Two Phase III Studies Show Cholesterol-Lowering Medication Evolocumab Significantly Reduced LDL Cholesterol in Patients with Serious Genetic Disorders

Amgen has announced The Lancet has published 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). Familial hypercholesterolemia 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 (140 mg every 2 weeks or 420 mg 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 70 mg/dL (1.8 mmol/L) was achieved by 68% of patients treated with evolocumab 140 mg every 2 weeks and by 63% of patients treated with evolocumab 420 mg monthly, versus 2% of patients in the placebo groups (p<0.0001 each). Similar results were seen for the mean of weeks 10 and 12 (both doses p<0.0001). The most common adverse events (AEs) reported in the publication in evolocumab-treated patients were nasopharyngitis, headache, contusion (i.e., bruise), back pain and nausea. Results from the RUTHERFORD-2 study were initially presented at the American College of Cardiology's 63rd Annual Scientific Session (ACC.14) in March 2014.

"Statin therapy has led to significant improvements in the treatment of familial hypercholesterolemia, 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 420 mg 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% (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 the TESLA study were initially presented at the 82nd Congress of the European Atherosclerosis Society (EAS 2014) in June 2014.

"Results from these two Phase III studies support the effectiveness of evolocumab as a treatment option for patients with both forms of familial hypercholesterolemia, who struggle to manage their cholesterol levels," said Sean E. Harper, MD, 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 US and EU filing submissions for evolocumab and we are working with regulatory authorities to bring this important treatment option to patients with significant unmet medical need."