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General Description:

Viltolarsen, identified by CAS number 2055732-84-6, 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 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 the production of shortened and partially functional dystrophin protein. Although corticosteroids are effective in slowing 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, which retains a productive reading frame and results in the production of truncated BMD-like dystrophin proteins. These shortened forms of dystrophin can restore partial muscle function and slow the progression of DMD. Viltolarsen 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. Hence, viltolarsen is similar to another PMO, , which gained FDA approval on September 19, 2016; however, is specific for exon 51 skipping while viltolarsen is specific for exon 53 skipping. Viltolarsen was granted accelerated FDA approval on August 12, 2020, based on data showing an increase in dystrophin levels in skeletal muscle of patients treated with viltolarsen; this approval is contingent on further verification in confirmatory trials. Viltolarsen was developed by Nippon Shinyaku Co LTD and is being marketed under the name VILTEPSO™.

Indications:

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

Metabolism:

Viltolarsen undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Viltolarsen are crucial for its therapeutic efficacy: 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_max 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_0-t 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_max varied between 0.667 ± 0.289 and 1.00 ± 0.00 hours, and viltolarsen has a documented median T_max of approximately one hour. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Viltolarsen is an important consideration for its dosing schedule: 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. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Viltolarsen exhibits a strong affinity for binding with plasma proteins: Viltolarsen _in vitro_ plasma protein binding is between 39 and 40% and is not concentration-dependent. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Viltolarsen from the body primarily occurs through: 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. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Viltolarsen is distributed throughout the body with a volume of distribution of: 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. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Viltolarsen is a critical factor in determining its safe and effective dosage: 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. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

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

Mechanism of Action:

Viltolarsen 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. 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. 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. 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. 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:

Viltolarsen is categorized under the following therapeutic classes: Antisense Oligonucleotides, 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 Viltolarsen include:

• Molecular Formula: C244H381N113O88P20