medwireNews: Daily treatment with subcutaneous vosoritide leads to a sustained increase in annualised growth velocity, with generally mild side effects, in children with achondroplasia, show data published in The New England Journal of Medicine.

Ravi Savarirayan (University of Melbourne, Victoria, Australia) and colleagues explain that “[a]chondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications.”

“Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification […], that was developed to have a longer half-life than its endogenous form in order to prolong pharmacologic activity.”

Following positive preclinical findings, the current phase II trial was initiated to find the optimal dose of vosoritide in 35 children (age 5–14 years, mean 7.6 years) with achondroplasia.

The children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg/kg (n=8), 7.5 μg/kg (n=8), 15.0 μg/kg (n=10), or 30.0 μg/kg (n=9).

At the end of the initial 6-month dose-finding phase, individuals receiving either 2.5 or 7.5 μg/kg vosoritide had their dose increased to 15.0 μg/kg for a further 18 months. The remaining patients continued to receive their starting dose for the same period. After 24 months, 30 patients enrolled in an ongoing long-term extension study.

During a median 42 months of follow-up, all patients experienced at least one adverse event, most commonly injection site reactions or erythema (86%) followed by pyrexia (54%) and cough (49%), which were typically mild and transient.

Four patients developed a serious adverse event, namely grade 3 obstructive sleep apnoea, grade 1 tonsillar hypertrophy, grade 3 thyroglossal cyst, and grade 3 syrinx. There were no deaths, adverse events related to disproportionate skeletal growth, or clinically significant adverse cardiovascular effects.

The researchers also investigated how vosoritide treatment affected annualised growth velocity. They observed a dose-dependent increase up to 15.0 μg/kg which then plateaued to 30 µg/kg. At 6 months, annualised growth velocity had fallen by 0.37 cm/year in the participants receiving vosoritide 2.5 µg/kg, but increased by 1.28, 2.01, and 2.08 cm/year among those receiving 7.5, 15.0, and 30.0 µg/kg, respectively, compared with their growth velocity during a 6-month run-in observational study.

The increase was sustained up to 42 months, and at this time point the mean annualized growth velocity was 5.51 cm/year among the patients who received vosoritide 15.0 µg/kg and 5.60 cm/year among those who received 30.0 µg/kg, which “approximated the annualized growth velocity of average-height children of similar age,” Savarirayan and co-authors remark.

A similar pattern was seen for height z-scores and the researchers note that there were no clinically relevant changes in the body-segment ratio.

Furthermore, biochemical analyses showed that both urinary cyclic guanosine monophosphate, a marker of drug activity, and serum collagen X marker, an indicator of endochondral ossification, increased in a dose-dependent manner during the first 6 months and remained elevated until month 24 in all four cohorts.

Savarirayan and co-authors conclude: “No difference in efficacy or safety could be identified between the once-daily doses of 15.0 and 30.0 μg per kilogram; thus, our findings support the choice of the lower dose for further evaluation in ongoing studies.”

They add that two phase III trials are currently underway to further evaluate the efficacy and safety of vosoritide until patients reach final adult height.

By Laura Cowen

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

N Engl J Med 2019; doi:10.1056/NEJMoa1813446