Sanofi and Regeneron Report Phase 2 Results for Lipid Drug

Potential first in class medication

/ Author:  / Reviewed by: Natasha Levin
Sanofi and Regeneron Pharmaceuticals, Inc. announced that data from two Phase 2 trials with 
SAR236553/REGN727, an investigational, high-affinity, subcutaneously administered, fully-human
antibody targeting PCSK9 (proprotein convertasesubtilisin/kexin type 9), were presented at the
American College of Cardiology’s (ACC) 61st Annual Scientific Meeting in Chicago.
 


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.
“Many patients are not able to lower their LDL-C sufficiently by diet and medication despite the availability
of statins. As guidelines are evolving, there is a real need for additional lipid-lowering medications,” said
Dr. James McKenney, President and CEO of National Clinical Research, Inc., Professor Emeritus of the
Virginia Commonwealth University School of Pharmacy, USA, and Principal Investigator of the study.
“These trial results suggest that SAR236553/REGN727 may enable patients for whom statins are
insufficient to further reduce LDL-C.” “Study DFI11565,” the Phase 2 dose-finding clinical trial enrolled
183 patients with elevated LDL-C (greater than or equal to 100 mg/dL) despite being on a stable
dose of atorvastatin.

The objective of the study was to evaluate the effect of adding SAR236553/REGN727 to existing statin
therapy. Across the five different dose regimens tested, patients receiving SAR236553/REGN727 for
12 weeks achieved and sustained a mean LDL-C reduction from baseline of 40% to 72%, compared
to 5% in patients receiving placebo (p<0.0001). Patients in the study were followed for a total of 20 weeks
for safety.
 
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. “So far,
SAR236553/REGN727 has demonstrated LDL-lowering efficacy and a generally acceptable safety
profile,” said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President
of Regeneron Research Laboratories. “PCSK9 inhibition is being investigated for its potential to lower
LDL-C in patients who cannot achieve their goals with standard therapies.”2/5 The PCSK9 mechanism
is an example of how the study of genetics can identify new targets for developing new therapies.
 
The role of PCSK9 in lipid metabolism was discovered a few years ago based on population studies. 
“Genetic data have shown that patients with natural loss-of-function mutations in PCSK9 have significantly
lower LDL-C and a lower risk of coronary heart disease,” said Dr. Elias Zerhouni, President, Global Research
& Development, Sanofi. “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 during an oral session of the ACC meeting.
The study enrolled patients with primary hypercholesterolemia with elevated LDLC (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.
 
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.
 
About PCSK9

PCSK9 is known to be a determinant of circulating LDL levels, as it binds to LDL receptors resulting
in their degradation so that fewer are available on liver cells to remove excess LDL-cholesterol from
the blood. Moreover, traditional LDL-lowering therapies such as statins actually stimulate the
production of PCSK9, which limits their own ability to lower LDL-cholesterol. Blocking the PCSK9
pathway is therefore a potentially novel mechanism for lowering LDL-cholesterol.
About SAR236553/REGN727 and the Phase II primary hypercholesterolemia trials
SAR236553/REGN727 is a fully human monoclonal antibody directed against PCSK9, administered
via subcutaneous injection. By inhibiting PCSK9, a determinant of circulating LDL-cholesterol levels
in the blood, SAR236553/REGN727 increases the number of free LDL receptors which can bind to
circulating LDL and clear it from the bloodstream. SAR236553/REGN727 was created using 
Regeneron’s pioneering VelocImmune technology
 
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 3/5
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.
 
About primary hypercholesterolemia
 
Hypercholesterolemia, particularly an increase in LDL-C levels, is a major risk factor for the
development of cardiovascular disease. LDL-C is identified as the primary target of cholesterol lowering
therapies such as statins, which have significantly helped in managing the risk for cardiovascular disease.
However, despite the availability of statins, many patients with hypercholesterolemia are not reaching their
recommended LDL-C goal and need new additional therapy.
Reviewed by: 
Review Date: 
March 30, 2012