• Lipid Disorders Clinical Trials

Proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) binds to low–density lipoprotein receptors (LDLRs) and plays a pivotal role in LDLR degradation [McKenney JM et al. J Am Coll Cardiol 2012]. James M. McKenney, PharmD, National Clinical Research, Inc., Richmond, Virginia, USA, reported outcomes on the low–density lipoprotein cholesterol (LDL–C)–lowering effects of SAR236553/REGN727 (SAR236553), a highly specific, fully human monoclonal antibody to PCSK9 [Efficacy and Safety Evaluation of SAR236553 (REGN727) In Patients With Primary Hypercholesterolemia and LDL–Cholesterol on Stable Atorvastatin Therapy; NCT01288443].

Three prior Phase 1 studies of SAR236553 have shown that the monoclonal antibody to PCSK9 significantly reduces LDL–C levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia [Stein EA et al. N Engl J Med 2012].

The current Phase 2 dose–ranging study was a double–blind, parallel–group, placebo–controlled, multicenter trial. It included patients aged 18 to 75 years with LDL–C ≥100 mg/dL (2.59 mmol/L) who were on stable–dose atorvastatin at 10 mg, 20 mg, or 40 mg for ≥6 weeks. A total of 183 individuals were randomized to either subcutaneous placebo every 2 weeks (Q2W); SAR236553 at 50 mg, 100 mg, or 150 mg (Q2W); or SAR236553 at 200 mg and 300 mg once every 4 weeks (Q4W) with an alternating placebo injection at 2 weeks.

The primary objective of the study was to evaluate the safety and LDL–C–lowering effect of 12 weeks of treatment with SAR236553 versus placebo. The primary study endpoint was the percentage change in calculated LDL–C from baseline (mean of Week −1 and Week 0) to Week 12.

The addition of SAR236553 resulted in a significant decrease in LDL–C from baseline. A clear dose–response relationship with respect to percentage of LDL–C lowering for both Q2W and Q4W administration was demonstrated: 40%, 64%, and 72% with 50 mg, 100 mg, and 150 mg Q2W, respectively, and 43% and 48% with 200 and 300 mg Q4W. At Week 12, LDL–C reduction with placebo was 5.1% (Table 1). SAR236553 also increased the rate of achievement of LDL–C goals (<70 mg/dL) compared with placebo. Of note, LDL–C reductions were generally unaffected by the baseline atorvastatin dose.

SAR236553 produced consistent and robust reductions in all other Apo B–containing lipoproteins (Table 2), with important decreases in lipoprotein(a)—a finding that is consistent with the prior Phase 1 studies [Stein EA et al. N Engl J Med 2012]. There was also a trend toward lower triglycerides and increases in high–density lipoprotein cholesterol (HDL–C) and Apo AI versus placebo—findings that were not entirely explained by the direct mechanism of action of PCSK9 inhibition. The biweekly injections appeared to deliver a more sustained LDL–C reduction over the Q4W dosing schedule.

SAR236553 was well tolerated during the study, with no signs of persistent or prevalent clinical or laboratory adverse events, including those that were associated with hepatic and muscle assessments. One patient who was assigned to the 300–mg Q4W regimen developed a rare complication, leukocytoclastic vasculitis, an inflammatory immune complex–mediated vasculitis of small–caliber blood vessels, although no similar reactions have been reported. No antidrug antibodies were observed 2 weeks before or after the incident.

According to Dr. McKenney, these results support further evaluation of this novel biologic lipid–lowering therapy in large, multicenter, randomized, controlled trials. Plans are underway to evaluate if PCSK9 antibody therapy can reduce adverse cardiovascular outcomes among an internationally diverse patient population who are taking a variety of different background lipid–lowering therapies.

• © 2012 MD Conference Express®