• Lipid Disorders
• Cardiology Clinical Trials
• Cardiology

• Lipid Disorders
• Cardiology Clinical Trials

Michel Farnier, MD, PhD, Point Medical, Dijon, France, presented results from the Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy trial [ODYSSEY FH I; NCT01623115] and the Study of Alirocumab (REGN727/SAR236553) in Patients With HeFH (Heterozygous Familial Hypercholesterolemia) Who Are Not Adequately Controlled With Their LMT (Lipid-Modifying Therapy) trial [ODYSSEY FH II; NCT01709500]. These trials demonstrated that, in patients with heterozygous familial hypercholesterolemia (HeFH) whose low-density lipoprotein cholesterol (LDL-C) levels were inadequately controlled by statin and other lipid-lowering therapy (LLT), alirocumab produced significantly greater reductions in LDL-C compared with placebo.

Mutations in the LDL receptor gene, which cause HeFH, lead to elevated plasma levels of LDL-C and an increased risk of premature atherosclerosis and cardiovascular disease (CVD) [Pijlman AH et al. Atherosclerosis. 2010].

According to Prof Farnier, patients with HeFH are challenging to treat in clinical practice. Statins are the drug of first choice; however, even at the maximum tolerated dose, approximately 80% of adult patients with HeFH fail to reach the LDL-C target of < 2.5 mmol/L (100 mg/dL) with monotherapy [Pijlman AH et al. Atherosclerosis. 2010]. The LDL-C target for adults with HeFH who also have coronary heart disease or diabetes is < 1.8 mmol/L (< 70 mg/dL) [Nordestgaard BG et al. Eur Heart J. 2013].

ODYSSEY FH I and II were double-blind, placebo-controlled trials, conducted in North America, Europe, and South Africa for ODYSSEY FH I and across Europe for ODYSSEY FH II, that enrolled a total of 735 participants (aged approximately 52 to 53 years). Inclusion criteria included patients who had HeFH, a history of CVD, LDL-C ≥ 1.81 mmol/L (≥ 70 mg/dL), or no history of CVD and LDL-C ≥ 2.59 mmol/L (≥ 100 mg/dL), and who were receiving a maximally tolerated daily statin dose with or without other LLT. Patients were randomized to alirocumab (75 to 150 mg subcutaneously Q2W; n = 490 across both studies), or matching placebo (n = 245 across both studies) for 78 weeks, in addition to current therapy.

The primary end point was the percentage change in LDL-C from baseline to week 24. At week 24, alirocumab significantly reduced LDL-C levels compared with placebo in both FH I and II trials (− 48.8% and − 48.7% vs 9.1% and 2.8%, respectively; P < .0001). To reach a prespecified LDL-C level < 1.81 mmol/L (70 mg/dL), an uptitration to 150 mg Q2W at week 12 was necessary in 43.4% and 38.6% of patients receiving alirocumab treatment in both trials.

Similarly, by week 24, significantly more alirocumab-treated patients compared to those on placebo had reached the LDL-C goal of a level < 2.59 mmol/L (100 mg/dL) in high-risk patients or < 1.81 mmol/L (70 mg/dL) in very high-risk patients (72.2% vs 2.4% in FH I, and 81.4% vs 11.3% in FH II; both P < .0001). Most patients receiving alirocumab achieved their LDL-C goals at week 24 in both trials (72.2% and 81.4% vs 2.4% and 11.3%; P < .0001), and this reduction was maintained to 52 weeks (1.7 mmol/L and 1.9 mmol/L [65.9 mg/dL and 74.3 mg/dL]).

In an analysis of pooled data from the 2 trials at week 52, alirocumab appeared to be well tolerated. Treatment-emergent adverse events (TEAEs) occurred in a similar proportion of patients treated with alirocumab and placebo (74.8% vs 75.4%) and led to discontinuation in 3.1% and 3.7% of patients, respectively. The most commonly reported TEAEs (occurring in ≥ 5% of patients in each treatment arm) were injection-site reactions, naso-pharyngitis, influenza, and headaches.

With such a large proportion of patients achieving their target LDL-C levels, and the lack of major adverse safety signals compared with placebo, alirocumab represents a very promising treatment approach for this very high-risk patient population, concluded Prof Farnier.

• © 2014 MD Conference Express®