PALISADE: Plozasiran Lowers Triglycerides in Familial Chylomicronemia Syndrome

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Topline data from the pivotal Phase 3 trial show plozasiran met the primary endpoint of triglyceride-lowering in patients with the ultrarare genetic disease.

Plozasiran Lowers Triglyceride Levels in Familial Chylomicronemia Syndrome | Image Credit: Arrowhead Pharmaceuticals

Bruce Given, MD

Credit: Arrowhead Pharmaceuticals

Topline results from the pivotal Phase 3 PALISADE study revealed investigational plozasiran successfully met the primary endpoint of triglyceride-lowering in patients with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome (FCS).1

Announced by Arrowhead Pharmaceuticals on June 3, 2024, plozasiran achieved statistically significant reductions in triglyceride levels up to 80%, with an average lowering in Apolipoprotein C-III (APOC3) up to 94%, at the primary endpoint of 10 months.

“The strong results from the Phase 3 PALISADE study, evaluating plozasiran in patients with FCS, significantly build upon the promising results from the Phase 2 SHASTA-2 and MUIR studies in patients with severe hypertriglyceridemia and mixed hyperlipidemia, recently published in JAMA Cardiology and the New England Journal of Medicine,” Bruce Given, MD, chief medical scientist at Arrowhead, said in a statement.1 “These findings highlight the potential of plozasiran as a promising therapy for patients with various cardiometabolic disorders.”

Previously known as ARO-APOC3, plozasiran is a first-in-class investigational RNA interference (RNAi) therapeutic designed to reduce the production of APOC3, leading to reductions in triglycerides and restoring lipids to normal levels. Across multiple clinical trials, plozasiran exhibited a lowering in triglycerides and multiple atherogenic lipoproteins in patients with FCS, severe hypertriglyceridemia (SHTG), and mixed hyperlipidemia.2

PALISADE is a Phase 3, placebo-controlled study evaluating the efficacy and safety of plozasiran in adults with genetically confirmed or clinically diagnosed FCS.1 The primary endpoint was a placebo-adjusted median change in triglyceride levels at Month 10.

Across 39 trial sites in 18 countries, 75 participants were randomized to 25 mg plozasiran, 50 mg plozasiran, or matching placebo once every three months. Those who completed the randomized period were eligible to continue the study in a two-part extension period in which all participants received plozasiran.

At the primary endpoint, participants treated with quarterly 25 and 50 mg plozasiran reached mean triglyceride reductions of –80% and –78%, respectively, with a maximum lowering of –98%. At 12 months, those treated with 25 and 50 mg plozasiran achieved median triglyceride reductions of –78% and –73%, with a maximum lowering of –99%.

By comparison, placebo-treated patients experienced median triglyceride reductions of –17% at Month 10 (P <.001) and –7% at Month 12. At Month 10, the mean decreases in APOC3 were –88% and –94%, respectively, at the 25 and 50 mg plozasirandose cohorts.

All key secondary endpoints were met with plozasiran treatment and displayed statistical significance compared with placebo. Multiplicity-controlled secondary endpoints included the percent change from baseline at Months 10 and 12 in fasting triglycerides, the percent change from baseline at Month 10 in fasting APOC3, the percent change from baseline at Month 12 in fasting APOC3, and the incidence of positively adjudicated events of acute pancreatitis during the randomized period.

The safety profile remained favorable in PALISADE – the number of reported treatment-emergent adverse events was similar between the plozasiran and placebo groups. Severe adverse events were fewer with plozasiran treatment than placebo, with the most common adverse events being abdominal pain, COVID-19, nasopharyngitis, headache, and nausea.

Plozasiran has been granted Orphan Drug Designation and Fast Track Designation by the US Food and Drug Administration (FDA) and Orphan Drug Designation by the European Medicines Agency (EMA).3

“We see plozasiran data as best in class and with the potential to address multiple cardiometabolic diseases with substantial unmet need,” Christopher Anzalone, PhD, president and chief executive officer at Arrowhead, added in a statement.1 “We will now communicate the results to the FDA and discuss filing a New Drug Application (NDA) for FCS. We will also continue to advance multiple additional Phase 3 studies for other patient populations.”

References

  1. Arrowhead Pharmaceuticals reports successful topline results for plozasiran from the pivotal phase 3 palisade study in patients with familial chylomicronemia syndrome. Arrowhead Pharmaceuticals Inc. June 3, 2024. Accessed June 3, 2024. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-reports-successful-topline-results.
  2. Iapoce C. Muir: Plozasiran reduces triglyceride levels in mixed hyperlipidemia. HCP Live. May 28, 2024. Accessed June 3, 2024. https://www.hcplive.com/view/muir-plozasiran-reduces-triglyceride-levels-mixed-hyperlipidemia.
  3. Arrowhead receives FDA Fast Track designation for aro-APOC3. Arrowhead Pharmaceuticals Inc. March 20, 2023. Accessed May 28, 2024. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-receives-fda-fast-track-designation-aro-apoc3.
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