APOC3 siRNA also reduces triglycerides in mixed hyperlipidemia
EAS 2024 – In the MUIR trial, plozasiran versus placebo reduced triglycerides, APOC3, remnant cholesterol, apoB, and non–HDL-c and increased HDL-c at 24 weeks in patients with mixed hyperlipidemia. The APOC3 siRNA had a favorable safety profile.
This summary is based on the presentation of Christie Ballantyne, MD (Houston, TX, USA) at the EAS Congress 2024 – MUIR Study Results – Plozasiran, an investigational RNAi therapeutic, silences apolipoprotein C3, and reduces atherosclerosis associated lipoproteins in patients with mixed hyperlipidemia
Introduction and methods
Patients with mixed hyperlipidemia who receive lipid-lowering therapy still have a high ASCVD residual risk due to the presence of atherogenic triglyceride-rich lipoproteins that carry remnant cholesterol. Plozasiran (formerly known as ARO-APOC3) is a novel siRNA molecule that suppresses the hepatic expression of APOC3, which encodes for apolipoprotein C-III. This protein in turn inhibits the formation and clearance of various lipids and lipoproteins, including triglycerides. In the MUIR trial, the safety, efficacy, and optimal dosing of plozasiran over 48 weeks were evaluated in patients with mixed hyperlipidemia.
In this international, double-blind, placebo-controlled, dose-ranging, phase 2b RCT, 353 adults with mixed hyperlipidemia (triglycerides 150–499 mg/dL and either LDL-c ≥70 mg/dL or non–HDL-c ≥100 mg/dL) despite stable maximum-tolerated statin therapy were randomized in a 3:1 ratio to plozasiran or placebo in 4 cohorts. Participants in the first 3 cohorts received a total of 2 doses of subcutaneous plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12. In the fourth cohort, participants received a total of 2 doses of subcutaneous plozasiran 50 mg or placebo on day 1 and at week 24. All patients were followed up through week 48, after which they could enroll in the open-label extension phase.
The primary endpoint was percent change in fasting triglyceride levels from baseline to 24 weeks. Key secondary and exploratory endpoints included percent changes in APOC3, non–HDL-c, HDL-c, apoB, and remnant cholesterol levels. Safety assessment comprised the frequencies of treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to discontinuation of the study drug.
Main results
- At 24 weeks, the placebo-corrected least-squares (LS) mean percent change from baseline in fasting triglyceride levels ranged from −44.2 percentage points (95%CI: −53.4 to −35.0) in patients treated with plozasiran 50 mg on day 1 and at week 24 to −62.4 percentage points (95%CI: −71.5 to −53.2) in those receiving plozasiran 50 mg on day 1 and at week 12 (both P<0.001 ).
- Plozasiran resulted in LS mean percent changes from baseline to 24 weeks in APOC3 levels of up to –80 percentage points (50-mg–quarterly dose) and remnant cholesterol of up to –54 percentage points (25-mg–quarterly dose) (both P<0.0001).
- At week 24, there were also differences in levels of other atherogenic lipoproteins: LS mean percent changes from baseline to 24 weeks with plozasiran were up to -27 percentage points for non–HDL-c, up to -18 percentage points for apoB, up to -10 percentage points for LDL-c and up to 51 percentage points for HDL-c.
- Similar results were observed at 48 weeks.
- The 4 plozasiran dosing groups and the placebo group showed comparable adverse event rates up to 48 weeks, and there were no apparent differences in platelet counts during treatment.
- Worsening glycemic control was observed in 10% of the placebo-treated patients and up to 21% of the plozasiran-treated patients (50-mg–half-yearly dose).
Conclusion
The MUIR trial showed that 2 doses of plozasiran versus placebo reduced levels of triglycerides, APOC3, remnant cholesterol, apoB, and non–HDL-c and increased HDL-c levels at 24 and 48 weeks in patients with mixed hyperlipidemia. Plozasiran had a favorable safety profile. Christie Ballantyne concluded “plozasiran is a promising potential treatment for patients with increased ASCVD risk due to elevated triglyceride-rich lipoproteins and these data support further development of plozasiran in phase 3 programs including a clinical outcomes trial.”
- Our reporting is based on the information provided at the EAS Congress 2024 -