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Viltolarsen | CAS No: 2055732-84-6 | GMP-certified suppliers
A medication that treats Duchenne muscular dystrophy in patients with specific genetic mutations, aiming to slow muscle degeneration by restoring functional dystrophin protein expression.
Therapeutic categories
Antisense OligonucleotidesMorpholinesMusculo-Skeletal SystemNucleic Acids, Nucleotides, and NucleosidesNucleotidesOligonucleotides
Generic name
Viltolarsen
Molecule type
biotech
CAS number
2055732-84-6
DrugBank ID
DB15005
Approval status
Approved drug, Investigational drug
ATC code
M09AX12
Primary indications
- Viltolarsen is indicated for the treatment of Duchenne muscular dystrophy in patients confirmed to have a _DMD_ gene mutation amenable to exon 53 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
- Viltolarsen is formulated as an injectable peptide solution for intravenous administration
- It is primarily used for the treatment of Duchenne muscular dystrophy with specific DMD gene mutations amenable to exon 53 skipping
- Viltolarsen holds accelerated approval status in the US market, with ongoing investigational studies required for continued authorization
Clinical Overview
Viltolarsen (CAS Number 2055732-84-6) is an antisense phosphorodiamidate morpholino oligonucleotide (PMO) indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with confirmed mutations amenable to exon 53 skipping. DMD is an X-linked recessive disorder characterized by the absence of functional dystrophin protein, resulting in progressive skeletal muscle degeneration, loss of ambulation, respiratory insufficiency, cardiomyopathy, and premature mortality typically in the second or third decade of life.
The mechanism of action of viltolarsen involves selective binding to exon 53 of the DMD pre-mRNA, disrupting normal splicing and promoting exon skipping. This process restores the reading frame disrupted by certain deletions, enabling the production of a truncated but partially functional dystrophin protein resembling that seen in Becker muscular dystrophy (BMD). Unlike corticosteroids, which modulate inflammation but do not correct the underlying genetic defect, viltolarsen addresses the molecular pathogenesis by enabling dystrophin expression in muscle tissue, potentially slowing disease progression.
Pharmacodynamically, viltolarsen exhibits a relatively short systemic half-life but induces sustained dystrophin expression with weekly dosing. Its PMO chemistry confers resistance to nuclease-mediated degradation, resulting in improved metabolic stability compared to conventional oligonucleotides. The drug undergoes limited metabolism, and its exact metabolic pathways and excretion profile remain under investigation.
Safety considerations include potential renal toxicity; therefore, kidney function monitoring is recommended. Serum creatinine is an unreliable biomarker in DMD patients due to altered muscle metabolism and should not be solely used for renal assessment. The accelerated approval granted by the FDA on August 12, 2020, based on increased dystrophin levels in skeletal muscle, is conditional upon confirmatory trials.
Viltolarsen is marketed as VILTEPSO™ and was developed by Nippon Shinyaku Co., Ltd. When sourcing the viltolarsen API, key quality considerations include stringent control of oligonucleotide purity, verification of phosphorodiamidate morpholino chemistry, and confirmation of sequence specificity to ensure efficacy and reduce off-target effects. Due to its complex synthesis, contract manufacturing organizations with expertise in PMO technology and regulatory compliance experience are preferred suppliers.
The mechanism of action of viltolarsen involves selective binding to exon 53 of the DMD pre-mRNA, disrupting normal splicing and promoting exon skipping. This process restores the reading frame disrupted by certain deletions, enabling the production of a truncated but partially functional dystrophin protein resembling that seen in Becker muscular dystrophy (BMD). Unlike corticosteroids, which modulate inflammation but do not correct the underlying genetic defect, viltolarsen addresses the molecular pathogenesis by enabling dystrophin expression in muscle tissue, potentially slowing disease progression.
Pharmacodynamically, viltolarsen exhibits a relatively short systemic half-life but induces sustained dystrophin expression with weekly dosing. Its PMO chemistry confers resistance to nuclease-mediated degradation, resulting in improved metabolic stability compared to conventional oligonucleotides. The drug undergoes limited metabolism, and its exact metabolic pathways and excretion profile remain under investigation.
Safety considerations include potential renal toxicity; therefore, kidney function monitoring is recommended. Serum creatinine is an unreliable biomarker in DMD patients due to altered muscle metabolism and should not be solely used for renal assessment. The accelerated approval granted by the FDA on August 12, 2020, based on increased dystrophin levels in skeletal muscle, is conditional upon confirmatory trials.
Viltolarsen is marketed as VILTEPSO™ and was developed by Nippon Shinyaku Co., Ltd. When sourcing the viltolarsen API, key quality considerations include stringent control of oligonucleotide purity, verification of phosphorodiamidate morpholino chemistry, and confirmation of sequence specificity to ensure efficacy and reduce off-target effects. Due to its complex synthesis, contract manufacturing organizations with expertise in PMO technology and regulatory compliance experience are preferred suppliers.
Identification & chemistry
| Generic name | Viltolarsen |
|---|---|
| Molecule type | Biotech |
| CAS | 2055732-84-6 |
| UNII | SXA7YP6EKX |
| DrugBank ID | DB15005 |
Pharmacology
| Summary | Viltolarsen is an antisense phosphorodiamidate morpholino oligonucleotide targeting exon 53 of the DMD pre-mRNA, modulating splicing to restore the dystrophin reading frame in patients with specific DMD gene mutations. This results in the production of a truncated, partially functional dystrophin protein, aiming to reduce muscle degeneration in Duchenne muscular dystrophy. The pharmacodynamic effect involves sustained dystrophin expression despite the drug's short half-life. |
|---|---|
| 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] 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. The disease progresses from loss of ambulatory function to ventilatory insufficiency and cardiomyopathy, with death typically occurring in the second or third decade of life.[A218171, A218176, A218181] 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.[A218161, A218171, A218176, A218181] Viltolarsen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to a specific region in exon 53 of the _DMD_ pre-mRNA and prevent its inclusion within the mature mRNA before translation. In patients with specific mutations, including those with deletions of exons 45-52, 47-52, 48-52, 49-52, 50-52, or solely of exon 52, this results in restoration of the expected reading frame and the production of a BMD-like dystrophin protein.[A218161, A218181, A218186, A218191, L15526] 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 | Viltolarsen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to and disrupt splicing of exon 53 in the human _DMD_ gene, which results in the expression of a partially functional dystrophin protein in patients who otherwise would not produce dystrophin.[A218161, A218166, L15526] Despite a relatively short half-life, the physiological effect of producing relatively stable dystrophin protein allows for effective therapeutic benefit with weekly dosing. Viltolarsen may cause renal toxicity, and so kidney function should be monitored in patients. However, due to the alteration of serum creatinine in Duchenne muscular dystrophy patients, creatinine should not be used as a marker of renal function. |
Targets
| Target | Organism | Actions |
|---|---|---|
| DMD gene (exon 53 viltolarsen target site) | Humans | binder |
ADME / PK
| Absorption | Viltolarsen is administered by intravenous infusion and is assumed to have a bioavailability of 100%. In a phase 1 dose-escalation trial of 10 patients given either 1.25, 5, or 20 mg/kg weekly for 12 weeks, the mean C<sub>max</sub> was 6040 ± 300 ng/mL in the low dose group and 70,200 ± 44,900 ng/mL in the high dose group on initial dose, with the corresponding final dose values of 5640 ± 2440 and 72,800 ± 26,400 ng/mL, respectively. Similarly, the AUC<sub>0-t</sub> for the initial/final dose was 8410 ± 1310/8410 ± 3520 ng\*hr/mL for the low dose and 98,900 ± 54,100/115,000 ± 56,000 ng\*hr/mL for the high dose. The T<sub>max</sub> varied between 0.667 ± 0.289 and 1.00 ± 0.00 hours, and viltolarsen has a documented median T<sub>max</sub> of approximately one hour. |
|---|---|
| Half-life | Viltolarsen has a reported elimination half-life of 2.5 hours (8% CV). When administered at either 40 or 80 mg/kg for 24 weeks, viltolarsen elimination half-life was 2.38 and 2.82 hours, respectively. |
| Protein binding | Viltolarsen _in vitro_ plasma protein binding is between 39 and 40% and is not concentration-dependent.[A218191, L15526] |
| Metabolism | Viltolarsen metabolism was not detected in serum or liver-derived microsomes, and it appears not to be metabolized by either DNase I or phosphodiesterase type 1 _in vitro_. This lack of metabolism is consistent with what is known regarding the stability of phosphorodiamidate morpholino oligonucleotides to enzymatic cleavage. |
| Route of elimination | Viltolarsen is mainly excreted in the urine unchanged; in a phase 1/2 study of 16 Japanese DMD patients, 92.0-93.1% of a single 80 mg/kg dose of viltolarsen was recovered unchanged in the patient urine within 24 hours of administration. |
| Volume of distribution | Viltolarsen has a steady-state volume of distribution of 300 mL/kg (14% CV) when given at 80 mg/kg. In patients given either 1.25, 5, or 20 mg/kg viltolarsen weekly for 12 weeks the volume of distribution was between 183 ± 14 and 264 ± 68 mL/kg. |
| Clearance | Viltolarsen has a reported plasma clearance of 217 mL/hr/kg (22% CV). Patients taking 1.25, 5, or 20 mg/kg viltolarsen weekly for 12 weeks had a total clearance of between 149 ± 21 and 239 ± 97 ml/hr/kg. |
Formulation & handling
- Viltolarsen is a biotech peptide formulated as an intravenous injectable solution.
- The liquid state requires controlled storage conditions to maintain stability and prevent degradation.
- Handling should minimize exposure to light and temperature fluctuations typical for biologic products.
Regulatory status
| Lifecycle | The API is protected by patents in the United States until August 31, 2031, indicating it is currently in the growth phase of its lifecycle within the US market. After patent expiry, generic competition may increase, leading to market maturation. |
|---|
| Markets | US |
|---|
Supply Chain
| Supply chain summary | Viltolarsen is primarily marketed in the US under the branded product Viltepso, with patents protecting it until August 2031. The manufacturing and supply landscape is centered around originator companies holding exclusive rights, indicating limited generic competition at present. The patent exclusivity suggests that generic entry is not expected in the near term. |
|---|
Safety
| Toxicity | Viltolarsen administered by subcutaneous injection in juvenile male mice resulted in deaths due to renal toxicity at high doses; in animals administered either 240 or 1200 mg/kg viltolarsen, dose-dependent increases in the incidence and severity of renal tubular effects were observed. Although renal toxicity in humans has not been observed, it is recommended to measure urine dipstick every month and serum cystatin C and urine protein-to-creatinine ratio every three months to detect renal toxicity. |
|---|
High Level Warnings:
- Viltolarsen exhibited dose-dependent renal tubular toxicity in juvenile male mice at high subcutaneous doses
- Renal toxicity monitoring is advised due to potential risk, despite lack of observed cases in humans
- Handling procedures should consider potential nephrotoxic effects
Viltolarsen 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.
