Evinacumab for Homozygous Familial Hypercholesterolemia

BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disorder characterized by the premature onset of cardiovascular disease, which is directly caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This condition is linked to genetic variants that lead to either a virtually absent (null-null) or significantly impaired (non-null) activity of the LDL receptor. Conversely, loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and confer protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody specifically targeting ANGPTL3, has demonstrated the potential to reduce LDL cholesterol levels across various genetic forms of hypercholesterolemia.

METHODS: We conducted a 24-week, double-blind, placebo-controlled, phase 3 clinical trial to assess the efficacy and safety of evinacumab in patients aged 12 years or older who had homozygous familial hypercholesterolemia. Patients were randomized in a 2:1 ratio to receive either intravenous evinacumab (at a dose of 15 mg per kilogram of body weight every 4 weeks) or placebo. All participants were already on other lipid-lowering therapies at the time of randomization. The primary endpoint of the study was the percentage change from baseline in the LDL cholesterol level at week 24. RESULTS: A total of 65 patients were enrolled in the trial. At week 24, the mean (±SE) percentage change from baseline in the LDL cholesterol level was –49.0±5.2% in the evinacumab group, compared to +1.9±6.4% in the placebo group. This represented a statistically significant difference of –51.0 percentage points (95% confidence interval [CI], –66.3 to –35.6; P<0.001). Significant reductions in LDL cholesterol were observed irrespective of the specific type of LDL-receptor variant or whether patients were undergoing apheresis. The most common adverse events reported with evinacumab were nasopharyngitis and influenza-like illness. Notably, no adverse events led to treatment discontinuation or death during the trial. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia, evinacumab demonstrated a significant reduction in LDL cholesterol levels and was not associated with new safety concerns throughout the 24-week trial period.

BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disorder characterized by the premature onset of cardiovascular disease, which is directly caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This condition is linked to genetic variants that lead to either a virtually absent (null-null) or significantly impaired (non-null) activity of the LDL receptor. Conversely, loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and confer protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody specifically targeting ANGPTL3, has demonstrated the potential to reduce LDL cholesterol levels across various genetic forms of hypercholesterolemia.

METHODS: We conducted a 24-week, double-blind, placebo-controlled, phase 3 clinical trial to assess the efficacy and safety of evinacumab in patients aged 12 years or older who had homozygous familial hypercholesterolemia. Patients were randomized in a 2:1 ratio to receive either intravenous evinacumab (at a dose of 15 mg per kilogram of body weight every 4 weeks) or placebo. All participants were already on other lipid-lowering therapies at the time of randomization. The primary endpoint of the study was the percentage change from baseline in the LDL cholesterol level at week 24. RESULTS: A total of 65 patients were enrolled in the trial. At week 24, the mean (±SE) percentage change from baseline in the LDL cholesterol level was –49.0±5.2% in the evinacumab group, compared to +1.9±6.4% in the placebo group. This represented a statistically significant difference of –51.0 percentage points (95% confidence interval [CI], –66.3 to –35.6; P<0.001). Significant reductions in LDL cholesterol were observed irrespective of the specific type of LDL-receptor variant or whether patients were undergoing apheresis. The most common adverse events reported with evinacumab were nasopharyngitis and influenza-like illness. Notably, no adverse events led to treatment discontinuation or death during the trial. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia, evinacumab demonstrated a significant reduction in LDL cholesterol levels and was not associated with new safety concerns throughout the 24-week trial period.