Amgen has announced data from two phase III studies, RUTHERFORD-2 and TESLA, that showed treatment with evolocumab, a novel investigational low-density lipoprotein cholesterol (LDL-C)-lowering medication, resulted in a statistically significant reduction in LDL-C compared to placebo in patients with different types of familial hypercholesterolemia (FH). FH is an inherited condition caused by a gene mutation, which leads to high levels of LDL-C, or "bad" cholesterol, and premature cardiovascular disease.
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 study evaluating 329 patients with heterozygous FH (HeFH) showed that adding subcutaneous evolocumab (140mg every two weeks or 420mg monthly) to a stable dose of statin and other lipid-lowering therapies significantly reduced mean LDL-C by 59%-66% from baseline compared to placebo at week 12 and weeks 10 and 12 (p<0.001).
At week 12, an LDL-C level of 70mg/dL (1.8mmol/L) was achieved by 68% of patients treated with evolocumab 140mg every two weeks and by 63% of patients treated with evolocumab 420 mg monthly, versus 2% of patients in the placebo groups (p
The most common adverse events (AEs) reported in evolocumab-treated patients were nasopharyngitis, headache, contusion (i.e., bruise), back pain and nausea.
"Statin therapy has led to significant improvements in the treatment of FH; however, many patients are still not able to achieve desirable LDL cholesterol levels despite intensive treatment," said lead investigator Frederick J. Raal, M.D., University of Witwatersrand, Johannesburg, South Africa. "Results from the RUTHERFORD-2 and TESLA studies show that evolocumab offers the potential to achieve significant further reductions in LDL cholesterol in these difficult-to-treat and high-risk populations."
The TESLA study evaluating 49 patients with homozygous FH (HoFH), not on apheresis, showed that adding evolocumab 420mg subcutaneous monthly to a stable dose of statin therapy and other lipid-lowering medications significantly reduced LDL-C by 31% (95% CI, -44, -18, p<0.001) from baseline at week 12 compared to placebo.
In patients with at least one defective LDL receptor mutation, evolocumab reduced LDL-C by 41 percent (95% CI, -53, -28, p<0.0001) compared to placebo. The most common AEs (more than one subject) in evolocumab-treated patients were upper respiratory tract infection, influenza, gastroenteritis and nasopharyngitis.
"Results from these two phase III studies support the effectiveness of evolocumab as a treatment option for patients with both forms of FH, who struggle to manage their cholesterol levels," said Sean E. Harper, M.D., executive vice president of R&D at Amgen. "These results, in combination with data from a number of other studies in our clinical trial program, formed the basis of our U.S. and E.U. filing submissions for evolocumab and we are working with regulatory authorities to bring this important treatment option to patients with significant unmet medical need."
High cholesterol, particularly elevated LDL-C, is the most common form of dyslipidemia, which is an abnormality of cholesterol and/or fats in the blood. Elevated LDL-C is recognized as a major risk factor for cardiovascular disease. FH is an inherited condition caused by genetic mutations which lead to high levels of LDL-C at an early age, and it is estimated that less than 1% of people with FH (heterozygous and homozygous forms) in the U.S. are diagnosed.
Patients can have either one of two types of FH. Heterozygous FH is the more common type of FH and occurs globally in approximately one in 200 to 500 people. It can cause LDL-C levels twice as high as normal (e.g., >190mg/dL). Individuals with HeFH have one altered copy of a cholesterol-regulating gene. Homozygous FH is the rare, more severe form, occurring in approximately one in a million individuals. It can cause LDL-C levels more than six times as high as normal (e.g., 650-1,000mg/dL). An individual with HoFH has two altered copies of cholesterol-regulating genes (one from each parent). In 2013, the FDA granted evolocumab an orphan drug designation for HoFH.
RUTHERFORD-2 (RedUction of LDL-C with PCSK9 InhibiTion in HEteRozygous Familial HyperchOlesteRolemia Disorder Study-2) is a phase III 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 >=100mg/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 (140mg every two weeks or 420mg monthly) with subcutaneous placebo (every two weeks or monthly).
The co-primary endpoints were the percent reduction from baseline in LDL-C at week 12 and the mean percent 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 <70mg/dL; and the percentage 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).
TESLA (Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities) is a two-part phase II/III trial designed to evaluate the safety, tolerability and efficacy of evolocumab.
The phase III 12-week, double-blind, randomized, placebo-controlled, multicenter part of the TESLA trial (TESLA Part B) evaluated evolocumab compared to placebo in 49 adults and adolescents aged 12 years and over with HoFH (LDL-C >130mg/dL) who were on a stable dose of statin therapy and other lipid-lowering medications and were not receiving apheresis. Patients were randomized to evolocumab 420mg subcutaneous monthly or placebo subcutaneous monthly. The primary endpoint was the percent reduction from baseline in LDL-C at week 12. Secondary endpoints included mean percent change from baseline in LDL-C, apolipoprotein B (ApoB) and lipoprotein(a) (Lp(a)) at weeks six and 12, and percent change from baseline in ApoB and Lp(a) at week 12.
The phase II 12-week, open-label, single-arm, multicenter part of the TESLA trial (TESLA Part A) evaluated eight patients with HoFH who were on stable drug therapy for four weeks or more. Patients received evolocumab 420mg subcutaneous once monthly for 12 weeks. The primary endpoint was the percent reduction from baseline in LDL-C at week 12.