New treatments for children with achondroplasia.

Achondroplasia is the most common form of dwarfism in humans, caused by a common pathogenic variant in the gene encoding fibroblast growth factor receptor 3, FGFR3, which impairs the process of endochondral ossification of the growing skeleton. In this Review, we outline the clinical and genetic hallmarks of achondroplasia and related FGFR3 conditions, the natural history and impact of achondroplasia over a patient's lifespan, and diagnosis and management options. We then focus on the new and emerging drug therapies that target the underlying pathogenesis of this condition. These new options are changing the natural growth patterns of achondroplasia, with the prospect of better long-term health outcomes for patients.

Development of a Weight-Band Dosing Approach for Vosoritide in Children with Achondroplasia Using a Population Pharmacokinetic Model.

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen. METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen. RESULTS: A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population. CONCLUSIONS: The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers. CLINICAL TRIAL REGISTRATION: NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.