Localized Delivery of Sirolimus to Hemodialysis Vascular Access Grafts

Abstract Cylerus Inc is developing an implantable sirolimus eluting cuff and reservoir system combined with a clinically approved drug pump to solve the difficult problem of prosthetic vascular graft failure Vascular grafts constructed using either synthetic polymers or native veins are widely used in vascular surgery The most common indications for these grafts are Hemodialysis access in which blood access is typically achieved by construction of an autogenous AV fistula or surgical placement of an expanded polytetrafluoroethylene ePTFE vascular graft Various factors govern the choice of access but in the US approximately ePTFE grafts are currently utilized in over patients undergoing chronic hemodialysis The costs of maintaining vascular access in hemodialysis patients are staggering and now exceed $ billion annually in the US alone Peripheral vascular disease PVD which results from the accumulation within arteries of fatty deposits plaque that ultimately restrict or completely block blood flow When used in AV access and PVD applications ePTFE vascular grafts most commonly develop stenotic intimal lesions near the downstream surgical junction between the graft and host blood vessel i e distal graft anastomotic intimal hyperplasia On average of grafts used in AV access and used in PVD applications will fail within year with large costs to the healthcare system and considerable patient morbidity The Cylerus solution is to locally deliver the well known anti proliferative drug sirolimus rapamycin directly through the porous wall of ePTFE grafts thereby achieving high local drug concentrations at the graft anastomosis and adjacent vascular sites while minimizing circulating drug levels Since sirolimus potently inhibits vascular cell proliferation and intimal hyperplasia it will sustain graft function i e ability to dialyze by prolonging graft patency and reducing the need for frequent graft revision Sirolimus analogs everolimus zotarolimus etc are currently utilized in FDA approved drug eluting stents and have successfully prevented the narrowing of stented vessels restenosis a process that is also due to intimal hyperplasia With stents short term andlt month elution of sirolimus is effective in part because stents have a small surface area and open structure consequently stents often heal quickly and completely by coverage with vascular endothelial cells a process that interrupts intimal hyperplasia Conversely because prosthetic vascular grafts rarely heal completely or fully endothelialize their flow surfaces inhibition of persistent graft intimal hyperplasia will likely require continuous longer term anti proliferative drug therapy perhaps weeks to months in duration in order to significantly prolong graft lifetimes beyond current averages months Accordingly to prolong prosthetic graft survival Cylerus is developing a novel drug delivery technology combined with a proprietary sirolimus formulation which is stable at body temperature for a month or more that can be continuously and efficiently targeted to graft anastomotic sites for extended periods using a clinically approved implantable pump Project Narrative Cylerus Inc is developing an implantable sirolimus eluting cuff and reservoir system combined with a clinically approved drug pump to solve the difficult problem of prosthetic vascular graft failure for patients with end stage renal disease or peripheral vascular disease Sirolimus inhibits vascular cell proliferation and intimal hyperplasia and thus will sustain graft function by prolonging graft patency and reducing the need for frequent graft revision This development will reduce the morbidity and very high costs associated with prosthetic graft failure revision and replacement