Pharmacokinetics and Exposure-Response of Vosoritide in Children with Achondroplasia

• Authors: Ming Liang Chan, BioMarin Pharmaceutical Inc.; Yulan Qi, BioMarin Pharmaceutical Inc.; Kevin Larimore, BioMarin Pharmaceutical Inc.; Anu Cherukuri, BioMarin Pharmaceutical Inc.; Lori Seid, BioMarin Pharmaceutical Inc.; Kala Jayaram, BioMarin Pharmaceutical Inc.; George Jeha, BioMarin Pharmaceutical Inc.; Elena Fisheleva, BioMarin UK Ltd; Jonathan Day, BioMarin UK Ltd; Alice Huntsman-Labed, BioMarin UK Ltd; Ravi Savarirayan, University of Melbourne; Melita Irving, Guy’s and St. Thomas’ NHS Foundation Trust; Carlos A. Bacino, Baylor College of Medicine; Julie Hoover-Fong, Johns Hopkins University; Keiichi Ozono, Osaka University; Klaus Mohnike, Otto von Guericke University; William Wilcox, Emory University; William A. Horton, Shriners Hospital for Children; Joshua Henshaw, BioMarin Pharmaceutical Inc.
• Journal Title: Clinical Pharmacokinetics
• Volume: Volume 61, Number 2
• Publisher: Springer Nature | 2021-08-25, Pages 263-280
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1007/s40262-021-01059-1
• Subjects: Health Sciences, Pharmacology; Health Sciences, Pharmacy; Biology, Genetics
• Keywords: Science & Technology; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Fibroblast growth factor 23; Overexpression; CNP; Overgrowth; Hormones; Translocations; Receptor

Abstract

Background and Objective Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5–14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5–18 years randomized to receive daily subcutaneous injections for 52 weeks). Methods Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. Results The exposure–response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 μg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 μg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 μg/kg to patients with achondroplasia aged 5–18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. Conclusions The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed.