VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeys.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of low-density lipoprotein cholesterol (LDL-C). LDL-C lowering drugs such as statins or monoclonal antibodies (mAbs) against proprotein convertase subtilisin/kexin type 9 (PCSK9) are known to reduce the risk of cardiovascular diseases, however statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a "high risk" patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30 to 40% reduction in blood LDL-C. In this paper, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C lowering effects in non-human primates (NHP). Additionally, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in NHP under good laboratory practices (GLP toxicity) indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD.

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Déclaration de conflit d'intérêts

DECLARATION OF INTERESTS All studies described herein were funded by Vaxxinity, Inc. All authors are past or current Vaxxinity employees and hold company stock/stock options. Madeline M. Vroom: Writing - Original draft preparation, Methodology, Formal analysis, Investigation, Visualization. Hanxin Lu: Conceptualization, Supervision. Resources. Maggie Lewis: Writing – Original draft preparation. Brett A. Thibodeaux: Investigation, Methodology, Validation. Jeanne K. Brooks: Investigation. Matthew S. Longo: Methodology, Formal analysis, Validation Investigation. Martina M Ramos: Investigation. Jaya Sahni: Investigation. Jonathan Wiggins: Investigation. Justin D. Boyd: Supervision, Writing – Review and editing. Shuang Ding: Supervision. Michael Hellerstein: Supervision, Writing – Review and editing. Valorie Ryan: Project administration. Peter Powchik: Conceptualization, Writing – Review and editing. Jean-Cosme Dodart: Conceptualization, Supervision, Writing – Review and editing.