PHARMACOLOGICAL TREATMENT OF ARTERIAL RESTENOSIS

PHARMACOLOGICAL TREATMENT OF ARTERIAL RESTENOSIS

PACLITAXEL VS RAPAMYCIN Paclitaxel essentially freezes the microtubules that are in place during cell division. The cells cannot complete cell division and recognizes that something is wrong and destroys itself. This process is called apoptosis or programmed cell death. Rapamycin works a little differently in that it affects a different pathway that essentially puts the cell to sleep and by doing that it prevents the cell from proliferating. Eventually the Rapamycin is metabolized and the cell wakes up and can operate normally again.

PACLITAXEL PREVENTS CELLULAR DIVISION AND REPLICATION, Drug PROVIDING A STRONG ANTI-RESTENOTIC EFFECT Paclitaxel (Cytotoxic) Interferes with cell division Rapamycin/Sirolimus (Cytostatic) Interferes with cell growth Cytotoxic drugs stabilize microtubules, preventing division in the final stages of the cellular replication cycle and leading to cell death (apoptosis) M G 2 Mitosis Cell prepares for mitosis G 1 Protein synthesis DNA synthesis S Cytostatic drugs hold a cell in G 0 phase, arresting growth but allowing cell to continue functioning 3 3 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

STUDIES SHOWING CHANGES IN NEOINTIMAL INHIBITION BASED ON VARYING CONCENTRATIONS OF PACLITAXEL Drug Dose-dependent response up to 3-4 µg/mm 2 (effective dose) Less than a ~2.5 μg/mm 2 dose shows a decreased therapeutic benefit Above a 4 μg/mm 2 dose indicates a limited, incremental efficacy gained 1. Margolis J, McDonald J, Heuser R, Klinke P,Waksman R,VirmaniR Desai N, Hilton D. Systemic nanoparticle paclitaxel (nab-paclitaxel) for in-stent restenosis I (SNAPIST-I): A first-in-human safety and dose-finding study. Clin Cardiol 2007;30:165-170 2. Cremers B et al. Comparison of two di erent paclitaxel-coated balloon catheters in the porcine coronary restenosis model. Clin Res Cardiol. 2009; 98:325-330 3. Cremers B. et al Drug-eluting balloon: Very short-term exposure and overlapping. Thromb Haemost 2009; 101: 201 206 4. Scheller B. et al. Paclitaxel Balloon Coating, a Novel Method for Prevention and Therapy of Restenosis Circulation. 2004;110:810-814 5. Speck U, Scheller B, Abramjuk C, et al. Neointima inhibition: comparison of effectiveness of nonstent-based local drug delivery and a drug-eluting stent in porcine coronary arteries. Radiology. 2006;240:411 418 6. Rowinsky EK, Donehower RC. Paclitaxel (Taxol).N engl J Med 1995;332:1004-1014 4 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

PACLITAXEL CONCENTRATIONS FOLLOWING TREATMENT SUGGEST BOTH SAFETY AND EFFICACY Drug Tissue Detectable levels of drug over 180 days in both arms (therapeutic dose and 3x safety margin) At 320 days no quantifiable drug is identified in the targeted tissue area (therapeutic dose) Plasma No drug quantified after 48 hours (therapeutic dose) No drug quantified after 672 hours (3x safety margin dose ) Drug concentrations drop 50% within the first 30 min Safety Margin=3x dose Porcine ilio-femoral model - Data on file at Medtronic Inc. 5 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

AN EXCIPIENT SUPPORTS THE UPTAKE OF DRUG BY VESSEL TISSUE Acts as a molecular spacer to increase paclitaxel surface exposure Facilitates paclitaxel transfer through its hydrophilic properties Excipient Tissue Concentration Blood Concentration R.Virmani CIRSE 2012 Oral Presentation 6 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

COATING TECHNOLOGY PROVIDES RELIABLE AND UNIFORM DRUG DELIVERY Coating DESIGN OBJECTIVE: DURABLE / SCALABLE COATING Balloon coating in semi-inflated shape: DESIGN OBJECTIVE: UNIFORM COATING Longitudinal Coating Thickness Circumferential Coating ~ 60-70% of dose protected within balloon folds 1 1 experimental data on file at Medtronic 7 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

Mechanism of Action DCB MECHANISM OF ACTION FACILITATES THE TRANSFER OF DRUG DEEP INTO VESSEL TISSUE IN.PACT Admiral balloon matrix coating: Paclitaxel Urea - excipient that controls drug release DCB inflation: Matrix coating contact with the blood Urea hydrates causing the release of paclitaxel Paclitaxel binds to the wall due to its hydrophobic and lipophilic properties Paclitaxel penetration: Through vessel wall deep into the media and adventitia Interferes with the causes of restenosis Can remain in the vessel wall for over 180 days at therapeutic levels 1 1 Data on file at Medtronic (GLP Study FS208; GLP Study PS516) 8 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

Treatment Strategy PROVISIONAL STENTING RATE IS DEPENDENT ON LESION LENGTH Scaffolds still needed but likely at rates proportional to lesion complexity Provisional stent rates in DCB trials are a function of lesion length [1] Rosenfield K TCT 2013; [2] Tepe G et al. N Engl J Med 2008; [3] Tepe CX 2014; [4] Werk M et al. Circulation 2008; [5] Micari A et al. J Am Coll Cardiol Intv 2012; [6] Zeller T CX 2013 oral presentation; [7] Werk et al. Circ Cardiovasc Interv. 2012; [8] Schmidt A LINC 2013 oral presentation 9 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

Primary Patency Late Lumen Loss DEB IS EFFECTIVE IN CALCIFIED Objective: Assess effect of calcium on IN.PACT DCB efficacy 60-patient registry SFA de-novo: average Lesion Length 6.1 cm Chronic Total Occlusion: 31.7% Systematic PTA pre-dilatation followed by IN.PACT DCB Treatment Strategy LESIONS Calcium distribution and severity affect Late Lumen Loss and Primary Patency Severe calcium may represent a barrier to drug absorption F.Fanelli LINC 2013 Calcium Evaluation Calcium distribution evaluation by CTA (circumferential) and DSA (longitudinal) 10 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

IN.PACT SFA Trial IN.PACT ADMIRAL IS THE NEW STANDARD FOR PRIMARY PATENCY Highest Reported Primary Patency of all SFA Technologies* (p<0.001 by log-rank test) Primary patency is defined as freedom from clinically-driven TLR and freedom from restenosis as determined by duplex ultrasound (DUS) Peak Systolic Velocity Ratio (PSVR) 2.4 *Qualitative Comparison. Not Meant for Head-to-Head Comparison. 11 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

DEB: THE NEW STANDARD FOR CD-TLR Lowest Reported Clinically-Driven TLR rate of all SFA Technologies* IN.PACT SFA Trial Clinically-Driven Target Lesion Revascularization (TLR) at 12 Months 25% 20% P<0.001 20.6% 15% 10% 5% 2.4% 0% IN.PACT Admiral PTA 1. Clinically-driven TLR defined as any re-intervention due to symptoms or drop of ABI/TBI of >20% or >0.15 compared to post-procedure ABI/TBI 2. Actual event rate by frequency ratio algorithm calculation *Qualitative Comparison. Not Meant for Head-to-Head Comparison. 12 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

Treatment Strategy TREATMENT STRATEGY AVOID GEOGRAPHIC MISS Pre-dilatation Drug-Coated Balloon (Primary Therapy) Spot Stent Postdilatation STAY WITHIN DCB AREA 1. PRE-DILATATION Required for all lesions, prior to DCB procedure Standard PTA 1 mm less than reference vessel diameter (RVD) Balloon length should not be greater than the planned DCB length 2. ATHERECTOMY Recommended in severely calcified lesions 3. DRUG-COATED BALLOON DCB diameter:rvd = 1:1; length 1 cm beyond lesion on both ends Inflation time 3 minutes Inflation pressure < RBP as required to reach full DCB expansion 4. POST-DILATATION If residual stenosis 50% or flow limiting dissection Standard or high pressure PTA balloon diameter 1:1 to RVD Short / focal length as necessary to treat the extent of residual stenosis or dissection 5. PROVISIONAL SPOT STENTING For persistent residual stenosis 50% or flow limiting dissections Minimum length as necessary to fully treat the residual stenosis or dissection 13 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14

Perivascular tissue Adventitia Media Lumen 14 RESTENOSIS SUMMARY Lumen loss INJURY Stretching Denudation Leukocyte adherence Negative remodeling Neointima Recoil Injury response programs Inflammation Phenotypic switch: quiescent proliferative and synthetic Recruitment Proliferation Fibrosis Inflammation Progenitor cell differentiation Myofibroblast proliferation Fibrosis Microvascular networks Paracrine factors Lumen loss

15 RESTENOSIS BEGINS WITH INFLAMMATION INJURY INFLAMMATION, RECRUITMENT PROLIFERATION, MIGRATION FIBROSIS, HYPERPLASIA Timeframe: Hours to Days Weeks Months Agents: Dexamethasone Paclitaxel, -limus compounds

16 INFLAMMATION IS AT THE ROOT OF RESTENOSIS

17 DANCE STUDY DESIGN clinical effectiveness evaluation of adventitial DEX after PAD intervention, vs contemporary published data Prospective, Single Arm, Multicenter Trial Subject population (n=300), 150 ATX / 150 PTA Assess safety and feasibility of perivascular dexamethasone delivery following SFA/popliteal artery revascularization OBJECTIVE: To evaluate effectiveness outcomes of adventitial DEX delivered by Bullfrog Device SFA / Pop Lesion Successful crossing of lesion & successful revasc. Dex Delivery Bullfrog Micro- Infusion Catheter injection Followup 1, 6, 12, 18, 24

18 DANCE N=300 De novo or non-stented restenotic SFA and/or popliteal lesions > 70% Lesions maximum 15 cm in length Rutherford 2-4 Enrollment complete 12/15/2015 Baseline angiogram and biomarker blood draw (1/3 of pts) Enrolled Subjects to be followed for 24 Months 150 PTA 150 atherectomy Adventitial DEX treatment 24-hour blood draw for biomarkers (1/3 of pts) 1-month blood draw for biomarkers (1/3 of pts) Clinical, hemodynamic and duplex U/S follow-up at 1, 6, 12, 18, 24 months

19 THE BULLFROG MICRO-INFUSION DEVICE

20 EXAMPLE BULLFROG CASE Angioplasty used to open vessel.... Bullfrog device inserted to distal target first After drug delivery to paint the vessel, follow up angiogram shows good result

SUCCESSFUL INFUSION 21 Bullfrog Device with balloon inflated After 3 minutes, Full perivascular dispersion >15cm of SFA Inflated Bullfrog Micro- Infusion Device

22 WHAT S NEXT BTK Study US Kicking off Q2 2016 BTK Study Germany/OUS Kicking off January 2016

Treatment Strategy TREATMENT STRATEGY AVOID GEOGRAPHIC MISS Pre-dilatation Drug-Coated Balloon/infusion (Primary Therapy) Postdilatation 1. PRE-DILATATION Required for all lesions, prior to DCB procedure Standard PTA 1 mm less than reference vessel diameter (RVD) Balloon length should not be greater than the planned DCB length 2. ATHERECTOMY Recommended in severely calcified lesions 3. DRUG-COATED BALLOON vs DIRECT MEDIAL INFUSION 4. PROVISIONAL SPOT STENTING For persistent residual stenosis 50% or flow limiting dissections Minimum length as necessary to fully treat the residual stenosis or dissection Spot Stent STAY WITHIN DCB AREA 23 UC201504192 EN Medtronic, Inc. 2014. All Rights Reserved. Medtronic Confidential. For distribution in the US only. 12/14