Angiopoietin-like 3 (ANGPTL-3) inhibition with the human monoclonal antibody, SHR-1918, reduces serum LDL-C by 22% to 30%, as well as triglyceride (TG) levels by 52% to 63%, in patients at moderate or higher risk of atherosclerotic cardiovascular disease (ASCVD), with the effect being dose and frequency dependent, according to research presented during a Clinical and Investigative Horizons session at ACC.25 in Chicago and simultaneously published in JACC.

In the double-blind, dose-escalation phase 2 study, conducted from November 2023 to April 2024 at 35 medical centers across China, 333 patients with hypercholesterolemia (mean baseline LDL-C level 2.8 mmol/L) were randomized 4:1 (active/placebo ratio) into eight cohorts to receive subcutaneous SHR-1918 doses at 150 mg, 300 mg or 600 mg every four weeks (Q4W), 600 mg every eight weeks (Q8W) or matching placebo at the same dose frequency for the 16-week treatment period. They were a mean age of 58 years old and most (61%) were men, and while nearly all were taking a statin, they had not achieved optimal LDL-C after 4-8 weeks of treatment.

After the treatment period ended, the trial was extended for the same doses at Q4W over 36 weeks or the 600 mg Q8W over 40 weeks.

Results showed a clear dose-response relationship for the primary endpoint of percentage change in serum LDL-C levels from baseline to week 16 with SHR-1918: 22%, 27% and 30% for 150, 300 and 600 for Q4W and 23% for 600 mg Q8W.

SHR-1918 also substantially reduced TG, non-HDL, apolipoprotein B and apolipoprotein A1. Investigators found that the efficacy was approaching a plateau at higher dose exposure.

SHR-1918 was generally well-tolerated. During the treatment period, 20% of patients in the treatment arm and 13% of patients in the placebo arm had treatment-related adverse events. The most common were hyperuricemia, increased blood creatine phosphokinase and nausea. Six patients in the treatment arm experienced clinically significant increases in alanine aminotransferase with one severe case among them. Injection site reactions occurred 3.4%. One patient in each group experienced a treatment-related serious adverse event.

Patient treatment adherence to the Q4W or Q8W regimen was high at 97%. "Although a slight reduction in efficacy was observed with the Q8W dosing regimen, the convenience of less frequent dosing may outweigh the lower efficacy in certain patient populations," write the study authors. "In terms of patient compliance, the Q8W regimen may benefit patients who face challenges with treatment adherence, such as those who live in remote areas or those who are averse to frequent injections."

Investigators note that a homogenous study population and lack of direct head-to-head comparison with other therapies limited the study and call for future long-term studies on the novel treatment.