Disclosures I am paid to talk about peripheral interventional - - PowerPoint PPT Presentation

4/17/2015 1 Drug Coated Balloons: How they work and what’s the evidence?

Christopher D. Owens, MD, MSc UCSF vascular surgery

Disclosures

• I am paid to talk about peripheral

interventional procedures by Medtronic and BARD

• I am director of a physiology laboratory

working on drug delivery

• I am the PI of drug delivery trials, Mercator

MedSystems

By show of hands, how many people here have used a DCB? How many people have heard a talk on DCBs?

4/17/2015 2

SFA IDE Trial Results: K-M Patency

6 6 83% 82% 81% 77%

50.0% 60.0% 70.0% 80.0% 90.0% 100.0% Zilver PTX Stroll Resilient Durability II

Reported 12 Month Primary Patency K-M

Standard Nitinol Stents

Drug-Coated

Stent Zilver PTX Smart LifeStent EverFlex Patient sample size 236 250 134 287 Diabetics (%) 49 47 38 43

• Avg. lesion length

(cm) 5.4 7.7 7.1 8.9 Fracture rate (%) 0.9 1.8 3.1 0.4 Occlusion (%) 27 24 17 48 PSVR 2.0 2.5 2.5 2.0

Months Primary Patency (lesions remaining at risk) Japan PMS (PSVR 2.4) 6 96.7% (535) 12 84.8% (469)

Primary Patency by Duplex Ultrasound of Japan Single Arm Study

Primary patency rate is 84.8% through 12 months in the Japan PMS

Months Primary Patency (lesions remaining at risk) Japan PMS (PSVR 2.4) 6 96.7% (535) 12 84.8% (469) Patency was assessed by ultrasound when it was standard of care and is reported for 58% of patients. There were no significant differences in demographics, lesion characteristics, TLR rate, or thrombosis rate compared to patients without ultrasound.

84.8%

4/17/2015 3

Similarity between Zilver PTX and DCB

How do we know if drugs do anything on devices? The biologic effect of a DES

is measured in the proliferative phase of intimal hyperplasia – the steep part of the slope.

Balloon angioplasty

Zilver PTX BARD DCB Medtronic DCB Resilient ASTRON FAST BASIL SURGERY VIBRANT 67% restenosis Tigris

In the beginning there was balloons: Geometry of

Claudication interventional RCTs

How they work?

4/17/2015 4

DCB technology overview

Inpact Admiral

• Invatec Admiral
• PTX 3.5 µg/mm2
• Urea

Lutonix

• Lutonix Balloon
• PTX 2 µg/mm2
• Polysorbate/sorbitol

G0

Cell prepares for mitosis DNA synthesis Mitosis Protein synthesis.

Cell prepares for mitosis DNA synthesis Mitosis Protein synthesis

Anti-Proliferative Agent Review

Paclitaxel (Cytotoxic)

Interferes with cell division

Rapamycin (Cytostatic)

Interferes with cell growth

Replication prep Growth Factor mTOR

Sirolimus (rapamycin) Paclitaxel

DCB mechanism of action facilitates the transfer of PTX deep into vessel tissue

DCB matrix coating:

• Paclitaxel
• Urea - excipient that

controls drug release DCB inflation:

• Matrix coating contact

with the blood

• Urea hydrates causing the

release of paclitaxel

• Paclitaxel binds to the wall

due to its hydrophobic and lipophilic properties Paclitaxel penetration:

• Through vessel wall deep into

the media and adventitia

• Interferes with the causes of

restenosis

• Can remain in the vessel wall

for over 60 days at therapeutic levels1

• Paclitaxel is approximately 200,000 times less water soluble than

heparin

• Partitiions into vessel wall rather than blood stream (Creel CJ Circ

Res 2000; 86:879-84

• Enhances cellular uptake and retention for prolonged anti-restenosis

effect (Axel D Circulation 1997; 96:636-45)

• PTX MW = 853 g/mol; Urea MW = 60 g/mol; Sorbitol C6H14O6 MW =

182 g/mol (stereoisomer of Mannitol); Polysorbate >1000 g/mol

Paclitaxel physicochemical properties

Drug Water Solubility (µg/mL) Lipophilicity (octanol/water partition coefficient Heparin 50,000 10-13 PTX 0.25 103 Comparison 200,000 times 1016

4/17/2015 5

• Detectable levels of drug in tissue over 180 days in both arms (therapy dose and safety margin)

after 48 hours

• Detectable levels of drug in tissue over 180 days in both arms (therapy dose and safety margin)
• At 320 days, no quantifiable drug is identified in the targeted tissue area in nominal dose
• Drug concentration levels in plasma are < 1/10 of that in tissue, drop 50% in 30 minutes, and not detectable

after 48 hours

Can a single balloon inflatation produced sustained drug

• concentrations. Preclinical data supporting safety and long-term

Porcine IleoFemoral Artery Days 200 50 100 150 20 40 60 80 Paclitaxel Concentration (ng/mg) 60 90 120 150 180 0.001 0.01 0.1 1 10 PTX Concentration (ng/mg) EC 50 Paclitaxel Time [Days] Nominal Dose 3X Safety Margin Dose

SAFETY

Paclitaxel crystals are released as excipients hydrates Crystals are embedded into arterial wall and sequestered by tissue Embedded crystals provide extended drug release to surrounding tissue

Histology images show sustained retention of low drug levels for extended neointimal inhibition

Sections shown are stained by Hematoxylin & Eosin (H&E)

• Dose-dependent response up to 2-4

µg/mm2

• Wide, stable therapeutic window with no

statistically significant differences in neointimal inhibition or local toxic effects from 4 up to 10 µg/mm2

• Clinically effective drug levels transfer

within 60 seconds, with no negative clinical effects from longer inflation time

Therapeutic range 2-4 µg/mm2 IN.PACT Admiral: 3.5 µg/mm2

% Inhibition of Neointimal Area 100 90 80 70 60 50 40 30 20 10 2 4 6 8 10 µg Paclitaxel/mm2 Balloon Surface

Paclitaxel offers a wide therapeutic window

• 1. Scheller B, et al. PTX Balloon Coating, a Novel Method for Prevention and Therapy of Restenosis. Circulation. 2004;110:810-814. 2. Speck U, Scheller

B, Abramjuk C, et al. Neointima inhibition: comparison of effectiveness of nonstent-based local drug delivery and a DES in porcine coronary arteries. Radiology. 2006;240:411– 418.

• 3. Cremers B, et al. Comparison of two different PTX-coated balloon catheters in the porcine coronary restenosis model. Clin Res Cardiol. 2009;98:325–

330.

• 4. Cremers B, et al DEB: Very short-term exposure and overlapping. Thromb Haemost. 2009; 101: 201–206. 5. Rowinsky EK, Donehower RC. Paclitaxel

(Taxol). N Engl J Med. 1995;332:1004-1014. 6. Margolis J, McDonald J, Heuser R, et al. Systemic nanoparticle PTX (nab-PTX) for ISR I (SNAPIST-I): A first-in- human safety and dose-finding study. Clin Cardiol. 2007;30:165-170

Paclitaxel therapy / disease Dosing (per course) Duration C max (plasma) IV / Ovarian 1ǂ 135 mg/m2 3 hours 2170 ng/mL IV / Ovarian 1ǂ 175 mg/m2 3 hours 3650 ng/mL IV / NSCLC 1 135 mg/m2 24 hours 195 ng/mL DEB 2/PAD3 4.8 mg/m2 60 sec (DEB inflation) 1.6 ng/mL

In comparison to PTX doses for oncolological treatment, maximum plasma concentration for IN.PACT is under 1/100th

• 1. TAXOL Package Insert BMS Princeton, NJ Rev April 2011
• 2. IN.PACT Admiral 6x120mm (data on file at Medtronic)
• 3. Based upon animal studies (data on file at Medtronic)

ǂ administered q 3 wks. with a median of six courses

4/17/2015 6

What is the evidence? DCB clinical evidence

INPACT ADMIRAL

• RCT
• PTA comparator
• Single blinded
• Randomized following

successful predil.

• 78% primary patency
• Appears safe in

claudication

• Core labs appropriate

LUTONIX

• RCT
• PTA comparator
• Double blinded
• Randomized following

successful predil.

• 74% primary patency
• Appears safe in

claudication

• Core labs appropriate

LEVANT 2 In.Pact SFA

Follow up 30d- 12 mos Blinded Non - Blinded Treatment assignment DCB control DCB control Lesion length (mm)* 6.3 6.4 8.9 8.8 Ca++ (%)** 10.4 8.1 8.1 6.2 Restenosis(%) 16 12 5 5.4 Provisional stenting (%) 2.5 6.9 7.3 12.6

• B. Restenosis

(%) 26 43 18 48 TLR(%) 11 15 2.4 21 73.5% 56.8%%

LEVANT 2 DCB Data

4/17/2015 7

IN.PACT SFA 12-Month Efficacy Outcomes

Clinically-Driven Target Lesion Revascularization (CD-TL Primary Patency Kaplan Meier (All ITT)1

• 1. Primary patency is defined as freedom from clinically-driven TLR and freedom from restenosis as determined by DUS PSVR ≤2.4
• 2. Clinically-driven TLR defined as any re-intervention due to symptoms or drop of ABI/TBI of >20% or >0.15 compared to post-procedure ABI/TBI

Primary Patency Through 390 Days 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 360 Days After Index Procedure 30 60 90 120 150 180 210 240 270 300 330 IN.PACT Admiral DCB PTA (P<0.001 by log-rank test) 66.8% 89.8% 360 10% 0% 5% 15% 20% 25% IN.PACT Admiral DCB CD-TLR at 12 Months PTA P<0.001 2.4% 20.6%

78.4 49.5 390

Summary of current SFA local drug delivery

• Cook, Medtronic, and BARD are to be

congratulated for advancing the science of drug delivery

• Each has made clinically meaningful

improvements for our patients

• Our collective consciousness of how to do

angioplasty has been raised – We are getting better results in our control arms with low bail out stenting

Summary of DCB technology

• It is difficult to compare the 2 programs
• BARD has an excellent safety profile still, there is

embolization with both devices. – My opinion Medtronic has more particles released during transit and BARD may have fewer but larger ones.

• Both programs provided consistent improvement
• ver PTA.
• Differences in CD-TLR may be, in part, due to bias

inherent in the Medtronic trial design.