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Positive Results Reported From Nine Phase III Trials of Alirocumab in Hypercholesterolemia

Antibody targets PCSK9 protein

Nine new phase III studies of alirocumab (Sanofi/Regeneron) in patients with hypercholesterolemia met their primary efficacy endpoint of a greater percent reduction from baseline in low-density lipoprotein cholesterol (LDL-C) at 24 weeks compared with placebo or an active comparator.

Alirocumab is an investigational, fully human monoclonal antibody that targets and blocks proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein secreted by liver cells. PCSK9 plays a role in the clearance of LDL-C by regulating the number of LDL receptors. By inhibiting this protein, alirocumab increases the number of LDL receptors on hepatocytes, thereby lowering LDL-C. The treatment is administered via subcutaneous injection.

The nine phase III ODYSSEY trials of alirocumab included LONG TERM, FH I, FH II, HIGH FH, COMBO I, COMBO II, OPTIONS I, OPTIONS II and ALTERNATIVE. All of the patients in these studies received alirocumab in addition to standard-of-care lipid-lowering therapy, with the exception of some patients in ODYSSEY ALTERNATIVE.

The ongoing ODYSSEY LONG TERM trial evaluated the long-term safety and efficacy of alirocumab compared with placebo in 2,341 patients. Both treatment groups received statins, and some patients also received additional lipid-lowering therapies. The trial met its primary efficacy endpoint at 24 weeks.

A pre-specified interim safety analysis was performed when all of the patients reached 1 year of treatment. A lower rate of adjudicated major cardiovascular events (i.e., cardiac death, myocardial infarction, stroke, and unstable angina requiring hospitalization) was observed in the alirocumab arm compared with the placebo arm in a post hoc analysis (P < 0.05). The potential of alirocumab to provide a cardiovascular benefit is being prospectively assessed in 18,000 patients in the ongoing ODYSSEY OUTCOMES trial.

The ODYSSEY ALTERNATIVE study evaluated patients with a history of intolerance to two or more statins, who were randomly assigned to receive alirocumab, ezetimibe (Zetia, Merck), or atorvastatin (Lipitor, Pfizer). This trial met its primary efficacy endpoint of a greater percent reduction from baseline in LDL-C at 24 weeks with alirocumab compared with ezetimibe. The rates of discontinuation due to adverse events were 18% for alirocumab, 25% for atorvastatin, and 25% for ezetimibe. These differences between treatment groups were not statistically significant.

The nine double-blind ODYSSEY trials, along with the previously reported MONO trial, included more than 5,000 patients studied for 24 to 104 weeks. Positive results were reported for ODYSSEY MONO in October 2013.

All of the studies included patients with LDL-C not at goal, with or without a documented history of cardiovascular disease. ODYSSEY OPTIONS I, OPTIONS II, COMBO II, MONO, and ALTERNATIVE included at least one active comparator (e.g., ezetimibe).

The trials evaluated two alirocumab dosing regimens: 150 mg every 2 weeks or 75 mg every 2 weeks (increasing to 150 mg if needed to reach protocol-specified LDL-C targets). The 150-mg and 75-mg doses were delivered with a single, self-administered 1-mL subcutaneous injection.

The ODYSSEY clinical trial program is ongoing and includes three additional studies — CHOICE I, CHOICE II (both evaluating monthly doses of alirocumab), and OUTCOMES. Primary outcomes data are expected in 2015 and beyond.

Sources: Sanofi; July 30, 2014; and Alirocumab Backgrounder; March 2014.

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