Arrowhead's Plozasiran Slashes Triglycerides 79-81% and Eliminates Pancreatitis in High-Risk Patients

Arrowhead Pharmaceuticals (ARWR) reported topline results from the Phase 3 SHASTA-3 and SHASTA-4 trials of plozasiran (REDEMPLO) in severe hypertriglyceridemia on July 22, 2026. Both trials met their primary endpoint and all prespecified secondary endpoints. The drug delivered median triglyceride reductions of 79% and 81% versus a 27% placebo reduction, and a statistically significant reduction in acute pancreatitis events that included a 100% reduction in the highest-risk patient subgroup.

The triglyceride numbers

SHASTA-3 (NCT06347003) and SHASTA-4 (NCT06347016) were global, double-blind, placebo-controlled studies enrolling approximately 750 participants total. Patients received 25 mg plozasiran or placebo as a subcutaneous injection once every three months for 12 months.

The primary endpoint was percent change in fasting serum triglycerides from baseline to month 12. Plozasiran produced median reductions of 79% in SHASTA-3 and 81% in SHASTA-4, compared with approximately 27% in the placebo arm. That is a deep, durable response from four injections per year.

Why the pancreatitis data steals the headline

Acute pancreatitis is the complication that makes severe hypertriglyceridemia dangerous. It sends patients to the hospital repeatedly and can be fatal. No existing therapy has demonstrated this level of pancreatitis prevention in a Phase 3 setting.

In a pre-planned pooled analysis, plozasiran reduced cumulative acute pancreatitis events by 78% across the broad sHTG population (TG >500 mg/dL, with or without prior AP history) compared with placebo. The statistical significance was solid: p<0.0221 for event rate and p<0.0077 for total incidence rate.

In the highest-risk subgroup, patients with triglycerides above 880 mg/dL and a prior history of acute pancreatitis, plozasiran showed a 100% reduction in AP events. Zero events in the treatment arm. That is the data point that changes the clinical conversation.

Clean safety profile

The safety data was clean. Treatment-emergent adverse events were consistent with plozasiran’s established profile from prior studies. No new safety signals emerged. There were no clinically meaningful differences in liver fat content by MRI-PDFF, no adverse liver enzyme changes, no thrombocytopenia signal, and no cases of hypersensitivity.

This matters for the competitive field. Ionis is developing olezarsiran for the same indication, and liver safety has been a watch item. Plozasiran’s clean liver profile is a differentiator.

The market opportunity

Plozasiran is already approved as REDEMPLO in the US, EU, China, Australia, and Canada for familial chylomicronemia syndrome (FCS), the most severe form of sHTG. FCS is a rare disease. Severe hypertriglyceridemia is a much larger population, and these Phase 3 results support expansion.

Arrowhead plans to file a supplemental NDA with the FDA before the end of 2026 to expand the approved indication to the broader sHTG population. Full results were presented as a HOT LINE Late Breaker at the European Society of Cardiology Congress on August 30, 2026: across the pooled studies plozasiran reduced acute pancreatitis events by 78% (relative risk 0.22, p=0.008), drove 79% (SHASTA-3) and 81% (SHASTA-4) median triglyceride reductions, and cut pancreatitis by 91% in the highest-risk subgroup (TG above 500 mg/dL with prior pancreatitis). See the full ESC data coverage.

For context on interpreting clinical trial press releases, see our guide to reading clinical trial data.

What to watch next

1. sNDA filing: Arrowhead plans to file before year-end 2026. The timeline depends on completing the full safety and efficacy analysis.
2. ESC presentation on August 30 (now delivered): The full 12-month dataset dropped at ESC on August 30, confirming the topline — 78% pancreatitis reduction (RR 0.22, p=0.008), 79-81% median triglyceride cuts, 91% pancreatitis reduction in the highest-risk subgroup, and a clean safety profile (8.3% serious TEAEs vs 10% placebo). See the full ESC data coverage.
3. Competitive positioning vs. Ionis: Olezarsiran is also in development for sHTG. Plozasiran’s pancreatitis data and clean liver safety set a high bar.

ARWR closed at $86.78 on July 23, up from the previous day’s close. Analysts at Morgan Stanley, Piper Sandler, and Chardan raised price targets following the readout, with targets ranging from $115 to $126.

Source: Arrowhead Pharmaceuticals press release | ClinicalTrials.gov SHASTA-3