One size doesn't fit all: A dose-dependent twist in PCSK9 monoclonal antibody therapy

Abstract

Background/Synopsis

Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies are important therapeutic options for LDL cholesterol (LDL-C) lowering in patients with high cardiovascular risk. While PCSK9 monoclonal antibody non-responders have been well-characterized, a differential effect to once monthly versus biweekly dose formulations has not been described in the literature. We present the case of a 77-year-old woman with hypercholesterolemia and statin intolerance who demonstrated superior LDL-C lowering with once monthly PCSK9 monoclonal antibody therapy compared with biweekly formulations.

Objective/Purpose

To describe a case of superior LDL-C lowering with once monthly PCSK9 monoclonal antibody therapy compared with biweekly formulations.

Methods

Literature review and retrospective review of electronic health records.

Results

A 77-year-old female with coronary atherosclerosis (90th percentile coronary calcium score) and hypercholesterolemia presented to our lipid clinic for evaluation. The patient experienced myalgias and gastrointestinal side effects to multiple statins, ezetimibe, and bile acid sequestrants. The patient declined bempedoic acid due to concerns about potential side effects.

Her off-treatment lipid testing revealed total cholesterol 186, HDL 64, LDL 114, triglycerides 40, apolipoprotein B 79 and lipoprotein(a) 45 nmol/L. She was initiated on evolocumab 140 mg biweekly, resulting in a modest LDL-C reduction from 114 mg/dL to 106 mg/dL over six months. Given the suboptimal response, she was transitioned to alirocumab 150 mg biweekly. Her LDL-C remained suboptimal at 101 mg/dL after three months. Timing of lab draws and injection technique were confirmed to be accurate.

Genetic testing revealed no pathogenic mutations related to cholesterol metabolism. Following a two-month treatment hiatus, she was prescribed evolocumab 420 mg monthly. This resulted in a more robust LDL-C reduction to 88 mg/dL, sustained over the following year. No other medication or lifestyle changes occurred over this timeframe.

Conclusions

This case illustrates a differential effect to once monthly versus biweekly PCSK9 monoclonal antibody formulations. It is notable that even with the evolocumab 420 mg monthly formulation, LDL-C lowering was less than what would be expected based on clinical trial data. However the LDL-C lowering was nearly double the biweekly formulations. While mechanisms of PCSK9 monoclonal antibody resistance are well-established, the variable response based on dosage formulation is not reported. This case illustrates that some PCSK9 monoclonal antibody “non-responders” may have more robust LDL-C lowering with an alternative dosing formulation. Further research is warranted to better understand the mechanisms and clinical implications of such formulation-dependent responses.