Embozene TANDEM (Microspheres for Embolization) · PRODUCT INFORMATION 4 •Embozene TANDEM...

Embozene TANDEM™

(Microspheres for Embolization)

1

PRODUCT INFORMATION

2

Embozene® Color-Advanced Microspheres

• Precise size calibration

• Structural integrity and compressibility

• Stable suspension

• Biocompatibility

PRODUCT INFORMATION

3

Polyzene®-F Shell

Hydrogel core

Polyzene®-F shell: highly biocompatible

ultrapure

high-molecular weight

Hydrogel core: flexible and compressible

hydrophilic

crosslinked methacrylate polymer

PRODUCT INFORMATION

4

• Embozene TANDEM Microspheres for Embolization combine the precision

and ease of use customers have always appreciated in Embozene®

Microspheres with full integration of drugs*.

• Due to the design characteristics, Embozene TANDEM Microspheres may

be loaded with up to 50 mg/ml microspheres:

– Doxorubicin-HCI for local, controlled, sustained dose elution to targeted

tumor sites such as hepatocellular carcinoma (HCC) after

embolization.

– Irinotecan-HCI for local, controlled, sustained dose elution to targeted

tumor sites such as metastatic colorectal cancer (mCRC) after

embolization.

* Embozene TANDEM microspheres are indicated for embolization according to the IFU. They may be loaded with a drug to

elute a local, controlled, sustained dose of said drug to targeted tumor sites after embolization. Loading of drug should be

under a physician’s direction, choice and responsibility, based on type and dose of drug most beneficial to the patient.

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[Dox]+

or [Iri]+

Doxo-

rubicin

Irino-

tecan or

DRUG-LOADING AND RELEASING MECHANISM

Ion-exchange mechanism

DEB-TACE

non-ionic CA drug releasing via ion exchange

PRODUCT INFORMATION

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Microsphere Doxorubicin Irinotecan Others Pt-drugs Others

TANDEM™

?

DC Bead®

?

DC Bead®M1

?

HepaSphere®

( ) ?

Indicated for use

Not indicated for use; drug may load

Not indicated for use; drug may not load (no known data)

Positively charged No charge

DRUG-ELUTING MICROSPHERES

Advantages

• Higher potential for standarized procedure versus cTACE1

• cTACE improves survival compared to BSC2

• Reduced systemic exposure to Doxorubicin versus cTACE3

• Reduced liver toxicity versus cTACE4

• Reduced drug-related side effects versus cTACE4

• Higher objective response for more advanced disease4

• Higher degree of necrosis5 and longer time-to-progression6 versus TAE

• Reduced systemic exposure to Irinotecan, higher and prolonged

tumor drug concentration, and higher necrosis versus IA and IV7

• Improved survival versus FOLFIRI8

Limitation

• Survival benefit for treatment of HCC9

1. Lewis 2012

2. Llovet 2002, Lo 2002, Cammà 2002,

Llovet 2003.

3. Varela 2007, Hong 2006, Gupta 2011, van

Mahlenstein 2011

4. Lammer 2010

5. Lewis 2006, Nicolini 2010

6. Malagari 2010

7. Rao 2012

8. Aliberti 2011

9. Lammer 2010 vs Dhanasekaran 2010

DRUG-ELUTING MICROSPHERES TREND TO SMALLER SIZE

Advantages of small over large microspheres

• Better/deeper tumor penetration1,3

• Higher degree of necrosis2

• Improved drug coverage3

1. Lee 2008, Bonomo 2010; 2. Pelage 2002, Namur 2010; 3. Dreher 2012.

→ next step: small, tightly size-calibrated drug eluting microsphere (≤ 100 µm)

close bandwidth calibrated particles large bandwidth calibrated particles

wide size range close size range

Slide from Prof. Orsi (Milan, Italy)

Embozene

PRODUCT INFORMATION

• TANDEM Microspheres Reference Numbers:

10

Size 2mL Syringe 3mL Syringe

40 ± 10 µm 10420-TS0 10430-TS0

75 ± 15 µm 10720-TS0 10730-TS0

100 ± 25 µm 11020-TS0 11030-TS0

To order Embozene TANDEM, please contact your local CeloNova representative,

or visit www.celonova.com

Embozene TANDEM is not currently available in the US.

• Use only non-ionic contrast

agent

• Use 4 to 5 mls of contrast per 1 ml

of TANDEM microspheres:

– 2 ml TANDEM syringe: 8 – 10

mls of contrast agent

– 3 ml TANDEM syringe: 12 – 15

mls of contrast agent

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Contrast agent strategy

Type Brand Name(s)

Lodixanol - Visipaque

Lohexol - Accupaque

- Omnipaque

Lopamidol - Loparimo

- Isovue

- Solutrast

Lopromide - Ultravist

Loversol - Optiject

- Optiray

DRUG-LOADING PROCEDURE

• Easier drug-loading procedure

• High drug-loading efficiency

1. 2. 3. 4.

Remove excess of

transport solution

Doxorubicin

(powder);

dilute with WFI

to get 20 mg/ml

Shake

according

to IFU

(at least every

5 mins for

the first 20 mins)

Aspire Doxorubicin

solution (20 mg/ml)

Remove excess of

transport solution

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[left] 1 ml Embozene TANDEM™ (75 µm) loaded

with 50 mg doxorubicin (picture taken after 2 h);

[right] 3 ml Embozene TANDEM™ 100 µm loaded

with 150 mg doxorubicin in total (2nd patient, May

4th 2012).

DRUG-LOADING PROCEDURE 2 ml TANDEM™ 100 µm

+ 100 mg Doxorubicin

0.5 h

2 h

1 h

WC IFU

DRUG-LOADING TIMES

Bead size Doxorubicin

Concentration [mg/ml]

Loading Time

[min]

Loaded Drug

[%]

Post-Loading Size Change

[%]

TANDEM™ 40 µm 50 60 98 ± 2 ≤ 5

TANDEM™ 75 µm 50 60 98 ± 2 ≤ 5

TANDEM™ 100 µm 50 60 98 ± 2 ≤ 5

Competitor (100-300 µm) 37.5 60 98 ± 3 ≤ 20*

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Loading of Doxorubicin

Bead size Irinotecan

Concentration [mg/ml]

Loading Time

[min]

Loaded Drug

[%]

Post-Loading Size Change

[%]

TANDEM™ 40 µm 50 30 98 ± 2 ≤ 5

TANDEM™ 75 µm 50 30 98 ± 2 ≤ 5

TANDEM™ 100 µm 50 30 98 ± 2 ≤ 5

Competitor (100-300 µm) 50 120 98 ± 3 ≤ 30

Competitor (70-150 µm) 50 120 98 ± 3 ≤ 30

Loading of Irinotecan

Tables represent typical measured values, not specifications

* for 25 mg/ml

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TANDEM™: TIGHT CALIBRATION AND SIZE STABILITY

Figures represent typical measured values, not specifications

0%

1%

2%

3%

0 50 100 150 200 250 300 350

Rela

tive p

art

icle

count

Size [µm]

0%

1%

2%

3%

4%

0 25 50 75 100 125 150 175 200

Size [µm]

unloaded

doxorubicin

irinotecan

unloaded

irinotecan unloaded

doxorubicin

irinotecan

0%

2%

4%

6%

8%

0 25 50 75 100 125 150 175 200

Size [µm]

40 µm 75 µm 100 µm

Competitor (100 – 300 µm) Embozene TANDEM™ Competitor (70 – 150 µm)

European Oncology & Haematology, 2012 (in press)

Microsphere Doxorubicin [mg/ml

microspheres]

Irinotecan [mg/ml

microspheres]

Embozene TANDEM™ 50 50

Competitor (100-300 µm) 37.5 50

Competitor (70-150 µm) - 50

SIZE STABILITY MATTERS

Model assumptions

• Packing density identical for unloaded and drug-loaded microspheres

• All microspheres have uniform size

5

ml

6

ml

3

ml

Embozene TANDEM™

4

ml

Unstable microspheres

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35 40

Vo

lum

e [

%]

Size decrease [%]

Total volume reduction due to size decrease during drug-loading

Theoretical calculation

0

10

20

30

40

50

0 20 40 60 80 100 120 140

Nu

mb

er

of

mic

ros

ph

ere

s [

10

6]

Microsphere size [µm]

Number of microspheres per ml in correlation to their size

Packing density 70%

Microsphere Microspheres

per ml [106]

Embozene TANDEM™ 40 µm 21

Embozene TANDEM™ 75 µm 4

Embozene TANDEM™ 100 µm 1.7

Competitor (100-300 µm) 0.1*

Competitor (70-150 µm) 0.65*

Typical measured values, not specifications

NUMBER OF MICROSPHERES

*from competitors homepage

DRUG-RELEASE TIMES

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Release of Irinotecan


Release profiles of Irinotecan-loaded DEB (50 mg/ml microspheres); release monitored in process via UV-VIS

spectroscopy at 37°C in SOTAX CE-1 elution system using isotonic medium, 5 ml/min flow rate.

Microsphere t75% [min]

Embozene TANDEM™

(40 µm) 67

Embozene TANDEM™

(75 µm) 49

Embozene TANDEM™

(100 µm) 60

Competitor

(100-300 µm) 9

Competitor

(70-150 µm) 9

European Oncology & Haematology, 2012 (in press)

75%

Embozene TANDEM™ (40 µm)



Competitor (70-150 µm)

Competitor (100 – 300 µm)

DRUG-RELEASE TIMES

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Release of Irinotecan

Bead size Irinotecan Concentration

[mg/ml]

Time to release

25 mg Irinotecan [h]

TANDEM™ 40 µm 49 ± 1 1

TANDEM™ 75 µm 49 ± 1 0.5

TANDEM™ 100 µm 49 ± 1 0.5

Competitor (100-300 µm) 49 ± 1.5 0.1

Competitor (70-150 µm) 49 ± 1.5 0.1


DRUG-RELEASE TIMES

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Bead size Doxorubicin Concentration

[mg/ml]

Time to Release

10 mg Doxorubicin [h]

TANDEM™ 40 µm 49 ± 1 3

TANDEM™ 75 µm 49 ± 1 3

TANDEM™ 100 µm 49 ± 1 3

Competitor (100-300 µm) 36.5 ± 1.5 1.5

Competitor (500-700 µm) 36.5 ± 1.5 8.5

Release of Doxorubicin

Small drug-eluting microspheres cause higher degree of necrosis1,2,4

Large drug-eluting microspheres release slower1,3

Large drug-eluting microspheres cause lower systemic drug levels1

Large drug-eluting microspheres cause higher drug tissue concentration4

Embozene TANDEM combines benefits of

small microspheres with slower drug release.

1. Lewis 2006; 2. Nicolini 2010; 3. Gonzales 2008, Taylor 2008, Tang 2008; 4. Namur 2010

TANDEM VERSUS COMPETITION

TANDEM DC BEAD®

Sizes 40 ± 10 µm

75 ± 15 µm

100 ± 25µm

100 – 300 µm

70 – 150 µm (DC Bead®M1)

Volumes 2 ml pre-filled syringe

3 ml pre-filled syringe

2 ml vial

Doxorubicin loading capacity 50 mg / ml 37.5 mg / ml

Doxorubicin loading time 98% in 60 minutes 98% in 60minutes

Size change after loading

doxorubicin

˂ 5% ≤ 20%

Irinotecan loading capacity 50 mg / ml 50 mg / ml

Irinotecan loading time 98% in 30 minutes 98% in ≥ 120 minutes

Size change after loading

irinotecan

˂ 5% ≤ 30%

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TANDEM VERSUS COMPETITION

Irinotecan T75 %

[min]

Time to release 10 mg of

Doxorubicin

TANDEM 40 µm 67 3

TANDEM 70 µm 49 3

TANDEM 100 µm 60 3

Competition 100 – 300 µm 9 1.5

Competition 70 – 150 µm 9 8.5

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TANDEM releases Irinotecan 5x to 8x slower than competitive product

TANDEM PRICING

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Because of the higher drug loading capacity and the offering of 3 ml syringes,

TANDEM will be more cost efficient for the hospital.

Example: a patient needs a dose of 150 mg of Doxorubicin

- TANDEM loads the drug faster, saving time and money

- TANDEM is capable of delivering 150 mg with one 3 ml syringe

- TANDEM can load 33% more drug in a 2 ml syringe

Competition TANDEM

Maximum drug loading capacity

per 2 ml vial or syringe 75 mg 100 mg


per 3 ml vial or syringe N/A 150 mg


per 4 ml vial or syringe 150 mg (need 2 x 2 ml vials) N/A

TANDEM KEY FEATURES

• Can load doxorubicin and irinotecan faster and easier

– Save time for the pharmacy (up to 90 minutes for loading irinotecan)

• Can load more drugs: up to 50 mg/ml microspheres

– Load 150 mg of drug in one 3 ml syringe

• Drugs release slower

– May reduce systemic side effects

• Microspheres do not change in size after drug loading

– Easy passage through microcatheters

– Ideal for targeted drug delivery near the tumor site

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VALUE PROPOSITION

TANDEM Microspheres are cost efficient and beneficial for:

• The Hospital:

– Capable of delivering drugs up to 150 mg with one 3 ml syringe

– Capable of delivering more drugs with a 2 ml syringe

• The Pharmacy:

– Easier drug loading, which saves time (up to 90 minutes faster for irinotecan)

• The Physician:

– Choice between 2 ml and 3 ml volumes (no need to use multiple vials or syringes

during the same procedure)

– Ease of use (better fit through microcatheters)

– Targeted embolizations (Tight calibration, less size changes after drug loading)

• The Patient

– TANDEM Microspheres have a slower and more controlled drug release, which may

result in fewer systemic effects and providing a higher level of patient care

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TANDEM™ POSITIONING

Precision

• Targeted drug delivery with tightly calibrated microspheres and super-

selective TACE

• Controlled and precise drug delivery and release at tumor site

• Microsphere size remains stable during drug loading and storage: typical

size change less than 5%

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TANDEM™ 40 µm TANDEM™ 75 µm

TANDEM™ 100 µm

TANDEM: TIGHT CALIBRATION AND SIZE STABILITY

Scale bar: 100 µm

Competitor (100 – 300 µm)

→ Tight size-calibration decreases risk

of premature vessel occlusion

TANDEM POSITIONING

Efficiency

• Deliver up to 150 mg of Doxorubicin-HCl or Irinotecan-HCl with one 3 ml

syringe

• Fast drug loading times with superior drug loading capacity up to 50 mg/ml

microspheres

• Controlled drug release rates for optimal localized drug delivery

Flexibility

• Available in three sizes (40 µm, 75 µm and 100 µm)

• Available in two volumes (2 ml & 3 ml syringes)

• Ideal for passage through micro catheters

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TANDEM POSITIONING

Safety

• Color coded labels for easy recognition of microsphere sizes

• Slow and controlled drug release times may result in fewer systemic side

effects

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TANDEM TARGETING

DC BEAD ACCOUNTS

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DEB MARKET POTENTIAL

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USD 2010 2011 2012 2013 2014 2015

US $13,046,784 $15,311,520 $17,930,400 $20,779,104 $24,226,816 $28,345,375

growth 17% 17% 16% 17% 17%

EU $10,820,267 $13,904,691 $16,727,242 $19,088,559 $21,430,719 $23,906,395

growth 29% 20% 14% 12% 12%

ROW $5,966,763 $7,304,053 $8,664,410 $9,966,916 $11,414,384 $13,062,942

growth 22% 19% 15% 15% 14%

TOTAL $29,835,823 $36,522,275 $43,324,064 $49,836,592 $57,073,933 $65,316,728

growth 22% 19% 15% 15% 14%

DEB MARKET SHARES

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Market share (%) Europe US

Biocompatibles 78% 90%

Merit Medical 22% 10%

Strengths:

• CeloNova has good relationships with interventional radiologists

• Trust and credibility of the sales force

• TANDEM microspheres can load more drugs and load faster than competition

• TANDEM microspheres allow physicians to give maximum drug dose to patients with one syringe

• TANDEM microspheres are tightly calibrated and do not change in size (<5%) after drug loading

Weaknesses:

• Lack of animal study data

• Lack of clinical data to support

reimbursement strategies

• Lack of relationships with

oncologists

• Limited sales force

• Limited publications about product

performance

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SWOT ANALYSIS

Opportunities:

• Develop customer testimonials and

use them for clinical updates to bridge

the gap until clinical data is available

• Develop cases studies with new users

• Develop training materials for sales

force, distributors and physicians

• Leverage of current relationships in

hospitals

• Promote drug eluting microspheres as

first line of treatment for HCC and

mCRC

Threats:

• Efficiency of bland microspheres

reduces the need for drug eluting

microspheres

• DC Bead is the market leader and

has a strong clinical compendium

• Other technologies to treat liver

cancer emerge

• TANDEM clinical studies do not

show the expected results

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SWOT Analysis

TANDEM CLINICAL STRATEGY

The following post-market clinical studies are being planned:

• Trial 1: MIRACLE I study

– A prospective pilot, multicenter trial for HCC with 75 µm

doxorubicin loaded TANDEM microspheres

• Trial 2:

– A randomized, multicenter trial for HCC with TANDEM - DOX

versus cTACE (Doxorubicin / Lipiodol, PVA)

• Trial 3:

– A prospective, multicenter mCRC trial with TANDEM – IRI

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CLINICAL STRATEGY

Trial 1: MIRACLE-I Study

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Sponsor CeloNova BioSciences, Inc.

Study Type

Prospective, Pilot, Multicenter Study of DEB-TACE using

Doxorubicin-Loaded 75 µm Embozene Tandem™ Microspheres to

treat HCC

Study Design

Non-Randomized

Efficacy Study

Safety Study Open label

Purpose Interventional Treatment

End Points Primary: Survival, Safety , TTP Secondary: Local Tumor Control, QOL

Principal Investigator TBD

Sites: TBD

Patient Number 25-50

CLINICAL STRATEGY

Trial 2: MIRACLE-II Study

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Study Type Randomized, Multicenter Study of DEB-TACE using 75 µm Embozene Tandem Microspheres versus cTACE to treat HCC

Study Design

Randomized Efficacy Study (Survival) Safety Study Parallel Assignment/Single Blind



Principal Investigator TBD

Sites: TBD


CLINICAL STRATEGY

Trial 3: MIRACLE-III Study

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Study Type Prospective, Multicenter Study of DEB-TACE using 75 µm Embozene Tandem™ Microspheres to treat mCRC

Study Design

Non-Randomized Efficacy Study Safety Study Open label



Principal Investigator Dr Franco Orsi

Sites: Milano, Italy Others to be determined


SUMMARY

Embozene TANDEM offers

• Small sizes

• Tight size calibration

• Size stability

• Fast drug-loading with high loading capacity

• Slow and controlled drug release

Embozene TANDEM is designed to

• Enable super-selective embolization

• Penetrate deeper into the tumor micro-vasculature

• Reduce systemic toxicity

• Improve drug coverage

• Increase tumor kill

Embozene TANDEM (Microspheres for Embolization) · PRODUCT INFORMATION 4 •Embozene TANDEM...

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