Update on drug eluting balloons –

are they all the same?

Frank Vermassen

Ghent University Hospital

Belgium

Disclosures

✓ I have the following potential conflicts of interest to report:

✓ Receipt of grants/research support

✓ Receipt of honoraria and travel support

Medtronic, Abbott Vascular, Bard, W.L. Gore, Terumo, Boston Scientific

Participation in a company sponsored speakers‘ bureau

Employment in industry

Shareholder in a healthcare company

Owner of a healthcare company

I do not have any potential conflict of interest

Thunder trial Fempac trial

Binary restenosis in SFA lesions

Tepe NEJM 2008

Freedom from TLR in SFA lesions

Werk Circulation 2008

Drug coated balloons: The start

1 Tepe G et al. NEJM 20082 Werk M et al. Circulation 20083 Scheinert D et al. JACC 20144 Scheinert D et al JEVT 2015

5 Werk M et al Circ Cardiovasc Interv 20126 Scheinert D LINC 2013 oral presentation7 Schroeder H Catheter Cardiovasc Interv 2015

Courtesy of T Zeller LINC 2016

7

DCB concept works!

5 DCBs showing a biologic effect Paccocath PTX 3 µg/mm2

+ Ultravist

Lutonix PTX 2 µg/mm2

+ Polysorbate

& Sorbitol

In.Pact PTX 3.5 µg/mm2

+ Urea

Passeo

18 Lux PTX 3.0 µg/mm2

+ BTHC

Advance

PTX PTX 3.0 µg/mm2

NO Excipient

Stellarex PTX 2.0 µg/mm2

PEG

1. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwälder U, Beregi JP, Claussen CD, Oldenburg A, Scheller B, Speck U. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008 Feb 14;358(7):689-99

2. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hosten N, Hamm B, Speck U, Ricke J. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial.

Circulation. 2008 Sep 23;118(13):1358-65

3. Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, Tepe G, Naisbitt S, Rosenfield K. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-

human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014 Jan;7(1):10-9

4. Scheinert D, Schulte KL, Zeller T, Lammer J, Tepe G. Paclitaxel-Releasing Balloon in Femoropopliteal Lesions Using a BTHC Excipient: Twelve-Month Results From the BIOLUX P-I Randomized Trial. J Endovasc Ther. 2015 Feb;22(1):14-21

5. Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, Eschenbach G, Hartmann H, Lange C, Schnorr B, Stiepani H, Zoccai GB, Hänninen EL. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the

randomized PACIFIER trial. Circ Cardiovasc Interv. 2012 Dec;5(6):831-40

6. D.Scheinert – LINC 2013 oral presentation

7. Schroeder H, Meyer DR, Lux B, Ruecker F, Martorana M, Duda S. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: Outcomes from the ILLUMENATE first-in-human study. Catheter Cardiovasc

Interv. 2015 Feb 23

Single arm

7 Trials/ 6 DEB technologies – 6 Mo Late Lumen Loss (Primary Endpoint)

Early Short term results

Manufacturer DCB DrugDose

(μg/mm2) Excipient

IN.PACT PTX 3.5 Urea

LUTONIX PTX 2.0 Polysorbate and Sorbitol

STELLAREX PTX 2.0 Polyethylene Glycol

PASSEO 18 LUX PTX 3.0 Butyryl-tri-hexyl Citrate

ADVANCE 18 PTX PTX 3.0 none

ELUTAX PTX 2.2 dextrane

FREEWAY PTX 3.0 shelloic acid

LEGFLOW PTX 3.0 shelloic acid

RANGER PTX 2.0 citrate ester

LUMINOR PTX 3.0 organic ester

SeQuent Please PTX 3.0 Iopromide

BIOPATH PTX 3.0 Shellac

ORCHID PTX 3,0 Magnesium stearate

SURVEIL PTX 3,0 unknown

Technical differences

Same drug (paclitaxel)

Different:

≠ Dose (2.0 - 3.5 μg/mm2)

≠ Drug Formulation

≠ Excipient

≠ Surface Energy

≠ Coating Method

Determinants of DCB Biological Effect

• Antiproliferative agent (Paclitaxel)– Drug content on balloon surface

• Tissue transfer efficiency– Coating characteristics (i.e,

hydrophobicity/hydrophilicity)

– Excipient

– Coating technique

• Loss to circulation (Insertion-

transit-inflation) and risk of:– Particulate embolization

– Systemic effects

• Paclitaxel tissue residency– Particle solubility

– Presence in tissue during restenotic

cascade7 (duration of retention)

– Homogeneity of distribution

1-20% to tissue

60-70% to distal circulation

Architecture of DCB - Coating

Drug-balloon surface bonding: strong enough to maintain drug integrity during transit while allowing efficient drug transfer:

• Minimal drug loss during transit

• Rapid and efficient drug transfer (<60 seconds)

Granada J. TCT 2009.Byrne, R.A. et al. Nat Rev Cerdiol. 11, 13-23 (2014).

Drug-coated Balloon Coating Characteristics

Polymer matrix coating: drug molecules diffuse through a matrix

Porous coating: drug molecules diffuse through pores

Resorbable polymer matrix

coating:

drug molecules are encapsulated in the

polymer and are released with resorption

Surface deposition: imprinting of the drug on the balloon surface

Paclitaxel Formulation Types

Amorphous CoatingCrystalline Coating

Crystalline Amorphous

Particles Released +++ ++

Uniform Coating ++ +++

Drug Transfer to Vessel +++ +++

Drug Retention vs. Time +++ +

Biological Effectiveness +++ ++

Vascular Toxicity +++ ++

Impact on Biological Performance

Coating techniques - evolution

Coating integrity

Paclitaxel vessel uptake

Simulated shake test

Coating Integrity: Adherence During Hydration

DCBs were submerged in phosphate buffered saline at 37°C and the coating was imaged at 300X. Data on file – Boston Scientific. Bench test results are not necessarily indicative of clinical performance.

3 min 10 minT = 0 min

Coating remained

adhered to the

balloon during

hydration

Balloon A

Coating

Balloon B

Coating

Coating started to

crack and flake off

after a few minutes

of hydration

Loss of particles during transfer

Gongora CA, et al. J of Am Coll Cardio:Cardiovasc Intv. July 2015.

• DCBs were delivered in a peripheral track model with fluid recirculation

• Particulates lost downstream were collected with a 5 µm polycarbonate filter and are shown as green dots

Vascular changes in downstream skeletal

muscle arteries

Lutonix 3x at 90 days

In.Pact 3x at 90 days

Kolodgie, JVIR 2016

No difference after 1 inflation; Difference after 3 inflations

Effect of embolisation on wound healing

Courtesy J. Granada

Excipient

Supports the uptake of drug by vessel tissue➢ Acts as a molecular spacer to increase paclitaxel surface exposure

➢ Facilitates paclitaxel transfer through its hydrophylic properties

Scheller et al. Circulation 2004;110:810 - 4

DCB- porcine restenosis study Excipient facilitates tissue transfer

Different excipients – different properties

PTX adherence to balloon

Iopromide versus urea coating

What happens in vessel wall?

▪ Transfer of paclitaxel into the tissue and “storage” in the tissue occurs in the “solid phase”.

▪ Afterwards “solid phase” paclitaxel is slowly dissoluted.

▪ Transition from solid-phase to soluble-phase occurs at different rates

▪ At 24 hours, IN.PACT™ Admiral™ DCB retains more drug in solid-phase than Lutonix™* 035

Sustained Drug Availability

Higher percentage of solid-phase drug is associated with higher drug

tissue concentration through 90 days.

IN.PACT™

Admiral™ DCB

Lutonix™* 035

DCB

1.Data on file with Medtronic; Study PS747.

2.Virmani R, “Arterial wall response to drug-coated balloon use” presented at Charing Cross, London 2016.

Clinical evidence

10 FIH trials with DCB: Treatment effect

1. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwälder U, Beregi JP, Claussen CD, Oldenburg A, Scheller B, Speck U. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008 Feb 14;358(7):689-99

2. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hosten N, Hamm B, Speck U, Ricke J. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial.

Circulation. 2008 Sep 23;118(13):1358-65

3. Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, Tepe G, Naisbitt S, Rosenfield K. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human

randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014 Jan;7(1):10-9

4. Scheinert D, Schulte KL, Zeller T, Lammer J, Tepe G. Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient: twelve-month results from the BIOLUX P-I randomized trial. J Endovasc Ther. 2015 Feb;22(1):14-21

5. Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, Eschenbach G, Hartmann H, Lange C, Schnorr B, Stiepani H, Zoccai GB, Hänninen EL. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the

randomized PACIFIER trial. Circ Cardiovasc Interv. 2012 Dec;5(6):831-40

6. D.Scheinert - Advance 18 PTX Study - LINC 2013 oral presentation

7. Schroeder H, Meyer DR, Lux B, Ruecker F, Martorana M, Duda S. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study. Catheter Cardiovasc Interv.

2015 Aug;86(2):278-86

8. T.Albrecht – Preliminary angiographic and clinical 6-month results of the CONSEQUENT trial - LINC 2016 oral presentation

9. W.Guo - AcoArt I First Prospective, Randomized, Multicenter Clinical Trial for the Use of the Orchid DCB in Femoropopliteal Artery Disease - LINC 2016 oral presentation

Difference in clinical evidence

3 DCBs

- approved by FDA

- characterized by robust level 1 Clinical Evidence beyond FIH

3 DCBs supported by Level 1 Evidence

IN.PACT SFA [1] LEVANT 2 [2]

ILLUMENATE

EU RCT [3]

ILLUMENATE

US Pivotal [4]

Study Device (DCB) In.Pact Lutonix Stellarex Stellarex

N Patients 331 476 328 300

Control PTA with provisional Stenting

Population / Vessel RC 2-3-4 / fem-pop

ObjectiveDemonstrate safety and efficacy of DCB vs. standard PTA for the

treatment of fem-pop arterial disease

Primary Safety EndpointFreedom from 30-day death and from 12-month major adverse events

(i.e. death, amputation, clinically-driven TLR or TVR)*

Primary Efficacy Endpoint 12-month Primary patency*

1. Tepe G et al. IN.PACT SFA Trial Investigators.. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015

2. K.Rosenfield et al. Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. N Engl J Med 2015

3. Schroeder H et al. Low-dose Paclitaxel-coated Versus Uncoated Percutaneous Transluminal Balloon Angioplasty for Femoropopliteal Peripheral Artery Disease: 1-year Results of the ILLUMENATE European Randomized Clinical Trial. Circulation. 2017 Apr 19. pii: CIRCULATIONAHA.116.026493

4. Krishnan P et al. Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease: Twelve-Month Outcomes From the Randomized ILLUMENATE Pivotal and Pharmacokinetic Studies. Circulation. 2017 Sep 19;136(12):1102-1113

Outcomes: 1-year Primary Patency

1. French National Commission of Medical Device Evaluation on IN.PACT SFA (May, 3rd 2016) - http://www.has-sante.fr/portail/jcms/c_2635037/fr/in-pact-admiral

2. K.Rosenfield et al. Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. N Engl J Med 2015

3. Schroeder H et al. Low-dose Paclitaxel-coated Versus Uncoated Percutaneous Transluminal Balloon Angioplasty for Femoropopliteal Peripheral Artery Disease: 1-year Results of the

ILLUMENATE European Randomized Clinical Trial. Circulation. 2017 Apr 19. pii: CIRCULATIONAHA.116.026493

4. Krishnan P et al. Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease: Twelve-Month Outcomes From the Randomized ILLUMENATE Pivotal and

Pharmacokinetic Studies. Circulation. 2017 Sep 19;136(12):1102-1113

Core-lab adjudicated* Primary Patency

p<0.001 p<0.001 p<0.001 p<0.002

Duplex derived Primary Patency based on PSVR ≤2.4 (● ) or ≤2.5 (○ ). KM survival estimates at 360 (†) or 365 (‡) days.

* VascCore Core laboratory - Boston, MA, USA)

Stellarex (ptx 2 µg/mm2)

In.Pact (ptx 3.5 µg/mm2)

Lutonix (ptx 2 µg/mm2)

Outcomes: 1-year clinically driven TLR

1. French National Commission of Medical Device Evaluation on IN.PACT SFA (May, 3rd 2016) - http://www.has-sante.fr/portail/jcms/c_2635037/fr/in-pact-admiral

2. K.Rosenfield et al. Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. N Engl J Med 2015

3. Schroeder H et al. Low-dose Paclitaxel-coated Versus Uncoated Percutaneous Transluminal Balloon Angioplasty for Femoropopliteal Peripheral Artery Disease: 1-year Results of the

ILLUMENATE European Randomized Clinical Trial. Circulation. 2017 Apr 19. pii: CIRCULATIONAHA.116.026493

4. Krishnan P et al. Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease: Twelve-Month Outcomes From the Randomized ILLUMENATE Pivotal and

Pharmacokinetic Studies. Circulation. 2017 Sep 19;136(12):1102-1113

CEC adjudicated clinically driven TLR

p=0.014 p=0.023p=0.21p<0.001

Calculated through the end of the 1-year follow up window

Stellarex (ptx 2 µg/mm2)

In.Pact (ptx 3.5 µg/mm2)

Lutonix (ptx 2 µg/mm2)

Beyond 1 year: Primary Patency

Core lab adjudicated Duplex derived Primary Patency*

• Schroeder H et al. Low-dose Paclitaxel-coated Versus Uncoated Percutaneous Transluminal Balloon Angioplasty for Femoropopliteal Peripheral Artery Disease: 1-year Results of the ILLUMENATE European Randomized Clinical Trial. Circulation. 2017 Apr 19. pii: CIRCULATIONAHA.116.026493

• Rosenfield K, et al. The New England journal of medicine. 2015;373:145-53• Laurich C. Oral Presentation. SVS. 2015• Krishnan P. Drug-Coated Balloons Show Superior Three-Year Outcomes vs Angioplasty: Results from the IN.PACT SFA Randomized Trial. Oral Presentation at VIVA 2016; September 19-22,2016; Las Vegas, NV• Jaff M. Drug-coated Balloon Treatment for Patients with Intermittent Claudication: Insights from the IN.PACT Global Full Clinical Cohort. (Updated data from IN.PACT SFA presented on slide 12) Oral Presentation at:

VIVA 2016; September 19-22,2016; Las Vegas, NV• M.Brodmann - ILLUMENATE European Randomized Trial: 2-Year Results – oral presentation, VIVA 2017

Stellarex 3-year

data pending

Lutonix 3-year

data not yet

reported

* KM estimates at nominal 1-year time-points

Peripheral Drug-Coated Balloons

IN.PACT

Admiral

Medtronic

LutonixTM

Bard

Stellarex™

Spectranetics

Ranger™

Boston

Scientific

Product Image

Paclitaxel Dose 3 µg/mm2 2 µg/mm2 2 μg/mm2 2 µg/mm2

Coating

Technology

FreePac™ hydrophilic

coating

(excipient: urea)

Proprietary hydrophilic

nonpolymeric carrier

EnduraCoat™ coating

(excipient: Poly-ethylene

Glycol)

TransPax coating

(excipient: Citrate ester)

Guidewire

Compatibility0.035 OTW 0.035 OTW 0.035 OTW 0.14/0.18

MatrixSFA: 4-7 mm; 40-120 mm

BTK: Recalled

SFA: 4-6 mm; 40-100 mm

SFA: 4-6 mm;40-120 mm

SFA: 4-8 mm;30-200 mm

BTK: 2-4 mm; up to 150 mm

CE Mark ✓ ✓ ✓ ✓

FDA Approval ✓ ✓ ✓

Conclusion

➢ DCB is a fastly growing market with a lot of interested

companies

➢ Many DCB’s have shown some treatment effect

➢ DCB is more than just a balloon: drug dose, drug

formulation, balloon surface, coating proces, excipient all

have their influence on drug availability in vessel wall,

efficacy and results.

➢ 3 DCB’s have completed all relevant regulatory

procedures. They differ in properties and results