1. Update on Sirolimus Coated Balloon Technologies
Robert M. Bersin, MD, FACC, FSCAI Medical Director, Endovascular Services
Swedish Medical Center
Seattle, Washington

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.
Robert M. Bersin, MD
Abbott Vascular C, P, SB
Ablative Solutions EI
Boston Scientific AB, C, EI, P, SB
Cook Medical, Inc. C, P
Med Alliance SA, AB, EI
Medtronic, Inc. C, P
Omeros Corp, EI
QT Vascular, EI
Transverse Medical AB, EI, SO
Vatrix Medical EI
W.L. Gore C, P
Company
AB: Advisory Board
C: Consulting Relationship
EI: Equity Interest
GS: Grant Support
P: Proctor or Training Course Sponsorships
SB: Speakers Bureau
SE: Spouse Employee
SO: Stock Options or Positions

3. PACLITAXEL DRUG COATED BALLOONS
Current status:
All DCBs that have received FDA and CE Mark approval use Paclitaxel as anti-restenotic drug
Cell death at target lesion is prominent feature of all Paclitaxel DCBs and has been shown to be dose dependent
Virmani et al. EVT Today August 2015;Suppl: 11-15

4. Drug Coated Balloon – Coronary Devices
Company
Device
Drug
Coating / Excipient
Drug Dose
μg/mm2 CE
Aachen Resonance
Elutax SV
PTX
None 2
Yes
Bard
Lutonix 014 PTCA
Polysorbate / Sorbitol No
B Braun
Sequent Please
Iopromide 3
Biotronik
Pantera Lux
Butyryl-tri-hexyl Citrate
Boston Scientific
Agent
Acetyl-tri-butyl Citrate
Cardionovum
Restore / Primus
Shellac
Eucatech
Support C
Eurocor / Biosensors
DIOR/ BioStream
Medtronic
IN.PACT Falcon
Urea
3.5
Minvasys
Danubio
2.5
Nano Therapeutics
Curex PTCA
2.3

5. Drug Coated Balloon – Peripheral Devices
Company
Device
Drug
Coating / Excipient
Drug Dose
μg/mm2 CE
Aachen Resonance
Elutax SV
PTX
None 2
Yes
Balton
mcPCB 3 No
Bard
Lutonix
Polysorbate / Sorbitol
Bayer-Medrad
Cotavance
Iopromide
Biotronik
Passeo-18 Lux
Butyryl-tri-hexyl Citrate
Boston Scientific
Ranger
Citrate Ester
Cardionovum
Legflow
Shellac
Cook
Advance 18 PTX
Covidien
Stellarex
Amphiphilic Polymer
Eurocor / Biosensors
Freeway / BioPath
iVascular
Luminor
Water Reducer Ester
Medtronic
IN.PACT
Urea
3.5
Meril
Mozec
Nano-particles
Nano Therapeutics
Curex PTA
2.3
Vascular Nanotransfer Technologies
Nano-encapsulation
Surmodics
Microcrystalline
AngioScore
AngioSculpt*
TriReme Medical
Chocolate Touch*
*Scoring Balloons

6. Sirolimus Drug Coated Balloons
Sirolimus offers potential benefits over Paclitaxel:
Sirolimus is drug of choice for coronary DES supported by solid clinical based evidence
Attribute
Sirolimus (or Analogs)
Paclitaxel
Mode of action
Cytostatic
Cytotoxic
Margin of safety
10’000 fold
100 fold
Therapeutic range
Wide
Narrow
Anti-restenotic
Yes – lower late lumen loss
Yes
Anti-inflammatory No
Tissue absorption
Slow
Fast
Tissue retention
Short
Long

7. Sirolimus Coated Balloon
Benefits, Challenges & Solution

8. Sirolimus Coated Balloon – Benefits
Point of no return:
cell committed to replication
CYTOTOXIC
cell dies
CYTOSTATIC
cell remains viable
S phase
DNA replication
G2 phase
Growth and
preparation for Mitosis
M phase
Mitosis
G1 phase
Growth and preparation for DNA synthesis
G0 phase
Resting
Sirolimus
Paclitaxel
© M.A. Med Alliance – Confidential.

9. Sirolimus Coated Balloon – Benefits
All currently available DCBs use Paclitaxel as anti-restenotic drug
Sirolimus (rapamycin) offers potential benefits over Paclitaxel:
Attribute
Sirolimus (or Analogs)
Paclitaxel
Mode of action
Cytostatic
Cytotoxic
Margin of safety
10’000 fold
100 fold
Therapeutic range
Wide
Narrow
© M.A. Med Alliance – Confidential.

10. Sirolimus Coated Balloon – Benefits
PACLITAXEL
10’000
TOXIC EFFECT
1’000
Concentration (μg/g)
Arterial Drug
100
Typical DCB
Curve
THERAPEUTIC
RANGE 10
Typical DES
Curve
NO EFFECT 1 25 50 75
100
Time (Days)
Source: Presentation Granada at CRT 2014.
© M.A. Med Alliance – Confidential.

11. Sirolimus Coated Balloon – Benefits
TOXIC EFFECT
10’000
1’000
THERAPEUTIC
RANGE
Concentration (μg/g)
Arterial Drug
100
Typical DCB
Curve 10
Typical DES
Curve
NO EFFECT 1 25 50 75
100
Time (Days)
Source: Presentation Granada at CRT 2014.
© M.A. Med Alliance – Confidential.

12. Sirolimus Coated Balloon – Challenges
All currently available DCBs use Paclitaxel as anti-restenotic drug
Sirolimus (rapamycin) offers potential benefits over Paclitaxel:
Attribute
Sirolimus (or Analogs)
Paclitaxel
Mode of action
Cytostatic
Cytotoxic
Margin of safety
10’000 fold
100 fold
Therapeutic range
Wide
Narrow
Anti-restenotic
Yes – lower late lumen loss
Yes
Anti-inflammatory No
Physician reception
Positive
Controversial
Tissue absorption
Slow
Fast
Tissue retention
Short
Long
Source: JACC 2006:47(4);708–14.

13. Sirolimus Coated Balloons – Challenges
Paclitaxel and Sirolimus act differently with tissue:
Paclitaxel absorbs quickly and tends to localize in sub-intimal space and partitions significantly in adventitia
Sirolimus absorbs slowly and spreads throughout entire artery where it dilutes down to sub-therapeutic levels
Sirolimus
Paclitaxel
Dextran
Balloon Surface
Drug Coating
Endothelium
Plaque or Neointima
Tunica Media
Tunica Adventitia
Tissue Binding Capacity (TBC) of labeled dextran, paclitaxel and sirolimus
in mm-thick bovine internal carotid tissue segments.
Source: PNAS 2004:101(25);9463–67.

14. Sirolimus Coated Balloons – Challenges
Enhance tissue absorption
Difficult to get sirolimus to enter into arterial tissue within 30 to 180 seconds of balloon dilatation; hence some kind of “instant glue” is required to transfer the drug from the balloon to the tissue efficiently
Extend tissue retention
Sirolimus must be continuously delivered over time, so some form of “time release mechanism” must be employed to maintain therapeutic levels

15. Sirolimus Coated Balloons - Landscape
Company
Product
Drug
Concentration
Delivery Agent
Abbott Vascular NA
zotarolimus
6-7 μg/mm2
iopromide matrix
Caliber Therapeutics
Virtue DCB
sirolimus nanoparticles
3 mg
porous balloon
Concept Medical
Magic Touch DCB
Xtreme Touch DCB
1.3 μg/mm2
3.0 μg/mm2
phospholipid excipient
MedAlliance SA
Selution DCB
1.0 μg/mm2
CAT-cell adherence technology
Sahajanand Medical Technologies
sirolimus
0.7 μg/mm2
PLGA/PVP coating

16. Granada J TCT 2015

17. Granada J TCT 2015

18. SABRE: Clinical Safety Outomes
12 Months Follow Up
Pieter Stella, MD on behalf of SABRE Investigators TCT 2016

19. Magic Touch Nanolute Technology
Bernardo Cortese MD TCT 2016

20. Magic Touch 12-month Clinical Outcomes
ISR Subset (N=167 lesions)
MACE (major adverse cardiac events)
Value (%)
Death
0.00
Myocardial infartction
0.67
TLR
5.33
Total MACE
6.00
NanoluteTM

21. Med Alliance SELUTION™ Sirolimus DCB
Micro-reservoirs made out of biodegradable polymer intermixed with Sirolimus:
Controlled and sustained drug release mechanism
Maintains therapeutic effect in tissue over long period of time
Novel Cell Adherent Technology – CAT™:
CAT™ transfer membrane houses and protects micro-reservoirs during balloon insertion, lesion crossing and expansion
CAT™ transfer membrane with embedded micro-reservoirs releases from balloon delivery system and adheres to vessel lumen with short balloon inflations
Extend tissue retention
Sirolimus must be continuously delivered over time, so some form of “time release mechanism” must be employed to maintain therapeutic levels
Enhance tissue absorption
Difficult to get Sirolimus to enter into arterial tissue within 30 to 180 seconds of balloon dilatation; hence some kind of “instant glue” required to transfer the drug from the balloon to the tissue efficiently

22. Sirolimus Coated Balloon – Solution
Use of micro-reservoirs made out of biodegradable polymer intermixed with Sirolimus
Controlled and sustained drug release
Long-term distribution of Sirolimus into tissue to maintain therapeutic levels
Novel Cell Adherent Technology – CAT™
Minimizes wash-off during insertion, tracking and lesion crossing
Optimizes drug transfer to tissue during short-term balloon dilatation

23. Med Alliance SELUTION™ vs. Competition
Medtronic
IN.PACT
BBraun
SEQUENT PLEASE
Biotronik
PANTERA LUX
© M.A. Med Alliance – Confidential.

24. Med Alliance SELUTION™ vs. Competition
NO FLAKING

25. Med Alliance SELUTION™ Sirolimus DCB
Drug Dispersion
Increased tissue transfer and reduced drug loss during procedure
Review of skeletal muscle from select territories in addition to coronary bands showed no evidence of skeletal infarction/scarring and/or emboli attributed to PCI
No indication of infarction/scarring or distal emboli involving micro-reservoirs in any of tissues assessed (i.e. lung, left and right kidney, liver, spleen and left gastrocnemius muscle)
Med Alliance – In vitro test data on file
Bard & Medtronic – Presentation J.F. Granada (TCT 2014)

26. Med Alliance SELUTION™ Sirolimus DCB
Arterial Tissue Drug Concentration
Sirolimus (RAP) versus Paclitaxel (PAX)
Drug Dose per Balloon Size
Therapeutic Effect ≥ 1 µg/g
Numerous micro-reservoirs coating central surface of artery wall
Fields of uniform micro-reservoirs are seen adherent to luminal surface
Pre-clinical studies demonstrated feasibility of long-term (up to 60-days) arterial tissue retention of Sirolimus with therapeutic levels having reduced drug dose of 1 ug/mm2
En Face Scanning Electron Microscope at 24 hours
Med Alliance – PK Study ( )
Medtronic – Presentation R.J. Melder (LINC 2012)
Bard – Catheterization and Cardiovascular Interventions 83:132–140 (2014)

27. Med Alliance SELUTION™ PK Study
Source: Med Alliance – PK Study ( ) / Bard – Catheterization and Cardiovascular Interventions 83:132–140 (2014) / Medtronic – Presentation Melder (LINC 2012).

28. Peripheral FIH – SELUTIONTM Fem-Pop Trial
To show non-inferiority of SELUTION™ DCB vs. FDA approved DCB in terms of safety and efficacy for treatment of Superficial Femoral (SFA) or Popliteal (PA) Artery lesions
Objective
Prospective, Multi-Center, Single Blinded, Randomized Controlled
N=110 (55 in each arm)
Design
Angiographic Late Lumen Loss (LLL) by QVA
6 months
Primary Endpoint
Major Adverse Events (Death, TLR, Thrombosis, Amputation)
6 months
Primary Patency – Freedom from CD-TLR and Restenosis by DUS
6, 12 and 24 months
Angiographic Binary Restenosis (ABR) by QVA
Composite of Freedom from Amputation and Freedom from CD-TVR
12 and 24 months
Change of ABI, WIQ and QoL
Secondary Endpoints

29. FIM – Study Design Pre-screening Screening NO Treatment Analysis NO
Non-Clinical Inclusion / Exclusion Criteria
Pre-screening
Clinical and Anatomic Inclusion / Exclusion Criteria
Screening Failure
(Treat per std practice)
Screening
Successful Pre-Dilatation? NO
Randomized
1:1
SELUTION™ DCB
FDA Approved DCB
Treatment
Analysis
Bailout Stenting? NO
Primary Endpoint Analysis
ITT Analysis
Bailout Stenting Analysis
© M.A. Med Alliance – Confidential.

30. Investigational Device
Coronary FIH - SELUTIONTM ISR Trial (incl small vessels & side branches)
SELUTION™ Sirolimus Coated Coronory Balloon (S-DCB)
Investigational Device
Assess safety and efficacy of the MedAlliance sirolimus-eluting micro-reservoirs DCB (SELUTIONTM) in comparison with currently approved paclitaxel DCB in ISR, side-branch bifurcation lesions, and small (≤2.5 mm) vessels
Design
Proof of efficacy
Proof of non-inferiority vs. Paclitaxel DCB
Collect data to obtain CE mark approval
Other Objectives

31. Prospective, open label, multi-center RCT with angiographic endpoints
SELUTION DSR
Prospective, open label, multi-center RCT with angiographic endpoints
Patients with CAD with ISR or Bifurcation with side-branch lesion or distal lesions in small vessels
Large centres in countries where Paclitaxel DCB are approved and reimbursed
SELUTION™
DCB
145 Patients
1:1 randomization
Paclitaxel
DCB
Clinical FU
1 mo mo mo yr yrs
Angio FU
Optional IVUS FU
Primary endpoint: S-DCB superiority for % diameter restenosis vs P-DCB at 9 months
Secondary endpoints: LLL at 9 months
Primary angiographic EP for each of the 3 groups
Device success (in cath lab)
Procedure success (at discharge)
Freedom from TVF at 360 and 720 days
Components of TVF at 360 and 720 days
Freedom from angina at 360 and 720 days
QOL & Cost-effectiveness at 360 days
IVUS determined minimal DSA at 9 months (optional)
DAPT: 30 days in both arms (if no stent in main branch for S group)

32. Sirolimus DCBs Potential to improve patient outcomes Efficacy
Sirolimus has lower late lumen loss
Nanoparticulate encapsulation provides sustained release of sirolimus – “DES like” but without leaving anything behind
Safety
Cytostatic sirolimus instead of cytotoxic paclitaxel with higher tissue tolerance
Substantially reduced drug dose (especially in case of multiple, longer or overlapping balloons)
Reduced wash-off and less harmful to operators
Healing
Less inhibition of healing in target lesion and in distal tissue beds due to lower drug toxicity and reduced embolization of coating (e.g. potentially better wound healing in CLI patients)