Donanemab (KISUNLA): A Bad Choice for Alzheimer’s Disease

In July 2024 the Food and Drug Administration (FDA) approved donanemab (KISUNLA) to treat Alzheimer’s disease in patients with mild cognitive impairment or who were in the mild stages of the disease, the population that was studied in clinical trials.[1],[2] 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.

Like other amyloid-targeting drugs, such as aducanumab (ADUHELM, which is no longer marketed in the United States)[3] and lecanemab (LEQEMBI),[4] donanemab has a boxed warning — the strongest warning the FDA can require — about amyloid beta-related imaging abnormalities (ARIA).[5] ARIA may be a precursor to severe, life-threatening swelling or bleeding in the brain. To monitor for such brain bleeds, periodic brain scans prior to and throughout treatment are recommended, adding substantially to the time and cost associated with administering the drug.

Public Citizen’s Health Research Group urged the FDA not to approve donanemab[6] because the drug’s small treatment benefits do not outweigh the serious safety concerns. We therefore designate donanemab as a Do Not Use drug.

About Alzheimer’s disease

Alzheimer’s disease is an irreversible, progressive disease of the brain that significantly impairs thinking, memory and — in the late stages — the ability to perform daily activities. It is the most common cause of dementia among the elderly, accounting for 60-80% of all dementia cases, and is the seventh leading cause of death among Americans.[7] In 2020, approximately 5.8 million Americans aged 65 or older had Alzheimer’s disease, a number that is expected to almost triple by 2060.

The cause of Alzheimer’s disease is not fully understood, and at present there is no cure. However, because the condition is associated with amyloid beta plaques, treatments that target these plaques have been developed.[8] It remains uncertain, however, whether removing amyloid beta has meaningful effects on patients’ cognitive function. In fact, amyloid-targeting drugs including aducanumab, lecanemab and donanemab have shown no or only minimal clinical benefit.[9]

Importantly, donanemab is not a cure for Alzheimer’s disease, and the drug cannot restore cognitive function or bring back lost memories. Although patients are likely to continue to get worse while receiving treatment, the goal is to slow the progression of the disease.

Evidence for donanemab’s efficacy

The data on donanemab’s efficacy was based on one trial that included 1,736 subjects between 59 and 86 years of age with mild Alzheimer’s disease who had a confirmed buildup of amyloid beta plaques.[10] The subjects were randomized to receive an intravenous infusion of either donanemab or placebo every four weeks.

Treatment with donanemab led to greater reduction of brain plaques and slightly better outcomes on several measures used to assess cognitive function as compared with placebo.

The primary endpoint of the study was a measure called the integrated Alzheimer’s Disease Rating Scale (iADRS, range of scores 0 to 144, with lower scores indicating greater impairment).[11] After 76 weeks of treatment, subjects in the donanemab group had a slower rate of Alzheimer’s disease progression on this scale (10.2 points) than those in the placebo group (13.1 points). Although this result was statistically significant, this 2% difference between groups is unlikely to be clinically meaningful. The differences between the groups in secondary endpoints also were small and of uncertain clinical significance.[12]

Unlike other amyloid-targeting treatments, donanemab is meant to be discontinued once brain scans show that amyloid beta plaque levels in the brain have been sufficiently reduced.[13] In the trial, subjects in the donanemab group were switched to the placebo group once a brain scan confirmed amyloid beta plaque clearance. However, because subjects who had switched from receiving donanemab to placebo were not compared with a group of subjects who continued to receive donanemab treatment after amyloid beta plaque reduction, the FDA cautioned that continued treatment effects were not adequately demonstrated after stopping donanemab treatment.

There were additional important shortcomings in the trial. For instance, the study only included a limited population of patients with Alzheimer’s disease. Many patients, including those with a history of brain bleeds, which are common among patients with Alzheimer’s disease, were excluded from the trial.[14] Subjects also were relatively young (with an average age of 73) compared with most people with Alzheimer’s disease, and only 2% were Black. This is of particular concern because of the high risk of Alzheimer’s disease in Black people.[15]

Amyloid-related imaging abnormalities

Donanemab, like other amyloid-targeting treatments, has a boxed warning about ARIA, which are associated with brain swelling and bleeding.[16] Although ARIA don’t always have noticeable symptoms, these abnormalities can result in headaches, visual changes, confusion, dizziness, gait difficulties and nausea, as well as symptoms that mimic those of a stroke. Of those in the donanemab group, 36% developed ARIA (6% were symptomatic with ARIA), whereas only 14% of subjects in the placebo group developed ARIA.[17] Moreover, 1.6% of subjects in the donanemab group had severe ARIA, which contributed to three deaths. In the placebo group, no deaths were associated with ARIA.[18],[19] Subjects in the donanemab group also were more likely to have more than one occurrence of brain swelling, and for about 15% of donanemab subjects the symptoms associated with their brain swelling did not resolve.[20]

Patients who are receiving donanemab and are also 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]) may be at a higher risk of brain bleeds.[21] Also, those with a genetic mutation called ApoE4 (which is the case for about 15% of patients with Alzheimer’s disease)[22] have a higher risk of ARIA with donanemab treatment, especially if they have two copies of this mutation.

Other safety concerns

Overall, there were more adverse events, including serious adverse events, in subjects treated with donanemab than in those who received placebo.[23] For instance, subjects in the donanemab group were more likely to experience headaches (13%) and infusion-related reactions (9%) than those in the placebo group (10% and 0.5%, respectively). Serious allergic reactions, including anaphylaxis (a sudden, potentially life-threatening, severe generalized allergic reaction) also were more common in the donanemab group (3%) than in the placebo group (0.7%).

As compared with the placebo group, subjects in the donanemab group had decreased whole brain volume after 76 weeks of treatment, and the volume of the brain ventricles that produce and store cerebrospinal fluid increased.[24] Both of these changes can be associated with Alzheimer’s disease progression.[25]

What You Can Do

Healthy lifestyle behaviors, including physical activity, a healthy diet, maintaining a healthy weight, avoiding excessive alcohol consumption and stopping smoking, are important for all people at risk of Alzheimer’s disease.[26] Conditions such as high blood pressure, diabetes, high cholesterol and substantial hearing or vision loss should be adequately treated. Although patients and their families need and deserve better treatments for Alzheimer’s disease, donanemab, as was the case for lecanemab and aducanumab, provides minimal benefit and significant health risks. Public Citizen’s Health Research Group has classified donanemab as a Do Not Use drug.
 

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 September 3, 2024.

[2] Eli Lilly. Label: donanemab-azbt (KISUNLA). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf. Accessed September 3, 2024.

[3] Biogen. News release. Biogen to realign resources for Alzheimer’s disease franchise. January 31, 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-realign-resources-alzheimers-disease-franchise. Accessed September 3, 2024.

[4] Eisai. Label: lecanemab-irmb (LEQEMBI). July 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761269Orig1s001lbl.pdf. Accessed September 3, 2024.

[5] Eli Lilly. Label: donanemab-azbt (KISUNLA). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf. Accessed September 3, 2024.

[6] 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 September 3, 2024.

[7] Centers for Disease Control and Prevention. Alzheimer’s disease and related dementias. October 26, 2020. https://www.cdc.gov/aging/aginginfo/alzheimers.htm. Accessed September 3, 2024.

[8] STAT News. The maddening saga of how an Alzheimer’s ‘cabal’ thwarted progress toward a cure for decades. June 25, 2019. https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/. Accessed September 3, 2024.

[9] Walsh S, Merrick R, Richard E, et al. Lecanemab for Alzheimer’s disease. BMJ. 2022;379(December 19):o3010.

[10] 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 September 3, 2024.

[11] Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527.

[12] Ibid.

[13] Food and Drug Administration. FDA briefing document, BLA# 761248, Drug name: donanemab-azbt, Peripheral and Central Nervous System (PCNS) Advisory Committee Meeting. June 10, 2024. https://www.fda.gov/media/179166/download. Accessed September 3, 2024.

[14] Eli Lilly. Label: donanemab-azbt (KISUNLA). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf. Accessed September 3, 2024.

[15] Matthews KA, Xu W, Gaglioti AH, et al. Racial and ethnic estimates of Alzheimer's disease and related dementias in the United States (2015-2060) in adults aged ≥65 years. Alzheimers Dement. 2019;15(1):17-24.

[16] Eli Lilly. Label: donanemab-azbt (KISUNLA). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf. Accessed September 3, 2024.

[17] Ibid.

[18] Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527.

[19] Food and Drug Administration. FDA briefing document, BLA# 761248, Drug name: donanemab-azbt, Peripheral and Central Nervous System (PCNS) Advisory Committee meeting. June 10, 2024. https://www.fda.gov/media/179166/download. Accessed September 3, 2024.

[20] Food and Drug Administration. FDA briefing document, BLA# 761248, Drug name: donanemab-azbt, Peripheral and Central Nervous System (PCNS) Advisory Committee meeting. June 10, 2024. https://www.fda.gov/media/179166/download. Accessed September 3, 2024.

[21] Eli Lilly. Label: donanemab-azbt (KISUNLA). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf. Accessed September 3, 2024.

[22] National Institute on Aging. Alzheimer's disease genetics fact sheet. Last reviewed March 1, 2023. https://www.nia.nih.gov/health/genetics-and-family-history/alzheimers-disease-genetics-fact-sheet. Accessed September 3, 2024.

[23] Eli Lilly. Label: donanemab-azbt (KISUNLA). July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf. Accessed September 3, 2024.

[24] Food and Drug Administration. FDA briefing document, BLA# 761248, Drug name: donanemab-azbt, Peripheral and Central Nervous System (PCNS) Advisory Committee Meeting. June 10, 2024. https://www.fda.gov/media/179166/download. Accessed September 3, 2024.

[25] Thambisetty M. Anti-amyloid drugs and the mystery of treatment-associated brain shrinkage. November 28, 2022. https://www.statnews.com/2022/11/28/anti-amyloid-drugs-treatment-associated-brain-shrinkage/. Accessed September 3, 2024.

[26] Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024;404(10452):572-628.