Plozasiran Shows Stunning Results: 86% Triglyceride Reduction in Phase 2 Trial Could Reshape Treatment Landscape

Arrowhead Pharmaceuticals just dropped some serious clinical data that’s turning heads in the cardiovascular space. Their investigational drug plozasiran has demonstrated dramatic reductions in triglycerides and APOC3 levels in patients with severe hypertriglyceridemia—and the numbers are genuinely impressive.

The Numbers That Matter

Here’s where it gets interesting. In the SHASTA-2 Phase 2 study, plozasiran achieved mean maximum reductions of up to 86% in triglycerides and 90% in APOC3—the latter being the protein that drives triglyceride metabolism. These weren’t one-off results; they were consistent across dosing groups and held strong through week 48, a full 36 weeks after the final dose.

Breaking down the specifics: patients receiving plozasiran showed dose-dependent reductions in triglycerides of -49%, -53%, and -57% compared to placebo at week 24 across the three treatment arms (10 mg, 25 mg, and 50 mg respectively). The APOC3 reductions were even more pronounced at -68%, -72%, and -77% for the same groups.

But here’s what really matters clinically: over 90% of treated patients achieved triglyceride levels below 500 mg/dL—the threshold associated with acute pancreatitis risk. Even more striking, 48.4% hit normal triglyceride ranges (below 150 mg/dL) after just two doses, starting from mean baseline levels around 900 mg/dL.

Why This Matters

Severe hypertriglyceridemia is a nightmare scenario for patients. It dramatically increases cardiovascular disease risk and recurrent pancreatitis attacks, yet treatment options have been severely limited. Plozasiran, an RNAi therapeutic designed to silence APOC3 production, appears to address this gap effectively.

The mechanism is elegant: by reducing APOC3, the drug prevents it from blocking triglyceride breakdown and hepatic uptake, essentially allowing the body’s natural lipid management systems to work properly again. The result is comprehensive lipid profile improvements including gains in HDL-cholesterol and reductions in remnant and non-HDL cholesterol.

Safety Profile Holds Up

The safety data supports advancing to later trials. The adverse event profile was consistent across treatment groups, with most events reflecting underlying patient comorbidities rather than drug effects. The most common adverse events—COVID-19 infection, glycemic control changes, diarrhea, UTIs, and headaches—appear unrelated to plozasiran. Notably, all serious adverse events were determined to be unrelated to treatment.

What’s Next

Arrowhead is confidently moving forward with two pivotal Phase 3 studies: SHASTA-3 and SHASTA-4. Both are planned as year-long, placebo-controlled trials evaluating plozasiran in the same severe hypertriglyceridemia population, and both are on track to begin dosing in the coming months. The Phase 3 PALISADE study in familial chylomicronemia syndrome patients is also progressing on schedule toward mid-2024 completion.

The Bottom Line

SHASTA-2 demonstrates that plozasiran could represent a meaningful therapeutic advance for a patient population with limited options. The combination of profound APOC3 and triglyceride reductions, durability of effect, favorable safety profile, and consistent inter-patient response makes this a compelling program heading into Phase 3. For patients with severe hypertriglyceridemia, these results suggest real hope for better disease management and reduced pancreatitis risk—outcomes that have been difficult to achieve with current treatment approaches.

The data were presented at the American College of Cardiology 73rd Annual Scientific Session in April 2024 and simultaneously published in JAMA Cardiology.