Plozasiran Slashes Triglycerides, Pancreatitis Events in sHTG

Plozasiran (Redemplo; Arrowhead Pharmaceuticals) reduced median triglycerides by 79% and 81% at month 12 in the phase 3 SHASTA-3 (NCT06347003) and SHASTA-4 (NCT06347016) studies, compared with an approximately 27% reduction with placebo, according to top-line results announced by the manufacturer. Both studies met their primary endpoint and all prespecified secondary endpoints—including a statistically significant reduction in acute pancreatitis (AP) events, the outcome that most directly drives hospitalization and mortality risk in severe hypertriglyceridemia (sHTG).^1,2,3

Pancreatitis Reduction Anchors the Data Set

In a pre-planned pooled analysis of AP events across both studies, plozasiran-treated patients had significantly lower rates of both the event rate—any individual patient with at least 1 AP event (P < .0221)—and the total incidence rate of AP events (P < .0077) versus placebo. In the broad sHTG population, defined as patients with triglycerides above 500 mg/dL with or without prior AP history, cumulative AP events fell by 78%. Among patients with triglycerides above 880 mg/dL and a prior medical history of AP—the highest-risk subgroup—the company reported a 100% reduction in AP events versus placebo.¹

Quarterly Subcutaneous Dosing Shapes the Pharmacy Workflow

Plozasiran is a small interfering RNA (siRNA) therapy that suppresses production of apolipoprotein C-III (APOC3), a liver-produced protein that raises triglycerides by slowing their breakdown and clearance. It is self-administered subcutaneously once every 3 months. In SHASTA-3 and SHASTA-4, approximately 750 participants across both trials were randomized to 4 doses of 25 mg plozasiran or placebo, with percent change in fasting serum triglycerides from baseline to month 12 as the primary endpoint.^1,4

A once-quarterly injection changes what adherence support looks like. Rather than refill-based monitoring, pharmacists are tracking a 4-dose annual schedule where a single missed appointment represents a full quarter without APOC3 suppression—a point On Chen, MD, and Tahmid Rahman, MD, of Stony Brook Medicine's Center for Advanced Lipid Management, raised this in a Pharmacy Focus discussion following the world's first commercial administration of plozasiran.⁴

Safety Profile Consistent With Prior Studies

Plozasiran demonstrated a favorable safety and tolerability profile, with overall treatment-emergent adverse events (TEAEs) and related TEAEs consistent with the drug's established profile from prior studies and no new safety signals. There were no clinically meaningful differences in routine clinical laboratory measurements. In a prespecified subgroup, there were no statistically significant differences between plozasiran and placebo in mean liver fat content assessed by MRI proton density fat fraction (MRI-PDFF) and no clinically meaningful adverse changes in liver enzymes. The company reported no cases of hypersensitivity and no thrombocytopenia signal.¹

Case Finding and Access Remain the Bottleneck

Plozasiran is already approved as Redemplo in the US, European Union, China, Australia, and Canada as an adjunct to diet to reduce triglycerides in adults with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome (FCS), the most severe form of sHTG, in which triglycerides typically exceed 880 mg/dL. Arrowhead intends to use data from SHASTA-3, SHASTA-4, and MUIR-3 to seek marketing authorization in the broader sHTG population, beginning with a supplemental new drug application to the FDA before the end of 2026.¹

That expansion would move the drug from a rare-disease population into one pharmacists encounter far more routinely. Chen and Rahman have described pharmacists as well-positioned to spot undiagnosed FCS through medication patterns, very high triglyceride readings, and recurrent pancreatitis admissions and to route those patients to specialized lipid centers—the same signals that identify candidates in the broader sHTG population. They also emphasized the pharmacist's role in prior authorization and benefit verification, which for a quarterly specialty injectable determines whether an approved therapy is actually administered on schedule.⁴

REFERENCES

1. Arrowhead Pharmaceuticals reports topline results from Phase 3 SHASTA-3 and SHASTA-4 studies of plozasiran in patients with severe hypertriglyceridemia. Arrowhead Pharmaceuticals, Inc. News Release. Released July 22, 2026. Accessed July 22, 2026. https://www.businesswire.com/news/home/20260722499878/en/Arrowhead-Pharmaceuticals-Reports-Topline-Results-from-Phase-3-SHASTA-3-and-SHASTA-4-Studies-of-Plozasiran-in-Patients-with-Severe-Hypertriglyceridemia

2. Study of plozasiran (ARO-APOC3) in adults with severe hypertriglyceridemia (SHASTA-3). ClinicalTrials.gov Identifier: NCT06347003. Last Updated July 15, 2026. Accessed July 22, 2026. https://clinicaltrials.gov/study/NCT06347003

3. Study of plozasiran in adults with severe hypertriglyceridemia (SHASTA-4). ClinicalTrials.gov Identifier: NCT06347016. Last Updated October 24, 2025. Accessed July 22, 2026. https://clinicaltrials.gov/study/NCT06347016

4. Chen O, Rahman T, Halpern L. From underdiagnosed to under control: plozasiran and pharmacists' role in FCS. Pharmacy Times. Published January 30, 2026. Accessed July 22, 2026. https://www.pharmacytimes.com/view/from-underdiagnosed-to-under-control-plozasiran-and-pharmacists-role-in-fcs