Plozasiran may be a promising therapy for patients across the sHTG spectrum.In the SHASTA-3 and SHASTA-4 trials, quarterly administration of plozasiran reduced triglyceride (TG) levels and acute pancreatitis (AP) events in individuals with severe hypertriglyceridaemia (sHTG; TG ≥500 mg/dL).
In both trials, the TG reductions with plozasiran at month 3 were sustained across the other timepoints (p<0.0001 for all). By month 12, the median percent change from baseline (%CFB) was substantially greater with plozasiran than with placebo (~80 percent vs ~27 percent; p<0.0001). [Watts, G, et al, ESC 2026]
Other lipid parameters that decreased with plozasiran at month 12 were remnant-C (median %CFB, SHASTA-3: 72 percent; SHASTA-4: 76 percent), non–HDL-C (median %CFB, 28 percent and 38 percent, respectively), and APOC3 (median %CFB, 82 percent and 84 percent; p<0.001 for all). In patients with baseline TG ≥880 mg/dL, plozasiran reduced TG levels by 85 percent in both trials.
Over 90 percent of participants on plozasiran achieved TG <500 mg/dL; with placebo, only 50 percent achieved this endpoint (odds ratios [ORs], 8.2 and 9.4 for SHASTA-3 and SHASTA-4, respectively). Similarly, more plozasiran vs placebo recipients achieved TG <150 mg/dL (SHASTA-3: 52 percent vs 8 percent; OR, 12; SHASTA-4: 55 percent vs 2 percent; OR, 52; p<0.0001 for all).
Reduced acute pancreatitis risk
There was also a commensurate reduction in AP frequency (absolute risk reduction [ARR], 4.1 percent; risk ratio [RR], 0.22; p=0.008) and a longer time to first adjudicated AP event (median, 283 vs 182 days; hazard ratio, 0.26; p=0.016) with plozasiran vs placebo.
This effect was similarly observed in patients with TG ≥500 mg/dL + history of AP (ARR, 34 percent; RR, 0.09; p=0.02). “In the highest risk subgroup (TG ≥880 mg/dL + history of AP), plozasiran reduced the AP event rate by 100 percent,” noted Prof Gerald Watts from the University of Western Australia, Perth, Australia, at ESC 2026.
Prof Gerald Watts from the University of Western Australia, Perth, Australia, presenting the results of the SHASTA-3 and SHASTA-4 trials at ESC 2026.Safety profile
Approximately three-quarters of participants reported treatment-emergent adverse events (TEAEs) in both plozasiran and placebo groups, the most common being worsening glycaemic control (14 percent and 8.7 percent), diarrhoea (5.6 percent vs 3.2 percent), and abdominal pain (2.6 percent and 6.7 percent). The rates of TEAEs leading to discontinuation were low (1.4 percent and 0.8 percent).
There were no reports of anaphylaxis or hypersensitivity, no clinically meaningful changes in platelet counts, and no significant increase in liver fat with plozasiran at month 12 (mean CFB, 1 percent; p=0.70). There were also no meaningful ALT/AST elevations with plozasiran vs placebo, with no cases meeting Hy’s law criteria, and no worsening of HbA1c over time.
APOC3: A validated therapeutic target
“Despite lifestyle changes and current lipid-lowering therapies, many sHTG patients do not achieve treatment goals (TG ≤500 mg/dL) and remain at high risk of AP,” Watts said.
Plozasiran, a hepatocyte-targeted small interfering RNA, reduces the synthesis of hepatic APOC3, a key regulator of TG-rich lipoprotein metabolism and a genetically validated therapeutic target. [Cardiovasc Res 2024;119:2843-2857]
The pooled SHASTA cohort comprised 757 participants (mean age 52 years, 77 percent men) who were randomized 2:1 to SC plozasiran 25 mg or placebo Q3M for 12 months. One in five participants had a history of AP, and one-third had TG ≥880 mg/dL.
The most frequently used TG-lowering treatments were fibrates (SHASTA-3: 62 percent; SHASTA-4: 57 percent), while the most common lipid-lowering therapies were statins (66 percent and 73 percent, respectively).
“[These results] build on the positive results from other plozasiran trials across various patient populations, including those with familial chylomicronaemia syndrome—the most severe form of HTG,” noted Watts in the ESC press release.
“These findings highlight the potential of plozasiran as a promising therapy for patients across the spectrum of sHTG [and] support the value of APOC3-targeted therapy with plozasiran for preventing AP in sHTG,” Watts concluded.