EFFECT OF PLOZASIRAN TARGETING APOC3 ON LIPOPROTEIN PARTICLE NUMBER AND SIZE MEASURED BY NMR IN PATIENTS WITH HYPERTRIGLYCERIDEMIA (HTG)

Abstract

Therapeutic Area

ASCVD /CVD Risk Reduction

Background

Plozasiran, an investigational siRNA targeting hepatic APOC3, reduces TG-rich lipoproteins (TRLs). The impact of plozasiran on lipoprotein (LP) particle numbers and size distributions is unknown; but reductions in the number of TRL particles (TRL-P) and a shift to possibly less atherogenic large LDL particles is expected.

Methods

Impact of plozasiran on LP particle concentration and size was measured by NMR in two phase 2 studies. 454 patients from SHASTA-2 (severe HTG) and MUIR (mixed hyperlipidemia) were administered 2 SQ doses of plozasiran (10, 25, or 50 mg) or placebo at baseline and week 12.

Results

In SHASTA-2, there was a dose-dependent reduction in TRL-P. With 25 mg PZN, total TRL-P level was reduced by -49%, with reductions across all particles. While total LDL-P was unchanged, large LDL-P concentration increased by +44%; medium by +84% while small LDL-P decreased by -20%. Total HDL-P increased by +7%, primarily driven by a +40% increase in large HDL-Ps. There was significant improvement in insulin resistance (IR) index of -24%.

In MUIR, dose-dependent reductions in TRL-P were also observed. In the 25 mg group, total TRL-P was significantly reduced by -51%, with reductions across all particles. While total LDL-P was unchanged, large and medium LDL-P levels increased by +103% and +55%, respectively, while small LDL-Ps decreased by -22%. Total HDL-Ps increased by +10%, driven by a +88% increase in large HDL-P. IR index was significantly reduced by -9%.

Conclusion

Plozasiran induced APOC3 decreases and quantitative and qualitative changes in LP evaluated by NMR in HTG patients. Plozasiran reduces TRL-P by ≈ 50%, shifts LDL to larger particles, and increases HDL-P concentration. Small dense LDL (sdLDL) are associated with IR and increased ASCVD risk. While high-potency TRL-lowering therapies can sometimes lead to an overall LDL-C increase, LDL-P is not increased and plozasiran shifts the LDL particle size distribution from sdLDL towards larger sizes. The 50% reduction in TRL-P coupled with potential benefits of qualitative changes in LDL without any increase in LDL-P, suggests a promising potential to lower ASCVD risk, which will be evaluated in a prospective outcomes trial.