A GROUNDBREAKING phase 2b randomized clinical trial has demonstrated that plozasiran, an investigational APOC3-targeted siRNA therapeutic, significantly reduces triglyceride levels in patients with severe hypertriglyceridemia (sHTG).
The SHASTA-2 trial assessed the efficacy, safety, and dose response of plozasiran in patients with sHTG, a condition linked to increased risks of cardiovascular disease and acute pancreatitis. Conducted across 74 centres globally, 229 adults with fasting triglyceride levels between 500 and 4000 mg/dL participated. Patients received either subcutaneous plozasiran (10, 25, or 50 mg) or placebo at day 1 and week 12, with follow-up through week 48. The primary endpoint was the placebo-subtracted change in triglyceride levels at 24 weeks.
Plozasiran achieved significant reductions in triglyceride and apolipoprotein C3 (APOC3) levels, with the highest dose yielding a placebo-adjusted triglyceride reduction of −57% (95% CI, −71.9% to −42.1%; P < .001) and APOC3 reduction of −77% (95% CI, −89.1% to −65.8%; P < .001). At 24 weeks, 90.6% of plozasiran-treated patients achieved triglyceride levels below 500 mg/dL. Additional lipid parameters improved, including decreases in non-HDL cholesterol and remnant cholesterol, despite a dose-dependent increase in LDL-C. Safety data were favourable, with adverse events mild to moderate and no treatment discontinuations or deaths.
These findings highlight plozasiran’s potential to address unmet needs in sHTG management, with significant triglyceride lowering and improvement in related lipid profiles. Although increases in LDL-C levels warrant further investigation, the lack of ApoB elevation suggests this may not translate into heightened cardiovascular risk. Future studies are essential to confirm long-term outcomes, including reductions in sHTG-associated complications such as acute pancreatitis. In clinical practice, plozasiran offers promise as an effective adjunct to existing lipid-lowering therapies, particularly for patients unresponsive to current options.
Katrina Thornber, EMJ
Reference
Gaudet D et al. Plozasiran (ARO-APOC3) for severe hypertriglyceridemia: the SHASTA-2 randomized clinical trial. JAMA Cardiol. 2024;9(7):620-30.
