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