Arrowhead Pharmaceuticals to Begin Phase 3 Cardiovascular Trial for RNAi-based Plozasiran

Arrowhead Pharmaceuticals has announced its intention to advance its investigational drug plozasiran into a Phase 3 cardiovascular outcomes trial named CAPITAN. This decision follows promising outcomes from several clinical trials in different patient groups, including the Phase 3 PALISADE study for familial chylomicronemia syndrome (FCS), the Phase 2 SHASTA-2 study for severe hypertriglyceridemia (SHTG), and the Phase 2 MUIR study for mixed hyperlipidemia. These studies were published in reputable journals such as JAMA Cardiology and the New England Journal of Medicine.

Bruce Given, M.D., Arrowhead's chief medical scientist, emphasized the significance of the PALISADE study's results. The study met its primary endpoint by significantly lowering triglyceride levels and achieved all key secondary endpoints, including reducing acute pancreatitis incidents compared to a placebo. Plozasiran, administered every three months, maintained consistent median and mean triglyceride levels throughout the study period with minimal variability. Given expressed enthusiasm about sharing these findings at upcoming medical conferences, noting that the data from plozasiran studies are robust and consistent across different patient populations, including those with FCS, SHTG, and mixed hyperlipidemia. Given these results, Arrowhead is dedicating substantial resources to the Phase 3 SHASTA studies for SHTG and the newly announced CAPITAN study for mixed hyperlipidemia and residual atherosclerotic cardiovascular disease (ASCVD).

Arrowhead's second cardiometabolic program, zodasiran, also showed positive results, including significant reductions in triglyceride levels and various atherogenic lipoproteins. Despite these encouraging outcomes, Arrowhead has decided to prioritize the advancement of plozasiran due to resource allocation considerations. Further development of zodasiran will depend on finding a suitable development and commercialization partner.

Arrowhead is hosting a cardiometabolic R&D webinar to discuss clinical data and future plans for plozasiran. The event features Arrowhead management and Christie M. Ballantyne, M.D., from Baylor College of Medicine, who is also the principal investigator for the MUIR study. The agenda includes presentations on various topics related to cardiometabolic disease and triglyceride management.

Plozasiran, previously known as ARO-APOC3, is an investigational RNA interference (RNAi) therapeutic designed to reduce the production of Apolipoprotein C-III (APOC3), a key regulator of triglyceride metabolism. APOC3 inhibits the breakdown of triglyceride-rich lipoproteins (TRLs) and their uptake by hepatic receptors, leading to increased triglyceride levels in the blood. The goal of plozasiran treatment is to lower APOC3 levels, thereby reducing triglycerides and normalizing lipid levels.

In multiple clinical studies, plozasiran has shown effectiveness in reducing triglycerides and various atherogenic lipoproteins in patients with FCS, SHTG, and mixed hyperlipidemia. The drug has demonstrated a favorable safety profile, with treatment-emergent adverse events reflecting the comorbidities and underlying conditions of the study populations. Plozasiran is currently being investigated in the PALISADE Phase 3 study for FCS, the SHASTA Phase 3 studies for SHTG, and the upcoming CAPITAN Phase 3 study for mixed hyperlipidemia.

Plozasiran has received Orphan Drug Designation and Fast Track Designation from the U.S. Food and Drug Administration, as well as Orphan Drug Designation from the European Medicines Agency.

The PALISADE study is a Phase 3, placebo-controlled study evaluating the efficacy and safety of plozasiran in adults with genetically confirmed or clinically diagnosed FCS. The primary endpoint is the percent change from baseline in fasting triglycerides at Month 10 compared to a placebo. The study successfully met its primary and key secondary endpoints, demonstrating a favorable safety profile with fewer severe and serious adverse events compared to the placebo group.

Familial chylomicronemia syndrome (FCS) is a severe genetic disorder characterized by extremely high triglyceride levels, leading to serious complications like acute pancreatitis, chronic abdominal pain, and diabetes. Severe hypertriglyceridemia (SHTG) involves triglyceride levels above 500 mg/dL, significantly increasing the risk of ASCVD and acute pancreatitis. Mixed hyperlipidemia, also known as mixed dyslipidemia, involves elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, contributing to residual ASCVD risk despite LDL-C-lowering therapies.