Casimersen

Identification

Summary

Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide used to treat Duchenne muscular dystrophy patients with mutations amenable to exon 45 skipping.

Brand Names

Amondys 45

Generic Name

Casimersen

DrugBank Accession Number

DB14984

Background

Duchenne muscular dystrophy (DMD) is an X-linked recessive allelic disorder characterized by a lack of functional dystrophin protein, which leads to progressive impairment of ambulatory, pulmonary, and cardiac function and is invariably fatal. A related, albeit a less severe, form of muscular dystrophy known as Becker muscular dystrophy (BMD) is characterized by shortened and partially functional dystrophin protein production. Although corticosteroids effectively slow disease progression in both DMD and BMD patients, they do not address the underlying molecular pathogenesis.^1,2,3

The application of antisense oligonucleotides in DMD patients with specific mutations allows for exon skipping to produce truncated BMD-like dystrophin proteins, which restore partial muscle function and slow disease progression.^1,2,4,5,7 Casimersen is a phosphorodiamidate morpholino oligonucleotide (PMO); PMOs are oligonucleotides in which the five-membered ribofuranosyl ring is replaced with a six-membered morpholino ring, and the phosphodiester links between nucleotides are replaced with a phosphorodiamidate linkage.^6,7 In this manner, PMOs are much less susceptible to endo- and exonucleases and exhibit drastically reduced metabolic degradation compared to traditional synthetic oligonucleotides.⁶ Casimersen is the most recent in a line of approved PMOs for treating DMD, including eteplirsen and viltolarsen. However, the specific mutations, and hence the precise exon skipping, targeted by each is different.

Casimersen was granted accelerated FDA approval on February 25, 2021, based on data showing an increase in dystrophin levels in skeletal muscle of patients treated with casimersen; this approval is contingent on further verification in confirmatory trials. Casimersen is currently marketed under the tradename AMONDYS 45™ by Sarepta Therapeutics, Inc.⁷

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Gene Therapies
Antisense oligonucleotides

Synonyms

• Casimersen

External IDs

• Exon-45: NG-12-0064
• SRP-4045
• WHO 10354

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Pharmacology

Indication

Casimersen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients confirmed to have a DMD gene mutation amenable to exon 45 skipping. This indication represents an accelerated approval based on observed efficacy; continued approval for this indication may be contingent on the verification of safety and efficacy in a confirmatory trial.⁷

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Duchenne's muscular dystrophy (dmd)		••••••••••••			•••••••••

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Pharmacodynamics

Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to exon 45 of the DMD pre-mRNA, preventing its inclusion in mature mRNA and allowing the production of an internally truncated dystrophin protein in patients who would normally produce no functional dystrophin. Due to the need for continuous alteration of mRNA splicing and its relatively short half-life, casimersen is administered weekly.⁷ Although casimersen is associated with mostly mild adverse effects, animal studies suggest a potential for nephrotoxicity, which has also been observed after administration of some oligonucleotides.^4,7 Measurement of glomerular filtration rate before starting casimersen is advised. Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting therapy. They should be measured monthly (urine dipstick) or every three months (serum cystatin C and urine protein-to-creatinine ratio) during treatment. Creatinine levels are not reliable in muscular dystrophy patients and should not be used. Any persistent alteration in kidney function should be further investigated.⁷

Mechanism of action

Duchenne muscular dystrophy (DMD) is an X-linked recessive allelic disorder that results in the absence of functional dystrophin, a large protein comprising an N-terminal actin-binding domain, C-terminal β-dystroglycan-binding domain, and 24 internal spectrin-like repeats.^1,2,3 Dystrophin is vital for normal muscle function; the absence of dystrophin leads to muscle membrane damage, extracellular leakage of creatinine kinase, calcium influx, and gradual replacement of normal muscle tissue with fibrous and adipose tissue over time.^1,2 DMD shows a characteristic disease progression with early functional complaints related to abnormal gait, locomotion, and falls that remain relatively stable until around seven years of age. The disease then progresses rapidly to loss of independent ambulatory function, ventilatory insufficiency, and cardiomyopathy, with death typically occurring in the second or third decade of life.^1,2,3

The human DMD gene contains 79 exons spread over approximately 2.4 million nucleotides on the X chromosome.¹ DMD is associated with a variety of underlying mutations, including exon duplications or deletions, as well as point mutations leading to nonsense translation through direct production of an in-frame stop codon, frameshift production of an in-frame stop codon, or aberrant inclusion of an intronic pseudo-exon with the concomitant production of an in-frame stop codon.^1,2 In all cases, no functional dystrophin protein is produced. Becker muscular dystrophy (BMD) is a related condition with in-frame mutations that result in the production of a truncated but partially functional dystrophin protein. BMD patients, therefore, have milder symptoms, delayed disease progression, and longer life expectancy compared to DMD patients.^1,2,3

Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to exon 45 of the DMD pre-mRNA and prevent its inclusion within the mature mRNA before translation.^4,7 It is estimated that around 8% of DMD patients may benefit from exon 45 skipping, in which the exclusion of this exon results in the production of an internally truncated and at least partly functional dystrophin protein.^4,7,5 Although fibrotic or fatty muscle tissue developed previously cannot be improved, this therapy aims to slow further disease progression through the production of partially functional dystrophin and alleviation of the pathogenic mechanism of muscle tissue necrosis.^1,2

Target	Actions	Organism
ADMD gene (exon 45 casimersen target site)	binder	Humans

Absorption

DMD patients receiving IV doses of 4-30 mg/kg/week revealed exposure in proportion to dose with no accumulation of casimersen in plasma with once-weekly dosing. Following a single IV dose, casimersen C_max was reached by the end of infusion. Inter-subject variability, as measured by the coefficient of variation, ranged from 12-34% for C_max and 16-34% for AUC.⁷

Pre-clinical studies in nonhuman primates (cynomolgus monkeys) investigated the pharmacokinetics of once-weekly casimersen administered at doses of 5, 40, and 320 mg/kg. On days 1 and 78, the 5 mg/kg dose resulted in a C_max of 19.5 ± 3.43 and 21.6 ± 5.60 μg/mL and an AUC_0-t of 24.9 ± 5.17 and 26.9 ± 7.94 μg*hr/mL. The 40 mg/kg dose resulted in a C_max of 208 ± 35.2 and 242 ± 71.1 μg/mL and an AUC_0-t of 283 ± 68.5 and 320 ± 111 μg*hr/mL. Lastly, the 320 mg/kg dose resulted in a a C_max of 1470 ± 88.1 and 1490 ± 221 μg/mL and an AUC_0-t of 1960 ± 243 and 1930 ± 382 μg*hr/mL.⁴

Volume of distribution

Casimersen administered at 30 mg/kg had a mean steady-state volume of distribution (%CV) of 367 mL/kg (28.9%).⁷

Protein binding

Casimersen binding to human plasma proteins is not concentration-dependent, ranging from 8.4-31.6%.⁷

Metabolism

Casimersen incubated with human hepatic microsomal preparations is metabolically stable, and no metabolites are detected in plasma or urine.⁷

Route of elimination

Casimersen is predominantly (more than 90%) excreted in the urine unchanged with negligible fecal excretion.⁷

Half-life

Casimersen has an elimination half-life of 3.5 ± 0.4 hours.⁷

Clearance

Casimersen administered at 30 mg/kg has a plasma clearance of 180 mL/hr/kg.⁷

Adverse Effects

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Toxicity

Studies in male mice and rats suggest potential nephrotoxicity. Casimersen was administered weekly to male rats by IV injection for 12 weeks (0, 12, 120, or 960 mg/kg) or 22 weeks (0, 300, 960, or 2000 mg/kg) or by subcutaneous injection for 26 weeks (0, 300, 600, or 960 mg/kg). In the 12-week study, microscopic findings in the kidney (cytoplasmic basophilia and microvacuolation) were observed at the highest dose tested. In the 22- and 26-week studies, renal tubular degeneration was observed at all doses. Male rats administered casimersen (0, 250, 500, 1000, or 2000 mg/kg) intravenously for 13 weeks also experienced renal tubular degeneration at all tested doses, as well as microscopic changes accompanied by blood urea nitrogen increase at the highest tested dose. A no-effect dose for adverse effects on the kidneys was not identified in any of these studies. Plasma exposure (AUC) at the lowest dose tested in the 26-week study (300 mg/kg) was approximately two times that in humans at the recommended human dose (RHD) of 30 mg/kg/week, while exposure in the rat studies at the lowest dose was approximately four times that in humans.⁷

Studies involving weekly administration in cynomolgus monkeys found similar tubular basophilia and microvacuolation at doses ≥40 mg/kg, which largely resolved by four weeks following the last dose. This study determined a no observed adverse effect level for repeated intravenous administration of 320 mg/kg.⁴

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Not Available

Food Interactions

No interactions found.

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International/Other Brands

Amondys 45 (Sarepta Therapeutics, Inc.)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Amondys 45	Injection	50 mg/1mL	Intravenous	Sarepta Therapeutics, Inc.	2021-02-25	Not applicable

Categories

ATC Codes

M09AX13 — Casimersen

• M09AX — Other drugs for disorders of the musculo-skeletal system
• M09A — OTHER DRUGS FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM
• M09 — OTHER DRUGS FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM
• M — MUSCULO-SKELETAL SYSTEM

Drug Categories

• Antisense Oligonucleotides
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
• Cytochrome P-450 CYP3A5 Inhibitors
• Cytochrome P-450 CYP3A5 Inhibitors (strength unknown)
• Cytochrome P-450 Enzyme Inhibitors
• Increased Protein Synthesis
• Morpholines
• Musculo-Skeletal System
• Nucleic Acids, Nucleotides, and Nucleosides
• Nucleotides
• Oligonucleotides
• Oxazines
• Polynucleotides

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

X8UHF7SX0R

CAS number

1422958-19-7

References

Synthesis Reference

Diane Elizabeth Frank and Richard K. Bestwick, "Exon skipping oligomers for muscular dystrophy." U.S. Patent US20190262375A1, issued August 29, 2019.

General References

1. Wein N, Alfano L, Flanigan KM: Genetics and emerging treatments for Duchenne and Becker muscular dystrophy. Pediatr Clin North Am. 2015 Jun;62(3):723-42. doi: 10.1016/j.pcl.2015.03.008. Epub 2015 Apr 20. [Article]
2. Verhaart IEC, Aartsma-Rus A: Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol. 2019 Jul;15(7):373-386. doi: 10.1038/s41582-019-0203-3. [Article]
3. Mercuri E, Bonnemann CG, Muntoni F: Muscular dystrophies. Lancet. 2019 Nov 30;394(10213):2025-2038. doi: 10.1016/S0140-6736(19)32910-1. [Article]
4. Carver MP, Charleston JS, Shanks C, Zhang J, Mense M, Sharma AK, Kaur H, Sazani P: Toxicological Characterization of Exon Skipping Phosphorodiamidate Morpholino Oligomers (PMOs) in Non-human Primates. J Neuromuscul Dis. 2016 Aug 30;3(3):381-393. doi: 10.3233/JND-160157. [Article]
5. Rodrigues M, Yokota T: An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases. Methods Mol Biol. 2018;1828:31-55. doi: 10.1007/978-1-4939-8651-4_2. [Article]
6. Smith CIE, Zain R: Therapeutic Oligonucleotides: State of the Art. Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:605-630. doi: 10.1146/annurev-pharmtox-010818-021050. Epub 2018 Oct 9. [Article]
7. FDA Approved Drug Products: AMONDYS 45 (casimersen) injection [Link]
8. FDA Approved Drug Products: AMONDYS 45 (casimersen) injection (March 2023) [Link]

External Links

RxNav

2480096

Wikipedia

Casimersen

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Duchenne Muscular Dystrophy (DMD)	1
3	Terminated	Treatment	Duchenne Muscular Dystrophy (DMD)	1
2	Completed	Treatment	Duchenne Muscular Dystrophy (DMD)	1
1	Completed	Treatment	Duchenne Muscular Dystrophy (DMD)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	50 mg/1mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9416361	No	2016-08-16	2021-05-04
US10533174	No	2020-01-14	2021-05-04
US8524880	No	2013-09-03	2026-04-02
US9758783	No	2017-09-12	2030-11-12
US10781450	No	2020-09-22	2030-11-12
US9447415	No	2016-09-20	2025-06-28
US10287586	No	2019-05-14	2030-11-12
US9228187	No	2016-01-05	2030-11-12
USRE48960	No	2005-06-28	2025-06-28

Properties

State

Liquid

Experimental Properties

Not Available

Targets

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Details1. DMD gene (exon 45 casimersen target site)

Kind

Nucleotide

Organism

Humans

Pharmacological action

Yes

Actions

Binder

Curator comments

Casimersen binds to exon 45 of the dystrophin pre-mRNA and induces skipping of this exon to produce a functional truncated protein.

The sequence of the region on the human DMD gene targeted by the antisense oligonucleotide casimersen.

References

1. FDA Approved Drug Products: AMONDYS 45 (casimersen) injection [Link]

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Drug created at May 20, 2019 14:39 / Updated at April 04, 2023 03:32