Amgen reports positive findings from AMG 145 Phase 3 studies in patients at risk for cardiovascular disease

AmgenMar 31 2014

Amgen (NASDAQ: AMGN) today announced new detailed data from three Phase 3 studies that showed treatment with its novel investigational cholesterol-lowering medication, evolocumab (AMG 145), resulted in a statistically significant reduction of 55-66 percent in low-density lipoprotein cholesterol (LDL-C) compared to placebo in patients with high cholesterol.

Results from the three separate Phase 3 studies, MENDEL-2, DESCARTES and RUTHERFORD-2, were presented today as Featured Clinical Research in a Special Session at the American College of Cardiology's 63^rd Annual Scientific Session (ACC.14). Data from DESCARTES, the long-term safety and efficacy study, were simultaneously published in the New England Journal of Medicine and data from MENDEL-2, the monotherapy study, were simultaneously published in the Journal of the American College of Cardiology.

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 three Phase 3 studies evaluated evolocumab in different patient populations: as monotherapy in patients with high cholesterol (MENDEL-2); as a long-term 52-week therapy in patients with high cholesterol on risk-based lipid-lowering therapy (DESCARTES); and in combination with statins and other lipid-lowering therapies in patients with heterozygous familial hypercholesterolemia (HeFH), a genetic disorder characterized by elevated LDL-C levels (RUTHERFORD-2).

In MENDEL-2, the most common adverse events (AEs) (≥2 percent in evolocumab combined group) were headache, diarrhea, nausea and urinary tract infection. The most common AEs (>5 percent in evolocumab) in the DESCARTES study were nasopharyngitis, upper respiratory tract infection, influenza and back pain. In RUTHERFORD-2, the most common AEs (≥2 percent in the combined evolocumab group) were nasopharyngitis, headache, contusion (i.e., bruise), back pain, nausea, arthralgia, upper respiratory tract infection, influenza, myalgia and pain in extremity.

"We are pleased to report positive detailed findings from three of our pivotal studies in key patient populations at risk for cardiovascular disease," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "These results add to the growing body of evidence from our comprehensive Phase 3 clinical trial program. We look forward to working with regulatory authorities on our global filing plan in the hopes of bringing this new treatment option to patients with high cholesterol who have an unmet medical need."

MENDEL-2, DESCARTES and RUTHERFORD-2 are three of five Phase 3 evolocumab studies being presented at ACC.14. Data from two other trials, LAPLACE-2 and GAUSS-2, will be featured in a Late-Breaking Clinical Trials session on Sunday, March 30, at 8 a.m. EDT.

"Positive results from these first Phase 3 studies provide encouragement that evolocumab will find use as a treatment for a range of at-risk patients," said Michael Koren, M.D., clinical investigator for the MENDEL-2 and DESCARTES studies and the chief executive officer of the Jacksonville Center for Clinical Research. "The newly released data support the potential of evolocumab in patients with high cholesterol who struggle to keep their LDL-C levels under control despite currently available treatments."

MENDEL-2 (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2) Primary Results

• The MENDEL-2 study showed that in 614 patients with high cholesterol (LDL-C ≥100 mg/dL and <190 mg/dL) who were not receiving lipid-lowering therapy, treatment with subcutaneous evolocumab significantly reduced mean LDL-C by 55-57 percent from baseline compared to placebo and 38-40 percent from baseline compared to ezetimibe (p<0.001).
  • Results of the study showed the mean percent reduction from baseline in LDL-C at weeks 10 and 12 were 57 percent for evolocumab 140 mg every two weeks and 57 percent for evolocumab 420 mg monthly compared to placebo; and 39 percent for evolocumab 140 mg every two weeks and 40 percent for evolocumab 420 mg monthly compared to ezetimibe.
  • At week 12, the percent reduction from baseline in LDL-C was 57 percent for evolocumab 140 mg every two weeks and 55 percent for evolocumab 420 mg monthly compared to placebo; and 39 percent for evolocumab 140 mg every two weeks and 38 percent for evolocumab 420 mg monthly compared to ezetimibe.
• The most common AEs (≥2 percent in evolocumab combined group) were headache (3.3 percent evolocumab; 3.2 percent ezetimibe; 2.6 percent placebo), diarrhea (2.9 percent evolocumab; 1.9 percent ezetimibe; 3.9 percent placebo), nausea (2.6 percent evolocumab; 1.9 percent ezetimibe; 0.6 percent placebo) and urinary tract infection (2.3 percent evolocumab; 1.9 percent ezetimibe; 1.3 percent placebo).

DESCARTES (Durable Effect of PCSK9 Antibody CompARed wiTh PlacEbo Study) Primary Results

• The DESCARTES study showed that in 901 patients with high LDL-C and a range of cardiovascular risk, evolocumab 420 mg subcutaneous monthly reduced mean LDL-C by 57 percent from baseline at week 52 compared to placebo (p<0.001).
  • LDL-C reduction for evolocumab at week 12 was consistent with the long-term efficacy at week 52.
  • Compared to placebo, the mean percent LDL-C reductions from baseline with evolocumab at week 52 are 56 percent, 62 percent, 57 percent and 49 percent in diet alone, atorvastatin 10 mg, atorvastatin 80 mg, and atorvastatin 80 mg plus ezetimibe 10 mg groups, respectively.
• The most common AEs (>5 percent in evolocumab) were nasopharyngitis (10.5 percent evolocumab; 9.6 percent placebo), upper respiratory tract infection (9.3 percent evolocumab; 6.3 percent placebo), influenza (7.5 percent evolocumab; 6.3 percent placebo) and back pain (6.2 percent evolocumab; 5.6 percent placebo).

RUTHERFORD-2 (RedUction of LDL-C with PCSK9 InhibiTion in HEteRozygous Familial HyperchOlesteRolemia Disorder Study-2) Primary Results

• The RUTHERFORD-2 study showed that in 329 HeFH patients on a stable dose of statin and other lipid-lowering therapies, treatment with subcutaneous evolocumab significantly reduced mean LDL-C by 59-66 percent from baseline compared to placebo (p<0.001).
  • Data show the mean percent reduction from baseline in LDL-C at weeks 10 and 12 were 60 percent for evolocumab 140 mg every two weeks and 66 percent for evolocumab 420 mg monthly compared to placebo.
  • At week 12, the percent reduction from baseline in LDL-C was 59 percent for evolocumab 140 mg every two weeks and 61 percent for evolocumab 420 mg monthly compared to placebo.
• The most common AEs (≥2 percent in the combined evolocumab group) were nasopharyngitis (8.6 percent evolocumab; 4.6 percent placebo), headache (4.1 percent evolocumab; 3.7 percent placebo), contusion (i.e., bruise) (4.1 percent evolocumab; 0.9 percent placebo), back pain (3.6 percent evolocumab; 0.9 percent placebo), nausea (3.6 percent evolocumab; 0.9 percent placebo), influenza (3.2 percent evolocumab; 0 percent placebo), myalgia (2.7 percent evolocumab; 0 percent placebo) and pain in the extremity (2.3 percent evolocumab; 2.8 percent placebo).

High cholesterol is the most common form of dyslipidemia, which is an abnormality of lipids in the blood.^2,3 There are approximately 300 million cases of dyslipidemia in the U.S., Japan and Western Europe.⁴ According to the Centers for Disease Control and Prevention, more than 71 million American adults have high LDL-C⁵, or "bad" cholesterol, and elevated LDL-C is recognized as a major risk factor for cardiovascular disease.⁶

Patients with familial hypercholesterolemia, an inherited condition that causes high levels of LDL-C beginning at birth, are at high-risk for cardiovascular events at an early age.⁷ Heterozygous familial hypercholesterolemia is one of the most common genetic disorders, affecting approximately one out of every 200 to 500 people worldwide.^8,9

Amgen will also host a webcast investor meeting at ACC.14 on Sunday, March 30, at 7 p.m. EDT. Sean E. Harper, M.D., executive vice president of Research and Development at Amgen, along with members of Amgen's clinical development team and clinical investigators, will participate at the investor meeting to discuss Amgen's cardiovascular program, including the primary analyses of five Phase 3 evolocumab studies being presented at ACC.14.

Live audio of the investor meeting will be simultaneously broadcast over the Internet and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen's business given by management at certain investor and medical conferences, can be found on Amgen's website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen's Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

MENDEL-2 Study Design
MENDEL-2 (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy For Easing Lipid Levels-2) is a Phase 3 randomized, multicenter, double-blind, double-dummy, placebo- and ezetimibe-controlled parallel group study designed to evaluate the efficacy and safety of evolocumab in 614 hyperlipidemic patients with a 10-year Framingham risk score of 10 percent or less who were not receiving lipid-lowering therapy. Patients were randomized to one of six treatment groups to compare two dosing regimens of evolocumab (140 mg every two weeks or 420 mg monthly) with placebo and ezetimibe (10 mg daily). 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 <70 mg/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).

DESCARTES Study Design
DESCARTES (Durable Effect of PCSK9 Antibody CompARed wiTh PlacEbo Study) is a Phase 3 randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the long-term (52-week) safety, tolerability and efficacy of evolocumab in patients with hyperlipidemia at risk for cardiovascular disease. Background lipid-lowering therapy was optimized to one of four treatment groups (diet alone; diet plus atorvastatin 10 mg; diet plus atorvastatin 80 mg; and diet plus atorvastatin 80 mg plus ezetimibe 10 mg) for individual patients based on their LDL-C and cardiovascular risk according to the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III risk categories. After optimization, patients were maintained on therapy for at least four weeks. A total of 901 patients with a fasting LDL-C ≥75 mg/dL were then randomized and received monthly subcutaneous evolocumab 420 mg or placebo in combination with background lipid-lowering therapy.

The primary endpoint was percent change from baseline in LDL-C, measured by the accepted standard, preparative ultracentrifugation, after 52 weeks of treatment. Secondary efficacy endpoints included the absolute change from baseline in LDL-C and LDL-C response (LDL-C <70 mg/dL [1.8 mmol/L]) at week 52, percent change from baseline in LDL-C and total cholesterol (TC) at week 12, and percent change from baseline at week 52 in TC, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), TC/HDL-C ratio, ApoB/apolipoprotein A1 (ApoA1) ratio, lipoprotein(a), triglycerides, HDL-C and very low density lipoprotein cholesterol (VLDL-C).

RUTHERFORD-2 Study Design
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 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 <70 mg/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).