Arrowhead Pharmaceuticals Shares New Data at AHA24 from Phase 3 PALISADE and Open-Label MUIR and SHASTA-2 Studies on Plozasiran

Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) recently shared the latest findings from its Phase 3 PALISADE study and the open-label extension (OLE) from the Phase 2 MUIR and SHASTA-2 studies, all concerning the investigational drug plozasiran. These findings were revealed during two oral presentations at the American Heart Association Scientific Sessions 2024 (AHA24) and the PALISADE data was also published in the AHA journal, Circulation.

Dr. Bruce Given, Arrowhead’s chief medical scientist, elaborated on the PALISADE study's outcomes, noting that plozasiran significantly reduced triglycerides and affected various lipoproteins involved in atherosclerotic cardiovascular disease, regardless of specific genetic variants of familial chylomicronemia syndrome (FCS). The OLE data from the Phase 2 MUIR and SHASTA-2 studies showed that 25 mg of plozasiran led to notable reductions in triglycerides over a 15-month follow-up period, achieving reductions up to -73% in the MUIR study and -86% in the SHASTA-2 study. Additionally, favorable decreases in remnant cholesterol and non-HDL-cholesterol were recorded, bolstering the case for plozasiran as a potential therapy for patients with FCS, severe hypertriglyceridemia, and mixed hyperlipidemia.

The PALISADE Phase 3 study involved 75 patients diagnosed with FCS, either genetically or clinically. Participants received 25 mg or 50 mg of plozasiran or a placebo every three months over a year. The results showed that plozasiran at 25 mg led to rapid, deep, and sustained reductions in apolipoprotein C-III (APOC3) and triglycerides, achieving greater than 90% and approximately 80% reductions, respectively. Notably, over half of the patients maintained triglyceride levels below 500 mg/dL, significantly reducing their risk of acute pancreatitis. Plozasiran also showed reductions in total cholesterol, non-HDL cholesterol, and very-low-density lipoprotein cholesterol, with increases in HDL cholesterol and apolipoprotein-AI.

In the OLE of the Phase 2 MUIR and SHASTA-2 studies, 418 patients with mixed hyperlipidemia or severe hypertriglyceridemia continued receiving 25 mg of plozasiran quarterly. The initial studies had demonstrated significant mean reductions in triglycerides, with these effects persisting through the 15-month follow-up. Reductions in APOC3, remnant cholesterol, and non-HDL cholesterol were maintained, alongside increased HDL cholesterol, with no adverse changes in LDL cholesterol or lipoprotein(a). Long-term safety appeared favorable, with no new onset diabetes or worsening of HbA1c observed.

Overall, plozasiran has been generally well-tolerated in clinical trials. The most common adverse events noted in the PALISADE study for the 25 mg dose included abdominal pain, COVID-19, nasopharyngitis, and nausea. Across various studies, other frequent adverse events included upper respiratory tract infections, headaches, Type 2 diabetes mellitus, and abdominal pain.

Familial chylomicronemia syndrome (FCS) is a rare and severe condition often caused by monogenic mutations leading to extremely high triglyceride levels. This condition can result in severe health issues such as acute pancreatitis, chronic abdominal pain, and diabetes. Currently, there are no adequate treatments available in the US for FCS.

Severe hypertriglyceridemia (SHTG), characterized by triglyceride levels exceeding 500 mg/dL, significantly raises the risk of atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis. Mixed hyperlipidemia, marked by elevated LDL cholesterol and triglycerides, also poses a considerable risk for ASCVD despite existing LDL-lowering therapies.

Plozasiran, an investigational RNA interference therapeutic, aims to reduce the production of APOC3, a key regulator of triglyceride metabolism. By decreasing APOC3 levels, plozasiran helps lower triglycerides and brings lipid levels closer to normal. Arrowhead continues to investigate plozasiran in several clinical studies, including the PALISADE Phase 3 study for FCS and the SHASTA and MUIR studies for SHTG and mixed hyperlipidemia.