Performance Expectations from Durable DES Coating vs Bioabsorbable

Performance Expectations from Durable DES Coating vs. Bioabsorbable DES Coating Are Design Specific, not General Syed Hossainy, Ph. D; Director, New Business Venture and Volwiler Fellow; Abbott Vascular Research Fellow, Institute of Computational and Engineering Science; U. Texas at Austin

Syed Hossainy, Ph. D Abbott Vascular Employee

Acknowledgement: Mikael Trollsas; Abbott Vascular Alexander Sheehy; Abbott Vascular Antonio Garcia; Abbott Vascular Prof. Edelman's lab, MIT: Drs M Balcells, S Schubert and ER Edelman Prof. Buddy Ratner’s lab, U. Washington. Seattle

Content 1. DES safety- Absorbable Vs Durable DES 2. Performance Matrix for characterization: A. Absorption rate highlights-Absorbable DES B. Coating integrity as f(t)-Absorbable and Durable DES C. Thromboresistance and Endothelialization testing-BMS Vs Durable DES 3. Conclusions based on data.

DES Coating Safety Assumptions*: Absorbable Vs Durable Absorbable DES Short-term DES safety: Longer-term DES safety: Thromboresistance and low inflammation Faster, complete, and functional endothelialization Minimal Coating defect, t=0 Evolved bare metal surface postabsorption Durable DES Minimal Coating defect; t=0 and f(t) Intrinsic Polymer host-material interaction property** Intrinsic Polymer blood-contact property** * Mechanical design and drug effect not included in discussion * * e. g. - PEG-ylation, Fluoropassivation, Biomimicry, Sulfonation

In vivo Degradation for PLGA 75/25 PLGA: No polymer detectable @3 mon Data on file at Abbott Vascular Engineering Aspect of DES Feb 2011 Company Confidential – NOT FOR DISTRIBUTION © 2011 Abbott

Absorption Rate of DES Coating - In vivo and In vitro • Mass loss In Vivo and In Vitro is a function of backbone architecture • Mass loss In Vivo is a function of coating thickness • PLA slow and fast system absorption In Vivo> In Vitro Data on file at Abbott Vascular Model developed at Abbott Vascular Engineering Aspect of DES Feb 2011 Company Confidential – NOT FOR DISTRIBUTION © 2011 Abbott

Coating integrity as f(t) during elution; Different absorbable DES t=4 wk t=0 PLA Coating PLGA 75/25 Coating t=16 wk t=8 wk t=0 t=13 wk t=6 wk Data on file at Abbott VASCULAR

The XIENCE Fluorinated Copolymer / Primer: Known Long-Term Durability 1 t=7 d ZES (Resolute) EES (XIENCE) t=0 Magnification = 200 x Data on File at Abbott Vascular 1. E. S. Lo US Patent 3. 178, 399. 1965 t = 56 d

Properties of Fluorinated Surfaces 1 Fluoropassivation: An observed and well-studied blood contact phenomena for over nearly 20 years 2, 3, 5 that demonstrates: – Fluorinated surfaces elicit a decreased local thrombotic and inflammatory response 4 -6, 8, 9 – Fluorinated surfaces conducive to faster rate of endothelialization 4, 6 Tightly bound absorbed albumin was cited as a possible mechanism 7, 10 1. Paton et al. US Patent 5, 356, 668. 1994. 2. Garfinkle AM et al. Trans Am Soc Artif Int Organs. 1984; 30: 432 -439 3. Kiaei D et al. J Biomater Sci Polym Ed. 1992; 4: 35 -44. 4. Guidoin et al, ASAIO Journal 1994; 40: M 870 -879 5. Peterson et al. Trans Am Soc Artif Int Organs. 1975; 21: 242 -248 6. Chinn et al. J Biomed Mater Res. 1998; 39: 130 -140 7. Horbett et al. Trans Annual Mtg Soc Biomater. 1984; v 7: p 361 8. Ashton, et al Proceedings of the 12 th Euro Conf. on Biomaterials. Portugal, 1995, Porto, 10 -13 Sept. 9. Rhee et al Cardiovasc Surg 1996; 4: 747 -752 10. Kandice Kottke-Merchant*, James M. Anderson, Yoshihiro Umemura and Roger E. Merchant; Biomaterials 1989, Vol 10

Thrombogenicity – 14 day post-elution 14 *Statistically significant (p<0. 050) relative to BMS – all pair wise multiple comparison (Holm-Sidak) §Statistically significant (p<0. 050) relative to BMS – multiple comparisons versus control (Dunnett’s) Data generated in collaboration with Prof. Edelman's lab with Drs M Balcells, S Schubert and ER Edelman Also see Paton et al. US Patent 5, 356, 668. 1994 ; Guidoin et al, ASAIO Journal 1994; 40: M 870 -879; Chinn et al. J Biomed Mater Res. 1998; 39: 130 -140

Number of Adherent Monocytes (cells/cm 2) Fluorinated surface elicits low Inflammatory Response: Known Phenomena Revisited Monocyte adhesion to surfaces pre-adsorbed with 1% human plasma 16000 14000 12000 10000 8000 6000 4000 2000 0 Fluorinated polymer (PVDF-HFP) PBMA SIBS 1 SIBS 2 Stainless Steel Data Developed in conjunction with Prof. Buddy Ratner (Univ of Wash) and on file at Abbott Vascular Also see Paton et al. US Patent 5, 356, 668. 1994 ; Guidoin et al, ASAIO Journal 1994; 40: M 870 -879; Chinn et al. J Biomed Mater Res. 1998; 39: 130 -140

Fluorocopolymer Vs Bare metal stent Endothelialization potential Tests performed and data on file at Abbott Vascular Also see Paton et al. US Patent 5, 356, 668. 1994 ; Guidoin et al, ASAIO Journal 1994; 40: M 870 -879; Chinn et al. J Biomed Mater Res. 1998; 39: 130 -140

Polymer coated DES vs BMS In-Vitro Reendothelialization: Data generated in collaboration with Prof. Edelman's lab with Drs M Balcells, S Schubert and ER Edelman Also see Paton et al. US Patent 5, 356, 668. 1994 ; Guidoin et al, ASAIO Journal 1994; 40: M 870 -879; Chinn et al. J Biomed Mater Res. 1998; 39: 130 -140

Conclusions: Durable versus Resorbable 1. Time-dependent phenomena for both resorbable and durable DES coating depends on coating design and polymer selection. 2. Safety of evolved Bare metal surface post-absorption in an absorbable DES is NOT generically better than durable polymer surface • Principles of host-material interaction in Biomaterials science such as, Concepts of PEG-ylation, Fluoropassivation, Biomimicry, and sulfonation, can be used to design short and long term thromboresistant DES coating. 3. True therapeutic differentiation may come from a scaffold that goes away completely, returning the vessel close to or more natural state. • Technology based on a permanent metallic stent does not address the issue of leaving a foreign body in the vessel with constant outward radial force. Unscaffolding the vessel may lead to beneficial biological and physiological changes within the vessel and improve long-term clinical outcomes.

DES Coating Safety Assumptions: Absorbable Vs Durable 1: Short and long-term Absorbable DES coating safety = A. Minimal as-coated defects at t=0 B. Evolved bare metal surface post-absorption = faster, complete functional endothelialization 2: Short and long-term Durable DES coating safety= A. Minimal as-coated defects at t=0 AND minimal evolved defects as f(t) B. Intrinsic Polymer property: PEG-ylation, Fluoropassivation, Biomimicry, Sulfonation Thromboresistance, low inflamamtion, and faster, complete, functional endothelialization

Absorbable Polymers - Absorption rate Highlights Absorption Modes Examples Physical dissolution PVP, PVA, PEG etc. Surface Erosion Chemical Breakdown PLA, PLGA, PEA, PHA, Polyanhydrides, Polyphosphazenes etc. • Surface Erosion • Bulk Degradation • Hydrolytic • Oxidative • Enzymatic • Backbone architecture • Physicochemical Engineering Aspect of DES Feb 2011 • Homogeneous • Heterogeneous Absorption process: Initial Implant, t=0 • Geometry; S/V ratio Macroscopic observation • Reaction kinetics • Mass-Transport Company Confidential – NOT FOR DISTRIBUTION © 2011 Abbott Mech property change, f(t) Mass Loss, g(t)

Goals of DES Coating Technology Functional Mechanical Integrity 1 Drug Release Kinetics Integrity over time and in calcified lesions Tailorability and reproducibility of drug release Biocompatibility 2 Tissue and blood compatibility DES coating technology should address three primary design requirements 1. E. S. LO et al. US Patent 3, 178, 399. 1965 2. Paton et al. US Patent 5, 356, 668. 1994