CSPC Pharmaceutical Unveils Positive Phase II Results of Novel PCSK9-Targeting siRNA SYH2053 at 2026 ESC Congress

At the 2026 European Society of Cardiology (ESC) Congress, held August 28-31 in Munich, Germany, CSPC Pharmaceutical Group presented positive Phase II results for SYH2053 injection, a novel PCSK9-targeting siRNA therapy for patients with primary hypercholesterolemia or mixed dyslipidemia. The oral presentation, delivered by Director Wang Fangfang from Professor Tang Yida's team at Peking University Third Hospital, demonstrated that SYH2053 achieved significant LDL-C reductions with a favorable safety profile in the Chinese patient population.

The Unmet Need in Lipid Management

Elevated low-density lipoprotein cholesterol (LDL-C) remains a primary driver of atherosclerotic cardiovascular disease. Current guidelines advocate a "lower is better" approach, emphasizing risk-stratified treatment and earlier, more aggressive primary prevention for high-risk patients to reduce lifetime cumulative LDL-C exposure and cardiovascular risk. While statins continue to serve as first-line therapy, many patients worldwide fail to reach guideline-recommended LDL-C targets even on maximally tolerated high-intensity statin therapy. This substantial unmet clinical need underscores the necessity for novel therapeutic agents to improve LDL-C goal attainment and long-term cardiovascular outcomes.

SYH2053, developed independently by CSPC Pharmaceutical Group, is a dual-strand small interfering RNA (siRNA) targeting PCSK9. The drug utilizes N-acetylgalactosamine (GalNAc) conjugation for liver-targeted delivery and employs an optimized full-sequence chemical modification strategy to achieve sustained gene silencing. Preclinical and Phase I clinical trials have previously demonstrated favorable safety and lipid-lowering activity, supporting its clinical development potential.

Study Design and Patient Population

This Phase II trial, led by Professor Tang Yida at Peking University Third Hospital, was a multi-center, randomized, double-blind, active-controlled and placebo-controlled study designed to evaluate the efficacy and safety of SYH2053 injection as monotherapy or in combination with other lipid-lowering therapies in Chinese patients with primary hypercholesterolemia or mixed dyslipidemia. The primary endpoint was the percentage change in LDL-C from baseline at Day 180.

The study enrolled patients aged 18-75 years with primary hypercholesterolemia or mixed dyslipidemia who had undergone at least 4 weeks of low-fat diet control prior to screening and were receiving stable-dose lipid-lowering therapy (stable statin dose or statin-intolerant) for at least 4 weeks, or had not used lipid-lowering therapy for at least 4 weeks. Inclusion criteria required fasting serum LDL-C ≥ 100 mg/dL (2.6 mmol/L) and fasting serum triglycerides ≤ 400 mg/dL (4.5 mmol/L) during screening.

Between December 3, 2024, and August 30, 2025, the study enrolled a total of 156 patients, who were randomly assigned to five treatment groups: SYH2053 150 mg (n=30), SYH2053 300 mg (n=32), SYH2053 600 mg (n=33), Inclisiran 300 mg (n=30), and placebo (n=31). The treatment period was defined as completion of 2 doses by participants.

Efficacy Results

At Day 180, all three SYH2053 dose groups demonstrated significant efficacy. LDL-C changes from baseline across the five treatment groups were: SYH2053 150 mg group decreased by 55.0%, SYH2053 300 mg group decreased by 61.3%, SYH2053 600 mg group decreased by 54.8%, inclisiran group decreased by 54.7%, and placebo group decreased by 8.4%.

After placebo adjustment, the LDL-C reductions for the three SYH2053 dose groups (150 mg, 300 mg, and 600 mg) were -46.6%, -52.9%, and -46.4%, respectively, with all three groups achieving statistical significance (p < 0.0001).

At Day 180, among the five treatment groups, the SYH2053 300 mg group showed the largest numerical reductions in both LDL-C and PCSK9. Throughout the study period, reductions in LDL-C and PCSK9 across all three SYH2053 dose groups emerged rapidly and were sustained through the final visit.

Subgroup analyses demonstrated that SYH2053 significantly reduced LDL-C and PCSK9 levels both as monotherapy and in combination with background therapy. Compared to 300 mg inclisiran, 300 mg SYH2053 showed numerically greater reductions in LDL-C and PCSK9 at Day 180 when used with combination background therapy.

Safety Profile

SYH2053 demonstrated a favorable safety profile throughout the study. Most treatment-emergent adverse events were Grade 1-2 in severity. The most common treatment-related adverse events were injection site reactions. Notably, the incidence of liver enzyme elevation was numerically lower across all three SYH2053 dose groups compared to the inclisiran group.

Conclusions and Future Directions

In patients with primary hypercholesterolemia or mixed dyslipidemia, SYH2053 rapidly, stably, and durably reduced LDL-C and PCSK9 levels, whether administered as monotherapy or in combination with background therapy. In this Phase II study with limited sample size, 300 mg SYH2053 demonstrated numerically greater LDL-C and PCSK9 reductions at Day 180 compared to 300 mg inclisiran when used with combination background therapy.

SYH2053 exhibited a favorable safety profile, with liver enzyme elevation rates numerically lower than those observed in the inclisiran group. While these preliminary Phase II results are promising, they await further validation in subsequent Phase III clinical trials. Three Phase III trials for this product are currently actively underway, with the potential to expand treatment options in this disease area and benefit more patients in the near future.