CiVi 007 is a third-generation proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense molecule being developed as an oral treatment for hypercholesterolemia and the prevention of atherosclerotic cardiovascular disease.
FIGHTING CARDIOVASCULAR DISEASE
While medications are currently available to treat high cholesterol, many patients are unable to achieve LDL targets set by their physicians despite use of these medications. Nearly 80% of cardiovascular deaths are due to heart attacks and strokes, the majority of which are due to the build-up of vulnerable atherosclerotic plaque in the vasculature. This leaves significant unmet need among patients with high LDL.
CiVi 007 joins the fight in lowering LDL-cholesterol using the latest technology available to block the production of a key enzyme, PCSK9, at the level of its synthesis by mRNA. By directing CiVi 007 to the liver and knocking out this protein, it dramatically increases the longevity of receptors in the liver that take up LDL and reducing the amount of harmful LDL cholesterol circulating in the bloodstream.
CiVi 007 has several potential advantages, as it blocks both Major and Minor cellular pathways compared to mAb’s, which only block Major extracellular pathways. As a result, CiVi 007’s mechanism of action more similarly mimics loss of function (LoF) mutations than mAbs, which has the potential to improve LDL lowering in mAb non-responders due to mutations on PCSK9 binding sites. Moreover, CiVi 007 may translate into improved outcomes as a result of its unique MOA.
CiVi 007 IN THE CLINIC
In early clinical studies, subcutaneous CiVi 007 demonstrated the expected profile associated with PCSK9 inhibition, including dose-responsive PCSK9 knockdown and robust, dose-dependent reduction in atherogenic lipoproteins and lipids. Importantly, the maximum effect (>90%) on PCSK9 occurred within a week of injection and remained stable for ~1 month following administration.
CiVi Biopharma expects to initiate additional clinical work to validate the mechanism of action of CiVi 007 and to support refinement of the assessment of optimal dose and dose regimen.
OUR VALUE PROPOSITION
Despite their unprecedented clinical profile, high prices and inconvenient dosing regimens of current PCSK9 therapies remain significant barriers to broad use. CiVi 007 is expected to provide improved lipid management in a more convenient, patient-friendly dosing format. This combined with an improved stability profile and significantly lower cost of goods should provide substantial advantages compared with mAbs and inclisiran.
Formulation work on the development of oral CiVi 007 is underway and CiVi Biopharma expects to begin non-human primate, toxicology and other Investigational New Drug-enabling studies in the second half of 2020.
External resource links:
1. World Health Organization (www.who.org)
2. American Heart Association (www.aha.org)
3. The FH Foundation (www.thefhfoundation.org)
4. Vascular Biology Working Group (vbwg.healio.com)
5. European Atherosclerosis Society (www.eas-society.org)
6. American College of Cardiology (www.acc.org)
7. National Lipid Association (www.lipid.org)