Donanemab for early Alzheimer disease

Background:
Alzheimer disease (AD) is the commonest form of dementia and is characterised by cognitive decline, behavioural change and amyloid deposits in the brain that precede the formation of neurofibrillary (tau protein) tangles and neurodegeneration. Established treatments for AD (cholinesterase inhibitors and memantine) provide some cognitive and behavioural symptom relief but do not alter the course of the disease. Although the degree of amyloid deposition is not directly proportional to clinical impact, reducing amyloid has been a target in development of new drugs for treatment of AD¹ and several anti-amyloid monoclonal antibodies have been trialled.

Donanemab was the first anti-amyloid monoclonal antibody to be approved in Australia. Its approval is limited to patients with early symptomatic AD, who must also be heterozygotes or noncarriers of apolipoprotein ε4 (APOE ε4) because there is lower response to therapy and increased risk of adverse events in people who are homozygous for APOE ε4.^2,3

Mechanism of action:
Donanemab is a humanised immunoglobulin gamma (IgG) monoclonal antibody that binds to amyloid and activates immune cells, which remove amyloid deposits in the brain.

Clinical trials:
The key pre-registration study was a 76-week, phase 3, randomised, double-blind, multicentre, placebo-controlled trial with participants screened at 277 sites in 8 countries (TRAILBLAZER-ALZ 2).^1,4 Participants aged 60 to 85 years with early symptomatic AD and brain amyloid and tau pathology on positron emission tomography (PET) were randomised 1:1 to receive donanemab (700 mg for the first 3 doses then 1400 mg, 860 participants) or placebo (876 participants) as a 4-weekly infusion for up to 72 weeks. Amyloid PET scans were repeated at 24 and 52 weeks and participants were switched to placebo (still blinded) if reduction in amyloid was observed (dose completion criteria met). Patients also had magnetic resonance imaging (MRI) scans at 4, 12, 25, 52 and 76 weeks to screen for amyloid-related imaging abnormality (ARIA), including oedema or haemorrhage. Participants with any ARIA detected had scans every 4 to 6 weeks until abnormalities resolved or stabilised, or participation in the trial was stopped.^1,4

Compared with placebo, donanemab was effective at reducing amyloid plaques and the rate of tau formation; however, these were secondary outcomes.

The primary outcome measure was the integrated Alzheimer Disease Rating Scale (iADRS), a composite measure of cognitive and daily functioning that scores from 0 to 144, with lower scores indicating greater impairment.

For analysis of the iADRS, patients were stratified at baseline into 2 groups based on their level of tau pathology (low/medium or high, consistent with the hypothesis that less tau indicates earlier disease). There was a statistically significant difference in decline in iADRS score between the donanemab group (−6.02 low/medium tau, −10.2 overall population) and the placebo group (−9.27 low/medium tau, 13.1 overall population). However, the difference between the donanemab and placebo groups (3.25 points in those with low/medium tau and 2.92 points overall) did not meet the minimal clinically important difference of 5 points for those with clinically mild cognitive impairment and 9 points for those assessed as having mild AD.^1,3,4

In a long-term extension study,⁵ patients who had achieved amyloid clearance on donanemab (plaque levels less than 24.1 centiloids) within 1 year continued 4-weekly placebo infusions out to 3 years. The rate of amyloid reaccumulation was comparable to the natural history of the disease and, when compared against a matched external group of patients who were amyloid-targeting therapy–naïve, treatment benefit continued to be evident out to 3 years.⁵

Adverse effects:
In the TRAILBLAZER-ALZ 2 trial, the most frequently reported adverse effects were ARIAs, with either oedema (ARIA-E) or haemorrhage (ARIA-H), and infusion-related reactions. ARIAs occurred in 36.8% of those receiving donanemab and 14.9% receiving placebo. Most of the ARIAs were mild to moderate, not symptomatic and spontaneously resolved.⁴ Infusion-related reactions, including hypersensitivity and anaphylaxis, were reported in 8.5% of the donanemab treatment group and 0.4% in the placebo group.²

Treatment was discontinued due to ARIAs and infusion-related reactions in 13.1% of participants receiving donanemab and 4.3% receiving placebo.⁴ A modified dosing regimen with a lower starting dose was trialled in TRAILBLAZER-ALZ 6 and reported lower rates of ARIAs;⁶ this has been adopted as the approved dosage regimen.²

Dosage and administration:
Donanemab is diluted in normal saline and administered every 4 weeks by intravenous infusion over at least 30 minutes. The recommended dose is 350 mg for the first dose, 700 mg for the second dose, 1050 mg for the third dose, and 1400 mg for the fourth and subsequent doses.²

Treatment with donanemab requires ongoing regular brain imaging to monitor amyloid and detect ARIAs. Treatment can be continued for up to 18 months and can be stopped sooner if amyloid clearance is confirmed by imaging.² Dosing interruption or cessation is recommended when moderate or severe asymptomatic ARIA are detected, and when symptomatic ARIA occurs.²

Precautions:
Donanemab should only be administered in specialist centres experienced in managing infusion reactions and with the expertise and capacity to detect, monitor and manage ARIAs.²

Place in therapy:
Donanemab effectively removes amyloid and can slow, but does not prevent, decline in early symptomatic AD. It is not indicated in people with more advanced AD or non-AD dementias. Use is limited by stringent eligibility and monitoring requirements, risk of harm, modest impact on functional improvement and cost (both time and financial commitment). Treatment is limited to 18 months and longer-term benefits and harms are unknown.

The pre-registration trial had an extensive list of exclusion criteria, so patients with concomitant medical conditions, many of which are typical of the population with AD, were not included, thereby potentially limiting the generalisability of the study results.¹ It has been estimated that fewer than 10% of people with AD would be eligible for donanemab therapy based on the inclusion criteria used in the clinical trial.^1,3

Ongoing research is evaluating donanemab in preclinical AD for potential use as preventive therapy in those with amyloid plaques who are asymptomatic (TRAILBLAZER-ALZ 3).⁷ No data are yet available, and this is not an approved indication. Biomarkers for diagnosis of AD are likely to be available in the foreseeable future to facilitate earlier identification of preclinical AD, and potentially other dementias, and have implications for therapies that could prevent or delay progression of disease.

A recent Cochrane review⁸ and Lancet commentary⁹ conclude that anti-amyloid monoclonal antibody therapy reduces amyloid without clinically significant benefit.

At the time of writing, donanemab is not listed on the Australian Pharmaceutical Benefits Scheme and has very limited availability.

This new drug comment was finalised on 25 June 2026. It was prepared by Mary Belfrage, Clinical Editor, Australian Prescriber, and reviewed by Louise Waite, Senior Staff Specialist Geriatrician, Head of Department, Geriatric Medicine, Clinical Professor, Concord Clinical School, University of Sydney and Peter Gonski, Associate Professor, University of New South Wales, Senior Geriatrician, Sutherland Hospital, South Eastern Sydney Local Health District.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

This article is peer reviewed.

 

References

1. Therapeutic Goods Administration. Australian Public Assessment Report for Kisunla. Department of Health, Disability and Ageing; 2025. [cited 2026 Jun 1]
2. Therapeutic Goods Administration. Australian Product Information - KISUNLA donanemab. Department of Health, Disability and Ageing; 2025. [cited 2026 Jun 1]
3. Waite LM. New and emerging drug therapies for Alzheimer disease. Aust Prescr 2024;47:75–9.
4. Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA 2023;330:512–27.
5. Zimmer JA, Sims JR, Evans CD, Nery ESM, Wang H, Wessels AM, et al. Donanemab in early symptomatic Alzheimer's disease: results from the TRAILBLAZER-ALZ 2 long-term extension. J Prev Alzheimers Dis 2026;13:100446.
6. Wang H, Serap Monkul Nery E, Ardayfio P, Khanna R, Otero Svaldi D, Gueorguieva I, et al. Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction. Alzheimers Dement 2025;21:e70062.
7. Pugh MAM. TRAILBLAZER-ALZ 3 – A Deeper Dive into Time-to-Event Trials. Alzheimer's & Dementia 2023;19:e070865.
8. Nonino F, Minozzi S, Sambati L, Del Giovane C, Baldin E, Bassi MC, et al. Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Cochrane Database Syst Rev 2026;4:CD016297.
9. Siva N. From hope to uncertainty: regulating novel drugs for Alzheimer's disease. The Lancet 2026;407:2158–62.

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by subject matter experts. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

Report all suspected adverse reactions to new drugs to enable continued monitoring of their benefit–harm balance.