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General Description:

Casimersen, identified by CAS number 1422958-19-7, is a notable compound with significant therapeutic applications. 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. 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. 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. In this manner, PMOs are much less susceptible to endo- and exonucleases and exhibit drastically reduced metabolic degradation compared to traditional synthetic oligonucleotides. Casimersen is the most recent in a line of approved PMOs for treating DMD, including and . 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.

Indications:

This drug is primarily indicated for: 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. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Casimersen undergoes metabolic processing primarily in: Casimersen incubated with human hepatic microsomal preparations is metabolically stable, and no metabolites are detected in plasma or urine. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Casimersen are crucial for its therapeutic efficacy: 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. 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Casimersen is an important consideration for its dosing schedule: Casimersen has an elimination half-life of 3.5 ± 0.4 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Casimersen exhibits a strong affinity for binding with plasma proteins: Casimersen binding to human plasma proteins is not concentration-dependent, ranging from 8.4-31.6%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Casimersen from the body primarily occurs through: Casimersen is predominantly (more than 90%) excreted in the urine unchanged with negligible fecal excretion. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Casimersen is distributed throughout the body with a volume of distribution of: Casimersen administered at 30 mg/kg had a mean steady-state volume of distribution (%CV) of 367 mL/kg (28.9%). This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Casimersen is a critical factor in determining its safe and effective dosage: Casimersen administered at 30 mg/kg has a plasma clearance of 180 mL/hr/kg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Casimersen exerts its therapeutic effects through: 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. 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. 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Casimersen functions by: 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. 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. 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. The human _DMD_ gene contains 79 exons spread over approximately 2.4 million nucleotides on the X chromosome. 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. 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. 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. 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. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Casimersen is categorized under the following therapeutic classes: 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. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Casimersen include:

• Molecular Weight: 7585.0
• Molecular Formula: C268H424N124O95P22