Key Takeaways:
- SHR-1918, an ANGPTL3 inhibitor, significantly reduced LDL cholesterol by approximately 22–30% and triglycerides by 52–63% in patients with ASCVD not optimally controlled by standard lipid-lowering therapy.
- The safety profile of SHR-1918 was favorable, with predominantly mild adverse events comparable to placebo, suggesting strong potential for clinical application to address residual cardiovascular risk.
In a multicenter, randomized, double-blind, placebo-controlled Phase 2 trial (NCT06109831), the novel angiopoietin-like 3 (ANGPTL3) monoclonal antibody SHR-1918 demonstrated significant reductions in LDL cholesterol (LDL-C) and triglycerides (TG) in patients with moderate or higher risk atherosclerotic cardiovascular disease (ASCVD) whose lipid levels remained suboptimal despite standard lipid-lowering therapies. The findings, presented at the American College of Cardiology Annual Scientific Session (ACC.25) and simultaneously published in the Journal of the American College of Cardiology, underscore the potential for ANGPTL3 inhibition as a potential therapeutic strategy to reduce residual cardiovascular risk.
The study enrolled 333 participants in 35 medical centers in China who had not achieved optimal LDL-C control despite receiving statins (99.1% of participants) and other lipid-lowering therapies such as cholesterol absorption inhibitors (12.0%) or PCSK9 inhibitors (0.9%). Patients were randomized to receive subcutaneous SHR-1918 (150 mg, 300 mg, or 600 mg every 4 weeks [Q4W], or 600 mg every 8 weeks [Q8W]) or placebo for 16 weeks, followed by an extended open-label phase lasting up to 56 weeks.
At week 16, SHR-1918 produced dose-dependent and statistically significant reductions in LDL-C compared with placebo, achieving reductions of 21.7% (150 mg Q4W), 27.3% (300 mg Q4W), 29.9% (600 mg Q4W), and 22.5% (600 mg Q8W) (all p<0.0001). Significant triglyceride reductions were also observed, ranging from 51.7% to 63.2% across SHR-1918 dosing groups (all P<0.0001). The percentage of patients achieving LDL-C targets at week 16 ranged from 59.1% to 71.2% in the SHR-1918 groups, significantly higher than placebo (approximately 31%).
Safety analyses indicated SHR-1918 was well tolerated, with adverse event rates comparable between treatment groups and placebo. Treatment-related adverse events were predominantly mild and occurred infrequently. The most common treatment-related events included injection-site reactions (3.4%), hyperuricemia (2.6%), and mild elevations in creatine phosphokinase and liver enzymes, none of which were associated with long-term safety concerns.
Dr. Xiaojie Xe and Dr. Jian’an Wang, the lead investigators of the study wrote, “The core advantage of SHR-1918 lies in its unique target of action by inhibiting ANGPTL-3 while enhancing the activity of LPL and EL, which achieves dual regulation of LDL-C and TG. The findings of this study support that SHR-1918 could be a novel treatment option for patients with moderate or higher risk of ASCVD who have not achieved optimal lipid control and need additional lipid reduction beyond statins and other lipid-lowering therapies.
Further research, including larger Phase 3 studies, will be essential to fully establish the clinical efficacy and long-term safety of SHR-1918.