ProHealing Drug Alternative for Coronary Drug Eluting Stents Our goal is to develop a novel, safer and more efficacious approach for treating Coronary Artery Disease, by incorporating a modulator of growth factor activity, PRM-100, within a Drug Eluting Stent (DES). Current DES elute anti-neoplastic (i.e. cytostatic or cytotoxic) agents to block the expansion of smooth muscle cells (SMC) and thereby prevent restenosis. However, as anti-neoplastics either kill or render endothelial cells at the stent site dysfunctiona for many years, patients face an increasing probability of restenosis with time and are predisposed toward life-threatening thrombotic events (e.g. fatal clots), a side effect that necessitates chronic or indefinite administration of potent Dual Anti-Platelet Therapies (DAPT). Notably, many patients are non-compliant with the DAPT treatment regime;furthermore, those that do comply with DAPT incur significant adverse effects (e.g. 6% major bleeding and 11% minor bleeding complications). To avoid these complications, we propose to replace anti-neoplastics with PRM-100, which works by down-regulating and modulation of growth factor activity, effectively inhibiting growth and proliferation of smooth muscle cells, while remaining non-toxic to endothelial cells. Reestablishment of an intact functional endothelium at the stented site provides a natural anti-thrombotic surface that actively controls arterial wall remodeling to limit restenosis. Our hypothesis is that we can find an optimal therapeutic dose of PRM-100 and effectively apply it with a coating for local delivery from a DES into a coronary artery which will perform better than current DES. To test this hypothesis, we propose the following specific aims:
Aim 1. Cell culture studies: Inhibition of smooth muscle cell and effect on endothelial cells by PRM-100. Milestone: Demonstration that PRM-100 effectively inhibits SMC proliferation while also being non-toxic to endothelial cells at a low and achievable dose and concentration [e.g., 5 - 30 ?g per ml, eluted for up to a 30 day period]. PRM-100 will be compared to drugs currently used on DES, specifically, sirolimus or a sirolimus analogue such as everolimus.
Aim 2. In vivo efficacy using a DES platform. Milestone. Improved therapeutic profile as compared to current technology as measured by decreased intimal hyperplasia, improved re-endothelialization, and absence of inflammation in PRM-100-eluting stents compared directly to polymer-only DES, but also indirectly to bare metal stents and other DES. On successful completion of this Phase I SBIR, we will have proof-of-concept for the use of PRM-100 in a drug eluting stent for the treatment of coronary artery disease, and be poised to launch a Phase II SBIR, which will include in-depth pharmacokinetics/dynamics, potentially a fully bioabsorbable stent, GLP Animal Studies and preparation for First-in-Man.
Our goal is to develop a novel approach for treating coronary artery disease, by incorporating a different class of drug, PRM-100, within a Drug Eluting Stent (DES). To avoid the complications that currently occur from the use of the cell-damaging or cell-killing drugs now used in DES, we propose to test PRM- 100, which inhibits growth and proliferation of smooth muscle cells, while remaining non-toxic to endothelial cells, in cell cultue and on metal discs that simulate a stent and also on stents in animal studies. On successful completion of this Phase I SBIR, we will have proof-of-concept for the use of PRM- 100 in a DES for the treatment of coronary artery disease, and be poised to launch a Phase II SBIR, which will allow us to prepare for clinical testing.