Elsevier

The Lancet

Volume 396, Issue 10252, 5–11 September 2020, Pages 684-692
The Lancet

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

https://doi.org/10.1016/S0140-6736(20)31541-5Get rights and content

Summary

Background

There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings.

Methods

This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 μg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11.

Findings

All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22–1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred.

Interpretation

Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be.

Funding

BioMarin Pharmaceutical.

Introduction

Achondroplasia is a primary skeletal dysplasia caused by heterozygous, gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene1 that leads to impaired endochondral ossification. This results in various medical complications, functional limitations and psychosocial challenges.2 Achondroplasia is the most common form of disproportionate short stature in humans, affecting approximately 250 000 people worldwide.3 Approved therapies that specifically address the underlying pathophysiology of this condition are currently lacking.

Previous studies in mouse models that recapitulate the skeletal phenotype observed in achondroplasia suggested that administration of vosoritide, a biological analogue of C-type natriuretic peptide, could restore and increase long-bone and craniofacial growth in these mice, through a mitogen-activated protein kinase-dependent pathway.4, 5 These results led to a phase 2, open-label, safety and dose finding study in 35 children aged 5 to 14 years with achondroplasia, all of whom had participated for at least 6 months in a lead-in growth study to calculate their baseline annualised growth velocity.6 This trial had an open-label, sequential cohort design to evaluate the safety and tolerability of vosoritide administered by daily subcutaneous injection at escalating doses of 2·5, 7·5, 15·0, and 30·0 μg/kg of bodyweight. Administration of vosoritide at the doses tested in these children was associated with a side-effect profile that was generally mild, and it resulted in sustained dose-related increases in annualised growth velocity for up to 42 months in patients compared with their baselines. The annualised growth velocity observed in patients who received doses of 15·0 μg/kg per day and 30·0 μg/kg per day were similar, and approximated those of age-matched, average-statured children.

Research in context

Evidence before this study

We searched PubMed on April 6, 2020, for original research and review articles published in English since January, 2000, with the following search terms: “achondroplasia”, “C-natriuretic peptide”, “growth hormone”, “FGFR3”, “management”, AND “treatment”. The literature indicates that treatment of achondroplasia, to date, has been solely focused on management of symptoms. Research is focusing on the therapeutic manipulation of fibroblast growth factor receptor 3 (FGFR3) activity with C-type natriuretic peptide, as this might be associated with increased skeletal growth. Human growth hormone has been administered to children with achondroplasia but does not have a significant or durable effect on growth or on final height and has unknown effects on body proportionality. A precision therapy to address the pathogenesis of this condition has been lacking. C-type natriuretic peptide is a potent stimulator of endochondral ossification through downregulation of the intracellular signalling pathway of the FGFR3 receptor. Achondroplasia is caused by a gain-of-function mutation in the FGFR3 gene, which results in constitutive overactivity of the receptor and impaired endochondral ossification. The first clinical trial to assess the safety of administration of the C-type natriuretic peptide analogue, vosoritide, was done in 35 children with achondroplasia, and reported in 2019. This phase 2, dose-finding study showed a generally mild side-effect profile and dose-related increases in annualised growth velocity. Limitations of this study were that participants acted as their own controls with regard to growth velocity comparisons, and that the design was open-label, with no placebo group enrolled.

Added value of this study

To our knowledge, this study is the first phase 3, randomised, double blind, placebo-controlled study done to assess the effect of vosoritide on growth in children with achondroplasia. Children administered vosoritide had a highly significant and potentially clinically important increase in annualised growth velocity over baseline after 1 year of treatment as compared with those who received placebo with similar adverse effect profiles. We believe that this study provides the first (level 1) randomised controlled trial evidence that vosoritide effectively enhances growth of children aged from 5 to less than 18 years with achondroplasia.

Implications of all the available evidence

This randomised controlled study provides strong evidence that daily subcutaneous administration of vosoritide (at a dose of 15·0 μg/kg of bodyweight) has a significant effect on growth velocity in children with achondroplasia aged 5 to less than 18 years. The balance of benefits and harms reported here are consistent with the previously published phase 2, open-label dose-finding studies. The children enrolled in these studies will be followed until they achieve final adult height to assess durability of response and whether a pubertal growth velocity increase is restored (as it is normally absent in children with achondroplasia). Studies are also under way to assess the use of vosoritide in children aged 0 to <5 years to evaluate whether earlier treatment will lead to better outcomes in terms of final height, body segment proportionality, and other comorbidities observed such as symptomatic foramen magnum stenosis, sleep disordered breathing, and spinal canal stenosis. We believe that this study provides the first, robust evidence for an effective, precision therapy for achondroplasia, underpinning a fundamental change in the clinical management policies, natural growth history, and treatment recommendations for children affected by this condition. It will serve as a benchmark against which other, emerging precision therapies for achondroplasia (including tyrosine kinase inhibitors, long acting forms of C-type natriuretic peptide, and fibroblast growth factor receptor ligand traps) can be measured.

The balance of benefits and harms from this study supported selection of the 15·0 μg/kg-per-day dose for further investigation of vosoritide in children with achondroplasia in larger, randomised controlled studies.

This study aimed to assess the change from baseline in mean annualised growth velocity (at 52 weeks) in patients administered vosoritide as compared with controls who received placebo injections.

Section snippets

Study design

This phase 3, randomised, double-blind, placebo-controlled, multicentre trial (study 111-301) compared once-daily subcutaneous administration of vosoritide, at a dose of 15·0 μg/kg of bodyweight, with placebo in children with achondroplasia. The trial was done in hospitals at 24 study sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). The studies were done in accordance with the provisions of the Declaration of Helsinki. The study protocol was approved by

Results

Participants were recruited to this trial between Dec 12, 2016, and Nov 7, 2018. 124 patients were screened for eligibility (figure 1) with 121 assessed as eligible (57 female patients, 64 male patients). These patients were enrolled and randomly assigned, with 60 assigned to receive vosoritide and 61 to receive placebo. The baseline characteristics were similar between the two treatment groups (table 1). As of Oct 31, 2019, the 52-week placebo-controlled study was completed, and 119 patients

Discussion

In this phase 3 trial, vosoritide, administered to children with achondroplasia at a dose of 15·0 μg/kg per day resulted in a highly significant increase in annualised growth velocity and height Z scores after 52 weeks of treatment as compared with placebo. There were no adverse effects on, or significant improvements in upper to lower body segment proportionality in children receiving vosoritide during this 52 week study. This suggests that either a longer treatment period or earlier treatment

Data sharing

The de-identified individual participant data that underlie the results reported in this Article (including text, tables, figures, and appendices) will be made available together with the research protocol and data dictionaries, for non-commercial, academic purposes. Additional supporting documents might be available on request. Investigators will be able to request access to these data and supporting documents via a website beginning at 6 months and ending 2 years after publication. Data

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