New Analysis of Donanemab (KISUNLA) Supports Do Not Use Designation

In July 2024 the Food and Drug Administration (FDA) approved donanemab (KISUNLA) to treat Alzheimer’s disease in patients with mild cognitive impairment or those in the mild dementia stage of the disease.[1] The drug, which is administered as an intravenous infusion over approximately 30 minutes every four weeks, is a monoclonal antibody that is designed to reduce the accumulation of abnormal protein deposits called amyloid beta plaques in the brains of patients with Alzheimer’s disease.[2]

Donanemab has a boxed warning (the strongest warning the FDA can require) about amyloid beta-related imaging abnormalities (ARIA) that may be a precursor to life-threatening swelling or bleeding in the brain.[3]

Because donanemab provides minimal benefit and has significant health risks, Public Citizen’s Health Research Group urged the FDA not to approve it.[4] We subsequently classified it as a Do Not Use drug.[5]

An analysis of new data from three clinical trials published in the May 2025 issue of JAMA Neurology provided further evidence for the increased risk of ARIA in patients treated with donanemab, confirming our Do Not Use designation.[6]

The efficacy and safety of donanemab

As discussed in more detail in the November 2024 issue of Worst Pills, Best Pills News, donanemab was approved based on the results of one clinical trial that used a measure called the integrated Alzheimer’s Disease Rating Scale (iADRS, range of scores 0 to 144, with lower scores indicating greater impairment) to assess the progression of Alzheimer’s disease.[7] The study found that after 76 weeks, those treated with donanemab had a slower rate of disease progression (10.2 points on the iADRS scale) than those who had received a placebo (13.1 points). However, the difference between the two groups was only 2% (2.9 points on the 144-point scale) and unlikely to be clinically meaningful.

The trial also found that many more participants treated with donanemab (36%) than those who had received a placebo (14%) developed ARIA. Although ARIA are not always associated with symptoms, this study found that some participants with ARIA experienced headaches, visual changes, confusion, dizziness, gait difficulties and nausea. Symptoms of ARIA also can mimic those of a stroke.[8] Moreover, in this trial 1.6% of those treated with donanemab had severe ARIA, which contributed to three deaths. In the placebo group, no deaths were associated with ARIA.

The risk of brain bleeding was found to be higher when participants taking donanemab were using aspirin (BAYER and generics), blood thinners such as warfarin (JANTOVEN and generics), or medications that inhibit the aggregation of platelets (such as clopidogrel [PLAVIX and generics]) at the same time.[9]

Importantly, as noted in the prescribing information for donanemab, patients with a genetic mutation called ApoE4 (which is found in about 15% of patients with Alzheimer’s disease) have a higher risk of ARIA with donanemab treatment, especially if they have two copies of this mutation.[10]

The new study

The new study is based on both prespecified and post hoc exploratory analyses; a post hoc analysis is not planned before the data are collected and thus can be difficult to interpret.[11] The analyses pooled data across three clinical trials in patients diagnosed with early

symptomatic Alzheimer’s disease and confirmed elevated amyloid levels. The analyses included the randomized, placebo-controlled trial that was used for donanemab’s approval (1,736 participants), the standalone unblinded extension (1,053 participants) of that trial, and a randomized placebo-controlled phase 2 trial (257 participants). Of the 3,046 possible participants, 3,030 were included in the new analysis.

The researchers found that, over 76 weeks, treatment with donanemab was associated with a higher frequency of ARIA development (32-37% across the three trials) than was treatment with placebo (14.2%). For instance, brain swelling (ARIA-E) occurred in 20-24% of those who had received donanemab and only 2% of the placebo-treated participants. Brain bleeding (ARIA-H) occurred in 27-31% of donanemab-treated participants and 13% in the placebo group.

Although most ARIA-E events were mild or moderate, 1.5% of participants in the placebo-controlled trials reported serious ARIA-E and 5.8% reported symptomatic ARIA-E. Headache (10-14%) and confusional state (4-5%) were the most frequently reported symptoms across all trials.

In 58% of the donanemab-treated participants, ARIA-E episodes occurred within the first three months of treatment. After the brain swelling resolved, 71% of those who had an ARIA-E event continued with at least one more dose of donanemab. Of participants who continued taking the drug, 31% had a subsequent ARIA-E event. The maximum number of recorded ARIA-E episodes in one participant was five.

The analysis also found that participants with the ApoE4 mutation were at an increased risk of ARIA. Across all trials, those who had two copies of the ApoE4 mutation had the highest risk of severe and symptomatic ARIA. For example, ARIA-E occurred in about 42% of those with two copies of ApoE4 across all trials, 22-24% of those with one copy of the gene, and 11-15% of those without the mutation. ARIA-H also was more frequent in those with two copies of the mutation (50-54%) than in those with one copy (29-31%) or no copies (18-19%).

Donanemab is also authorized for marketing in the United Kingdom. Because of the higher risks associated with ApoE4, patients who have two copies of the mutation are not eligible for treatment.[12] Moreover, based on the minimal benefit and significant health risks, the European Union decided in March 2025 not to recommend donanemab for marketing authorization at all. As of June 2025 the European Union had not finalized this decision; the drug manufacturer is seeking a reevaluation.[13]

What You Can Do

If you or a loved one is diagnosed with mild cognitive impairment or early-stage Alzheimer’s disease, do not use donanemab or lecanemab (LEQEMBI), another drug approved for the treatment of Alzheimer’s disease that targets amyloid beta.

At best, donanemab and lecanemab may modestly slow the progression of Alzheimer’s disease; they do not reverse cognitive decline, bring back lost memories, or cure Alzheimer’s disease.

For anyone at risk of Alzheimer’s disease, healthy lifestyle behaviors are recommended. These behaviors include physical activity, a healthy diet, maintaining a healthy weight, avoiding excessive alcohol consumption, and stopping smoking. Moreover, conditions such as high blood pressure, diabetes, high cholesterol, and substantial hearing or vision loss should be adequately treated.[14]
 

References

[1] Food and Drug Administration. FDA approves treatment for adults with Alzheimer’s disease. July 2, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-adults-alzheimers-disease. Accessed June 9, 2025.

[2] Eli Lilly. Label: donanemab-azbt (KISUNLA). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf. Accessed June 9, 2025.

[3] Ibid.

[4] Public Citizen. Testimony before the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee regarding donanemab. June 10, 2024. https://www.citizen.org/wp-content/uploads/2685.pdf. Accessed June 9, 2025.

[5] Donanemab (KISUNLA): A bad choice for Alzheimer’s disease. Worst Pills, Best Pills News. November 2024. https://www.worstpills.org/newsletters/view/1626. Accessed June 9, 2025.

[6] Zimmer JA, Ardayfio P, Wang H, et al. Amyloid-related imaging abnormalities with donanemab in early symptomatic Alzheimer disease: Secondary analysis of the TRAILBLAZER-ALZ and ALZ 2 randomized Clinical Trials. JAMA Neurol. 2025;82(5):461-469.

[7] Donanemab (KISUNLA): A bad choice for Alzheimer’s disease. Worst Pills, Best Pills News. November 2024. https://www.worstpills.org/newsletters/view/1626. Accessed June 9, 2025.

[8] Lilly. News release. Lilly’s statement about the CHMP opinion issued for donanemab. March 28, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-statement-about-chmp-opinion-issued-donanemab. Accessed June 9, 2025.

[9] Donanemab (KISUNLA): A bad choice for Alzheimer’s disease. Worst Pills, Best Pills News. November 2024. https://www.worstpills.org/newsletters/view/1626. Accessed June 9, 2025.

[10] Eli Lilly. Label: donanemab-azbt (KISUNLA). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf. Accessed June 9, 2025.

[11] Zimmer JA, Ardayfio P, Wang H, et al. Amyloid-related imaging abnormalities with donanemab in early symptomatic Alzheimer disease: Secondary analysis of the TRAILBLAZER-ALZ and ALZ 2 randomized clinical trials. JAMA Neurol. 2025;82(5):461-469.

[12] Lilly. News release. Lilly’s kisunla™ (donanemab-azbt) receives marketing authorization in Great Britain for the treatment of mild cognitive impairment and mild dementia due to Alzheimer’s disease in adult patients who are apolipoprotein E Ε4 heterozygotes or non-carriers. October 23, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-kisunlatm-donanemab-azbt-receives-marketing-authorization. Accessed June 9, 2025.

[13] Lilly. News release. Lilly’s statement about the CHMP opinion issued for donanemab. March 28, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-statement-about-chmp-opinion-issued-donanemab. Accessed June 9, 2025.

[14] Lancet Commission: Nearly half of dementia cases are preventable. Worst Pills, Best Pills News. January 2025. https://www.worstpills.org/newsletters/view/1637. Accessed June 9, 2025.