Supplementary Material for: 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 growth velocity (AGV) 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 females, mean age 5.9+/-2.3 years, mean height -3.29+0.68 SD). Plasma vosoritide levels were assayed using an electrochemiluminescence assay. Pharmacodynamic markers including serum collagen X biomarker (CXM) and urine 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 hour and peaked at 2 hours 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 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.

引言：维洛索肽（Vosoritide）是一种C型利钠肽（C-type natriuretic peptide, CNP）类似物，可与其在软骨细胞上的受体结合，通过抑制ERK1/2-MAPK通路促进骨骼生长。我们此前曾报道过一项针对软骨发育不全儿童的II期临床试验结果。维洛索肽可使年化生长速率（annualized growth velocity, AGV）平均提升1.81 cm/年，12个月内身高标准差评分（height SD）升高0.36。本文报道该研究的药代动力学/药效学（pharmacokinetic/pharmacodynamic, PK/PD）数据，并分析这些参数与生长结局之间的相关性。
方法：我们纳入24名软骨发育不全的青春期前受试者（12名女性，平均年龄5.9±2.3岁，平均身高标准差评分为-3.29±0.68），每日皮下注射维洛索肽（15 mcg/kg/日）开展II期试验。采用电化学发光检测法测定血浆中维洛索肽浓度。在给药第1天、第6个月及第12个月随访时点，检测包括血清X型胶原标志物（CXM）及尿液环磷酸鸟苷（cGMP）生成量在内的药效学标志物。采用Pearson相关分析及回归分析，探究药代动力学、药效学参数与生长结局的关联。
结果：维洛索肽的药代动力学参数与此前在软骨发育不全患者中报道的结果相似。治疗12个月后，血清CXM水平从基线均值22.5±6.5 ng/ml升高至41.6±15.9 ng/ml（p < 0.0001）。尿液cGMP水平在给药后1小时内即升高，并于给药后2小时达到峰值。各随访时点的cGMP生成量曲线下面积（AUC）均值无显著差异。cGMP AUC的最大变化量与药代动力学AUC呈显著相关（r=0.46, p=0.0001）。然而，以平均PK AUC衡量的药物暴露量与任何生长结局均无相关性。血清CXM水平与此前6个月的身高生长速率呈显著相关（偏相关系数=0.40, p=0.0048）。但治疗期间CXM的变化量与身高生长速率变化量及身高标准差评分变化量均无相关性。
结论：维洛索肽治疗可改善软骨发育不全儿童的年化生长速率及身高标准差评分。药代动力学分析显示，药物暴露量与以尿液cGMP衡量的整体CNP活性相关，但与生长结局无关联。未来需开展更多研究以明确可预测治疗应答及临床结局的特定患者特征。