Plozasiran Meets Primary Endpoint in SHASTA-3, SHASTA-4 sHTG Trials

Arrowhead Pharmaceuticals has announced topline results for the global phase 3 SHASTA-3 and SHASTA-4 clinical studies of plozasiran in patients with severe hypertriglyceridemia.¹

As described in a July 22, 2026, release from the Company, SHASTA-3 and SHASTA-4 successfully met the primary endpoint of triglyceride reduction versus placebo and met all prespecified secondary endpoints in both studies, including a statistically significant reduction in the rate of acute pancreatitis compared to placebo.¹

“We continue to see plozasiran data as best in class with respect to safety, activity, efficacy, and convenience, with dosing only four times per year, and we are more confident than ever in its promise,” Christopher Anzalone, PhD, President and CEO at Arrowhead, said in a statement. “These compelling Phase 3 data in a broad sHTG study population that closely resembles today’s diverse patient landscape demonstrate plozasiran’s potential to dramatically change the way people are treated. We now begin the process of seeking regulatory approval in multiple global geographies with the goal of bringing plozasiran to the millions of patients seeking new effective treatment options as quickly as possible.”

Anzalone additionally described plans to submit a first planned filing of an sNDA in the US before the end of the year, with additional planned submissions thereafter.

What is Plozasiran?

Plozasiran is designed to suppress the production of apolipoprotein C-III (APOC3). By targeting APOC3 with sustained silencing, plozasiran delivers significant reductions in triglyceride levels. It is self-administered via subcutaneous injection once every three months.

Plozasiran is currently approved by the US Food and Drug Administration as an adjunct to diet to reduce triglycerides for adults with FCS. In the latest release, Arrowhead described plans to leverage the data from the phase 3 SHASTA-3, SHASTA-4, and MUIR-3 studies to request marketing authorization for sHTG in multiple global geographies, beginning with a planned sNDA with the FDA before the end 2026.

Plozasiran Phase 3 SHASTA-3 and SHASTA-4 Trial Design and Triglyceride Reduction

SHASTA-3 and SHASTA-4 are global double-blind, placebo-controlled, phase 3 studies to evaluate the efficacy and safety of plozasiran in adults with severe hypertriglyceridemia. Between the 2 studies, approximately 750 participants were randomly assigned to receive 4 doses (once every 3 months) of 25 mg plozasiran or placebo.

The primary endpoint is percent change in fasting serum triglyceride levels from baseline to month 12 compared to placebo. After month 12, eligible participants are offered an opportunity to continue in an optional open-label extension.

Results showed plozasiran administered as a subcutaneous injection once every 3 months led to median triglyceride reductions of 79% and 81%, respectively, at month 12, versus a placebo reduction of approximately 27%. In a pre-planned pooled analysis of AP events in SHASTA-3 and SHASTA-4, there was a statistically significant reduction in both the event rate (any individual patient with ≥ 1 AP event, p<0.0221), as well as the total incidence rate of AP events (P <.0077) in plozasiran treated patients versus placebo.

In the broad sHTG study population, defined as patients with triglycerides above 500 mg/dL with or without a prior history of AP, cumulative AP events were reduced by 78% in treated patients versus placebo. In a subset of patients with triglycerides above 880 mg/dL and a prior medical history of AP, widely considered to be at the highest risk for AP, plozasiran treatment demonstrated a 100% reduction in AP events versus placebo.

Plozasiran Safety Profile in sHTG

Plozasiran demonstrated a favorable safety and tolerability profile in SHASTA-3 and SHASTA-4, with overall treatment emergent adverse events (TEAE) and related TEAEs consistent with its established safety profile from prior studies. There were no clinically meaningful differences in routine clinical laboratory measurements, and no new safety signals.

No statistically significant differences were observed between plozasiran and placebo in mean liver fat content assessed by MRI-PDFF in a prespecified subgroup, and no clinically meaningful adverse changes in liver enzymes. Additionally, there were no cases of hypersensitivity and no thrombocytopenia signal.

“These strong results from the Phase 3 SHASTA-3 and SHASTA-4 studies, evaluating plozasiran in patients with sHTG, build upon the promising results from prior Phase 2 and Phase 3 studies across various patient populations, including those with moderate hypertriglyceridemia, mixed hyperlipidemia, severe hypertriglyceridemia, and genetically confirmed and clinically diagnosed familial chylomicronemia syndrome,” James Hamilton, MD, Chief Medical Officer and Head of R&D at Arrowhead, said in a statement. “Plozasiran continues to demonstrate deep and durable pharmacodynamic effects with a consistently favorable safety and tolerability profile, including a highly encouraging liver safety profile. These findings highlight the potential of plozasiran as a promising therapy for patients across the spectrum of sHTG.”

According to Arrowhead, detailed results will be presented as a HOT LINE Late Breaker at the European Society of Cardiology (ESC) Congress on August 30, 2026.

References

1. Arrowhead Pharmaceuticals. Arrowhead Pharmaceuticals Reports Topline Results from Phase 3 SHASTA-3 and SHASTA-4 Studies of Plozasiran in Patients with Severe Hypertriglyceridemia. 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. Livingston R. FDA Approves Plozasiran for Adults With Familial Chylomicronemia Syndrome. HCPLive. November 18, 2025. Accessed July 22, 2026. https://www.hcplive.com/view/fda-approves-plozasiran-for-adults-with-familial-chylomicronemia-syndrome