Olezarsen Sodium

Although Arrowhead Pharmaceuticals' apoC-III–directed RNA therapy is commercially lagging behind Ionis Pharmaceuticals' rival genetic silencer, investors are excited about the potential of Redemplo (plozasiran) to take on the first-to-market leader — if the company's 19% stock bump on Wednesday is any indicator. Arrowhead reported that Redemplo met its primary triglyceride-lowering endpoint in both the Phase III SHASTA-3 and SHASTA-4 trials in patients with severe hypertriglyceridaemia (sHTG), while also achieving a statistically significant reduction in the rate of acute pancreatitis. When the FDA approved Ionis' Tryngolza (olezarsen) in June for sHTG, the agency noted the  apoC-III–targeting antisense oligonucleotide (ASO) was the first treatment for the disease to demonstrate a risk-reducing effect for pancreatitis (see – Spotlight On: Pancreatitis benefit could set Ionis' Tryngolza apart in sHTG). Prior to its label expansion into sHTG, Tryngolza was initially cleared in the US for familial chylomicronaemia syndrome (FCS), a rare subtype of sHTG with several thousand US patients; the broader sHTG indication affects some 3 million people in the country. Now, it looks like Arrowhead's Redemplo has accomplished a similar risk-reducing feat for acute pancreatitis, but with less frequent dosing and a cleaner safety profile. Like Tryngolza, the siRNA was originally greenlit by the FDA for FCS; with the latest data in-hand, however, Arrowhead is planning to submit a supplemental FDA application by year-end for sHTG, which would set Redemplo up to compete directly against Ionis' ASO. 'Unprecedented' acute pancreatitis event reductionAcross the two Phase III trials, about 750 adults with sHTG were randomised to receive a 25-mg subcutaneous injection of Redemplo every three months or placebo, for four total doses.At the 12-month mark, patients taking Redemplo in SHASTA-3 and SHASTA-4 saw median triglyceride reductions of 79% and 81%, respectively, versus 27% for placebo, meeting the primary endpoint. In a pre-planned pooled analysis spanning both studies, Redemplo-treated patients had a statistically significant reduction in both acute pancreatitis event rate, measured as any individual with at least one event (p<0.0221), as well as total incidence rate (p<0.0077).Looking at the broad population of patients in the two studies with triglycerides above 500 mg/dL with or without a prior history of acute pancreatitis, cumulative events were reduced by 78% in those taking Redemplo versus placebo. That effect was amplified in a subset of patients at the highest risk for acute pancreatitis — those with triglycerides above 880 mg/dL and a prior medical history of the inflammatory condition — with the siRNA achieving a 100% reduction in events versus placebo, a result Arrowhead called "unprecedented."The findings are comparable with those from the Phase III CORE and CORE2 trials, which supported Tryngolza's approval for sHTG. Pooled data across both studies showed that the ASO led to a highly statistically significant 85% reduction in adjudicated acute pancreatitis events.However, while Redemplo can be dosed quarterly, Tryngolza is given monthly via an auto-injector. Ionis' RNA therapy is also linked to liver enzyme increases, with physicians advised to conduct liver enzyme testing in patients before they start Tryngolza or increase its dosage. Arrowhead said Wednesday that Redemplo had a "favourable" safety and tolerability profile, with no statistically significant differences between the siRNA and placebo in mean liver fat content, nor any clinically meaningful adverse changes in liver enzymes.Across both SHASTA-3 and SHASTA-4, the treatment-emergent adverse events were consistent with prior studies of Redemplo, and no new safety signals were observed.  RBC Capital Markets analyst Luca Issi called the efficacy and safety data "a best-case scenario" for Arrowhead, as Redemplo succeeded in acute pancreatitis risk reduction though the SHASTA studies were primarily designed to evaluate the drug's triglyceride-lowering capabilities. "Bottom line, Ionis is first to market, but Arrowhead is poised to join the race with a drug that has shown a comparable benefit in [acute pancreatitis] and can offer a dosing advantage…and potentially spare the liver fat signal," Issi wrote in a note.

Arrowhead Pharmaceuticals, Inc. (Nasdaq: ARWR) reported topline results from two pivotal Phase III trials of plozasiran in severe hypertriglyceridemia, data that could expand the drug’s use well beyond the ultra-rare genetic disease for which it is already approved. The California-based company said the SHASTA-3 and SHASTA-4 studies both hit their primary endpoint and showed a statistically significant reduction in acute pancreatitis events. For a company whose only approved product currently serves a population estimated at roughly 6,500 patients in the US, positive results in the much larger severe hypertriglyceridemia population would transform the molecule into a mainstream cardiometabolic drug. SHASTA-3 and SHASTA-4 are global, double-blind, placebo-controlled trials that together randomized approximately 750 adults with severe hypertriglyceridemia — defined as fasting triglycerides above 500 mg/dL — to four quarterly doses of 25 mg plozasiran or placebo. At month 12, plozasiran produced median triglyceride reductions of 79% and 81% in the two studies, respectively, compared with roughly 27% for placebo. Arrowhead also reported a statistically significant reduction in acute pancreatitis events across the pooled study population, with what it described as a 100% reduction among high-risk patients, though the company did not disclose the underlying p-value or confidence intervals in the topline release. Safety findings were consistent with plozasiran’s existing profile with no new signals, and particularly no meaningful change in liver fat on MRI-PDFF imaging or in liver enzymes. Arrowhead has consistently emphasized a clean liver profile as a differentiator. Full efficacy and safety data will be presented as a Hot Line late-breaker at the European Society of Cardiology Congress in Munich on August 30. Plozasiran silences production of apolipoprotein C-III, a liver-derived protein that normally slows the breakdown and clearance of triglyceride-rich lipoproteins. By reducing apoC-III through RNA interference, the drug allows lipoprotein lipase to clear those particles more efficiently, driving triglycerides down. The mechanism is the same one underlying plozasiran’s existing approval: the drug is marketed as Redemplo in the US, EU, China, Australia and Canada as an adjunct to diet for adults with familial chylomicronemia syndrome, a rare genetic disorder representing the most extreme end of the hypertriglyceridemia spectrum. Arrowhead intends to file a supplemental new drug application with the FDA before the end of 2026, drawing on data from SHASTA-3, SHASTA-4 and the related MUIR-3 study, which enrolled patients with more moderate hypertriglyceridemia. The company has already built commercial infrastructure around Redemplo’s FCS launch, including a dedicated patient support program and a pricing model designed to hold steady across indications — a structure explicitly built in anticipation of this broader sHTG approval. Plozasiran is not the only APOC3-targeted therapy chasing this population. Ionis Pharmaceuticals’ Tryngolza (olezarsen), an antisense oligonucleotide against the same target, won FDA approval for FCS in December 2024 and has already reported pooled data from its CORE and CORE2 trials showing an 85% reduction in acute pancreatitis risk and 66% triglyceride lowering in patients with baseline triglycerides above roughly 880 mg/dL. That program carries a US FDA action date of June 30, 2026, for the broader severe hypertriglyceridemia indication. Olezarsen is dosed monthly in contrast woth plozasrian’s quarterly schedule. Access the AllSci platform to explore the science behind the news. Your email address will not be published. Required fields are marked * Comment * Name * Email * Website Privacy Terms About Us Copyright © 2026. AllSci Corp. All rights reserved.