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Publications

Journal Article Clinical Trial, Phase III Randomized Controlled Trial Multicenter Study Ppublish

PubMed: 42713641 DOI: 10.1056/EVIDoa2600257

A Phase 3 Trial of Vosoritide in Children with Hypochondroplasia.

NEJM Evid 5(11):EVIDoa2600257

Authors: Andrew Dauber, Ravi Savarirayan, Philippe M Campeau, Ricki S Carroll, Moira Cheung, Valérie Cormier-Daire, Josep Maria de Bergua, Thomas Edouard, Michaela Veronika Gonfiantini, Julie Hoover-Fong, Peter Kannu, Yutaka Kinoshita, Takuo Kubota, Roberto Mendoza-Londono, Noriyuki Namba, Yasuhisa Ohata, Roberta Onesimo, Katja Palm, Carlos E Prada, Rachel Reynaud, Massimiliano Rossi, Oliver Semler, Kei Takasawa, Roberto Bassi, Sajda Ghani, Alice Huntsman Labed, Dane Osmond, Ian Sabir, Jeanette White, Mohamad Maghnie

Affiliations

  • Division of Endocrinology, Children's National Hospital, Washington, DC, USA.
  • Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
  • Molecular Therapies, Murdoch Children's Research Institute, Parkville, VIC, Australia.
  • Royal Children's Hospital, Parkville, VIC, Australia.
  • Department of Pediatrics, University of Melbourne, Parkville, VIC, Australia.
  • Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada.
  • Department of Pediatrics, Nemours Children's Hospital, Wilmington, DE, USA.
  • National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London, United Kingdom.
  • Department of Genomic Medicine for Rare Diseases, Reference Center for Skeletal Dysplasia, Necker-Enfants Malades Hospital, Paris Cité University, National Institute of Health and Medical Research Joint Research Unit 1163, Imagine Institute, Paris, France.
  • Arthroscopic Surgery Unit, MiKS Hospital, Vitoria-Gasteiz, Spain.
  • Endocrine, Bone Diseases and Genetics Unit, Reference Center for Rare Growth and Bone Disorders, OSCAR and CRESCENDO Network, ERN-BOND and Endo-ERN, Pediatric Research Unit CIC 1436, Children's Hospital, Toulouse University Hospital, Toulouse, France.
  • Rare Diseases and Medical Genetics Unit, Bambino Gesù Children's Hospital, Scientific Institute for Research, Hospitalization and Healthcare, Rome, Italy.
  • Greenberg Center for Skeletal Dysplasias, Departments of Genetic Medicine and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • University of Alberta-Stollery Children's Hospital, Edmonton, AB, Canada.
  • Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan.
  • Department of Pediatrics, Graduate School of Medicine, The University of Osaka, Suita, Japan.
  • Department of Pediatric Nephrology and Metabolism, Osaka Women's and Children's Hospital, Osaka Prefectural Hospital Organization, Izumi, Japan.
  • Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
  • Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, Yonago, Japan.
  • Pediatric Unit, Gemelli University Hospital, Scientific Institute for Research, Hospitalization and Healthcare, and Catholic University of Sacred Heart, Rome, Italy.
  • Department of Pediatrics, Faculty of Medicine and University Hospital, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
  • Edwards Family Division of Genetics and Rare Diseases, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
  • Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Aix Marseille University, Assistance Publique-Hopitaux de Marseille, National Institute of Health and Medical Research, Marseille Medical Genetics, Joint Research Unit 1251, Multidisciplinary Pediatric Department, La Timone Children's Hospital, Marseille, France.
  • Genetics Department, Reference Center for Skeletal Dysplasias, Femme Mère Enfant Hospital, Hospices Civils de Lyon, and National Institute of Health and Medical Research U1028, National Center for Scientific Research Joint Research Unit 5292, Lyon Neuroscience Research Centre, GENDEV Team, Claude Bernard Lyon 1 University, Lyon, France.
  • Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Department of Pediatrics and Developmental Biology, Institute of Science Tokyo, Tokyo, Japan.
  • BioMarin Pharmaceutical, San Rafael, CA, USA.
  • BioMarin (UK), London, United Kingdom.
  • Department of Pediatrics, Giannina Gaslini Scientific Institute for Research, Hospitalization and Healthcare, Genoa, Italy.
  • Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.

Abstract

BACKGROUND

Hypochondroplasia, a fibroblast growth factor receptor 3 (FGFR3)-related skeletal condition characterized by disproportionate short stature and a spectrum of clinical features, has no available targeted therapies. Vosoritide, a C-type natriuretic peptide analogue approved for the treatment of achondroplasia, is being investigated for hypochondroplasia.

METHODS

In this phase 3, multicenter trial, children with hypochondroplasia who were 3 to less than 18 years of age were randomly assigned to receive once-daily subcutaneous injections of vosoritide or placebo for 52 weeks per weight-band dosing regimen. The primary end point was change from baseline in annualized growth velocity at week 52 versus placebo. Confirmatory statistical testing using hierarchical procedures to control for type I error at the one-sided 0.025 significance level (equivalent to the two-sided 0.05 level) was performed for the primary and six key secondary efficacy end points. The safety and side effect profile of vosoritide versus placebo was assessed.

RESULTS

A total of 81 participants were randomly assigned to receive vosoritide (n=41) or placebo (n=40). At week 52, the least squares mean (LSM) change from baseline in annualized growth velocity was 1.95 cm/year with vosoritide versus -0.39 cm/year with placebo (LSM difference of 2.33 cm/year; 95% confidence interval, 1.85-2.82 cm/year; two-sided P<0.0001). Most participants in the vosoritide group (87.8%) and the placebo group (72.5%) experienced at least one adverse event (AE). There were no reports of grade 3 or higher AEs, AEs leading to treatment discontinuation, or deaths.

CONCLUSIONS

One year of vosoritide treatment significantly increased linear growth in children with hypochondroplasia. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT06455059.).

MeSH

Growth, Therapeutics, Child