By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration (FDA) has approved the third anti-amyloid beta monoclonal antibody for the treatment of Alzheimer’s disease, following aducanumab and lecanemab. Donanemab is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta.1 It was granted Fast Track Priority review, accelerated approval, and breakthrough designation.2 Donanemab is distributed by Eli Lilly as Kisunla.
Indications
Donanemab is indicated for the treatment of Alzheimer’s disease.1 It should be initiated in patients with mild cognitive impairment or mild dementia stage of disease. The presence of amyloid beta pathology should be confirmed before treatment initiation, and recent baseline brain magnetic resonance imaging (MRI) should be obtained prior to treatment initiation.
Dosage
The recommended dose is 700 mg administered as an intravenous infusion over approximately 30 minutes every four weeks for the first three doses, followed by 1,400 mg every four weeks.1 Pretreatment with antihistamines, acetaminophen, or corticosteroids should be considered to reduce infusion-related reactions. An MRI should be obtained prior to the second, third, fourth, and seventh infusions to assess radiograph presence and severity of amyloid-related imaging abnormalities (ARIA), including edema (ARIA-E) and hemosiderin deposition (ARIA-H). Dosage suspension is recommended based on the severity of ARIA-E or ARIA-H or on the reduction of amyloid plaques to minimal levels based on amyloid positron emission tomography imaging.1 Donanemab is available as a 350 mg/20 mL single-dose vial.
Potential Advantages
In a population of study participants with early symptomatic Alzheimer’s disease and amyloid and tau pathology, donanemab resulted in amyloid beta clearance and slowed clinical progression compared to placebo.1,3
Potential Disadvantages
As with previous monoclonal antibodies directed at amyloid beta, donanemab can cause ARIA-E and ARIA-H. The frequency of ARIA-E was 24% for donanemab vs. 2% for placebo. Meanwhile, the frequency of ARIA-H was 31% and 13%, respectively. Overall, symptomatic ARIA occurred in 6% of participants, and approximately 85% resolved.1 The risk of symptomatic and serious ARIA increased in those homozygous for apolipoprotein E 4 (APOE4) compared to heterogenous, and noncarriers.1 The rates (vs. placebo) were 55% (22%), 36% (13%), and 25% (12%), respectively.
Other adverse reactions included signs and symptoms of infusion-related reactions (e.g., headache, chest pain, and nausea/vomiting). Compared to placebo, donanemab resulted in a decrease in whole brain volume, a lesser decrease in the hippocampal volume, and an accelerated increase in ventricular volume. The latter is a marker of neurodegeneration.4
Comments
The efficacy of denanemab was evaluated in a double-blind, placebo-controlled study in participants (n = 1,736) with Alzheimer’s disease with confirmed amyloid pathology and mild cognitive impairment or mild dementia state (stage 3 and 4 disease) (TRAILBLAZER-ALZ 2).1,3 The overall study population had a mean age of 73 (± 6.2) years, was 57% female, was 91% white, consisted of 71% APOE4 carriers (17% homozygous), and 68% had low/medium tau levels in the cerebral spinal fluid.
They were randomized to donanemab (n = 860) or placebo (n = 876) up to 72 weeks. If amyloid plaque levels improved at the 24-week and 52-week assessment, donanemab was switched to placebo in a blinded procedure.3 The primary efficacy endpoint was change in the integrated Alzheimer’s Disease Rating Scale (iADRS) score from baseline to week 76. This is a combination of Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog13) and Alzheimer Diseases Cooperative Study- Instrumental Activities of Daily Living (ADCS-iADL).
Secondary outcomes included changes from baseline to week 76 of the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), ADAS-Cog13, ADCS-iADL, and percent of participants who reached amyloid clearance (negative scan measured by positron emission tomography). Donanemab showed a 22.3% slowing of disease progression compared to placebo based on iADRS, 20% based on ADAS-Cog13, and 28% based on ADCS-iADL. Overall, 29.7% (34.2% in the low/medium tau group) reached the prespecified threshold for amyloid clearance at week 24, compared to 0% for placebo.
The percentages of participants eligible to switch to placebo based on amyloid clearance were 17%, 47%, and 69% on weeks 24, 52, and 76, respectively.1 Post hoc evaluation of high tau subjects showed no benefit on the primary outcome.3
Clinical Implications
Alzheimer’s disease is an irreversible, progressive, neurodegenerative brain disorder affecting more than 6.5 million Americans.2 The disease is characterized by accumulation of amyloid beta plaques and neurofibrillary, or tau, tangles in the brain, leading to cognitive decline. Passive anti-amyloid beta immunotherapies have been the focus of pharmacotherapy.
Donanemab is the third agent approved by the FDA, after aducanumab and lecanemab. These agents appear to delay cognitive decline but have no effect on improving cognitive performance.5 They may differ depending on the outcome evaluated.6 Lecanemab has a more favorable effect on ADCS-ADL, but it may cause more adverse reactions, while donanemab performs better on ADAS-Cog13. Disease progression with donanemab at week 76 in the low/medium tau population was estimated to be delayed by 4.36 months based on iADRS and 7.53 months based on CDR-SB.3 Donanemab likely provides the most meaningful benefit when initiated at an earlier disease stage (e.g., low/medium tau).
The cost of donanemab is $32,000 for the first year of treatment, compared to $26,500 per year for lecanemab. An increased proportion of patients, over the treatment course, could stop treatment when reaching amyloid clearance, potentially reducing the lifetime cost of the drug. However, the long-term safety and effectiveness of donanemab (i.e., continuation or suspension of treatment) have not been established.
References
- Kisunla prescribing information. Eli Lilly. July 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761248s000lbl.pdf
- U.S. 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
- Sims JR, Zimmer JA, Evans CD, et al; TRAILBLAZER-ALZ 2 Investigators. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 2023;330:512-527.
- Qiao Y, Gu J, Yu M, et al. Comparative efficacy and safety of monoclonal antibodies for cognitive decline in patients with Alzheimer’s disease: A systematic review and network meta-analysis. CNS Drugs 2024;38:169-192.
- Alves F, Kalinowski P, Ayton S. Accelerated brain volume loss caused by anti-beta-amyloid drugs: A systematic review and meta-analysis. Neurology 2023;100:e2114-e2124.
- Li J, Wu X, Tan X, et al. The efficacy and safety of anti-beta-amyloid agents for delaying cognitive decline in Alzheimer’s disease: A meta-analysis. Front Aging Neurosci 2023;15:1257973.
The U.S. Food and Drug Administration has approved the third anti-amyloid beta monoclonal antibody for the treatment of Alzheimer’s disease, following aducanumab and lecanemab.
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