The European Commission (EC) has granted marketing authorization for alirocumab for the treatment of elevated LDL cholesterol, in adult patients with primary hypercholesterolemia (heterozygous familial hypercholesterolemia [HeFH] and non-familial) or mixed dyslipidemia. Alirocumab is the only EC-approved PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor that is available in two starting doses as a single 1-milliter (mL) injection (75 mg and 150 mg) once every two weeks, offering two levels of efficacy. Alirocumab will be available in a single-dose pre-filled pen that patients self-administer.

"The availability of two different alirocumab dosing strengths provides for dosing flexibility. In clinical practice, this will enable physicians to tailor treatment based on an individual patient's LDL-cholesterol-lowering needs," said Michel Farnier, M.D., Ph.D., Point Medical, Dijon, France. "In the Phase 3 trials, the majority of patients who started on the lower alirocumab 75 mg dose were able to achieve their pre-defined LDL-cholesterol goals, and maintained treatment at this dose throughout the assessment period."

The EC approved alirocumab for the treatment of adult patients with primary hypercholesterolemia (HeFH and non-familial) or mixed dyslipidemia as an adjunct to diet:
- in combination with a statin, or statin with other lipid-lowering therapies in patients unable to reach their LDL-cholesterol goals with the maximally-tolerated statin or
- alone or in combination with other lipid-lowering therapies for patients who are statin intolerant, or for whom a statin is contraindicated.

The EC marketing authorisation is based on data from 10 pivotal Phase 3 ODYSSEY trials, including five placebo-controlled and five ezetimibe-controlled. The data showed consistent, robust reductions in LDL-cholesterol for alirocumab compared to placebo or ezetimibe, when added to current standard-of-care, which included maximally-tolerated statins. All trials met their primary efficacy endpoint, demonstrating significantly greater reductions from baseline in LDL-cholesterol at week 24, compared to placebo or ezetimibe.

The ability of alirocumab to reduce major CV events is being investigated in the ongoing ODYSSEY OUTCOMES trial, with results anticipated in 2017. In pre-specified final analyses of the ODYSSEY LONG TERM study, major CV events confirmed by adjudication were reported in 1.7% of patients in the alirocumab group and 3.3% of patients in the placebo group. Hazard ratios were calculated post-hoc; HR=0.52 (95% CI: 0.31-0.90). In pre-specified analyses of pooled Phase 3 studies, major CV events were reported in 1.6% of patients in the alirocumab group and 1.8% of those in the control group, which included either placebo or ezetimibe (HR=0.81; 95%CI: 0.52-1.25).
Across the Phase 3 trials all-cause mortality was 0.6% in the alirocumab group and 0.9% in the control group, with CV events being the primary cause of death in the majority of these patients.

In clinical trials, alirocumab was generally well-tolerated with an acceptable safety profile. Local injection site reactions including erythema/redness, itching, swelling or pain/tenderness where the injection is given were the most common events (6% with alirocumab versus 4% with placebo) in clinical trials. Most injection site reactions were transient and of mild intensity. The discontinuation rate due to local injection site reactions was comparable between the two groups (0.2% alirocumab and 0.3% control groups). Other common adverse events occurring more frequently in the alirocumab group than placebo included upper respiratory tract signs and symptoms, and pruritus.

In July, the companies announced that alirocumab was approved for use in the U.S. as an adjunct to diet and maximally-tolerated statin therapy for the treatment of adults with HeFH or clinical atherosclerotic CVD (ASCVD), who require additional lowering of LDL-cholesterol.
 Press release Regeron/Sanofi September 28, 2015