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| Primary information |
|---|
| ID | 13823 |
| Therapeutic ID | Th1438 |
| Protein Name | Vosoritide |
| Sequence | >Th1438_Vosoritide
PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC
|
| Molecular Weight | 4100 |
| Chemical Formula | C176H290N56O51S3 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | The mean half-life following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 21.0 to 27.9 minutes.[L39229] |
| Description | Achondroplasia is an autosomal dominant genetic disease and the most common cause of dwarfism in humans.[A242277] 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.[A242273,A242277] 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.[A242273] 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,[A242273] 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.[L39229] 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,[L39245,L39241] becoming the first pharmacological intervention approved for the treatment of achondroplasia in both regions. |
| Indication/Disease | 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.[L39229] |
| Pharmacodynamics | 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.[L39229] 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.[L39229] 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.[L39229] |
| Mechanism of Action | Achondroplasia is a congenital disease resulting from a missense mutation in the fibroblast growth factor receptor 3 (_FGFR3_) gene,[A242273] resulting in a gain-of-function that negatively regulates endochondral bone growth.[L39229] 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.[A242277] Vosoritide is an analog of C-type natriuretic peptide (CNP),[L39229] a signaling molecule that appears primarily responsible for the stimulation of chondrocytes and the growth of long bones.[A242273] 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.[L39229,A242273] |
| Toxicity | Doses of two- to three-fold the recommended daily dose of 15 mcg/kg were administered to patients in clinical trials with no evidence of associated adverse reactions.[L39237] If an overdose is suspected, implement supportive measures as clinically indicated. |
| Metabolism | As with other therapeutic proteins, vosoritide is likely metabolized via catabolic pathways into smaller peptides and amino acids.[L39229] |
| Absorption | In patients receiving daily subcutaneous injections of vosoritide 15 mcg/kg, the mean Cmax ranged from 4.71-7.18 ng/mL and the mean AUC0-t ranged from 161-290 ng-min/mL.[L39229] The median Tmax following subcutaneous injection was approximately 15 minutes.[L39229] |
| The mean apparent volume of distribution following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 2880 to 3020 mL/kg.[L39229] |
| Clearance | The mean apparent clearance following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 79.4 to 104 mL/min/kg.[L39229] |
| Categories | Hormones, Hormone Substitutes, and Hormone Antagonists |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Atrial natriuretic peptide receptor 2 |
| Brand Name | Voxzogo |
| Company | Biomarin International Limited |
| Brand Description | Biomarin International Limited |
| Prescribed For | Subcutaneous |
| Chemical Name | 0.4 mg |
| Formulation | None. |
| Physical Appearance | injection site reactions (redness, swelling, hives), vomiting, joint pain, decreased blood pressure, and gastroenteritis. |
| Route of Administration | Voxzogo is a prescription medicine used to increase linear growth in children with achondroplasia who are 5 years of age and older with open bone growth plates (epiphyses). It is not known if Voxzogo is safe and effective in children with achondroplasia under 5 years of age. Before giving you child Voxzogo... |
| Recommended Dosage | Voxzogo is a prescription medicine used to treat the symptoms of Achondroplasia in pediatric patients 5 years or older. Voxzogo may be used alone or with other medications. |
| Contraindication | NA |
| Side Effects | VOXZOGO contains vosoritide, a human C type natriuretic peptide (CNP) analog. Vosoritide is a 39 amino acid peptide. Its amino acid sequence includes the 37 C terminal amino acids of the human CNP53 sequence plus Pro Gly on the N terminus to convey resistance to neutral endopeptidase (NEP) degradation. Vosoritide is manufactured from Escherichia coli using recombinant DNA technology. Vosoritide has a chemical formula of C176H290N56O51S3 with a molecular weight of 4.1 kDa. |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |