背景:脓毒症的特征是免疫反应失调和代谢改变,包括高密度脂蛋白胆固醇(HDL-C)水平降低。HDL表现出有益的特性,如脂多糖(LPS)清除,发挥抗炎作用并提供内皮保护。我们调查了CER-001,一种工程HDL模拟物,在LPS诱导的急性肾损伤(AKI)的猪模型和2a期临床试验中,旨在更好地了解其在全身炎症和肾功能中的分子基础。
方法:我们进行了一种转化方法来研究HDL给药对脓毒症的影响。通过LPS输注在猪中诱导无菌全身性炎症。动物随机进入LPS(n=6),CER20(单剂量CER-00120mg/kg;n=6),和CER20×2(CER-00120mg/kg;n=6)组。存活率,内皮功能障碍生物标志物,促炎介质,LPS,评估载脂蛋白A-I(ApoA-I)水平。分析肾脏和肝脏的组织学和生物化学。随后,我们表演了一个开放标签,随机化,剂量范围(2a期)研究包括20例因腹腔感染或尿脓毒血症引起的脓毒症患者,随机分为A组(常规治疗,n=5),B组(CER-0015mg/kgBID,n=5),C组(CER-00110mg/kgBID,n=5),和D组(CER-00120mg/kgBID,n=5)。主要结果是预防AKI发作和严重程度的安全性和有效性;次要结果包括炎症和内皮功能障碍标志物的变化。
结果:CER-001增加中位生存期,减少炎症介质,补体激活,内毒素血症猪的内皮功能障碍。它通过胆汁和保存的肝和肾实质增强了LPS的消除。在临床研究中,CER-001耐受性良好,没有与研究治疗相关的严重不良事件。快速的ApoA-I正常化与增强的LPS去除和免疫调节相关,改善了临床结果。与脓毒症的类型和严重程度无关。CER-001治疗的患者发生和进展为严重AKI(2或3期)的风险降低,在一部分危重病人中,对器官支持的需求减少,ICU住院时间缩短。
结论:CER-001有望作为脓毒症治疗的治疗策略,改善预后,减轻炎症和器官损伤。
背景:该研究得到了意大利Farmaco机构(AIFA)和当地伦理委员会的批准(N°EUDRACT2020-004202-60,方案CER-001-SEP_AKI_01),并于2021年1月13日被添加到欧盟临床试验注册。
Sepsis is characterized by a dysregulated immune response and metabolic alterations, including decreased high-density lipoprotein cholesterol (HDL-C) levels. HDL exhibits beneficial properties, such as lipopolysaccharides (LPS) scavenging, exerting anti-inflammatory effects and providing endothelial protection. We investigated the effects of CER-001, an engineered HDL-mimetic, in a swine model of LPS-induced acute kidney injury (AKI) and a Phase 2a clinical trial, aiming to better understand its molecular basis in systemic inflammation and renal function.
We carried out a translational approach to study the effects of HDL administration on sepsis. Sterile systemic inflammation was induced in pigs by LPS infusion. Animals were randomized into LPS (n = 6), CER20 (single dose of CER-001 20 mg/kg; n = 6), and CER20 × 2 (two doses of CER-001 20 mg/kg; n = 6) groups. Survival rate, endothelial dysfunction biomarkers, pro-inflammatory mediators, LPS, and apolipoprotein A-I (ApoA-I) levels were assessed. Renal and liver histology and biochemistry were analyzed. Subsequently, we performed an open-label, randomized, dose-ranging (Phase 2a) study included 20 patients with sepsis due to intra-abdominal infection or urosepsis, randomized into Group A (conventional treatment, n = 5), Group B (CER-001 5 mg/kg BID, n = 5), Group C (CER-001 10 mg/kg BID, n = 5), and Group D (CER-001 20 mg/kg BID, n = 5). Primary outcomes were safety and efficacy in preventing AKI onset and severity; secondary outcomes include changes in inflammatory and endothelial dysfunction markers.
CER-001 increased median survival, reduced inflammatory mediators, complement activation, and endothelial dysfunction in endotoxemic pigs. It enhanced LPS elimination through the bile and preserved liver and renal parenchyma. In the clinical study, CER-001 was well-tolerated with no serious adverse events related to study treatment. Rapid ApoA-I normalization was associated with enhanced LPS removal and immunomodulation with improvement of clinical outcomes, independently of the type and gravity of the sepsis. CER-001-treated patients had reduced risk for the onset and progression to severe AKI (stage 2 or 3) and, in a subset of critically ill patients, a reduced need for organ support and shorter ICU length of stay.
CER-001 shows promise as a therapeutic strategy for sepsis management, improving outcomes and mitigating inflammation and organ damage.
The study was approved by the Agenzia Italiana del Farmaco (AIFA) and by the Local Ethic Committee (N° EUDRACT 2020-004202-60, Protocol CER-001- SEP_AKI_01) and was added to the EU Clinical Trials Register on January 13, 2021.