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Disclosure
Speaker name: Dr. med. Arne Schwindt
.................................................................................
I have the following potential conflicts of interest to report:
Consulting
Employment in industry
Stockholder of a healthcare company
Owner of a healthcare company
Other(s)
I do not have any potential conflict of interest
X
Drug Coated Balloon outcomes: what part does technology play?
Dr. med. Arne Schwindt St. Franziskus-Hospital
Münster, Germany
Drug Coated Balloons offer physicians an attractive value proposition for the treatment of lower limb
disease
Encouraging results have been seen in de novo, restenotic lesions, in-stent restenosis, & in A-V access stenosis.
Some logical indications might include: “no-stent” zones e.g. CFA lesions segments prone to restenosis e.g. long AK lesions
Benefits Anti-proliferative therapy while leaving nothing behind Broad anatomical applicability Easily repeatable Avoid stent fracture and ISR burden Preserve future options Matches patient’s quality of life expectations (improvement in
walking capacity, Rutherford class
Limitations Not proven in highly calcified lesions majority of RCTs in TASC A and B lesions problem of elastic recoil and dissection is not adressed by DCB When provisional stent is required= higher procedural cost
Inhibition of cell proliferation and migration is required for
at least 2 weeks after balloon inflation
after Ferns et al. Int. J. Exp. Path. 2000; 81: 63–88
DCB has to provide PTX effect for at least 14 days to inhibit migration and proliferation Restenotic cascade after DES is prolonged, hence requiring longer drug effect
Restenotic Cascade
Inflammatory Cells
SMC Proliferation
SMC Migration
ECM
0–2 Days
2–4 Days
4–10 Days 10–14 Days
2–4 Weeks
Platelet Aggregation
Endothelialization
Passeo-18 Lux delivers sufficient drug to give long lasting therapeutic effect
A high tissue concentration is achieved after balloon inflation Drug concentration rapidly declines within 7d Therapeutic effect is sustained beyond 28d Prolonged presence of drug in vessel tissue is important for clinical efficacy
Source: . Data on file at BIOTRONIK AG - SFA Porcine model
Economic impact of Drug Coated Balloons
Per year: DEB c. 90,000 Swiss Fr. less costly than PTA therapy due to lower repeat intervention costs, despite the greater DEB purchase costs
Sources: Zeller. T. LINC 2013, Diehm et al. JEVT 2013;20:819-825, Kearns BC et al. Cost-effectiveness analysis of enhancements to angioplasty for infrainguinal arterial disease. Br J Surg. 2013 Aug;100(9):1180-8
€ 3'200€ 3'400€ 3'600€ 3'800€ 4'000€ 4'200€ 4'400
PTA BMS DES DEB
2yr Comparative Budget Impact: German Healthcare Payers.
Reproduced from Zeller T. LINC 2013
DEB dominated all other options by lower lifetime costs and greater effectiveness DEB represents a cost-effective alternative to PTA with bail-out BMS
BIOTRONIK Cook Eurocor Aachen Resonance BARD Medtronic Boston
Scientific Cardio novum
Device name Passeo-18 LUX Advance PTX Freeway Elutax Lutonix
IN.PACT (Admiral,
Pacific) Ranger Legflow
Paclitaxel Drug
Concentration 3 µg/mm2
2.2 μg/mm² 2 μg/mm² 3.5 μg/mm² 2 μg/mm²
Excipient
peel away insertion aid
Positive randomized data
against PTA
4F compatible *
Sources: company web sites Passeo-18 Lux: BIOLUX P-I. Scheinert et al. JEVT Feb 2015. In Print Freeway: FREERIDE Schulte KL Poster presentation LINC 2014 Lutonix: LEVANT-I. JACC 2014; 7:10-9 InPact Pacific: PACIFIER 12m data CCI. 2012;5:00-00.
* At least 1 or more sizes
Not all DCBs are equal. Not all DCBs are proven.
DCB clinical study results illustrate performance differences
0%
20%
40%
60%
80%
100%
Study Name
Vessels Time-Point
84.3% 88.5%
BIOLUX P-I
SFA 6m BR
BIOLUX P-II BTK
6m TLP
Passeo-18 Lux (3 µg/mm²)
LEVANT I
SFA 6m PP
Lutonix (2 µg/mm²)
82.2% 91.4%
In.PACT I
SFA 12m PP
PACIFIER
SFA 6m BR
In.Pact (3.5 µg/mm²)
65.2%
LEVANT II
SFA 12m PP
77%
Myers NSW
SFA-ISR 27m PP
59%
In.PACT Deep BTK
12m PP
97%
72% 83.7%
In.PACT SFA-IT
SFA 12m PP
What coating technology factors could influence clinical results? • Drug Concentration: 3 - 3.5 µg/mm² vs. 2 µg/mm² • Excipient: Hydrophobic vs. hydrophilic
Coating:
• PTX Drug 3 µg/mm²
• Butyryl-Tri Hexcyl Citrate (BTHC)
Passeo-18 Lux DCB combines proven technologies
SafeGuard Insertion aid
• Improves ease of handling
• Protects the user and balloon from contact and damage
• Ø: 3-7mm
• L: 40-120mm
Passeo-18 Balloon
Platform
Excipients improve tissue uptake of Paclitaxel
0
1000
2000
3000
1 hr 24 hrs 72 hrs
Tissue Concentration
0
1000
2000
3000
4000
5 min 30 min 1 hr 3 hrs 24hrs
Blood Concentration
5 min 30 min 1 hr 3 hrs 24 hrs
3346.7 11.0 6.2 2.4 0.4
712.8 7.6 5.1 3.4 1.8
Non-atherosclerotic Rabbit Iliac Model – 28 days
PTX + Iopromide
PTX Only PTX + Iopromide (SeQuent)
PTX only
DD
Source: Virmani, presented at Linc 2012
ng/m
L
ng/m
L
Excipient Butyryl-Trihexyl Citrate (BTHC)
Common uses of BTHC
Used in medical devices & cosmetics Additive in blood bags to keep the crystalline structure of the plastic malleable Safe: it is approved to be dissolved into the blood and used in the body
Metabolism Quickly metabolized by the body and excreted via urine, bile and expired air¹ Degrades to citric acid and alcohol (n-hexanol¹)
BTHC is hydrophobic and less dissolvable in blood and saline/water used during interventional procedures compared to other common hydrophilic excipients
1 European Commission SCENIHR Report Feb 2008
Characteristics
Lux coating technology uses BTHC excipient Biocompatible, safe and effective
BTHC in the “Lux” formulation allows to balance good coating adhesion to the balloon surface and rapid drug delivery upon vessel contact
BTHC assures micro-crystalline Paclitaxel structure in “Lux” formulation for optimal tissue absorption and retention
“Lux” formulation with BTHC is safe and biocompatible
BTHC fulfills the requirements of an ideal excipient for DCB applications
Coating technology: PTX concentration strongly influences total drug load
0,0
1000,0
2000,0
3000,0
Passeo-18 Lux Lutonix 035 In.Pact Admiral
μg
Drug Content Normalized Surface of a 5x40mm balloon
0,0
1,0
2,0
3,0
4,0
Passeo-18 Lux Lutonix 035 In.Pact Admiral
μg/m
m2
Drug Concentration Label Claim
PTX concentration of 3 μg/mm2 may result in more drug available at the lesion site Safety profile was assessed in animal studies1 and is confirmed in human clinical trials2
Safety and efficacy of 3 μg/mm2 technologies is also supported by long term evidence in coronary and peripheral applications3
3 μg/mm2 2 μg/mm2 3.5 μg/mm2
Source: 1. Data on file at BIOTRONIK AG 2. BIOLUX P-I 12m Scheinert D. presented at TCT 2013; InPact Pacific: PACIFIER 12m data CCI. 2012;5:00-00 3. Tepe et al. THUNDER N Engl J Med 2008; Werk et al. FEMPAC Circulation. 2008; Paccocath 5y Scheller B. J. Am. Coll. Cardiol. Intv. 2012;5;323-330
3 μg/mm2 2 μg/mm2 3.5 μg/mm2
Coating Technology: Excipient behaviour
* In water
Coating characteristics are modified when surface is wetted Hydrophilic excipients are more soluble and degrade faster Hydrophobic excipients are less soluble and have reduced drug loss in physiological
environments
Device Excipient Type Solubility*
Passeo-18 Lux Butyryl-tri-hexyl citrate (BTHC) Hydrophobic Very low
IN.PACT Urea Hydrophilic Fast dissolving
Lutonix Polysorbate/sorbitol Hydrophilic/hydrophobic Fast dissolving
Source: Data on file at BIOTRONIK AG
97.1%
74.2% 88.4%
Simulated use of a 5mm x 40mm DCB in physiological solution at 37°C
Coating technology: Drug loss
Simulated use of a 5mm x 40mm DCB in physiological solution at 37°C
51.5%
87.9%
46.2%
1438 µg
148 µg
1130 µg
Drug loss during track is normal and expected. Drug release at the lesion site mandates coating fragility to ensure coating ‘leaves’ the balloon surface.
However, remaining PTX quantity should be sufficient to have a therapeutic effect. DCBs with 3 μg/mm2 appear to retain higher quantities of PTX after track and inflation
Source: Data on file at BIOTRONIK AG
Coating Technology: influencing clinical outcomes
A correlation between drug availability seen in vitro testing1 and reported clinical data 2,3,4 can be observed
DCBs with higher PTX concentration (3 -3.5 µg/mm2) may create higher drug availability at the lesion site, despite coating losses during track/inflation.
6m Binary Restenosis rates (%)
1438 µg
148 µg
1130 µg
*Study device in Pacifier was Medtronic In.Pact Pacific, which uses the same coating technology as the In.Pact Admiral
. Source: 1. Data on file at BIOTRONIK AG 2. BIOLUX P-I 12m Scheinert D. presented at TCT 2013; 3, InPact Pacific: PACIFIER 12m data CCI. 2012;5:00-00. 4. LEVANT-I: Scheinert et al.: JACC: Cardiovasc Interv. 2014; 7(1): 10-19
Lux in-vivo testing : The quantity of Paclitaxel reaching the lesion was optimal to have a therapeutic effect. Additional drug quantity had no additional effect.
IN-VIVO RESULTS: 6m Follow Up
Source: Data on file at BIOTRONIK AG
Passeo-18 Lux x 2
Passeo-18 Lux x 1
PTA
Single dose: Therapeutic effect evidence- reduced Neointimal-Hyperplasia vs. PTA control
‘Double-dosing’ with second DCB had no additional therapeutic or toxic effect.
Passeo-18 Lux Clinical Program – Evidence Collection
Safe
ty
Perf
orm
ance
Cor
e la
b.
All-
Com
ers
SFA
Popl
iteal
BTK
AV A
cces
s
Cal
c.
Long
lesi
ons
ISR
Vess
el P
rep.
TASC
C&
D
PRO
s
Study Design Study
Scheinert DE
Zeller DE
Tepe DE
Bosiers BE
Terasse CA
Myers AU Robertson AU
Mwipatayi AU
FIM RCT: SFA Passeo-18 Lux vs. PTA 60 subjects
Single-arm, SFA Passeo-18 Lux+Pulsar-18 120 subjects
RCT, AV Fistula Passeo-18 Lux vs. PTA 120 subjects
Single-centre Pulsar-18 +Passeo-18 Lux 100 subjects
All-Comers Registry Passeo-18 Lux 700 subjects
Retrospective Registries Passeo-18 Lux in ISR 55 & 29 subjects
Registries Passeo-18 Lux 100-1000 per Satellite Satellites
JEVT – to be published Feb 2015
JEVT – planned submission Jan 2015
FIM RCT: Infrapopliteal Passeo-18 Lux vs. PTA 72 subjects
BIOLUX P-III All-comers registry
Study Design
DESIGN: Prospective, international, multi-centre, open label, all-comers registry to expand and understand the safety and efficacy data on the Passeo-18 Lux DRB in a real world population with infrainguinal artery disease.
PRINCIPAL INVESTIGATOR: Prof. Gunnar Tepe, Rosenheim (DE)
PRIMARY ENDPOINT: Freedom from clinically-driven TLR within 12 months post-index procedure. SECONDARY ENDPOINTS: (selected) • Freedom from clinically-driven TLR within 24 months post-index procedure • Primary patency at 12 and 24 months • MAE at 6, 12 and 24 months • Quality of Life (QOL) assessment: Pain scale, SF-12, WIQ at 6, 12 and 24 months.
600 patients at ca. 55 clinical sites EU & APAC First patient inclusion: Q4/2014
12 months: freedom from TLR, primary patency, MAE, change in ABI
6 months: MAE, change in ABI, RC
Passeo-18 Lux
24 months: freedom from TLR, primary patency, MAE, change in ABI
Drug loss during in-vitro testing seems to correlate with
reported clinical data DCBs with higher PTX concentration (3 - 3.5 µg/mm2) may
create higher drug availability at the lesion site, despite coating losses during track/inflation. Coating characteristics are modified when DCBs are exposed
to aqueous environments Therefore, due to differences coating technology all DCBs
should be evaluated based on clinical evidence- no class effect can be concluded
CONCLUSIONS
Drug loss during in-vitro testing seems to correlate with
reported clinical data DCBs with higher PTX concentration (3 - 3.5 µg/mm2) may
create higher drug availability at the lesion site, despite coating losses during track/inflation. Coating characteristics are modified when DCBs are exposed
to aqueous environments Therefore, due to differences coating technology all DCBs
should be evaluated based on clinical evidence- no class effect can be concluded
CONCLUSIONS