SHASTA-3 and SHASTA-4 — Double-blind, Placebo-controlled, Phase 3 Studies to Evaluate the Efficacy and Safety of Plozasiran in Adults With Severe Hypertriglyceridemia

SHASTA-3/4

Patient / Population Intervention / Exposure Comparison Outcome

In 757 patients with severe hypertriglyceridaemia, plozasiran every 3 months reduced the change in fasting triglycerides at 12 months compared with placebo.

N

757patients

Design

Two identically designed multinational, randomised, double-blind (quadruple-masked), placebo-controlled, parallel-group phase 3 trials; 2:1 allocation to plozasiran or placebo; four quarterly subcutaneous injections over a 12-month double-blind period, then post-treatment evaluation or open-label extension; randomisation stratified by baseline triglyceride level and acute pancreatitis within 5 years; primary completion June 2026.

Endpoint

Placebo-adjusted percent change in fasting serum triglycerides from baseline to month 12

Relevance

2Important — one of several pillars.

ResultMedian triglycerides fell 79% (SHASTA-3) and 81% (SHASTA-4) with plozasiran against 27% on placebo at 12 months. Acute pancreatitis was 78% less frequent; in the subgroup above 880 mg/dL with prior pancreatitis, no events occurred on plozasiran. Discontinuation for a treatment-related adverse event 1.4% vs 0.8%, with no meaningful difference in liver enzymes.

Watts GF, et al. Presented at ESC Congress 2026, Hot Line 9, 30 August.

Discussion & critique

An APOC3 silencer given four times a year takes triglycerides down by four fifths in people who start above 500 mg/dL, and the pancreatitis signal — 78% fewer events, none at all in the highest-risk subgroup — is the outcome that matters in this disease rather than the lipid number. Pancreatitis was not the primary endpoint and the absolute counts are small, so the effect size is an estimate with wide edges. Twelve months and 757 patients across two identical trials say nothing yet about cardiovascular events, which is the other reason to lower triglycerides and the one no drug in this class has yet delivered.