M. G. Emery,1 J. P. Gibbs,1 J. G. Slatter,2 L. Hamilton,3 S. M. Wasserman,1 M. Geller,1 C. Dias1; 1Amgen Inc., Thousand Oaks, CA, 2Amgen Inc., Seattle, WA, 3Amgen Ltd., Uxbridge, United Kingdom
BACKGROUND: The monoclonal antibody evolocumab binds to PCSK9, a soluble protein secreted by the liver, thereby reducing LDL-C levels. We compared evolocumab PK/PD in subjects with and without hepatic impairment.
METHODS: An open-label, parallel-group study in 24 Child-Pugh Class A or B subjects and healthy volunteers (N=8/group). Subjects were aged 18-55 years with LDL-C 70-190 mg/dL and BMI 18-35 kg/m2. Fasted subjects received 140 mg evolocumab SC, with PK/PD and safety data assessed over 8 weeks. Principal endpoints are unbound serum evolocumab AUClast, serum LDL-C area under the effect curve and safety.
RESULTS: PK: Geometric mean (SD) AUClast values were 96.8 (71.3), 58.8 (62.3) and 51.5 (32.5) day∙μg/mL in healthy subjects and those with mild or moderate hepatic impairment, respectively. These values were 39% and 47% lower in mild and moderate hepatic impairment, respectively, than in healthy volunteers, although p-value for trend was non-significant. PD: Baseline mean (SD) PCSK9 and LDL-C were 322 (45), 390 (73) and 343 (111) ng/mL and 121 (32), 112 (31), 96 (38) mg/dL in the 3 groups, respectively. No difference in the extent and time course of PCSK9 or LDL-C suppression was observed in patients with hepatic impairment. Safety: No trends of clinically important adverse events or abnormalities in vital signs, ECG or clinical laboratory data were observed.
CONCLUSION: Mean evolocumab exposure decreased by up to 47% (NS) with increasing hepatic impairment without affecting LDL-C lowering. Baseline PCSK9 and safety profiles were similar across groups. These results support evolocumab use without dose adjustment in patients with mild or moderate hepatic impairment.