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Published on: August 28, 2018
VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeys
Madeline M Vroom1, Hanxin Lu1, Maggie Lewis1
1Vaxxinity, Inc, Dallas, TX, USA.
Insights
A new peptide vaccine, VXX-401, effectively lowers LDL-C by inducing antibodies against PCSK9. This promising therapy offers a safe and accessible option for managing hypercholesterolemia and preventing atherosclerotic cardiovascular disease.
Area of Science:
- Cardiovascular Medicine
- Immunology
- Pharmacology
Background:
- Atherosclerotic cardiovascular disease (ASCVD) is a major global health burden, strongly linked to elevated low-density lipoprotein cholesterol (LDL-C).
- Current LDL-C-lowering therapies like statins have limitations in efficacy and adherence, while PCSK9 inhibitors are reserved for high-risk patients.
- Existing monoclonal antibodies demonstrate efficacy and safety, providing a basis for novel therapeutic approaches.
Purpose of the Study:
- To develop and evaluate VXX-401, a novel peptide-based vaccine targeting PCSK9, as an alternative treatment for hypercholesterolemia and ASCVD prevention.
- To assess the immunogenicity, efficacy, and safety profile of VXX-401 in preclinical models.
Main Methods:
- Development of a peptide-based vaccine (VXX-401) designed to elicit a humoral immune response against PCSK9.
- Evaluation of VXX-401's immunogenicity and LDL-C-lowering effects in nonhuman primates.
- Assessment of antibody binding affinity to human PCSK9 and functional blockade of PCSK9's effect on LDL-C uptake in a hepatic cell model.
- Conducting a repeat-dose toxicity study in nonhuman primates under Good Laboratory Practices.
Main Results:
- VXX-401 demonstrated robust immunogenicity and sustained LDL-C reduction (30-40%) in nonhuman primates.
- Induced antibodies exhibited high affinity for human PCSK9 and effectively blocked PCSK9-mediated inhibition of LDL-C uptake.
- Toxicity studies revealed a favorable safety and tolerability profile, with injection site reactions as the primary finding.
Conclusions:
- VXX-401 shows significant potential as a safe and effective LDL-C-lowering therapy.
- The peptide vaccine may offer a broadly accessible and convenient treatment option for hypercholesterolemia and ASCVD prevention.
Abstract:
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies 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 30-40% reduction in blood LDL-C. In this article, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C-lowering effects in nonhuman primates. In addition, 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 nonhuman primates under good laboratory practices 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.
