Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study

Abstract

Background: The PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low-density lipoprotein-cholesterol (LDL-C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin-associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone.

Methods and results: Patients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL-C target levels were not met. The primary efficacy endpoint was LDL-C percentage change from baseline to W24. Mean baseline LDL-C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n=59), 154.5 mg/dL (alirocumab 75 mg Q2W, n=116), and 158.5 mg/dL (placebo, n=58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least-squares mean LDL-C changes from baseline to W24 were -51.7% and -53.5%, respectively (placebo [+4.7%]; both groups P<0.0001 versus placebo). In total, 63.9% and 70.3% of alirocumab-treated patients achieved their LDL-C targets at W24. Treatment-emergent adverse events occurred in 77.6% (alirocumab 150 mg Q4W), 73.0% (alirocumab 75 mg Q2W), and 63.8% (placebo) of patients, with injection-site reactions among the most common treatment-emergent adverse events.

Conclusions: Alirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL-C.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02023879.

Keywords: alirocumab; cardiovascular risk; low‐density lipoprotein cholesterol; placebo‐controlled; proprotein convertase subtilisin/kexin type 9.

Figure 1

CHOICE II study design. *Patients were to be randomized to 2:1:1 alirocumab 150Q4W: alirocumab 75Q2W: placebo. However, a systematic randomization error occurred in alirocumab treatment allocation. ^†Blind was maintained in all patients, including those receiving dose adjustments, by giving the study treatment as a single 1‐mL subcutaneous injection Q2W in all groups. 75Q2W indicates 75 mg every 2 weeks (with possible dose adjustment to 150 mg every 2 weeks); 150Q4W, 150 mg every 4 weeks (with possible dose adjustment to 150 mg every 2 weeks); LDL‐C, low‐density lipoprotein cholesterol; NCEP ATP III TLC, National Cholesterol Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes; Q2W, every 2 weeks; Q4W, every 4 weeks; R, randomization; W, week.

Figure 2

Calculated LDL‐C mean (SE) absolute values from baseline (ITT analysis) (A) and free PCSK9 levels (B) over time (PK analysis). ΔW 9 to 12 defined as percentage change in calculated LDL‐C from baseline to averaged values from weeks 9 to 12 vs placebo in the ITT analysis; ΔW 24 defined as percentage change in calculated LDL‐C from baseline to week 24 vs placebo in the ITT analysis. 75Q2W indicates 75 mg every 2 weeks (with possible dose adjustment to 150 mg every 2 weeks); 150Q4W indicates150 mg every 4 weeks (with possible dose adjustment to 150 mg every 2 weeks); ITT, intent‐to‐treat; LDL‐C, low‐density lipoprotein cholesterol; LS, least‐squares; PCSK9, proprotein convertase subtilisin/kexin type 9; SE, standard error.

Figure 3

Impact of dosing regimen adjustment on LDL‐C levels (ITT analysis*) (A) and free PCSK9 levels (B) in patients in the 150 mg Q4W alirocumab cohort: time profile from baseline to Week 24 (PK analysis*). *Patients who received dose adjustment at Week 12 and had at least 1 subsequent injection. LDL‐C indicates low‐density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error.