Sirolimus Coated Balloon Technologies Robert M Bersin MD

Sirolimus Coated Balloon Technologies Robert M. Bersin, MD, FACC, FSCAI Medical Director, Endovascular Services Swedish Medical Center Seattle, Washington

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Robert M. Bersin, MD Abbott Vascular C, P, SB Ablative Solutions EI Boston Scientific AB, C, EI, P, SB Cook Medical, Inc. C, P Med Alliance SA, AB, EI Medtronic, Inc. C, P Omeros Corp, EI QT Vascular, EI Transverse Medical AB, EI, SO Vatrix Medical EI W. L. Gore C, P AB: Company Advisory Board C: Consulting Relationship EI: Equity Interest GS: Grant Support P: Proctor or Training Course Sponsorships SB: Speakers Bureau SE: Spouse Employee SO: Stock Options or Positions

Drug Coated Balloon – Coronary Devices Drug Dose Company Device Drug Coating / Excipient Aachen Resonance Elutax SV PTX None 2 Yes Bard Lutonix 014 PTCA PTX Polysorbate / Sorbitol 2 No B Braun Sequent Please PTX Iopromide 3 Yes Biotronik Pantera Lux PTX Butyryl-tri-hexyl Citrate 3 Yes Boston Scientific Agent PTX Acetyl-tri-butyl Citrate 2 Yes Cardionovum Restore / Primus PTX Shellac 3 Yes Eucatech Support C PTX Butyryl-tri-hexyl Citrate 3 Yes Eurocor / Biosensors DIOR/ Bio. Stream PTX Shellac 3 Yes Medtronic IN. PACT Falcon PTX Urea 3. 5 Yes Minvasys Danubio PTX Butyryl-tri-hexyl Citrate 2. 5 Yes Nano Therapeutics Curex PTCA PTX 2. 3 No μg/mm 2 CE

Drug Coated Balloon – Peripheral Devices Company Device Drug Coating / Excipient Aachen Resonance Elutax SV PTX None Balton mc. PCB PTX Bard Lutonix PTX Bayer-Medrad Cotavance Biotronik Drug Dose μg/mm 2 CE 2 Yes 3 No Polysorbate / Sorbitol 2 Yes PTX Iopromide 3 Yes Passeo-18 Lux PTX Butyryl-tri-hexyl Citrate 3 Yes Boston Scientific Ranger PTX Citrate Ester 2 Yes Cardionovum Legflow PTX Shellac 3 Yes Cook Advance 18 PTX None 3 Yes Covidien Stellarex PTX Amphiphilic Polymer 2 Yes Eurocor / Biosensors Freeway / Bio. Path PTX Shellac 3 Yes i. Vascular Luminor PTX Water Reducer Ester 3 Yes Medtronic IN. PACT PTX Urea 3. 5 Yes Meril Mozec PTX Nano-particles 3 No Nano Therapeutics Curex PTA PTX 2. 3 No Vascular Nanotransfer Technologies PTX Nano-encapsulation Surmodics PTX Microcrystalline Angio. Score Angio. Sculpt* PTX Tri. Reme Medical Chocolate Touch* PTX No 3 No No

SIROLIMUS DRUG COATED BALLOONS • Sirolimus offers potential benefits over Paclitaxel: Attribute Sirolimus (or Analogs) Paclitaxel Mode of action Cytostatic Cytotoxic Margin of safety 10’ 000 fold 100 fold Wide Narrow Yes – lower late lumen loss Yes Anti-inflammatory Yes No Tissue absorption Slow Fast Tissue retention Short Long Therapeutic range Anti-restenotic • Sirolimus is drug of choice for coronary DES supported by solid clinical based evidence

Sirolimus Coated Balloon – Benefits PACLITAXEL Arterial Drug Concentration (μg/g) 10’ 000 TOXIC EFFECT 1’ 000 100 Typical DCB Curve 10 THERAPEUTIC RANGE Typical DES Curve 1 NO EFFECT 0 0 Source: Presentation Granada at CRT 2014. 25 50 Time (Days) 75 © M. A. Med Alliance – 2015. Confidential. 100

Sirolimus Coated Balloon – Benefits SIROLIMUS TOXIC EFFECT Arterial Drug Concentration (μg/g) 10’ 000 1’ 000 THERAPEUTIC RANGE 100 Typical DCB Curve 10 Typical DES Curve 1 NO EFFECT 0 0 Source: Presentation Granada at CRT 2014. 25 50 Time (Days) 75 © M. A. Med Alliance – 2015. Confidential. 100

Sirolimus Coated Balloon – Challenges Paclitaxel and Sirolimus act differently with tissue: � Paclitaxel absorbs quickly and tends to localize in sub-intimal space and partitions significantly in adventitia � Sirolimus absorbs slowly and spreads throughout entire artery where it dilutes down to sub-therapeutic levels Balloon Surface Drug Coating Endothelium Plaque or Neointima Tunica Media Sirolimus Paclitaxel Dextran Tunica Adventitia Tissue Binding Capacity (TBC) of labeled dextran, paclitaxel and sirolimus in 0. 040 -mm-thick bovine internal carotid tissue segments. Source: PNAS 2004: 101(25); 9463– 67.

Sirolimus Coated Balloon – Challenges Enhance tissue absorption � Difficult to get Sirolimus to enter into arterial tissue within 30 to 180 seconds of balloon dilatation; hence some kind of “instant glue” required to transfer the drug from the balloon to the tissue efficiently Extend tissue retention � Sirolimus must be continuously delivered over time, so some form of “time release mechanism” must be employed to maintain therapeutic levels

Granada J TCT 2015

Sirolimus Coated Balloon – Solution Use of micro-reservoirs made out of biodegradable polymer intermixed with Sirolimus � Controlled and sustained drug release � Long-term distribution of Sirolimus into tissue to maintain therapeutic levels Novel Cell Adherent Technology – CAT™ � Minimizes wash-off during insertion, tracking and lesion crossing � Optimizes drug transfer to tissue during short-term balloon dilatation © M. A. Med Alliance – 2016. Confidential.

Med Alliance SELUTION™ vs. Competition Medtronic IN. PACT BBraun SEQUENT PLEASE Biotronik PANTERA LUX © M. A. Med Alliance – 2015. Confidential.

Med Alliance SELUTION™ vs. Competition F A L I K G N Medtronic IN. PACT BBraun SEQUENT PLEASE Biotronik PANTERA LUX © M. A. Med Alliance – 2015. Confidential.

Med Alliance SELUTION™ vs. Competition O N ING K A L F © M. A. Med Alliance – 2015. Confidential.

MED ALLIANCE SELUTION™ SIROLIMUS DCB • Micro-reservoirs made out of biodegradable polymer intermixed with Sirolimus: ¡ Controlled and sustained drug release mechanism ¡ Maintains therapeutic effect in tissue over long period of time • Novel Cell Adherent Technology – CAT™: ¡ CAT™ transfer membrane houses and protects micro-reservoirs during balloon insertion, lesion crossing and expansion ¡ CAT™ transfer membrane with embedded micro-reservoirs releases from balloon delivery system and adheres to vessel lumen during short balloon inflation

MED ALLIANCE SELUTION™ SIROLIMUS DCB % of Total Device Drug Load Drug Dispersion 100% 80% 60% 40% 20% 0% Med Alliance. SELUTION Lost during procedure 36% Retained on balloon 25% Transferred to vessel (1 hr) 39% Bard. LUTONIX Medtronic. IN. PACT 83% 12% 5% 83% 14% 3% Med Alliance – In vitro test data on file Bard & Medtronic – Presentation J. F. Granada (TCT 2014)

MED ALLIANCE SELUTION™ SIROLIMUS DCB Arterial Tissue Drug Concentration Sirolimus (RAP) versus Paclitaxel (PAX) Drug Dose per Balloon Size 10 262 250 Med Alliance SELUTION - RAP 9 Med Alliance SELUTION - 1. 0 μg/mm 2 Bard LUTONIX - PAX 8 Bard LUTONIX - 2. 0 μg/mm 2 7 Medtronic IN. PACT - 3. 5 μg/mm 2 Drug Dose [mg] Tissue Drug Concentration [ug/g] 300 Medtronic IN. PACT - PAX 200 150 100 Therapeutic Effect ≥ 1 µg/g 59 50 35 44 0 1 hour 6 5. 7 5 4 3 2. 8 2 1 11 7 days 21 0. 3 3 28 days 19 0 0 60 days 9. 9 1. 8 1 0 0. 5 1. 0 4. 0 x 40 6. 0 x 150 En Face Scanning Electron Microscope at 24 hours Med Alliance – PK Study (2014 -004) Medtronic – Presentation R. J. Melder (LINC 2012) Bard – Catheterization and Cardiovascular Interventions 83: 132– 140 (2014)

Med Alliance SELUTION™ – PK Study Mean Arterial Tissue – Drug Concentration (Sirolimus vs Paclitaxel) 300 Drug Concentration [µg/g] 262 Med Alliance SELUTION - RAP 1. 0 ug/mm 2 250 Medtronic IN. PACT - PAX 3. 5 ug/mm 2 200 Bard LUTONIX - PAX 2. 0 ug/mm 2 150 100 44 50 19 21 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 Time Point [Days] Source: Med Alliance – PK Study (2014 -004) / Bard – Catheterization and Cardiovascular Interventions 83: 132– 140 (2014) / Medtronic – Presentation Melder (LINC 2012). 85 90

Peripheral FIM – Study Overview Objective Design Primary Endpoint Secondary Endpoints To show non-inferiority of SELUTION™ DCB vs. FDA approved DCB in terms of safety and efficacy for treatment of Superficial Femoral (SFA) or Popliteal (PA) Artery lesions � Prospective, Multi-Center, Single Blinded, Randomized Controlled � N=110 (55 in each arm) � Angiographic Late Lumen Loss (LLL ) by QVA 6 months � Major Adverse Events (Death, TLR, Thrombosis, Amputation) 6 months � Primary Patency – Freedom from CD-TLR and Restenosis by DUS 6, 12 and 24 months � Angiographic Binary Restenosis (ABR) by QVA 6 months � Composite of Freedom from Amputation and Freedom from CD-TVR 12 and 24 months � Change of ABI, WIQ and Qo. L 6, 12 and 24 months © M. A. Med Alliance – 2015. Confidential. 11/22/2020

FIM – Study Design Non-Clinical Inclusion / Exclusion Criteria Pre-screening Clinical and Anatomic Inclusion / Exclusion Criteria Screening Failure Screening (Treat per std practice) Successful Pre-Dilatation? NO Treatment Randomized 1: 1 SELUTION™ DCB Analysis FDA Approved DCB Bailout Stenting? NO Primary Endpoint Analysis ITT Analysis © M. A. Med Alliance – 2015. Confidential. Bailout Stenting Analysis

Coronary FIM - SELUTIONTM ISR Trial (incl small vessels & side branches) Investigational Device � SELUTION™ Sirolimus Coated Coronory Balloon (S-DCB) Design � Assess safety and efficacy of the Med. Alliance sirolimus-eluting micro-reservoirs DCB (SELUTIONTM) in comparison with currently approved paclitaxel DCB Other Objectives � Proof of efficacy Proof of non-inferiority vs. Paclitaxel DCB Collect data to obtain CE mark approval � � © M. A. Med Alliance – 2015. Confidential. 11/22/2020

SELUTION DSR Prospective, open label, multi-center RCT with angiographic endpoints Patients with CAD with ISR or Bifurcation with side-branch lesion or distal lesions in small vessels Large centres in countries where Paclitaxel DCB are approved and reimbursed SELUTION™ DCB 145 Patients 1: 1 randomization Paclitaxel DCB Clinical FU 1 mo 3 mo 9 mo 1 yr Angio FU Optional IVUS FU Primary endpoint: Secondary endpoints: S-DCB superiority for % diameter restenosis vs P-DCB at 9 months LLL at 9 months Primary angiographic EP for each of the 3 groups Device success (in cath lab) Procedure success (at discharge) Freedom from TVF at 360 and 720 days Components of TVF at 360 and 720 days Freedom from angina at 360 and 720 days QOL & Cost-effectiveness at 360 days IVUS determined minimal DSA at 9 months (optional) DAPT: 30 days in both arms (if no stent in main branch for S group) 2 yrs

SIROLIMUS DCBs • Potential to improve patient outcomes ¡ ¡ ¡ Efficacy • Sirolimus has potential to reduce late lumen loss • Micro-reservoirs provide sustained release of Sirolimus – “DES like” but without leaving something behind Safety • Cytostatic Sirolimus instead of cytotoxic Paclitaxel with higher tissue tolerance • Substantially reduced drug dose (especially in case of multiple, longer or overlapping balloons) • Reduced wash-off and less harmful to operators Healing • Less inhibition of healing in target lesion and in distal tissue beds due to lower drug toxicity and reduced embolization of coating (e. g. better wound healing in CLI patients)