Localized Delivery of Sirolimus to Hemodialysis Vascular Access Grafts

Abstract CylerusIncis developing an implantablesirolimus eluting cuff and reservoir systemcombined with a clinically approved drug pumpto solve the difficult problem of prosthetic vascular graft failureVascular grafts constructed using either synthetic polymers or native veins are widely used in vascular surgeryThe most common indications for these grafts areHemodialysis accessin which blood access is typically achieved by construction of an autogenous AV fistula or surgical placement of an expanded polytetrafluoroethyleneePTFEvascular graftVarious factors govern the choice of accessbut in the US approximatelyePTFE grafts are currently utilized in overpatients undergoing chronic hemodialysisThe costs of maintaining vascular access in hemodialysis patients are staggeringand now exceed $billion annually in the US alonePeripheral vascular diseasePVDwhich results from the accumulation within arteries of fatty depositsplaquethat ultimately restrict or completely block blood flowWhen used in AV access and PVD applicationsePTFE vascular grafts most commonly develop stenotic intimal lesions near the downstream surgical junction between the graft and host blood vesseli edistal graft anastomotic intimal hyperplasiaOn averageof grafts used in AV accessandused in PVD applicationswill fail withinyearwith large costs to the healthcare system and considerable patient morbidityThe Cylerus solution is to locally deliver the well known anti proliferative drugsirolimusrapamycindirectly through the porous wall of ePTFE graftsthereby achieving high local drug concentrations at the graft anastomosis and adjacent vascular sites while minimizing circulating drug levelsSince sirolimus potently inhibits vascular cell proliferation and intimal hyperplasiait will sustain graft functioni eability to dialyzeby prolonging graft patency and reducing the need for frequent graft revisionSirolimus analogseverolimuszotarolimusetcare currently utilized in FDA approveddrug eluting stents and have successfully prevented the narrowing of stented vesselsrestenosisa process that is also due to intimal hyperplasiaWith stentsshort termandltmonthelution of sirolimus is effectivein partbecause stents have a small surface area and open structureconsequentlystents often heal quickly and completely by coverage with vascular endothelial cellsa process that interrupts intimal hyperplasiaConverselybecause prosthetic vascular grafts rarely heal completely or fully endothelialize their flow surfacesinhibition of persistent graft intimal hyperplasia will likely require continuouslonger termanti proliferative drug therapyperhaps weeks to months in durationin order to significantly prolong graft lifetimes beyond current averagesmonthsAccordinglyto prolong prosthetic graft survival Cylerus is developing a novel drug delivery technology combined with a proprietary sirolimus formulationwhich is stable at body temperature for a month or morethat can be continuously and efficiently targeted to graft anastomotic sites for extended periods using a clinically approved implantable pump Project Narrative CylerusIncis developing an implantablesirolimus eluting cuff and reservoir systemcombined with a clinically approved drug pumpto solve the difficult problem of prosthetic vascular graft failure for patients with end stage renal disease or peripheral vascular diseaseSirolimus inhibits vascular cell proliferation and intimal hyperplasiaand thus will sustain graft function by prolonging graft patency and reducing the need for frequent graft revisionThis development will reduce the morbidity and very high costs associated with prosthetic graft failurerevision and replacement