Vosoritide for Selected Genetic Causes of Short Stature

NCT04219007 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: Pro00013585
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

Short stature can be caused by a number of genetic etiologies, many of which directly affect the growth plate. The FGFR3/CNP pathway is central to growth of the chondrocyte. The study team hypothesizes that patients with selected genetic causes of short stature that interact with this pathway will benefit from treatment with vosoritide, a CNP analog, a selective NPR-B agonist which directly targets the growth plate. This study will enroll patients with short stature in selected genetic categories and will follow them for a 6 month observation period to obtain a baseline growth velocity, safety profile and quality of life assessment. Patients will then be treated with vosoritide for 12 months and will be assessed for safety monitoring and improvement in height outcomes.

Conditions

Short Stature

Keywords

Hypochondroplasia; SHOX Deficiency; Rasopathy; NPR2; CNP; Noonan Syndrome; Aggrecan; ACAN

Outcome Measures

Primary Outcomes (4)

• Incidence of Treatment Emergent Adverse Events [Safety and Tolerability]

  Number of treatment-emergent adverse events or serious adverse events per study participant

  12 months

• Incidence of Symptomatic Hypotension events [Safety and Tolerability]

  Number of symptomatic hypotension events per study participant

  12 months

• Change from Baseline in annualized growth velocity

  To evaluate the change from baseline in age-sex standardized annualized growth velocity in cm/year after 12 months of daily SC injections of vosoritide in patients with selected genetic causes of short stature.

  12 months

• Change from Baseline in standardized height SDS

  To evaluate the change from baseline in age-sex standardized height SDS after 12 months of daily SC injections of vosoritide in patients with selected genetic causes of short stature.

  12 months

Secondary Outcomes (3)

• Changes in the seated height ratio as a measure of body proportions

  12 months

• Changes in the difference between arm span and height from baseline

  12 months

• Changes from Baseline in bone age/chronological age

  12 months

Other Outcomes (9)

• Characterize the area under the plasma concentration time-curve from time 0 to infinity (AUC0-∞)

  3 hours at each visit

• Characterize the area under the plasma concentration-time curve from 0 to the time of last measurable concentration (AUC0-t)

  3 hours at each visit

• Characterize maximum concentration (Cmax) of vosoritide in plasma

  3 hours at each visit

Study Arms (1)

Genetic Short Stature

EXPERIMENTAL

Vosoritide, also known as BMN 111 or modified recombinant human C-type natriuretic peptide (CNP), is a 39-amino-acid peptide analog that includes the 37 C-terminal amino acids of the human CNP53 sequence plus the addition of 2 amino acids (Pro-Gly) on the N-terminus. This structural modification conveys resistance to neutral endopeptidase (NEP) degradation, resulting in prolonged half-life (t1/2) in comparison to endogenous CNP. This increase in t1/2 allows once daily subcutaneous (SC) administration. Vosoritide will be administered as a single 15 μg/kg subcutaneous injection given daily for 12 months.

Drug: Vosoritide

Interventions

Vosoritide DRUG

After enrollment, subjects will be followed for a 6 month observation only period to establish a baseline height velocity as well as safety profile and quality of life assessment. Vosoritide will then be administered daily via subcutaneous injection at a dose of 15 µg/kg/day for 12 months.

Also known as: BMN-111

Genetic Short Stature

Eligibility Criteria

• Age: 3 Years - 10 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Parent(s) or guardian(s) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, subjects under the age of 18 are willing and able to provide assent (if required) after the nature of the study has been explained and prior to performance of any research-related procedure.
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Age \>3 years 0 days AND \<10 years 364 days for males, \<9 years 364 days for females
• Pre-pubertal defined as Tanner Stage 1 breasts in females and testicular volumes \<3 cc in males. This must be confirmed at the Day 1 visit prior to initiation of vosoritide.
• Patient height \<-2.25 SDS. All height SDS values are calculated using the CDC growth charts/data tables (Center for Disease Control and Prevention, 2000).
• A. CNP deficiency due to mutations in NPPC - Subjects with heterozygous or homozygous defects in NPPC are eligible.
• B. Hypochondroplasia - Subjects with heterozygous variants in FGFR3 gene associated with hypochondroplasia are eligible. Subjects with variants in FGFR3 known to cause achondroplasia or thanatophoric dysplasia or SADDAN syndrome will be excluded. (NOTE: Hypochondroplasia cohort is closed to enrollment).
• C. Patients with heterozygous defects in NPR2 are eligible. Patients with homozygous defects in NPR2 will be excluded.
• D. Rasopathy patients (including Noonan syndrome, Costello syndrome, Cardiofaciocutaneous syndrome, Neurofibromatosis Type 1) - This include patients with heterozygous variants in the following genes:
• i. BRAF ii. CBL iii. HRAS iv. KRAS v. LZTR1 vi. MAP2K1 vii. MAP2K2 viii. MRAS ix. NF1 x. NRAS xi. PPP1CB xii. PTPN11 xiii. RAF1 xiv. RRAS xv. RIT1 xvi. SHOC2 xvii. SOS1 xviii. SOS2
• E. Patients with SHOX deficiency - Patients with either heterozygous, compound heterozygous or homozygous defects in SHOX including patients with heterozygous or homozygous deletions of the SHOX regulatory region known to cause SHOX deficiency.
• F. Patients with heterozygous defects in ACAN - Patients must be heterozygous for a mutation in the ACAN gene. As there are no validated in vitro assays that reliably assess an individual variant's effect on aggrecan function, for the purpose of this clinical trial a mutation in ACAN will be defined as:
• A heterozygous deletion of the entire gene or of \>1 complete exons of the gene
• Any truncating mutation including frameshift, nonsense, splice site mutations within 2 bases of the exon/intron boundary, and start loss variants
• Any missense mutation which meets all of the following criteria:

You may not qualify if:

• Growth plate fusion - Defined as a bone age via the Greulich and Pyle method of 13 years in females and 15 years in males. These patients have limited remaining growth potential.
• Concomitant treatment with growth hormone or recombinant IGF-1. Patients may have been previously treated with growth hormone or IGF-1 therapy. If the patient is currently on one of these therapies, they will be required to discontinue treatment in order to begin the baseline observation period for this trial. That decision will be deferred to their treating clinical endocrinologists in conjunction with the patient's guardians. We anticipate that only patients who are having a poor response to their therapy will be interested in enrolling in the current study as there is no rationale for a patient who is receiving growth hormone therapy and having a positive response to enroll in the current study.
• Prior treatment with a GnRH analog, aromatase inhibitor or oxandrolone
• History of any type of malignancy
• Chronic medical condition known to affect growth including but not limited to:
• A. Cystic fibrosis B. Diabetes C. Inflammatory Bowel Disease D. Celiac Disease E. Asthma requiring a daily inhaled steroid dose \> 400 micrograms of inhaled budesonide per day or equivalent F. Taking daily oral glucocorticoids for any reason G. Note - ADHD treated with a stimulant and treated hypothyroidism with a normal TSH will NOT exclude the subject from participating in the trial.
• Malnutrition - Defined as a BMI \<5th percentile (CDC growth charts)
• Any clinically significant abnormality on screening tests as determined by the principal investigator. Abnormal screening labs may be repeated during the 6 month observation period prior to Day 1. If they return to normal or non-clinically significant deviations per the PI's determination, the subject may proceed with the study.
• Known or suspected allergy to trial medication, excipients, or related products
• The receipt of any investigational drug within 90 days prior to this trial

Sponsors & Collaborators

• Andrew Dauber: lead

Study Sites (1)

Children's National Hospital

Washington D.C., District of Columbia, 20010, United States

Location

Related Publications (1)

• Dauber A, Zhang A, Kanakatti Shankar R, Boucher K, McCarthy T, Shafaei N, Seaforth R, Castro MG, Dham N, Merchant N. Vosoritide treatment for children with hypochondroplasia: a phase 2 trial. EClinicalMedicine. 2024 Apr 11;71:102591. doi: 10.1016/j.eclinm.2024.102591. eCollection 2024 May.

  PMID: 38813446 DERIVED

MeSH Terms

Conditions

Dwarfism; Hypochondroplasia; Noonan Syndrome

Interventions

vosoritide

Condition Hierarchy (Ancestors)

Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Endocrine System Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Study Officials

• Andrew Dauber, MS MMSc

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Chief of Endocrinology

Study Record Dates

• First Submitted: December 26, 2019
• First Posted: January 6, 2020
• Study Start: August 4, 2020
• Primary Completion: August 14, 2025
• Study Completion (Estimated): June 1, 2035
• Last Updated: March 18, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)