The Biotronik Magnesium Alloy Bioabsorbable Stent Program: Lessons Learned and Future Directions Ron Waksman, MD Professor of Medicine (Cardiology) Georgetown University, Associate Director of Cardiology Washington Hospital Center Washington DC

Ron Waksman, MD DISCLOSURES Consulting Fees Grants/Contracted Research Abbott Vascular, Biotronik, Medtronic CardioVascular, Inc, Boston Scientific Corporation Grants/Contracted Research Abbott Vascular, Biotronik, Boston Scientific Corporation, The Medicines Company, GlaxoSmithKline, Schering-Plough, sanofi-aventis U.S. LLC

Magnesium shows positive effects on the vascular system, even in high doses An essential element for the human body involved in the synthesis of more than 300 enzymes Quantity in human body: ~ 20 g Daily need (adult): ~ 350 mg Weight of Magnesium stent: ~ 3 mg High concentration of Magnesium (e.g. 2 g infusion) has shown … to cause vasodilation [Seelig et al. 1983] to promote the development of collateral vessels in ischemia [Maier et al. 2004] to directly inhibit acute stent thrombosis [Rukshin et al. 2001 & 2002] to act antiarrhythmic [Arnold et al. 2000] to have neuroprotective effects [Kohno et al. 2007] San Pellegrino: Mg: 53.5 mg/l

AMS allows non-invasive imaging of the stented vessel Headline IVUS/OCT stent visibility MRI 16 MSCT Erbel et al, Herz 32 · 2007 · Nr. 34 Left pictures: Coronary magnesium stent implantation into segment 1 of the right coronary artery and visualization by intravascular ultrasound. The stent was not visible by magnetic resonance imaging, but the invisible stent allowed free imaging of the coronary lumen of the artery despite coronary stenting. Right picture: 16‑slice computed tomography of a magnesium stent in segment 6 of the left coronary artery. The magnesium stent is not visible allowing a free imaging of the artery lumen MRI/MSCT No stent artefact Optimal vessel lumen imaging Source: Erbel et al, Herz 32 · 2007 · Nr. 4 * … Source: … * … Source: …

First in Man Coronary Study of AMS-1: PROGRESS-I Clinical Performance and Angiographic Results of the Coronary Stenting with Absorbable Metal Stents

Results PROGRESS 1 - IVUS Post implantation 4 months follow-up Negative remodeling/ recoil Thickening of extra-stent tissue In-stent neointima Contribution to lumen loss 42% 13.5% 41% Waksman et al. JACC Intervention 2009

TLR occurrence in PROGRESS 1 100 80 60 4-month ANGIO Ischemic TLR Occurrence 40 20 30 60 90 120 150 180 210 240 270 300 330 Days Post Intervention

NLD 014-002 Post Implantation 4 Months 28 Months Waksman et al. JACC Intervention 2009

AUS 004-001 Post Implantation 4 Months 16 Months Waksman et al. JACC Intervention 2009

IVUS Analysis Waksman et al. JACC Intervention 2009

Vessel Reactivity Intracoronary ISDN induced vasodilatation in Permanent Metal Stent (PMS) control patients and Absorbable Metal Stent (AMS) patients within stent and in proximal reference segments at 4 months post implant. Courtesy of Dr Miles Dalby Royal Brompton & Harefield

15 months after AMS implantation in human Very thin neointima Perfect ingrowth of AMS Completed healing of the stented vessel IVUS OCT Dr. Carlo di Mario, London

AMS-1 studies demonstrated safety and gave valuable input for improvements Safe in human coronary and peripheral arteries (150 patients) No death, no MI, no stent thrombosis, no distal embolization Device success rate of 99.4% Absorbed as intended in several months Fully CT/MRI compatible Clinical performance comparable to PTA in BTK lesions High TLR in coronary indication, compared with DES and modern BMS (despite PROGRESS AMS-1 having met the safety and efficacy primary endpoint) The AMS technology is feasible (high procedural success and technical success, absorption of the device allows natural vasomotion) The AMS provided safety (no death, no MI, no stent thrombosis, no distal embolization, no excessive inflammation) PROGRESS AMS-1 met the safety and efficacy primary endpoints (MACE <30%) High TLR, so further improvement of the AMS-1 technology is needed to improve efficacy BIOTRONIK opted to further improve the AMS-1 technology to improve efficacy

neointima hyperplasia The next generations of AMS address the two main levers for improvement AMS-1 is being improved by ... AMS-2 ... prolonged mechanical stability AMS-3 ... reduction of neointima hyperplasia Improved stent design Surface passivation “DREAMS” = Drug elution Modified Alloy

AMS-2 technology: A leap forward Strut Cross-Sections AMS-1 AMS-2 165µm 120µm Changes made Alloy with slower degradation Lower strut thickness Surface modifications Modern 6-crown design Effects (in animal) Prolonged scaffolding and stent integrity Less neointima proliferation Increased radial strength

AMS-2.1 provides competitive mechanical performance Tailor-made specialty Magnesium alloy with slow degradation Available sizes Diameters of 3.0/3.25/3.5mm Lengths of 12/16/20mm Proven SDS based on „ProKinetic“ bare metal stent system Favorable mechanical properties (values for 3.0mm stent version) Elastic recoil: 5% Collapse pressure: 1.2 bar Crossing profile: 1.3mm 6F compatible

BIOTRONIK DREAMS AMS 3 Eluting Stent System Drug: Fast degradable carrier with a proven, anti-proliferative drug First animal trials show sustained anti-proliferative effect up to 1 month Drug elution kinetic is currently optimized Stent: Bioabsorbable Magnesium Alloy This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Carrier: Bioresorbable Matrix Modifications for control drug release

DREAMS: Drug Eluting Absorbable Metal Stent POLYMER Δ Drug Elution Rate Drug Degradation DRUG STENT Drug Degradation

DREAMS: Drug Eluting Absorbable Metal Stent DE Formulation identified that demonstrates controlled release of conventional anti-proliferative drug from AMS % Cummulative Release Controlled Drug Elution DE Coating on Mg demonstrating Mechanical Integrity & Stability (Post-Sterile) In Vitro Drug Elution from Mg AMS Stent

DREAMS: Drug Eluting Absorbable Metal Stent Significant Improvement in MLD with DREAMS at 14d and 28d vs. Bare AMS in Porcine Model TIME

DREAMS: Drug Eluting Absorbable Metal Stent Demonstration of Drug Activity in Porcine Coronary Model at 28 days with DREAMS Bare AMS DREAMS Significant Reduction in Neointima Thickness Between DREAMS and Bare AMS TIME

Summary The BIOTRONIK's Mg Absorbable Metal Stent technology is based on a specialty Magnesium alloy that offers superior stent mechanics and biocompatibility The first generation of Absorbable Metal Stents (AMS-1) showed promising results regarding mechanical properties as well as feasibility and safety in several human applications (150 cases) The second generation (AMS-2) shows improved scaffolding and efficacy in animal based on a more slowly degrading Magnesium alloy and an optimized stent design The preclinical studies of AMS-3 have demonstrated positive results allowing the clinical program to resume in 2010 22