Amgen announced that the phase 3 TESLA (Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities) trial evaluating evolocumab met its primary endpoint of the percent reduction from baseline at week 12 in low-density lipoprotein cholesterol (LDL-C). The percent reduction in LDL-C, or "bad" cholesterol, was clinically meaningful and statistically significant. 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.
TESLA was a two-part phase 2/3 trial evaluating evolocumab in patients with homozygous familial hypercholesterolemia (HoFH), a rare and serious genetic disorder characterized by severely elevated LDL-C at an early age. The phase 3 TESLA trial evaluated the safety, tolerability and efficacy of evolocumab compared to placebo in 49 adult and adolescent (12 to less than 18 years of age) patients with HoFH who were on a stable dose of statin therapy and other lipid-lowering medication. Patients were randomized to evolocumab 420 mg subcutaneous monthly or placebo subcutaneous monthly.
Safety was generally balanced across treatment groups. The most common adverse events in the evolocumab group (more than one subject) were upper respiratory tract infection, influenza, gastroenteritis and nasopharyngitis.
"Homozygous familial hypercholesterolemia is a rare and devastating disease characterized by extremely high LDL-C levels that increase cardiovascular risk in these patients, many of whom are affected at an early age," said Sean E. Harper, executive vice president of research and development at Amgen. "We are encouraged by the results of the TESLA trial, the first phase 3 data of a PCSK9 inhibitor in homozygous familial hypercholesterolemia patients, which suggest evolocumab may offer a new treatment option for these patients who currently have significant unmet medical needs."
Elevated LDL-C is recognized as a major risk factor for cardiovascular disease. HoFH is a rare, serious inherited condition that can lead to/cause high levels of LDL-C at an early age. It is a rare form of familial hypercholesterolemia occurring in approximately one in a million individuals, who have two altered copies of a cholesterol regulating gene (one from each parent) that result in absent or defective LDL receptor function.2,4 HoFH can cause a four-fold increase in LDL-C levels (e.g., 400-1,000 mg/dL).
"We are encouraged by the data from another phase 3 trial in our clinical development programme showing that evolocumab reduces LDL cholesterol and in this case, in patients with a rare and serious genetic condition," Harper added. "These results add to the data from our five previously announced positive phase 3 studies of evolocumab in other patient populations."
Details of the phase 3 TESLA trial will be submitted to a future medical conference and for publication.
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 2 12-week, open-label, single-arm, multicenter part of the TESLA trial 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 a minimum of 12 weeks, followed by every two weeks for another 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 2013 European Atherosclerosis Society (EAS) meeting and published in Circulation.
The phase 3 12-week, double-blind, randomized, placebo-controlled, multicenter part of the TESLA trial evaluated evolocumab in 49 patients with HoFH (LDL-C >130 mg/dL) who were on a stable dose of statin therapy and lipid-lowering medication. 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.
Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9).1 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.7 Evolocumab, being developed by Amgen scientists, is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of the liver to remove LDL-C from the blood.
PROFICIO, which stands for the Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different POpulations, is a large and comprehensive clinical trial program evaluating evolocumab in 20 clinical trials, with a combined planned enrollment of nearly 30,000 patients.
The phase 3 programme includes 14 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; as well as the administration of evolocumab (THOMAS-1 and THOMAS-2).
Five studies in the evolocumab phase 3 programme 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; DESCARTES (Durable Effect of PCSK9 Antibody CompARed wiTh PlacEbo Study) in patients with hyperlipidemia at risk for cardiovascular disease; 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.
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