Arrowhead Pharmaceuticals Reports Positive Phase 3 Results for Plozasiran in Severe Hypertriglyceridemia, Demonstrating Significant Triglyceride Reduction and Lower Risk of Acute Pancreatitis
Arrowhead Pharmaceuticals, Inc. has announced positive topline results from its pivotal global Phase 3 SHASTA-3 and SHASTA-4 clinical trials evaluating plozasiran in patients with severe hypertriglyceridemia (sHTG). The studies achieved their primary efficacy objectives while also meeting all key secondary endpoints, reinforcing the therapy’s potential to become an important treatment option for individuals at high risk of complications associated with elevated triglyceride levels.
The findings are particularly significant because severe hypertriglyceridemia is associated with a markedly increased risk of acute pancreatitis (AP), a painful and potentially life-threatening condition that frequently results in emergency hospitalizations and recurring medical complications. In addition to demonstrating profound and sustained reductions in triglyceride levels, plozasiran also significantly lowered the occurrence of acute pancreatitis compared with placebo, highlighting its potential to address both the biochemical and clinical consequences of the disease.
Addressing an Important Unmet Medical Need
Severe hypertriglyceridemia remains a challenging metabolic disorder affecting a substantial patient population worldwide. Individuals with triglyceride levels exceeding 500 mg/dL face increased risks of cardiovascular complications and acute pancreatitis, while patients with triglyceride concentrations above 880 mg/dL are especially vulnerable to recurrent pancreatitis episodes.
Current treatment options—including dietary modification, fibrates, omega-3 fatty acids, and statins—often fail to adequately reduce triglyceride levels in many patients. Consequently, there remains a strong demand for therapies capable of producing durable triglyceride lowering while reducing serious clinical complications.
Plozasiran, an investigational RNA interference (RNAi) therapy administered by subcutaneous injection once every three months, has been developed to provide long-lasting triglyceride reduction with convenient quarterly dosing.
Successful Outcomes Across Both Phase 3 Studies
The SHASTA-3 and SHASTA-4 studies were randomized, placebo-controlled global Phase 3 trials evaluating the efficacy, safety, and tolerability of plozasiran in patients with severe hypertriglyceridemia.
Both studies successfully achieved their primary endpoint by demonstrating statistically significant reductions in triglyceride levels compared with placebo after 12 months of treatment.
Patients receiving 25 mg plozasiran once every three months experienced remarkable improvements:
- Median triglyceride reduction of 79% in SHASTA-3
- Median triglyceride reduction of 81% in SHASTA-4
By comparison, patients receiving placebo experienced reductions of approximately 27%, emphasizing the substantial therapeutic benefit associated with plozasiran treatment.
These results further validate earlier clinical studies that suggested plozasiran could deliver deep, sustained triglyceride lowering across diverse patient populations.
Significant Reduction in Acute Pancreatitis
Beyond lowering triglycerides, one of the most clinically meaningful findings from the Phase 3 program was the therapy’s impact on acute pancreatitis.
A prespecified pooled analysis combining data from SHASTA-3 and SHASTA-4 demonstrated statistically significant reductions in pancreatitis events among patients receiving plozasiran.
Specifically, investigators observed:
- A statistically significant reduction in the number of patients experiencing at least one episode of acute pancreatitis.
- A statistically significant reduction in the total number of pancreatitis events during the study period.
Among the overall severe hypertriglyceridemia population, cumulative acute pancreatitis events were reduced by approximately 78% compared with placebo.
Even more striking were the results in patients considered at the highest clinical risk—those with triglyceride levels above 880 mg/dL and a previous history of acute pancreatitis.
Within this subgroup, investigators reported no acute pancreatitis events among patients treated with plozasiran, representing a 100% reduction compared with placebo during the study period.
These findings suggest that plozasiran may offer protection against one of the most serious complications associated with severe hypertriglyceridemia.
Consistent Safety and Tolerability Profile
The Phase 3 studies also reinforced the favorable safety profile previously observed across the plozasiran clinical development program.
Overall treatment-emergent adverse events were generally comparable to previous studies, and investigators reported no unexpected safety findings.
Importantly:
- No new safety signals were identified.
- Routine laboratory testing remained stable throughout treatment.
- Liver enzyme measurements showed no clinically meaningful deterioration.
- MRI assessments demonstrated no statistically significant differences in liver fat accumulation compared with placebo.
- No hypersensitivity reactions were reported.
- No thrombocytopenia signal was observed.
The favorable liver safety findings are particularly noteworthy because therapies affecting lipid metabolism may sometimes influence hepatic function. The absence of clinically meaningful liver-related safety concerns provides additional confidence regarding long-term treatment.
Executive Leadership Highlights Clinical Progress
Christopher Anzalone, Ph.D., President and Chief Executive Officer of Arrowhead Pharmaceuticals, emphasized the significance of the Phase 3 findings and their potential impact on patient care.
According to Anzalone, the latest results strengthen confidence in plozasiran’s clinical profile, highlighting its combination of strong efficacy, favorable safety, and convenient quarterly dosing schedule.
He noted that the broad patient population enrolled in the studies closely reflects real-world clinical practice, suggesting that the therapy could benefit a large number of patients currently struggling to manage severe hypertriglyceridemia despite available treatments.
The company now plans to pursue regulatory approvals in multiple international markets, beginning with a supplemental New Drug Application (sNDA) submission to the U.S. Food and Drug Administration before the end of 2026.
Clinical Development Builds Upon Earlier Success
James Hamilton, M.D., Chief Medical Officer and Head of Research & Development at Arrowhead Pharmaceuticals, stated that the SHASTA-3 and SHASTA-4 outcomes build upon encouraging evidence generated in earlier Phase 2 and Phase 3 studies.
Across previous clinical programs, plozasiran has consistently demonstrated:
- Deep triglyceride lowering
- Durable pharmacodynamic activity
- Favorable tolerability
- Encouraging liver safety
- Convenient quarterly administration
These studies have included patients with:
- Moderate hypertriglyceridemia
- Mixed hyperlipidemia
- Severe hypertriglyceridemia
- Familial chylomicronemia syndrome (FCS)
The consistency observed across multiple patient populations further strengthens confidence in the therapy’s potential as a broadly applicable treatment for disorders characterized by elevated triglycerides.
Regulatory Momentum Continues
Plozasiran has already achieved regulatory approval under the brand name REDEMPLO® for adults with genetically confirmed or clinically diagnosed familial chylomicronemia syndrome (FCS), the most severe inherited form of hypertriglyceridemia.
The therapy has received approval in multiple major markets, including:
- United States
- European Union
- China
- Australia
- Canada
Arrowhead now intends to expand the approved indication to include patients with severe hypertriglyceridemia using data generated from SHASTA-3, SHASTA-4, and the MUIR-3 clinical trial.
The planned U.S. supplemental NDA submission is expected before the conclusion of 2026, with additional international regulatory filings anticipated thereafter.
Scientific Presentation Planned at ESC Congress
Comprehensive analyses from both pivotal studies are continuing, with complete efficacy and safety datasets expected to be presented at upcoming scientific meetings and published in peer-reviewed journals.
The first detailed presentation will take place during the European Society of Cardiology (ESC) Congress 2026 as part of a prestigious HOT LINE Late Breaker session.
The presentation will feature the complete 12-month results from SHASTA-3 and SHASTA-4 and will be delivered by Gerald Watts, M.D.
Following the scientific presentation, Arrowhead plans to host a conference call and webcast to discuss the clinical findings and outline its regulatory strategy.
The positive Phase 3 results position plozasiran as a potentially transformative treatment for patients living with severe hypertriglyceridemia, particularly those at high risk for acute pancreatitis. By combining substantial triglyceride reductions with a meaningful decrease in pancreatitis events and a favorable safety profile, the therapy addresses critical unmet needs that have persisted despite existing treatment options.
As Arrowhead advances toward regulatory submissions and broader commercialization, plozasiran has the potential to reshape the treatment landscape for severe hypertriglyceridemia. If approved for this expanded indication, the therapy could offer physicians a powerful new option that not only improves lipid control but also helps prevent one of the disease’s most serious and potentially life-threatening complications, ultimately improving long-term outcomes and quality of life for patients worldwide.
About Severe Hypertriglyceridemia
Severe hypertriglyceridemia (sHTG) is characterized by triglyceride (TG) levels greater than 500 mg/dL, with the most severe form being familial chylomicronemia syndrome (FCS) where TGs typically exceed 880 mg/dL. SHTG significantly increases the risk of acute pancreatitis (AP), which can often include recurrent attacks requiring repeat hospital admissions and worsening outcomes. AP risk is proportional to the number, characteristics, and concentration of triglyceride rich lipoproteins (TRLs), particularly chylomicrons, and increases as TGs rise. Elevated TGs can also increase the risk of atherosclerotic cardiovascular disease (ASCVD). Limited treatment options exist to sustainably reduce TGs below guideline directed risk thresholds.
About SHASTA-3 and SHASTA-4 Phase 3 Studies
SHASTA-3 (NCT06347003) and SHASTA-4 (NCT06347016) are global double-blind, placebo-controlled, Phase 3 studies to evaluate the efficacy and safety of plozasiran in adults with severe hypertriglyceridemia. Between the two studies, approximately 750 participants were randomized to receive 4 doses (once every 3 months) of 25 mg plozasiran or placebo. The primary endpoint is percent change in fasting serum triglyceride levels from baseline to month 12 compared to placebo. After month 12, eligible participants are offered an opportunity to continue in an optional open-label extension.
About REDEMPLO® (plozasiran)
REDEMPLO (plozasiran) is currently approved by the U.S. Food and Drug Administration, Health Canada, China’s National Medical Products Administration, the Australian Therapeutic Goods Administration, and by the European Commission as an adjunct to diet to reduce triglycerides for adults with FCS. REDEMPLO is the first and only siRNA treatment approved in these countries to be studied in both clinically diagnosed and genetically confirmed patients living with FCS.
REDEMPLO is designed to suppress the production of apolipoprotein C-III (APOC3), a protein produced in the liver that raises triglyceride levels by slowing their breakdown and clearance. By targeting APOC3 with sustained silencing, REDEMPLO delivers significant reductions in triglyceride levels. REDEMPLO is self-administered via subcutaneous injection once every three months.
REDEMPLO has been granted Orphan Medicinal Product Designation by the EMA for the treatment of patients with FCS, and Breakthrough Therapy Designation, Fast Track Designation, and Orphan Drug Designation by the U.S. FDA for the treatment of patients with FCS and was also granted Breakthrough Therapy designation by the U.S. FDA in severe hypertriglyceridemia.
Sanofi acquired the rights to develop and commercialize REDEMPLO in Greater China, with Arrowhead retaining rights to REDEMPLO in all geographies, outside of Greater China.
About Arrowhead Pharmaceuticals
Arrowhead Pharmaceuticals (NASDAQ: ARWR) is a commercial-stage pharmaceutical company developing medicines that treat intractable diseases by silencing the genes that cause them, harnessing the natural RNA interference (RNAi) mechanism. The company has built a broad portfolio of clinical and commercial RNAi therapeutics through its industry-leading targeted RNAi molecule (TRiM™) platform, which can precisely silence genes in a wide range of cell types, including liver, lung, muscle, adipose, and central nervous system tissue. At Arrowhead, we rapidly advance potential best- and first-in-class RNAi treatments for diseases with significant unmet medical need, because every day matters to the patients we serve.