SHASTA-3/4: Plozasiran Could Cut Acute Pancreatitis Risk by 78% Across sHTG Spectrum

Plozasiran (Redemplo), a small interfering RNA (siRNA) targeting apolipoprotein C3 (APOC3), reduced acute pancreatitis events across the spectrum of severe hypertriglyceridemia (sHTG), including in patients below the 880 mg/dL chylomicronemia threshold, according to a pooled analysis of the phase 3 SHASTA-3 and SHASTA-4 trials presented at the American Heart Association (AHA) Scientific Sessions 2026.^1,2

Plozasiran reduced the rate of adjudicated acute pancreatitis events by 78% vs placebo, an absolute risk reduction (ARR) of 4.1% with a number needed to treat (NNT) of approximately 24.^1,2

Among patients with acute pancreatitis within the previous 5 years, the acute pancreatitis event rate fell by 91% (ARR, 33.8%; NNT, approximately 3). The ARR was 3.8% (NNT, approximately 26) in patients with baseline triglycerides (TGs) of 500 to less than 880 mg/dL and 4.9% (NNT, approximately 20) in those with TGs of 880 mg/dL or higher.^1,2

“These findings highlight the importance of looking beyond triglyceride levels alone to understand a patient’s risk of acute pancreatitis,” said James Hamilton, MD, MBA, chief medical officer and head of research and development at Arrowhead Pharmaceuticals. “In the SHASTA-3 and SHASTA-4 pooled analysis, plozasiran reduced acute pancreatitis event rates by 78% overall versus placebo and by 91% among patients who had experienced pancreatitis within five years before screening.”

SHASTA-3/4 pooled analysis design and acute pancreatitis risk by triglyceride level

SHASTA-3 and SHASTA-4 were global, double-blind, placebo-controlled phase 3 trials randomizing 757 adults with TGs of 500 mg/dL or higher 2:1 to subcutaneous plozasiran 25 mg or placebo every 3 months.^1,2 In both trials, plozasiran reduced TGs by approximately 80% and acute pancreatitis risk by approximately 80%, meeting the primary and key secondary endpoints.¹ The pooled analysis examined how baseline TG level and acute pancreatitis history within the previous 5 years related to acute pancreatitis events over 12 months, with ARR and NNT calculated overall and by subgroup.^1,2

APOC3 and TG reductions with plozasiran were consistent across demographic and clinical subgroups.¹ Among patients with prior acute pancreatitis and baseline TGs of 500 to less than 880 mg/dL, the AP event rate fell by 82% (ARR, 36.4%; NNT, approximately 3). Among patients with prior AP and TGs of 880 mg/dL or higher, no AP events occurred in 35 plozasiran-treated patients compared with 5 events in 17 placebo-treated patients (ARR, 29.4%; NNT, approximately 3).^1,2

Plozasiran safety and tolerability in severe hypertriglyceridemia

Treatment-emergent adverse events (TEAEs) occurred in 73% of both groups, and serious TEAEs occurred in 8.3% of plozasiran-treated patients and 10% of placebo-treated patients.^1,2

TEAEs led to discontinuation in 1.2% of patients, and safety was evaluated through month 15. According to Arrowhead, worsening glycemic control was reported in 14% of the plozasiran group and 8.7% of the placebo group, while the abstract reported no clinically meaningful worsening of hemoglobin A1c over time.^1,2

No treatment-related thrombocytopenia, hypersensitivity adverse events, clinically meaningful aminotransferase elevations, or significant increases in hepatic fat were observed with plozasiran.¹ Three deaths in the plozasiran group were attributed to preexisting cardiovascular or hematologic disease and assessed as unrelated to treatment.²

The investigators concluded the findings support a risk-based approach to acute pancreatitis prevention incorporating both persistent sHTG and prior acute pancreatitis history.¹

Topline SHASTA-3 and SHASTA-4 results showing approximately 80% TG reductions with plozasiran were reported in August 2026.³ In the PALISADE open-label extension in familial chylomicronemia syndrome (FCS), median reductions were 76% for TGs and 89% for APOC3 through up to 36 months of total treatment, according to Arrowhead.²

References

1. Ballantyne C, Gaudet D, Blanco Echevarria A, et al. Triglyceride lowering and acute pancreatitis (AP) risk reduction with plozasiran in severe hypertriglyceridemia (sHTG): a pooled analysis of SHASTA-3 and SHASTA-4. Presented at: American Heart Association Scientific Sessions 2026; November 7, 2026; Chicago, IL.

2. Arrowhead Pharmaceuticals. Arrowhead Pharmaceuticals presents plozasiran data highlighting sustained triglyceride reductions and reduced acute pancreatitis rates. Published November 7, 2026. Accessed November 8, 2026.

3. HCPLive. Plozasiran cuts triglycerides by 80% in SHASTA-3/4 trials. https://www.hcplive.com/view/plozasiran-cuts-triglycerides-by-80-in-shasta-3-4-trials. Published August 30, 2026. Accessed November 8, 2026.