How does donanemab work?

Donanemab‑azbt is a humanized IgG1 monoclonal antibody directed against insoluble N‑truncated pyroglutamate amyloid beta. The mechanism is reduction of amyloid beta plaques in the brain, as evaluated in the clinical studies supporting approval.

Q3 What is the recommended dose of donanemab (KISUNLA)?

KISUNLA is administered by intravenous infusion every 4 weeks with the following recommended titration: Infusion 1: 350 mg; Infusion 2: 700 mg; Infusion 3: 1,050 mg; Infusion 4 and beyond: 1,400 mg. The label recommends baseline and interval MRI monitoring and allows consideration of stopping dosing based on reduction of amyloid plaques to predefined PET thresholds. Clinicians should consult current prescribing information for complete dosing guidance.

Q4 What are the most common side effects of donanemab?

The most common adverse reactions listed in the label include amyloid related imaging abnormalities with edema (ARIA‑E), ARIA‑H microhemorrhage, ARIA‑H superficial siderosis, and headache. Infusion‑related reactions and hypersensitivity including anaphylaxis are described in the warnings and precautions. In the placebo‑controlled trials, ARIA‑E and ARIA‑H were more frequent with donanemab than with placebo; serious ARIA‑E and symptomatic ARIA‑E were observed and the most frequent symptoms reported with ARIA‑E included headache and confusional state. If symptoms suggestive of ARIA occur, clinical evaluation and MRI are recommended.

FDA Approves donanemab for Alzheimer: iADRS Benefit 2.92 Points

Direct Clinical Takeaway & Evidence Summary

FDA Approves donanemab for Alzheimer: iADRS Benefit 2.92 Points

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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