Key Points:
- Familial chylomicronemia syndrome (FCS) is characterized by extremely high plasma triglycerides (TGs) due to failure of clearance of chylomicrons, of which the most severe sequela is acute pancreatitis (AP)
- The PALISADE trial investigated a novel siRNA therapeutic, plozasiran, hypothesized to treat FCS by targeting the main regulator implicated, APOC3, which precipitates persistent chylomicronemia by inhibiting lipolysis and decreasing hepatic clearance of triglyceride-rich lipoproteins (TRLs)
- The investigators previously randomized groups to low-dose or high-dose plozasiran vs placebo to investigate primary outcome of median percent change in TGs at 10 months, as well as notable secondary outcomes, including overall reduction in TGs and APOC3 as well as reduced risk of AP, finding that plozasiran met all clinical endpoints, including reduction in TGs, APOC3, and reduced risk of AP
- The authors now present the longer-term effects of therapy, noting rapid and significant (>80%) reductions in TGs and APOC3, independent of gene variants, as well as sustained reduction of TG levels below the threshold to prevent AP among >50% of included patients
Persistent chylomicronemia is defined by extremely high plasma level of triglycerides (> 880 mg/dL) due to failure of clearance of chylomicrons, the physiologic storage of consumed fat, from the circulation. The mechanism is thought to be from ultrarare bi-allelic recessive variants of the lipolytic enzyme, lipoprotein lipase (LPL), or more common genetic variants that impair triglyceride (TG) lipolysis. Chylomicronemia causes multiple symptoms, most severely acute pancreatitis (AP), and current therapeutic agents (fibrates, n-3 fatty acids, statins, and niacin) are generally ineffective.
Plozasiran (ARO-APOC3) is an investigational siRNA therapeutic targeting APOC3, a major TG and triglyceride-rich lipoprotein (TRL) regulator. APOC3 inhibits lipolysis and hepatic clearance of TRLs, thereby increasing triglycerides in the circulation. Plozasiran silences APOC3, enhancing lipolysis, increasing hepatic clearance of TRLs, and overall reducing TGs in the circulation. The PALISADE trial (ClinicalTrials.gov ID, NCT05089084) previously randomized 25 patients to placebo, 26 patients to plozasiran 25mg, and 24 patients to plozasiran 50mg every three months to investigate primary outcome of median percent change in TGs at 10 months, as well as notable secondary outcomes, including overall reduction in TGs and APOC3 as well as reduced risk of AP. The investigators found that plozasiran met all trial endpoints, with significant reductions in TGs among FCS patients at 10 months, achievement of TG treatment goals, and reductions in TG and APOC3 apparent at one month of treatment and sustained through at least 1 year. Notably, plozasiran also significantly reduced rates of AP at 12 months with a favorable tolerability profile compared to placebo. The authors now present the longer-term effects of low-dose plozasiran as well as the influence of genetics on response to therapy, and the proportion of included patients who achieved guideline-directed goal for lowering AP risk.
The investigators note a number of updated results. Plozasiran engendered quick, significant (>80%), and sustained reductions in ApoC3 and TG, independent of gene variant causing FCS. 75% of patients reached TGs < 800mg/dL, and 50% reached < 500mg/dL. No significant difference between reduction of TGs or APOC3 were observed in those with genetic confirmation of FCS and those without. In addition, plozasiran reduced the incidence of AP with time to experiencing an AP event occurring in 20% of placebo group versus 4% of the plozasiran group. Plozasiran demonstrated significantly lower total cholesterol (TC), non-HDL, and VLDL with increases in HDL and apolipoprotein-AI (ApoA-I) at 12 months. Lastly, plozasiran increased LDL concentration without changing concentration of ApoB or ApoB-100.
The authors discuss various implications of these new findings. First, the significant and sustained reductions in TG with plozasiran were closely related to reductions in ApoC3. Notably, these were independent of statin use, background TG-lowering therapy, and baseline ASCVD risk score. The authors suggest that the TG reductions may be due to better clearance due to restored LPL activity as well as hepatic clearance.
They also considered that plozasiran undoing repressed LPL may increase endogenous production of LDL from VLDL via intermediate density lipoprotein. A different hypothesis suggests that reduced TRL due to plozasiran decreases the cholesterol ester transfer protein-mediated exchange of TRL-TG for cholesterol esters in LDL, thereby leading to a net increase in LDL particle size. However, ultimately, the authors conclude that increased LDL is unlikely to have atherosclerotic implications for FCS patients due to very low baseline LDL and Apo-B100 concentrations.
Given these updated results in addition to the original PALISADE trial, the authors conclude the plozasiran demonstrates significant reduction in TG and APOC3 with sustained reduction in TGs below the threshold thought to cause AP for at least one year. The investigators conclude that given these results and its favorable safety profile, plozasiran is a promising therapy for FCS, and as such, is likely to prevent cases of pancreatitis.