Ascendis Pharma A/S, Hellerup, Denmark.
Ascendis Pharma, Inc., Palo Alto, CA, USA.
Br J Clin Pharmacol. 2022 Nov;88(11):4763-4772. doi: 10.1111/bcp.15369. Epub 2022 Jun 1.
TransCon CNP is a novel prodrug designed to provide sustained release of C-type natriuretic peptide (CNP) for once-weekly therapy, addressing the pathology leading to aberrant skeletal development in achondroplasia. This phase 1 trial was initiated to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of TransCon CNP.
This randomized, placebo-controlled, single-ascending dose phase 1 trial was performed at two sites in Australia and enrolled 45 healthy adult males. Subjects received placebo or TransCon CNP (single-ascending dose cohorts [3, 10, 25, 75 or 150 μg CNP/kg]). The primary endpoint was frequency of adverse events and other safety outcomes. Other endpoints included PK and PD measured by cyclic guanosine-monophosphate (cGMP) and amino-terminal propeptide of CNP (NTproCNP).
TransCon CNP provided continuous systemic exposure to CNP over at least 7 days post-dose. Plasma and urine levels of cGMP were significantly increased in subjects administered TransCon CNP at 75-150 μg CNP/kg, indicating target engagement of active CNP at the natriuretic peptide receptor-B (NPR-B) for at least 1 week post-dose. TransCon CNP was well-tolerated, with no serious treatment-emergent adverse events or discontinuations. Extensive cardiac safety assessments did not reveal any clinically relevant effects on electrocardiogram parameters, including heart rate, PR, QRS and QTcF intervals.
Safety and PD data from this phase 1 trial support that TransCon CNP is well tolerated, with a PK profile compatible with a once-weekly dosing regimen. Further studies are ongoing to evaluate the potential of TransCon CNP to positively impact abnormal endochondral ossification in children with achondroplasia.
TransCon CNP 是一种新型前药，旨在为每周一次的治疗提供 C 型利钠肽（CNP）的持续释放，以解决导致软骨发育不全骨骼发育异常的病理。这项 1 期试验旨在评估 TransCon CNP 的安全性、耐受性、药效学（PD）和药代动力学（PK）。
这项随机、安慰剂对照、单递增剂量 1 期试验在澳大利亚的两个地点进行，共纳入 45 名健康成年男性。受试者接受安慰剂或 TransCon CNP（单递增剂量组[3、10、25、75 或 150μg CNP/kg]）。主要终点是不良事件的频率和其他安全性结果。其他终点包括通过环鸟苷一磷酸（cGMP）和 CNP 的氨基末端前肽（NTproCNP）测量的 PK 和 PD。
TransCon CNP 在给药后至少 7 天内提供了 CNP 的持续全身暴露。在给予 75-150μg CNP/kg 的 TransCon CNP 的受试者中，cGMP 的血浆和尿液水平显著增加，表明活性 CNP 至少在给药后 1 周内与利钠肽受体-B（NPR-B）结合。TransCon CNP 耐受性良好，无严重治疗相关不良事件或停药。广泛的心脏安全性评估未发现心电图参数（包括心率、PR、QRS 和 QTcF 间隔）有任何临床相关影响。
这项 1 期试验的安全性和 PD 数据支持 TransCon CNP 耐受性良好，PK 特征与每周一次的给药方案一致。正在进行进一步的研究，以评估 TransCon CNP 对软骨发育不全儿童异常软骨内骨化的潜在积极影响。
