Abstract 4139852: Plozasiran and Triglyceride Levels in Hypertriglyceridemia: Long-Term Efficacy and Safety Data From Subjects in an Open-Label Extension Trial

Despite current modestly effective triglyceride (TG) lowering therapies, the availability of more effective agents for persistently lowering elevated TGs and risk of acute pancreatitis remains a continuing need. More recently identified triglyceride-rich lipoproteins (TRLs), specifically remnant cholesterol (RC)-rich particles, are important drivers of ASCVD risk independent of LDL-C, driving development of more effective TG-directed therapies. Apolipoprotein C3 (APOC3) raises TGs by inhibiting lipoprotein lipase (LPL) dependent and -independent pathways. Plozasiran, a RNAi agent targeting APOC3 mRNA in hepatocytes, demonstrated large reductions in circulating APOC3, TGs, TRL-RC with a good safety profile in placebo-controlled trials. Here we report extension data to characterize long term safety and efficacy of plozasiran in subjects with elevated TGs. Plozasiran was studied in subjects with mixed hyperlipidemia (entry TGs 150-499 mg/dl) and severe hypertriglyceridemia (entry TGs > 500-4000 mg/dl) in separate Phase 2 trials (MUIR and SHASTA-2). Subjects completing double-blind, placebo-controlled treatment could enter this open-label extension. Endpoints included changes in fasting TG levels, other lipid and lipoprotein parameters and safety assessments for up to 24 months. Data cut-off was 5/16/24 for this analysis, (up to 15 months of follow up) in the ongoing study. 251 and 165 subjects from MUIR and SHASTA-2 entered the extension in which all received plozasiran 25 mg SQ dosed quarterly. 10, 25 or 50 mg of plozasiran under blinded conditions produced mean reductions in TGs of -52 to -64% (MUIR) and -69 to -74% (SHASTA-2), 12 weeks (trough) after the second dose. Corresponding trough reductions in the extension ranged from -44 to -73% (MUIR) and -62 to -86% (SHASTA-2) through 15 months follow-up. Common reported AEs were consistent with the index studies and patient populations and mean HbA1c did not increase, providing further evidence that long-term safety remains favorable with repeated dosing and longer observation periods. Extended open-label treatment with plozasiran in subjects with moderate to severely elevated TGs continue to show reductions of TG levels and safety consistent with the blinded index studies, demonstrating incidence rate and severity of TEAEs remain favorable with repeated dosing and longer observation. Results of additional lipid and lipoprotein parameters are also consistent with the blinded index data and will also be reported.