Metabolism Xagena
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 ) were presented at the ESC Congress 2014 in Barcelona, Spain.
The ongoing 2,341-patient, double-blind ODYSSEY LONG TERM trial is designed to evaluate the long-term safety and efficacy of 150 mg Alirocumab every two weeks versus placebo in patients with hypercholesterolemia who are at high or very-high cardiovascular 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% of patients reached 18 months of treatment.
On the primary efficacy endpoint of the trial, at 24 weeks, there was a 61% reduction from baseline in LDL-C levels in the Alirocumab group as compared to a 1% increase in the placebo group ( 62% reduction in Alirocumab group compared to placebo; p less than 0.0001 ).
At 52 weeks, there was a 57% reduction from baseline in LDL-C levels in the Alirocumab group as compared to a 4% increase in the placebo group ( 61% reduction in Alirocumab group compared to placebo; p less than 0.0001 ).
81% of Alirocumab patients achieved their pre-specified LDL-C goal ( either 70 mg/dL or 100 mg/dL depending on patients' baseline cardiovascular risk ) compared to 9% for placebo ( p less than 0.0001 ).
The most common adverse events ( greater than or equal to 5% of patients ) were nasopharyngitis ( 13% Alirocumab; 13% placebo ), upper respiratory tract infection ( 7% Alirocumab; 8% placebo ), and injection site reactions ( 6% Alirocumab; 4% placebo ).
In a post hoc safety analysis, there was a lower rate of adjudicated major cardiovascular events ( cardiac death, myocardial infarction, stroke, and unstable angina requiring hospitalization ) in the Alirocumab group compared to placebo ( 1.4% compared to 3.0%, nominal p-value less than 0.01 ). These cardiovascular 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 cardiovascular benefit.
Three additional trials ( ODYSSEY COMBO II, FH I and FH II ) have been presented. 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 mL injection.
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 cardiovascular risk and had inadequate LDL-C reduction at baseline despite stable maximally-tolerated statin therapy.
On the primary endpoint of the trial, at 24 weeks, there was a 51% reduction from baseline in LDL-C levels in the Alirocumab group compared to a 21% reduction in the Ezetimibe group ( 30% reduction in Alirocumab group compared to Ezetimibe group; p less than 0.0001 ).
At 52 weeks, there was a 50% reduction from baseline in LDL-C levels in the Alirocumab group compared to an 18% reduction in the Ezetimibe group ( 32% reduction in Alirocumab group compared to Ezetimibe group; p less than 0.0001 ).
77% of patients in the Alirocumab group achieved an LDL-C level of 70 mg/dL at 24 weeks.
Approximately 80% 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% of patients ) were upper respiratory tract infection ( 6.5% Alirocumab; 6% Ezetimibe ), accidental overdose ( 6% Alirocumab; 7% Ezetimibe ), dizziness ( 5% Alirocumab; 5% Ezetimibe ), and myalgia ( 4% Alirocumab; 5% Ezetimibe ).
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 ).
On the primary endpoint of the trials, at 24 weeks, there was a 49% reduction from baseline in LDL-C levels in both FH I and FH II Alirocumab groups compared to an increase of 9% in FH I and 3% in FH II in the placebo groups ( 58 and 51% reduction compared to placebo; p less than 0.0001 ).
At 52 weeks, in FH I, there was a 47% reduction from baseline and, in FH II, a 50% reduction from baseline in LDL-C levels in the Alirocumab groups compared to an increase of 9 and 8% in the placebo groups, respectively ( 56 and 58% reduction compared to placebo; p less than 0.0001 ).
72% of Alirocumab-treated patients in FH I, and 81% of 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% in the placebo groups, respectively ( p less than 0.0001 ).
Approximately 50% 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% of patients ) were injection site reactions ( 11.5% Alirocumab; 9% placebo ), nasopharyngitis ( 10% Alirocumab; 11% placebo ), influenza ( 9% Alirocumab; 6% placebo ), and headache ( 5.5% Alirocumab; 7% placebo ). ( Xagena )
Source: Sanofi & Regeneron, 2014
XagenaMedicine_2014
