Introduction
Lowering Triglycerides Through Targeting the Anabolism and/or Catabolism of Lipoproteins
Target | Drug & mode of action | Phase of development | Targeted populations | Average reduction in plasma TG levels from baseline | References |
---|---|---|---|---|---|
APOC3 | Volanesorsen ASO to block ApoC-III synthesis Conditionally approved by EMA for FCS in 2019 | Phase 3 (NCT02211209) | FCS (N = 66; fasting TG ≥ 750 mg/dL) | -77% (after 13 weeks) | Witztum et al. (2019) [20] |
Phase 3 (NCT02300233) | Severe hypertriglyceridemia (N = 86; fasting TG ≥ 500 mg/dL) | -71% (after 13 weeks) | Gouni-Berthold et al. (2021) [19] | ||
AKCEA-APOCIII-LRx* ASO to block ApoC-III synthesis | Phase 3 (NCT04568434) | FCS (N = 60) | Completed in June 2023 | NCT04568434 | |
Phase 2 (NCT03385239) | Hypertriglyceridemia and established CVD (N = 114; fasting TG 200–500 mg/dL) | -62% [50 mg] (after 6 months) | Ionis pharmaceuticals (2020) [23•] | ||
Phase 1/2a (NCT02900027) | Healthy volunteers with elevated TGs (N = 16; fasting TG ≥ 200 mg/dL) | -73% to -77% [90–120 mg] (after 14 days) | Alexander et al. (2019) [22] | ||
ARO-APOC3* siRNAs to block ApoC-III synthesis | Phase 3 | FCS | Expected to start in 2021 | A) Arrowhead pharmaceuticals (2021) [26] | |
Phase 2b | Mixed dyslipidaemia | Expected to start in 2021 | Arrowhead pharmaceuticals (2021) [26] | ||
Phase 2b (NCT04720534) | Severe hypertriglyceridemia (N = 300; fasting TG ≥ 500 mg/dL) | Completed in July 2022 | Arrowhead pharmaceuticals (2021) [26] NCT04720534 | ||
Phase 1/2a (NCT03783377) | Healthy volunteers (n = 40; fasting TG ≥ 80 mg/dL) and Severe hypertriglyceridemia (n = 3; fasting TG ≥ 300 mg/dL)** | Healthy volunteers: -53% to -64% [10–100 mg] (after 4 weeks); Severe hypertriglyceridaemic patients: -95% [50 mg] (after 29 days) | Ballantyne (2020) [25], Arrowhead pharmaceuticals (2020) [27••] | ||
STT-5058 Monoclonal antibody targets ApoC-III in plasma | Phase 1 (NCT04419688) | Healthy volunteers (N = 104; fasting TG ≥ 70 mg/dL to ≤ 400 mg/dL) | Completed in May 2021 | NCT04419688 | |
ANGPTL3 | Evinacumab Monoclonal antibody targets ANGPTL3 in plasma FDA approved for HoFH in 2021 | Phase 3 (NCT03399786) | HoFH (N = 65; Median baseline TGs = 91 mg/dL) | -55% (after 24 weeks) | Raal et al. (2020) [34•] |
Phase 2 (NCT04863014) | Severe Hypertriglyceridemia (n = 120; fasting TG > 880 mg/dL) | Expected to start in 2021 | NCT04863014 | ||
Phase 2 (NCT03452228) | Severe Hypertriglyceridemia (n = 51; fasting TG at screening ≥ 500 mg/dL and history of fasting TG ≥ 1000 mg/dL of more than 1 occasion | -57% (after 12 weeks) | Rosenson et al. (2021) [35••] | ||
Phase 2 (NCT02265952) | HoFH (N = 9) | -47% (after 4 weeks) | Gaudet et al. (2017) [33] | ||
IONIS-ANGPTL3-LRx* ASO to block ANGPTL3 synthesis | Phase 2b (NCT04516291) | Dyslipidaemia, Hyperlipidaemia, Hyperlipoproteinemia (N = 260; fasting TG ≥ 150 to ≤ 500 mg/dL; fasting non-HDL-C ≥ 100 mg/dL) | Completed in 2022 | NCT04516291 | |
Phase 2 (NCT03371355) | Hypertriglyceridemia, T2DM and NAFLD (N = 105; fasting TG ≥ 150 mg/dL) | -36% to -53% [20–80 mg] (after 27 weeks) | Gaudet et al. (2020) [37•], | ||
Phase 1 (NCT02709850) | Healthy volunteers (N = 44; fasting TG 90–150 or ≥ 150 mg/dL) | -33% to -63% [10–60 mg] (after 6 weeks) | Graham et al. (2017) [36] | ||
ARO-ANG3* SiRNAs to block ANGPTL3 synthesis | Phase 2b (NCT04832971) | Dyslipidaemia, FCS, Hypertriglyceri-demia (N = 180; fasting TG ≥ 150 mg/dL to ≤ 500 mg/dL; LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL) | Completed in May 2021 | NCT04832971 | |
Phase 1 (NCT03747224) | Healthy volunteers (n = 40) and Severe hypertriglyceridemia (n = 5)** | Healthy volunteers: -47% to -53% [35–200 mg] (after 8 weeks) Severe hypertriglyceridemic patients: -79% [200 mg] (after 29 days) | |||
DGAT1 | Pradigastat DGAT1 inhibitor | Phase 3 (NCT01589237) | FCS (N = 38) | Prematurely terminated in 2015*** | NCT01589237 |
Phase 2 (NCT04620161) | Functional constipation (N = 180) | Completed in May 2022 | NCT04620161 | ||
Phase 2 (NCT01474434) | CAD and hypertriglyceridemia (N = 41) | Prematurely terminated in 2014*** | NCT01474434 | ||
Phase 2 (NCT01146522) | FCS (N = 8) | -41% to -70% [20–40 mg] (after 3 weeks) | Meyers et al. (2015) [46] | ||
FGF21 | BIO89-100 GlycoPEGylated analog of FGF21 | Phase 2b/3 | Fibrosis stage 2 or 3 NASH | Expected to start in 2021 | 89BIO (2021) [50] |
Phase 2 (NCT04541186) | Severe hypertriglyceridemia (N = 90; fasting TG ≥ 500 mg/dL and ≤ 2000 mg/dL) | Completed in November 2021 | NCT04541186 | ||
Phase 1b/2a (NCT04048135) | NAFLD patients at high risk of NASH or and NASH patients (N = 71) | -18% to -28% [3–36 mg] In subgroup with baseline TG ≥ 200 mg/dL) (-33% to -49% [3–36 mg] (after 13 weeks) | Frias et al. (2021) [49••] | ||
Phase 1a | Healthy volunteers (N = 46) | -33 to -51% [9–78 mg] (after 8 days) | 89BIO (2020) [48] |
APOC3 Antagonists
ANGPTL3 Antagonists
Alternative Options to Lowering Triglycerides
Gene Therapy
DGAT1 Inhibition
FGF21
Conclusions and Perspectives
Target | Drug | Route of administration | Drug use regimen / Duration of intervention | Notes | Pricing (May, 2021) | Reference |
---|---|---|---|---|---|---|
APOC3 | Volanesorsen ASO | Subcutaneous injection | Weekly / maximum of 52 weeks tested | Combined with dietary interventions Side effects: injection site reactions, thrombocytopenia, immunogenicity | €903.819,80 patient/year (the Netherlands) [53] | Witztum et al. (2019) [20] |
AKCEA-APOC3-LRx GalNac-ASO | Subcutaneous injection | Weekly, biweekly or monthly / maximum of 52 weeks tested | Side effects: mild injection site reactions | n.a | ||
ARO-APOC3 siRNA | Subcutaneous injection | Single injection / 16 weeks tested | Side effects: mild injection site reactions, moderate transient ALT elevation | n.a | ||
STT-5058 mAb | Intravenous injection | Biweekly, 3–6 doses in total / maximum of 14 weeks tested | Still recruiting | n.a | NCT04419688 | |
ANGPTL3 | Evinacumab mAb | Intravenous injection | Monthly / maximum of 24 weeks tested | Combined with existing lipid-lowering regimens* Side effects: nasopharyngitis, influenza-like illness, dizziness, rhinorrhoea, and nausea. May cause harm to fetus | $450,000 patient/year (USA) [54] | Raal et al. (2020) [34•] |
IONIS-ANGPTL3_LRx GalNAc-ASO | Subcutaneous injection | Monthly / maximum of 27 weeks tested | Side effects: mild injection site reactions, dizziness, headache | n.a | ||
ARO-ANG3 siRNA | Subcutaneous injection | Single injection / 16 weeks tested | Side effects: mild injection site reactions, mild transient ALT elevations | n.a | ||
DGAT1 | Pradigastat DGAT1 inhibitor | Oral administration | Daily / 3 weeks tested | 2 trials were terminated based on interim results (no details available) Side effects: mild, transient gastrointestinal adverse events | €396.396 patient/year (the Netherlands) [55] | Meyers et al. (2015) [46] |
FGF21 | BIO89-100 FGF21 analog | Subcutaneous injection | Biweekly / 12 weeks tested | Side effects: mild injection site reactions and headache | n.a | Frias et al. (2021) [49••] |