Sanofi and Regeneron Pharmaceuticals, Inc. has reported positive preliminary results from the phase II study programme in which patients with elevated low-density lipoprotein cholesterol (LDL-C) were treated with REGN727/SAR236553.

REGN727/SAR236553 is a novel, high-affinity, subcutaneously administered, fully-human antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9). Blocking the PCSK9 pathway is a novel mechanism for lowering LDL-C, the leading known risk factor for coronary artery disease.

One phase II trial studied patients with heterozygous familial hypercholesterolemia (heFH) with elevated cholesterol (LDL-C=100mg/dL) despite lipid lowering therapy (statins with or without ezetemibe). The objective of the study was to compare the effect of adding REGN727/ SAR236553 to the existing lipid lowering therapy in heFH patients. In the primary efficacy analysis of the study, after 12 weeks of treatment, patients who received different dosing regimens of REGN727/SAR236553 achieved mean LDL-C reductions from baseline ranging from approximately 30% to greater than 65% depending on dosing regimen of REGN727/SAR236553 compared to a mean reduction of 10% with placebo (p<0.05 for all dose groups). Patients in the study are being followed for a total of 20 weeks for safety.

In this trial, REGN727/SAR236553 was generally well tolerated over 12 weeks. There were no elevations in LFTs >3 times the upper limit of normal and no cases of elevated CPK reported. The most common adverse event was injection site reaction. There were no serious adverse events on active treatment. Full safety data from the 8-week post-treatment monitoring period will be presented at a future medical congress upon final analysis.

Another phase II trial studied patients with primary hypercholesterolemia with elevated cholesterol (LDL-C= 100mg/dL) who were on a stable low dose of atorvastatin (10 mg). The primary objective of the study was to compare the effect of switching to a high dose of atorvastatin alone (80mg) versus a high dose of atorvastatin combined with REGN727/SAR236553. In the primary endpoint of the study, after eight weeks of treatment, patients who received REGN727/SAR236553 plus atorvastatin 80mg achieved a greater than 65% reduction in mean LDL-C compared to a mean reduction of 17% for atorvastatin 80mg only (p<0.001). The study also included a third arm in which REGN727/SAR236553 was added to the stable low dose of atorvastatin and the patients achieved a greater than 65% reduction in mean LDL-C. Patients in the study were followed for a total of 16 weeks for safety.

In this trial, REGN727/SAR236553 was generally well tolerated over 16 weeks. There was one serious adverse event of dehydration in the REGN727/SAR236553 + atorvastatin 80mg group that was deemed not treatment related. One patient in the REGN727/SAR236553 + atorvastatin 80mg group with mildly elevated AST prior to randomization (>ULN and = 3ULN) experienced an elevation of AST>3ULN and =5ULN and one patient discontinued therapy due to a hypersensitivity reaction (rash).

A third study of this phase 2 programme is still ongoing.

“The preliminary phase II results with our anti-PCSK9 antibody are very encouraging,” said Elias Zerhouni, president, Global Research & Development, Sanofi. “We look forward to analysing and presenting the complete data set and remain committed to advancing this programme into phase III development as soon as possible.”

“Despite the availability of statins, elevated cholesterol and coronary artery disease remain a leading cause of morbidity and mortality in the US and the rest of the world,” said George D Yancopoulos, MD, PhD, chief scientific officer of Regeneron and president of Regeneron Research Laboratories. “We are encouraged that blocking PCSK9 with our anti-PCSK9 antibody has the potential to offer a novel mechanism for lowering LDL-C in a broad range of patients. We look forward to further exploring the safety and efficacy of REGN727/SAR236553 in our phase III clinical programme.”

REGN727/SAR236553 is the first fully human monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9). REGN727/SAR236553 is a high affinity, sub-cutaneously delivered, specific inhibitor of PCSK9. It blocks the binding of PCSK9 to the low density lipoprotein (LDL) receptor and interrupts the resultant internalization and degradation of the LDL receptor. In a 15-year retrospective epidemiological analysis from the Atherosclerosis Risk in Communities Study (ARIC) study, patients with nonsense mutations in PCSK9 had a 28% reduction in mean LDL cholesterol and an 88% reduction in the risk of coronary heart disease1. REGN727/SAR236553 was developed using Regeneron’s VelocImmune antibody technology.