Arrowhead Plozasiran Cuts Pancreatitis 100% in Trial

Arrowhead Pharmaceuticals (ARWR) reported positive topline results from two Phase 3 trials of plozasiran in severe hypertriglyceridemia on July 22, 2026. The drug cut triglycerides by up to 81% and, in the highest-risk patients, eliminated acute pancreatitis events entirely.

The trial results

SHASTA-3 and SHASTA-4 were global, double-blind, placebo-controlled Phase 3 studies enrolling approximately 750 participants combined (446 in SHASTA-3, 311 in SHASTA-4). Patients received four once-every-three-months injections of 25 mg plozasiran or placebo.

The triglyceride reductions were substantial: median reductions of 79% and 81% from baseline at 12 months, compared with a 27% placebo reduction. Both trials met their primary endpoints and all prespecified secondary endpoints.

The pancreatitis data stands apart. In a pre-planned pooled analysis, plozasiran produced a statistically significant reduction in acute pancreatitis events across the entire severe hypertriglyceridemia population (p=0.0221 for event rate, p=0.0077 for total incidence). The reduction was 78% in the broad population. In patients with triglycerides above 880 mg/dL and a prior history of pancreatitis, the reduction was 100%. Zero events in the treatment arm versus placebo.

Severe hypertriglyceridemia, defined as triglycerides above 500 mg/dL, carries direct clinical consequences: acute pancreatitis attacks that require repeat hospital admissions and can be fatal. The condition is distinct from garden-variety high cholesterol. Triglycerides are a different blood fat, and at severe levels they inflame the pancreas.

What this means for Arrowhead

Plozasiran is an RNA interference therapy targeting APOC3, a protein that normally inhibits triglyceride clearance. The drug is already approved as REDEMPLO for familial chylomicronemia syndrome, a related condition. These Phase 3 results support a supplemental NDA filing for the broader severe hypertriglyceridemia indication before the end of 2026.

Analysts responded quickly. Morgan Stanley raised its price target to $120, Piper Sandler to $126, and Chardan to $115. ARWR closed at $86.78 on July 22 with a market cap of approximately $12.5 billion.

The RNAi approach is mechanistically distinct from existing triglyceride-lowering therapies. Ionis Pharmaceuticals’ volanesorsen (Waylivra) targets the same pathway but uses an antisense oligonucleotide rather than RNAi. The competitive dynamics in this space are still forming.

What to watch next

The risk factor is the sNDA filing timeline. Arrowhead says it will file before the end of 2026, but the FDA review process for label expansions can surface safety questions. The pooled pancreatitis analysis, while statistically significant, draws on event rates that are relatively low in absolute terms. The FDA will scrutinize whether the 100% reduction in the high-risk subgroup holds up under review.

For context on FDA approval decisions, see our coverage of Vertex’s suzetrigine PDUFA.

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