Localized Delivery of Sirolimus to Hemodialysis Vascular Access Grafts

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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: 1) 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 100,000 ePTFE grafts are currently utilized in over 400,000 patients undergoing chronic hemodialysis. The costs of maintaining vascular access in hemodialysis patients are staggering, and now exceed $1 billion annually in the US alone. 2) 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, 60% of grafts used in AV access, and 20% used in PVD applications, will fail within 1 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 (<1 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 (12-18 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.