Sanofi and Regeneron present detailed positive results from four pivotal Alirocumab trials at ESC Congress 2014

Sanofi (EURONEXT: SAN and NYSE: SNY) and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced detailed positive results from four Phase 3 ODYSSEY trials of alirocumab in people with hypercholesterolemia. Alirocumab is an investigational monoclonal antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9). Results from the four ongoing trials, all of which met their primary efficacy endpoint, will be presented today at a Hot Line session at the ESC Congress 2014 in Barcelona, Spain.

“Across these four trials, alirocumab showed significant and sustained reductions in LDL-C over one year on top of standard-of-care statin therapy across different patient types,” said Jennifer Robinson, M.D., M.P.H., Director of the Prevention Intervention Center, Professor, Departments of Epidemiology & Medicine, College of Public Health at the University of Iowa. “We are also encouraged by the consistent safety profile across the trials, including in ODYSSEY LONG TERM, the largest Phase 3 trial of a PCSK9 inhibitor, with the longest follow-up period reported to date.”

ODYSSEY LONG TERM Trial

The ongoing 2,341-patient, double-blind ODYSSEY LONG TERM trial is designed to evaluate the long-term safety and efficacy of 150 milligrams (mg) alirocumab every two weeks versus placebo in patients with hypercholesterolemia who are at high or very-high cardiovascular (CV) risk, including patients with an inherited form of high cholesterol known as heterozygous familial hypercholesterolemia (HeFH). Both study groups are treated with statins at a maximally-tolerated dose and some patients also receive additional lipid-lowering therapies.  A pre-specified interim analysis was performed when all patients reached one year and approximately 25 percent of patients reached 18 months of treatment.  Key data presented today include:

• On the primary efficacy endpoint of the trial, at 24 weeks, there was a 61 percent reduction from baseline in LDL-C levels in the alirocumab group as compared to a 1 percent increase in the placebo group (62 percent reduction in alirocumab group compared to placebo), p<0.0001.  
• At 52 weeks, there was a 57 percent reduction from baseline in LDL-C levels in the alirocumab group as compared to a 4 percent increase in the placebo group (61 percent reduction in alirocumab group compared to placebo), p<0.0001.
• 81 percent of alirocumab patients achieved their pre-specified LDL-C goal (either 70 milligrams/deciliter [mg/dL] or 100 mg/dL depending on patients’ baseline CV risk) compared to 9 percent for placebo (p<0.0001).
• The most common adverse events (greater than or equal to 5 percent of patients) were nasopharyngitis (13 percent alirocumab; 13 percent placebo), upper respiratory tract infection (7 percent alirocumab; 8 percent placebo), and injection site reactions (6 percent alirocumab; 4 percent placebo).
• In a post hoc safety analysis, there was  a lower rate of adjudicated major CV events (cardiac death, myocardial infarction, stroke, and unstable angina requiring hospitalization) in the alirocumab group compared to placebo (1.4 percent compared to 3.0 percent, nominal p-value <0.01). These CV events comprise the composite primary endpoint of the ongoing 18,000-patient ODYSSEY OUTCOMES trial, which is prospectively evaluating the potential of alirocumab to demonstrate CV benefit. 

Three additional trials (ODYSSEY COMBO II, FH I and FH II) will also be presented today.

In these three trials, alirocumab-treated patients receive an initial dose of alirocumab 75 mg every two weeks, increasing to 150 mg if needed to reach pre-specified LDL-C levels. The 75 mg and 150 mg alirocumab doses were delivered as a single, self-administered 1 milliliter (mL) injection.

“As physicians, we often start patients on a lower dose of a medication and only increase it if needed.  In these trials, the majority of patients who were started at a 75 mg dose of alirocumab, were able to achieve their target LDL-C goals while remaining on their initial dose,” said Christopher Cannon M.D., Professor of Medicine, Harvard Medical School

ODYSSEY COMBO II trial

ODYSSEY COMBO II is a double-blind, 720-patient trial designed to evaluate the safety and efficacy of alirocumab compared to ezetimibe in patients with hypercholesterolemia who are at high CV risk and at baseline had inadequate LDL-C reduction despite stable maximally-tolerated statin therapy.  Key data to be presented today include:

• On the primary endpoint of the trial, at 24 weeks, there was a 51 percent reduction from baseline in LDL-C levels in the alirocumab group compared to a 21 percent reduction in the ezetimibe group (30 percent reduction in alirocumab group compared to ezetimibe group), p<0.0001.
• At 52 weeks, there was a 50 percent reduction from baseline in LDL-C levels in the alirocumab group compared to an 18 percent reduction in the ezetimibe group (32 percent reduction in alirocumab group compared to ezetimibe group), p<0.0001.
• 77 percent of patients in the alirocumab group achieved an LDL-C level of 70 mg/dL at 24 weeks.
• Approximately 80 percent of patients in the alirocumab group remained on the initial 75 mg alirocumab dose.
• The most common adverse events (greater than or equal to 5 percent of patients) were upper respiratory tract infection (6.5 percent alirocumab; 6 percent ezetimibe), accidental overdose (6 percent alirocumab; 7 percent ezetimibe), dizziness (5 percent alirocumab; 5 percent ezetimibe), and myalgia (4 percent alirocumab; 5 percent ezetimibe).

ODYSSEY FH I and FH II trials

The ODYSSEY FH I and FH II trials enrolled a total of 738 HeFH patients and compare alirocumab to placebo. All patients are on maximally-tolerated daily statin therapy and the majority of patients also receive ezetimibe.  Despite receiving this high level of background therapy, patients in these studies had mean baseline LDL-C levels of 145 mg/dL (FH I) and 134 mg/dL (FH II). Key data to be presented today for FH I and FH II include:

• On the primary endpoint of the trials, at 24 weeks, there was a 49 percent reduction from baseline in LDL-C levels in both FH I and FH II alirocumab groups compared to an increase of 9 percent in FH I and 3 percent in FH II in the placebo groups, (58 and 51 percent reduction compared to placebo), p<0.0001.
• At 52 weeks, in FH I, there was a 47 percent reduction from baseline and in FH II, a 50 percent reduction from baseline in LDL-C levels in the alirocumab groups compared to an increase of 9 and 8 percent in the placebo groups, respectively (56 and 58 percent reduction compared to placebo), p<0.0001.
• 72 percent of alirocumab-treated patients in FH I and 81 percent of patients alirocumab-treated patients in FH II  achieved their pre-specified LDL-C goal (either 70 mg/dL or 100 mg/dL) at 24 weeks compared to 2 and 11 percent in the placebo groups, respectively (p<0.0001).
• Approximately 50 percent of patients in the alirocumab groups remained on the 75 mg dose.
• In pooled data from both trials, the most common adverse events (greater than or equal to 5 percent of patients) were injection site reactions (11.5 percent alirocumab; 9 percent placebo), nasopharyngitis (10 percent alirocumab; 11 percent placebo), influenza (9 percent alirocumab; 6 percent placebo), and headache (5.5 percent alirocumab; 7 percent placebo).  

“Heterozygous FH patients often have high LDL-C despite treatment with statins and other options,” said Michel Farnier, M.D., Ph.D., Point Medical, Dijon, France.  “Although a large majority of patients in ODYSSEY FH I and FH II had high LDL-C at baseline, at least 70 percent of alirocumab-treated patients reached their treatment goals.”

The four ODYSSEY trials reported today, along with results from six other Phase 3 studies, encompass more than 5,000 patients studied in double-blind trials for 24-104 weeks. Sanofi and Regeneron anticipate alirocumab regulatory submissions in the U.S. and EU by the end of 2014. In the U.S., the companies intend to use a Priority Review Voucher to obtain priority review status for the alirocumab regulatory submission. 

The ODYSSEY clinical trial program remains ongoing. Click here for more information on the ODYSSEY studies presented at ESC Congress 2014. Alirocumab is currently under clinical development and its safety and efficacy have not been evaluated by any regulatory authority.