Are Drug Coated Balloons a Game Changer? Kenneth Rosenfield, MD, FACC, FAHA Section Head, Vascular Medicine and Intervention Massachusetts General Hospital Boston, Massachusetts, U.S.A.

Kenneth Rosenfield, MD, MHCDS Conflicts of Interest Research or Fellowship Support Abbott Vascular Atrium NIH InspireMD Lutonix-Bard Board Member VIVA Physicians (Not For Profit 501(c) 3 Organization) www.vivapvd.com Consultant Abbott Vascular Capture Vascular Cardinal Health Contego CRUZAR Systems Endospan InspireMD MD Insider Micell Shockwave Surmodics Valcare Equity CardioMEMs Contego Embolitech Icon Janacare Micell PQ Bypass Primacea Shockwave Vortex

What is a “Game-Changer”? Definitions: an event, idea, or procedure that effects a significant shift in the current manner of doing or thinking about something a newly introduced element or factor that changes an existing situation or activity in a significant way A person or idea that transforms the accepted rules, processes, strategies and management of business functions

What does it take to be a “Game-Changer”? Examples in Vascular Intervention PTA (Dotter) and PTCA (Greuntzig) Fixed GW  Coaxial GW motion  monorail Stent  DES Rotational atherectomy Examples in Imaging IVUS, Cardiac CTA, Fractional Flow Examples in Structural TAVR Examples in Healthcare Delivery models ACA AUC

Do DCB’s Qualify as a “Game-Changer”? Are the results different from other therapies? Does it represent an improvement…and how much? Is the impact important enough for patients? Do they fill an unmet clinical need…accomplish something important that other technology cannot? Will this lead to alter MD behavior? Will the effect be long-lasting?

History of Present Illness: 86 year-old female with AS status post TAVI, COPD, CHF and intermittent claudication. Now reports left leg pain that occurs at night and is relieved by sitting up/dangling leg over side of bed (new rest pain/CLI) No wounds/ulcers  Rutherford category 4

Baseline Angiography Occluded Popliteal Rx options (before DCB) POBA or cutting/scoring/“chocolating” Atherectomy (directional, laser, rotational) Stent Bypass Benefits and liabilities of each… Which therapy would you use?

Unmet Needs: For Certain Territories, No Matter How Good the Initial Result, Mechanical Treatments Alone lack durability SFA/Pop Laser/PTA 8 mos later – rest pain Pre Post

Patency - SFA Stent Trials Study Stent Subjects Avg. Lesion Length(cm) % CTO Freedom from TLR Fracture Rate (%) 12 M Primary Patency Leipzig SUPERA 107* 10.9 30 - 86 Zilver Trial Zilver PTX 489 6.6 .9 83 Sirocco II SMART (DES) 57 8.1 91 8 82** Resilient LifeStent 134 6.2 17 3.4 80 Saxon Viabahn 76 14.2 42 87 Durability Everflex 151 9.6 40 79 72 FAST Luminexx 244 4.5 37 85 12 67 Super-SL SMART 96 13.4 75 23 65 Vienna Absolute 104 13 54.3 2 63 Vibrant BMS Arm 16 50+ >30 58 Viabahn Arm 20 53 * Data available from 91 patients. **18 month data. BMS arm patency 82%, DES arm 79%. 9

Stent Fracture

Endovascular Procedures Limitations of Current Endovascular Treatments for Femoropopliteal Artery Endovascular Procedures PTA Stents restenosis rates of 30-60% at 1 year1 TLR rates of 17.5% to as high as 54.9% at 1 year3,4 restenosis rates of 20-40% at 1 year2 ongoing stimulus for restenosis “no stent zones” segments limit use in femoropopliteal artery concerns of stent fracture permanent implants limit future treatment options Endovascular procedures may be effective in restoring blood flow but there are also significant drawbacks. Concerns about stent fracture and in-stent restenosis have lead some practice guidelines to advise against primary stenting of femoropoliteal lesions for intermittent claudication. Previously, there have been few options to achieve lower restenosis rates without stent implantation Other stent talking points: Dynamic forces may result in stent fracture Presence of stent can initiate inflammatory response leading to restenosis Permanent implant limits future options Although the DES performs betters, they carry the same complications as bare metal stents once drug elution ceases The presence of a stent (a foreign body opposing the vessel wall) can initiate an inflammatory response. The immunologic cascade stimulates the proliferation and migration of vascular smooth muscle cells resulting in neointimal hyperplasia and ISR. For example, restenosis in the femoropopliteal arteries after stenting is high and reaches up to 20% - 40% within the first 12 months of intervention [15, 21]. This high rate of restenosis is problematic because there is no durable treatment for ISR. The repeat failure rate runs in excess of 70% at one to two years [22, 23], which leads to the need for repeat intervention in a significant portion of patients in order to achieve clinical goals. Furthermore, the presence of a metallic implant limits future treatment options of the target vessel. Reference: (1) Dick et al.; Laird et al. (2) Laird et al.; Armstrong et al 3. Dake M et al; 4. Laird JR et al. .

Significant Unmet Clinical Need Significant clinical need remains for a therapy that Achieves more durable patency by reducing restenosis Reduces rates of repeat interventions Does not require a permanent implant Preserves future treatment options Despite improvements in endovascular therapy long term patency rates remain unsatisfactory in the femoropopliteal artery

Are DCBs the ANSWER? Why All the Hype? Novelty! Potential to fulfill unmet clinical needs… Opportunity to reduce restenosis Eliminate liabilities associated with permanent implant (stent) Chronic inflammation, stimulus for hyperplasia & ISR Issue of repeat access & intervention Fracture Better treatment of “no-stent” zones Reduce need for anti-platelet therapy (DAPT) Simplicity? Cost reduction? Better safety profile?

We all Want DCB to be a game changer We all Want DCB to be a game changer! … to simplify treatment and fulfill the unmet clinical need for our patients!

Agenda Principles – how DCBs work DO they work – what data is available and what do they show Might DCB “change the game”…and how

Mechanism of Action: Summary Brief (30-90 second) balloon inflation transfers PTX to endoluminal surface PTX diffuses into the arterial wall from an “endoluminal surface reservoir.” Therapeutic drug levels sustained in deep cell layers after endothelial drug levels become sub-therapeutic. Drug continues to inhibit restenosis in arterial wall while allowing the lumen to re-endothelialize. “reservoir”

DCB vs DES Total Arterial Drug Levels Total Paclitaxel in DCB-treated porcine arteries (blue) Paclitaxel remaining in tissue after removal of stent scaffold (red) DCB stent

Elements of drug-coated balloon systems Standard Wrapped configuration Surface modified Anti-proliferative Paclitaxil Limus family Others? Excipient iopromide urea polymers nanoparticles

Drug-Coated Balloon Angioplasty Drug-coated balloon (DCB) angioplasty…a novel treatment modality for peripheral atherosclerosis dual action: combines acute restoration of vessel patency (via angioplasty) with inhibition of restenosis response triggered by angioplasty (by paclitaxel delivery) stent-free, drug-based therapy no permanent implant, preserves future treatment options eliminates difficult-to-treat in-stent restenosis offers the potential for higher efficacy without safety trade-offs Highlighting two mechanisms of action as mentioned before – angioplasty (mechanical dilatation) and drug delivery – distinct from plain angioplasty The role of paclitaxel drug is to inhibit the restenotic response triggered by the angioplasty and the resulting vessel injury, DCB offers the advantage of uniform drug distribution improves angioplasty outcomes and avoids complications associated with stents dual therapeutic benefits: angioplasty (restores vessel patency) and drug delivery (prevents restenosis) does not leave a permanent foreign body in the vessel treats lesions where stents are not viable

6-month Late Lumen Loss in SFA-Popliteal DEB Trials SFA-Popliteal: Early DCB Trials 6-month Late Lumen Loss in SFA-Popliteal DEB Trials J Lammer LINC 2014

LEVANT 2 Trial: Study Design *Strict criteria Protocol- defined pre-dilation Balloon group N=476 Stent group 1 mo fup DCB PTA Bailout option 2:1 *Strict criteria

Efficacy Endpoint: Primary Patency at 12 Months Primary patency of the target lesion defined as both Absence of core lab adjudicated target lesion binary restenosis AND Freedom from CEC adjudicated target lesion revascularization (TLR) The efficacy endpoint was primary patency of the target lesion at 12 months. Patency was defined by two parameters, both of which must have been satisfied. First, the absence of target lesion binary restenosis by duplex ultrasound as adjudicated by the core-lab. Second, freedom from TLR, as adjudicated by the CEC. 26

Levant 2: Study Flow and Patient Enrollment Patients Enrolled & PTA Pre-dilatation N=543 Roll-in N=56 Lutonix DCB N=316 Standard PTA N=160 Randomized N=476 Treat per Standard Practice 30-day follow-up for safety Suboptimal PTA N=11 Here you see the flow diagram for patients entered into the study. 543 patients were enrolled. [CLICK] Each site was to perform a proctored Lutonix DCB procedure prior to enrolling a randomized patient.   These roll-in patients were intended to familiarize site personnel with the clinical trial data collection process and the usage of DCB. There were 53 roll-in patients plus 3 live demonstration cases performed during conferences in Europe that were also categorized as roll-ins. Consented patients underwent the pre-dilatation previously described. After pre-dilatation, only 11 patients were identified with sub-optimal PTA who were deemed unlikely to achieve a successful result with balloon angioplasty alone. These patients were not randomized. 476 patients were randomized, 316 to the Lutonix DCB and 160 to standard PTA. 23

Efficacy Endpoint of Primary Patency Achieved = 12.6% p=0.015 Percent (%) Measure Test DCB %(n/N) [95% CI] Control PTA %(n/N) [95% CI] Differenc e % [95% CI] P- valu e2 Primary Patency1 65.2% (172/264) [59.4, 70.9] 52.6% (71/135) [44.2, 61.0] 12.6% [2.4, 22.8] 0.015 Here you see the primary patency results. The primary efficacy endpoint at 12 months was achieved, showing superiority for Lutonix DCB at 65.2% to that of standard PTA at 52.6%, an absolute difference of 12.6% between the groups. Additionally, after adjusting for prespecified covariates, the treatment effect was robust with a p value of 0.015. n=172 n=71 32

Primary Patency Kaplan-Meier 100 90 PTA DCB 80 Free from Primary Patency Event (%) 70 60 50 40 30 This is the Kaplan-Meier survival analysis of primary patency. At 6 months the lines separate at the time of follow up ultrasound. This time to event analysis shows superior patency in the Lutonix DCB group and the difference is sustained through 12 months. The difference between arms at 12 months was significant, with a log rank p-value of less than 0.001. Survival % Time Lutonix DCB Standard PTA P-value 365 days 73.5% 56.8% 0.001 20 10 1 2 3 4 5 6 7 8 9 10 11 12 13 Months from Randomization Date Lutonix DCB (N) 291 Standard PTA (N) 146 261 116 179 69 33

Months from Randomization Date All subjects without a failure event who have not died or withdrawn are censored on day 730. Subjects who have died or withdrawn are censored on date of death or withdrawal. Primary Efficacy Endpoint Through 24 Months (Non-exited Pts. Not Censored) Test DCB Control PTA Time1 Survival %[95% CI] Subjects with Event Censored Subjects Subjects at Risk Log-Rank P-value2 30 days 94.9% [91.8, 96.9] 16 4 296 93.7% [88.7, 96.6] 10 1 149 0.599 183 days 89.0% [85.0, 92.0] 34 13 269 79.2% [72.0, 84.7] 33 3 124 0.005 365 days 74.5% [69.2, 79.1] 77 24 215 59.0% [50.9, 66.3] 64 86 <.001 730 days 63.6% [57.8, 68.8] 108 35 173 55.5% [47.3, 62.9] 69 14 0.022 100 - 90 - 80 - 70 - DCB Free from Primary Patency Event (%) 60 - 50 - PTA 40 - 30 - Survival % Time Lutonix DCB Standard PTA P-value 730 days 63.6% 55.5% 0.022 Though follow-up is not complete at 24 months - additional post-hoc analysis imputing non-exited subjects to 24 months shows continued separation and significant benefit for the DCB. These results further support the durable benefit in patency for the DCB arm over control PTA. 20 - 10 - 0 - 6 12 18 24 Months from Randomization Date Lutonix DCB (N) 296 215 173 34 Standard PTA (N) 149 89 77 Analysis not previously reviewed by FDA

Summary of Secondary Endpoints at 12 Months Favors Control PTA Favors Lutonix DCB Total TLR Total TVR Composite Safety Events DUS by PSVR > 3.0 DUS by PSVR > 2.5 DUS by PSVR > 2.0 Secondary Patency DUS Clinical Patency Clinically-driven TLR Change in Rutherford Classification (x100) Change in ABI (x100) WIQ Total WIQ Pain WIQ Walking Distance Score WIQ Walking Speed Score WIQ Stair Climbing Score 6-Minute Walk EQ-5D (x100) SF-36 Physical Score SF-36 Mental Score Here is a summary of secondary endpoints at 12 months. There were two sets of pre-specified analyses for secondary endpoints. The first [CLICK] had hypothesis tests, which included Target lesion Revascularization, Target Vessel Revascularization and Composite Safety Events at 12 months. There were numerous other secondary endpoints that were analyzed with descriptive statistics. None of the secondary endpoints were expected to show a significant difference. The trends favor the Lutonix DCB and are encouraging. Change in Rutherford classification and the walking distance component of the Walking Impairment Questionnaire indicate improved physical functioning of patients. These are key functional outcomes, which were sustained over 12 months. [PAUSE] 35

Freedom from TLR – All DCB Patients Lutonix patients treated in IDE studies Levant 2 Roll – In = 56 Levant 2 Randomized = 316 Levant 2 Safety Registry = 657 Total = 1,029 Time Roll-in DCB %(n/N) [95% CI] Randomized DCB %(n/N) [95% CI] Registry DCB %(n/N) [95% CI] All DCB %(n/N) [95% CI] 1 Month 100.0% (54/54) [100.0, 100.0] 99.7% (307/308) [99.0, 100.0] 99.7% (644/646) [99.3, 100.0] 99.7% (1005/1008) [99.4, 100.0] 6 Months 96.1% (49/51) [90.8, 100.0] 94.0% (280/298) [91.3, 96.7] 98.7% (585/593) [97.7, 99.6] 97.0% (914/942) [95.9, 98.1] 12 Months 93.8% (45/48) [86.9, 100.0] 87.8% (251/286) [84.0, 91.6] 95.5% (423/443) [93.6, 97.4] 92.5% (719/777) [90.7, 94.4] Freedom from TLR Time Roll-In % (n/N) Randomized Registry% (n/N) 12 Months 93.8 (45/48) 87.8% (251/286) 95.5% (423/443) 37

Freedom from TLR Comparison *Kaplan-Meier Analysis 38

IN.PACT SFA Trial Design Objective Assess the safety and efficacy of Medtronic IN.PACT Admiral DCB vs. PTA for the treatment of femoropopliteal arterial disease due to claudication and rest pain Design Two-phase, prospective, multicenter, single- blind, randomized (2:1) trial No. sites / subjects 44 US, 13 EU sites enrolled 331 subjects + 25 PK subjects Lesion length 4-18 cm, CTO ≤ 10 cm State objective, phased RCT. Lesion length studied is important and results will be presented later. Primary patency is a standard endpoint for assessing impact of SFA interventional therapies. Additional secondary endpoints assess imaging efficacy, clinical benefit, safety and functional improvements. Costs of index procedure and those related to index limb in follow-up collected.

Substantially improved primary patency in IN Substantially improved primary patency in IN.PACT Admiral DCB compared to PTA (p<0.001 by log-rank test) Primary patency at 360 days was 90% and reflects a substantial improvement compared to PTA. These are highly competitive patency rates compared to past SFA studies. From CSR Table 42: Primary patency failures through 390 days: 34/191 DCB and 49/103 PTA CD-TLR failures through 390 days: 7/152 DCB and 27/83 PTA BR failures through 390 days: 31/188 DCB and 29/86 PTA 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

Highly significant decrease in re-interventions IN.PACT PTA p Clinically-driven TLR 2.4% (5/207) 20.6% (22/107) <0.001 Clinically-driven TVR 4.3% (9/207) 23.4% (25/107) Clinically-driven TLR is a critical data point to physicians, patients and payers given the need for additional hospitalizations. Rate and KM are presented here. There was a highly significant decrease in the number of target lesion revascularizations. The 2.4% rate reported in the study is unprecedented in SFA studies and is impressive given the long lesion lengths in the study. (p<0.001 by log-rank test)

Effectiveness outcomes at 12 months demonstrate a decrease in restenosis IN.PACT PTA p Primary Patency (PSVR ≤ 2.4) 82.2% (157/191) 52.4% (54/103) <0.001 Binary Restenosis (PSVR >2.4) 16.5% (31/188) 33.7% (29/86) 0.001 Clinically-driven TLR 2.4% (5/207) 20.6% (22/107) Primary Sustained Clinical Improvement [1] 85.2% (167/196) 68.9% (73/106) Ankle-Brachial Index (ABI) 0.951 0.886 0.002 A summary of key effectiveness outcomes demonstrates a significant reduction in recurrence of restenosis. Burden of restenosis was reduced by imaging and translated to significantly less revascularizations within 12 months. These improvements resulted in a clinical benefit to the patients. Freedom from target limb amputation, TVR, and increase in Rutherford class at 12 months post-procedure

Lower target limb hospitalization from discharge to 12 months IN.PACT PTA p Target limb care hospitalization costs - discharge to 12 mo [1] $1324 ± 9148 $1975 ± 5260 0.002 Total target limb follow-up costs – discharge to 12 mo [2] $1777 ± 9699 $2530 ± 5823 0.067 An interim cost effectiveness analysis at one year was carried out using detailed billing data on follow up hospitalizations, medications, and physician fees. Results found substantial follow up cost offsets from use of DCB in the one year following discharge after the index procedure demonstrating that even in the short term, DCB can lead to substantial savings to the health system in follow-up limb care costs. Follow-up Costs offsets = -$753/pt treated with DCB Salisbury A et al, Economic Outcomes of Endovascular Femoropopliteal Intervention using Drug-Coated Balloons vs. Standard PTA: 1-year Results from the IN.PACT SFA II Trial; TCT 2014 Includes medications, physician fees, hospitalization costs for discharge to 12 months post index procedure from SFA II trial

IN.PACT Admiral performs favorably to existing therapies with no metal left behind This slide gives a visual representation of IN.PACT SFA PP and CD-TLR outcomes versus DES and BMS. While we cannot do direct comparison, it allows us to put the outcomes in perspective to other currently approved technologies. The PP represented in the light gray bar is highly competitive compares favorably with results from recent stent trials including Zilver ptx – a drug eluting stent. In addition, as you can see the rate of CD-TLR in the SFA trial are notably lower at 2.4% at one year, vs 8-13% in the stent trials. in the yellow bar and reflect a considerable need for revascularization within 12 months. Thus, IN.PACT Admiral performs favorably to these existing therapies without the need for a metallic implant. [1] G.Tepe Charing Cross 2014; [2] Dake MD et al. Circ Cardiovasc Interv. 2011; [3] Scheinert D LINC 2013; [4] Laird JR et al. Circ Cardiovasc Interv. 2010; [5] Garcia L LINC 2013

SUMMARY 12 Month Outcomes from DCB Trials PTA 66.8% PTA 56.8% PTA 55.0% PTA 39.6% No Con-trol Arm Of note, the average lesion length in the DCB trials was from 6.3 to 8.9. This represents a significantly longer lesion length compared to previous SFA pivotal trials. PTA 16.3% PTA 33.0% PTA 20.6% PTA 35.3% Sources: Lutonix Drug Coated Balloon PTA Catheter; PMA P130024 Panel Package Executive Summary; Scheinert D et al. Lutonix 1st in Human RCT, JACC Cardiovasc Interv 2014; Tepe G. IN.PACT SFA. Charing Cross International Symposium. April 5, 2014. London; Fanelli F, The “DEBELLUM” – Lower limb multilevel treatment with drug eluting balloon: 1 year results. J Cardiovasc Surg 2014; Micari A et. al. Clinical evaluation of a paclitaxel-eluting balloon for treatment of femoropopliteal arterial disease: 12-month results from a multicenter Italian registry. JACC. Cardiovascular interventions 2012

Evidence from the Pivotal DCB Trials Results demonstrate substantial and significant clinical improvements for patients in a number of ways: Improved primary patency (reduced restenosis) Substantial reduction in clinically driven TLR/TVR (reduced need for repeat intervention) Improvements in claudication symptoms, ABI and primary sustained clinical improvement Decrease in hospitalizations and total follow-up target limb care costs Improvements in QOL and functional outcomes The safety and effectiveness results from this pivotal trial demonstrate that IN.PACT Admiral DCB fulfills the criteria for substantial clinical improvement compared to the current treatment of PTA in the following areas: substantially improved primary patency, substantial and significant reduction in target lesion and vessel revascularization, significant improvement in ABI and primary sustained clinical improvement, decrease in rate of hospitalizations and lower medical care costs, improvements in symptoms, quality of life and functional outcomes.

Substantial Clinical Improvement with DCB vs PTA Drug Coated Balloon Angioplasty fulfills criteria for substantial clinical improvement compared to PTA by addressing the significant clinical unmet need with a therapy that Achieves significantly higher and more durable patency by reducing restenosis Reduces rates of repeat interventions and associated hospitalizations/medical costs Decreases the recurrence of symptoms Does not require a permanent implant Preserves future treatment options

Intervention on my patient Occluded popliteal and distal SFA pre-dilated with 3.5mm Popliteal  4.0mm DCB Distal SFA  5.0mm DCB

DCB Conclusions – Game Changer Proven “class” effect Drug delivery to deep layers after single contact (dependent on good carrier) Acceptable safety profile Many potential advantages Reduce restenosis; no stent; avoid DAPT, etc. Initial results promising Cost ? Much more comparative data required CMS opinion…

GAME CHANGER??...Jury is still out! Current Unknowns with DCB’s Simple lesions studied to date Unknown interaction with stents, atherectomy, etc. Unknown effect in heavy calcification Question of coating uniformity and durability Comparability of safety & efficacy for different DCB formulations and manufacturers

Additional Game Changer…Peripheral trial design Rigorous trials designed to reduce bias Controlled pre-dilatation prior to randomization to limit the number of bail-out stents Defined criteria for provisional stenting Did not count provisional stenting as TLR Blinding of clinicians