Efficacy and safety of SYH2053 in patients with primary hypercholesterolemia or mixed dyslipidemia: a phase II, multicenter, randomized, double-blind, placebo- and active-controlled trial

Background SYH2053 is a novel small interfering RNA (siRNA) drug targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), with optimized full-sequence chemical modification and N-acetylgalactosamine conjugation, which demonstrated a stable and sustained lipid-lowering efficacy in the phase I study in heathy participants with mild elevated low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (2.6 mmol/L) and < 190 mg/dL (4.9 mmol/L), triglyceride (TG) ≤ 400 mg/dL (4.5 mmol/L). Purpose This phase II study aims to evaluate the efficacy and safety of multiple doses of SYH2053 injection in patients (pts) with primary hypercholesterolemia or mixed dyslipidemia either add on to statin or as a mono therapy. Methods In this phase II study, eligible pts were aged 18-75 years and had primary hypercholesterolemia or mixed dyslipidemia, with LDL-C ≥ 100 mg/dL (2.6 mmol/L) and TG ≤ 400 mg/dL (4.5 mmol/L). At screening, they had either received stable-dose statin with or without ezetimibe for ≥ 4 weeks, or no lipid-lowering therapy for ≥ 4 weeks. Pts were randomized to receive SYH2053 at 150 mg, 300 mg, or 600 mg, placebo, or 300 mg inclisiran. All five groups were dosed on Day 1 and Day 90; except for the 600 mg group, which received a second dose of 300 mg on Day 180.The primary endpoint was percent change from baseline in LDL-C at Day 180. Results 156 pts were randomly assigned to study groups (N = 30-33 per group). 67.3% of pts received stable lipid-lowering therapy. The LDL-C and PCSK9 reductions were evident at Day 30 and were sustained through Day 270 (Table). At Day 180, SYH2053-300 mg group exhibited the numerically greatest reductions in LDL-C and PCSK9 among the five groups, with placebo-adjusted changes were -52.94% (95% CI: -62.16, -43.73; p < 0.0001) and -91.50% (95% CI: -99.80, -83.21; p < 0.0001), respectively. SYH2053 achieved substantial efficacy at all dose groups based on subgroup (add on to statin or as a mono therapy) analyses (Table). At Day 270, SYH2053-300 mg group demonstrated numerically superior reductions in LDL-C and PCSK9 versus the inclisiran group. The incidence of treatment-emergent adverse events (TEAEs) in groups 150 mg, 300 mg, 600 mg, placebo and inclisiran was 72.4%, 66.7%, 81.8%, 80.0% and 77.4%, respectively. The most TEAEs were Grade 1–2. Treatment-related hepatic transaminase elevation was observed in 0, 0, 3.0%, 3.3%, and 12.9% of pts across the five groups, respectively, and all of which were Grade 1-2. Conclusions SYH2053 exhibited rapid, stable and sustained reductions in LDL-C and PCSK9 in primary hypercholesterolemia or mixed dyslipidemia pts. At an equivalent dose of 300 mg, SYH2053 may yield greater reductions in LDL-C and PCSK9 compared with inclisiran. These observations warrant further-validation in future phase III clinical trial.