Comparison of particulate embolization in different DCB formulations. Aloke V. Finn, MD CVPath Institute Inc. Gaithersburg, MD.

Transcription

1 Comparison of particulate embolization in different DCB formulations. Aloke V. Finn, MD CVPath Institute Inc. Gaithersburg, MD. USA

2 Conflict of Interest Declaration Institution grant/research support 48 Biomedical, Abbott Vascular, Atrium, BioSensors International, Biotronik, Boston Scientific, Cook Medical, Cordis J&J, GSK, Kona, Medtronic, MicroPort Medical, CeloNova, OrbusNeich Medical, ReCore, SINO Medical Technology, Terumo Corporation, and W.L. Gore, Spectronics, CSI, Lutonix Bard, Surmodics, Microport, Meril Life Sciences Speaking Honoraria Abbott, Cook Medical, Lutonix, Boston Scientific

3 Elements of an Effective DCB Formulation Must deliver large quantities of the drug within seconds Distribute within the media in the first few days Therapeutic drug levels must be maintained for more than 4 weeks Must allow rapid healing as compared to DES No need for long-term anti-platelet therapy Biologic effects must be observed by histology at 28-days Effective drug delivery to target tissue while avoiding non-target effect (i.e. minimize emboli)

4 Three Case Reports for Downstream Effect of DCB Use: Particulate Embolization Related? Downstream Panniculitis Secondary to Drug Eluting Balloon Angioplasty. Ibrahim T et al, JACC Cardiovasc Interv. 216;12;9(17):e Vasculitis resulting from a superficial femoral artery angioplasty with a paclitaxel-eluting balloon. Thomas SD et al, J Vasc Surg. 214;59(2):52-3 Acute hypersensitivity reaction to femoral drug-coated balloons. Lake E et al, Vasa. 217 May;46(3):

5 Drug Coated Balloon Devices (Peripheral artery) Device Company Coating Drug dose (µg/mm 2 ) Advance 18 PTX Cook Medical, Bloomington, IN, USA Paclitaxel 3. Yes Cotavance Bayer Schering Pharma AG, Berlin, Germany Paclitaxel iopromide 3. Yes Freeway Eurocor, Bonn, Germany Paclitaxel shellac 3. Yes IN.PACT Admiral, Medtronic Vascular, Santa Clara, CA, USA Paclitaxel urea 3.5 Yes Lutonix 35 DCB BARD, Murray Hill, NJ, USA Paclitaxel polysorbate/sorbitol 2. Yes Ranger Boston Scientific Paclitaxel Acetyl Tributyl Citrate 2 2. Yes Passeo-18 Lux Biotronik, Bülach, Switzerland Paclitaxel butyryl-tri-hexyl citrate 3. Yes Stellarex Covidien, Mansfield, MA, USA Paclitaxel-polyethylene glycol 2. Yes SurVeil TM DCB SurModics, MN, USA Paclitaxel-proprietary photolink 2. Yes CE mark * Lutonix IN.PACT SurModics ELUTAX Pantera Lux Sequent Please

6 D ru g in T is s u e (n g /m g ) D ru g in T is s u e (n g /m g ) Drug in Tissue (ng/mg) IN.PACT ADMIRAL MAINTAINS GREATER DRUG IN TISSUE While there is expected variability across studies, IN.PACT Admiral consistently provides higher PTX tissue concentration than Lutonix * DCB through 9 days Paclitaxel available for both IN.PACT Admiral and Lutonix * DCB post-24 hours, but IN.PAC T Admiral achieves sustained effect through slow release of solid-phase paclitaxel reservoirs Arterial Tissue Concentration 5 IN.P A C T 8 7 BSX Boston Ranger DCB* Ranger DCB 4 3 L u to n ix 6 MDT IN.PACT Admiral DCB In.Pact Admiral DCB Lutonix DCB Bard Lutonix DCB D a y s D a y s 1 4 hours 1 Day 7 Day 21 Day 3 Day 45 Day 6 Day Note: Data on file with Medtronic Granada, J; JACC INT, 215

7 Downstream Sampling for Paclitaxel Analysis and Histopathology Assessment Angiogram of the SFA Gracillis Rectus Femoris IFA EFA Arteries not shown Semitendonosis Coronary band Gastrocnemius Semimembranosis Gluteus Maximus Evaluated skeletal muscle and coronary band for potential embolic changes Distal paclitaxel concentration Histology Distal embolization Vascular changes

8 Left or Right SFA Randomly Treated by LUTONIX, In.Pact or POBA Histo only Treatment Scheme: A total of 2 DCB treated sites (1/vessel) in the external femoral arteries of one leg (left or right). PK and histo Treatment Scheme: A total of 2 treated sites in the external femoral arteries of one leg (left or right). IN.PACT 1x or 3x Tx site LUTONIX1x or 3x Tx site 1x or 3x LUTONIX or IN.PACT Tx site POBA 1x or 3x Tx site REF 1x or 3x OL RIF LEF 1x or 3x OL LIF RIF REF LEF:1x or LEF 3x POBA 1x or

9 Distal Embolization (%) A Downstream Incidence of Distal Embolization (%) 28-Day Survival 9-Day Survival Single Balloon (1x) Overlapping Balloons (3x) Overlapping Balloons (3x) P= P= P= Lutonix % (-11.5) n=5 IN.PACT 15.4% ( ) n=5 Lutonix % (-15.4) n=5 IN.PACT 38.5% ( ) n=5 Lutonix 35 % (-11.5) N=5 IN.PACT 46.2% ( ) N=5 B Number of micro-vessels with paclitaxelassociated findings Survival Treatment & Arteries Lutonix 35 IN.PACT P-value 28-day (1x, n=5) 1 (-2) 4 (2-12).3 28-day (3x, n=5) 1 (-12) 26 (11-34).7 9-day (3x, n=4) (-3) 11 (5-15).2 C Survival Treatment & Arteries Lutonix 35 IN.PACT P-value Paclitaxel concentration in downstream tissues (ng/g) 28-day (1x, n=5) 28-day (3x, n=5) 9-day (3x, n=4) Skeletal muscle 1.3 (.6-2.3) 3.7 ( ).6 (.5-6.4) Coronary band 1.5 ( ) 31.5 ( ) 2.7 (.-25.5) Skeletal muscle 6.8 ( ) 17.9 ( ) 16.1 ( ) Coronary band 189. ( ) 871. ( ) 158. ( ) Skeletal muscle Coronary band

10 Downstream Findings in Porcine Skeletal Muscle (28-Day) Lutonix (1x) Vascular Change IN.PACT (1x) Vascular Change High (2x and 4x) power images of vascular changes in skeletal muscle at 28 days. Vascular changes include pyknotic nuclei embedded in homogenous pink material (yellow arrow), representing fibrinoid necrosis (black arrows), with surrounding inflammatory cells (blue arrows). IN.PACT (1x) Crystalline Material IN.PACT (3x) Crystalline Material High (4x) power images of crystalline material (red arrows) at 28d

11 In. Pact DCB vs. Stellarex vs. Ranger The Second Comparative Study Same swine model - 28 day study Treatment Scheme: A total of 2 treated sites in the external femoral arteries (left or right) in each pig 3x dose, same size DCB DCB inflated for 6 secs 3x IN.PACT Tx site 3x Ranger or Stellarex Tx site Blinded-device ID Same sampling method and evaluation endpoints as the first Lutonix vs. IN.PACT comparative study RIF REF LEF LEF 1x or LIF

12 Distal Embolization Paclitaxel concentration Paclitaxel concentration Downstream Incidence of Distal Embolization (%) Overlapping Balloons (3x), 28-Day Survival (%) 1 Histologic sections showing Distal Embolization p=.2 (ng/g) 8 Paclitaxel concentration in downstream Skeletal muscle p=.1 (ng/g) 5 Paclitaxel concentration in downstream Coronary band p= IN.P AC T R a n g e r S te lla r e x IN.P AC T R a n g e r S te lla r e x IN.P A C T R a n g e r S te lla re x Percentage of sections with vascular changes in downstream nontarget tissues (%) Survival Treatment Second Comparative Study IN.PACT (n=12) Ranger (n=6) Stellarex (n=6) 28-day (3x) First Comparative Study Lutonix (n= 5) IN.PACT (n=5) Survival Treatment Second Comparative Study IN.PACT Ranger Stellarex First Comparative Study Lutonix IN.PACT Paclitaxel concentration in downstream tissues (ng/g) 28-day (3x) Skeletal muscle ( ) Coronary band Skeletal muscle 91.5 Coronary band Skeletal muscle 11.9 ( ) ( ) ( ) ( ) Coronary band ( ) Skeletal muscle 3.7 ( ) Coronary band 31.5 ( ) Skeletal muscle 17.9 ( ) Coronary band 871. ( )

13 Downstream changes following IN.PACT vs. Ranger vs. Stellarex, dose 3X, at 28 days IN.PACT Ranger Stellarex CV381 R GASTRO1_2x CV3811 L SEMM1_2x CV3812 L SEMM2_2x CV387 Right Gracilis CV387 Left Gracilis CV381 Left Gastrocnemius

14 Efficacy DCB Design: All About Balancing Safety, Efficacy, and Biologic Response Not all balloons are created equal. More Less Less neointima Absence of restenosis No early or late thrombosis Biologic changes, but no emboli Rapid vascular healing Good re-endothelialization No distal emboli Safety Less Goal of Efficacy No Restenosis Drug Load Use of Carrier / Excipient Drug Retention Repeat Inflations More Goal of Safety No Aneurysms No Emboli

15 Funding CVPath Institute Inc. Acknowledgments CVPath Institute Sho Torii, MD Kazuyuki Yahagi, MD Hiroyoshi Mori, MD Emanuel Harari, MD Elena Ladich, MD Robert Kutz, MS Ed Acampado, DVM Youhui Liang, MD Abebe Atiso, HT Jinky Beyer Lila Adams, HT Frank D Kolodgie, PhD Liang Guo, PhD Renu Virmani, MD Washington DC My afinn@cvpath.org

16

17 Clinical Relevance In the absence of randomized clinical data, preclinical studies can provide excellent information about the relative performance of different technologies Randomized studies generally exclude high risk patients who probably would be affected most by downstream adverse events DCBs which obtain effective drug transfer into the arterial wall while minimizing downstream embolic effects are the goal

18 Lutonix 35 vs. In.Pact Admiral First Comparative Study in Swine Blinded study Side-by-side 1x and 3x dose Evaluated skeletal muscle and coronary band at 28 and 9 days Distal drug concentration Histology Distal embolization Vascular changes Different test methods may yield different results. Pre-clinical test data on file. Pre-clinical results may not be indicative of clinical performance.

19 Histologic Parameters for Evaluation of DCB Efficacy Key parameters include: Endothelial loss Fibrin / Platelets Inflammation Injury Medial smooth muscle cell loss Matrix replacement Proteoglycan Collagen Adventitial fibrosis Fibrin H&E SMC loss α-sma Proeoglycan Movat

20 Left or Right SFA Randomly Treated by LUTONIX, or In.Pact Histo only Treatment Scheme: A total of 2 DCB treated sites (1/vessel) in the external femoral arteries of one leg (left or right). IN.PACT 3x Tx site LUTONIX 3x Tx site REF 3x OL LEF 3x OL RIF LIF Kolodgie, FD et al. J Vasc Interv Radiol. 216 Sep 15. pii: S (16)

21 Histologic Vascular Changes following Lutonix vs. In.Pact DCB Treatment (3x) Lutonix 3x-28d In.Pact 3X-28d POBA-28d Luminal Stenosis, % P=.2 P=.44 Lutonix 35 IN.PACT POBA Lutonix 35 IN.PACT POBA 28 days 9 days Lutonix 3x-9d In.Pact 3x-9d POBA-9d Neointimal Area, mm 2 P=.2 P=.3 1 Lutonix 35 IN.PACT POBA Lutonix 35 IN.PACT 28 days 9 days POBA Kolodgie, FD et al. J Vasc Interv Radiol. 216 Sep 15. pii: S (16)

22 Histologic Vascular Changes following Lutonix 35 vs. IN.PACT DCB Treatment (3x) at 28 and 9 days Lutonix 35: n=5, In.Pact DCB: n=5, POBA: n=4 SMC loss score (Depth) SMC loss score (Circumference) 4 P=.4 P=.2 4 P=.1 P= Lutonix 35 IN.PACT POBA Lutonix 35 IN.PACT POBA Lutonix 35 IN.PACT POBA Lutonix 35 IN.PACT POBA 28 days 9 days 28 days 9 days Medial proteoglycan score Fibrin/thrombus score P=.1 P=.7 P=.41 P= Lutonix 35 IN.PACT POBA Lutonix 35 IN.PACT POBA Lutonix 35 IN.PACT POBA Lutonix 35 IN.PACT POBA 28 days 9 days 28 days 9 days Kolodgie, FD et al. J Vasc Interv Radiol. 216 Sep 15. pii: S (16)