Take Home Message
Two newly published manuscripts in the New England Journal of Medicine (N Engl J Med) support the efficacy of reducing triglyceride levels with two new drugs in the treatment of Familial Combined Hyperlipidemia (FCH). These two phase 2 trials, ARCHES-2 and MIUR, separately investigate the impact of inhibiting two different proteins, ANGPTL3 and APOC3, in reducing triglyceride levels. Both trials reached similar results for safety and efficacy, speculating that the combination of these two treatments could lead to groundbreaking results, reducing the residual risk of atherosclerotic cardiovascular disease in FCH patients.
Background
Familial Combined Hyperlipidemia (FCH), or mixed hyperlipidemia, is a common lipid disorder with an hereditary component. It is characterized by elevated levels of circulating lipids such as cholesterol, triglycerides, LDL cholesterol, ApoB-containing lipoproteins, and low HDL cholesterol. This disease mainly results from two pathways: increased production of ApoB-containing lipoproteins by the liver (LDL and VLDL) with reduced peripheral lipoprotein metabolism. Due to its polygenic inheritance, many genes are involved, and mutations in different genes have been highlighted over the years. Among these genes, LDLr is one of the main ones affected, but other genes, such as Lipoprotein Lipase (LPL), also play a clear role in disease’s development. While LDLR is involved in the uptake of circulating lipoproteins by the liver (mainly cholesterol), LPL is involved in the lysis of triglycerides from lipoproteins, mediating their release to peripheral organs for use as metabolic substrates. In this context, two proteins play key roles as inhibitors of LPL and endothelial lipase (EL): Angiopoietin-like 3 (ANGPTL3) and Apolipoprotein C3 (ApoC3). The role of ANGPTL3 and ApoC3 in LPL functionality was evident from GWAS studies showing an association between genetic polymorphisms and circulating triglycerides. This evidence led to the development of many pharmacological approaches targeting ANGPTL3, including ASOs and monoclonal antibodies. Both ANGPTL3 and APOC3 are selectively expressed by the liver, making their expression relatively easy to target with silencing RNA (siRNA). Both Zoldasiran (ARO-ANG3) and Plozasiran are newly investigated drugs that can selectively target hepatic ANGPTL3 and APOC3 in the liver, thanks to the addition of N-acetylgalactosamine (NAG). The results of the phase 2 trials have been simultaneously published in the New England Journal of Medicine (N Engl J Med).
Summary of the Findings
The phase 2b trial (ARCHES-2) was a multicentric, double-blind, randomized, placebo-controlled clinical trial that enrolled patients with mixed hyperlipidemia. The study showed that Zoldasiran treatment at the highest dosage of 200 mg resulted in a significant reduction in triglycerides of 63.1% at 24 weeks and 51.2% at 36 weeks. The authors also highlighted a significant reduction in other atherogenic lipoproteins, such as LDL cholesterol, with a reduction of 20% at the highest dose at 24 weeks. Additionally, Zoldasiran, compared to Vupanorsen, an antisense oligonucleotide (ASO), did not lead to an increase in liver fat content or serum aminotransferase levels.
Similarly, the MIUR trial was a multicentric, double-blind, randomized, placebo-controlled clinical trial that enrolled patients with mixed hyperlipidemia. In line with the ARCHES-2 study, Plozasiran led to a significant decrease in triglyceride levels of 62.4% with the 50 mg quarterly dose at 24 weeks.
Novelty of the Results in the Field
As further highlighted by the authors of both manuscripts, the use of Zoldasiran and Plozasiran is groundbreaking news for the treatment of mixed hyperlipidemia. The authors suggest that FCH patients may now be treated with Zoldasiran and Plozasiran together, potentially reducing the residual risk of atherosclerotic cardiovascular disease in FCH patients who have reached their LDL cholesterol goal.
https://www.nejm.org/doi/full/10.1056/NEJMoa2404147
https://www.nejm.org/doi/full/10.1056/NEJMoa2404143
By: Lorenzo Da Dalt