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Alirocumab Reduces LDL Cholesterol in Six Phase III Trials

FDA submission expected later this year

Positive results have been reported from six phase III studies of alirocumab (Regeneron Corporation/Sanofi), an investigational fully human monoclonal antibody targeting the protein PCSK9 (proprotein convertase subtilisin/kexin type 9) that is being evaluated for its ability to reduce low-density lipoprotein cholesterol (LDL-C), or “bad” cholesterol.

In all six studies, alirocumab significantly lowered LDL-C levels in hypercholesterolemic patients.

All of the trials –– ODYSSEY LONG TERM, COMBO I, ALTERNATIVE, OPTIONS I, OPTIONS II, and HIGH FH –– met their primary efficacy endpoint of a greater reduction in LDL-C at 24 weeks versus either an active comparator or placebo, which included standard-of-care therapy. Results from these trials were presented November 17 at the American Heart Association Scientific Sessions in Chicago, Illinois.

The studies evaluated alirocumab in hypercholesterolemic patients who were at high cardiovascular (CV) risk, had an inherited form of high cholesterol known as heterozygous familial hypercholesterolemia (HeFH), and/or had a history of intolerance to two or more statins, including one at the lowest dose. All of the patients received alirocumab in addition to standard-of-care lipid-lowering therapy, with the exception of some patients in the ODYSSEY ALTERNATIVE study.

In an interim analysis of the ongoing, 78-week ODYSSEY LONG TERM safety, tolerability, and efficacy trial, generally comparable rates of adverse events (AEs) were observed among the 37% (n = 562) of alirocumab-treated patients who achieved two consecutive LDL-C values of less than 25 mg/dL compared with the overall alirocumab patient population in this study.

ODYSSEY ALTERNATIVE is the first trial of a PCSK9 inhibitor to reassess statin intolerance (as measured by skeletal-muscle AEs) by including a validation arm (atorvastatin 20 mg). In clinical practice, 10% to 25% of patients report intolerance to statins, and many have poorly controlled LDL-C, which puts them at increased risk of CV events. In this trial, fewer skeletal-muscle AEs occurred in the alirocumab group compared with patients treated with atorvastatin (33% vs. 46%; hazard ratio, 0.61; nominal P value = 0.042), and there was no significant difference compared with the ezetimibe group (41%).

In addition, there were numerically fewer discontinuations for skeletal-muscle AEs in the alirocumab group, but this did not reach statistical significance (16% for alirocumab, 20% for forezetimibe, and 22% for atorvastatin). In comparison, the overall rate of discontinuations for skeletal-muscle AEs across the phase II and phase III placebo-controlled studies of alirocumab, in which most patients were also receiving statins, was 0.4% for alirocumab (n = 2,476) and 0.5% for placebo (n = 1,276).

Patients in all six randomized, double-blind, phase III ODYSSEY trials received alirocumab via a single self-administered 1-mL subcutaneous injection every 2 weeks. Alirocumab-treated patients received the 150-mg dose in ODYSSEY LONG TERM and HIGH FH, and the 75-mg dose (increasing to 150 mg, if needed, to reach prespecified LDL-C levels) in ODYSSEY ALTERNATIVE, OPTIONS I, OPTIONS II, and COMBO I. In the trials that used an individualized approach with 75-mg and 150-mg doses, most of the patients reached their LDL-C goal while remaining on the 75-mg dose. Average baseline LDL-C levels in all six trials were between approximately 100 and 120 mg/dL, with the exception of ODYSSEY ALTERNATIVE and HIGH FH, in which baseline LDL-C levels were greater than 190 mg/dL.

An FDA submission is expected before the end of this year.

Alirocumab is currently under clinical development, and its safety and efficacy have not been evaluated by any regulatory authority.

Source: Sanofi; November 19, 2014.

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