Emerging therapies for Achondroplasia: changing the rules of the game

ABSTRACT

Introduction

Achondroplasia is the most common genetic cause of disproportionate short stature, affecting over 360,000 individuals. Serious complications contributing to significant morbidity in affected individuals include cranio-cervical junction compression and obstructive sleep apnea. Current clinically available treatments are predominantly symptomatic and associated with variable outcomes. We summarize the new precision investigational products that are currently in Phase 2 and Phase 3 clinical trials for the treatment of individuals with achondroplasia.

Areas covered

Fibroblast growth factor receptor 3 (FGFR3), a membrane-spanning tyrosine kinase receptor, binds various fibroblast growth factors (FGF) to regulate the normal process of endochondral bone growth. Gain of FGFR3 function in individuals with achondroplasia results in inhibition of normal endochondral ossification. A greater understanding of these molecular pathways through animal models has led to the development of several targeted therapies being tested in children, which we discuss in this review.

Expert opinion

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. The next decade will see how these therapies compare, if they might be used in combination, and evaluate the balance of their long-term benefits and harms.

KEYWORDS:

• Achondroplasia
• clinical trials
• fibroblast growth factor receptor 3 (FGFR3)
• precision therapies

Funding

This paper was not funded.

Abbreviations

Fibroblast growth factor receptor 3 (FGFR3)

Fibroblast growth factors (FGF)

Fibroblast growth factor 2 (FGF2)

Recombinant human growth (r-hGH)

Standard Deviations (SD)

Mitogen-activated protein kinase (MAPK)

C-type natriuretic peptide (CNP)

Cyclic Guanosine Monophosphate (cGMP)

Declaration of interest

R Savarirayan had received honoraria from BioMarin, QED pharma, Ascendis and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.