Drug- Coated Balloons for the SFA: Overview of Technology and Results

Transcription

1 Drug- Coated Balloons for the SFA: Overview of Technology and Results NCVH Latin American 2015 Bogota, Colombia April 9-11, 2015 Brian G. DeRubertis, M.D. Associate Professor of Surgery Division of Vascular Surgery Gonda Vascular Center at UCLA

2 Decreasing Amputation Rates: Impact of Percutaneous Intervention? Goodney PP, et al. J Vasc Surg. 2009; 50:54-60.

3 Endovascular Therapy for PAD: Balloon Angioplasty Balloon Angioplasty Ø Ø Ø 1964 Charles Dotter introduces concept of arterial remodeling 1977 Andreas Gruentzig performs first peripheral angioplasty s Development of OTW & RX balloon angioplasty systems Disadvantages ü Elastic recoil of vessel ü Dissections / mechanical forces ü Intimal hyperplasia / Restenosis

4 Endovascular Therapy for PAD: Nitinol Stents Self Expanding Laser Cut Nitinol Stents - 12m Primary Patency of 6070% Problem with Stents in the SFA: 1. Impact on subsequent interventions Balloon Angioplasty - 12m Primary Patency of 30-50% 2. Restenosis = Biologic Phenomenon Zeller T. DES vs. for long lesions. LINC 2013.

5 Nothing Left Behind Approach to the SFA Ideal Characteristics of a Leave Nothing Behind Treatment Modality: Ø Simple and straightforward to use Technology: Ø Low complication rates - Simple Ø Appropriate for a range of lesions and locations - User friendly Ø Stent- like results without the permanent implant - Low risk Ø Effective in in- stent restenosis - No implant Ø Addresses the biologic of restenosis - Biologic basis

6 Drug- Coated Balloons Case 5: Recurrent Occlusion after Stenting Technology & Therapeutic Rationale Angioplasty Balloon + + Anti- Restenosis Drug Excipient Basic Components of a Drug Coated Balloon

7 Drug- Coated Balloons Case 5: Recurrent Occlusion after Stenting Technology & Therapeutic Rationale Angioplasty Balloon + Standard Non-compliant 0.035, Anti- Restenosis Drug 0.018, or OTW Angioplasty Balloons + Antiproliferative agent (Paclitaxol) Excipient Hydrophilic bonding agent that facilitates transfer of drug into endothelium of target artery

8 Drug- Coated Balloons Mechanism of Action Excipient Mediated Anti- Restenosis Drug Delivery matrix coating: Paclitaxel + Excipient During transit to lesion: Majority of matrix protected within folds of the balloon inflation: Matrix contacts blood Blood hydrates excipient Excipient releases paclitaxel Due to its hydrophobic and lipophilic properties, paclitaxel binds to vessel wall Paclitaxel penetration: Through vessel wall deep into the media and adventitia Interferes with SMC proliferation Can remain in the vessel wall for over 180 days at therapeutic levels

9 Drug- Coated Balloons Drug Choice Vessel cross section illustrating drug delivery in vivo at 1 hour. After 30 second Inflation Paclitaxel Preclinical animal study Oregon green labeled paclitaxel Animal Data on File for Lutonix 035

10 Drug- Coated Balloons Drug Choice Both Paclitaxel and Rapamycin can limit restenosis, but key differences make Paclitaxel more suitable for Paclitaxel (Cytotoxic) Rapamycin (Cytostatic) Interferes with cell division Interferes with cell growth Cytotoxic drugs halt cellular replication cycle, inducing apoptosis Cytostatic drugs hold a cell in G0 phase, arresting growth PTX Rapid transfer via excipient allows acute delivery, especially beneficial if no artificial reservoir is present ~limus Prolonged elution via polymeric reservoir allows sustained delivery, especially beneficial when foreign body is present

11 Drug- Coated Balloons Dose Selection PTX Concentration (ng/mg) P acl itax el C oncentration (ng/m g) Paclitaxel concentrations following treatment support both safety and long- term efficacy in preclinical studies EC50Paclitaxel Time [Days] Nominal Dose X Safety Margin Dose Porcine IleoFemoral Artery Days Ø SAFETY Ø Ø Detectable levels of drug in tissue over 180 days in both arms (therapy dose and safety margin) At 320 days, no quantifiable drug is identified in the targeted tissue area in nominal dose Drug concentration levels in plasma are < 1/10 of that in tissue, drop 50% in 30 minutes, and not detectable after 48 hours

12 Courtesy of M.Werk MD Bilateral SFA Disease PTA baselin e baselin e Post PTA Post 6mo FU 6mo FU

13 Drug- Coated Balloons Case 5: Recurrent Occlusion after Stenting US FDA Approval Medtronic IN.PACT Admiral Bard Lutonix 035 IN.PACT SFA Trial LEVANT II Trial Ø Ø U.S. and European RCT of 476 pts 2:1 Randomization to v POBA Ø Ø U.S. & European RCT of 331 pts 2:1 Randomization v POBA

14 LEVANT II : Lutonix 1,2 Clinical Trial Summary Trial Design U.S. and European prospective, randomized, multi-center study Required successful PTA prior to randomization to Test or Control PTA patients randomized Test n= 316 Control PTA n= 160 LEVANT 2 Clinical Trial Presentation. D. Scheinert. VIVA 2013 Bard Lutonix Instructions for Use

15 IN.PACT SFA Trial Clinical Trial Summary Trial Design U.S. and European prospective, randomized, multi-center study Required successful PTA prior to randomization to Test or Control PTA Independent and blinded duplex ultrasound core lab, angiographic core lab and clinical events committee Subjects followed up to 5 years IN.PACT SFA 12- Month Outcomes Clinical Trial Presentation. J. Laird TCT 2014 IN.PACT Admiral

16 IN.PACT SFA Trial Trial Endpoints and Inclusion Criteria Primary Endpoints: 1 Efficacy : 12-month Primary Patency Freedom from clinicallydriven TLR and duplex ultrasound derived restenosis (PSVR 2.4) 2 Safety : 30-day device/procedure death, 12-month amputation, 12month clinically-driven TVR 1. Primary Efficacy Analysis on all ITT non- stented subjects based on superiority assumption of vs. PTA 2. Primary Safety Analysis on all ITT non- stented subjects based on non- inferiority of vs. PTA Key Inclusion Criteria: Rutherford SFA and proximal popliteal Lesion length 4-18 cm Total occlusion 10 cm

17 Drug- Coated Balloons Patients and Lesions in Trials 1 II Patient Characteristics Lesion Characteristics 1 Lutonix IFU 2 IN.PACT Admiral IFU 2 SFA LEVANT ( arm) IN.PACT ( arm) Diabetes 43.4% 40.5% Renal Insufficiency 3.5% 8.3% Claudicants 100% 95% Rest pain 0% 5% Tissue loss 0% 0% ABI Contralateral limb 0.87 n/a Lesion length 6.2cm 8.9cm Occlusions 20.6% 25.8% Severe Calcification 10.4% 8.1% TASC A-B 97.8% 87.4% SFA lesion 90.2% 97.7% Pop lesion 9.7% 6.8%

18 LEVANT II : Lutonix Efficacy Endpoints Primary Patency at 12 month time point Free from Primary Patency Event (%) % Improvement over Standard PTA Time LUTONIX 035 Standard PTA P- value 365 days 74% 57% days 65% 53% PTA r = 12.6% Months from Randomization Date

19 LEVANT II: Lutonix 12 Month Primary Patency in Women Primary Patency Rates by Gender 70.4% 56.4% 61.4% 50.7% PTA All females All PTA US only U.S. Only Females 1. FDA Panel Presentation 2. Bard Lutonix Instructions for Use FDA mandated a PMA RCT in women as condition of device approval for Lutonix

20 IN.PACT SFA Trial Results: Primary Patency 12 month Primary Patency by Kaplan Meier Estimates 58% Improvement over Standard PTA r = 28.9% [1] 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 IN.PACT SFA 12- Month Outcomes Clinical Trial Presentation. J. Laird TCT 2014

21 IN.PACT SFA Trial Primary Patency Subgroup Analysis Relative Risk (95% CI) Control IN.PACT PTA % % Overall ITT 52.4% Subgroups Rutherford Category % Rutherford Category % Rutherford Category % Diabetes Mellitus 49.0% Age % Lesion Length <5 cm 73.9% Lesion Length 5 cm and <10 cm 57.1% Lesion Length 10 cm and <18 cm 39.4% Total Occlusion 40.9% Female Gender 43.8% Male Gender 56.3% Favors Favors IN.PACT Control PTA 82.2% 82.2% 82.4% 80.0% 77.3% 84.4% 93.3% 83.3% 74.6% 83.3% 75.7% 86.0% 0 There were no significant treatment- by- subgroup interactions (P>0.15). The 95% confidence intervals were unadjusted for multiplicity. 5 10

22 LEVANT II: Lutonix 12 Month TLR Rates 16.8% 12.3% No statistical difference vs PTA (p=0.208) Patient Baseline Ave. Lesion Length (cm) Fracture Rate (%) % Distal SFA/PPZ Occlusions (%) Severe Calcium (%) FDA Executive Summary, Bard LUTONIX«035 Drug Coated Balloon PTA Catheter, June 12, FDA.gov.pdf PTA NA

23 IN.PACT SFA Trial Primary Outcome Measures Clinically-Driven Target Lesion 2 Revascularization (CD-TLR) 25% CD-TLR at 12 Months 20% P< % 15% 10% 5% Effect of Lack of Blinding? 2.4% 0% IN.PACT Admiral PTA 1. Primary patency is defined as freedom from clinically- driven TLR and freedom from restenosis as determined by DUS PSVR 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

24 Drug- Coated Balloons Limitations, Tips, & Techniques LEVANT II: 12 Month Primary Patency by Lesion Length 72.3% 60.6% 69.2% 64.7% 64.7% 53.8% 45.7% PTA PTA PTA PTA PTA 39.4% PTA PTA < 3cm 3-5 cm 5-9 cm > 9cm Primary patency decreases as lesion length increases Lutonix Instructions for Use

25 Drug- Coated Balloons Limitations, Tips, & Techniques IN.PACT SFA: 12 Month Primary Patency by Lesion Length 93.3% 83.3% 74.6% 73.9% 57.1% 39.4% PTA <5cm PTA 5 cm to 10 cm PTA 10 cm to 18 cm Primary patency decreases as lesion length increases IN.PACT Admiral Summary of Safety and Effectiveness Datta

26 Limitations of s: Lesion Length Scaffolds still needed, likely at rates proportional to lesion complexity Provisional stent rates in trials trend with lesion length 30% Stent (%) 30 Lesion Length (cm) 25% % % % 10% 5% 0% % % % 4.0% 2.5% LEVANT 9.0% % THUNDER IN.PACT 3 SFA 4 FEMPAC IT 5 Registry Bad 6 Krozigen 7 PACIFIER Leipzig 8 Reg. 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

27 Limitations of s: Lesion Length IN.PACT and Calcium Registry Study (n=60) 12 month Results 100% 100% 100% 100% 90% 90% % % % % 0% 2a 2b 3a 3b ++ Ca represents a barrier to optimal drug absorption 0.2 Primary Patency LLL 1b % 1a % Calcium distribution and severity affect LLL and primary patency a Calcium distribution evaluation by CTA (circumf.) and DSA (longitud.) 4b (F.Fanelli Cardiovasc Intervent Radiol 2014)

28 IN.PACT Global Trial Real World Application of Baseline Lesion and Clinical Characteristics IN.PACT SFA IN.PACT Global Lesion Length 8.9 cm 12.2 cm CTO 25.8% 35.8% ISR* 0.0% 21.4% N=220) N=655 Bailout stent Rate 7.3% 24.7% CD-TLR 2.4% 8.7% CD-TVR 4.3% 9.5% Thrombosis 1.4% 3.8% 0.0% (0) 0.3% (2) No Primary Patency Data Baseline RC >3 5.0% 14.5% ABI/TBI (mmhg ratio) Available Yet on Imaging Cohorts IN.PACT SFA (Long Lesions, CTOs, and ISR) IN.PACT Global ( Arm, Results (12-month analysis) Target Limb Major Amputation

29 Drug- Coated Balloons Limitations, Tips, & Techniques Question: Will s become our new workhorse, stand-alone therapy for the SFA??? Answer: Depends on what you treat

30 Conclusions s represent exciting new technology There are potential differences between different devices s have been best studied in short non- calcified lesions Areas for future study include use of s in more complex lesions Long- term follow- up is necessary to fully evaluate the effectiveness of these devices

31 Division of Vascular Surgery UCLA Ronald Reagan Medical Center Thank You