Vosoritide keeps achondroplastic children’s hopes high

Long-term administration of vosoritide, a potent stimulator of endochondral bone growth, led to persistent and stable growth outcomes in children aged 5–18 years with achondroplasia, according to the ongoing phase III extension study results presented at ENDO 2021.

According to the National Organization for Rare Disorders, achondroplasia occurs in ~1 in every 20,000–30,000 births. [https://rarediseases.org/rare-diseases/achondroplasia, accessed April 12, 2021] While there is no proven effective method to increase height in individuals with achondroplasia, treatment goals are directed towards improving medical, functional, and psychosocial outcomes, noted lead investigator Professor Ravi Savarirayan from the Murdoch Children’s Research Institute at the Royal Children’s Hospital, Parkville, Victoria, Australia.

Vosoritide is under investigation for children whose growth plates are still open. The drug may be administered up until the time wherein the final adult height could be achieved (around 16–18 years old), noted Savarirayan.

“Vosoritide … [targets] the overactive signal in the growth plate that prevents bone growth in children with achondroplasia … [Our study is] the first robust evidence of a precision therapy for achondroplasia,” he said.

The extension phase results come on the heels of the 1-year results that Savarirayan and his team initially presented, which reflected a statistically significant improvement in annualized growth velocity (AGV) with vosoritide vs placebo (adjusted mean difference, 1.57 cm/year, 95 percent confidence interval, 1.22–1.93; p_two-sided<0.0001). [Lancet 2020;396:684-692]

The current findings are based on 119 children who completed the initial 52 weeks of the trial. These participants either continued SC vosoritide 15 μg/kg/day (n=58) or switched from placebo to vosoritide (n=61) for another year. [ENDO 2021; abstract OR24-1]

Among children who were on vosoritide throughout the trial, by year 2, mean AGV was 5.65 cm/year – which was a >1-cm jump from the baseline mean AGV of 4.26 cm/year. There were also improvements in height Z-score (mean change from baseline, +0.45) and upper-to-lower body segment ratio (mean change from baseline, –0.09).

Among participants who switched from placebo to vosoritide, by the end of year 2, mean AGV was 5.65 cm/year (from 3.94 cm/year at end of year 1), mean change in height Z-score was +0.24, and change in upper-to-lower body segment ratio was –0.03. These findings imply that growth improvements were still evident even if the participants initially took placebo.

Most adverse events (AEs) tied to vosoritide use were mild, with no serious or new AEs observed. The most common AE is injection site reaction, which was reported as mild and transient.

According to Savarirayan, the improvements in body proportions translate to better functioning, such as the performance of self-care activities or improved ability to reach objects.

“[Taken together,] we hope that the improved height and body proportion will increase independence and alleviate some of the long-term issues, such as spinal stenosis,” said Savarirayan. Other complications tied to this rare genetic disorder are spinal cord compression, bowlegs, a permanent swayback, and sleep apnoea.

Despite the durable treatment effect of vosoritide observed in the study, Savarirayan underscored the need for further investigation to ascertain its clinical benefit. “Longer-term follow-up is ongoing where additional data on quality of life, functional measures, and final adult height will help to confirm the clinical relevance of these improvements in growth and proportionality.”