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Clinical Trial
. 2024 Nov;17(11):e70061.
doi: 10.1111/cts.70061.

Clinical pharmacokinetics and pharmacodynamics of ongericimab: A potential long-acting PCSK9 monoclonal antibody in healthy subjects and patients with hypercholesterolemia: Randomized, double-blind, placebo-controlled phase Ia and Ib/II studies

Juanjuan Jiang  1 , Li Xu  1 , Lin Chai  1 , Xiaoyuan Guan  1 , Li Zhang  1 , Hong Liu  1 , Yan Yan  1 , Lili Li  2 , Yi Zhao  2 , Xuelian Bai  2 , Lei Tian  1 , Youhong Jia  3
Affiliations
Clinical Trial

Clinical pharmacokinetics and pharmacodynamics of ongericimab: A potential long-acting PCSK9 monoclonal antibody in healthy subjects and patients with hypercholesterolemia: Randomized, double-blind, placebo-controlled phase Ia and Ib/II studies

Juanjuan Jiang et al. Clin Transl Sci. 2024 Nov.

Abstract

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 (t1/2) 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.

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Conflict of interest statement

L.L., Y.Z. and X.B. are employees of Shanghai Junshi Biosciences Co., Ltd. All other authors declared no competing interests for this work.

Figures

FIGURE 1
FIGURE 1
The mean and log‐transformed mean serum ongericimab concentration versus time profiles. (a) and (c) Health subjects (phase Ia). (b) and (d) Patients with hypercholesterolemia (phase Ib/II). i.v., intravenous; ONG, ongericimab; Q2W, once every 2 weeks; Q4W, once every 4 weeks; SC, subcutaneous.
FIGURE 2
FIGURE 2
Percentage change in LDL‐C levels of participants enrolled in the phase Ia study (a) and phase Ib/II study (b). i.v., intravenous; ONG, ongericimab; Q2W, once every 2 weeks; Q4W, once every 4 weeks; SC, subcutaneous.
FIGURE 3
FIGURE 3
Free and total PSCK9 levels in serum. (a) and (b) Health subjects (phase Ia). (c) and (d) Patients with hypercholesterolemia (phase Ib/II). i.v., intravenous; ONG, ongericimab; Q2W, once every 2 weeks; Q4W, once every 4 weeks; SC, subcutaneous.
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