OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Donanemab – Kisunla®

DRUG CLASS

Alzheimer Disease Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 04 October 2024

Abbreviations used: iv, intravenously.

• Roberson ED. Alzheimer Disease. Treatment of central nervous system degenerative disorders. In, Brunton LL, Hilal-Danan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 333-5.

  (Textbook of pharmacology and therapeutics).
• FDA. Clinical Review. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2024/761248Orig1s000MedR.pdf

  (Multidisciplinary FDA review of data on the safety and efficacy of donanemab in support of its approval for use in Alzheimer disease in the US, mentions that in prelicensure studies there were no “clinically meaningful changes in laboratory values,” no differences in rates of ALT elevation between donanemab- vs placebo-treated patients [0.4% vs 0.3%], and no instances of clinically apparent liver injury).
• Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med 2016; 8: 595-608. [PMC free article: PMC4888851] [PubMed: 27025652]

  (Analysis of the role of amyloid-β in the etiology of Alzheimer disease supported by findings that the dominant mutations in amyloid precursor protein [APP] or the protease that metabolizes presenilin and generates amyloid-β are associated with early onset dementia, suggesting that imbalance of generation and clearance of amyloid-β is the early and perhaps initiating factor in Alzheimer disease, and that monoclonal antibody therapy by increasing clearance might help correct the dyshomeostasis).
• Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 2016; 537: 50-6. [PubMed: 27582220]

  (Among 165 patients with early Alzheimer disease treated with 1 of 4 doses of aducanumab [1, 3, 6, or 10 mg/kg] or placebo monthly for one year, those treated with the higher doses showed evidence of decrease in brain amyloid-β accumulation and a trend for clinical improvement, but also higher rates of vasogenic edema [37% to 40%] compared with placebo [5%]; ALT elevations arose in 4 of 125 [3.2%] on aducanumab vs none of 40 on placebo).
• Alexander GC, Emerson S, Kesselheim AS. Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility. JAMA 2021; 325: 1717-8. [PubMed: 33783469]

  (Summary of the conclusions of the FDA advisory committee on aducanumab which were based upon results of two phase III randomized controlled trials in early Alzheimer disease patients, both of which were terminated early after interim analyses indicated futility; but on post-hoc reanalysis, statistically significant benefit was found with the higher dose in one of the 2 trials; because of discrepancies in outcomes in the two trials and only slight clinical benefit achieved in one arm of the 2 studies, the committee recommended that aducanumab not be approved until another trial confirms the efficacy and safety of the high dose regimen).
• Lowe SL, Duggan Evans C, Shcherbinin S, Cheng YJ, Willis BA, Gueorguieva I, Lo AC, et al. Donanemab (LY3002813) phase 1b study in Alzheimer's disease: rapid and sustained reduction of brain amyloid measured by florbetapir F18 imaging. J Prev Alzheimers Dis. 2021;8:414-424. [PMC free article: PMC12280776] [PubMed: 34585215]

  (Among 61 patients with Alzheimer disease enrolled in a placebo controlled phase 1 study of single and multiple doses of 10 to 40 mg/kg of intravenous donanemab in single or multiple doses, there was rapid decrease in brain amyloid as detected by PET scanning, and adverse events included infusion reactions, vasogenic cerebral edema, cerebral microhemorrhages, and headaches, but “there were no clinically significant changes in …safety laboratories”).
• Lowe SL, Willis BA, Hawdon A, Natanegara F, Chua L, Foster J, Shcherbinin S, et al. Donanemab (LY3002813) dose-escalation study in Alzheimer's disease. Alzheimers Dement (N Y). 2021;7:e12112. [PMC free article: PMC7882532] [PubMed: 33614890]

  (In a dose escalation study of single followed by multiple doses of donanemab, infusion reactions occurred in 16% of patients with Alzheimer disease but “there were no significant findings on clinical labs”).
• Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, Shcherbinin S, et al. Donanemab in early Alzheimer's disease. N Engl J Med. 2021;384:1691-1704. [PubMed: 33720637]

  (Among 257 patients with early symptomatic Alzheimer disease treated with iv donanemab or placebo every 4 weeks for 72 weeks, the decrease in amyloid plaque levels was greater and decline in disease rating scales less with the monoclonal antibody, while adverse event rates were similar in the two groups except for infusion reactions and amyloid-related imaging abnormalities of edema and microhemorrhage; no mention of ALT elevations or hepatotoxicity).
• Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, Wessels AM, et al.; TRAILBLAZER-ALZ 2 Investigators. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330:512-527. [PMC free article: PMC10352931] [PubMed: 37459141]

  (Among 1736 patients with early symptomatic Alzheimer disease treated with donanemab or placebo iv every 4 weeks for up to 72 weeks, therapy was associated with a slowing but not reversal or prevention of decline in clinical dementia rating scores, and with complications of infusion reactions and brain edema and microhemorrhages; no mention of ALT elevations or hepatotoxicity).
• Donanemab (Kisunla) for Alzheimer's disease. Med Lett Drugs Ther. 2024;66:129-131. [PubMed: 39137173]

  (Concise summary of the mechanism of action, clinical efficacy, safety, and costs of donanemab shortly after its approval in the US as therapy of Alzheimer disease with mild cognitive impairment or mild dementia, mentions side effects of symptomatic brain amyloid related edema and microhemorrhages, infusion reactions and headache; no mention of ALT elevations or hepatotoxicity).
• Kang C. Donanemab: first approval. Drugs. 2024 Sep 6. . In Press.10.1007/s40265-024-02103-7 [PubMed: 39237715] [CrossRef]

  (Summary of the mechanism of action, history of development, pharmacology, clinical efficacy, and safety of donanemab shortly after its approval for use in mildly symptomatic Alzheimer disease in the US, does not mention or discuss ALT elevations or hepatotoxicity).