Pre-clinical comparison of drug coated balloons. Renu Virmani, MD CVPath Ins5tute Inc. Gaithersburg, MD. USA

Transcription

1 Pre-clinical comparison of drug coated balloons Renu Virmani, MD CVPath Ins5tute Inc. Gaithersburg, MD. USA

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. Consultant: 48 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. Employment in industry: No Honorarium: 48 Biomedical, Abbott Vascular, Boston Scientific, Cordis J&J, Lutonix, Medtronic, Merck, Terumo Corporation, and W.L. Gore. Institutional grant/research support: 48 Biomedical, Abbott Vascular, Atrium, BioSensors International, Biotronik, Boston Scientific, Cordis J&J, GSK, Kona, Medtronic, MicroPort Medical, CeloNova, OrbusNeich Medical, ReCore, SINO Medical Technology, Terumo Corporation, and W.L. Gore. Owner of a healthcare company: No Stockholder of a healthcare company: No

3 Elements of an Effective DCB Formulation Must deliver large quan55es of the drug within seconds Distribute within the media in the first few days Therapeu5c drug levels must be maintained for at least several weeks Must allow rapid healing as compared to DES No need for long-term an5coagula5on Biologic effects at 28-days at least

4 Drug Coated Balloon Devices (Peripheral artery) Device Company Coa5ng Drug dose (µg/mm 2 ) CE mark * 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 Legflow Cardionovum, Warsaw, Poland Paclitaxel shellac 3. Yes Passeo-18 Lux Biotronik, Bülach, Switzerland Paclitaxel butyryl-tri-hexyl citrate 3. Yes Stellarex Spectrone5c, Mansfield, MA, USA Paclitaxel/Polyethylene glycol 2. No SurVeil TM DCB SurModics, MN, USA Paclitaxel-proprietary photolink 2. Yes FDA approval First in man in USA Clinical trial FDA Byrne RA, Joner M. et al. Nat Rev Cardiol. 214;11:13-23 Lutonix In.Pact SurModics ELUTAX Pantera Lux Sequent Please

5 Coa5ng Integrity is Variable SurVeil TM DCB (dry-expanded) 2x Lutonix 35 DCB(dry-expanded) 2x In.Pact TM (dry expanded) 2x

6 PTX Adherence to Balloon: iopromide versus urea coa5ng Split-off during dry infla5on Loss during passage** Remnant on balloon ajer defla5on *** * p=.2 ** through a blood-filled hemosta5c valve and guiding catheter and 1min in s5rred blood *** not released during expansion in a coronary artery Kelsch et al. Invest Radiol.

7 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 SMC loss Proeoglycan

8 Vascular Pharmacokinetic Responses to Treatment with a Lutonix 35 in a Swine Femoral Artery Yazdani SK, et al. Catheter Cardiovasc Interv. 214;83(1):132-4

9 Vascular response following Lutonix 35 DCB treatment in Porcine Iliac arteries 1x dose 28-days 9-days 18-days Yazdani SK, et al. Catheter Cardiovasc Interv. 214;83(1):132-4

10 Paclitaxel uptake in the Arterial Wall µg/ mg Iopromide matrix coating Urea matrix coating Lutonix, 2µg/mm 2 Polysorbate+sorbitol 58.8± min Paclitaxel uptake in arterial wall minutes Post stent implantation (n= 6 arteries each) Paclitaxel Concentra5on (g/mg) Lutonix, 2 µg/mm2 deployed in Swine Femoral Artery model at 1x Kellsch B, et al. Investigative Radiology 211;46(4): Yazdani SK, et al. Catheter Cardiovasc Interv. 214;83(1):132-4

11 DRUG PHASE DETERMINES DURATION OF BIOLOGIC ACTIVITY: IN.PACT ADMIRAL DRUG COATED BALLOON Not all drug concentrations are equal Solid-Phase Paclitaxel Equal Amounts Drug 5 µm Long-Term Biologic Activity as Solid Phase Paclitaxel Dissolves Short-Term Biologic Activity as Paclitaxel is Cleared DC31638

12 IN.PACT ADMIRAL MAINTAINS GREATER DRUG IN TISSUE THAN LUTONIX * DCB 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 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 ) D a y s D a y s IN.P A C T L u to n ix Drug in Tissue (ng/ mg) hours Ranger BSX Boston DCB Ranger DCB* In.Pact MDT IN.PACT Admiral Admiral DCB DCB Lutonix Bard Lutonix DCB DCB 1 Day 7 Day 21 Day 3 Day 45 Day 6 Day Note: Data on file with Medtronic Granada, J; JACC INT, 215 Note: Boston Scientific Ranger DCB is not available in the United States. DC31638

13 1 M e d ia l S M C L o s s S c o re (D e p th ) TISSUE RESPONSE AT 28 DAYS SMC Loss due to Toxic Injury *P =. 2 8 IN.PACT 2 S u rfa c e F ib rin /P la te S c o re Fibrin Deposition due Paclitaxel *P = IN.PACT M e d ia l S M C L o s s S c o re (C irc.) *P =. 7 8 Lutonix M e d ia l/in tim a l F ib rin S c o re *P = IN.P A C T L u to n ix IN.P A C T L u to n ix Lutonix Burst release of soluble paclitaxel leads to higher short-term SMC loss, but acute toxic injury, signified by fibrin deposition and extended SMC loss Note: Data on file with Medtronic DC31638

14 TISSUE RESPONSE AT 28 DAYS K I-6 7 P o s itiv e C e lls K I6 7 D e n s ity (P o s. N u c le i/m m 2 ) Rebound Proliferation due to Paclitaxel Depletion IN.P AC T L u t o n ix IN.PACT Lutonix Resulting Neointima Formation IN.P A C T L u to n ix IN.P A C T L u to n ix 4 N e o in tim a l T h ic k n e s s (m m ) N e o in tim a l A re a (m m 2 ) *P =. 3 6 *P = IN.PACT Lutonix Burst release of soluble paclitaxel leads to higher short-term SMC loss, but acute toxic injury, signified by fibrin deposition and extended SMC loss Moderated release of soluble paclitaxel via solid phase drug depots yields prolonged anti-proliferative effect resulting in less neointima formation Note: Data on file with Medtronic DC31638

15 IN.PACT TM Drug Elu5ng Balloon: Medtronic Preclinical Response Histomorphometry of Treated Porcine Arteries* Neointimal / Medial Inflammation Score Neointimal Proteoglycan / Collagen Score 4 3 Control DEB 5 4 * Control DEB Score 2 1 * * Score Day post-treatment Day post-treatment Medial SMC Loss (Depth) Medial SMC Loss (Circumf) Score * * * * Control DEB Score * * * Control DEB Day post-treatment Day post-treatment Paclitaxel ac5on *Medtronic data on file Very mild neointimal / medial inflammation resolved by 18 days SMC loss at indicating pharmacological activity of paclitaxel

16 PRE-CLINICAL EVALUATION SUPPORTS EFFICACY 28-Days 9-Days 18-Days Control (POBA) Therapeutic Dose (1x) The optimal features of DCB response Safety Margin Dose (3x) DC31638

17 Biological Drug Effect following SurVeil TM DCB treatment at 28- days in Porcine Iliofemoral arteries POBA Control MINIMUM MEDIAN MAXIMUM 3,5 3, 2,5 2, 1,5 1,,5, Medial PG/ Collagen Semi-Quan5ta5ve Scoring Medial SMC Loss (Depth) Medial SMC Loss (Circumf) EC Loss Medial/ In5mal Fibrin Medial/ In5mal Inflamm Markers of Drug Effect at 28-days SurModics Uncoated

18 Tissue drug concentra5on following SurVeil TM DCB treatment 1 4mm Balloons Tissue Concentra5on (µg/g) 1 1 SurModics SurVeil 1 day 7 day 14 day 21 day 28 day

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20 Vascular response following Stellarex DCB treatment in Porcine Iliac arteries Medial SMC Loss Score(Depth) 4 Medial SMC Loss Score (Circumf) day 9-day 18-day 28-day 9-day 18-day 28-day 9-day 18-day 28-day 9-day 18-day POBA Stellarex POBA Stellarex 4 Neoin5mal Proteoglycan Collagen Score 4 Adven55al Fibrosis Score day 9-day 18-day 28-day 9-day 18-day 28-day 9-day 18-day 28-day 9-day 18-day POBA Stellarex POBA Stellarex

21 Vascular response following Stellarex DCB treatment in Porcine Iliac arteries 28-Days 9-Days 18-Days Control (POBA) Therapeutic Dose (1x) The optimal features of DCB response Safety Margin Dose (3x)

22 Summary The effect of drug-coated balloon is characterized by smooth muscle cell loss accompanied with proteoglycan and collagen deposi5on of media in animal models. Endothelial loss and inflamma5on was minimal. The peak effect was observed from 28-day to 9-day. Coa5ng excipient is what makes the difference. Success will be clinically determined and is dependent on the dura5on paclitaxel remains within the arterial wall. This must be accompanied by absence of thrombosis, persistent vessel patency, and absence of restenosis. Improvement in Rutherford class must be observed and absence of chronic limb ischemia.

23 DCB Design: All About Balancing Safety, Efficacy, and Biologic Response Not all balloons are created equal. More Less Efficacy 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 Drug Load Use of Carrier / Excipient Drug Retention Repeat Inflations More

24 Acknowledgments CVPath Ins5tute Frank D Kolodgie, PhD Erica Pacheco, MS Kazuyuki Yahagi, MD Hiroyoshi Mori, MD Elena Ladich, MD Christoph Luter, MD Emanuel Harari, MD Robert Kutz, MS Russ Jones Ed Acampado, DVM Youhui Liang, MD Abebe A5so, HT Jinky Beyer Hedwig Avallone, HT Lila Adams, HT Hengying Ouyang, MD Michael Joner, MD Washington DC