Analysis of the Relationship of PCSK9 and LDL Cholesterol Reductions in Patients in the Gauss Study

Background: AMG 145, a fully human anti-PCSK9, reduced LDL-C up to 63% in the GAUSS study; a randomised, double-blind, placebo- and ezetimibe-controlled 12-week study in 157 statin-intolerant patients. Statin-mediated LDL-C lowering causes an increase in PCSK9 levels, but the relationship between LDL-C reduction and PCSK9 levels after AMG 145 treatment is unknown. We investigated the correlation between the changes in serum LDL-C and PCSK9 levels at 12-weeks in the GAUSS study participants. Methods: A linear regression analysis was performed on the five cohorts randomised to: AMG 145 280 mg, 350 mg, or 420 mg; 420 mg plus 10 mg of ezetimibe; or 10 mg of ezetimibe plus placebo. The primary analysis and secondary analyses were: the correlation between the changes in PCSK9 and LDL-C in each sub-group; changes in PCSK9, non-HDL-C and Apo B. Results: No correlation between changes in LDL-C and PCSK9 was found within each of the five cohorts (ranging from −0.27 to −0.01). Furthermore, correlation for the aggregate group of patients receiving any dose of AMG145 alone was not significant. The correlation for the whole-group analysis of changes in LDL-C and PCSK9 was significant (0.31, P < 0.001). Change in PCSK9 levels did not correlate with changes in levels of non-HDL-C or Apo B. Conclusion: The results of the whole-group analysis suggest a linear relationship between the changes in LDL-C and PCSK9 in response to the lipid-lowering potency of each treatment regimen, whereas a lack of correlation between change in PCSK9 levels and change in levels of LDL-C, non-HDL cholesterol or Apo B may reflect pharmacokinetic considerations.