ESPE Yearbook of Paediatric Endocrinology

New England Journal of Medicine 391, 899-912 (2024). doi: 10.1056/NEJMoa2404143

Brief Summary: This double-blind, randomized trial evaluated the safety and efficacy of plozasiran, a small interfering RNA (siRNA) that reduces hepatic expression of APOC3, in adults with mixed hyperlipidemia.

Comment: Mixed hyperlipidemia is marked by elevated levels of both low-density lipoprotein (LDL) cholesterol, triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol. It affects an estimated 0.5% to 4% of the population and is associated with increased risk of developing atherosclerosis cardiovascular disease (ASCVD). 1 Triglycerides serve as a surrogate marker for atherogenic triglyceride-rich lipoproteins (TRLs), including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and chylomicron remnants. These TRLs carry up to 4-times more cholesterol per particle than LDL, contributing significantly to ASCVD risk, even in patients receiving LDL-lowering therapy. Despite its prevalence and potential health consequences, it is often underdiagnosed and undertreated.

Apolipoprotein C-III (APOC3), a glycoprotein produced primarily in the liver, is present on most major lipoproteins, including chylomicrons, VLDL, LDL, HDL, and lipoprotein(a). 2 It plays a central role in lipid metabolism by inhibiting lipoprotein lipase activity and decreasing hepatic uptake of TRLs. This leads to elevated circulating levels of triglycerides and TRLs. Conversely, APOC3 loss-of-function variants are associated with lower triglyceride levels, a 40% reduction in ASCVD risk, and increased longevity.

RNA interference (RNAi) is a natural cellular mechanism that regulates gene expression after transcription. Discovered in the late 1990s by Andrew Fire and Craig Mello, RNAi reshaped our understanding of how genes are controlled.3 Small interfering RNAs (siRNAs), typically 21–23 nucleotides long and double-stranded, are engineered to match specific mRNA sequences. Once inside the cell, siRNAs trigger the formation of RNA-induced silencing complexes (RISCs), which bind to the target mRNA and promote its degradation, thereby blocking the production of disease-related proteins.

Plozasiran is a small interfering RNA (siRNA) specifically designed to reduce hepatic expression of APOC3. Plozasiran was evaluated in 353 adults with mixed hyperlipidemia who were already on stable statin therapy. Three groups received plozasiran injections every three months (10, 25, or 50 mg), while a fourth group received 50 mg every six months. Placebo injections matched each dosing schedule for comparison. By week 24, plozasiran significantly lowered fasting triglyceride levels in all dosing groups, albeit with some worsening of glycemic control. Importantly, these effects were sustained through week 48, 36 weeks after the final dose. Considering both efficacy and the risk of glycemic deterioration, the 25 mg quarterly dose was selected, as it provided substantial triglyceride reduction with the lowest rate (7%) of glycemic worsening.

References: 1. Brouwers MCGJ, Klop B, Ribalta J, Castro Cabezas M. Familial Combined Hyperlipidemia: Myth or Reality? CurrAtheroscler Rep. 2025 Apr 1;27(1):45. doi: 10.1007/s11883-025-01289-9. PMID: 40167575; PMCID: PMC11961474.2. Maidman SD, Hegele RA, Rosenson RS. The Emerging Potential of Apolipoprotein C-III Inhibition for ASCVD Prevention: A State-of-the-Art Review. CurrAtheroscler Rep. 2024 Nov 14;27(1):3. doi: 10.1007/s11883-024-01258-8. PMID: 39541062.3. Ebenezer O, Oyebamiji AK, Olanlokun JO, Tuszynski JA, Wong GK. Recent Update on siRNA Therapeutics. Int J Mol Sci. 2025 Apr 8;26(8):3456. doi: 10.3390/ijms26083456. PMID: 40331977; PMCID: PMC12026779.