Disclosure Information Bioengineered AV Grafts: They Are Finally Happening! Lawson JH, FINANCIAL DISCLOSURE: Jeffrey H. Lawson, M.D., Ph.D. Consultant and Research Funding; Humacyte, Inc. Departments of Surgery and Pathology Duke University Medical Center None of the data presented in this lecture is intended to Durham, North Carolina be perceived as “claims” for the potential clinical use of the bioengineered vascular graft discussed today. Synthetic Vascular Dialysis Grafts Vascular Grafts and Failure – Poor long-term patency • 40% of CABG vein grafts are occluded • Neointimal hyperplasia at 1 year. 1 • Stenosis • Primary patency of lower leg vein • Thrombosis bypass is 70% at 5 years in the best • Graft infections hands. 2 • Graft wall deterioration/abuse – DAC study indicated loss of patency in 75% of • Significant wound issues related to vein AVGs at one year 1 harvest sites (nearly 15%). 3 1. Prevent IV. JAMA, 294(19):2446-55, 2005 2. Rutherford, 5 th Edition, Chapter 69, pp. 1012-13, 2000 3. Duke Vascular Surgery NSQIP Data, 2013 1 Dixon et al. N Engl J Med 2009;360:2191-201. Page 1
Concepts and Beliefs Histology of Implanted ePTFE Grafts • Blood likes to move through tubes lined by cells • Blood likes to move through tubes that wiggle • Even the best veins don’t like being arteries Bioengineered Blood Vessels: Created from Bioengineered Blood Vessels Human Vascular Smooth Muscle Cells 1. Human Cells Isolated and Banked 2. Cells are Used to Culture Bioengineered Vessels in Bioreactors • Bioengineered blood vessels represent a potentially unlimited source of bypass grafts • However, in vivo implantation studies 4. Bioengineered Vessel 3. Decellularization Without Branches Removes Cells have been marked by acute graft rupture, thrombosis and failure Niklason, L et. al. Science 284:489-93, 1999. Page 2
Bioengineered Blood Vessels: Mechanically Bioengineered Blood Vessels: Matrix of Similar to Native Vasculature Acellular Vascular Grafts 6mm diameter, 40cm length 6mm diameter, 40cm length Silicone tube through side arm Bioreactor PGA mesh scaffold Dacron sleeve Suture Strength Burst Pressure (g) (mmHg) HAVG 181 ± 18 (16) 3337 ± 343 (10) Human saphenous vein 196 ± 29 (7) 1599 ± 877 (7) Human internal mammary artery 138 ± 50 (6) 3196 ± 1264 (16) Kink Radius SEM shows fluid No weeping at tight surface, with physiologic porous interior for pressures (N=31) cell infiltration. Bioengineered Blood Vessels: Human Bioengineered Blood Vessels for AV Access: Prototype Implanted into Primates (Baboon) Baboon with Graft Cannulation Bioengineered Vessel Bioengineered Axillary Brachial Vessel Artery Vein (Armpit): (Elbow): 3-4mm 2-3mm Diameter Diameter Artery Bioengineered Vessel Bioengineered Vessel Outflow Vein • Arteriovenous model, 1-6 months • No immunosuppression • No increase in PRA • Accessible at 4 weeks, 16G needle • No delayed hypersensitivity • Overall patency of 80% (11/14 animals), • No graft calcification including 5 animals patent at 6 months Page 3
Observations in Preclinical Studies (Baboon Model): Investigational Bioengineered Vessels Repopulate with Post-Implant Gross Observations of Bioengineered Blood Vessels Host Vascular Cells and Remodel: Baboon Investigational PTFE Graft Bioengineered Vessel No Cells Pre-Implant Smooth muscle Alpha Actin 6 Months Pre-implant Baboon Model CD 31 (endothelial) Post-implant In preclinical studies, investigational bioengineered vessels: • repopulate with vascular cells 1 1 Dahl et al., Sci Transl Med , 2011, 68ra9. Investigational Bioengineered Vessels Repopulate Little Intimal Hyperplasia in Investigational with Host Vascular Cells and Remodel the Matrix Bioengineered Vessels in Preclinical Studies Venous anastomosis in a baboon Collagen Type I Immunostain Movat’s stain - Elastin Bioengineered Vessel ePTFE Intimal to Medial Ratio (3 months) 100 µ m Pre-Implant 6 Months 6 Months Suture Strength (g) Burst Pressure (mmHg) Bioengineered Vessel, Pre-Implant 180 ± 44 (N=12) 3415 ± 1011 (N=4) Bioengineered Vessel, Post explant 276 ± 84 (N=11) 3669 ± 1305 (N=5) • Little foreign body reaction 1 P-Value (Pre- vs Post-Implant) 0.01 0.13 • Less mTOR activated smooth muscle proliferation than autologous vein 2 1 Prichard et al., J Cardiovasc Translational Med, 2011, 674. 2 Quint et al., Proc Natl Acad Sci , 2011, 9214. Page 4
Surgical Teams First Experience in Man Study Design • Open label, single arm study, 3 sites in Poland, initiated in Dec. 2012 • Upper arm arteriovenous (AV) access for hemodialysis • End stage renal disease (ESRD) patients who are not candidates for fistula creation Regional Specialist Hospital in Wroclaw University of Medicine in Lublin Wojewódzki Szpital Specjalistyczny we Wrocławiu • Uniwersytet Medyczny w Lublinie Use for dialysis from 8 weeks Prof. Wojciech Witkiewicz Prof. Tomasz Zubilewicz • Dr. Jakub Turek Monthly clinical and ultrasound monitoring for first 6 months Dr. Stanislaw Przywara Dr. Norbert Zapotoczny Dr. Marek Ilzecki • Patients followed for up to 2 years • 28/30 patients enrolled Objectives • Evaluation of safety and tolerability in dialysis patients • Evaluation of patency and intervention rates Medical University of Warsaw • Assess changes in Panel Reactive Antibody (PRA) Akademia Medyczna Warszawie Prof. Jacek Szmidt • 6 Month primary endpoint Dr. Thomasz Jakimowicz Dr. Bodhan Solonynko Study Patient Population and First Human Implant Initial Data on Investigational Bioengineered Vessels • 28 Caucasians [17 Male, 11 Female] • 4.1 ± 1.7 prior access procedures/patient 100% Overall Patency • Mean Age: 60 years (Range: 30 – 73) • All 28 vessels patent 8 8 • 20/28 without intervention • Mean BMI 28 (Range: 16 – 38) 6 6 Pa ents • No infections, no aneurysm • Concomitant diseases 4 4 • Hypertension in 82% 1 2 Secondary 2 Survival Distribution • Diabetes in 46% patency 0 0 0.8 0 1 2 3 4 5 6 7 8 100% 0 1 2 3 4 5 6 7 8 • Vascular disease in 39% Prior Dialysis Access Procedures Function 0.6 Primary First Human Implant of an Investigational Bioengineered Vessel patency 0.4 (9 patients at 6 month 0.2 follow up) 0 0 1 2 3 4 5 6 Venous Anastomosis Arterial Anastomosis Vessel in Upper Arm Months Page 5
Investigational Bioengineered Vessel for Dialysis Initial Data on Investigational Bioengineered Vessels Bioengineered Vessel Being Used for Dialysis Bioengineered Vessel No indication of immune response Diameter (mm) No dilata on or aneurysms [N=25] 8 " 10 # " 6 No change in PRA Class I % Reac vity to PRA Reac vity [N=6] Class I An bodies 8 # " 4 0" 50" 100" 150" 200" 250" 300" 0 50 100 150 200 250 300 6 Days on Study # 4000 Flow rate (mL/min) " 4 # Flow rates suitable for dialysis [N=25] • Flow rates suitable for dialysis: >500ml/min 3000 • 22 patients using bioengineered vessels for dialysis 3 times per week " 2 # • >800 accesses, up to 9 months experience per graft 0 2000 # " Pre-Implant 3 Months • Grafts easy to cannulate using standard techniques Post-Implant 1000 " • Only one delayed hemostasis requiring intervention • 0% reac vity to PRA Class 2 in pre- & • Patient had low fibrinogen levels (0.2g/L; Normal range: 2-4g/L) 0 " post-implant measurements [N=6] 0 50 100 150 200 250 300 Days on Study Summary Thank You � Off-the-shelf bioengineered vascular grafts are possible � Non immunogenic � Integrate with native tissue, repopulate and remodel � Post implant with increased strength and little intimal hyperplasia � First-in-man pilot clinical trial underway in Poland and the US for hemodialysis access and PAD Page 6
Duke Hospital: June 5, 2013 Initial Data on Investigational Bioengineered Vessels CURRENT OVERALL PATENCY 100% 8 of 28 patients lost primary patency since December 2012 • 10 patency interventions in these 8 patients • 8 thrombectomies (1 with revision of anastomosis, 1 with Pa ents angioplasty) • 2 venous anastomosis angioplasties without thrombosis Thrombosis • 71% Primary unassisted patency Stenosis 1 steal syndrome: cuff placed 0 1 2 3 4 5 6 7 8 9 10 11 Dura on of Implanta on (Months) Page 7
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