Drug-Coated Balloons: Clinical Role in Coronary and Peripheral Interventional Therapy

Transcription

1 Drug-Coated Balloons: Clinical Role in Coronary and Peripheral Interventional Therapy Juan F. Granada, MD Executive Director and Chief Scientific Officer Skirball Center for Cardiovascular Research Cardiovascular Research Foundation Columbia University Medical Center, New York

2 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. Affiliation/Financial Relationship Grant/Research Support Consulting Fees/Honoraria Major Stock Shareholder/Equity Royalty Income Ownership/Founder Intellectual Property Rights Other Financial Benefit Company Abbott, BSCI, Medrad, Medtronic. Medrad.

3 Origin of the Paclitaxel Coated Balloon Concept Exp. Radiologie, Charité Mitte (Berlin, Germany) Ulrich Speck Klinik für Innere Medizin III, Homburg/Saar, Germany Michael Böhm Bodo Cremers Yvonne Clever Nicole Hollinger Bianca Werner Dennis Andree Institut für Medizintechnologie GmbH (Magdeburg), Dirk Mahnkopf InnoRa GmbH (Berlin, Germany) Anakat GmbH (Berlin, Germany) B.Braun Vascular Systems (Berlin, Germany) Bayer Schering Pharma AG (Berlin, Germany) Medrad (Warrendale, PA, USA)

4 Cell density compared to control [-] Differential Effects of Short-Term Application Exposure of EPC and hcasmc to Paclitaxel or Paclitaxel Iopromide EPC hcasmc Control Paclitaxel 1.5 µm Pacl. 1.5 µm + Iopromide Paclitaxel 15 µm Pacl. 15 µm + Iopromide Control Paclitaxel 1.5 µm Pacl. 1.5 µm + Iopromide Paclitaxel 15 µm Pacl. 15 µm + Iopromide days Paclitaxel Paclitaxel Iopromide 1.0 ns ns ns p= ns 0.6 p= Control 1.5 µm 3 sec 15 µm 3 sec Control 1.5 µm 3 sec 15 µm 3 sec EPC hcasmc Clever, Eur Heart J 2008; 29 (Suppl):

5 Effect of Iopromide on Drug Transfer to the Arterial Tissue in Vivo: It is a Drug Carrier Necessary? ~8 Fold Increase Pure Drug Carrier Figures Courtesy of Caliber Therapeutics

6 Mechanism of Drug Transfer on PCB Tissue Retention of Paclitaxel

7 The Carrier Facilitates the Transfer of Paclitaxel into the Vessel Wall (<60 sec) 33 Pigs 28 Days 5 mcg/mm 2 BMS DES DEB 10s Luminal Area (mm 2 ) 3.14 ± ± ± 0.89 Neointimal Area (mm 2 ) 4.26 ± ± ± 0.40 DEB 60s DEB 2 x 60s 2 x DEB 60s Luminal Area (mm 2 ) 5.97 ± ± ± 0.90 Neointimal Area (mm 2 ) 1.68 ± ± ± 0.46 Cremers B. Thromb Haemost Jan;101(1):201-6

8 Paclitaxel Delivery Directly into the Vessel Wall Using a DEB: PACCOCATH Uncoated Balloon Coated Balloon Taxus Cypher 7 Days Uncoated Balloon Coated Balloon Taxus Cypher 28 Days 90 Days Uncoated Balloon Coated Balloon Taxus Cypher

9 PACCOCATH Clinical Data: ISR & SFA

10 The PEPCAD Program Paclitaxel-Eluting PTCA-Catheter in Coronary Artery Disease : PEPCAD I SVD Sequent in 2.8mm. 120 Patients. Multi-Center, Germany PEPCAD II ISR Sequent vs. Taxus in ISR. 131 Patients. Multi-Center, Germany PEPCAD III Sequent + Crimped Coroflex Blue vs. Cypher. 637 Patients. Multi- Center, Europe PEPCAD IV DM Sequent vs. Taxus in DM. 160 Patients. Multi-Center, Thailand and Malaysia PEPCAD V BIF PEPCAD CTO INDICOR PEPCAD WW Sequent. 28 Patients. Dual- Center, Germany Sequent, 50 Patients. Single- Center, Germany Sequent + Crimped Coroflex Blue. 125 Patients. Real World, India Studies Worldwide (RCTs additional indications) Coroflex Blue (uncoated balloon and CoCr stent) Coroflex DEBlue (SeQuent Please / uncoated CoCr stent) Coroflex DEBlue is manufactured based on the PACCOCATH technologywith 3 µg paclitaxel / mm²; CE mark since

11 New DCB Programs Under Development Lutonix Biotronik 2 µg/mm 2 3 µg/mm 2 BTHC Invatec 3 µg/mm 2 Eurocor 3 µg/mm 2 Urea Shellac

12 PACLITAXEL (NG/G) Concentration vs. Depth at 90 Days 100,0 10,0 Log Concentration vs. Depth at Follow Up Times 1 HOUR 1 DAY 7 DAYS 30 DAYS 90 DAYS 1,0 0, Endothelium Neointima Media (SMC Layer) Adventitia TRANSMURAL TISSUE DEPTH (ΜM) Slide courtesy of Lutonix Inc

13 % of load Pharmacokinetic Profile of Different PCB Technologies FREE-PAC (Invatec) MOXY (Lutonix) COTAVANCE (Medrad) 5 min 1 h 2 h 24 h 72 h Time After Intervention High short term transfer Rapid decline Sustained (90 days) retention

14 Comparative DCB - Dose Finding Study Porcine Coronary Stent Model B. Kelsch, Invest Radiol Apr;46(4):

15 In-Segment Binary Restenosis (%) PCB for the Treatment of ISR Angiographic Outcomes (Absence of Stent) % RRR 0.80 ±0.79 Total of 216 Patients! PCB Control 55% RRR (Taxus) 0.45 ± ±0.44 N=54 N=54 N= 23 (BMS + DES) 0.31 ± ± ± ±0.50 N=66 N=65 N=39 N=34 PACOCCATH I/II INPACT ISR PEPCAD II PERVIDEO I Spanish Registry

16 Clinical Outcomes Among 250 Patients Presenting with ISR (DES and BMS) Frequency of Stent Implantation 4.9% DIOR II PCB Technology (3 µg/mm 2 ) 40.6% Diffuse ISR Length Covered by PCB 24±9.1 mm ,8 13,4 2,6 2 1,2 1,31,2 1,2 1,2 0 5,9 9,8 7,2 12,2 BMS DES Silber S, Presented at CRT 2011.

17 Late Lumen Loss (mm) Binary Restenosis (%) PCB for the Treatment of SVD Angiographic Outcomes (Absence of Stent) PEPCAD I: De-novo lesions, RVD: mm; SeQuent Please Spanish Registry: De-novo lesions, RVD: <2.5 mm; Dior I (87%) ± ±0.23 PEPCAD I Spanish Registry PEPCAD I Spanish Registry N=120 N=51 N=120 N=51 0 mm %

18 PCB for the Treatment of De Novo SFA Disease (ITT= PTA Only) LEVANT I Fem-PAC N=35 N= N=34 N= POBA PCB Fem-PAC N=31 N= POBA PCB Thunder N=41 N= Thunder N=41 N= Angiographic Late Loss (mm) Binary Restenosis (%) FAST Trial (Luminexx, LL ~4.5 cms) Binary Restenosis by DU: PTA 36.6% versus Stent 23.8% (p=0.073) Absolute Trial (LL ~13 cms) Binary Restenosis by DU: PTA 45% versus Stent 25% (p=0.06)

19 DEB SFA Italian Registry De-Novo SFA Disease Multicenter SFA Observational Registry 94 patients / 103 lesions Lesion length mm Ruth Class 2: 23.4 %; 3: 68.1 %; 4: 7.4 % PTA alone: 86.4% / + Stent: 13.6% G.Biamino EuroPCR 2010

20 Vascular Healing Following PCB Use De Novo vs. ISR Applications Can we extrapolate the data gathered from ISR trials towards the development of DCB technologies aimed to treat de novo lesions? In-Stent Restenosis Ballooning inside of a stent. Quiescent disease state. Mature neointima. Smaller degree of injury induced. No additional material left behind. ISR De Novo De-Novo (+Stent) Emerging Disrupting DCB a plaque. Trial Designs Active disease state. Presence of necrotic tissue. Higher degree of injury. Stent left behind. Plaque drug uptake? Best mechanism of delivery? Pre, post, crimped stent? Stent healing in vivo? DES Market

21 Angiographic Outcomes: PCB Trials for De Novo Applications PEPCAD III: BMS Crimped on PCB (3 µg/mm 2 ) versus Cypher Stent Lutonix De Novo Registry: Pre or Post Dilatation Using PCB (2 µg/mm 2 ) Angiographic Late Loss (mm) Binary Restenosis (%) PEPCAD III N= P<0.001 N= Control PCB PEPCAD III N= N= 312 P< Lutonix Pre- DCB N= Lutonix Pre- DCB N= Control PCB Lutonix Post DCB N= Lutonix Post DCB N=

22 Synergistic Use of PCB and BMS Lessons Learned From the PEPCAD Trials PEPCAD I (SVD): Binary Restenosis: DEB Only (5.5%) versus DEB+BMS (41.3%) Stent Thrombosis: DEB Only (0%) versus DEB+BMS (1.7%) PEPCAD III (De Novo + BMS): Definite Stent Thrombosis: DEB+BMS (1.3%) versus Cypher (0.3%) PEPCAD V (28 Patients Bifurcation Study) Late Stent Thrombosis Rate (7.1%)

23 Now, Where Are We in 2011? DES Technologies What do DCB need to prove to become mainstream therapy? Regulatory Challenges Emerging DCB Field Emerging DCB Field

24 (1) Systemic Release of Paclitaxel Clinical Indication: SFA 120 mm balloon 7 mm diameter Overlapping balloons?% of Systemic Dose Acute drug loss during transit Short term human PK studies Biodistribution (other tissues).

25 (2) Mechanism of Action of DCB Sustained Tissue Retention of Paclitaxel Transit Drug Loss DCB Acute Drug Transfer TISSUE LEVEL ENDPOINTS Below toxic threshold Homogeneous distribution Sustained therapeutic levels Acute Drug Transfer Drug Transfer Technology

26 Mean Score Mean Score Mean Score Mean Score (3) Local Tissue Effects (Safety) Vascular Healing According to Dose 1= Minimal 2= Slight 3= Moderate 4= Marked 5= Massive Delayed Endothelialization Fibrin (Endothelial + Medial) Uncoated 0 Control 2x 4x 6x 0 Control 2x 4x 6x IEL Rupture Presence Amorphous Material Cotavance (1x) Cotavance (6x) Control 2x 4x 6x Control 2x 4x 6x Histology picture obtained from CVPath

27 (4) Particulate Coating Formation Local Tissue Effects Transit Drug Loss Acute Drug Transfer Micro-Particles DCB Acute Drug Transfer Macro-Particles Vascular occlusions. Tissue drug effect. End-organ effects.

28 Challenges and Trade-Offs in DCB Optimization Development Third Generation DCB Design State of the art PTA platform Improved coating uniformity Improved tissue drug transfer (uptake) Optimal tissue drug retention (homogeneous) Minimal amount of particulate formation Design Trade-Offs Optimum coating uniformity and low particulate may be trade-off with drug uptake and retention Drug uptake and retention are separate variables

29 Paclitaxel DCB Types Impact on Biological Performance Crystalline Coating Amorphous Coating Fully Crystalline Fully Amorphous Particles Released Uniform Coating Drug Transfer to Vessel Drug Retention vs. Time +++ +

30 Tissue Uptake vs. Tissue Retention Separate Variables to be Optimized Coating 1: high uptake, high retention Coating 3: high uptake, lower retention

31 Conclusions: PCB Technologies PCB technologies continue to show efficacy in reducing restenosis in specific clinical scenarios (i.e., ISR). However, the synergistic use of stents must be carefully studied in a prospective manner in a larger population. Newer generations of PCB appear to offer improved coating platforms providing more precise drug transfer to the tissue. Preliminary data suggests that specific features of the coating regulates the long-term transfer and retention of the drug. The real clinical effect of micro-particle drug release into distal tissues needs to be carefully evaluated against the potential therapeutic benefit of this technology. If proper technical balance is achieved (acute transfer-tissue levels-particulate formation), PCB have the potential to become a strong competitor in the PCI arena.