The New England Journal of Medicine ( NEJM ) has published the results from a phase 2 dose-finding and extension study for Vosoritide, an investigational analog of C-type natriuretic peptide ( CNP ), in children with achondroplasia.
The data have demonstrated that Vosoritide was generally well tolerated with a mild side effect profile and resulted in a sustained increase in annualized growth velocity for up to 42 months in children aged 5 to14 years with achondroplasia, the most common form of disproportionate short stature in humans.
The NEJM publication described results of an ongoing open-label, phase 2 study in children with achondroplasia, where Vosoritide has demonstrated a sustained increase in height and associated height Z scores for up to 42 months of treatment in children in cohort 3 receiving a continuous dose of 15 mcg/kg/day.
Annualized growth velocity increased from baseline in all cohorts during each 12-month interval by 1.10 to 2.34 cm/year through 42 months.
In cohort 3 ( n=10 ) receiving 15 mcg/kg continuous dosing from baseline, the mean annualized growth velocity derived between 30 and 42 months was 5.51 cm/year representing a 1.46 cm/year ( 95% CI −0.15, 3.07 ) change from baseline.
In cohort 4 ( n=9 ) receiving 30 mcg/kg continuous dosing from baseline, the mean annualized growth velocity between 18 and 30 months was 5.60 cm/year representing a 1.10 cm/year ( 95% CI −0.27, 2.48 ) change from baseline.
Once-daily subcutaneous administration of Vosoritide was associated with a side-effect profile that was generally mild.
Injection-site reactions were mild and transient.
Blood pressure and pulse rate were monitored frequently after the initial dose was administered.
All reductions in blood pressure from test to test were reported as non-serious and transient and resolved without medical intervention; none resulted in interruption or discontinuation of the study-drug regimen.
Serious adverse events occurred in four children and included grade 3 obstructive sleep apnea, grade 1 tonsillar hypertrophy, grade 3 thyroglossal cyst, and grade 3 syrinx.
No deaths occurred.
No adverse events related to disproportionate skeletal growth or clinically significant adverse cardiovascular effects were observed.
In addition, there were no reports of grade 3 or higher or serious hypersensitivity reactions.
Height Z-scores also continued to improve over 42 months and there was proportional growth between the upper and lower body segments.
Standing height was converted to an age and sex appropriate Z-score by comparison with Centers for Disease Control and Prevention ( CDC ) reference standards for average-height children.
Dose-dependent increases in height Z-scores were observed in the children who received a dose of up to 15.0 mcg/kg/day for 6 months; those who received a dose of 30.0 mcg/kg/day had a similar increase.
Vosoritide resulted in a sustained increase in height Z-score for up to 42 months; the mean increase from baseline to 42 months was 1.03±0.57 ( 95% CI 0.62, 1.43 ) in cohort 3; the mean increase from baseline to 30 months was 1.06±0.30 ( 95% CI 0.81, 1.31 ) in cohort 4.
These improvements in Z-scores represent closure of approximately 15-20% of the growth gap of 5-6 SD between average-height and children with achondroplasia in 42 months.
Confidence intervals evaluating changes from baseline in annualized growth velocity, Z-scores, and upper-to-lower body segment ratio were considered descriptive and no adjustment for multiplicity was made.
Achondroplasia, the most common form of disproportionate short stature in humans, is characterized by failure of normal conversion of cartilage into bone, which results in disproportionate short stature.
This condition is caused by a mutation in the fibroblast growth factor receptor 3 gene ( FGFR3 ), a negative regulator of bone growth.
Beyond disproportionate short stature, people with achondroplasia can experience serious health complications, including foramen magnum compression, sleep apnea, bowed legs, mid-face hypoplasia, permanent sway of the lower back, spinal stenosis and recurrent ear infections.
Some of these complications can result in invasive surgeries such as spinal cord decompression and straightening of bowed legs.
In addition, studies show increased mortality at every age.
More than 80% of children with achondroplasia have parents of average stature and have the condition as the result of a spontaneous gene mutation.
The worldwide incidence rate of achondroplasia is about one in 25,000 live births. ( Xagena )
Source: BioMarin, 2019