Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies

John J P Kastelein, Jennifer G Robinson, Michel Farnier, Michel Krempf, Gisle Langslet, Christelle Lorenzato, Daniel A Gipe, Marie T Baccara-Dinet, John J P Kastelein, Jennifer G Robinson, Michel Farnier, Michel Krempf, Gisle Langslet, Christelle Lorenzato, Daniel A Gipe, Marie T Baccara-Dinet

Abstract

Background: Individuals with heterozygous familial hypercholesterolemia (heFH) have higher levels of low-density lipoprotein cholesterol (LDL-C) and are predisposed to premature cardiovascular disease. Alirocumab is a fully-human, monoclonal antibody targeted to proprotein convertase subtilisin/kexin type 9 currently in Phase 3 development for the treatment of hypercholesterolemia. Described here are three ODYSSEY Phase 3 trials, FH I (NCT01623115), FH II (NCT01709500) and HIGH FH (patients with heFH and LDL-C levels ≥160 mg/dL) (NCT01617655), in which alirocumab is further evaluated in the heFH population.

Methods: Multicenter, multinational, randomized, double-blind, placebo-controlled studies have been designed to evaluate efficacy and safety of alirocumab in more than 800 patients with heFH who are not adequately controlled with a maximally-tolerated stable daily dose of statin for ≥4 weeks prior to the screening visit, with or without other lipid-lowering therapy. Patients are randomized (2:1) to receive alirocumab or placebo via a 1-mL subcutaneous auto-injection every 2 weeks (Q2W) for 78 weeks. In studies FH I and II, if their Week 8 LDL-C level is ≥70 mg/dL, patients will undergo a dose uptitration from 75 to 150 mg alirocumab Q2W at Week 12. In HIGH FH, patients will receive alirocumab 150 mg Q2W throughout the entire treatment period. The primary efficacy endpoint in all three studies is the percent change in calculated LDL-C from baseline to Week 24.

Conclusions: The ODYSSEY FH studies are three Phase 3 studies aiming to further evaluate the efficacy and long-term safety of alirocumab as an effective therapeutic option for patients with heFH.

Figures

Fig. 1
Fig. 1
Study designs. a ODYSSEY FH I, b ODYSSEY FH II and c ODYSSEY HIGH FH. CV cardiovascular, heFH heterozygous familial hypercholesterolemia, LDL-C low-density lipoprotein cholesterol, LLT lipid-lowering therapy, NCEP ATP III TLC National Cholesterol Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes, Q2W every 2 weeks, R randomization, SC subcutaneous. aAt the end of the double-blind treatment period, patients will be offered the possibility to enter an open-label extension study, in which they will receive alirocumab. If patients opt out of entering the open-label treatment period, they will enter the 8-week follow-up period

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