29 Oct New Drug Class Offers Hope for Calcified Blood Vessels
MedicalResearch.com Interview with:
Dr Mattias Ivarsson PhD
CEO, Inositec, co-author of data
MedicalResearch.com: What is the background for this study?
Response: When control of factors in the blood that regulate mineral balance in the body is lost, the subsequent build-up of calcium deposits in the arterial walls and cardiac valves lead to an increase in cardiac events, particularly in patients with chronic kidney disease or diabetes, as well as all-cause mortality.
There is a significant unmet need for therapeutic agents capable of reducing pathological mineral accumulation regardless of their root cause. To date, there is no approved therapy for treating calcification-dependent cardiovascular disease.
MedicalResearch.com: What are the main findings?
Response: To develop a new class of inhibitors of vascular calcification, we conducted multi-step syntheses, starting from protected myo-inositol species, involving selective PEGylation, phosphorylation or sulfation to build a library of novel myo-inositol hexaphosphate (IP6) analogs with improved drug-like properties. IP6 has previously been shown to be a potent inhibitor of calcification. Data presented from in vitro experiments showed that one of the compounds, named INS-3001, was superior to natural IP6 with regard to efficacy and stability in a serum calcification propensity assay. INS-3001 also had efficacy superior to IP6 in cell culture studies performed on primary human vascular smooth muscle cells treated with either calciprotein particles or calcification medium to induce formation of calcified deposits.
In rats, INS-3001 administration significantly blunted carotid calcification following vitamin D overdose, reducing the amount of calcium in tissues by a factor of two compared to controls while a numerical decrease was observed at the level of abdominal aorta. INS-3001 also showed a beneficial effect on the renal function of animals in this model.
The effect of INS-3001 was further evaluated in vitamin D-warfarin induced calcification in rats. In the abdominal aorta, significantly lower total calcium content was measured in the INS-3001 groups compared to the vehicle group following bolus subcutaneous dosing. The von Kossa positivity (area% of stained tissue representing the extent of calcification) of the abdominal aorta was also significantly lower in the INS-3001 groups compared to the vehicle group. The effects on both the total calcium and the von Kossa positivity were dose-dependent and correlated with mortality. Similar reductions in total calcium content and area% von Kossa positivity were seen in the thoracic aorta, and the femoral and carotid arteries.
The uremic state appeared to significantly influence the rat plasma pharmacokinetics of INS-3001 after subcutaneous and intravenous administration, suggesting that uremia extended plasma exposure of INS-3001 without increasing peak plasma levels.
MedicalResearch.com: What should readers take away from your report?
Response: At present, there is no approved pharmacological treatment for vascular calcification and affected individuals are left at great risk of experiencing cardiovascular events and death. These data show that this new class of IP6 analogs, designed specifically to have improved drug-like properties, show promise in the treatment of vascular calcification.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Research is continuing with INS-3001 to generate the required data to start first-in-human studies.
Citation: Kidney Week 2018
Dr Mattias Ivarsson of Inositec regarding data presented at Kidney Week on a novel vascular calcification inhibitor, INS-3001.
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