ODYSSEY COMBO I - ODYSSEY COMBO I

Description:

The current trial sought to study the safety and efficacy of alirocumab, a PCSK9 inhibitor, compared with placebo in patients who were on maximal tolerated doses of a statin, but had low-density lipoprotein cholesterol (LDL-C) levels higher than recommended goals.

Hypothesis:

Alirocumab would be superior to placebo in reducing LDL-C levels in patients with suboptimal LDL-C control despite being on maximal tolerated doses of a statin with or without other lipid-lowering therapy.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • High CV risk on maximally tolerated statin ± other lipid-lowering therapy
  • LDL-C ≥70 mg/dl (if manifest CV disease), or LDL-C ≥100 mg/dl (diabetes mellitus with other risk factors/chronic kidney disease)

Number of enrollees: 316
Duration of follow-up: 24 weeks
Mean patient age: 63 years
Percentage female: 33%

Primary Endpoints:

  • Percent LDL-C change from baseline at 24 weeks

Secondary Endpoints:

  • Percent LDL-C change from baseline at 12 weeks
  • Percent change in apo-B, non–HDL-C, total cholesterol, Lp(a), HDL-C, triglycerides, and apo-A1 from baseline

Drug/Procedures Used:

Patients were randomized in a 2:1 fashion to either self-administered alirocumab 75 mg subcutaneous Q2W or matching placebo. Alirocumab was increased to 150 mg Q2W at week 12 if LDL ≥70 mg/dl at week 8 (required in 16.8%).

Principal Findings:

A total of 316 patients were randomized, 209 to alirocumab and 107 to placebo. Baseline characteristics were fairly similar between the two arms. About 42% had diabetes, and 78% had a history of coronary heart disease. Nearly two thirds of patients were on a high-dose statin at enrollment, and 45% were also on another lipid-lowering agent including ezetimibe in 8%. The mean baseline LDL-C was 103 mg/dl, triglycerides were 126 mg/dl, and high-density lipoprotein cholesterol (HDL-C) was 48 mg/dl.

Alirocumab significantly reduced LDL-C at 24 weeks compared with placebo at 24 weeks; % decrease from baseline was 48.2% vs. 2.3%, difference 45.9, p < 0.0001. The absolute values of LDL-C at 24 weeks were also significantly lower (51.4 vs. 97.8 mg/dl). LDL-C lowering with alirocumab reached peak efficacy around 4 weeks, and was sustained thereafter. Patients in the alirocumab arm were more likely to achieve a target LDL-C <70 mg/dl (75% vs. 9%, p < 0.0001). There were also significant reduction from baseline in Apo B (36.7% vs. 0.9%, p < 0.0001) and Lp(a) (20.5% vs. 5.9%, p < 0.0001) with alirocumab.

Injection-site reactions were numerically higher in the alirocumab arm (5.3% vs. 2.8%), as was nasopharyngitis (7.2% vs. 4.7%). On safety analysis, adjudicated cardiovascular (CV) events were similar (2.9% vs. 2.8%). Transaminitis (1.5% vs. 0.9%) and creatine kinase >3 x upper limit of normal (2.0% vs. 4.9%) were similar.

Interpretation:

The results of this trial indicate that alirocumab is superior to placebo in dramatically lowering LDL-C levels and achieving target levels in high CV risk patients already on maximal tolerated doses of statins (with or without other lipid-lowering therapy). This trial adds to the growing body of literature with PCSK9 inhibitors. Other large outcomes-based trials are ongoing.

References:

Presented by Dr. Dean J. Kereiakes at the American Heart Association Scientific Sessions, Chicago, IL, November 19, 2014.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Creatine Kinase, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Coronary Disease, Risk Factors, Apolipoproteins B, Azetidines, Maximum Tolerated Dose, Cholesterol, HDL, Nasopharyngitis, Triglycerides, Diabetes Mellitus, Renal Insufficiency, Chronic, AHA Annual Scientific Sessions


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