Pharmacokinetics and Exposure-Response of Vosoritide in Children with Achondroplasia
Ming Liang Chan, Yulan Qi, Kevin Larimore, Anu Cherukuri, Lori Seid, Kala Jayaram, George Jeha, Elena Fisheleva, Jonathan Day, Alice Huntsman-Labed, Ravi Savarirayan, Melita Irving, Carlos A Bacino, Julie Hoover-Fong, Keiichi Ozono, Klaus Mohnike, William R Wilcox, William A Horton, Joshua Henshaw, Ming Liang Chan, Yulan Qi, Kevin Larimore, Anu Cherukuri, Lori Seid, Kala Jayaram, George Jeha, Elena Fisheleva, Jonathan Day, Alice Huntsman-Labed, Ravi Savarirayan, Melita Irving, Carlos A Bacino, Julie Hoover-Fong, Keiichi Ozono, Klaus Mohnike, William R Wilcox, William A Horton, Joshua Henshaw
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.
Clinical trials registration: NCT02055157, NCT03197766, and NCT01603095.
Conflict of interest statement
Ming Liang Chan, Yulan Qi, Kevin Larimore, Anu Cherukuri, Lori Seid, Kala Jayaram, Elena Fisheleva, Jonathan Day, Alice Huntsman Labed and Joshua Henshaw are employees of BioMarin Pharmaceutical Inc. Ravi Savarirayan and Klaus Mohnike have received consulting fees and grants from BioMarin. Melita Irving has received consulting fees from BioMarin. Carlos A. Bacino has received consulting fees, honoraria and grants from BioMarin. Julie Hoover-Fong has received consulting fees from BioMarin, Therachon and Ascendis, and grants from BioMarin. Keiichi Ozono has received consulting fees and honoraria from BioMarin. William R. Wilcox was a consultant to BioMarin and received an honoraria, and was the principal investigator for the clinical trial contract with Emory University. William A. Horton is an inventor on a patent application “Type X collagen assay and methods of use thereof”, submitted by Shriners Hospitals for Children. He has consulted for and/or received speaker honoraria from BioMarin, TherAchon (Pfizer), Ascendis, QED, Relay Therapeutics, Fortress Biotech, OPKO, and Medicell Technologies.
© 2021. The Author(s).
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