Key Points:
- Familial chylomicronemia syndrome (FCS) is a clinically or genetically defined syndrome of extremely high plasma triglycerides due to failure of clearance of chylomicrons
- A novel siRNA therapeutic, plozasiran, is hypothesized to treat FCS by targeting the main regulator implicated in FCS, APOC3, which precipitates persistent chylomicronemia by inhibiting lipolysis and decreasing hepatic clearance of triglyceride-rich lipoproteins (TRLs)
- The investigators randomized groups to low-dose or high-dose plozasiran vs placebo to investigate primary outcome of median percent change in triglycerides at 10 months, as well as notable secondary outcomes, including overall reduction in triglycerides and APOC3 as well as reduced risk of pancreatitis
- Plozasiran, compared to placebo, met all clinical endpoints, including significant reductions in triglycerides, APOC3, and reduced risk of pancreatitis, with a favorable safety profile
Persistent chylomicronemia is a clinical syndrome of an extremely high plasma level of triglycerides (>10 mmol/L or > 880 mg/dL). This is 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 more common genetic variants that impair the lipolytic enzyme, lipoprotein lipase (LPL). Chylomicronemia causes multiple symptoms, most severely acute pancreatitis, and current therapeutic agents (fibrates, n-3 fatty acids, statins, and niacin) are generally ineffective.
Plozasiran (ARO-APOC3) is an investigational siRNA therapeutic that targets APOC3, a major regulator of triglycerides (TGs) and triglyceride-rich lipoproteins (TRLs). APOC3 inhibits lipolysis and hepatic clearance of TRLs, thereby increasing triglycerides in the circulation. Plozasiran silences APOC3, thereby enhancing lipolysis, increasing hepatic clearance of TRLs, and overall reducing TGs in the circulation. The PALISADE trial aimed to determine the efficacy of this therapy based on this known mechanism.
The PALISADE trial randomized a total of 75 patients, 25 patients to placebo, 26 patients to plozasiran 25mg, and 24 patients to plozasiran 50mg every three months after screening with diet, medications, and lab values less than 8 weeks before randomization. Enrollment was limited to patients with clinical criteria and/or genetic confirmation of familial chylomicronemia syndrome (FCS). Genetic testing was done on all patients without prior testing for FCS genetic variants. The primary endpoint was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary endpoints included percent change in fasting triglycerides at months 10 and 12, percent changes in fasting APOC3 at months 10 and month 12, and incidence of acute pancreatitis.
Patient characteristics were overall well-balanced between groups. Average age was 47 (SD 11) in the placebo group, 48 (SD 14) in the 25mg group, and 43 (SD 11) in the 50mg group. Mean BMI was normal between groups (25 [SD 4] vs 26 [SD 4] vs 25 [SD 5])) and mean triglycerides were in the mid-2000s across groups, even though nearly half of patients across groups were on statin therapy. Lastly, nearly a quarter of all patients included had a prior episode of pancreatitis.
The study found that plozasiran significantly reduced both median triglycerides and median APOC3 after 10 months and 12 months. Regarding median triglycerides, placebo showed a mean 17% decrease whereas plozasiran 25mg and 50mg showed an 80% decrease (p<0.0001) and 78% decrease (p=0.0002) at 10 months, respectively. Regarding median APOC3, placebo showed no change whereas plozasiran 25mg and 50mg showed a decrease of 93% (p<0.0001) and 96% (p<0.0001), respectively. The study authors also found that this effect started at one month and persisted through 12 months of treatment. Also of note, the study found that a higher proportion of patients reached target reduction in triglycerides below that of pancreatitis prevention: 21% of patients on placebo therapy reached triglycerides < 10 mmol/L (or 880 mg/dL) whereas 75% of patients on plozasiran 25mg and 55% of patients on plozasiran 50mg reached this therapeutic target. Furthermore, plozasiran reduced the incidence of acute pancreatitis: when pooling all included patients on plozasiran therapy, there was an 83% relative risk reduction in pancreatitis compared to placebo (OR 0.17 [95% CI: 0.03, 0.94]; p=0.029). Regarding adverse events, a higher proportion of placebo-treated patients experienced symptomatic adverse events (20 with placebo, compared to 23 with plozasiran 25mg and 20 with plozasiran 50mg) with fewer premature discontinuations with plozasiran (6 with placebo, compared with 3 with plozasiran 25mg and 2 with plozasiran 50mg).
Ultimately, the study found that quarterly-dosed plozasiran met all trial endpoints, with significant reductions in triglycerides 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. Furthermore, plozasiran significantly reduced rates of acute pancreatitis at 12 months with a favorable tolerability profile compared to placebo. The study authors argue that this demonstrates that plozasiran is a safe and efficacious novel therapeutic candidate to reduce plasma TG levels, and therefore, reduce risk of acute pancreatitis in patients with persistent chylomicronemia.