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General Description:

Vosoritide, identified by CAS number 1480724-61-5, is a notable compound with significant therapeutic applications. Achondroplasia is an autosomal dominant genetic disease and the most common cause of dwarfism in humans. It results from a gain-of-function missense mutation in _FGFR3_ that results in a dramatic suppression of bone growth, both in volume and in length. Treatment for achondroplasia includes both surgical and pharmacological interventions, the latter of which includes C-type natriuretic peptide (CNP) analogs. Endogenous CNP, first described in 1998, is primarily responsible for the stimulation of chondrocytes and long bone growth via activity at the NPR-B receptor, making it an attractive target in the treatment of a condition like achondroplasia. While the remarkably short half-life of endogenous CNP - 2 to 3 minutes due to its rapid degradation by endopeptidases - makes it ineffective as a therapeutic intervention, the development of a peptidase-resistant formulation has allowed for its use as a viable treatment option in achondroplasia. Vosoritide is an analog of CNP with proline-glycine on its N-terminus to convey resistance to neutral endopeptidase. It was approved for use under the brand name Voxzogo (BioMarin Pharmaceutical Inc.) in the EU in August 2021 and the US in November 2021, becoming the first pharmacological intervention approved for the treatment of achondroplasia in both regions.

Indications:

This drug is primarily indicated for: Vosoritide is indicated for the promotion of linear growth in pediatric patients with achondroplasia who are 5 years of age and older with open epiphyses. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Vosoritide undergoes metabolic processing primarily in: As with other therapeutic proteins, vosoritide is likely metabolized via catabolic pathways into smaller peptides and amino acids. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Vosoritide are crucial for its therapeutic efficacy: In patients receiving daily subcutaneous injections of vosoritide 15 mcg/kg, the mean C_max ranged from 4.71-7.18 ng/mL and the mean AUC_0-t ranged from 161-290 ng-min/mL. The median T_max following subcutaneous injection was approximately 15 minutes. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Vosoritide is an important consideration for its dosing schedule: The mean half-life following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 21.0 to 27.9 minutes. This determines the duration of action and helps in formulating effective dosing regimens.

Volume of Distribution:

Vosoritide is distributed throughout the body with a volume of distribution of: The mean apparent volume of distribution following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 2880 to 3020 mL/kg. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Vosoritide is a critical factor in determining its safe and effective dosage: The mean apparent clearance following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 79.4 to 104 mL/min/kg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Vosoritide exerts its therapeutic effects through: Vosoritide is an analog of C-type natriuretic peptide that promotes bone growth to combat growth suppression in children with achondroplasia. Urinary cyclic guanosine monophosphate (cGMP) and serum collagen type X marker (CXM) are both elevated following daily therapy with vosoritide and serve as biomarkers for evidence of increased endochondral bone growth, with cGMP indicative of NPR-B binding activity and CXM indicative of bone metabolism. Although relatively well-tolerated, transient episodes of hypotension have been observed in clinical studies. Patients with pre-existing cardiovascular disease and those taking antihypertensive medications were excluded from clinical trials. The risk of hypotension may be reduced by ensuring adequate food and fluid intake prior to the administration of vosoritide. The use of vosoritide in patients with an eGFR <60 mL/min/1.73m² should also be avoided as there are no data on the influence of renal impairment on its pharmacokinetics. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Vosoritide functions by: Achondroplasia is a congenital disease resulting from a missense mutation in the fibroblast growth factor receptor 3 (_FGFR3_) gene, resulting in a gain-of-function that negatively regulates endochondral bone growth. Under normal conditions, _FGFR3_ is expressed during both embryonic and postnatal development, but serves a different role in each. During initial development, FGFR3 signaling promotes proliferation of chondrocytes (i.e. growth), whereas postnatal skeletal growth is actually inhibited by FGFR3 - as a result, the pathologic activation of FGFR3 observed in patients with achondroplasia leads to suppressed pre-pubertal skeletal growth. Vosoritide is an analog of C-type natriuretic peptide (CNP), a signaling molecule that appears primarily responsible for the stimulation of chondrocytes and the growth of long bones. The binding of CNP (or vosoritide) with its corresponding receptor, NPR-B, results in a signaling cascade that ultimately inhibits the MAPK/ERK pathway via inhibition of RAF-1 and stimulates the proliferation and differentiation of chondrocytes. This activity serves to antagonize the downstream signaling resulting from FGFR3 and its resultant effects on bone growth. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Vosoritide belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Vosoritide is categorized under the following therapeutic classes: Amino Acids, Peptides, and Proteins, C-type Natriuretic Peptide Analog, Drugs Affecting Bone Structure and Mineralization, Drugs for Treatment of Bone Diseases, Hormones, Hormones, Hormone Substitutes, and Hormone Antagonists, Musculo-Skeletal System, Natriuretic Peptides, Peptide Hormones, Peptides. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Vosoritide include:

• Molecular Weight: 4100.0
• Molecular Formula: C176H290N56O51S3