Amgen announced that the Phase 3 RUTHERFORD-2 (RedUction of LDL-C with PCSK9 InhibiTion in HEteRozygous Familial HyperchOlesteRolemia Disorder Study-2) trial evaluating evolocumab in combination with statins and other lipid-lowering therapies in patients with heterozygous familial hypercholesterolemia (HeFH) met its co-primary endpoints: the % reduction from baseline in low-density lipoprotein cholesterol (LDL-C) at week 12 and the mean % reduction from baseline in LDL-C at weeks 10 and 12. The mean % reductions in LDL-C, or ‘bad' cholesterol, were consistent with the results observed for the same doses in the Phase 2 RUTHERFORD trial for evolocumab compared to placebo. Evolocumab is an investigational fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces the liver's ability to remove LDL-C from the blood.

The RUTHERFORD-2 trial evaluated safety, tolerability and efficacy of evolocumab in 329 HeFH patients on a stable dose of statin and other lipid-lowering therapies. Patients were randomized to one of four treatment groups to compare subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) with subcutaneous placebo (every two weeks or monthly). Safety was balanced across treatment groups except for the following most common adverse events (>= 2% in evolocumab combined group and >= 2% compared to placebo): nasopharyngitis (8.6% evolocumab; 4.6% placebo), contusion (4.1% evolocumab; 0.9% placebo), back pain (3.6% evolocumab; 0.9% placebo), nausea (3.6% evolocumab; 0.9% placebo), influenza (3.2% evolocumab; 0.0% placebo), and myalgia (2.7% evolocumab; 0.0% placebo).

In a separate Phase 3 study that enrolled 164 patients with high cholesterol on statin therapy, 95% or greater of patients were able to self-administer at least one full home administration of evolocumab 420 mg subcutaneously by one injection with an automated mini-doser or by three injections with a standard spring-based autoinjector. Reductions in LDL-C were comparable with both devices and consistent to those seen in the Phase 2 LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 MonoclonaL Antibody Inhibition Combined with Statin ThErapy -Thrombolysis In Myocardial Infarction-57) trial. Safety was balanced between the treatment groups and no new safety concerns were identified.

According to the Centers for Disease Control and Prevention, more than 71 million American adults have high LDL-C. Elevated LDL-C is recognized as a major risk factor for cardiovascular disease.(4-5) Patients with familial hypercholesterolemia, an inherited condition that causes high levels of LDL-C levels beginning at birth, are at high-risk for cardiovascular events at an early age. Heterozygous familial hypercholesterolemia is one of the most common genetic disorders, affecting approximately one out of every 300 to 500 people worldwide. RUTHERFORD-2 (RedUction of LDL-C with PCSK9 InhibiTion in HEteRozygous Familial HyperchOlesteRolemia Disorder Study-2) is a Phase 3 randomized, multicenter, double-blind, placebo-controlled trial designed to evaluate the safety, tolerability and efficacy of evolocumab in 329 patients with HeFH and an LDL-C >100 mg/dL who were on a stable dose of statin therapy and lipid-lowering medication.

Patients were randomized to one of four treatment groups to compare subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) with subcutaneous placebo (every two weeks or monthly). The co-primary endpoints were the % reduction from baseline in LDL-C at week 12 and the mean % reduction from baseline in LDL-C at weeks 10 and 12. Co-secondary efficacy endpoints included means at weeks 10 and 12 and at week 12 for the following: absolute change from baseline in LDL-C; LDL-C < 70 mg/dL; and the % change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC)/HDL-C ratio, ApoB/apolipoprotein A1 (ApoA1) ratio, lipoprotein(a), triglycerides, HDL-C and very low-density lipoprotein cholesterol (VLDL-C).