A prospective clinical trial of prolonged autologous erythropoietin (EPO) secretion from TARGTEPO in EPO-dependent end stage renal disease patients showed EPO independence for over 8 months

Background: Recombinant human Erythropoietin (rHuEPO) along with iron supplementation corrects anemia in most patients with End Stage Renal Disease (ESRD) but is associated with supra-physiological peak serum concentration (Cmax) of EPO and may cause thromboembolic complications in these patients. The Transduced Autologous Restorative Gene Therapy system (TARGT™) is an ex-vivo gene therapy platform that provides autologous, continuous protein or peptide therapy in the physiological range. The system consists of several 2x30 mm pieces of dermal tissue (Micro-Organ, MO), extracted under local anesthetic in which its fibroblasts cells are transduced with a viral vector containing a gene of interest. TARGTEPO refers to a TARGT that provides EPO. After culture, and measurement of in-vitro EPO production, one or more transduced MOs secreting EPO (TARGTEPOs) are reimplanted subcutaneously as required for delivering the target dose. Patients are treated with local steroid injection to stabilize secretion. The system allows dose flexibility and the TARGTs may be added or removed according to the in-vivo secretion levels. Aims: We present here initial results from an-ongoing open label ascending dose exploratory clinical study of TARGTEPO in patients with anemia due to ESRD. Methods: This study was approved by the Ethics Committees of the participating sites in Israel and the TARGTEPO product was cleared for clinical testing by the Israeli Ministry of Health. All patients have signed an informed consent prior to enrollment in the study. We have completed the enrollment of patients in the first out of 3 cohorts (the low dose) with 6 EPO-dependent patients treated with a total of up to 3 TARGTEPO units each, secreting a total of 25 IU/Kg/Day of autologous EPO. All patients continued their previous regimen of intravenous supplemental iron. Results: Efficacy data in this ongoing study is being continuously assessed as per protocol. Patient follow-up post implantation is ongoing, while the first patient implanted has completed 8 months of follow up with stable EPO secretion and stable Hb. Results obtained from the 6 patients enrolled thus far suggest stabilization of serum EPO levels at the physiological range of ≤20 mIU/ml and the resulting Hb levels between 9-12 g/dL without rHuEPO or transfusion while TARGTEPOs are still functioning. Comparative analysis of serum EPO levels revealed significantly lower Cmax with TARGTEPO compared to rHuEPO. Also, comparison of extrapolated Area Under the Curve (AUC) of rhEPO vs actual TARGTEPO AUC, revealed that TARGTEPO maintained Hb within the desired range in these patients with an order of magnitude smaller exposure to EPO compared to rHuEPO. This observation may have significant clinical benefits. No treatment related serious adverse events have been reported. Summary and Conclusions: TARGTEPO is a promising novel therapy for anemia and the TARGT platform may have promise for other diseases requiring protein or peptide based treatment.