Vosoritide

Identification

Summary

Vosoritide is an analogue of C-type naturietic peptide used to promote bone growth in pediatric patients with achondroplasia.

Brand Names
Voxzogo
Generic Name
Vosoritide
DrugBank Accession Number
DB11928
Background

Achondroplasia is an autosomal dominant genetic disease and the most common cause of dwarfism in humans.2 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.1,2 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.1 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,1 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.3 It was approved for use under the brand name Voxzogo (BioMarin Pharmaceutical Inc.) in the EU in August 2021 and the US in November 2021,6,5 becoming the first pharmacological intervention approved for the treatment of achondroplasia in both regions.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Peptides
Protein Chemical Formula
C176H290N56O51S3
Protein Average Weight
4100.0 Da
Sequences
Not Available
Synonyms
  • Vosoritide
External IDs
  • BMN 111
  • BMN-111

Pharmacology

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.3

This indication is approved under accelerated approval based on an improvement in annualized growth velocity. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).7

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Contraindications & Blackbox Warnings
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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.3

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.3 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.3

Mechanism of action

Achondroplasia is a congenital disease resulting from a missense mutation in the fibroblast growth factor receptor 3 (FGFR3) gene,1 resulting in a gain-of-function that negatively regulates endochondral bone growth.3 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.2

Vosoritide is an analog of C-type natriuretic peptide (CNP),3 a signaling molecule that appears primarily responsible for the stimulation of chondrocytes and the growth of long bones.1 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.3,1

TargetActionsOrganism
AAtrial natriuretic peptide receptor 2
agonist
Humans
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.3 The median Tmax following subcutaneous injection was approximately 15 minutes.3

Volume of distribution

The mean apparent volume of distribution following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 2880 to 3020 mL/kg.3

Protein binding

Not Available

Metabolism

As with other therapeutic proteins, vosoritide is likely metabolized via catabolic pathways into smaller peptides and amino acids.3

Route of elimination

Not Available

Half-life

The mean half-life following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 21.0 to 27.9 minutes.3

Clearance

The mean apparent clearance following the subcutaneous administration of 15 mcg/kg of vosoritide ranged from 79.4 to 104 mL/min/kg.3

Adverse Effects
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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.4 If an overdose is suspected, implement supportive measures as clinically indicated.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
  • Drink plenty of fluids. To reduce the risk of hypotension, patients should drink 240-300 mL of fluid in the hour prior to administration.
  • Take with food. To reduce the risk of hypotension, patients should ensure adequate food intake prior to vosoritide injection.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VoxzogoInjection, powder, for solution0.4 mgSubcutaneousBiomarin International Limited2021-10-06Not applicableEU flag
VoxzogoInjection, powder, for solution1.2 mgSubcutaneousBiomarin International Limited2021-10-06Not applicableEU flag
VoxzogoInjection, powder, for solution0.56 mgSubcutaneousBiomarin International Limited2021-10-06Not applicableEU flag
VOXZOGO 0.4mgInjection, powder, lyophilized, for solution; Kit0.4 mg/0.5mLSubcutaneousBioMarin Pharmaceutical Inc.2021-11-19Not applicableUS flag
VOXZOGO 0.56mgInjection, powder, lyophilized, for solution; Kit0.56 mg/0.7mLSubcutaneousBioMarin Pharmaceutical Inc.2021-11-19Not applicableUS flag

Categories

ATC Codes
M05BX07 — Vosoritide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
7SE5582Q2P
CAS number
1480724-61-5

References

General References
  1. Wrobel W, Pach E, Ben-Skowronek I: Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review. Int J Mol Sci. 2021 May 25;22(11). pii: ijms22115573. doi: 10.3390/ijms22115573. [Article]
  2. Ornitz DM, Legeai-Mallet L: Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn. 2017 Apr;246(4):291-309. doi: 10.1002/dvdy.24479. Epub 2017 Mar 2. [Article]
  3. FDA Approved Drug Products: Voxzogo (vosoritide) injection for subcutaneous use [Link]
  4. EMA Summary of Product Characteristics: Voxzogo (vosoritide) for subcutaneous injection [Link]
  5. FDA News Release: FDA Approves First Drug to Improve Growth in Children with Most Common Form of Dwarfism [Link]
  6. EMA European Public Assessment Report: Voxzogo (vosoritide) [Link]
  7. FDA approved drug product: VOXZOGO (vosoritide) for injection, for subcutaneous use (October 2023) [Link]
PubChem Substance
347911258
RxNav
2586354
Wikipedia
Vosoritide

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
3Active Not RecruitingTreatmentAchondroplasia1somestatusstop reasonjust information to hide
3CompletedTreatmentAchondroplasia1somestatusstop reasonjust information to hide
3Enrolling by InvitationTreatmentHypochondroplasia1somestatusstop reasonjust information to hide
2Active Not RecruitingTreatmentAchondroplasia3somestatusstop reasonjust information to hide
2Active Not RecruitingTreatmentShort Stature1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionSubcutaneous0.4 mg
Injection, powder, for solutionSubcutaneous0.56 mg
Injection, powder, for solutionSubcutaneous1.2 mg
Injection, powder, lyophilized, for solution; kitSubcutaneous0.4 mg/0.5mL
Injection, powder, lyophilized, for solution; kitSubcutaneous0.56 mg/0.7mL
Injection, powder, lyophilized, for solution; kitSubcutaneous1.2 mg/0.6mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
USRE48267No2020-10-202030-05-20US flag
US8198242No2012-06-122030-06-11US flag
US10646550No2020-05-122036-08-01US flag
US9907834No2018-03-062036-08-01US flag

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Transmembrane signaling receptor activity
Specific Function
Receptor for the C-type natriuretic peptide NPPC/CNP hormone. Has guanylate cyclase activity upon binding of its ligand. May play a role in the regulation of skeletal growth.
Gene Name
NPR2
Uniprot ID
P20594
Uniprot Name
Atrial natriuretic peptide receptor 2
Molecular Weight
117020.97 Da
References
  1. FDA Approved Drug Products: Voxzogo (vosoritide) injection for subcutaneous use [Link]

Drug created at October 20, 2016 21:01 / Updated at October 24, 2023 01:30