On November 16, at the American Heart Association (AHA) 2024 Annual Scientific Sessions in Chicago, Illinois, USA, results from the Phase III PALISADE clinical trial (NCT05089084) of plozasiran, formerly known as name of ARO-APOC3, were presented. This trial targeted adults with genetically or clinically diagnosed familial chylomicronemia syndrome (FCS), a rare genetic disorder characterized by extremely high triglyceride levels that significantly increase the risk of acute pancreatitis.

Plozasiran is a small interfering RNA (siRNA) therapy developed to specifically target and reduce the production of apolipoprotein C-III (APOC3), thereby reducing triglyceride levels and decreasing the health risks associated with FCS. APOC3 is a key component of triglyceride-rich lipoproteins (TRL) and plays a crucial role in regulating triglyceride metabolism. It increases blood triglyceride levels by inhibiting the breakdown of TRL by lipoprotein lipase and blocking the uptake of leftover TRL by hepatic receptors in the liver. The primary goal of plozasiran treatment is to reduce APOC3 levels, thereby reducing triglycerides and helping to normalize lipid profiles.

Seventy-five patients with genetically or clinically defined FCS, who had persistent chylomicronemia despite standard care, were randomized to receive quarterly doses of plozasiran (25 mg or 50 mg) or placebo for 12 months. Results of the phase III clinical trial, presented by Gerald Watts, professor of cardio-metabolic medicine at the University of Western Australia, showed that the study met its primary endpoint, demonstrating that participants receiving doses of 25 mg and 50 mg of plozasiran reduced median triglycerides by 80%. compared to baseline at month 10, a marked improvement compared to the smaller reductions seen in the placebo group. Secondary endpoints, including further reduction in triglyceride and APOC3 levels, as well as decreased incidence of acute pancreatitis, showed statistically significant improvements in patients treated with plozasiran. Reductions in triglycerides and APOC3 were evident as early as 1 month and sustained throughout 12 months, with similar efficacy observed in genetically and clinically defined patients. Reductions in atherogenic triglyceride-rich lipoprotein (TRL) were noted, alongside a minor increase in LDL-C, with no change in apo B. Plozasiran also significantly reduced the incidence of acute pancreatitis, responding thus a major concern for people with FCS. The treatment demonstrated a favorable safety profile, with adverse events similar to those observed with placebo. Severe and serious adverse events were less common in the plozasiran group, primarily due to fewer episodes of acute pancreatitis.

According to key opinion leaders (KOLs) surveyed by GlobalData, there is a significant unmet need for therapies treating serious genetic disorders such as FCS. Currently, no FDA-approved treatment exists for FCS, creating a critical gap in the management of this disease. Plozasiran offers a promising solution by targeting the underlying causes of FCS, effectively lowering triglyceride levels and preventing complications associated with the disease. Plozasiran significantly reduced triglyceride levels and the incidence of acute pancreatitis in patients with persistent chylomicronemia, regardless of genetic status. Due to its effectiveness in a wide range of patients with hypertriglyceridemia, plozasiran is being further studied for its potential in treating chylomicronemia-related pancreatitis as a possible treatment to reduce the risk of Atherosclerotic cardiovascular disease (ASCVD) in people with mild to moderate hypertriglyceridemia. According to GlobalData’s report on ‘Dyslipidemia: Seven Market Drug Forecast and Market Analysis“, plozasiran is expected to achieve sales of $707 million by 2032.