OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Casimersen – Amondys 45®

DRUG CLASS

Genetic Disorder Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Casimersen	1422958-19-7	C22-H40-N7O9-P

ANNOTATED BIBLIOGRAPHY

References updated: 29 November 2022

Abbreviations: siRNA, small interfering RNA; RNAi, RNA interference.

• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to siRNA or antisense therapies or other medications for muscular dystrophy).
• Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based therapeutics. Drug Discov Today. 2017;22:823–833. [PubMed: 28159625]

  (Oligonucleotide and siRNA based treatments are currently being evaluated in several diseases and have been found to have unexpected toxicities including antisense thrombocytopenia [mipomersen, drisapersen] and peripheral neuropathy [revusiran]; no discussion of hepatotoxicity).
• Levin AA. Treating disease at the RNA level with oligonucleotides. N Engl J Med. 2019;380:57–70. [PubMed: 30601736]

  (Review of the mechanism of action, current status and future promise of RNA based therapies that use synthetic oligonucleotides to modulate RNA function and have been applied to diseases ranging from hemophilia, amyloidosis, muscular dystrophy and hyperlipidemia).
• Messina S, Vita GL. Clinical management of Duchenne muscular dystrophy: the state of the art. Neurol Sci. 2018;39:1837–1845. [PubMed: 30218397]

  (Review of current optimal clinical management of Duchenne muscular dystrophy focusing upon standard respiratory, cardiovascular, orthopedic and nutritional support as well as recent innovative approaches to therapy including exon skipping and premature stop codon suppression).
• Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019;18:421–446. [PubMed: 30846871]

  (Extensive review of gene silencing using RNA interference pathways and the potential of RNAi therapeutics which have promise in many genetic and acquired diseases including transthyretin amyloidosis [transthyretin], HIV infection [CCR5], HBV [HBV mRNA], alpha-1-antitrypsin deficiency [zz A1AT], hypercholesterolemia [PCSK9]).
• Verhaart IEC, Aartsma-Rus A. Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol. 2019;15:373–386. [PubMed: 31147635]

  (Review of mechanisms of action, challenges, and clinical efficacy of new molecular approaches to therapy of muscular dystrophy including gene therapy with viral vectors, exon skipping using antisense oligonucleotides [casimersen, eteplirsen, drisapersen, golodirsen, viltolarsen], stop coding readthrough [ataluren], gene addition, CRISPR-Cas9 genome editing, and myoblast transplantation).
• FDA Multi-Disciplinary Review and Evaluation. Casimersen. 2021. Available at: https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2021/213026Orig1s000MedR.pdf.

  (The FDA clinical review of casimersen for efficacy and safety found increases in dystrophin levels in muscle biopsies after 48 weeks of treatment; therapy required intravenous infusions once weekly and sometimes necessitated insertion of a venous access port which can have major complications, but there were no serious adverse events attributable to the medication itself and no hepatic related serious adverse events or discontinuations because of liver toxicity; no mention of changes in ALT levels during therapy except that there were no changes in laboratory values indicative of toxicity).
• Shirley M. Casimersen: first approval. Drugs. 2021;81:875–879. [PubMed: 33861387]

  (Review of the mechanism of action, chemical structure, history of development, clinical efficacy and safety of casimersen makes no mention of ALT elevations during therapy or hepatotoxicity).
• Casimersen (Amondys 45) for Duchenne muscular dystrophy. Med Lett Drugs Ther. 2021;63(1627):e104–e105. [PubMed: 34181634]

  (Concise summary of the mechanism of action, clinical efficacy and safety of casimersen shortly after its approval for use in the US mentions that it is the fifth agent approved for therapy of Duchenne muscular dystrophy and the first to target exon 45 of the dystrophic gene; does not mention ALT elevations or hepatotoxicity).
• Wagner KR, Kuntz NL, Koenig E, East L, Upadhyay S, Han B, Shieh PB. Safety, tolerability, and pharmacokinetics of casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: a randomized, double-blind, placebo-controlled, dose-titration trial. Muscle Nerve. 2021;64:285–292. [PMC free article: PMC9290993] [PubMed: 34105177]

  (Preliminary report of pharmacokinetic and safety studies of casimersen in 12 boys ages 7 to 21 years with Duchenne muscular dystrophy who were treated for 12 weeks with either casimersen [in gradually increasing doses] or placebo during which adverse events were mostly mild and considered unrelated to the active drug; with extended open label therapy for another 132 weeks in all 12 children, casimersen was well tolerated with no drug discontinuations or dose adjustments and no hepatic adverse events, although one child developed sepsis, septic emboli and vena cava thrombosis due to a venous port being used to administer the antisense molecule).
• Alhamadani F, Zhang K, Parikh R, Wu H, Rasmussen TP, Bahal R, Zhong XB, Manautou JE. Adverse drug reactions and toxicity of the Food and Drug Administration-approved antisense oligonucleotide drugs. Drug Metab Dispos. 2022;50:879–887. [PubMed: 35221289]

  (Review of the adverse side effects of oligonucleotide therapies approved in the US or Europe, including specific discussions of fomivirsen, mipomersen, nusinersen, inotersen, eteplirsen, golodirsen, viltolarsen and casimersen; hepatotoxicity has been described with use of mipomersen [now withdrawn] and inotersen but not with the agents used for Duchenne muscular dystrophy).
• Zakeri SE, Pradeep SP, Kasina V, Laddha AP, Manautou JE, Bahal R. Casimersen for the treatment of Duchenne muscular dystrophy. Trends Pharmacol Sci. 2022;43:607–608. [PubMed: 35581038]

  (Brief and pictorial description of the structure, mechanism of action and clinical effects of casimersen as therapy for Duchenne muscular dystrophy; no mention of hepatotoxicity or ALT elevations during therapy).