Arrowhead Pharmaceuticals' investigational drug plozasiran has demonstrated promising results in reducing both cholesterol and triglyceride levels in patients with mixed hyperlipidemia, according to recent clinical trial data. This hepatocyte-targeted APOC3 small interfering RNA offers potential benefits for patients who cannot take statins or have residual atherosclerotic cardiovascular disease (ASCVD) risk.
Mixed hyperlipidemia, characterized by elevated levels of both low-density lipoprotein cholesterol (LDL-C) and triglycerides, significantly increases the risk of poor cardiovascular outcomes. While statins are commonly prescribed to manage this condition, many patients face barriers to their use, including contraindications or interactions with other medications.
Clinical Trial Results Show Significant Lipid Reductions
In the phase 2 MUIR trial (NCT04998201), a double-blind, placebo-controlled study, plozasiran demonstrated favorable efficacy in adults with mixed hyperlipidemia. The drug significantly reduced fasting triglyceride levels across multiple doses and led to improved glycemic control, with higher rates observed at larger doses.
The phase 2 SHASTA-2 trial, which evaluated plozasiran in patients with severe hypertriglyceridemia (SHTG), showed significant dose-dependent, placebo-adjusted reductions in triglyceride levels driven by reductions of APOC3. Results published in JAMA Cardiology revealed that while plozasiran was associated with dose-dependent increases in LDL-C, it did not alter apolipoprotein B and significantly decreased non-HDL cholesterol levels. The treatment also durably reduced remnant cholesterol.
"We see plozasiran clinical data as strong and consistent across multiple studies in patients with FCS, SHTG, and mixed hyperlipidemia, and believe plozasiran has the potential to address significant unmet needs in all 3 patient populations," said Bruce Given, MD, chief medical scientist at Arrowhead Pharmaceuticals.
Effectiveness in Rare Genetic Disorders
The phase 3 PALISADE trial investigated plozasiran in patients with familial chylomicronemia syndrome (FCS), a rare genetic disorder characterized by severely high triglyceride levels that can cause acute pancreatitis if untreated. The treatment induced sustained reductions in apolipoprotein C-III and triglycerides. Importantly, total cholesterol, non-HDL-C, and very low LDL-C were all meaningfully reduced with plozasiran treatment.
These combined results from multiple clinical trials provide substantial evidence of plozasiran's effectiveness in reducing harmful blood lipids across different patient populations.
Addressing Unmet Needs in Cardiovascular Risk Management
The positive outcomes from these trials address a significant gap in treatment options for patients with mixed hyperlipidemia who have residual ASCVD risk. This residual risk is often attributed to elevated non-high-density lipoprotein (non-HDL) by remnant cholesterol in triglyceride-rich proteins.
For patients who cannot take statins due to preconditions or medication interactions, plozasiran represents a potential alternative therapy that specifically targets the underlying mechanisms of mixed hyperlipidemia.
Future Development Plans
Based on the encouraging results from the MUIR, PALISADE, and SHASTA-2 trials, Arrowhead Pharmaceuticals has announced plans to advance plozasiran into a phase 3 cardiovascular outcomes clinical trial called CAPITAN. This trial will enroll patients with mixed hyperlipidemia and a residual risk of ASCVD.
If the positive data trend continues, plozasiran could become an effective novel treatment option to lower cholesterol in adults with mixed hyperlipidemia, particularly for those who cannot tolerate statins or require additional therapy to manage their cardiovascular risk.
Healthcare providers, including pharmacists, should continue to monitor plozasiran's progress through clinical development and prepare to counsel patients on its potential use if it receives regulatory approval.
