Evinacumab
Details
Evinacumab (REGN1500) is a fully human monoclonal antibody targeting ANGPTL3, developed using the VelocImmune platform (replacement of 6 Mb of murine immunoglobulin genes with human counterparts). It inhibits ANGPTL3 protein function, preventing LPL and endothelial lipase inhibition, thereby reducing TG and LDL-C through a mechanism independent of the LDL receptor.
Key Facts
- Drug class: Anti-ANGPTL3 fully human monoclonal antibody
- Mechanism: Binds and inhibits ANGPTL3 → restores LPL + endothelial lipase activity → reduces TG and LDL-C; LDL-C lowering is LDLR-independent (via EL-dependent VLDL clearance pathway) (sources/angptl3-inhibition-tcm-2024 — high)
- FDA approval (2021): Adjunct therapy for adults and children ≥12 years with homozygous familial hypercholesterolemia (HoFH) on maximum tolerated lipid-lowering therapy; IV 15 mg/kg every 4 weeks (sources/angptl3-inhibition-tcm-2024 — high)
- EMA approval: Identical indications in Europe (sources/angptl3-inhibition-tcm-2024 — high)
Phase 3 Clinical Efficacy (Raal et al.; n=65; HoFH; 24 weeks)
- LDL-C: −47% (placebo: −3.8% to +16.2% depending on LDLR genotype)
- TG: −55%
- Null-null LDLR: −43.4% LDL-C; non-null: −49.1% — LDLR-independent effect confirmed across all LDLR genotypes (sources/angptl3-inhibition-tcm-2024 — high)
- No serious adverse events; low incidence of treatment-emergent adverse events
Phase 2 Refractory Hypercholesterolemia (Rosenson et al.; n=272; 16 weeks)
- 450 mg SC weekly: −56% LDL-C, −62% TG
- 15 mg/kg IV: −50% LDL-C
- Effective in patients with and without HeFH who are refractory to statins ± ezetimibe ± PCSK9 inhibitors (sources/angptl3-inhibition-tcm-2024 — high)
Guideline Recommendations
- ACC/AHA 2026: COR 2b — HoFH with LDL-C ≥100 mg/dL on max statin + ezetimibe + PCSK9 mAb
- ESC 2025: COR IIa B — should be considered in HoFH ≥5 years not at LDL-C goal on maximum LLT (broader indication; includes paediatric patients ≥5 years)
- See concepts/Familial-Hypercholesterolemia for full guideline comparison
Contradictions / Open Questions
- No cardiovascular outcomes trial: Approved on surrogate endpoint (LDL-C reduction) in HoFH only; MACE data in broader residual-risk populations absent (sources/angptl3-inhibition-tcm-2024 — high)
- Access and cost: Intravenous administration every 4 weeks and high drug cost limit real-world use; oral alternatives not available
- ACC/AHA vs ESC COR discordance: ESC 2025 IIa B vs ACC/AHA 2026 2b for HoFH; ESC explicitly extends to paediatric ≥5 years vs ACC/AHA adult focus
Connections
- Related to concepts/ANGPTL3-Inhibition — mechanism and clinical trial data
- Related to concepts/Familial-Hypercholesterolemia — primary approved indication
- Related to concepts/Lipid-Gene-Therapy — ANGPTL3 gene editing (CTX310, VERVE-201) as emerging competitors/alternatives