Table 1. ASOs targeting apoCIII, apo(a), and ANGPTL3.
| Target | ApoCIII | Apo(a) | ANGPTL3 |
|---|---|---|---|
| Rationale for target identification | • Observational evidence | • Observational and genetic evidence | • Loss-of-function mutations in ANGPTL3 gene |
| • Loss-of-function mutations in APOC3 gene | • Mendelian randomization studies | ||
| Pharmacology | • Volanesorsen (ISIS 304801, ISIS-APOCIIIRx): weekly subcutaneous injection | • Pelacarsen (AKCEA-APO[a]LRx, IONIS-APO[a]LRx, TQJ230): GalNAc-conjugated ASO, subcutaneous injection, administration every 1 to 4 weeks | • Vupanorsen (AKCEA-ANGPTL3-LRx, IONIS-ANGPTL3-LRx, ISIS 703802): GalNAc-conjugated ASO, subcutaneous injection, administration every 1 to 4 weeks |
| • IONIS-APOCIII-LRx (AKCEA-APOCIII-LRx, ISIS 678354): GalNAc-conjugated volanesorsen, subcutaneous injection, administration every 1 to 4 weeks | |||
| Clinical trial results | • Volanesorsen: significant reductions in apoCIII and triglycerides (>70%) in hypertriglyceridemia and FCS | • Phase 1 and 2 trials: reduction of lipoprotein(a) by up to 80% | • Phase 1 trial of vupanorsen with reductions in triglyceride (47% to 85%) and LDL-C (1% to 33%) levels |
| • Volanesorsen: injection site reactions and thrombocytopenia in FCS | • Phase 2 study of vupanorsen in patients with hypertriglyceridemia, type 2 diabetes, and nonalcoholic fatty liver disease: reductions in triglyceride levels (36% to 47%) | ||
| • Volanesorsen: European Union approval in adult patients with FCS (2019) | |||
| • IONIS-APOCIII-LRx: significant reductions in apoCIII, triglycerides, and apoB in mild hypertriglyceridemia | |||
| <Ongoing> | <Ongoing> | ||
| • Phase 2/3 trial of volanesorsen in patients with hypertriglyceridemia and familial partial lipodystrophy (NCT02527343) | • A phase 3 trial of pelacarsen in patients with established ASCVD and Lp(a) levels of >70 mg/dL (NCT04023552) | ||
| • Phase 3 trial of IONIS-APOCIII-LRx in patients with FCS (NCT04568434) |
ASO, antisense oligonucleotide; apoCIII, apolipoprotein CIII; apo(a), apolipoprotein(a); ANGPTL3, angiopoietin-like protein 3; GalNAc, N-acetyl galactosamine; FCS, familial chylomicronemia syndrome; apoB, apolipoprotein B; LDL-C, low-density lipoprotein cholesterol; ASCVD, atherosclerotic cardiovascular disease; Lp(a), lipoprotein(a).