RARE Daily

Arrowhead Reports Positive Topline Results from Phase 3 Study of Plozasiran in FCS

June 3, 2024

Rare Daily Staff

Arrowhead Pharmaceuticals reported positive topline results from the pivotal phase 3 PALISADE study of investigational plozasiran in patients with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome.

The study successfully met the primary endpoint of lowering triglycerides and met all key secondary endpoints, including reducing the incidence of acute pancreatitis compared to placebo.

Familial chylomicronemia syndrome (FCS) is a severe and ultrarare genetic disease often caused by various monogenic mutations. FCS leads to extremely high triglyceride (TG) levels, typically over 880 mg/dL. Such severe elevations can lead to various serious signs and symptoms including acute and potentially fatal pancreatitis, chronic abdominal pain, diabetes, hepatic steatosis, and cognitive issues. Currently, the therapeutic options that can adequately treat FCS are limited.

Plozasiran is a first-in-class investigational RNA interference therapeutic designed to reduce production of Apolipoprotein C-3 (APOC3) which is a component of triglyceride rich lipoproteins (TRLs) and a key regulator of triglyceride metabolism. APOC3 increases triglyceride levels in the blood by inhibiting breakdown of TRLs by lipoprotein lipase and uptake of TRL remnants by hepatic receptors in the liver. The goal of treatment with plozasiran is to reduce the level of APOC3, thereby reducing triglycerides and restoring lipids to more normal levels.

The primary endpoint for the PALISADE study was placebo adjusted median change in triglycerides at Month 10. At that timepoint, patients treated with quarterly doses of 25 and 50 mg plozasiran achieved median triglyceride reductions of -80 percent and -78 percent, respectively, with a maximal reduction of -98 percent. At month 12, patients treated with 25 and 50 mg plozasiran achieved median triglyceride reductions of -78 percent and -73 percent, respectively, with a maximal reduction of -99 percent. These compared with median triglyceride reductions in placebo-treated patients of -17 percent at month 10 and -7 percent at month 12. Mean reductions in APOC3 at month 10 were -88 percent and -94 percent at 25 and 50 mg plozasiran, respectively.

In addition to meeting the primary endpoint, plozasiran met all key secondary endpoints and demonstrated statistical significance versus placebo. There were 4 multiplicity-controlled key secondary endpoints: 1) percent change from baseline at Months 10 and 12 (averaged) in fasting triglycerides; 2) percent change from baseline at Month 10 in fasting APOC3; 3) percent change from baseline at Month 12 in fasting APOC3; 4) incidence of positively adjudicated events of acute pancreatitis during the randomized period.

Plozasiran demonstrated a favorable safety profile in the PALISADE study. The number of subjects reporting treatment emergent adverse events (AEs) were similar in plozasiran and placebo groups. Severe and serious AEs were less common with plozasiran than with placebo. The most common AEs reported were abdominal pain, COVID-19, nasopharyngitis, headache and nausea.

Christopher Anzalone, Ph.D., president and CEO at Arrowhead, added, “We see plozasiran data as best in class and with the potential to address multiple cardiometabolic diseases with substantial unmet need,” said Christopher Anzalone, president and CEO at Arrowhead. “We will now communicate the results to the FDA and discuss filing a New Drug Application for FCS. We will also continue to advance multiple additional phase 3 studies for other patient populations.”

Arrowhead plans to highlight recent data for its cardiometabolic pipeline at its June 25, 2024, Cardiometabolic event as part of the 2024 Summer Series of R&D Webinars. The company also plans to present full results from the Phase 3 PALISADE study at upcoming medical congresses and will begin to engage with global regulatory authorities about these data.

Plozasiran has been granted Orphan Drug and Fast Track designations by the U.S. Food and Drug Administration and Orphan Drug designation by the European Medicines Agency.

“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,” said Bruce Given, chief medical scientist at Arrowhead. “These findings highlight the potential of plozasiran as a promising therapy for patients with various cardiometabolic disorders.”

Photo: Bruce Given, chief medical scientist at Arrowhead


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