Vosoritide
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Product Description
Vosoritide is a modified recombinant C-type natriuretic peptide analog, sold under the brand name Voxzogo, designed to promote linear growth in children and adolescents with achondroplasia who still have open epiphyses. This synthetic peptide drug, consisting of a 39-amino acid chain with disulfide bonds, acts as an agonist of the natriuretic peptide receptor-B (NPR-B), stimulating signaling pathways that increase intracellular cyclic GMP and counteract the overactive FGFR3 signaling responsible for impaired bone growth in achondroplasia. Administered via daily subcutaneous injections, Vosoritide has been FDA-approved to enhance linear growth in affected children and has not been associated with elevations in serum aminotransferase levels or clinically apparent liver injury.
Key Distinguishing Properties
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Type of Drug: Recombinant peptide therapeutic (biologic).
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Primary Target: Natriuretic Peptide Receptor-B (NPR-B) on chondrocytes.
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Key Mechanism: Counteracts overactive FGFR3 signaling by increasing cGMP, which inhibits the MAPK pathway.
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Therapeutic Goal: To increase linear growth in children with achondroplasia.
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Key Differentiator: First approved pharmaceutical treatment targeting the root cause of achondroplasia, not just managing symptoms.
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Brand Name: Voxzogo®
Pharmacological Properties
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Mechanism of Action: Vosoritide counteracts the overactive Fibroblast Growth Factor Receptor 3 (FGFR3) signaling pathway, which impairs bone growth in achondroplasia. It binds to and activates the Natriuretic Peptide Receptor B (NPR-B) on chondrocytes, increasing intracellular cGMP levels, which inhibit the MAPK pathway (ERK1/2), promoting endochondral ossification and bone growth.
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Pharmacokinetics:
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Route of Administration: Daily subcutaneous injection.
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Half-life: Approximately 30 minutes.
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Metabolism and Elimination: Metabolized primarily through proteolytic cleavage in the kidneys and by neutral endopeptidases (NEP), followed by renal elimination.
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Therapeutic Properties (Clinical Use)
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Indication: Treatment of achondroplasia in children aged 5 years and older with open epiphyses (open growth plates).
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Efficacy: Clinical trials show a sustained increase in annualized growth velocity (AGV) and improved height Z-scores over time.
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Dosing: Daily subcutaneous injection, weight-based (15 µg per kilogram of body weight).
Chemical and Physical Properties
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Molecular Formula: C₁₇₆H₂₉₀N₅₆O₅₁S₃
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Molecular Weight: Approximately 4,100 Daltons (g/mol)
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Chemical Structure: Vosoritide is a recombinant analog of human C-type Natriuretic Peptide (CNP). Its structure is identical to the 39-amino acid C-terminal fragment of human CNP-53, with an added N-terminal methionine residue for stability.
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Amino Acid Sequence: M-D-L-R-M-D-K-G-S-G-C-F-G-L-K-L-D-R-I-G-S-M-S-G-L-G-C-NP (where NP is the disulfide-linked ring structure).
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Appearance: White to off-white lyophilized (freeze-dried) powder or cake.
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Solubility: Soluble in water, supplied as a lyophilized powder to be reconstituted with sterile water for injection.
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Storage: Lyophilized product must be stored refrigerated at 2°C to 8°C (36°F to 46°F). After reconstitution, it should be used immediately or stored in a refrigerator for a very limited time.
Safety and Side Effects
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General Tolerance: Generally well-tolerated.
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Common Adverse Reactions:
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Injection site reactions: Redness, itching, swelling.
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Hypotension: Transient and mild decreases in blood pressure shortly after injection.
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Hypotension-related symptoms: Dizziness, nausea, vomiting, fatigue.
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Other side effects: Cough, joint pain, gastrointestinal issues.
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Important Safety Considerations:
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Blood pressure monitoring: Recommended for at least 6 hours after the first several doses.
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Contraindications: Caution advised in patients with severe renal or hepatic impairment, or those on medications that affect blood pressure.
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