Rudzki Piotr J, Jarus-Dziedzic Katarzyna, Włodarczyk Dorota, Kaza Michał, Pankiewicz Piotr, Gierczak-Pachulska Agnieszka, Banach Martyna, Zygmunt Beata, Piwowarczyk Cezary, Żero Paweł, Rabczenko Daniel, Segiet-Święcicka Agnieszka, Wieczorek Maciej
R&D Center, Celon Pharma S.A., Kazuń Nowy, Poland.
Clinical Site, BioResearch Group, Kajetany, Poland.
Front Pharmacol. 2025 Apr 1;16:1583723. doi: 10.3389/fphar.2025.1583723. eCollection 2025.
CPL'116 is a novel Janus kinase (JAK) and Rho-associated coiled-coil containing protein kinase (ROCK) dual inhibitor and a promising drug candidate for the treatment of inflammatory and fibrotic diseases. We conducted this first-in-human, Phase I clinical trial to evaluate the safety, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of CPL'116 in healthy subjects.
Phase I clinical trial in healthy White volunteers was conducted after single (n = 21, 10-300 mg) and multiple (n = 32, 30-240 mg or placebo, 14-day b.i.d.) administrations of CPL'116 including a food effect study (n = 12, 120 mg). The multiple ascending dose part was double-blinded and placebo-controlled. The primary endpoint was safety evaluation, and the secondary endpoint was PK. Exploratory PD was studied by measuring the inhibition of JAK and ROCK in the blood by assessing STAT1, STAT5, and MLC phosphorylation.
Safety parameters were comparable between the placebo and active treatment groups, with no clinically meaningful variations in the safety parameters between the cohorts. No deaths or serious adverse events (SAEs) were reported. No influence on hematological parameters (neutrophil count, red cell distribution width, and mean corpuscular volume) was observed. Plasma C and AUC increased proportionally in the dosing range of 60-240 mg. Median t ranged 2-3 h. Food increased the absorption of CPL'116. Compared to placebo, CPL'116 at 240 mg dose showed a decrease in the phosphorylation of STAT1 (Days 1 and 14, p < 0.05) and STAT5 (Day 14, p < 0.05). A decrease in MLC phosphorylation indicated a potential trend at p < 0.1.
CPL'116 was safe and well-tolerated by healthy subjects. The PK profile is well suited for twice-daily administration and justifies further clinical development. Exploratory PD studies indicated the ability of CPL'116 to affect the JAK and ROCK pathways in humans, hinting at its potential therapeutic role in diseases benefiting from its dual mode of action. The positive results of this study indicate the possibility of developing a novel class of therapeutics that address both inflammatory and fibrotic processes.
clinicaltrials.gov, identifier NCT04670757.
CPL'116是一种新型的Janus激酶（JAK）和Rho相关卷曲螺旋蛋白激酶（ROCK）双重抑制剂，是治疗炎症性和纤维化疾病的一种很有前景的候选药物。我们开展了这项首次人体I期临床试验，以评估CPL'116在健康受试者中的安全性、药代动力学（PK）和探索性药效学（PD）。
在健康白人志愿者中开展I期临床试验，单次（n = 21，10 - 300毫克）和多次（n = 32，30 - 240毫克或安慰剂，每日两次，共14天）给予CPL'116，包括食物影响研究（n = 12，120毫克）。多次递增剂量部分为双盲且安慰剂对照。主要终点是安全性评估，次要终点是PK。通过评估信号转导和转录激活因子1（STAT1）、信号转导和转录激活因子5（STAT5）以及肌球蛋白轻链（MLC）磷酸化来测量血液中JAK和ROCK的抑制情况，以此研究探索性PD。
安慰剂组和活性治疗组之间的安全参数具有可比性，各队列之间的安全参数无临床意义上的差异。未报告死亡或严重不良事件（SAE）。未观察到对血液学参数（中性粒细胞计数、红细胞分布宽度和平均红细胞体积）有影响。在60 - 240毫克的给药范围内，血浆药物浓度（C）和药时曲线下面积（AUC）成比例增加。中位达峰时间（t）为2 - 3小时。食物可增加CPL'116的吸收。与安慰剂相比，240毫克剂量的CPL'116在第1天和第14天使STAT1磷酸化水平降低（p < 0.05），在第14天使STAT5磷酸化水平降低（p < 0.05）。MLC磷酸化水平降低表明在p < 0.1时有潜在趋势。
CPL'116在健康受试者中安全且耐受性良好。其药代动力学特征非常适合每日两次给药，为进一步的临床开发提供了依据。探索性PD研究表明CPL'116能够影响人体中的JAK和ROCK信号通路，提示其在受益于双重作用模式的疾病中具有潜在治疗作用。本研究的阳性结果表明开发一类既能解决炎症又能解决纤维化过程的新型治疗药物具有可能性。
clinicaltrials.gov，标识符NCT04670757 。
