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Casimersen | CAS No: 1422958-19-7 | GMP-certified suppliers
A medication that treats Duchenne muscular dystrophy in patients with a specific gene mutation by promoting production of functional dystrophin to slow muscle degeneration.
Therapeutic categories
Antisense OligonucleotidesCytochrome P-450 CYP2C19 InhibitorsCytochrome P-450 CYP2C19 inhibitors (strength unknown)Cytochrome P-450 CYP2C9 InhibitorsCytochrome P-450 CYP2C9 Inhibitors (strength unknown)Cytochrome P-450 CYP3A Inhibitors
Generic name
Casimersen
Molecule type
biotech
CAS number
1422958-19-7
DrugBank ID
DB14984
Approval status
Approved drug, Investigational drug
ATC code
M09AX13
Primary indications
- 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
Product Snapshot
- Casimersen is an injectable peptide formulated for intravenous administration
- It is primarily used for the treatment of Duchenne muscular dystrophy in patients with a specific DMD gene mutation amenable to exon 45 skipping
- Casimersen is approved for use in the US under accelerated approval with ongoing investigational status pending confirmatory trial results
Clinical Overview
Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide (PMO) indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 45 skipping. DMD is a severe X-linked recessive disorder characterized by the absence of functional dystrophin protein, leading to progressive muscle degeneration, loss of ambulation, respiratory failure, and cardiomyopathy, typically resulting in death in early adulthood.
Pharmacologically, casimersen binds specifically to exon 45 of the dystrophin (DMD) pre-mRNA, inhibiting its inclusion in the mature mRNA transcript. This exon skipping modifies the reading frame, enabling production of an internally truncated but partially functional dystrophin protein analogous to that seen in Becker muscular dystrophy, a milder dystrophinopathy. This restoration of truncated dystrophin aims to slow disease progression by mitigating muscle membrane damage and necrosis.
Casimersen exhibits improved metabolic stability compared to traditional oligonucleotides due to its PMO backbone, which replaces the ribofuranosyl ring with a morpholino ring and phosphodiester linkages with phosphorodiamidate bonds. It demonstrates reduced susceptibility to nuclease degradation. Because dystrophin production requires ongoing modulation of mRNA splicing, casimersen is administered on a weekly schedule.
Safety data indicate primarily mild adverse effects; however, preclinical findings and clinical experience with related oligonucleotides suggest a potential risk of nephrotoxicity. Baseline and periodic monitoring of renal function using glomerular filtration rate, serum cystatin C, urine dipstick, and protein-to-creatinine ratio are recommended. Creatinine levels are not reliable markers in DMD patients due to muscle disease.
Casimersen was granted accelerated approval by the US Food and Drug Administration in February 2021 and is marketed under the trade name AMONDYS 45™ by Sarepta Therapeutics. Its approval is contingent upon confirmatory trials demonstrating clinical benefit.
For API sourcing, it is essential to ensure the bacterial endotoxin levels and oligonucleotide purity meet pharmacopeial standards. Given the complexity of PMO chemistry, rigorous characterization of sequence fidelity and chemical integrity is critical to maintain batch-to-batch consistency and ensure therapeutic efficacy.
Pharmacologically, casimersen binds specifically to exon 45 of the dystrophin (DMD) pre-mRNA, inhibiting its inclusion in the mature mRNA transcript. This exon skipping modifies the reading frame, enabling production of an internally truncated but partially functional dystrophin protein analogous to that seen in Becker muscular dystrophy, a milder dystrophinopathy. This restoration of truncated dystrophin aims to slow disease progression by mitigating muscle membrane damage and necrosis.
Casimersen exhibits improved metabolic stability compared to traditional oligonucleotides due to its PMO backbone, which replaces the ribofuranosyl ring with a morpholino ring and phosphodiester linkages with phosphorodiamidate bonds. It demonstrates reduced susceptibility to nuclease degradation. Because dystrophin production requires ongoing modulation of mRNA splicing, casimersen is administered on a weekly schedule.
Safety data indicate primarily mild adverse effects; however, preclinical findings and clinical experience with related oligonucleotides suggest a potential risk of nephrotoxicity. Baseline and periodic monitoring of renal function using glomerular filtration rate, serum cystatin C, urine dipstick, and protein-to-creatinine ratio are recommended. Creatinine levels are not reliable markers in DMD patients due to muscle disease.
Casimersen was granted accelerated approval by the US Food and Drug Administration in February 2021 and is marketed under the trade name AMONDYS 45™ by Sarepta Therapeutics. Its approval is contingent upon confirmatory trials demonstrating clinical benefit.
For API sourcing, it is essential to ensure the bacterial endotoxin levels and oligonucleotide purity meet pharmacopeial standards. Given the complexity of PMO chemistry, rigorous characterization of sequence fidelity and chemical integrity is critical to maintain batch-to-batch consistency and ensure therapeutic efficacy.
Identification & chemistry
| Generic name | Casimersen |
|---|---|
| Molecule type | Biotech |
| CAS | 1422958-19-7 |
| UNII | X8UHF7SX0R |
| DrugBank ID | DB14984 |
Pharmacology
| Summary | Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide targeting exon 45 of the _DMD_ pre-mRNA to induce exon skipping and restore the reading frame, enabling production of a truncated but partially functional dystrophin protein. This mechanism aims to mitigate the progressive muscle degeneration characteristic of Duchenne muscular dystrophy (DMD) by addressing the underlying genetic mutations that prevent functional dystrophin expression. Pharmacodynamically, casimersen requires continuous administration to sustain modified mRNA splicing and dystrophin production. |
|---|---|
| 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.[A218171, A218176, A229988] 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.[A218171, A218176] 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.[A218171, A218176, A229988] 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.[A218171, A218176] 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.[A218171, A218176, A229988] 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.[A229993, L32118] 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.[A229993, L32118, A188574] 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.[A218171, A218176] |
| 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. 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.[A229993, L32118] 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. |
Targets
| Target | Organism | Actions |
|---|---|---|
| DMD gene (exon 45 casimersen target site) | Humans | binder |
ADME / PK
| 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<sub>max</sub> was reached by the end of infusion. Inter-subject variability, as measured by the coefficient of variation, ranged from 12-34% for C<sub>max</sub> 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<sub>max</sub> of 19.5 ± 3.43 and 21.6 ± 5.60 μg/mL and an AUC<sub>0-t</sub> of 24.9 ± 5.17 and 26.9 ± 7.94 μg\*hr/mL. The 40 mg/kg dose resulted in a C<sub>max</sub> of 208 ± 35.2 and 242 ± 71.1 μg/mL and an AUC<sub>0-t</sub> of 283 ± 68.5 and 320 ± 111 μg\*hr/mL. Lastly, the 320 mg/kg dose resulted in a a C<sub>max</sub> of 1470 ± 88.1 and 1490 ± 221 μg/mL and an AUC<sub>0-t</sub> of 1960 ± 243 and 1930 ± 382 μg\*hr/mL. |
|---|---|
| Half-life | Casimersen has an elimination half-life of 3.5 ± 0.4 hours. |
| Protein binding | Casimersen binding to human plasma proteins is not concentration-dependent, ranging from 8.4-31.6%. |
| Metabolism | Casimersen incubated with human hepatic microsomal preparations is metabolically stable, and no metabolites are detected in plasma or urine. |
| Route of elimination | Casimersen is predominantly (more than 90%) excreted in the urine unchanged with negligible fecal excretion. |
| Volume of distribution | Casimersen administered at 30 mg/kg had a mean steady-state volume of distribution (%CV) of 367 mL/kg (28.9%). |
| Clearance | Casimersen administered at 30 mg/kg has a plasma clearance of 180 mL/hr/kg. |
Formulation & handling
- Casimersen is a biotech peptide administered via intravenous injection, indicating parenteral formulation requirements. The liquid state necessitates careful handling to maintain stability, likely requiring refrigeration. Due to its intravenous route and peptide nature, it is unsuitable for oral formulation and may be sensitive to proteolytic degradation.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient is marketed in the United States with key patents having expired in 2021 and some remaining patent protection until 2030. This indicates a market with both generic availability and ongoing exclusivity for certain formulations or uses. |
|---|
| Markets | US |
|---|
Supply Chain
| Supply chain summary | Casimersen is represented by a single originator company with branded products marketed primarily in the US. The patent protection extends through 2030, indicating that generic competition is unlikely to emerge in the near term. There is no current presence noted in the EU or other global markets for this product. |
|---|
Safety
| 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. 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. |
|---|
High Level Warnings:
- Casimersen administration resulted in dose-dependent renal tubular degeneration and microscopic kidney changes in male rodents, with no identified no-effect dose for nephrotoxicity
- Renal tubular basophilia and microvacuolation were observed in non-human primates at doses ≥40 mg/kg, with partial reversal noted after cessation of treatment
- Monitoring and handling procedures should account for potential nephrotoxic effects observed in preclinical species at exposure levels exceeding clinical doses
Casimersen is a type of Antifibrotic agents
Antifibrotic agents belong to the pharmaceutical API category that focuses on treating fibrosis, a condition characterized by the excessive accumulation of fibrous connective tissue in organs. These agents target the underlying mechanisms involved in fibrosis and help prevent or slow down the progression of the disease.
One commonly used antifibrotic agent is Pirfenidone, which has shown efficacy in treating idiopathic pulmonary fibrosis (IPF). It works by inhibiting the production of pro-inflammatory and fibrotic factors, such as transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). By reducing the levels of these factors, Pirfenidone helps suppress the proliferation and activation of fibroblasts, which are responsible for excessive collagen deposition in fibrotic tissues.
Another antifibrotic agent, Nintedanib, also targets IPF. It is a tyrosine kinase inhibitor that blocks the activity of various growth factor receptors, including PDGF, fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR). By inhibiting these receptors, Nintedanib disrupts the signaling pathways involved in fibrosis, thereby reducing fibroblast activation and collagen production.
These antifibrotic agents have shown promising results in clinical trials and have been approved for the treatment of IPF in several countries. They represent a significant advancement in the management of fibrotic diseases and offer hope to patients by slowing down disease progression and improving overall outcomes.
In conclusion, antifibrotic agents are a vital category of pharmaceutical APIs that target the underlying mechanisms of fibrosis. Through their action on key molecular pathways involved in fibrotic tissue deposition, these agents help reduce the accumulation of fibrous connective tissue and provide potential therapeutic benefits for patients with fibrotic diseases.
