for team education and training meeting in APAC region

1. Healing Is A Journey
Biodegradable Polymer & Drug : The Correlation in Achieving
Clinical Outcome and Arterial Healing
David Chang
Asia Pacific, Marketing Manager
+886 922 859 982

9. Hey, David
Hold on!
one question here,
what about Strut Thickness
for my patient !!?

10. 10
Strut thickness argument should always be
put in perspective with clinical outcomes
• PCR 2015: It has been discussed that BioMatrix Family of stent has
excellent and impressive long term data which suggests the outcomes
can not be only attributed to strut thickness
• PCR 2015: David Hildick-Smith commented that given the excellent
long term clinical results of LEADERS and e-BioMatrix, strut thickness
is not an issue.
• SORT OUT VIII OCT study showed No statistical difference in one-
month Coronary Stent Healing Index between Synergy™ and
BioMatrix Family ™DES
internal use only

11. 11
SORT OUT VIII OCT study : No statistical difference
was detected in one-month Coronary Stent Healing
Index between Synergy and Biomatrix DES
BioMatrix Family of stent has excellent and
impressive long term data which suggests the
outcomes can not be only attributed to strut
thickness internal use only

13. 13

14. 14
 Higher number of covered struts
 Lower number of unvovered struts

15. 15

16. 16

28. Comparison of 2nd Generation DES
with Durable Polymer and SES
STUDY N FOLLOW-UP RESULTS
EES vs SES
Basket –Prove
STEMI subgroup1
732 pts with
STEMI
2 years
No difference in CV death, or non fatal MI,
no difference in TVR
Excellent
AMI subgroup2 139 pts with AMI 1 year No difference in TLF
SORT-OUT IV
STEMI subgroup3
267 pts with
STEMI
3 years No difference in MACE
XAMI4 625 pts with AMI 3 years
No difference in MACE, Cardiac death,
non-fatal MI, TVR and definite ST
ZES vs SES
ZEST AMI 5 328 pts with
STEMI
1 year
SES better in in-segment LL & restenosis at
8 months
No difference in MACE
1. BASKET PROVE STEMI substudy- Pedersen et al., Improved two-year outcomes of STEMI patients treated with drug-eluting compared with bare-metal stents. Experiences
from the randomized BASKET-PROVE trial, ESC 2011
2. EXCELLENT STEMI substudy - Park, K.W., et al. Everolimus-eluting versus sirolimus-eluting stents in patients undergoing percutaneous coronary intervention: the
EXCELLENT (Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting) randomized trial. J Am Coll Cardiol 58, 1844-1854 (2011).
3. SORT-OUT IV - Jensen et al., SORT OUT IV 3-Year: A Prospective, Randomized Trial of Everolimus-Eluting vs. Sirolimus-Eluting Stents, TCT 2012
4. Hofma et al, Long-term (final) results of the XAMI trial, a multicentre randomised trial to compare first generation sirolimus-eluting stents with second generation everolimus-
eluting stents in acute myocardial infarction, EuroPCR 2013
5. ZEST AMI - Lee, C.W., et al. Comparison of the efficacy and safety of zotarolimus-, sirolimus-, and paclitaxel-eluting stents in patients with
ST-elevation myocardial infarction. Am J Cardiol 104, 1370-1376 (2009).

31. Biolimus A9™ DES has maintained non-inferiority and improved
long-term clinical through 5 years LEADERS trial

32. *P values for superiority
Windecker, S., oral presentation ,TCT 2010
STEMI
1.0
2.0
3.0
%
2.6%
5.1%
0 6 12 18 24 3630
Months
2.6%
5.1%
4.6%
2.6%
3-year HR
0.50 [0.18 to 1.34]
P = 0.16*
0
4.0
Δ2.0% Δ3.5% Δ3.5%
5.0
6.0
High SYNTAX SCORE (>16)
1.0
2.0
3.0
%
2.0%
4.3%
0 6 12 18 24 3630
Months
2.0%
3.8%
2.5%
2.0%
3-year HR
0.46 [0.16 to 1.35]
P = 0.15*
0
4.0
Δ0.5%
Δ1.8%
Δ2.3%
5.0
6.0
Bifurcation
1.0
2.0
3.0
%
1.5%
5.2%
0 6 12 18 24 3630
Months
1.5%
5.2%
3.4%
1.5%
3-year HR
0.28 [0.08 to 1.03]
P = 0.04*
0
4.0
Δ1.9%
Δ3.7% Δ3.7%
5.0
6.0
MultiVessel
2.0
4.0
6.0
%
BES
SES
0 6 12 18 24 3630
Months
3.8%
8.1%8.1%
3.0%
3-year HR
0.45 [0.16 to 1.31]
P = 0.14*
0
8.0
Δ 5.1%
Δ 4.3%
10.0
3.8%
8.1%
Δ 4.3%

33. Patient Oriented Composite Endpoint
(POCE)
Showing 1-year POCE from COMFORTABLE AMI on the left and from EXAMINATION on the right:
•Sabate M et al., Everolimus-eluting stent versus bare-metal stent in ST-segment elevation myocardial infarction (EXAMINATION): 1 year results of a randomized controlled trial, The Lancet Volume
380, Issue 9852, 2012(1482–1490)
•Raeber et al., LBT Euro PCR 2012
COMFORTABLE AMI EXAMINATION
BES is the ONLY DES Reducing Patient Oriented
Composite Endpoint Compared to BMS in STEMI

35. 35

38. Because it is What We Believe In

40. Adapted from: Clark RA, In: Goldsmith, LA, ed. Physiology, biochemistry and molecular
biology of the skin, 2nd Edition, Volume 1 (Oxford University Press; New York, 1991); p 577.
Phases of wound healing
ECM: Extracellular matrix
Maximumresponse
II Inflammatory phase
III Proliferative phase
IV Remodeling
IHaemostasis
VMaturation
Alterations in one or more of these phases could results in
chronic wounds
• ECM formation: fibroplasia, synthesis
of collagen, adhesive glycoproteins and
proteoglycans
• Angiogenesis and granulation tissue
formation
• Re-endothelialisation
• Further synthesis of ECM, degradation
and remodeling
•Coagulation
•Plateletactivation
• Neutrophils
• Phagocytosis
• Macrophages
• Lymphocytes
Days after wounding (log scale)
0.1 0.3 1 3 10 30 100 300
Cytokines and growth factors

41. Does healing always occur at the same rate?
NO. Numerous factors can influence the healing process.1–4 For this reason, it’s
not often possible to reliably predict how quickly a particular wound might take to
heal.
Particular types of patients may be slower healer than others. Factors that may slow
wound healing include the presence of:1–4
• More severe CAD
• Chronic disease (e.g. diabetes)
• Immunocompromising
conditions
• Older age
• Certain concomitant medications
• Poor nutritional status
• Obesity
• Smoking, alcoholism and stress

45. What do we mean by ‘local bioavailability’?
• Local bioavailability is the extent and rate to which a substance (active moiety) is
locally delivered from the drug product (device) and becomes available locally.1
• Availability to local sites of action is a function of: 1
– Release factors (release profile)
– Absorption across tissue (vessel wall)
– Rate of elimination from tissue
• Key product quality characteristics1
– Release profile
– Dosage
• Bioavailability can be impacted by formulation1

48. A closer look at biodegradable polymer-coated stents
An ideal biodegradable polymer:1
 Should not elicit an inflammatory or toxic response
 Should be compatible with the drug it is intended to carry throughout the degradation cycle
 Should degrade at a rate that will help to optimize drug delivery
 Degradants should be easily processed and eliminated from the body

49. *Lactate is used as an efficient source of energy in cellular metabolism
TCA: Tricarboxylic acid cycle.
Biodegradation pathways: Common polymers 1–7
Polymer
Component monomers or
Polymer repeating unit
Intermediate Products Final products
PLA Lactic acid or Lactide
Lactic acid 
Lactate*  TCA H2O + CO2
PLGA
Lactic acid or Lactide
Lactic Acid 
Lactate*  TCA H2O + CO2
Glycolic acid or
Glycolide
Glycolic Acid
 TCA
 Uri
ne
H2O + CO2
& can be excreted in
urine
PGA
Glycolic acid or
Glycolide
Glycolic Acid
 TCA
 Uri
ne
H2O + CO2
& can be excreted in
urine

50. Some key points on lactic acid and lactate
• Lactic Acid exists in two forms: D and L chiral forms1
– Both D- and L-lactic acid have been found to naturally occur in mammals
– Although L-lactic acid is more prevalent, studies have shown that both D & L-lactic acid are
efficiently metabolized in mammals
• Lactate plays a key role in:
– cellular, regional and whole body metabolism 1
– normal wound healing processes 1,2
 Has both aerobic and anaerobic activity
 Enhances cellular repair
 Enhances Vascular Endothelial Growth Factor (VEGF) production by macrophages

51. Many factors can influence polymer degradation and, in turn, the drug
elution characteristics of a particular stent:1–5
• Composition (e.g. PLA, PGA, ratio of PLA to PGA in co-polymers)
• Molecular weight & molecular weight distribution
• Morphology (e.g. degree of crystallinity, amorphousness)
• Coating characteristics (abluminal coatings vs entire stent coating)
• Metabolic activity at the treatment site (i.e. may depend on wound healing
characteristics of individual patients)
Not all biodegradable polymers are the same
NO TWO BRANDS ARE THE SAME!

52. How do drug elution & polymer degradation profiles compare?
Presented at TCT 2012
The SYNERGY™ stent is an investigational device in the US and Japan and not for sale.
Time (Months)
15
SYNERGY (PLGA)
ELIXIR DESYNE BD (PLA)
FIREHAWK (PLA)
BIOMATRIX (PLA)
ORSIRO (PLA)
BVS (PLA)
100 5 20 25 30
3
6
3
3
6
1
≤
4
>24
9
9
6-
9
1
5
Drug
Polymer
ULTIMASTER (PDLLA-PCL) 3-
4
3-
4

54. A closer look at this ‘healing cascade’
Adapted from: Clark RA, In: Goldsmith, LA, ed. Physiology, biochemistry and molecular
biology of the skin, 2nd Edition, Volume 1 (Oxford University Press; New York, 1991); p 577.
Phases of wound healing
ECM: Extracellular matrix
Maximumresponse
II Inflammatory phase
III Proliferative phase
IV Remodeling
IHaemostasis
VMaturation
Alterations in one or more of these phases could results in chronic
wounds
• ECM formation: fibroplasia, synthesis of
collagen, adhesive glycoproteins and
proteoglycans
• Angiogenesis and granulation tissue
formation
• Re-endothelialisation
• Further synthesis of ECM, degradation
and remodeling
•Coagulation
•Plateletactivation
• Neutrophils
• Phagocytosis
• Macrophages
• Lymphocytes
Days after wounding (log scale)
0.1 0.3 1 3 10 30 100 300
Cytokines and growth factors

55. How do drug elution & polymer degradation profiles compare?
SYNERGY™ + Synchrony™ Orsiro™
Polymer Coating: PLLA
Absorption Time: >12 months
Absorb™ BVS
Polymer Scaffold: PLLA
Polymer Coating: PDLLA
Absorption Time: >2 years
Other DES with biodegradable polymer Bioresorbable scaffold
BioMatrix Flex™ + Nobori™
Polymer Coating: PLA
Absorption Time: ~9 months