Evinacumab, an angiopoietin-like 3 inhibitor, was evaluated in a Phase 3 open-label, single-arm trial for long-term safety and efficacy in adult and adolescent patients with homozygous familial hypercholesterolaemia (HoFH). The study enrolled 116 patients (102 adults, 14 adolescents) aged ≥12 years, with 57 (49.1%) being female. Patients received intravenous evinacumab 15 mg/kg every 4 weeks alongside stable lipid-lowering therapy. The median treatment duration was 104.3 weeks. Evinacumab significantly reduced LDL-C by 43.6% from baseline to Week 24, with further reductions observed at Week 48 (43.9%) and Week 120. LDL-C reductions were consistent across age, sex, and LDLR genotype. The mean LDL-C reduction was 41.7% in adults and 55.4% in adolescents. Evinacumab was generally well tolerated, with most treatment-emergent adverse events (TEAEs) being mild or moderate. Two deaths were reported, neither related to evinacumab. Three patients discontinued treatment due to TEAEs, none related to evinacumab. Evinacumab also reduced other lipid parameters, including Apo B, non-HDL-C, total cholesterol, fasting triglycerides, and Lp(a). The drug showed sustained efficacy and safety over the long term, with no clinically relevant changes in liver function parameters. The study supports the long-term safety and efficacy of evinacumab in reducing LDL-C levels in HoFH patients, regardless of age, sex, or treatment duration. Evinacumab is well tolerated and effective in patients with null–null LDLR variants, who typically do not respond to other lipid-lowering therapies. The findings suggest that evinacumab may fulfill an important unmet need in the treatment of HoFH.Evinacumab, an angiopoietin-like 3 inhibitor, was evaluated in a Phase 3 open-label, single-arm trial for long-term safety and efficacy in adult and adolescent patients with homozygous familial hypercholesterolaemia (HoFH). The study enrolled 116 patients (102 adults, 14 adolescents) aged ≥12 years, with 57 (49.1%) being female. Patients received intravenous evinacumab 15 mg/kg every 4 weeks alongside stable lipid-lowering therapy. The median treatment duration was 104.3 weeks. Evinacumab significantly reduced LDL-C by 43.6% from baseline to Week 24, with further reductions observed at Week 48 (43.9%) and Week 120. LDL-C reductions were consistent across age, sex, and LDLR genotype. The mean LDL-C reduction was 41.7% in adults and 55.4% in adolescents. Evinacumab was generally well tolerated, with most treatment-emergent adverse events (TEAEs) being mild or moderate. Two deaths were reported, neither related to evinacumab. Three patients discontinued treatment due to TEAEs, none related to evinacumab. Evinacumab also reduced other lipid parameters, including Apo B, non-HDL-C, total cholesterol, fasting triglycerides, and Lp(a). The drug showed sustained efficacy and safety over the long term, with no clinically relevant changes in liver function parameters. The study supports the long-term safety and efficacy of evinacumab in reducing LDL-C levels in HoFH patients, regardless of age, sex, or treatment duration. Evinacumab is well tolerated and effective in patients with null–null LDLR variants, who typically do not respond to other lipid-lowering therapies. The findings suggest that evinacumab may fulfill an important unmet need in the treatment of HoFH.