Serum PCSK9 plays an active role in controlling the expression of LDL receptors by targeting them for lysosomal destruction.  REGN727/SAR236553 (REGN727) is a novel human monoclonal antibody which inhibits PCSK9 binding to the LDL receptor; a previous phase 1 proof of concept trial suggested the potential for significant reductions in LDL in familial hypercholesterolaemia.

The goal of this phase 2 study was to assess the efficacy and safety of REGN727 in a larger, more diverse, and more severely affected group of patients with familial hypercholesterolaemia.  The trial was carried out at 16 lipid clinics in the USA and Canada, and recruited 77 patients with heterozygous familial hypercholesterolaemia and LDL concentrations of 2·6 mmol/L or higher on a stable diet and statin dose, with or without ezetimibe.  Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks.  The primary endpoint was mean percent reduction in LDL-C from baseline at week 12.

Least squares mean LDL-C reduction for patients on placebo was 10.65% compared to 42.53% for 300mg every 4 weeks (p<0.0001), and all treatment groups showed significant reductions in LDL, regardless of the use of ezetimibe.  No significant CK or liver enzyme rises were noted, although one patient stopped treatment due to an injection site reaction.

Conclusions:

The monoclonal antibody REGN727 achieved significant further LDL-C reduction in patients with familial heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe.

• Stein EA, Gipie D, Bergeron J et al.  Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial.  Lancet 2012; 380, 29-36.