Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial

@article{Savarirayan2020OncedailySV,
  title={Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial},
  author={Ravi Savarirayan and Louise Tofts and Melita D. Irving and William Wilcox and Carlos A. Bacino and Julie E. Hoover-Fong and Rosendo Ullot Font and Paul R. Harmatz and Frank Rutsch and Michael B. Bober and Lynda E Polgreen and Ignacio Ginebreda and Klaus Mohnike and Joel Charrow and Daniel G. Hoernschemeyer and Keiichi Ozono and Yasemin Alanay and Paul Arundel and Shoji Kagami and Natsuo Yasui and Klane K White and Howard M. Saal and Antonio Leiva-Gea and Felipe Luna-Gonz{\'a}lez and Hiroshi Mochizuki and Donald G Basel and Dania M Porco and Kala Jayaram and Elena Fisheleva and Alice Huntsman-Labed and Jonathan R S Day},
  journal={The Lancet},
  year={2020},
  volume={396},
  pages={684-692}
}

Figures and Tables from this paper

Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study
TLDR
Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.
Pharmacokinetics and Exposure–Response of Vosoritide in Children with Achondroplasia
TLDR
The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed and suggest that the additional bioactivity was likely in tissues not related to endochondral bone formation.
Rationale, design, and methods of a randomized, controlled, open-label clinical trial with open-label extension to investigate the safety of vosoritide in infants, and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery
TLDR
This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis.
Advantages and Disadvantages of Different Treatment Methods in Achondroplasia: A Review
TLDR
The criteria for a good drug for achondroplasia are best met by recombinant human growth hormone at present and will potentially be met by vosoritide in the future, while the rest of the drugs are in the early stages of clinical trials.
Vosoritide: First Approval
TLDR
Vosoritide acts to restore chondrogenesis through its binding to natriuretic peptide receptor B (NPR-B), resulting in the inhibition of downstream signalling pathways of the overactive FGFR3 gene.
Emerging therapies for Achondroplasia: changing the rules of the game
TLDR
The last decade has been game-changing in terms of new precision therapies for children with achondroplasia that have the potential to fundamentally change the natural history of this condition.
International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia
TLDR
A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process.
Non-GH Agents and Novel Therapeutics in the Management of Short Stature
TLDR
Alternative agents for the management of short stature include the use of gonadotropin releasing hormone analogs (GnRHas) to delay puberty, and aromatase inhibitors in boys to postpone epiphyseal fusion, and the C-type natriuretic peptide analog vosoritide is an experimental agent that is emerging as a potential treatment for a few specific conditions including achondroplasia.
Cardiovascular risk factors and body composition in adults with achondroplasia
TLDR
Despite a high BMI, the cardiovascular risks appeared similar or lower in achondroplasia compared with controls, indicating that other factors might contribute to the increased mortality observed in this condition.
...
1
2
3
4
...

References

SHOWING 1-10 OF 14 REFERENCES
C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia.
TLDR
In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild and resulted in a sustained increase in the annualized growth velocity for up to 42 months.
Final adult height in long-term growth hormone-treated achondroplasia patients
TLDR
Long-term GH treatment contributes to 2.6 and 2.1% of final adult height in male and female ACH patients, respectively.
Achondroplasia
Optimal management of complications associated with achondroplasia
TLDR
The complexity of this presentation, whereby individual impairments may impact upon multiple activity and participation areas, requires consideration and discussion under a broad framework to gain a more thorough understanding of the experience of this condition for individuals with achondroplasia.
A height‐for‐age growth reference for children with achondroplasia: Expanded applications and comparison with original reference data
TLDR
A new HA reference is available for longitudinal growth assessment in achondroplasia, taking advantage of statistical modeling techniques and allowing for Z‐score calculations, which is an important contribution to clinical care and research endeavors for the aChondro Plasia population.
TransCon CNP, a Sustained-Release C-Type Natriuretic Peptide Prodrug, a Potentially Safe and Efficacious New Therapeutic Modality for the Treatment of Comorbidities Associated with Fibroblast Growth Factor Receptor 3–Related Skeletal Dysplasias
TLDR
Preclinical data show great promise for TransCon CNP to be an effective and well-tolerated drug that provides sustained levels of CNP in a convenient once-weekly dose, while avoiding high systemic CNP bolus concentrations that can induce cardiovascular side effects.
Postnatal Soluble FGFR3 Therapy Rescues Achondroplasia Symptoms and Restores Bone Growth in Mice
TLDR
A recombinant soluble fibroblast growth factor receptor 3 (FGFR3) restored normal skeletal growth and prevented disease-related complications in a mouse model of achondroplasia and it is suggested that s FGFR3 could be a potential therapy for children with a chondro Plasia and related disorders.
Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway
TLDR
It is demonstrated that activation of the CNP–GC-B system in endochondral bone formation constitutes a new therapeutic strategy for human achondroplasia.
Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model.
TLDR
The pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH, and support TKIs as a potential therapeutic approach for ACH.
...
1
2
...