Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, Bari, Italy.
Veterinary Surgery Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, Bari, Italy.
BMC Med. 2023 Nov 2;21(1):392. doi: 10.1186/s12916-023-03057-5.
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.
败血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 具有有益的特性，如内毒素（LPS）清除、抗炎作用和提供内皮保护。我们研究了 CER-001，一种工程化的 HDL 模拟物，在 LPS 诱导的急性肾损伤（AKI）猪模型和 2a 期临床试验中的作用，旨在更好地了解其在全身炎症和肾功能中的分子基础。
我们采用转化方法研究了 HDL 给药对败血症的影响。通过 LPS 输注在猪中诱导无菌全身炎症。动物随机分为 LPS（n=6）、CER20（单剂量 CER-001 20mg/kg；n=6）和 CER20×2（两剂量 CER-001 20mg/kg；n=6）组。评估存活率、内皮功能障碍生物标志物、促炎介质、LPS 和载脂蛋白 A-I（ApoA-I）水平。分析肾和肝组织学和生化。随后，我们进行了一项开放标签、随机、剂量范围（2a 期）的研究，纳入了 20 名因腹腔内感染或尿败血症引起的败血症患者，随机分为 A 组（常规治疗，n=5）、B 组（CER-001 5mg/kg BID，n=5）、C 组（CER-001 10mg/kg BID，n=5）和 D 组（CER-001 20mg/kg BID，n=5）。主要结局是预防 AKI 发作和严重程度的安全性和疗效；次要结局包括炎症和内皮功能障碍标志物的变化。
CER-001 增加了内毒素血症猪的中位存活率，降低了炎症介质、补体激活和内皮功能障碍。它通过胆汁增强了 LPS 的消除，并保护了肝脏和肾脏实质。在临床研究中，CER-001 耐受性良好，与研究治疗相关的严重不良事件发生率为零。快速的 ApoA-I 正常化与增强 LPS 清除和免疫调节有关，改善了临床结局，与败血症的类型和严重程度无关。接受 CER-001 治疗的患者发生严重 AKI（第 2 或 3 期）的风险降低，在危重症患者亚组中，器官支持的需求减少，ICU 住院时间缩短。
CER-001 作为败血症管理的治疗策略具有潜力，可以改善结局并减轻炎症和器官损伤。
该研究得到了意大利药品管理局（AIFA）和当地伦理委员会的批准（N°EUDRACT 2020-004202-60，协议 CER-001-SEP_AKI_01），并于 2021 年 1 月 13 日添加到欧盟临床试验注册处。
