Arrowhead Pharmaceuticals: RNA interference Medication Plozasiran Lowers Triglycerides in Dyslipidemia

1. Patients with familial chylomicronemia syndrome (FCS) treated with plozasiran demonstrated a maximum reduction of 98% in triglyceride levels at month 10.
2. Plozasiran demonstrated favorable safety profiles with a similar number of subjects reporting treatment-emergent adverse events in the plozasiran and placebo groups.

The Latest

The PALISADE study conducted by Arrowhead Pharmaceuticals is a Phase 3 placebo-controlled study designed to evaluate the efficacy and safety profile of plozasiran in adults with genetically confirmed or clinically diagnosed FCS. A total of 75 subjects distributed across 39 different sites in 18 countries participated in the study. Patients were randomized to receive either 25 mg of plozasiran, 50 mg of plozasiran, or a matching placebo dose once every three months. The primary endpoint was the percent change from baseline of fasting triglycerides with plozasiran versus the placebo at 10 months. Patients who received 25 mg and 50 mg of plozasiran had 80% and 78% reductions in triglycerides, respectively, with a maximum reduction of 98%. At 12 months, patients had 78% and 73% reductions, respectively, with a maximum reduction of 99% recorded. Patients on placebo had just a 17% reduction at month 10 and 7% at month 12.

Physician’s Perspective

Dyslipidemias are a family of diseases which includes FCS, a severe hyperlipidemia and mixed hyperlipidemia in which lipids or lipoproteins are found in abnormally high or low amounts in the blood. This is a significant risk factor for heart disease. FCS is an ultrarare, but severe genetic disease often caused by monogenic mutations. FCS results in extremely high triglyceride levels, typically over 880 mg/dL. Severely elevated triglyceride levels can manifest as acute and potentially fatal pancreatitis, chronic abdominal pain, diabetes, hepatic steatosis, and cognitive issues. Current therapeutic options for adequately treating FCS are limited.

Molecular Targets

Plozasiran previously known as ARO-APOC3 is an RNA interference drug designed to lower production of apolipoprotein C-III (APOC3). APOC3 is part of triglyceride-rich lipoproteins and is a key regulator of triglyceride metabolism. APOC3 increases triglyceride levels in the body by inhibiting the breakdown of triglyceride-rich lipoproteins by lipoprotein lipase and causes an increased uptake of triglyceride-rich lipoprotein remnants by hepatic receptors in the liver. Therefore, plozasiran reduces the levels of APOC3 in patients with FCS which results in reduced triglyceride levels.

Company History

Arrowhead Pharmaceuticals is a biopharmaceutical company based in Pasadena, California. The company develops RNA interference medicines that work on intractable diseases by silencing the specific genes that cause them. Arrowhead therapies focus on using RNA interference mechanisms to induce rapid and durable knockdown of target genes. In addition to FCS, the company is looking to expand its therapeutics to address other forms of dyslipidemia including severe hyperlipidemia and mixed hyperlipidemia.

Further Reading: https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-advance-rnai-based-plozasiran-phase-3

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