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The C-type natriuretic peptide analogue vosoritide significantly increased growth velocity in children with achondroplasia, a phase III trial found.

Among 119 children who completed 52 weeks of daily subcutaneous vosoritide, 15 mg/kg, the adjusted mean difference in annualized growth velocity was 1.57 cm/year (95% CI 1.22-1.93, P<0.0001) compared with those receiving placebo, reported Lynda Polgreen, MD, of the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center in Torrance, California.

There also was a highly statistically significant difference in height Z-score, with a least squares mean difference between the vosoritide and placebo groups of 0.28 (95% CI 0.17-0.39, P<0.0001), she reported at the virtual American Society for Bone and Mineral Research meeting.

"Achondroplasia is the most common form of disproportionate short stature, having an estimated prevalence of 1 in 25,000. It is cause by a dominant mutation in the fibroblast growth factor receptor 3 gene (FGFR3), which constitutively activates the downstream inhibitory signaling pathway in chondrocytes," she explained.

Disease manifestations can include cervicomedullary compression, sleep apnea, spinal stenosis, and genu varum. Current treatments include surgical interventions such as foramen magnum decompression and limb lengthening. No pharmacologic therapies have been approved for this condition, with the exception of growth hormone, used with limited efficacy in Japan.

C-type natriuretic peptide and its receptor stimulate endochondrial ossification, and infusions of the peptide have restored bone growth in animal studies. In a previous open-label, , administration of the recombinant form of C-type natriuretic peptide, vosoritide, resulted in sustained increases in growth velocity.

Similar results have been seen in the current pivotal phase III randomized trial, which evaluated the efficacy and safety of vosoritide versus placebo in patients whose mean age was 9 years.

At baseline, after at least 6 months of observation to determine baseline growth velocity, the vosoritide and placebo groups were similar, with annualized growth velocities of 4.26 and 4.06 cm/year, respectively, and height Z-scores of -5.13 and -5.14. The upper-to-lower body segment ratios were 1.98 and 2.01, while standing heights were 100.20 and 102.94 cm.

Serum collagen X degradation marker was measured to support the clinical findings of growth increases. This marker of endochondrial bone formation correlates with growth velocity in average stature populations, and in the vosoritide group it increased during the first 13 weeks of treatment and was sustained over the remainder of the 52-week trial. There were no changes in this marker in the placebo group.

Vosoritide treatment was not associated with changes in the upper-to-lower body segment ratios.

"The daily injections were well tolerated, with mostly mild adverse events reported," Polgreen said.

The most common adverse events (AEs) were self-limiting injection site reactions, which had no clinical consequences and were not associated with hypersensitivity, she noted.

Grade 3 AEs occurred in 3% of patients in both groups, and serious AEs were observed in 3% of the vosoritide and 4% of the placebo groups. None of the severe AEs were considered related to the study drug, but represented either common pediatric illnesses or manifestations of achondroplasia.

For example, one patient in the vosoritide group experienced sleep apnea, one in the placebo group had appendicitis, another in the placebo group had intracranial pressure increases, and one in the vosoritide group had a radius fracture.

"Of note, the radius fracture healed without complications and the patient is continuing in the extension phase of the trial," she said.

Blood pressure and heart rate were monitored frequently during the initial study visits, for 2 hours post-dose during the first 3 days of treatment and for 1 hour on all subsequent visits.

Decreases in systolic blood pressure were similar in the vosoritide and placebo groups, being seen in 14 and 15 patients, respectively, but diastolic pressure decreases were reported more often in the vosoritide group, at 10 versus 6 patients. All blood pressure decreases were asymptomatic, with the exception of one event that was associated with a patient sitting up suddenly, she said. These transient hemodynamic changes were consistent with the biologic effects of C-type natriuretic peptide on vascular tone.

In conclusion, "daily subcutaneous administration of 15 mg/kg vosoritide in children with achondroplasia resulted in highly significant improvements in annualized growth velocity and height Z-score compared with placebo after 52 weeks," she said. The long-term effects in these children will be followed to their final adult height, and a study in patients younger than age 5 is ongoing.

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