Arrowhead Pharmaceuticals (NASDAQ:ARWR) presented 12-month results from its Phase 3 SHASTA-3 and SHASTA-4 trials evaluating plozasiran in adults with severe hypertriglyceridemia, reporting substantial reductions in triglycerides and acute pancreatitis events versus placebo. The company said the data were presented at the European Society of Cardiology Congress in Munich and have been accepted for publication in a major medical journal.
Plozasiran, marketed as REDEMPLO for familial chylomicronemia syndrome, or FCS, is approved to reduce triglycerides in FCS patients in the U.S., European Union, Canada, Australia and China. The severe hypertriglyceridemia indication remains investigational and has not been reviewed or approved by regulators, Arrowhead said.
Phase 3 results
Watts said plozasiran produced triglyceride reductions of about 80% from baseline at three months, with reductions sustained through 12 months. More than 90% of plozasiran-treated patients reached triglyceride levels below 500 milligrams per deciliter, a threshold associated with elevated acute pancreatitis risk. More than half of treated patients achieved normal fasting triglyceride levels below 150 milligrams per deciliter.
Secondary measures also showed reductions in remnant cholesterol, non-HDL cholesterol and apolipoprotein C3, or ApoC3, according to the presentation. Plozasiran is designed to reduce hepatic production of ApoC3, a regulator of triglyceride metabolism.
In a pooled analysis of the two studies, plozasiran reduced cumulative acute pancreatitis events by roughly 80% relative to placebo, Watts said. The presentation cited a 44.1% absolute risk reduction and a number needed to treat of 24 over one year for the overall trial population.
In exploratory analyses of higher-risk groups, the company reported more than a 90% relative reduction in acute pancreatitis among patients with a prior history of the condition. In a smaller subgroup with triglycerides above 880 milligrams per deciliter and prior acute pancreatitis, Arrowhead reported no acute pancreatitis events among plozasiran-treated patients. Watts cautioned that the subgroup involved small numbers and was exploratory.
Safety observations
Watts said patient retention exceeded 90% and adherence to the four-dose regimen was nearly 100%. Treatment discontinuations due to adverse events were low and similar between treatment groups, according to the presentation.
The company reported no anaphylaxis, systemic hypersensitivity or meaningful changes in platelet counts, liver enzymes or liver fat fraction relative to placebo. Investigators observed a small increase in measures related to glycemic control in some analyses, though Watts described the change in glycated hemoglobin, or HbA1c, as small and not clinically meaningful at the end of treatment.
Børge Nordestgaard, professor and chief physician at Copenhagen University Hospital, said the glycemic-control observation appeared consistent with the broader ApoC3 inhibitor class. He described the safety profile presented for plozasiran as promising while noting that longer-term follow-up will be needed.
Market focus and regulatory plans
Jennifer Hellawell, Arrowhead’s head of clinical development in cardiometabolic disease, said severe hypertriglyceridemia affects approximately 1% of the population, or more than 3 million people in the U.S. The company defines a high-risk segment of about 1 million U.S. patients as those with triglycerides at or above 880 milligrams per deciliter, or those above 500 milligrams per deciliter with a prior history of acute pancreatitis.
Andy Davis, Arrowhead’s head of cardiometabolic commercial operations, said the company intends to initially focus a potential severe hypertriglyceridemia launch on those high-risk patients. Arrowhead has identified more than 20,000 healthcare professionals across lipidology, endocrinology, preventive cardiology, internal medicine and primary care who treat these patients, Davis said.
Vince Anzalone, Arrowhead’s senior vice president of finance and investor relations, said the company remains on schedule to file a supplemental new drug application seeking approval for plozasiran in severe hypertriglyceridemia before year-end. Arrowhead recently purchased a priority review voucher, which Anzalone said could accelerate the potential U.S. review timeline. Subject to a positive regulatory review, the company is targeting a potential launch in 2027.
Arrowhead estimates the U.S. severe hypertriglyceridemia opportunity could represent $3 billion to $4 billion in annual sales over the long term. The company also highlighted other cardiometabolic programs, including zodasiran for homozygous familial hypercholesterolemia and ARO-DIMER-PA, an investigational dual-targeting therapy for mixed hyperlipidemia.
About Arrowhead Pharmaceuticals (NASDAQ:ARWR)
Arrowhead Pharmaceuticals, Inc is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of RNA interference (RNAi) therapeutics. Since its founding in 2008, Arrowhead has leveraged its proprietary delivery platform—known internally as the Advanced RNAi Compound (ARC) technology—to silence disease-causing genes in patients suffering from genetically defined diseases. The company’s approach aims to offer durable, targeted treatments across a range of therapeutic areas.
The company’s pipeline includes multiple candidates in various stages of development.
