Biotronik’s PLLA Biodegradable DES Program Ron Waksman MD Associate Chief of Cardiology Washington Hospital Center Georgetown University, Washington DC, USA

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.

Orsiro Hybrid Drug Eluting Stent PROBIO® passive coating encapsulates the stent and minimizes interaction between the metal stent and the surrounding tissue BIOlute® active coating contains a highly biocompatible polymer which delivers a Limus drug via a biodegradable matrix PRO-Kinetic Energy Stent System brings good deliverability for reaching complex lesions BIOlute® achieves a controlled drug release Quick facts Passive coating PROBIO® amorphous silicon carbide coating Active coating BIOlute® bioabsorbable PLLA eluting Sirolimus Drug dose 1.4 µg/mm2 Stent material Cobalt chromium L-605 Strut thickness 60 µm (3.00 mm stent) Approval status CE approved The BIOlute® polymer matrix gently degrades into CO2 and H2O Only a PROBIO® sealed stent is left in the arterial wall

In vivo drug release in mini pig coronary arteries* BIOlute contains sirolimus with an elution kinetic optimized to release over 12-14 weeks Orsiro elutes one of the most proven drugs for a DES In vivo drug release in mini pig coronary arteries* 10 20 30 40 50 60 70 80 90 100 % Drug Release Time (days) In vivo studies show complete sirolimus release between 90-100 days Drug load is 1.4 μg/mm2 Elution curve is in-line with other Limus-based stents * Residual drug remaining of stent after explantation. Source: Preclinical Orsiro animal studies, data on file, BIOTRONIK AG.

BIOlute contains a high molecular PLLA allowing precise control of mechanical and pharmaceutical properties Orsiro has an asymmetric coating and excellent polymer integrity 60μm 7.4μm 3.5μm Asymmetric coating allows greater drug dose on abluminal side of stent strut Release kinetic is controlled by coating and process design (no additional top coatings are needed) Surface drug load of 1.4 µg/mm2 strut surface Mechanical properties are good in general due to the mechanical strength of the polymer No flaking or pealing at expansion areas Source: SEM images from IIB Test Report 66/2009.

BIOlute degrades gently in less than 2 years to avoid increased inflammation Elimination of the polymer removes the threat for polymer related long-term events Real-time degradation of sirolimus loaded PLLA Time (days) Molecular weight [a.u.] 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 50 100 150 200 250 300 350 400 450 500 Source: Preclinical Orsiro animal studies, data on file, BIOTRONIK AG.

Benign histology beyond polymer degradation shown in mini-pigs Masterlayout 28.08.2018 Benign histology beyond polymer degradation shown in mini-pigs Minimal or no inflammatory response of vessel tissue upon degrading polymer 12m 24m 36m Polymer coating visible at one year Appearance different morphology; however, analysis shows that there is no residual PLLA Similar to the Absorb platform, there is only a morphometric imprint left * … Source: … © BIOTRONIK

Differences among bioabsorbable and permanent polymer DES Masterlayout 28.08.2018 Differences among bioabsorbable and permanent polymer DES Pre-clinical histology, mean values at 28 day Intimal area (mm) Inflammation score Fibrin score Orsiro formulation PEVA/PBMA SES PUR SES PEVA/PBMA – permanent cypher-like PUR – Pellethane, permanent PLLA SES PLGA SES BMS © BIOTRONIK

PLLA is our best choice for BIOLute Masterlayout 28.08.2018 PLLA is our best choice for BIOLute Key requirements and performance goals of degradable polymers Assure stability of properties of DES over time (drug stability, release stability,…) Safe transport the drug to the target lesion Controlled release of the drug After those jobs are done, the polymer isn‘t needed any more, that means: Don‘t interact with the body: Either it is completely inert (not feasible) or it goes away without interaction = slow and without provoking inflammation PLLA PDLLA PLGA Mechanical strength and performance ++ + Drug release control (done by diffusion control, NOT by degradation of carrier) Biocompatibility = no inflammation before/during/after degradation Stability against humidity (for polymer AND drug) - Processability © BIOTRONIK

The PK Energy platform offer exceptional deliverability, conformability in a thin-strut device Deliverability is crucial for treatment of complex lesions PK Energy Features … translates into performance Expect PK Energy-like performance with the Orsiro stent PK Energy stent design is optimal for a drug coating and allows for maximum coating integrity during expansion Optimized delivery system allows for higher pressure inflations, as seen with DES (RBP 16 atm, Mean Burst Pressure [MBP] 24-30 atm depending on diameter) Double helical design gives excellent flexibility without compromising scaffolding or fatigue resistance Cobalt chromium alloy allows for thinner struts (60 μm) resulting in flexibility and better results Advanced stent crimping technology ensure a low crossing profile (0.99 mm) Optimized delivery system with Pantera-based catheter design customized for DES usage

Compared to other drug eluting stents, Orsiro has among the thinnest struts Orsiro Hybrid DES SEM images Strut thickness 140 μm 91 μm 81 μm 60 μm Polymer thickness* 12.6 μm 4.8 μm 7.8 μm 7.4 μm Total thickness 153 μm 99 μm 95 μm 71 μm * Only abluminal coating thickness represented.

BIOlute® coating integrity is superior to what is commonly seen for other DES Selection of Orsiro pictures ESEM images of Orsiro as provided by IIB

First in Man Experience With a Drug Eluting Stent in De Novo Coronary Artery Lesions (BIOFLOW-I) Study Design DESIGN: Prospective, multi-centre, non-randomized, first in man trial OBJECTIVE: To assess the safety and clinical performance of the ORSIRO hybrid drug eluting stent in patients with single de-novo coronary artery lesions CLINICAL COORDINATING INVESTIGATOR: Prof. Martial Hamon, University Hospital of Caen, France PRINCIPAL INVESTIGATORS: Dr. Rodica Niculescu, MD, PhD, FESC Dr. Dan Deleanu, MD, FESC 30 patients enrolled July 2009 in 2 clinical sites in Romania Clinical follow-up at 1 month Clinical & angiographic follow-up at 4 months Clinical & angiographic follow-up at 9 months Clinical follow-up at 12, 24 & 36 months Primary Endpoint In-stent late lumen loss at 9 months by QCA

Baseline clinical characteristics Patient demographics show multiple co-morbidities and moderate level of diabetics N=30 Age, years 58.10 yrs ± 9.80 Male sex 60.0% 18/30 Hyperlipidemia 93.3% 28/30 History of MI 73.3% 22/30 Hypertension 66.6% 20/30 Smoker 53.3% 16/30 Diabetes 23.3% 7/30 CHF 20.0% 6/30

Baseline lesion characteristics Lesion characteristic show 1/3 of complex lesions with high device success Pre-Procedure N=30 RVD (mm) 2.75 ± 0.34 MLD (mm) 0.95 ± 0.29 % Diameter stenosis 65.52 ± 9.47 Mean Lesion length (mm) 11.71 ± 4.40 Procedural Stent length per lesion (mm) 19.93 ± 5.33 Stent diameter per lesion (mm) 3.08 ± 0.37 Direct stenting 20.0% Device success* 100.0% * Defined as In-Stent < 30% residual stenosis by offline QCA

Angiographic follow-up results Primary Endpoint Late Lumen Loss @ 9 Months 4-month FUP 9-month FUP RVD (mm) 2.81 ± 0.28 2.81 ± 0.30 Minimal Lumen Diameter In-stent (mm) 2.50 ± 0.36 2.56 ± 0.38 In-segment (mm) 2.20 ± 0.35 2.21 ± 0.31 Diameter Stenosis In-stent (%) 15.19 ± 4.55 13.60 ± 4.27 In-segment (%) 23.66 ± 9.80 23.55 ± 8.06 Late Loss 0.12 ± 0.19 0.05 ± 0.22 0.06 ± 0.23 0.05 ± 0.26 Binary Restenosis 0% 0.05±0.22 0.05±0.26

Cumulative frequency of Diameter Stenosis lkjlökj 18 18

Cumulative Frequency of Minimum Lumen Diameter lkjlökj 19 19

Cumulative Frequency of In-Stent Late Lumen Loss Mean In-Stent LLL: 4 Months 0.12 ± 0.21 9 Months 0.05 ± 0.22 lkjlökj 20 20

Clinical outcomes at 9 months 9-month clinical results N % MACE 2 6.7 Cardiac Death 0.0 MI Stent thrombosis TLR (clinically driven) MACE defined as: Composite of cardiac death, MI attributed to the target vessel, stent thrombosis and clinically driven target lesion revascularization 21

BIOFLOW-I conclusions In this FIM study the Orsiro Hybrid DES showed promising results in a mixed and atypical population for a FIM study, with relatively high rates of diabetic patients and complex lesions At 9 months follow-up, no late catch-up was seen in the LLL values and a narrow standard deviation suggests that these study results are quite robust A larger randomized, comparative study is currently running to prove the safety and effectiveness of this promising device

Clinical strategy for the Orsiro will collect comparative and long-term data Imperative: prove equivalence to the market leader and long-term safety Study design A prospective, multi-centre, single treatment clinical trial Endpoint: LLL 9 months, N=30 A prospective, multi-center, non-inferiority, randomized study, Orsiro vs. Xience Prime Endpoint: LLL at 9 months, N=440 Clinical strategy FIM study, results submitted to TÜV in the CE-mark approval process Comparative, non-inferiority trial testing safety and effectiveness Study design A prospective, multi-centre, single treatment clinical registry Endpoint: LLL at 9 months, N=120 A prospective, multi-centre, single treatment clinical registry Endpoint: TLF at 12 months, N=1,000+ Clinical strategy Pivotal trial for market approval in India, testing safety and effectiveness All comers open label real world evaluation

Study Design Primary Endpoint BIOTRONIK-Safety and Clinical Performance of the Drug Eluting Orsiro Stent in the Treatment of Subjects With single de novo Coronary Artery Lesions (BIOFLOW-II) Study Design DESIGN: A prospective, multicenter, international, two-arm, non-inferiority, randomized controlled clinical study enrolling up to 440 subjects. All subjects will be randomized 2:1 to receive the BIOTRONIK Orsiro or the Abbott Xience Prime™ OBJECTIVE: To compare the BIOTRONIK Orsiro with the Abbott Xience Prime™ with respect to in-stent Late Lumen Loss (LLL) in a non-inferiority study in de novo coronary lesions at 9 months. COORDINATING INVESTIGATORS: Prof. Stephan Windecker Head of Interventional Cardiology University Hospital Bern, Switzerland Dr. Thierry Lefevre Hospital Jacques Cartier, Massy, France Clinical follow-up at 12 months Clinical follow-up at 1 month 440 patients Enrollment started July 2011 Clinical, angiographic, IVUS* and OCT* follow-up at 9 months Orsiro Xience PrimeTM 2:1 * Pre specified sub groups with 60 patients in each Clinical follow-up annually out to 5 years Primary Endpoint In-stent late lumen loss at 9 months post procedure by QCA analysis

Conclusions Biodegradable polymer technology has shown to improve outcomes compared with the previous gold-standard of durable polymer SES Orsiro Hybrid DES applies biodegradable polymer based drug elution with an attractive platform, and has shown promising results in a FIM study, with high rates of diabetic patients and complex lesions BIOFLOW-II will provide further data on this novel device by directly comparing angiographic outcomes with durable polymer EES (Xience PrimeTM)