Safety profile and adherence of vosoritide in young children with achondroplasia in Japan
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
Achondroplasia (ACH) is caused by a pathogenic variant of the fibroblast growth factor receptor 3 gene (FGFR3) that causes impaired endochondral bone growth. Vosoritide, a recombinant C-type natriuretic peptide, potently stimulates endochondral bone growth by inhibiting FGFR3 signaling. Vosoritide is approved in several countries in children with ACH until the closure of epiphyses. In June 2022, Japan became the first country to approve vosoritide treatment from birth; however, data on vosoritide use in younger children are limited. Here, we use data from an ongoing drug use survey in Japan to report real-world vosoritide safety and adherence.
Methods:
A drug use survey (111-604) was required by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) as a condition of approval to evaluate the long-term safety and effectiveness of vosoritide treatment in children with ACH. As vosoritide is an orphan drug, all exposed cases are expected to be included in the survey. Enrollment began in January 2023; retrospective data were collected from the start of vosoritide exposure (August 2022), and participants will be followed until treatment termination or the PMDA-required end of survey (August 2031), whichever comes first. Safety was assessed by collecting serious adverse events (SAEs), suspected adverse drug reactions (ADRs), and adverse events of special interest (events associated with a reduction in blood pressure and bone- or joint-related events), and effectiveness was assessed by change in height/length Z-scores (using US Centers for Disease Control and Prevention [CDC] reference) and annualized growth velocity. Participants’ legal guardians provided written informed consent to allow sharing of deidentified data for publication. Safety and adherence data are presented for ≤23 months of follow-up from young children who began treatment aged ≤3 years.
Results:
At the data cutoff (July 26, 2024), 523 participants were enrolled and 266 provided consent for publication; of those, 175 were available for analysis. Among 175 children, 55 (31%) were aged ≤3 years at treatment initiation, with mean (standard deviation [SD]) age at treatment initiation of 16.4 (11.4) months; 24 of 55 started therapy aged ≤1 year (minimum, 1 month). Most (58.2%) children aged ≤3 years were male, and participants enrolled from all regions of Japan. Mean (SD) height/length CDC Z-score was −3.94 (1.41) at treatment initiation for children aged ≤3 years.
The cumulative mean (SD) duration of treatment exposure was 17.46 (4.40) months and 15.38 (5.06) months for children aged ≤3 and ≤1 years, respectively. Since the start of commercial vosoritide treatment, 1 SAE unrelated to vosoritide (respiratory syncytial virus infection) was reported. There were no ADRs, bone- or joint-related safety events, or safety events associated with a reduction in blood pressure. Five ACH-related surgical events were reported (1 adenoidectomy, 1 hydrocephalous-related surgery, 3 foramen magnum decompressions); 2 of these foramen magnum decompressions were in children ≤1 years of age. There were no reported dose interruptions for any enrolled children, and 1 non-safety-related discontinuation was reported (reason, “other”). Effectiveness analyses are in progress.
Conclusion:
Overall, the vosoritide safety profile in children with ACH under 3 years of age remained favorable in real-world clinical practice in Japan. Treatment adherence was high, with no reported dose interruptions.
Achondroplasia (ACH) is caused by a pathogenic variant of the fibroblast growth factor receptor 3 gene (FGFR3) that causes impaired endochondral bone growth. Vosoritide, a recombinant C-type natriuretic peptide, potently stimulates endochondral bone growth by inhibiting FGFR3 signaling. Vosoritide is approved in several countries in children with ACH until the closure of epiphyses. In June 2022, Japan became the first country to approve vosoritide treatment from birth; however, data on vosoritide use in younger children are limited. Here, we use data from an ongoing drug use survey in Japan to report real-world vosoritide safety and adherence.
Methods:
A drug use survey (111-604) was required by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) as a condition of approval to evaluate the long-term safety and effectiveness of vosoritide treatment in children with ACH. As vosoritide is an orphan drug, all exposed cases are expected to be included in the survey. Enrollment began in January 2023; retrospective data were collected from the start of vosoritide exposure (August 2022), and participants will be followed until treatment termination or the PMDA-required end of survey (August 2031), whichever comes first. Safety was assessed by collecting serious adverse events (SAEs), suspected adverse drug reactions (ADRs), and adverse events of special interest (events associated with a reduction in blood pressure and bone- or joint-related events), and effectiveness was assessed by change in height/length Z-scores (using US Centers for Disease Control and Prevention [CDC] reference) and annualized growth velocity. Participants’ legal guardians provided written informed consent to allow sharing of deidentified data for publication. Safety and adherence data are presented for ≤23 months of follow-up from young children who began treatment aged ≤3 years.
Results:
At the data cutoff (July 26, 2024), 523 participants were enrolled and 266 provided consent for publication; of those, 175 were available for analysis. Among 175 children, 55 (31%) were aged ≤3 years at treatment initiation, with mean (standard deviation [SD]) age at treatment initiation of 16.4 (11.4) months; 24 of 55 started therapy aged ≤1 year (minimum, 1 month). Most (58.2%) children aged ≤3 years were male, and participants enrolled from all regions of Japan. Mean (SD) height/length CDC Z-score was −3.94 (1.41) at treatment initiation for children aged ≤3 years.
The cumulative mean (SD) duration of treatment exposure was 17.46 (4.40) months and 15.38 (5.06) months for children aged ≤3 and ≤1 years, respectively. Since the start of commercial vosoritide treatment, 1 SAE unrelated to vosoritide (respiratory syncytial virus infection) was reported. There were no ADRs, bone- or joint-related safety events, or safety events associated with a reduction in blood pressure. Five ACH-related surgical events were reported (1 adenoidectomy, 1 hydrocephalous-related surgery, 3 foramen magnum decompressions); 2 of these foramen magnum decompressions were in children ≤1 years of age. There were no reported dose interruptions for any enrolled children, and 1 non-safety-related discontinuation was reported (reason, “other”). Effectiveness analyses are in progress.
Conclusion:
Overall, the vosoritide safety profile in children with ACH under 3 years of age remained favorable in real-world clinical practice in Japan. Treatment adherence was high, with no reported dose interruptions.