Title: The role of vosoritide in achondroplasia management
Professor Ravi Savarirayan
Victorian Clinical Genetics Services（consultant clinical geneticist）,
Murdoch Children's Research Institute（Group leader）
University of Melbourne, Australia（Professorial fellow）
Summary
Achondroplasia (ACH) is a condition associated with a gain-of-function variant in the FGFR3 gene, causing short stature. While growth hormone therapy is approved in Japan, there is a lack of global treatment options, necessitating consideration of the optimal therapeutic approach. In the management of ACH, timely prenatal and postnatal diagnosis, utilizing methods such as ultrasound, becomes crucial when contemplating early intervention. ACH presents with various complications, including not only short stature but also significant spinal issues. Given the elevated risk of sudden death associated with foramen magnum stenosis, MRI evaluation is essential. In cases of sleep apnea, prompt inpatient assessment and intervention are desirable due to the associated risk of sudden death. Pain, such as back pain, can impact walking ability significantly, as indicated by studies showing a high prevalence of impaired walking ability in individuals with ACH. Early examination and intervention are crucial for all these aspects.
On the social front, bullying can be a concern in school and on social media. Interventions, including counseling, are necessary. Understanding the developmental milestones specific to ACH children is crucial, given the differences from typically developing children. Worldwide guidelines for managing ACH have been developed and translated into 14 languages, and guidelines for treatment are currently under development.
While growth hormone therapy is approved for ACH only in Japan, a new treatment, vosoritide, has received approval. Vosoritide, an analog of CNP, promotes cartilage cell growth by inhibiting RAF1 activated by the FGFR3 pathogenic variant in ACH. Clinical trials for vosoritide commenced from the age of 5 for safety considerations and extended to 0-5 years later. Prior to the trials, an observational study of 363 patients under the age of 17 years was conducted, observing the natural history of growth rates and body proportions over 7 years. Growth rates were 11.4 cm/year for males and 14.6 cm/year for females under 1 year, decreasing to 7.4 cm/year for males and 7.1 cm/year for females over 1 year. At 10 years, the rate was 3.6 cm/year. Upper-to-lower body segment ratio was uneven, reaching 2 after the age of 4. A phase 2 trial showed sustained growth rates improvement in vosoritide groups compared to the placebo one, with positive effects on height SDS. Bone age was not accelerated, and no serious adverse events requiring treatment were reported, though some cases paused treatment during adolescence or due to family burdens.
In phase 3 trial, growth rates increased in the vosoritide group compared to the placebo group. Administering vosoritide to the placebo group post-comparison led to improved growth rates. Subgroup analysis of the 2-year data showed promising results, with no adverse events noted. Follow-up at 3.5 years indicated substantial improvement in growth velocity in boys, reaching nearly typical growth rates. Height SDS and body proportions also improved, while bone age was not accelerated. Clinical trial results for children up to 5 years of age are publishing soon, but adverse events were minimal, and substantial increases in growth rates and height SDS were observed, along with improved body proportions in the second year of treatment. A 15-year follow-up is planned.
Furthermore, facial and foramen magnum studies using MRI are underway. Although the sample size is small, there are indications of improvement in foramen magnum size. Since the foramen magnum typically grows within the first 6 months after birth, early vosoritide administration may have the potential to improve foramen magnum stenosis. We have established the Skeletal Dysplasia Management Consortium (SDMC) to create guidelines for the treatment of skeletal disorders (https://www.skeletaldysplasia.org/). Vosoritide has paved the way for ACH treatment, and we express gratitude for the collaboration received in Japan.
（文責：中山尋文、窪田拓生）
