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Bococizumab Reduces LDL Cholesterol in Phase II Study

Monoclonal antibody blocks function of PCSK9 protein

Positive results have been reported from a phase IIb dose-ranging study of bococizumab (formerly RN316, Pfizer), an injectable monoclonal antibody, in statin-treated patients with high cholesterol.

The patients were randomly assigned to various doses of bococizumab (once- or twice-monthly subcutaneous injection) or placebo. The study met its primary endpoint across all doses, showing that bococizumab significantly reduced low-density lipoprotein cholesterol (LDL-C) from baseline compared with placebo in adults with high cholesterol who were also receiving statin therapy.

The percentage of patients reporting adverse events (AEs) or serious AEs was similar across the bococizumab and placebo treatment groups.

Elevated LDL-C is recognized as a major risk factor for cardiovascular disease, the number one cause of death worldwide despite the widespread availability of statin therapy.

The dose-ranging, double-blind, placebo-controlled, phase IIb trial examined two bococizumab dosing regimens — once monthly (200 mg or 300 mg) or twice monthly (50 mg, 100 mg, or 150 mg) — in 354 patients. For both regimens, the bococizumab dose was lowered if LDL-C was reduced to ≤ 25 mg/dL. The first opportunity for a dose reduction was at week 8 for the once-monthly regimen and at week 6 for the twice-monthly regimen.

The primary efficacy analysis was the placebo-adjusted change from baseline in LDL-C at week 12. The mean baseline LDL across doses was 109 mg/dL.

Once- and twice-monthly dosing regimens of bococizumab were associated with significant placebo-adjusted reductions in LDL-C at week 12. The greatest reductions were seen with 300 mg for the once-monthly regimen and with 150 mg for the twice-monthly regimen. Before the majority of dose reductions due to an LDL-C ≤ 25 mg/dL, the LDL-C changes seen with these regimens were greater than those observed at week 12 (the study’s primary endpoint).

The mean changes from baseline in LDL-C at week 12 (placebo-adjusted) were –44.9 mg/dL for the 300-mg once-monthly regimen and –53.4 mg/dL for the 150-mg twice-monthly regimen.

A phase III program for bococizumab was initiated in October 2013. This program consists of two cardiovascular (CV) outcome studies as well as multiple lipid-lowering studies in more than 22,000 patients. One of the two CV outcome trials, SPIRE-1, will assess whether lowering LDL-C to levels well below current guideline-recommended targets will lead to a further reduction in CV events. This study includes a high-risk patient population with baseline levels of LDL-C ranging from 70 to 100 mg/dL.

The second CV outcome study, SPIRE-2, will evaluate the efficacy and safety of bococizumab in a range of high-risk patients who have not achieved LDL levels lower than 100 mg/dL despite the use of high-dose statins or who are partially or completely intolerant to statins.

This phase III program will evaluate the efficacy and safety of 150 mg twice monthly as a starting dose.

Bococizumab is an injectable monoclonal antibody that works by blocking the function of proprotein convertase subtilisin kexin type 9 (PCSK9), which interferes with the clearance of LDL-C. Bococizumab is an investigational compound and has not received regulatory approval in any country.

Source: Pfizer; March 27, 2014.

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