Table 8.
Novel pharmacotherapeutic agents for severe hypertriglyceridaemia.
| Drug | Mechanism of Action | Effect on TG | Phase of Development | Comments |
|---|---|---|---|---|
| Approved Pharmacotherapies | ||||
| Volanesorsen (ISIS-ApoCIIIRx) |
ASO against hepatic ApoC3 | 50–70% reduction | Approved by EMA and NICE for use in FCS in 2019. | Thrombocytopenia remains a predominant side effect requiring close monitoring. Not advisable to start if the platelet count is <140 × 109/L. |
| Lomitapide * | MTP inhibitor | Up to 70% reduction | Approved by EMA in 2013 for HoFH. | Individual case reports of the progression of steatohepatitis to fibrosis occurred after 10 years of treatment. |
| Pharmacotherapies in development | ||||
| Olezarcen (AKCEA ApoCIII-LRx) |
GalNAc3 conjugated ASO against hepatic ApoC3 | 70% reduction | First Phase III trial is expected to be completed in 2023. | Targets the ASGPR in hepatocytes with similar efficacy as compared to native ASO with 20–30-fold lower dose, therefore minimizing side effects including thrombocytopenia. |
| Evinacumab | Monoclonal antibody against ANGPTL3 | 55% reduction | Phase II trial for SHTG and AP expected to be completed in 2023. | Reduces LDL cholesterol by 47% and was approved by EMA for use in HoFH in 2019. |
| ARO ApoCIII | siRNA against ApoC3 | 40–70% reduction | Phase II trial is expected to be completed in 2023. | In phase I, along with TG reduction, a dose-dependent increase in HDL (40–80%) was also observed. |
| ARO-ANG3 | siRNA against ANGPTL3 | Up to 66% reduction | Phase II trial is expected to be completed in 2024. - |
|
| STT-5058 | Monoclonal antibody against ApoC3 | - | Phase I trial was expected to be completed in December 2022—no updates at the time of writing. | |
| Others, Suspended therapies | ||||
| Alipogene Tiparvovec (Glybera) |
Gene replacement | 40–60% reduction initially. | Approved by EMA in 2012 for clinical use but withdrawn from the market owing to poor commercial prospects in 2017. | Sustained gene expression and reduced risk of pancreatitis despite the transient effect on hypertriglyceridaemia. |
| Vupanorsen (AKCEA-ANGPTL3-LRx) | ASO against ANGPTL3 | 50–60% reduction | Development halted in 2022 after a review of the Phase 2b (TRANSLATE-TIMI) study. | Data from the Phase 2b trial did not support the clinical development of the drug for CV risk reduction or SHTG. It was also associated with dose-dependent hepatotoxicity. |
| Pradigastat | DAGT inhibitor | 40% reduction | No updates since 2015. | |
* Not approved for FCS. ANGPTL 3: angiopoietin-like 3, SHTG: severe hypertriglyceridaemia; AP: acute pancreatitis; ASGPR: asialoglycoprotein receptors; ASO: antisense oligonucleotide; DAG: diacylglycerol transferase; EMA: European Medicine Agency; FCS: familial chylomicronaemia syndrome; GALNAc3: N-acetyl galactosamine; HoFH: homozygous familial hypercholesterolemia; MTP: microsomal triglyceride transfer protein; siRNA: small interfering RNA; TRANSLATE-TIMI: targeting ANGPTL3 with an antisense oligonucleotide in adults with dyslipidaemia.