BioMarin’s Achondroplasia Drug Shows Sustained Increase in Growth Velocity in Mid-Stage Study

A mid-stage dose-finding and extension study of vosoritide, BioMarin Pharmaceutical’s experimental treatment for achondroplasia, showed sustained increase in annualized growth velocity for up to 42 months in children ages 5 to 14 years.

The results were published online in the New England Journal of Medicine. The data also demonstrated that vosoritide was generally well tolerated with a mild side effect profile. The company also said that it had met its enrollment goal of the first cohort of 30 patients for a separate phase 2 study of vosoritide in infants and young children ages 2 to 5 years.

“Our research continues to investigate the potential of vosoritide to assist in skeletal growth in children with achondroplasia,” said Ravi Savarirayan, lead author of the NEJM study and investigator from the Murdoch Children’s Research Institute, Royal Children’s Hospital at University of Melbourne in Australia. “I am hopeful that this ongoing clinical development program will be able to demonstrate a meaningful difference for children with achondroplasia.”

Achondroplasia is the most common form of disproportionate short stature in humans and is characterized by failure of normal conversion of cartilage into bone. Besides 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.

Vosoritide, an investigational analog of C-type Natriuretic Peptide (CNP), is being tested in children whose growth plates are still open, typically those less than 18 years of age. This is approximately 25 percent of people with achondroplasia. There are currently no licensed medicines for achondroplasia in the United States, Europe, Latin America, and the Middle East. Vosortide has been granted orphan drug designation in both the United States and Europe.

In the published results of the ongoing open-label, phase 2 study in children with achondroplasia, vosoritide delivered subcutaneously once-daily demonstrated a sustained increase in height and associated height Z scores (standard deviation score) for up to 42 months of treatment in children in cohort 3 receiving a continuous dose of 15 µg/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 μg/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 change from baseline. In cohort 4 (n=9) receiving 30 μg/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 change from baseline.

Side effects were generally mild. Serious adverse events occurred in four children and there were no adverse events related to disproportionate skeletal growth or clinically significant adverse cardiovascular effects.

“The results published today by NEJM demonstrate the importance of researching a therapeutic option that explicitly addresses the underlying cause of achondroplasia,” said Hank Fuchs, president of Worldwide Research and Development at BioMarin.

Height Z-scores 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 reference standards for average-height children. Improvements in Z-scores represent closure of approximately 15-20 percent of the “growth gap” between average-height and children with achondroplasia in 42 months.

BioMarin is also conducting two additional trials of vosoritide: a phase 2 to evaluate its safety, tolerability, and efficacy in approximately 70 infants and young children with achondroplasia, aged zero to less than 60 months, for a period of 52 weeks, followed by a subsequent open-label extension trial when all subjects receive active treatment; and a global phase 3 study in 110 children ages five to 14 for which the company expects top line results by the end of 2019.

BioMarin is also conducting lifetime impact of achondroplasia studies in Europe and Latin America to contribute to the understanding of the impact of achondroplasia.

Author: Rare Disease Staff