BioMarin Expands Vosoritide Clinical Program

BioMarin Pharmaceutical announced the Company is expanding its clinical program for vosoritide, an investigational analog of C-type Natriuretic Peptide (CNP), with two new Phase 2 studies. The first study is sponsored by BioMarin to investigate the safety of vosoritide in infants with achondroplasia at risk of life-threatening foramen magnum compression. The second study is an investigator-initiated study sponsored by Children's National Hospital in Washington, D.C. to investigate vosoritide in children with selected genetic forms of short stature, which together represent addressable patient populations of approximately 275,000.

The Company has enrolled the first child in a Phase 2 randomized, controlled, open-label clinical trial with an open-label extension to investigate the safety of vosoritide in infants with achondroplasia at risk of requiring cervicomedullary decompression surgery to alleviate compression at the foramen magnum, the opening in the base of the skull through which the spinal cord passes. In addition, the study will also measure a secondary endpoint to evaluate the effect of vosoritide on growth of the foramen magnum volume through MRI scans.

Foramen magnum compression is the foremost life-threatening complications of achondroplasia in infants. This study investigates the safety of vosoritide in infants aged 0 -1 years of age with achondroplasia who have evidence of foramen magnum compression at-risk for requiring cervicomedullary decompression surgery. Those infants are under close observation for the appearance of neurological signs of progressive foramen magnum compression, and the current standard of care is palliative with many eventually requiring surgery. The study aims to enroll approximately 20 infants, who will be randomized to either current standard of care plus vosoritide treatment or current standard of care alone for a two-year period. After the two-year randomized period, children in the study would be eligible to receive vosoritide in an open-label, 3-year additional extension period. The study will examine the incidence of adverse events between the two groups, volume MRI measurements of the foramen magnum, skull and spine, and progression to requiring decompression surgery.

"We continue to expand our clinical program of vosoritide for the treatment of achondroplasia with the first study specifically looking at the safety of vosoritide administered to infants at risk of serious and potentially fatal medical complications resulting from achondroplasia," said Hank Fuchs, M.D., President, Worldwide Research and Development at BioMarin. "We are committed to understanding whether vosoritide can safely reduce the number of adverse outcomes in this high-risk population and are pleased to support this study as part of our commitment to advancing the standard of care for children affected by achondroplasia."

This investigator-initiated study will enroll approximately 35 children with short stature in specific genetic categories and will follow them for a six-month observation period to obtain baseline growth velocity, safety profile and quality of life assessment. Study participants will then be treated with vosoritide for 12 months and will be assessed for safety and improvement in growth outcomes. The primary endpoints include incidence of treatment emergent adverse events, change from baseline in annualized growth velocity and change from baseline in height Z-score.

"Many patients who present with short stature likely have genetic mutations in genes involved in growth plate physiology. Those patients with selected causes of short stature that interact with the CNP pathway may benefit from treatment with vosoritide, which directly targets the growth plate," said Andrew Dauber, M.D., MMSc, Chief of Endocrinology at Children's National Hospital, Washington D.C. and lead investigator of this clinical study. "In this study, our goal is to understand if vosoritide may be a safe and effective treatment option for certain genetically defined short stature syndromes."

Achondroplasia, the most common form of skeletal dysplasia in humans, is characterized by slowing of endochondral ossification, which results in disproportionate short stature and disordered architecture in the long bones, spine, face and base of the skull. 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 the need for 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. Vosoritide is being tested in children whose growth plates are still "open", typically those under 18 years of age. This is approximately 25% of people with achondroplasia. In the U.S., Europe, Latin America, the Middle East, and most of Asia Pacific, there are currently no approved medicines for achondroplasia.

Short stature can be caused by a number of genetic etiologies, many of which directly affect the growth plate. The CNP/NPR2 pathway is central to growth of the chondrocyte, therefore patients with selected genetic causes of short stature that interact with this pathway could benefit from treatment with vosoritide, which directly targets the growth plate. This study specifically focuses on five different genes related to the CNP/NPR2 pathway, including patients with deficiency in CNP itself or defects in its receptor encoded by the NPR2 gene; patients with hypochondroplasia; patients with defects in the SHOX gene; and patients with a Rasopathy (a group of genetic disorders that includes Noonan Syndrome and Neurofibromatosis type 1 amongst other disorders). Collectively, these categories of genetic short stature affect approximately 275,000 of the addressable patient population globally based on incidence rate, diagnosis rate, and age under 18.