Safety and Pharmacokinetics of an Injectable Encapsulated Cell Technology Implant

Abstract

Purpose:: Three concurrent studies of an encapsulated cell technology (ECT) implant device delivering ciliary neurotrophic factor (CNTF) are in human clinical to treat early and late-stage retinitis pigmentosa and age-related macular degeneration. ECT devices used in these trials are implanted in patient's eyes using conjunctival excision, sceral incision, and inter-ocular placement and securing of the device followed by suture closure of the sclera and conjunctiva. The current study reports on the research efforts to develop the long-term pharmacokinetics and safety profile of a smaller geometry, micro-ECT device capable of delivering efficacious therapeutics, implanted using sutureless 23-gauge injection procedures.

Methods:: Human retinal pigment epithelial cells genetically modified to continuously secrete CNTF were encapsulated in 350 micron diameter hollow fiber semi-permeable polymer membranes and delivered by inter-ocular implantation into the rabbit vitreous cavity. Trans-conjunctival implantation of the devices was performed using a modified version of the 23-gauge sutureless sclerotomy technique and both safety and CNTF protein pharmacokinetics over the course of a 1-year period are the eventual outcome endpoints of this study. Vitreous CNTF levels and explanted micro-device CNTF output were evaluated by a commercial ELISA. Clinical and pathalogical evaluations were performed over the course of the implantation period in order to assess implant safety.

Results:: At the three month time point explanted device production and vitreous levels of CNTF are 3.2 ng/day and 0.2 ng/ml, respectively. Preliminary fitted kinetics (k) and half-life (t_1/2) constants for the explanted devices are k = 0.0167 weeks^-1 and t_1/2 = 41 weeks, respectively. Vitreous level k = 0.036 weeks^-1 and t_1/2 = 19 weeks. No evidence of ocular toxicity was observed in eyes that were implanted using the sutureless sclerotomy implant method. Clinical and pathohistological evaluation of the implant site showed normal wound healing response that was consistent with expected tissue reaction following surgical incision; additionally, no adverse pan-retinal, optic nerve or vascular toxicity was observed in any of the implanted eyes.

Conclusions:: Preliminary results of this study indicate that microECT implant devices are capable of sustaining long term intra-ocular delivery of CNTF in the rabbit. Additionally, the safety profile of a trans-conjunctival implant procedure that mitigates the necessity to suture the device shows promise for the potential of an injectable ECT device .

Keywords: protective mechanisms • growth factors/growth factor receptors • cell survival