Date: 2012-03-26
Type of information:
phase: 2
Announcement: results
Company: Sanofi (France) Regeneron Pharmaceuticals (USA)
Product: REGN727/SAR236553
Action mechanism: REGN727/SAR236553 is a fully-human monoclonal antibody directed against PCSK9 (proprotein convertase subtilisin/kexin type 9), administered via subcutaneous injection. By inhibiting PCSK9, a determinant of circulating LDL-cholesterol levels in the blood, REGN727 increases the number of free LDL receptors which can bind to circulating LDL and clear it from the bloodstream. REGN727 was created using Regeneron\'s pioneering VelocImmune® technology and is being developed by Regeneron in collaboration with Sanofi.
Disease: primary hypercholesterolemia
Therapeutic area: Cardiovascular diseases - Metabolic diseases
Country:
Trial
details: Study 11565 was a randomized, double-blind, multi-dose, placebo-controlled, 183-patient trial in patients with primary hypercholesterolemia and on stable doses of atorvastatin. In this trial, patients on a stable dose of atorvastatin 10, 20 or 40 mg for at least 6 weeks with LDL-cholesterol levels greater than or equal to 100 mg/dL, or who had LDL-cholesterol levels greater than or equal to 100 mg/dL after a run-in period on atorvastatin 10, 20 or 40 mg, were randomized to one of five different dose regimens of SAR236553/REGN727 (i.e. either 50, 100, or 150 mg Q2W, or 200 or 300 mg Q4W alternating with placebo at 2 weeks) plus continued atorvastatin or placebo. The primary endpoint of the study was the change in LDL-cholesterol from baseline over the 12-week study period. Patients were followed for a total of 20 weeks for safety.
Study 11566 was a randomized, double-blind, multi-dose, placebo-controlled, 92-patient trial in patients with primary hypercholesterolemia. In this trial, patients on a stable dose of atorvastatin 10 mg for at least 6 weeks with LDL-cholesterol levels greater than or equal to 100 mg/dL, or who had LDL-cholesterol levels greater than or equal to 100 mg/dL after a run-in period on atorvastatin 10 mg, were randomized to either (a) titration from atorvastatin 10 mg to atorvastatin 80 mg plus SAR236553/REGN727 150 mg Q2W, (b) titration from atorvastatin 10 mg to atorvastatin 80 mg plus placebo, or (c) continued atorvastatin 10 mg plus SAR236553/REGN727 150 mg Q2W. The primary endpoint of the study was the change in LDL-cholesterol from baseline over the 8-week study period. Patients were followed for a total of 16 weeks for safety.
Latest
news: Sanofi and Regeneron Pharmaceuticals have announced that data from two Phase 2 trials with SAR236553/REGN727, an investigational, high-affinity, subcutaneously administered, fully-human antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), were presented at the American College of Cardiology’s (ACC) 61st Annual Scientific Meeting in Chicago (1,2).
The data showed that treatment with SAR236553/REGN727 over 8 to 12 weeks significantly reduced mean low-density lipoprotein-cholesterol (LDL-C, or “bad” cholesterol) by 40% to 72% in patients with elevated LDL-C on stable dose of statins. These trial results suggest that SAR236553/REGN727 may enable patients for whom statins are insufficient to further reduce LDL-C. The most common adverse events (AEs) with SAR236553/REGN727 were injection site reactions. Serious AEs occurred in one patient receiving placebo and three patients in the active treatment arms, including a patient on active treatment who experienced a skin rash diagnosed as leukocytoclastic vasculitis. Six patients, all on active treatment, prematurely discontinued therapy due to AEs. Muscle complaints were infrequent and similar across all treatment groups. There were no significant elevations in liver enzymes or other lab values in patients on active treatment.
Based on this finding and the results of our Phase 2 trials, Sanofi and Regeneron plan to initiate the SAR236553/REGN727 Phase 3 program in the second quarter.
Data from a separate trial, “Study DFI11566,” were presented y during an oral session of the ACC meeting. The study enrolled patients with primary hypercholesterolemia with elevated LDL-C (greater than or equal to 100 mg/dL) who were on a stable low dose of atorvastatin (10 mg). The primary objective of the study was to compare the effect on LDL-C lowering of switching to a high dose of atorvastatin alone (80 mg) versus a high dose of atorvastatin combined with SAR236553/REGN727. Patients who received SAR236553/REGN727 plus atorvastatin 80 mg achieved a mean reduction of 73% in LDL-C, compared to a mean reduction of 17% for patients who switched to atorvastatin 80 mg alone (p<0.001) after eight weeks. The study also included a third arm in which SAR236553/REGN727 was added to the stable low dose of atorvastatin. Patients in this arm achieved a 66% reduction in mean LDL-C. Patients in the study were followed for a total of 16 weeks for safety.
In this trial, the most common AE with SAR236553/REGN727 was infection. There was one serious AE in the SAR236553/REGN727 plus atorvastatin 80 mg group (dehydration) that was deemed not to be treatment-related.
A long-term safety and tolerability study of SAR236553/REGN727 (NCT01507831) is ongoing in patients with hypercholesterolemia who are not adequately controlled with their current lipid-modifying therapy.6 Sanofi and Regeneron are intending to initiate Phase III clinical studies for SAR236553/REGN727 in Q2 2012. Sanofi and Regeneron are co-developing SAR236553/REGN727 as part of their research and development collaboration agreements.
1 McKenney JM, et al. A randomized, double-blind, placebo-controlled trial of the safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, REGN727/SAR236553, in patients with primary hypercholesterolemia. Presented at the 61st ACC Annual Meeting, Chicago, IL, USA; March 26, 2012. Abstract No. #306-10.
2 Roth E, et al. The effects of co-administering a monoclonal antibody to proprotein convertase subtilisin/kexin 9, REGN727/SAR236553, with 10 and 80 mg atorvastatin compared to 80 mg alone in patients with primary hypercholesterolemia. Presented at the 61st ACC Annual Meeting, Chicago, IL, USA; March 26, 2012. Abstract No. #911-5.
The results of the Phase 1 clinical program with their investigational product REGN727/SAR23655
were published in the March 22, 2012 issue of the New England Journal of Medicine.
