Lev-OR, A New Guide Wire “Sheath” for Resistant Lesion Crossing and Collagenase Update Dr. Bradley Strauss CIHR Team in Vascular Occlusive Disease Reichmann Chair in Cardiovascular Research Sunnybrook Health Sciences Centre University of Toronto Toronto, Canada

Bradley H. Strauss, MD, PhD DISCLOSURES Bradley H. Strauss, MD, PhD Royalty Baylis Medical Consulting Fees Abbott Vascular, Interface Biologics Ownership Interest (Stocks, Stock Options or Other Ownership Interest) Matrizyme Pharma

Conflict of Interest I disclose the following financial relationships: Receipt of Intellectual Property Rights / Patent Holder: Collagenase for chronic total occlusions CTO guide sheath Angiogenic therapy for chronic total occlusions Contracted Research: Abbot Vascular, Baylis Medical Ownership Interest: Matrizyme Pharma I intend to reference unlabeled/unapproved uses of a products in my presentation: CTO guide wiresheath for Chronic Total Occlusions

Why I failed CTO PCI? Could not cross with a guide wire (95%) Could not cross with a balloon catheter (5%) But occurs very commonly (10-20% cases), prolonging procedure and increasing complexity

Why I failed CTO PCI? Could not cross with a balloon catheter

The Spectrum of Lumen Morphology in CTO: Clinical Challenges of a Fibrotic Plaaque Large recanalization channels Small recanalization channels Proteoglycan-rich Fibrotic plq: Negative remodelling Necrotic core Calcification Inflammation

Proximal Fibrous Cap at 12 weeks EEL PFC L PFC L M EEL Proximal Fibrous Cap at 12 weeks

What are the Crossing Profiles? Guide wire 360 μm (0.014”) Fixed-wire balloon (ACE): 610 μm RX balloon (1.5 mm Maestro): 900 μm OTW balloon (Opensail): 1100 μm Microcatheter (Excelsior): 670 μm Non-Balloon Devices 0.9 mm high-energy excimer pulsed laser catheter (X80, Spectranetics) Rotational atherectomy

Tornus- Asahi Vascular - 8 stainless steel wires stranded into the coil OD 700 μm -tip profile 620 μm, stainless-platinum alloy

Desired Characteristics of Crossing Device Flexible Low-profile Distal tip strength Monorail design

Lev-ORTM Device Concept Flexible Nitinol Sleeve Ultra-low Distal Profile OD 559 μm (0.022”) ID 432 μm (0.017”) Hydrophilic coating Gradual Taper “Dotter” and stretch the lesion Option of progressively larger sleeves

Guidewire Sheath Device Radiopaque Marker Tapered Distal Tip 2. Intermediate Shaft Section - Polymer shaft 1. Distal Section - Flexible nickel-titanium alloy (Nitinol) Tapered distal tip Polymer coat (except distal taper) 3. Proximal Shaft Section -Polymer shaft -Stainless steel wire for pushing - monorail port The Lev-ORTM is not approved for sale in the USA

Lev-ORTM Final Design Distal Section Handle The Lev-ORTM is not approved for sale in the USA

Current Status First clinical cases planned for March 2010

Novel Biologic Therapies: Intralesional Treatments for Improved Guidewire Crossing

Therapy Target Onset of Action Current Status Contrast Collagenase Enlarge Microchannels Immediate Clinical Use Collagenase Degrade Collagen Hours FIM Nov 2009 Angiogenic Factors Induce new microchannels Days Pre-clinical Studies Fefer P, Can J Cardiol 2010 In press

The microchannel technique The MCT is an anterograde method of percutaneous revascularization of CTO that utilizes already existing channels within occluded vessels. 17

Collagenase Total Occlusion-1 (CTO-1) Clinical Trial Study Design Prospective, two-centre, Phase I Safety and Feasibility Study 4 dose cohorts of acute intracoronary injected collagenase (300 – 1200 µg) prior to routine percutaneous revascularization procedures. 5 subjects / dose cohort, previously failed attempt Dose escalation only upon successful dosing of each subject in the cohort and a favorable safety review of the entire cohort

Milestones of CTO-1 Trial GMP Collagenase production completed, with stability data at 6 months Jan 2009: Canadian Institute of Health Research Approved Funding Health Canada Approval-August 2009 1st patient enrolled November 4, 2009

Patient #1 52 years old labourer, inferior wall infarction in 2006 New changes in stress test Dec 2008 Angiogram now shows complete blockage of LAD (CTO) Unsuccessful attempt in June 2009 Currently shortness of breath and some chest pains walking up hill

June 11, 2009: Initial Attempt

November 3, 2009

Balloon Positioned in Occlusion

Injection of Collagenase Into Chronic Total Occlusion

November 4, 2009

Guidewire Crossing with Whisper GW

Full Crossing of CTO

Follow Up No acute changes in echo or cardiac biomarkers Clinically well and asymptomatic at 3 months Unremarkable CTA at 3 months Stents in LAD widely patent No myocardial changes

Summary Lev-ORTM is a rapid exchange device for facilitating balloon crossing after successful guidewire crossing in CTO Intralesional therapies represent a novel approach for improving guidewire crossing in CTO CTO-1 trial expected to be completed December 2010