A prospective clinical trial of autologous TARGT prolonged EPO secretion showed EPO-independence in EPO-dependent ESRD patients

Transcription

1 A prospective clinical trial of autologous TARGT prolonged EPO secretion showed EPO-independence in EPO-dependent ESRD patients September 19, 2015

2 TARGT TM (Transduced Autologous Restorative Gene Therapy) DermaVac #1 Micro-organ #3 #2 Cryo Bank Transduced Micro- organ (TARGT EPO ) Gutless adeno- viral vector 1. Harvest Micro-Organs from abdominal dermis using the proprietary DermaVac device. 2. Transduce fibroblasts in Micro-Organs via ex vivo gene therapy to create TARGT EPO. 3. Wash out HDAd vector, measure production and choose TARGT EPO for implantation. 4. Implant TARGT EPO into patient where it produces endogenous EPO (eepo). 2

3 Locating implanted TARGT in patient skin using Ultra Sound Dermis subcutaneous fat TARGT * Cross section of TARGT in subcutaneous fat 3

4 TARGT platform mimics the natural system Autologous proteins and peptides Natural post translation modification Living drug /restorative therapy Continuous secretion at physiologic levels Avoids supra-therapeutic spikes; Lower overall exposure than IV administration Dosing guided by in-vitro secretion prior to implant Individualized dosing: better dosing control Reimplantation possible Safe Simple, well-tolerated procedure Avoids systemic exposure to viral antigen: less immunogenicity No viral DNA integration: low risk of cancer Interruptible therapy through excision/ablation 4

5 ESRD patients and EPO ESRD patients (on Hemo or Peritoneal Dialysis) have significantly reduced or no secretion of endogenous EPO (eepo) ESRD patients suffer from anemia to various factors (including Low eepo, chronic disease, inflammation, uremia etc ) Anemia in hemodialysis patients aggravated due to blood loss during dialysis Injectable rhuepo is used to control anemia and avoid blood transfusions which result in iron overload Injectable rhuepo has shown to increase the risk of CVD events (morbidity and mortality) 5

6 MG-EP-RF-02 Study using MDGN-201 in ESRD (HD) patients; Trial In progress Study Summary Prospective, Open label, Dose Escalation study, to evaluate Safety and Efficacy (control of Hb 9-11 and <12 g/dl) of TARGT EPO TM in ESRD patients. Group Treatment N A Low dose EPO IU/kg/day 3 + 3* B Mid dose EPO IU/kg/day 3 + 3* C High dose EPO IU/kg/day 3 + 3* MDGN-201 Phase I/II Trial Design 9 days 12 months 6 months Screening Enrollment and dose selection Harvest procedure Ex vivo viral transduction Implantation procedure Treatment and follow-up Safety follow-up 4 weeks run- in Endpoints: 1. Pharmacokinetics of TARGT EPO TM secreted erythropoietin, 2. Hemoglobin levels: target range (9-11 and 12 g/dl), 3.Safety * Initial cohort of 3, expandable to 6 based on response 6

7 MG-EP-RF-02 - Summary patient status Low Dose Cohort Subject # Age Gender Dialysis (years) Medical History rhuepo Run-in Dose (IU/wk) # of TARGTs Months Post Implant Status E M 4 E M 0.8 E F 1.4 E M 9 hypertension, diabetes hypertension, IgA nephropathy hypertension, diabetes, stroke hypertension, stroke, MI 12K 3 14 Ongoing; stable Hb Returned to baseline; 12K 2 5 received rhuepo. Exited study. Required rhuepo 20K 1 2 following surgery unrelated to therapy. Exited study. 20K 2 7 Returned to baseline; received rhuepo. E M 1 diabetes 20K 3 6 E F 0.75 hypertension 8K 3 7 Returned to baseline; received rhuepo. Ongoing; temporary rescue with rhuepo d/t Pneumonia 7

8 MG-EP-RF-02 summary patient status Mid Dose Cohort Subject # Age Gender Dialysis (years) Medical History rhuepo Run-in Dose (IU/wk) # of TARGTs Months Post Implant Status E M 0.7 Pseudo gout, FSGS, Thalassemia minor 20K 3 <1 Received rhuepo. Exited study.* E M 2 HTN, CHF, DM 16K 3 5 Ongoing; stable Hb E M 4.6 HTN, DM, PVD 2K 5 3 Ongoing; phlebotomized 3 times d/t Hb above 13 E F 0.5 HTN 5K 2 <1 Implanted Aug 20 *Pa&ent E206 had EPO and Hb levels in the expected range post implanta&on. He had a long rhuepo washout period (24 days) and developed fever and suspected viral infec&on within 2 weeks of implanta&on. This may have resulted in marrow hyporesponsiveness. 8

9 Patient One run-in period Supra-therapeutic doses of rhuepo required to maintain hemoglobin levels Serum rhuepo, miu/ml Days Pre-implantation 13 Serum Hb, g/dl Patient Description: Age: 70, Sex: Male Dialysis: 4 years, Underlying disease: HTN & T2DM Days Pre-implantation rhuepo dependent: dose prior to enrollment 6,000 IU twice 9 a week Target Hb 9-11 Target Hb 11-12

10 Patient One interim results Serum eepo, miu/ml Serum Hb, g/dl months post implantation renal anemia is well controlled Predicted eepo baseline * Days from implantation 4mU/ml Days from implantation 3 Transduced Micro- Organs (TARGT EPO ) implanted Patient stabilizes after approximately 30 days Target Hb is reached with approx. 100x lower C MAX than rhuepo Patient appears to have the ability to auto regulate Hb levels * Possible hemoconcentration Target Hb 9-11 Target Hb Patient Description: Age: 70, Sex: Male Dialysis: 4 years. Underlying disease: HTN & T2DM 10 rhuepo dependent: dose prior to enrollment 6,000 IU twice a week

11 Patient One Actively regulated reticulocytosis 100 Reticulocytes (10 9 /L) Ongoing reticulocytosis is evidence of response to eepo Repeated peaks and troughs may be indicative of auto-regulation Days from implantation (3 TARGT EPO implanted) Patient Description: Age: 70, Sex: Male Dialysis: 4 years. Underlying disease: HTN & T2DM rhuepo dependent: dose prior to enrollment 6,000 IU twice a week 11

12 Low Dose Cohort interim results eepo + Hb 12

13 Mid Dose Cohort interim results eepo + Hb 13

14 MG-EP-RF-02 Key data 10 patients implanted (6 low dose, 4 mid dose) data available for 9. Age range: 26yr-76yr average: 59yr 7 male, 3 Female Low dose: 5/6 at or above 5 months One patient at 14 months post implantation As of Aug 31: Average duration in low dose: 6.8 months As of Aug 31: 5/10 overall patients in the study are still ongoing One patient in the mid dose cohort had to undergo phlebotomy 3 times d/t Hb exceeding

15 MG-EP-RF-03/04 Study using MDGN-201 in PD patients; Trials in progress Study Summary Prospective, Open label, Dose Escalation study, to evaluate Safety and Efficacy (control of Hb 9-11 and <12 g/dl) of TARGT EPO TM in ESRD patients. Group Treatment N A Low dose EPO IU/kg/day 3 + 3* B Mid dose EPO IU/kg/day 3 + 3* MDGN-201 Phase I/II Trial Design 9 days 12 months 6 months Screening Enrollment and dose selection Harvest procedure Ex vivo viral transduction Implantation procedure Treatment and follow-up Safety follow-up 4 weeks run- in Endpoints: 1. Pharmacokinetics of TARGT EPO TM secreted erythropoietin, 2. Hemoglobin levels: target range (9-11 and 12 g/dl), 3.Safety * Initial cohort of 3, expandable to 6 based on response 15

16 MG-EP-RF-03/04 summary patients results Low Dose Subject # Age Gender Dialysis (years) Medical History rhuepo Run-in Dose (IU/wk) # of TARGTs Months Post Implant Status E F 0.8 HTN 6K 1 4 Ongoing; Stable Hb E M 1.25 HTN 3K 2 3 Ongoing; evaluated for potential phlebotomy but stabilized E M 1.75 DM, HTN 6K 2 1 Ongoing; Stable Hb E M 3.25 DM, HTN 20K N/A N/A Patient enrolled 16

17 PD patients Mean Serum eepo, miu/ml Mean Serum Hb, g/dl Month Post Implantation Month Post Implantation Patient 1 Patient 2 Patient 3 Patient 1 Patient 2 Patient 3 17

18 Conclusions TARGT technology allows for continuous administration of therapeutic proteins at physiologic levels. TARGT procedures are well tolerated and good safety has been observed thus far with TARGT EPO. A total of 13 patients have been implanted to date. All patients demonstrated a good initial secretion of EPO from TARGT EPO as measured by serum EPO levels above baseline and showed good response with reticulocytosis; all but 1 patient (E206) showed adequate Hb maintenance (see below). One patient (after long washout) was unable to maintain Hb on TARGT EPO despite adequate initial eepo levels and reticulocytosis. This patient also had a relatively poor response to injectable rhuepo suggesting marrow hyporesonsiveness. He developed a viral illness early in his course of therapy. Anti-EPO antibodies were negative. 18

19 Conclusions cont. One patient in the mid dose cohort had to undergo phlebotomy 3 times d/t Hb exceeding 13. Thus far, 5/6 patients in the low dose cohort had 5 or more months of TARGT EPO secretion with stable Hb response. One patient is nearing 15 months with stable EPO secretion and Hb. TARGT is a platform technology allowing for administration of a variety of therapeutic proteins, including antibodies and peptides, in numerous clinical indications with significant unmet needs. 19