ESPE Abstracts

Objectives: 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 growth velocity (GV) of 1.81 cm/year and gain of 0.36 in height 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 mcg/kg/day) in 24 prepubertal subjects with hypochondroplasia (12 female, mean age 5.9+/-2.3 years, mean height -3.29+0.68 SD). Plasma vosoritide levels were assayed using an electrochemiluminescence assay. PK parameters were analyzed by non-compartmental methods using Phoenix WinNonlin. Pharmacodynamic markers including serum collagen X biomarker (CXM), a marker of endochondral ossification, and urine cGMP production, a marker of CNP activity, were measured at Day 1, Month 6 and Month 12. CXM levels in serum were measured via an ELISA assay. Urine samples were obtained for cGMP measurement at baseline and 60, 120, and 240 minutes after vosoritide injections and were normalized to urine creatinine levels. Pearson correlations were performed between PK and PD parameters and growth outcomes.

Results: PK parameters were similar to previously reported for achondroplasia. The PK AUC was highly correlated with Cmax (r =0.87, P <0.0001 at Day 1 visit). 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 hour and peaked at 2 hours after injection. The mean AUC for cGMP production was not significantly different at each study visit. The cGMP AUC correlated with PK parameters (r =0.45, P = 0.0004 for Cmax; r =0.49, P = 0.0001 for PK AUC). 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 GV (partial correlation coefficient=0.40, P = 0.0048). However, change in CXM did not correlate with change in GV or height SD.

Conclusion: Vosoritide treatment showed improvement in AGV 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.