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 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
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
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