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The Lancet Publishes Two Phase 3 Studies Showing Cholesterol-Lowering Medication Evolocumab Significantly Reduced LDL Cholesterol In Patients With Serious Genetic Disorders That Cause High Cholesterol
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.4
The RUTHERFORD-2 study evaluating 329 patients with heterozygous FH (HeFH) showed that adding subcutaneous evolocumab (140 mg every two weeks or 420 mg monthly) to a stable dose of statin and other lipid-lowering therapies significantly reduced mean LDL-C by 59-66 percent 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 percent of patients treated with evolocumab 140 mg every two weeks and by 63 percent of patients treated with evolocumab 420 mg monthly, versus 2 percent 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
"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
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 percent (95 percent 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 percent 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
"Results from these two Phase 3 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
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.5,6 Elevated LDL-C is recognized as a major risk factor for cardiovascular disease.7,8 Familial hypercholesterolemia is an inherited condition caused by genetic mutations which lead to high levels of LDL-C at an early age,3 and it is estimated that less than one percent of people with FH (heterozygous and homozygous forms) in the U.S. are diagnosed.9
Patients can have either one of two types of FH.3 Heterozygous FH is the more common type of FH and occurs globally in approximately one in 200 to 500 people.9 It can cause LDL-C levels twice as high as normal (e.g., >190 mg/dL).10 Individuals with HeFH have one altered copy of a cholesterol-regulating gene.10 Homozygous FH is the rare, more severe form, occurring in approximately one in a million individuals.11 It can cause LDL-C levels more than six times as high as normal (e.g., 650-1,000 mg/dL).11 An individual with HoFH has two altered copies of cholesterol-regulating genes (one from each parent).3 In 2013, the
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).
TESLA Study Design
TESLA (Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities) is a two-part Phase 2/3 trial designed to evaluate the safety, tolerability and efficacy of evolocumab.
The Phase 3 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 >130 mg/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 420 mg 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 6 and 12, and percent change from baseline in ApoB and Lp(a) at week 12.
The Phase 2 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 420 mg subcutaneous once monthly for 12 weeks. The primary endpoint was the percent reduction from baseline in LDL-C at week 12. Positive results from the Phase 2 TESLA trial were presented at the 81st
Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9).4 PCSK9 is a protein that targets LDL receptors for degradation and thereby reduces the liver's ability to remove LDL-C, or "bad" cholesterol, from the blood.13 Evolocumab, being developed by
The Phase 3 program includes 16 trials to evaluate evolocumab administered every two weeks and monthly in multiple patient populations, including in combination with statins in patients with hyperlipidemia (LAPLACE-2 and YUKAWA-2); in patients with hyperlipidemia who cannot tolerate statins (GAUSS-2 and GAUSS-3); as a stand-alone treatment in patients with hyperlipidemia (MENDEL-2); in patients whose elevated cholesterol is caused by genetic disorders called heterozygous (RUTHERFORD-2 and TAUSSIG) and homozygous (TESLA and TAUSSIG) familial hypercholesterolemia; the effects of evolocumab on lipoprotein metabolism (FLOREY); and the administration of evolocumab in statin-treated hyperlipidemic patients (THOMAS-1 and THOMAS-2).
Five ongoing studies in the evolocumab Phase 3 program will provide long-term safety and efficacy data. These include FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), which will assess whether treatment with evolocumab in combination with statin therapy compared to placebo and statin therapy reduces recurrent cardiovascular events in approximately 22,500 patients with cardiovascular disease; EBBINGHAUS (Evaluating PCSK9 Binding AntiBody Influence oN CoGnitive HeAlth in High CardiovascUlar Risk Subjects), which will evaluate the effect of evolocumab on cognitive function in a subset of patients enrolled in FOURIER; OSLER-2 (Open Label Study of Long TERm Evaluation Against LDL-C Trial-2) in patients with high cholesterol who completed any of the Phase 3 studies; GLAGOV (GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound), which will determine the effect of evolocumab on coronary atherosclerosis in approximately 950 patients undergoing cardiac catheterization; and TAUSSIG (Trial Assessing Long Term USe of PCSK9 Inhibition in Subjects with Genetic LDL Disorders), which will assess the long-term safety and efficacy of evolocumab on LDL-C in patients with severe familial hypercholesterolemia including patients with homozygous familial hypercholesterolemia. The DESCARTES (Durable Effect of PCSK9 Antibody CompARed wiTh PlacEbo Study) study, a long-term safety and efficacy trial in patients with hyperlipidemia at risk for cardiovascular disease, has been completed, presented and published.
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1. Raal F, Stein EA, Dufour R, et al. PCSK9 Inhibition with Evolocumab (AMG 145) in Heterozygous Familial Hypercholesterolaemia: Results of a Randomised, Double-blind, Placebo-controlled Trial. Lancet. 2014. In press.
2. Raal F, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with Evolocumab in Homozygous Familial Hypercholesterolaemia: Results of a Randomised, Double-blind, Placebo-controlled Trial. Lancet. 2014. In press.
4. Amgen Data on File, Investigator Brochure.
6. Merck Manuals website. Dyslipidemia. http://www.merckmanuals.com/professional/endocrine_and_metabolic_disorders/lipid_disorders/dyslipidemia.html. Accessed
9. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial Hypercholesterolaemia is Underdiagnosed and Undertreated in the General Population: Guidance for Clinicians to Prevent Coronary Heart Disease. Eur Heart J. 2013;34:3478-3490.
10. Hopkins PN, Toth PP, Ballantyne CM, et al. Familial Hypercholesterolemias: Prevalence, Genetics, Diagnosis and Screening Recommendations From the
11. Daniels SR, Samuel SG, de Ferranti SD. Pediatric Aspects of Familial Hypercholesterolemias: Recommendations from the
12. Stein EA, Honarpour N, Wasserman SM, et al. Effect of the Proprotein Convertase Subtilisin/Kexin 9 Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia. Circulation. 2013;128(19):2113-2120. http://circ.ahajournals.org/content/128/19/2113.full.pdf. Accessed
13. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 Cause Autosomal Dominant Hypercholesterolemia.