NHC Key Laboratory of Clinical Research for Cardiovascular Medications, National Clinical Research Center of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Shanghai Junshi Biosciences, Shanghai, China.
Clin Transl Sci. 2024 Nov;17(11):e70061. doi: 10.1111/cts.70061.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein-cholesterol (LDL-C) by decreasing the expression of the LDL-receptor on hepatic cells. Ongericimab (JS002) is a novel PCSK9 monoclonal antibody that exhibits a long-acting LDL-C lowering effect by exclusively inhibiting PCSK9 in pre-clinical studies. Two randomized, double-blind, placebo-controlled trials were conducted to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacokinetic, and pharmacodynamic profiles of ongericimab in healthy subjects and patients with hypercholesterolemia. Eighty-four healthy subjects in the phase Ia study received a single dose of placebo or ongericimab (15-450 mg). Ninety patients with hypercholesterolemia in the phase Ib/II study received placebo or ongericimab 150 mg Q2W, 300 mg Q4W, or 450 mg Q4W for 12 weeks. Ongericimab exhibited non-linear kinetics. The apparent clearance decreased as the dosage increased, with terminal elimination half-life (t) values of 4.5-6.5 days. Overall, ongericimab was well tolerated in both studies. A single dose of ongericimab reduced LDL-C levels by 30%-73% in healthy subjects, and repeated doses of ongericimab reduced LDL-C levels by 67%-80% in patients with hypercholesterolemia. At the end of the dosing interval in the phase Ib/II study, over 70% of patients' LDL-C levels decreased by more than 50% from baseline. The results showed that ongericimab had a significant long-acting LDL-C lowering effect with good safety and potential for clinical application.
前蛋白转化酶枯草溶菌素 9（PCSK9）通过降低肝细胞中 LDL 受体的表达来增加血浆低密度脂蛋白胆固醇（LDL-C）。ongericimab（JS002）是一种新型的 PCSK9 单克隆抗体，在临床前研究中通过专门抑制 PCSK9 发挥长效 LDL-C 降低作用。两项随机、双盲、安慰剂对照试验评估了 ongericimab 在健康受试者和高胆固醇血症患者中的安全性、耐受性、疗效、免疫原性、药代动力学和药效学特征。在 I 期研究中，84 名健康受试者接受了安慰剂或 ongericimab（15-450mg）单次给药。在 Ib/II 期研究中，90 名高胆固醇血症患者接受了安慰剂或 ongericimab 150mg Q2W、300mg Q4W 或 450mg Q4W 治疗，持续 12 周。ongericimab 表现出非线性药代动力学特征。随着剂量的增加，表观清除率降低，终末消除半衰期（t）值为 4.5-6.5 天。总体而言，在两项研究中，ongericimab 均具有良好的耐受性。在健康受试者中，单次给药可使 LDL-C 水平降低 30%-73%，重复给药可使高胆固醇血症患者的 LDL-C 水平降低 67%-80%。在 Ib/II 期研究的给药间隔期末，超过 70%的患者的 LDL-C 水平较基线降低了 50%以上。结果表明，ongericimab 具有显著的长效 LDL-C 降低作用，且安全性良好，具有临床应用潜力。
