FCS ― FCS is a rare genetic disorder (estimated prevalence 1-2 cases per million persons) in which impaired lipoprotein lipase function causes severe hypertriglyceridemia and pancreatitis. Before approval of olezarsen and plozasiran, treatment of FCS was limited to a low-fat diet and exercise. Genetic testing for FCS is available, but it is not routinely performed.

MECHANISM OF ACTION ― ApoC-III, which is synthesized primarily in the liver, increases plasma triglyceride levels by inhibiting lipoprotein lipase and reducing hepatic clearance of triglyceride-rich lipoproteins. Plozasiran is a chemically modified siRNA that binds to apoC-III mRNA in hepatocytes, leading to mRNA degradation, a reduction in apoC-III protein synthesis, and increased clearance of serum triglycerides.

CLINICAL STUDIES ― FDA approval of plozasiran was based on the results of a double-blind trial (PALISADE) in 75 adults with FCS and fasting triglyceride levels ≥1000 mg/dL. Patients were randomized to receive plozasiran 25 mg, plozasiran 50 mg (not an FDA-approved dose), or placebo subcutaneously once every 3 months for 12 months in addition to a low-fat diet. Median reductions from baseline in fasting triglyceride levels at 10 months, the primary endpoint, were significantly greater with both doses of plozasiran than with placebo (-80% with the 25-mg dose and -78% with the 50-mg dose vs -17% with placebo). Plozasiran also reduced apoC-III and non-high-density lipoprotein cholesterol levels. Acute pancreatitis occurred in 2 patients who received plozasiran and in 7 of those who received placebo.2

No trials directly comparing plozasiran with olezarsen are available. In a double-blind trial, the mean reduction from baseline in triglyceride levels at 6 months with olezarsen 80 mg SC every 4 weeks was 30% (vs +12% with placebo). At 53 weeks, 11 cases of acute pancreatitis had been reported in the placebo group compared to one in the olezarsen group.1,3

ADVERSE EFFECTS ― The most common adverse effects (frequency ≥10%) of plozasiran in clinical trials were hyperglycemia, headache, nausea, and injection-site reactions. Increases in liver enzymes within the normal range were observed. Reduced platelet counts, which can occur with olezarsen, have not been reported to date with plozasiran.

PREGNANCY AND LACTATION ― No data are available on the safety of plozasiran use in women who are pregnant or breastfeeding. In animal studies, administration of plozasiran during organogenesis was not associated with adverse pregnancy outcomes.

DOSAGE, ADMINISTRATION, AND COST ― Redemplo is supplied in single-dose prefilled syringes containing 25 mg of plozasiran in 0.5 mL of solution. The recommended dosage is 25 mg injected subcutaneously once every 3 months (olezarsen is supplied in autoinjectors for once-monthly SC administration). The cost for one year of treatment is about $60,0004 with Redemplo and about $40,000 (according to the manufacturer) with Tryngolza.

CONCLUSION ― In one small clinical trial in patients with familial chylomicronemia syndrome (FCS), subcutaneous administration of plozasiran (Redemplo) once every 3 months significantly reduced triglyceride levels and the risk of acute pancreatitis. Plozasiran has not been compared directly with olezarsen (Tryngolza), which is given once monthly.

REFERENCES