Tissue Engineered Vascular Grafts

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1 Tissue Engineered Vascular Grafts Jeffrey H. Lawson, M.D., Ph.D. Chief Medical Officer Humacyte Incorporated Professor of Surgery and Pathology Duke University Medical Center

2 Disclosure Information Financial Disclosure and Conflicts: Humacyte Chief Medical Officer: Salary, Stock Options and (past) Research Funding Disclaimer: The Humacyte investigational bioengineered vessel is an investigational biologic currently being studied in Poland and the US to evaluate its potential safety and preliminary efficacy when used as a vascular access in patients with End Stage Renal Disease requiring hemodialysis and in patients with Peripheral Arterial Disease. This investigational product has not been submitted for regulatory approval by the FDA or any other regulatory authority. Both the clinical significance of the data reviewed in this presentation, and any potential future indication(s), warnings, precautions, and adverse reactions are unknown at this time. This presentation includes unpublished data as of December, 2015.

3 AV Fistula Access Problems Maturation failure is main issue small vessels low blood flow inadequate vessel remodeling High prevalence of diabetes and hypertension DAC study indicated 60% of AVFs failed to mature and become usable for dialysis within 5 months 1 1 Dember et al. JAMA. 2008;299(18):

4 AV Graft Materials Bovine vein Polyether urethane urea 1. Dixon et al. NEJM, 360(21): , 2009 DAC study reported a loss of primary patency in 75% of AVGs at 1 one year. eptfe

5 Explanted PTFE Mag x10

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7 Xenografts Non-human biomaterials that mimic the function of a human blood vessel.

8 Xenograft Morphology ProCol Artegraft

9 Procol for Salvage Dialysis Access: Assisted Patency of Procol vs. Last PTFE Assisted Patency (%) Procol P= PTFE Time (Months)

10 Tissue incorporation? Aneurysmal dilation? Vascular wall calcification?

11 Tissue Engineering Making human biomaterials that mimic the function of a human blood vessel.

12 Elastin-based Materials Fig. 1 Synthetic elastin tissue engineered constructs. Scanning electron microscopy images of (A) synthetic elastin electrospun fibers and (B) hydrogel. (C) Digital image of an electrospun conduit (EC) compared to a human artery (HA). Chem. Soc. Rev., 2010, 39,

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19 Polymer scaffold is designed to guide tissue shape... PGA A Smooth muscle cell Dacron sleeve B... and designed to degrade... Silicone tube Engineered vessel

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24 6mm diameter, 40cm length Suture Strength (g) Burst Pressure (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

25 1 week 4 weeks 52 weeks Dahl et al., Sci Transl Med, 68ra9, Long-term durability

26 Bioengineered Vessel Bioengineered Vessel Bioengineered Vessel Artery Bioengineered Vessel Outflow Vein Dahl et al., Sci Transl Med, 2011, 68ra9.

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28 Collagen Type I Immunostain Pre-Implant 6 Months Movat s stain - Elastin 100μm 6 Months

29 No Cells Pre-Implant 6 Month Explant Smooth muscle Alpha Actin CD 31 (endothelial)

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34 Initial Clinical Outcomes of First-in-Man Human Implants (6 months) Diameter (mm) No indication of immune response No change in PRA Class I Reac vity [N=6] 8# 6# 4# 2# 0# Pre-Implant 3 Months Post-Implant 0% reac vity to PRA Class 2 in pre- & post-implant measurements [N=6] Flow rate (ml/min) % Reac vity to PRA Class I An bodies 10# No dilata on or aneurysms [N=25] 8" 6" 4 " 0" " 5050" 100" 150" 200" Days on Study 250" " 300 Flow rates suitable for dialysis [N=25] 3000" 2000" 1000" 0" Days on Study Lawson et al., American Heart Association Meeting, Dallas TX,

35 Summary Off-the-shelf bioengineered vascular tissues are possible Non immunogenic, integrate with native tissue, repopulate and remodel Post implant with increased strength and little intimal hyperplasia Phase II clinical trials underway in Poland and the US for hemodialysis access and PAD Global Phase III clinical trial in hemodialysis access 2016

36 Federal Funding NIH: 1R43DK , 2R44DK , 5R44DK , 9R44HL , 5R44HL , 5R44HL , 1R43HL Contract # HHSN C DOD: W81XWH W81XWH W81XWH

37 Thank You