August 31, 2026
2 min read
Key takeaways:
- Plozasiran reduced triglycerides by up to 81% in patients with severe hypertriglyceridemia.
- Plozasiran prevented events of acute pancreatitis compared with placebo and was well-tolerated.
MUNICH — In patients with severe hypertriglyceridemia, plozasiran was well-tolerated, reduced triglycerides by up to 81% and prevented acute pancreatitis events compared with placebo, a speaker reported.
“Severe hypertriglyceridemia is probably one of the largest gaps in the management of lipid disorders. Above 5 mmol/L is a gateway for all sorts of conditions that preventative cardiologists [and] diabetologists have difficulty accessing and treating because the treatments are not very effective,” Gerald F. Watts, DSc, MD, PhD, FRCP, FRACP, FCSANZ, Winthrop Professor of Cardiometabolic Medicine at the University of Western Australia in Perth, said during a press conference at the European Society of Cardiology Congress. “But we now have a great opportunity through gene silencing therapy to lower these triglyceride levels incremental to diet and background treatment by a very large extent.”
Plozasiran reduced triglycerides by up to 81% in patients with severe hypertriglyceridemia. Image: Adobe Stock
In the prior phase 2 trial, researchers enrolled 229 patients with severe hypertriglyceridemia and randomly assigned them plozasiran (Redemplo, Arrowhead) or placebo and evaluated percent change in fasting triglycerides over time. Plozasiran is FDA-approved for reduction of triglyceride levels in patients with familial chylomicronemia syndrome but is not yet approved for treatment of patients with severe hypertriglyceridemia.
A Healio previously reported, plozasiran durably reduced triglycerides, apolipoprotein C-III and remnant cholesterol in patients with severe hypertriglyceridemia out to 48 weeks, which propelled further study of the medication.
SHASTA-3, which included 446 patients, and SHASTA-4, which included 311 patients, were multicenter, double-blind, randomized, placebo-controlled trials, in which researchers evaluated the efficacy and safety of plozasiran 25 mg in adults with severe hypertriglyceridemia. Participants were randomly assigned plozasiran or placebo, which were both administered once every 3 months for 1 year. The studies were simultaneously published in The New England Journal of Medicine.
The trials were designed identically, and there were two of them because of a request by the FDA, Watts said during the press conference.
Participants were asked to maintain a stable low-fat diet and also received standard lipid- and triglyceride-lowering therapies, according to the study methods.
The primary outcome was percent change in fasting serum triglycerides from baseline to 12 months.
The researchers observed significant reductions in triglycerides as early as 3 months into the trial, which were sustained out to 1 year, with an average median reduction of 79% in SHASTA-3 and 81% in SHASTA-4 (P for all time points < .0001)
Pooled data from both trials showed that plozasiran reduced frequency of acute pancreatitis events at 1 year (rate ratio = 0.22; 95% CI, 0.07-0.67; P = .008; number needed to treat to prevent one event at 1 year = 24), as well as time to first pancreatitis event compared with placebo (182 days vs. 283 days; HR = 0.26; 95% CI, 0.09-0.78; P = .016), according to the presentation.
The researchers reported plozasiran showed a favorable safety and tolerability profile that was consistent with prior studies.
“The treatment-emergent adverse effects with discontinuation were low, 1.2%, because it was well tolerated. Similar between groups, no cases of anaphylaxis or hypersensitivity. Worsening glycemic control in 14% [of the plozasiran group] compared with 9% [of the placebo group]. But that was not a primary endpoint,” Watts said during the press conference. “No clinically meaningful changes in platelet count, which was a problem with these [small interfering RNA agents]overcome now by ligand conjugation. No elevation in liver enzymes, and no statistically significant treatment emergent increases in hepatic fat.
“These studies are important. They are consistent with other findings, and after incorporation into clinical guidelines and regulatory approval, it will have a major impact in changing clinical practice,” Watts said.
Sources/Disclosures
Source:
Watts GF, et al. Hot line 9. Presented at: European Society of Cardiology Congress; Aug. 28-31, 2026; Munich.
Disclosures:
Watts reports receiving grants and/or honoraria from Amgen, Arrowhead, AstraZeneca, CSL Seqirus, Esperion, Novartis, Novo Nordisk, Pfizer, Sanofi/Regeneron and Silence Therapeutics. The studies were funded by Arrowhead.
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