Assessment of the 1% of Patients with Consistent < 15% Reduction in Low-Density Lipoprotein Cholesterol: Pooled Analysis of 10 Phase 3 ODYSSEY Alirocumab Trials

Abstract

Purpose: Clinical trials of statins and other lipid-lowering therapies (LLTs) often report large inter-individual variations in their effects on low-density lipoprotein cholesterol (LDL-C). We evaluated apparent hyporesponsiveness to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab (defined as < 15% LDL-C reduction from baseline at all timepoints) using data from 10 Phase 3 trials (3120 hypercholesterolemic patients). Methods: This report assessed the LDL-C percent reduction from baseline at weeks 4–104 (depending on study), and alirocumab serum levels and antidrug antibodies, in patients with apparent hyporesponsiveness. Results: Among the 3120 patients evaluated, 98.9% responded to alirocumab, and 33 (1.1%) had < 15% LDL C reduction at all measured timepoints. Pharmacokinetics data indicated that 13/33 apparent hyporesponders had not received alirocumab; no pharmacokinetics data were available for 14/33, and 6/33 had detectable alirocumab. For the six patients with confirmed alirocumab receipt, the degree of adherence to pre-study concurrent LLTs could not be determined after study start; one of these patients had persistent antidrug antibodies. Conclusions: Apparent hyporesponsiveness to alirocumab appeared to be due to lack of receipt of alirocumab determined by serum alirocumab levels, possible lack of adherence to concurrent LLTs, a theoretical and rare possibility of biological non-responsiveness due to persistent antidrug antibodies, or other causes, as yet unidentified.