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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.
5
[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
6
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
11
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
13
[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*
14
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
15
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
18
Release of Irinotecan
Typical measured values, not specifications
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)
Embozene TANDEM™ (75 µm)
Embozene TANDEM™ (100 µm)
Competitor (70-150 µm)
Competitor (100 – 300 µm)
DRUG-RELEASE TIMES
19
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
Typical measured values, not specifications
DRUG-RELEASE TIMES
20
Typical measured values, not specifications
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%
21
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
22
TANDEM releases Irinotecan 5x to 8x slower than competitive product
TANDEM PRICING
23
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
Maximum drug loading capacity
per 3 ml vial or syringe N/A 150 mg
Maximum drug loading capacity
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
24
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
25
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%
26
27
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
28
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
29
TANDEM TARGETING
DC BEAD ACCOUNTS
30
DEB MARKET POTENTIAL
31
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
32
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
33
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
34
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
35
CLINICAL STRATEGY
Trial 1: MIRACLE-I Study
36
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
37
Sponsor CeloNova BioSciences, Inc.
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
Purpose Interventional Treatment
End Points Primary: Survival, Safety , TTP Secondary: Local Tumor Control, QOL
Principal Investigator TBD
Sites: TBD
Patient Number 200-400
CLINICAL STRATEGY
Trial 3: MIRACLE-III Study
38
Sponsor CeloNova BioSciences, Inc.
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
Purpose Interventional Treatment
End Points Primary: Survival, Safety , TTP Secondary: Local Tumor Control, QOL
Principal Investigator Dr Franco Orsi
Sites: Milano, Italy Others to be determined
Patient Number 25-50
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