ACC.24 – In a phase 2b trial, the RNAi therapeutic plozasiran resulted in reduced levels of triglycerides, APOC3, remnant cholesterol and increased levels of HDL-c for all doses at 24 weeks in patients with severe hypercholesterolemia, with a generally favorable safety and tolerability profile

This summary is based on the presentation of Daniel Gaudet, MD, PhD (Montreal, QB, Canada) at the ACC.24 Scientific Session -Plozasiran (ARO-APOC3, an Investigational RNAi Therapeutic, Demonstrates Profound and Durable Reductions in APOC3 and Triglycerides (TG) in Patients With Severe Hypertriglyceridemia (SHTG)- SHASTA-2 Final Study Results

Introduction and methods

Plozasiran is an RNA interference (RNAi) therapeutic. It is a double-stranded oligonucleotide which penetrates the hepatocytes and interferes with mRNA translation of APOC3, resulting in silencing of this gene. APOC3 inhibits triglyceride-rich lipoprotein (TRL) catabolism and hepatic clearance through lipoprotein lipase (LPL) dependent and LPL independent mechanisms, resulting in increased levels of triglycerides (TGs). Silencing of APOC3 therefore enables TRL catabolism and hepatic clearance leading to reduced TGs levels.

The SHASTA-2 trial was a double-blind, phase 2b, placebo-controlled, dose ranging study evaluating plozasiran in patients with severe hypertriglyceridemia (SHTG), defined as history of TG≥500 mg/dL and fasting TG of 500-4000 mg/dL during screening period. 229 Patients were randomized to plozasiran 10 mg, 25 mg, 50 mg or placebo (1:1:1:1) and received injections at week 0 and 12.

Primary endpoint was the percentage change in TG from baseline at week 24. Key secondary endpoints included changes in lipid parameters and safety. Patients were followed until end of the study at week 48.

Main results

• The LS mean % changes in TG levels from baseline at week 24 were -66%, -70%, -74% and -17% in the 10 mg, 25 mg, 50 mg plozasiran and placebo groups, respectively (for all plozasiran groups P<0.0001).
• At week 48, LS mean % change in TG levels from baseline were -31% (P<0.05), -58% (P<0.0001), -53% (P<0.0001) and -7% in the 10 mg, 25 mg, 50 mg and placebo groups, respectively.
• The LS mean % changes in APOC3 levels from baseline at week 24 were -79%, -72%, -78% and -1% in the 10 mg, 25 mg, 50 mg and placebo groups, respectively (for all plozasiran groups P<0.0001).
• At week 48, LS mean % change in APOC3 levels from baseline were -34%, -48%, -47% and 4% in the 10 mg, 25 mg, 50 mg and placebo groups, respectively (for all plozasiran groups P<0.0001).
• Remnant cholesterol was decreased (up to 62% at week 24, and 45% at week 48) and HDL-c levels were increased (up to 68% at week 24, and 38% at week 48). 
• Over 90% of patients treated with plozasiran achieved TG<500 mg/dL at week 24 and below the risk threshold for acute pancreatitis. Moreover, 50% of patients reached values <150 mg/dL.
• Plozasiran was well tolerated. There was a signal for increased worsening glycemic control in patients receiving plozasiran, but this was transient.

Conclusion

The RNAi plozasiran decreased levels of TGs, APOC3 and remnant cholesterol while increasing HDL-c at 24 weeks for all dose levels in patients with SHTG. These effects persisted at 48 weeks.

Daniel Gaudet said that these findings support further development of plozasiran in planned phase 3 trials for the treatment of patients with chylomicronemia and SHTG.

- Our reporting is based on the information provided at the ACC.24 Scientific Session -

The findings of this study were simultaneously published in JAMA Cardiology