Update on the BIOSOLVE Clinical Trial Using DREAMS Absorbable Magnesium Scaffold Ron Waksman, MD, FACC, FSCAI Professor of Medicine, Georgetown University, Associate Chief of Cardiology, Washington Hospital Center, Washington DC

Ron Waksman, MD Consulting Fee Abbott Laboratories Biotronik, Inc. Boston Scientific Corporation Medtronic, Inc. Merck and Company, Inc.

Honoraria Abbott Laboratories Boston Scientific Corporation Medtronic, Inc. Consulting Fee Merck and Company, Inc.

AMS is a metallic stent with favorable mechanical properties Design & Manufacturing Based on Finite Element Analysis Laser cut and polished surface San Pellegrino: Mg: 53.5 mg/l Mechanical parameters Low bending stiffness Low crossing profile (1.2 mm) Low recoil (<5%) High radial strength (~1 bar) Clinical effects Good trackability and device success rate of 99.4%* Good stent apposition

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: … Source: Erbel et al, Herz 32 · 2007 · Nr. 4 * … Source: …

Degradation product composition in vivo Magnesium of the AMS scaffold is completely replaced with conversion products The polymeric drug coating is fully degraded Degradation process and conversion product composition in clinical and preclinical use is similar 5 months after AMS 1.0 implantation Staining indicates a nearly complete replacement of magnesium (pediatric). Elemental composition of conversion product Residual magnesium core, degradation products in the surrounding conversion zone (minipig). Sources: J. Riedmüller; Yucatan Minipig, 42 days FUP // Zartner P. First Successful Implantation of a Biodegradable Metal Stent Into the Left Pulmonary Artery of a Preterm Baby. Catheterization and Cardiovascular Interventions 66:590–594 (2005))

Previous bare AMS devices demonstrated safety, but… IVUS OCT Perfect in growth of AMS Safe in human coronary and peripheral arteries (150 patients) No death, no MI, no scaffold thrombosis, no distal embolization, no excessive inflammation Device success rate of 99.4% Absorbed as intended in several months Fully CT/MRI compatible Source: Courtesy Dr Di Mario: PROGRESS AMS-1, long term results (15 months) showed perfect ingrowth

Lessons learned from the AMS PROGRESS-I showed the bare AMS concept to be safe and feasible Post implantation 4 month follow-up Contribution to lumen loss Loss of scaffolding area In-stent neointima 53% 47% Results of PROGRESS* (AMS I FIM): LLL 1.08 mm; TLR 23.8% Optimization of device with prolonged scaffolding time and an anti-proliferative drug * Erbel R. et al., Lancet 2007;369:1869-75, Waksman et.al, JACC Cardiovasc Intervent 2009;2:312-320

From bare AMS to DREAMS Bare AMS DREAMS Histology at 28 days PROGRESS-I DREAMS BIOSOLVE-I Prolong scaffolding time and inhibit cell proliferation 80x165µm 130x120µm + 1μm coating Strut Geometry Alloy Refinement Drug/polymer matrix added with Paclitaxel Histology at 28 days Scaffold design

DREAMS: DRug-Eluting Absorbable Metal Scaffold - Design Overview - Drug carrier 1 µm bioabsorbable PLGA Polymer Scaffold Backbone Proprietary Mg-alloy Excellent biocompatibility 120µm strut thickness Drug Paclitaxel Proven elution behaviour Delivery system Modified PRO-Kinetic Energy Sizes used in FIM 3.25/3.5 x 16 6F compatible

DREAMS provides scaffolding and paclitaxel release up to 3 months acute 3 months 6 months 9 months Mg Scaffolding Paclitaxel release Mg + 2H2O  Mg(OH)2 + H2 Soft Hydroxyapatite Biodegradation Bioabsorption Mg degradation completed Drug release completed Degradation of polymer ongoing Conversion of degradation product completed Drug carrier layer degradation completed Beginning of structural disintegration Mg alloy Mg degradation product Polymer

First generation DREAMS shows in vitro elution behavior comparable with Taxus DREAMS drug elution Cumulated DREAMS High stability of paclitaxel allows to control processes in this system comprising a degradable backbone and a degradable drug carrier Based on preclinical tests, elution time in-vivo elution is estimated at 3 months Taxus Liberté DREAMS Source: in vitro measurements, data on file

DREAMS shows low inflammation scores - comparable to Taxus Comparison between DREAMS and Taxus Liberté control shows low inflammation scores at 28, 90 and 180 days Minor increase of inflammation at 28 days seen in the DREAMS arm due to degradation of base materials Inflammation Score [28/90/180d] Histopathology, Mean Values 4.0 3.0 2.0 1.0 1.31 0.65 0.66 0.56 0.70 0.38 0.0 DREAMS Taxus Liberté n=8/8/8/4 n=6/6/6 Source: AccelLAB preclinical studies, data on file

DREAMS late lumen loss is comparable to Taxus Taxus Liberté N=6/6/6/6 DREAMS N=8/8/8/8 Source: AccelLAB preclinical studies, data on file

Histological Images at 28 days show fast healing of DREAMS Reference (Taxus) Source: AccelLAB preclinical studies, data on file All photos same magnitude and scale

BIOSOLVE-I study design Prospective, multi-center, first-in-man trial, single de novo coronary artery lesions with RVD between 3.0 and 3.5 mm and lesion length ≤ 12 mm Primary Endpoint: Cohort 1: TLF* at 6 months Cohort 2: TLF* at 12 months 46 patients with de novo coronary artery stenosis Cohort 1 (n=22) Cohort 1 (n=22) Cohort 2 (n=24) Cohort 2 (n=24) 6-month FUP Clinical (n=22) Imaging (n=20**) Clinical (n=24) Imaging (n=16***) * Composite of cardiac death, target vessel myocardial infarction and clinically driven TLR 12-month FUP ** 2 pts withdrew consent for imaging FUP at 6 months *** 16 pts from cohort 2 consented for the optional 6-month imaging FUP Clinical (ongoing) Imaging (ongoing) Clinical (ongoing) Imaging (ongoing) QCA and IVUS are mandatory imaging follow-ups, while OCT is optional 24 and 36-month FUP mandatory optional

Baseline clinical characteristics Cohort 1+2 N=46 Age (mean ± SD) 65.3 ± 9.7 Men (N/%) 34 73.9 % Hypertension 40 87.0 % Hyperlipidemia 41 89.1 % History of MI 15 32.6 % Previous PCI 27 58.7% Renal Insufficiency 12 26.1% Congestive Heart Failure 7 15.2% Diabetes Smoking 6 13.0% History of stroke of TIA 3 6.5%

Baseline angiographic characteristics Pre-Procedure (N=46) RVD (mm) 2.73 ± 0.48 MLD (mm) 1.21 ± 0.52 % Diameter stenosis 56.0 ± 17.1 Mean lesion length (mm) 10.69 ± 4.5 Procedure (N=46) Scaffold length used (mm) 16 Scaffold diameter used (mm) 3.25 / 3.5

Procedural and primary endpoints for both cohorts up to 6 months % Device success* 46 100 Procedural success** 6-month clinical results TLF 2 4.3 Cardiac death 0.0 MI Scaffold thrombosis TLR (clinically-driven)*** * Defined as: successful delivery of the scaffold to the target lesion site in the coronary artery appropriate scaffold deployment successful removal of delivery system after release of the scaffold safe removal of the device in case of deployment failure ** Defined as: device success plus attainment of a final residual stenosis of < 50% of the target lesion absence of a major adverse cardiac event during the hospital stay to a maximum of first seven days post procedure *** TLR occurred during 6 M FUP, both pts had angina, 1 pt received an additional DREAMS in the target lesion during the initial procedure because of a flow-limiting bailout situation 19

Comparison of angiographic LLL between bare AMS and DREAMS BIOSOLVE-I 6-month FUP 0.64± 0.50 mm -41% Cumulative Frequency (%) PROGRESS 4-month FUP 1.08 ± 0.49 mm LLL (mm)

OCT evaluation: few malappositions post-procedure and at 6 months Scaffold Strut Apposition – Baseline Scaffold Strut Apposition – 6 Mo FUP 3.6% 6.4% 1.1% 5.3% 93.6% 90.0% Apposed ISA Apposed Persistent ISA Late Acquired ISA Resolved ISA N=4 scaffolds, 3,226 struts Apposed N=4 scaffolds, 3,226 struts ISA – Incomplete Strut Apposition Koolen J. et al; TCT 2011

Six-month follow-up evaluation of OCT images shows 100% strut coverage Scaffold Strut Coverage – 6 Mo FUP 0.0% (0 struts) 100.0% (9,487 struts) Complete Incomplete N=15 scaffolds, 9,487 struts Koolen J. et al; TCT 2011 Complete

Vasomotion result-cohort 1 Proximal Segment 0.5 4.0 4.5 5.0 3.5 3.0 2.5 2.0 1.5 1.0 Mean lumen diameter (mm) Pre-ACH Post-ACH Nitro- glycerine Mean Scaffolded Segment Distal Segment P=0.515 2.55______2.25______2.64 p=0.013 p=0.012 P=0.493 2.40______2.25______2.55 p=0.079 p=0.006 P=0.959 2.37______2.08______2.40 p=0.057 p=0.012

Koolen J. et al; Poster Presentation, TCT 2011 Case presentation 1 Pre Post 6 Mo FUP BEL006-002 76 yrs old female Hyperlipidemia, LBBB, aortic valve stenosis, De novo lesion in the mid LAD Pre-dilatation with 3.0/ 12mm balloon, treatment with 3.5/ 16 mm Dreams No signs of angina at 6 month follow-up Post 6 Mo FUP Koolen J. et al; Poster Presentation, TCT 2011

Koolen J. et al; Poster Presentation, TCT 2011 Case Presentation 2 6 Mo FUP Pre Pre Post Post 6 Mo FUP 6 Mo FU NLD014-001 72 yr-old male with hypertension, renal insufficiency De novo lesion in the mid LAD Pre-dilatation with 2.5/ 12mm balloon, treatment with 3.5/ 16 mm DREAMS Stable angina class II at 6-month follow-up Post Koolen J. et al; Poster Presentation, TCT 2011

Future Development BIOTRONIK is evaluating the option of adding a Limus compound to improve patient outcome in vitro drug release kinetik of DREAMS vs. Sirolimus-eluting ORSIRO (Fast Release Method) 10 20 30 40 50 60 70 80 90 100 in vitro elution time [h] Total release [% LC] Reference. ORSIRO Sirolimus-eluting stent DREAMS Sirolimus-eluting Absorbable Metal Scaffold 26

In development Radiopaque markers will be added to improve x-ray visualization 27

Conclusions The DREAMS device demonstrates an excellent safety profile without death, MI, or scaffold thrombosis at 6 months A TLF rate of 4.3% at 6 months after DREAMS implantation is comparable to permanent DES DREAMS demonstrated significantly improved efficacy compared to the bare AMS: Reduction in LLL of 41% (1.08 vs. 0.64mm) Reduction of TLR rate by 82% (23.8 vs 4.3%) Future Directions continued improvement in design, markers and moving to a limus drug 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) 28 28