Phase 2 Trial of Vosoritide Use in Patients with Hypochondroplasia: A Pharmacokinetic/Pharmacodynamic Analysis.

Introduction: Vosoritide is a C-type natriuretic peptide (CNP) analog that binds its receptor on chondrocytes, promoting growth by inhibiting the ERK1/2-MAPK pathway. We previously reported the results of a phase II study in children with hypochondroplasia. Vosoritide led to an average increase in annualized height velocity (AHV) of 1.81 cm/year and gain of 0.36 in height standard deviation (SD) over 12 months. We present here the pharmacokinetic/pharmacodynamic (PK/PD) data from this study and examine the correlations between these parameters and growth outcomes. Methods: We conducted a phase II trial of daily subcutaneous vosoritide (15 μg/kg/day) in 24 prepubertal subjects with hypochondroplasia (12 females, mean age 5.9 ± 2.3 years, mean height −3.29 + 0.68 SD). Plasma vosoritide levels were assayed using an electrochemiluminescence assay. PD markers including serum collagen X biomarker (CXM) and urine cyclic guanosine monophosphate (cGMP) production were measured at day 1, month 6, and month 12 visits. Pearson correlations and regression analyses were performed between PK and PD parameters and growth outcomes. Results: Vosoritide PK parameters were similar to those previously reported in patients with achondroplasia. CXM levels increased from a baseline mean of 22.5 ± 6.5 to 41.6 ± 15.9 ng/mL after 12 months of treatment (p < 0.0001). Urine cGMP increased within 1 h and peaked at 2 h after injection. The mean AUC for cGMP production was not significantly different at each study visit. The maximum change in cGMP AUC correlated with PK AUC (r = 0.46, p = 0.0001). However, drug exposure, as measured by average PK AUC, did not correlate with any growth outcome. CXM levels correlated with the prior 6-month interval height velocity (partial correlation coefficient = 0.40, p = 0.0048). However, change in CXM did not correlate with change in height velocity or change in height SD during treatment. Conclusions: Vosoritide treatment showed improvement in AHV and height SD in children with hypochondroplasia. PK analysis indicates that drug exposure was correlated to global CNP activity as measured by urine cGMP but did not correlate with growth outcomes. More studies are needed to identify specific patient characteristics that can predict response to therapy and clinical outcomes. [ABSTRACT FROM AUTHOR]