medwireNews: The C-type natriuretic peptide analogue vosoritide significantly increases the growth rate of children with achondroplasia, indicate the results of a randomised, double-blind phase 3 study published in The Lancet.

“This trial establishes vosoritide as the first precision therapy for achondroplasia and confirms that it is effective and safe and significantly increases annual growth velocity in children aged 5 to 18 years with this condition”, lead investigator Ravi Savarirayan, from the University of Melbourne in Victoria, Australia, told medwireNews.

The trial of 121 children attending one of 24 centres in Australia, Germany, Japan, Spain, Turkey, the USA and the UK follows the phase 2 study of the agent designed to downregulate the fibroblast growth factor receptor 3 (FGFR3) signalling pathway, fixing the recommended daily subcutaneous dose at 15.0 µg/kg.

After 52 weeks of treatment, there was a significant 1.57 cm/year increase in the mean annualised growth velocity of the 60 children given vosoritide compared with the 61 children receiving placebo.

Forest plot analysis indicated that the difference in growth velocity favoured vosoritide across patient subgroups specified by sex, age, Tanner stage, height Z score and change in annualised growth velocity category, the researchers report.

The key secondary endpoint of change from baseline in height z score at 52 weeks also significantly favoured vosoritide, at a least squares mean difference of 0.28, and again this was supported across subgroup analyses.

But the key secondary outcome of change from baseline in the upper to lower body segment ratio was nonsignificant –0.01 and there was no change in extremity body proportion ratios for lower and upper limb or arm span.

“We believe earlier treatment has the potential to affect proportionality favourably”, Savarirayan commented. “That is why we are now conducting a trial in children aged 3 months to 5 years.”

The researchers did not detect “clinically meaningful differences” between the vosoritide and placebo patient groups in health-related quality of life using the Pediatric Quality of Life Inventory and the Quality of Life of Short Statured Youth assessments, or find any difference in the Functional Independence Measure for children at 52 weeks.

The majority of adverse events were mild in the study. Injection site reactions occurred in 73% of patients given vosoritide and 48% of controls but “all were non-serious and transient”, and there were no episodes of grade 3 or more severe hypersensitivity reactions or anaphylaxis, the investigators say.

None of the nine serious adverse events reported by three vosoritide-treated patients and four controls were attributed to the study drug, and there were no adverse events associated with lower body proportionality or bone maturation.

Overall, 119 of the 121 patients are expected to continue with treatment until around age 18 years and near adult height. “We will directly be able to observe final height benefits, pubertal growth and any long-term harms of therapy”, said Savarirayan.

He added that recruitment is nearly complete for the trial of children age 3 months to 5 years and is ongoing for a third trial comparing vosoritide with standard-of-care management for children with risk of foramen magnum compression.

The team notes that a second C-type natriuretic agent with a half-life designed to allow weekly subcutaneous administration is also undergoing clinical development for achondroplasia, as is the soluble FGFR3 molecule recifercept and the oral tyrosine kinase/FGFR3 inhibitor infigratinib.

“It will be of interest to compare the safety and efficacy profiles of these potential therapeutic options with vosoritide as they progress through clinical trials, and whether any of their actions might be synergistic for possible future combination therapy”, the investigators remark.

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2020 Springer Healthcare Ltd, part of the Springer Nature Group

Lancet 2020; 396: 684–692

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