Assessment of the efficacy of vosoritide therapy in children with achondroplasia in clinical trials

The topic of achondroplasia and its treatment methods is of interest to many authors around the world. Until recently, the only treatment option for achondroplasia was symptomatic treatment and alleviation of its health effects. Patients required numerous painful surgical procedures to correct spinal deformities and limb lengthening procedures using the Ilizarov method with a special stabiliser, which consists of metal rings connected to each other by rods and connected to the bones by wires and screws (1). The novelty, and to date the only form of causal treatment, is a recombinant C-type natriuretic peptide analogue—vosoritide. The U.S. Food and Drug Administration (FDA) from birth as has Australia and Japan and European Medicines Agency (EMA) from age 4 months and Brazil from age 6 months approved vosoritide, developed by BioMarin, for children with achondroplasia until growth plate closure.

Vositoride binds to the natriuretic peptide receptor B (NPR-B), activates it and restores the normal process of chondrogenesis. Activation of NPR-B leads to inhibition of excessive FGFR-3 gene signalling caused by an achondroplasia-inducing mutation. Inhibition of RAF-1 kinase, a MAPK (mitogen-activated protein kinase) signalling pathway, occurs and consequently increases proliferation and maturation of growth plate chondrocytes and promotes longitudinal bone growth (2).

The medicine acts at the base of the molecular pathology and results in an improvement in growth rate. In a study involving 121 children (aged 5–17 years) with genetically confirmed achondroplasia, Voxzogo was more effective than placebo (sham treatment) in terms of increasing growth rate after 52 weeks of treatment. Children who received Voxzogo grew approximately 1.57 cm more at one year of treatment than those receiving placebo. The findings of the above study were published in a paper entitled ‘Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial’ (3). The study confirmed the mild safety profile of vosoritide and that the observed changes in blood pressure are small and self-limiting. The authors noted no harmful effects of the drug on either skeletal maturation or body proportions of children with achondroplasia. However, they pointed out that these phenomena require further research, including younger age groups and prolonged follow-up until patients reach adulthood.

Savarirayan et al.’s study, ‘Vosoritide therapy in children with achondroplasia aged 3–59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial’ responded to the need for research in younger children. The authors also demonstrated the safety of vosoritide, mild side effects and no adverse effects on body proportion disorders in a group of younger children with achondroplasia (4).

The study involved 75 participants—11 sentinels, 32 receiving vosoritide and 32 receiving placebo. Moreover, patients were divided into three cohorts with respect to age: the first from 24–59 months, the second from 6–23 months and the third from 0–5 months (4).

Younger children with achondroplasia treated with vosoritide gained a change in growth Z score from baseline, but the annual growth velocity in this study was only 0.78 cm/year after 52 weeks, while children with achondroplasia over 5 years of age showed a growth velocity of 1.57 cm/year. When analysing the above difference, it is important to bear in mind the limitation of the small number of participants in the sample, a common problem in rare disease research. In addition, it is important to be aware of the difficulty of taking reliable measurements in young uncooperative children and the skeletal deformities associated with this disease also impact measurement variability (4).

The authors also took into account the possibility that vosoritide might not be effective in the youngest group of children. However, looking at the bigger picture, one cannot overlook the optimistic result, which is that in the study group of youngest children with achondroplasia, the use of vosoritide showed greater changes in facial volume, facial sinus volume and great aperture area after 52 weeks compared to the placebo group. This may suggest a profit in terms of improved ventilation, a reduced risk of recurrent respiratory infections and even a reduced risk of death in infancy in patients with achondroplasia due to apnoea (4).

Perhaps instead of focusing on gaining height, more attention should be paid to the other tangible health benefits of using vosoritide in terms of reducing complicated and risky surgical interventions and the associated pain that worsens the quality of life of these children.

Acknowledgments

Funding: None.

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References

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4. Savarirayan R, Wilcox WR, Harmatz P, et al. Vosoritide therapy in children with achondroplasia aged 3-59 months: a multinational, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Child Adolesc Health 2024;8:40-50. [Crossref] [PubMed]