C-type natriuretic peptide analogue therapy in children with achondroplasia

Ravi Savarirayan, Melita Irving, Carlos A. Bacino, Bret Bostwick, Joel Charrow, Valerie Cormier-Daire, Kim Hanh Le Quan Sang, Patricia Dickson, Paul Harmatz, John Phillips, Natalie Owen, Anu Cherukuri, Kala Jayaram, George S. Jeha, Kevin Larimore, Ming Liang Chan, Alice Huntsman Labed, Jonathan Day, Julie Hoover-fong

Research output: Contribution to journalArticle

Abstract

BACKGROUND Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months. CONCLUSIONS In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.)

Original languageEnglish (US)
Pages (from-to)25-35
Number of pages11
JournalNew England Journal of Medicine
Volume381
Issue number1
DOIs
StatePublished - Jul 4 2019

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C-Type Natriuretic Peptide
Achondroplasia
Therapeutics
Osteogenesis
Growth
Inborn Genetic Diseases
Body Weight
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Savarirayan, R., Irving, M., Bacino, C. A., Bostwick, B., Charrow, J., Cormier-Daire, V., ... Hoover-fong, J. (2019). C-type natriuretic peptide analogue therapy in children with achondroplasia. New England Journal of Medicine, 381(1), 25-35. https://doi.org/10.1056/NEJMoa1813446
Savarirayan, Ravi ; Irving, Melita ; Bacino, Carlos A. ; Bostwick, Bret ; Charrow, Joel ; Cormier-Daire, Valerie ; Le Quan Sang, Kim Hanh ; Dickson, Patricia ; Harmatz, Paul ; Phillips, John ; Owen, Natalie ; Cherukuri, Anu ; Jayaram, Kala ; Jeha, George S. ; Larimore, Kevin ; Chan, Ming Liang ; Labed, Alice Huntsman ; Day, Jonathan ; Hoover-fong, Julie. / C-type natriuretic peptide analogue therapy in children with achondroplasia. In: New England Journal of Medicine. 2019 ; Vol. 381, No. 1. pp. 25-35.
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abstract = "BACKGROUND Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100{\%}), and serious adverse events occurred in 4 of 35 patients (11{\%}). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months. CONCLUSIONS In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.)",
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Savarirayan, R, Irving, M, Bacino, CA, Bostwick, B, Charrow, J, Cormier-Daire, V, Le Quan Sang, KH, Dickson, P, Harmatz, P, Phillips, J, Owen, N, Cherukuri, A, Jayaram, K, Jeha, GS, Larimore, K, Chan, ML, Labed, AH, Day, J & Hoover-fong, J 2019, 'C-type natriuretic peptide analogue therapy in children with achondroplasia', New England Journal of Medicine, vol. 381, no. 1, pp. 25-35. https://doi.org/10.1056/NEJMoa1813446

C-type natriuretic peptide analogue therapy in children with achondroplasia. / Savarirayan, Ravi; Irving, Melita; Bacino, Carlos A.; Bostwick, Bret; Charrow, Joel; Cormier-Daire, Valerie; Le Quan Sang, Kim Hanh; Dickson, Patricia; Harmatz, Paul; Phillips, John; Owen, Natalie; Cherukuri, Anu; Jayaram, Kala; Jeha, George S.; Larimore, Kevin; Chan, Ming Liang; Labed, Alice Huntsman; Day, Jonathan; Hoover-fong, Julie.

In: New England Journal of Medicine, Vol. 381, No. 1, 04.07.2019, p. 25-35.

Research output: Contribution to journalArticle

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T1 - C-type natriuretic peptide analogue therapy in children with achondroplasia

AU - Savarirayan, Ravi

AU - Irving, Melita

AU - Bacino, Carlos A.

AU - Bostwick, Bret

AU - Charrow, Joel

AU - Cormier-Daire, Valerie

AU - Le Quan Sang, Kim Hanh

AU - Dickson, Patricia

AU - Harmatz, Paul

AU - Phillips, John

AU - Owen, Natalie

AU - Cherukuri, Anu

AU - Jayaram, Kala

AU - Jeha, George S.

AU - Larimore, Kevin

AU - Chan, Ming Liang

AU - Labed, Alice Huntsman

AU - Day, Jonathan

AU - Hoover-fong, Julie

PY - 2019/7/4

Y1 - 2019/7/4

N2 - BACKGROUND Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months. CONCLUSIONS In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.)

AB - BACKGROUND Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 μg per kilogram of body weight (8 patients in cohort 1), 7.5 μg per kilogram (8 patients in cohort 2), 15.0 μg per kilogram (10 patients in cohort 3), or 30.0 μg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 μg per kilogram and then to 15.0 μg per kilogram, and in cohort 2, the dose was increased to 15.0 μg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 μg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 μg per kilogram for up to 42 months. CONCLUSIONS In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.)

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