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Children with achondroplasia, the genetic bone growth disorder that causes disproportionate dwarfism, saw sustained increases in annualized growth velocity with an investigational C-type natriuretic peptide analogue called vosoritide, researchers said.

In addition, vosoritide -- given subcutaneously once a day -- had a side-effect profile that was generally mild in a phase II dose-finding study.

"Children with achondroplasia face functional and medical complications," the study's lead author, Ravi Savarirayan, MB, MD, of Murdoch Children's Research Institute, Royal Children's Hospital, in Parkville, Victoria, told 名媛直播.

"This treatment has been shown to be relatively safe, and we hope might address some of those medical complications. "It is also the first medication that appears to have a positive and sustained effect on growth velocity, which we hope will translate to better function and access to the environment for these children, he added. "In the end it's about health, not height."

As Savarirayan and his colleagues explained in their study online in the , in achondroplasia a mutation in the FGFR3 gene prevents the conversion of cartilage into bone (ossification), particularly the long bones in the arms and legs. In addition to disproportionate short stature, achondroplasia is associated with several severe medical complications, such as foramen magnum compression, spinal stenosis, sleep apnea, bowed legs, mid-face hypoplasia, and long-term chronic pain.

No pharmacologic therapies have been approved for this condition in the U.S. (although growth hormone therapy has been approved in Japan). Limb-lengthening surgery increases height, but is controversial.

C-type natriuretic peptide is a potent stimulator of endochondral bone growth, the study authors explained. In this open-label, sequential-cohort, dose-finding study, the researchers aimed to evaluate the safety and side-effect profile of vosoritide in children with achondroplasia.

Patients eligible for the study were ages 5 to 14, had achondroplasia diagnosed by genetic testing, and had completed a 6-month observational growth study to establish baseline annualized growth velocity.

A total of 35 children were enrolled in the study. It also included a 6-month dose-finding phase in which the children were divided into four sequential cohorts to receive vosoritide in the following manner:

• Once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (eight patients in cohort 1)

• 7.5 μg per kilogram (eight patients in cohort 2)

• 15.0 μg per kilogram (10 patients in cohort 3)

• 30.0 μg per kilogram (nine patients in cohort 4)

After 6 months, patients in cohort 1 had their dose increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, while patients in cohort 2 had their dose increased to 15.0 μg per kilogram. Dosing remained the same in cohorts 3 and 4.

Patients who completed the 24-month dose-finding study were eligible to enroll in a long-term extension study in which they continued to receive their preassigned doses.

All 35 of the patients had adverse events (AEs), but only four had AEs considered serious (grade 3 obstructive sleep apnea, grade 1 tonsillar hypertrophy, grade 3 thyroglossal cyst, and grade 3 syrinx). The most common treatment-related AEs were mild, transient injection-site reactions, the researchers reported.

At 6 months, increases in annualized growth velocity from baseline were observed in cohort 2 (1.28 cm per year; 95% confidence interval [CI], 0.07 to 2.48), in cohort 3 (2.01 cm per year; 95% CI, 0.58 to 3.44), and in cohort 4 (2.08 cm per year; 95% CI, 0.30 to 3.87), but not in cohort 1 (−0.37 cm per year; 95% CI, −1.84 to 1.10).

Additionally, a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months.

Savarirayan and colleagues also found that height-Z scores improved over 42 months and that proportional growth was observed between upper and lower body segments, as well.

The researchers noted that they could identify no differences in safety or efficacy between once-daily doses of vosoritide, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months. "Thus, our findings support the choice of the lower dose for further evaluation in ongoing studies," the team said.

"We are further exploring these issues in larger randomized controlled trials in children and infants," Savarirayan said. These include a that is currently evaluating the efficacy and safety of the 15.0 μg per kilogram dose of vosoritide in up to 110 children with achondroplasia from the ages of 5 and 18, as well as an evaluating the efficacy and safety of vosoritide until patients reach final adult height.

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