Repositioning Candidate Details
| Candidate ID: | R1418 |
| Source ID: | DB11928 |
| Source Type: | approved; investigational |
| Compound Type: | biotech |
| Compound Name: | Vosoritide |
| Synonyms: | Vosoritide |
| Molecular Formula: | -- |
| SMILES: | -- |
| DrugBank Description: | 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. |
| CAS Number: | 1480724-61-5 |
| Molecular Weight: | |
| DrugBank Indication: | 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. |
| DrugBank Pharmacology: | 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/1.73m<sup>2</sup> should also be avoided as there are no data on the influence of renal impairment on its pharmacokinetics. |
| DrugBank MoA: | 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. |
| Targets: | Atrial natriuretic peptide receptor 2 agonist |
| Inclusion Criteria: | Therapeutic strategy associated |
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