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Evolocumab Shows Promise in Patients With Familial Hypercholesterolemia

Positive phase III results reported

The phase III TESLA (Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities) study evaluating evolocumab (Amgen) has 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 a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that targets LDL receptors for degradation, thereby reducing the liver’s ability to remove LDL-C from the blood. Evolocumab is designed to bind to PCSK9 and to inhibit it 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.

The TESLA trial was a two-part phase II/III study evaluating evolocumab in patients with homozygous familial hypercholesterolemia (HoFH), a rare and serious genetic disorder characterized by severely elevated LDL-C levels at an early age.

The phase II 12-week, open-label, single-arm part of the trial evaluated eight patients with HoFH who had received stable drug therapy for 4 weeks or more. The patients received subcutaneous (SC) evolocumab 420 mg once monthly for a minimum of 12 weeks, followed by every 2 weeks for another 12 weeks. The primary endpoint was the percent reduction from baseline in LDL-C at week 12. Positive results from this phase II trial were published in Circulation.

The phase III 12-week, double-blind, randomized, placebo-controlled part of the TESLA study evaluated evolocumab in 49 patients with HoFH (LDL-C > 130 mg/dL) who were receiving a stable dose of statin therapy and lipid-lowering medications. The patients were randomly assigned to receive either SC evolocumab 420 mg or SC placebo once monthly. The primary endpoint was the percent reduction from baseline in LDL-C at week 12.Secondary endpoints included the mean percent change from baseline in LDL-C, in apolipoprotein B (ApoB), and in lipoprotein(a) [Lp(a)] at weeks 6 and 12, and the percent change from baseline in ApoB and Lp(a) at week 12.

Safety was generally balanced across treatment groups. The most common adverse events in the evolocumab group were upper respiratory tract infection, influenza, gastroenteritis, and nasopharyngitis.

Elevated LDL-C is recognized as a major risk factor for cardiovascular disease. HoFH 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. HoFH can cause a four-fold increase in LDL-C levels (e.g., 400 to 1,000 mg/dL).

Source: Amgen; March 17, 2014.

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