1. THE SCIENCE BEHIND IN.PACTTM Drug Coated Balloon technology: Understand the science behind the latest evidence     FRANCESCO Jatta, Ph.D. IN.PACT DCB PROGRAM manager Medtronic Peripheral Vascular

2. All DCBs are DIFFERENT in Drug dose and excipient
Manufacturer
DCB
Dose (µg/mm2)
Excipient
RCT with 12-Month Primary Endpoints
IN.PACT
3.5
Urea
BARD
Lutonix
2.0
Polysorbate & Sorbitol
Spectranetics
STELLAREX
PEG
BIOTRONIK
Passeo Lux
3.0
BTHC
Boston Scientific
Ranger
Citrate Ester
Vascular
Luminor
???
COOK
Advance PTX
none
Aachen Resonance
Elutax SV
2.2
BIOSENSORS
BioPath (prev. FREEWAY)
Shellac
CARDIONOVUM
Legflow √ √
How does this compare to other DCBs currently in the EU market?
All DCBs are different – even though they all use PTX, the dose is different, the excipient is different and the platform is different
However, majority of them do not have solid level 1 clinical evidence (if at all); so it makes it very difficult to determine their efficacy profile
Only 2 DCBs that have solid clinical evidence is Medtronic and Bard – so these are the only two DCBs that we can make some sorts of comparison
In that case, let’s take a look at the clinical results of IN.PACT and Lutonix
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

3. IN.PACT DCB TECHNOLOGY: Mechanism of Action
PACLITAXEL
& UREA
Manufacturing:
Balloon coated with matrix in semi-inflated state, then wrapped
During transit to lesion:
Majority of matrix protected within folds of the balloon
DCB matrix coating:
Paclitaxel + Urea
DCB inflation:
Matrix contacts blood
Blood hydrates urea
Urea releases paclitaxel
Paclitaxel Hydrophobic and Lipophilic Properties:
Facilitates transfer from balloon and stickiness to vessel wall
Diffuses through vessel wall deep into the media and adventitia
Remains in vessel wall for over 180 days at therapeutic levels1
How drug is transferred from the balloon surface into tissue.
Mechanism of action is not through high pressure and pushing drug into tissue, but through a chemical transfer that occurs as the excipient, urea, hydrates and helps to expel paclitaxel from the balloon wall into tissue.
Additional Detail:
During inflation, the coating on the IN.PACT Admiral DCB comes into contact with blood.
Urea, the excipient in the coating, has a strong affinity for water; that is, it is hydrophilic. This characteristic facilitates the release of paclitaxel from the balloon, which essentially pushes the paclitaxel into the vessel wall.
Within the first 60 seconds of balloon inflation, a therapeutic dose of paclitaxel – 3.5 micrograms per millimeter squared – is delivered to the vessel wall.
With its lipophilic properties, paclitaxel binds to the vessel wall.
On a cellular level, its hydrophobic and lipophilic characteristics allow paclitaxel to enter the media and adventitia layers of the vessel, reaching smooth muscle cells – the cells most responsible for restenosis.
Paclitaxel binds to and stabilizes the microtubules of the smooth muscle cells. This action prevents smooth muscle cell division and leads to apoptosis (cell death).
This in turn minimizes cell proliferation and neointimal thickening, effectively maximizing the arterial lumen and “turning off” the process that leads to restenosis.
Data on file at Medtronic (FS208; PS516) 3
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

4. Duration of paclitaxel is important for durable effect
DES
Relies on scaffold and polymers on prolonged contact with the tissue to elute paclitaxel over time
Without scaffold and polymers, DCB relies on efficient transfer and long-term residence of paclitaxel in-tissue
Presence of solid phase paclitaxel in tissue provides a reservoir for sustained release of soluble drug
DCB
Solid-Phase Paclitaxel
50 mm
The mechanism of action seems simple, but the science behind it is very complex
The comparison with DES will give us a better appreciation of this complexity:
In DES, the scaffold and polymers provides a platform to deliver drug over a long period of time
In DCB, however, there is no scaffold polymer. The only chance to deliver drug is during the 1 minute of balloon inflation. It is during that 1 minute, you will need to deliver enough PTX that will stay in tissue long enough to cover the restenotic cascade
Therefore, it is critical that sufficient amount of solid phase PTX is delivered into tissue; and this solid phase PTX serves as a depot/reservoir to ensure long-term bioavailability as it slowly dissolves into soluble PTX
IN.PACT DCB-treated iliofemoral artery section.
Transfer of solid phase paclitaxel into the tissue to provide source of soluble drug over time is key to success of a DCB Technology
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

5. Drug phase determines duration of biologic activity
Not all Drug concentrations are equal
Solid Paclitaxel
Equal Amounts Drug
Soluble Paclitaxel
In fact, one of the key factors to determine the success of a DCB technology is the delivery of solid phase of paclitaxel
Paclitaxel can be in 2 phases:
Solid phase: Inactive; needs to be dissolved into soluble paclitaxel before it becomes bioavailable and can kill cells. However, its presence serve as a reservoir and as it dissolves into soluble phase PTX over long period of time, it provides long-term biologic effect
Soluble phase: Bioactive, immediately bioavailable and kills cells; downside is that it is readily metabolized and can only sustain short-term activity
So even if all DCBs have the same drug concentration on label, they may not all have the same level of efficacy. And part of this attributes to the PTX that it delivers into tissue
Long-Term Biologic Activity
as solid phase paclitaxel Dissolves
Short-Term Biologic Activity
as soluble paclitaxel is Metabolized
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

6. SERIES of Pre-clinical EXPERIMENTS conducted to investigate differences between IN.PACT™ DCB And LUTONIX DCB 1
Characterize the transition of Paclitaxel from solid phase to soluble phase with IN.PACT and Lutonix DCB (in vitro)
If we hypothesize that the delivery of solid-phase PTX into tissue is critical to the success of DCB technology, let’s do some experiments and see how this differ between IN.PACT and Lutonix.
Hypothesis:
Balance between solid and soluble phase paclitaxel moderates prolonged tissue response
Methods:
1. Characterize the transition of paclitaxel from solid to soluble phases with IN.PACT Admiral and Lutonix
2. Assess 28-day tissue response from the two coating formulations in terms of smooth muscle cell (SMC) loss and injury
3. Assess 28-day tissue response in terms of cell proliferation and neointima formation 2
Assess 90-day concentration of Paclitaxel in arterial tissue (swine model)
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

7. influence of excipient on dissolution of solid phase paclitaxel1
influence of excipient on dissolution of solid phase paclitaxel
Paclitaxel Available in Solid Phase through 24 Hours
93% - IN.PACT™ Admiral™DCB
% Solid-phase Paclitaxel Available to Tissue
1st experiment: To study the how excipient influences the balance between solid phase vs. soluble phase PTX
Methodology for in vitro experiment: Six IN.PACT Admiral balloons and six Lutonix balloons were placed into tubes containing of porcine plasma (room temp and deployed with gentile agitation for 20 seconds). The balloons were then removed from the tubes and agitated in a 37ºC shaking air bath at 50rpm. IN.PACT Admiral sample aliquots of 0.5mL were taken at 1, 2, 4, 6, and 24 hours. Lutonix sample aliquots of 0.5mL were taken at (10 min), 0.5, 1, 2, 4, 6, and 24 hours. All aliquots were filtered with a 5µm filter to remove solid phase material and then analyzed by LCMSMS.
What we observe:
Level of solid phase PTX in IN.PACT remained high after 24 hours; however, solid phase PTX of Lutonix pretty much decreased to zero after 24 hours
What we conclude:
1) IN.PACT formulation exhibits prolonged solid phase drug presence – Urea does not interact with PTX dissolution since it is extremely hydrophilic
2) Lutonix has burst release of soluble PTX – Polysorbate/sorbital acts as emulsifier and accelerates PTX dissolution into soluble state – making them immediately bioavailable but also exhausting PTX early for long-term prevention of restenosis
Conclusion: Coating formulations (drug dose + excipient) affect availability of solid phase drug
0% - Lutonix
Coating formulations (drug dose + excipient) affect availability of solid phase drug
IN.PACT DCB formulation exhibits prolonged solid phase drug presence vs. burst release of Lutonix
IN.PACT DCB’s excipient urea does not impact rate of paclitaxel dissolution; Lutonix’s excipient polysorbate/sorbitol based acts as an emulsifier and accelerates drug dissolution
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

8. Arterial Tissue Concentration2
solid phase paclitaxel dictates the level and duration of drug in tissue
Paclitaxel is available for both IN.PACT™ Admiral™ DCB and Lutonix post- 24 hours, but IN.PACT Admiral achieves sustained effect through slow release of solid-phase paclitaxel reservoirs
Arterial Tissue Concentration
Based on experiment #1, if indeed solid-phase PTX stays longer in tissue than soluble-phase, we would expect that IN.PACT have a longer drug-in-tissue level in comparison to Lutonix. So is this the case?
2nd experiment: We measured the PTX concentration in porcine tissue for both IN.PACT and Lutonix
What we observe:
IN.PACT consistently provides higher PTX tissue concentration than Lutonix through 90 days
Paclitaxel available for both IN.PACT and Lutonix post-24 hours, but IN.PACT Admiral achieves sustained effect through slow release of solid-phase paclitaxel reservoirs
This is validated by an independent study by Dr. Granada which showed very similar trend with Lutonix, where you see an initial burst of PTX into tissue but the PTX level drops rapidly in comparison to IN.PACT
What we conclude:
IN.PACT Admiral paclitaxel concentration decline slower and less abrupt than Lutonix
IN.PACT Admiral provides greater drug exposure between 0 and 90 days, allowing therapeutic effect aligned to disease cascade.
Methodology of the experiment:
24 IN.PACT Admiral balloons and 24 Lutonix balloons were deployed in the ileofemoral arteries of 24 farm swine. At days 0, 30, 60 and 90 post treatment animals were sacrificed (n=6)  and six treated arterial segments per arm were collected in cryovials and snap frozen in liquid nitrogen. Concentrations of paclitaxel in tissue was determined by LCMSMS.    
Granada, J; JACC INT, 2015
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

9. Primary Patency at 2 Years Re-intervention at 2 Years
In.pact™ DCB has proven long-term efficacy through Level 1 Clinical Evidence
IN.PACT DCB demonstrates best-in-class efficacy1,2 and excellent safety outcomes3 through two years
Primary Patency at 2 Years
Re-intervention at 2 Years
As Dr. Cleveland has just presented, the IN.PACT DCB has generated some of the best results seen amongst all SFA technologies.
2 observations in these results:
Highest reported Primary Patency at 2 years (78.9%); Lowest reported re-intervention at 2 years (91%)
No catchup effect after year 1 where DCB and PTA arm essentially travel in parallel
Freedom from core laboratory-assessed restenosis (duplex ultrasound PSVR ≤2.4) and clinically-driven target lesion revascularization through 24 months (adjudicated by a Clinical Events Committee blinded to the assigned treatment)
Clinically-driven TLR adjudicated by an independent Clinical Event Committee, blinded to the assigned treatment based on any re-intervention at the target lesion due to symptoms or drop of ABI of ≥20% or >0.15 when compared to post-procedure baseline ABI
Freedom from 30-day device and procedure-related death and target limb major amputation and clinically-driven TVR within 12 (24) months
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

10. IN.PACT SFA reported the highest primary patency rate and lowest re-intervention rate of all SFA technologies
IN.PACT Admiral DCB is cost effective for the treatment of SFA disease compared to alternatives, largely due to the significant difference in TLR rates
As part of a cost-effectiveness model created by a consultant from Stanford University, the results from an extensive literature search were analyzed and resulted in the above graph showing estimated TLR rates at 24 months for several common fempop therapies.
These results are similar to a Bayesian Network Meta-Analysis from Katsanos (JVS : ), which showed TLR was lowest with drug-coated balloons. *
Qualitative comparison for illustration purposes only. Not meant for head-to-head comparison.
1. Adapted from Pietzsch et al. CCI Comprehensive list of studies used in analysis on file at Medtronic
*Based on 2-year primary patency and clinically driven TLR outcomes from FDA pivotal trials.
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

11. Difference in Drug Coating may explain the difference in clinical efficacy
Product Feature
IN.PACT™ DCB
Lutonix
Paclitaxel Dose
3.5 µg/mm2
2.0 µg/mm2
Excipient
Urea
Polysorbate + Sorbitol
Solid-Phase vs. Soluble PTX
Drug-in-Tissue Overtime
Tissue Response to PTX Release
Primary patency rates, target lesion revascularization rates, and mean lesion lengths may be calculated differently, and therefore may not be directly comparable; chart is for illustration only.
IN.PACT SFA: Laird J, et al. 24-Month Results from the IN.PACT SFA Trial. JACC 2015, Article in Press.
LEVANT 2: 2-year data presented by Laurich C, SVS Chicago 2015; p-value between Lutonix and PTA 24-mo TLR not reported.

12. conclusions
The coating formulation (drug dose + excipient) plays an important role in sustaining solid phase paclitaxel in the tissue
Presence of solid phase paclitaxel is critical to ensuring prolonged tissue response
IN.PACT™ DCB employs a slower rate of paclitaxel dissolution, allowing solid phase drug to be retained in tissue for a longer duration
This mechanism of action may explain the differences in clinical efficacy observed between IN.PACT SFA and LEVANT 2 pivotal trials both at 12- and 24-months
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016

13. Thank You
© 2015 Medtronic. All rights reserved. Medtronic and Medtronic logo are trademarks of Medtronic. Other brands are trademarks of a Medtronic company. 13
INDICACIONES, TECNICAS Y MATERIAL DE RECANALIZACION VASCULAR | IN.PACT DCB Technology | February 26th , 2016