Plozasiran (ARO-APOC3): A Comprehensive Clinical and Strategic Analysis of a Novel RNAi Therapeutic for Hypertriglyceridemia

Section 1: Foundational Pharmacology and Mechanism of Action

The development of plozasiran (ARO-APOC3) represents a significant advancement in lipid-lowering therapy, rooted in a deep understanding of the central, causal role that Apolipoprotein C-III (APOC3) plays in the pathophysiology of hypertriglyceridemia. This section delineates the scientific rationale for targeting APOC3, details the precise molecular mechanism of plozasiran as a state-of-the-art RNA interference therapeutic, and describes the pharmacodynamic consequences of its action.

1.1 The Pathophysiological Role of Apolipoprotein C-III (APOC3) as a Central Regulator of Triglyceride Metabolism

Apolipoprotein C-III is a 79-amino acid glycoprotein, synthesized predominantly by hepatocytes in the liver and to a lesser extent by enterocytes in the small intestine.[1] In circulation, it is found on the surface of various lipoproteins, primarily associating with triglyceride-rich lipoproteins (TRLs) such as hepatically-derived very-low-density lipoproteins (VLDL) and intestinally-derived chylomicrons, as well as their metabolic remnants. It also resides on high-density lipoprotein (HDL) particles, which act as a circulating reservoir.[1]