1. New Magnesium Alloy Program
Prof. Michael Haude. MD
Städtische Kliniken Neuss
Lukaskrankenhaus GmbH
Neuss. Germany

2. Prof. Michael Haude. MD
I have the following potential conflicts of interest to report:
Consultant: BIOTRONIK, ORBUSNEICH
Institutional grant/research support: ABBOTT VASCULAR, BIOTRONIK,
MEDTRONIC, ORBUSNEICH,
VOLCANO, CARDIAC DIMENSIONS

3. Absorbable Mg Scaffold Programs
BIOTRONIK AMS
Mg-Alloy
BIOTRONIK DREAMS 1G
Mg-Alloy + Paclitaxel
BIOTRONIK DREAMS 2G
Mg-Alloy + Sirolimus
Medtronic
BSCI
QualiMed UNITY
Mg-Alloy + Polymer (Hybrid)

4. Key characteristics of absorbable scaffold materials
Stainless Steel (316L)3
PLLA1
Iron4
Magnesium
Alloy2
Tensile Strength (MPa)
500
~30-45
300
280
Tensile Modulus (GPa)
193
1.2 – 3.0
200 45
Elongation (%) 48
2 – 6 25 23
Total Degradation Time
N/A
2-3 Years
> 4 years
~ 12 months
Advantages of magnesium:
Well-suited mechanical properties
Deployment capabilities similar to other metals
Very good biocompatibility
Magnesium is an essential element in the human body
Total magnesium in body: 30 g
daily need: ~ 350 mg
Total Mg mass of a scaffold: 8.5 mg
12.7x
Gerolsteiner:
Mg: 108 mg/l
1 Ratner BD, et al., editors, Biomaterials Science, An Introduction to Materials in Medicine, 2nd Edition (2004).
3 Poncin P, et al., Stent Tubing: Understanding the Desired Attributes, Materials & Processes for Medical Devices Conference (2003).
2/4 H. Hermawan et al. / Acta Biomaterialia 6 (2010) 1693–1697

5. Not all magnesium alloys are created equally
Absorption speed of various magnesium alloys
Mg Release
(mg/l)mm2)
Immersion time (250ml, flowing SBF, 37°C) / h
Alloy 1
Alloy 2
Alloy 3
Alloy 4
Alloy 5
Adding alloying elements to magnesium can significantly alter the absorption speed
Goal
Impact of purity and processing (Alloy Design x) on degradation speed
Residual Mg core
Alloy Design 1
Alloy Design 2
Alloy Design 3
28days
Porcine coronary model
Original strut shape

6. In-vivo magnesium bioabsorption
Animal histopathology demonstrates the process of bioabsorption: Magnesium is completely absorbed and replaced by a soft amorphous calcium phosphate
SEM
EDX*
* Energy-dispersive X-ray spectroscopy was used to make can make elemental characterizations
Source: Wittchow E, et al. EuroIntervention 2013;8:

7. Magnesium absorption process
acute
3-6 months
6-12 months
H2O
Mg(OH)2
Soft amorphous
calcium phosphate Mg
Mg absorption Mg
Mg absorption
pH↑
Alkaline environment attracts Ca and P from surrounding tissue
Mg + H20  Mg(OH)2 + H2
Ca2+ & PO43-
Mg scaffold absorption starts:
Magnesium scaffold is hydroxylated to metal ions*: Mg2+
Mg absorption ongoing
Mg2+ ions equilibrate slowly across cell membranes*
Mg(OH)2 formation
Mg absorption completed
Conversion into a soft and gel-like amorphous calcium phosphate**
Presence of Mg disturbs formation of crystalline structures ***
~12 months: macrophage clearance, cell intrusion
Structural dismantling starts
Mg2+
*Y.F. Zheng, X.N. Gu, F. Biodegradable metals; Materials Science and Engineering R 77 (2014) 1–34
**Wittchow et al., EuroIntervention 2013;8:
***LeGeros RZ, Contiguglia SR, Alfrey AC. Pathological calcifications associated with uremia. Calcif Tissue Res 1973; 13: 173–185.

8. Absorbable Magnesium Scaffold (AMS) device evolution
BIOTRONIK AMS
Proprietary Mg-alloy
Low crossing profile (1.2 mm)
High radial strength (~1 bar)
Low bending stiffness
Low recoil (<5%)
Excellent biocompatibility
4-crown design
Clinical Study:
No drug coating
165µm
80µm
28-day histology

9. Clinical Study PROGRESS-AMS
Study design
Prospective, multi-center, consecutive, non-randomized First In Man (FIM) trial
Primary endpoint (reached)
MACE *at 4 months <30 %
Results (at 4 months)
LLL 1.08 mm
TLR 23.8%
Conclusion
Bare AMS (Absorbable magnesium Scaffold) concept is safe and feasible
Need for prolonged scaffolding time and an anti-proliferative drug
63 patients enrolled at
8 international clinical sites
4-month FUP
Clinical, angiographic, IVUS
6-month clinical FUP (n=61)
12-month clinical FUP (n=60)
Long-term FUP (~7 yrs) clinical
Optional angiographic FUP
* Composite of cardiac death, nonfatal MI, ischemia driven TLR
Source: Erbel et al. Lancet 2007; 369: 1869–75.
Waksman et.al, JACC Cardiovasc Interv 2009;2:

10. Device evolution - from AMS to DREAMS G1
(Absorbable Magnesium Scaffold)
DREAMS 1st generation
(Drug Eluting AMS 3.0 )
No drug/polymer coating
Paclitaxel + PLGA
165µm
80µm
130µm
120µm
Refined Mg-alloy with slower absorption rate
Optimized scaffold design (6 crown)
Reduced strut thickness
PLGA polymer carrier
Paclitaxel drug elution
Used in BIOSOLVE-I study
28-day histology
28-day histology

11. DREAMS 1st generation animal study results
Taxus
eucaTax
N=6
*statistically significant
Source: Wittchow E, et al. EuroIntervention 2013, 8:

12. DREAMS 1st generation animal study results
DREAMS 1st generation histology
DREAMS
Taxus Liberté
eucaTAX
28 days
90 days
180 days
Source: Wittchow E, et al. EuroIntervention 2013; 8:

13. Clinical Study BIOSOLVE-I
Study design
Prospective, multi-center First In Man (FIM) trial. Single, de novo lesions mm and ≤ 12mm long
Primary endpoints
Cohort 1: TLF at 6 months Cohort 2: TLF at 12 months
Results
TLF at 6 months 4.3%
TLF at 12 months 6.8%
Remains constant at 36 months
LLL improved compared to AMS
Vasomotion restored at 6-month FUP
46 patients with de novo coronary artery stenosis
Cohort 1 (n = 22)
Cohort 2 (n = 24)
Mandatory 6mo: Clinical FUP (n = 22) Imaging FUP (n = 201)
Optional 6mo: Clinical FUP (n = 24) Imaging FUP (n = 16)
Optional 12mo: Clinical FUP (n = 202) Imaging FUP (n = 13)
Mandatory 12mo: Clinical FUP (n = 232) Imaging FUP (n = 201)
Device Success: successful delivery of the scaffold to the target lesion, appropriate deployment, successful removal of delivery system.
Procedure Success: device success plus attainment of a final residual stenosis of <50% of the target lesion. absence of MACE during the hospital stay up to 7 days.
Mandatory 24mo: Clinical FUP (n = 202)
Mandatory 24mo: Clinical FUP (n=24)
1 6 pts withdrew consent for imaging FUP (2 at 6-month and 4 at 12-month FUP)
2 1 pt died a non-cardiac death (Cohort 1). 2 pts withdrew consent (1 Cohort 1 and 1 Cohort 2)
3 1 pt died of a non-cardiac death 1 pt withdrew consent
Mandatory 36mo: Clinical FUP (n = 203)
Mandatory 36mo: Clinical FUP (n=24)
Source: M Haude. et al. Lancet 2013; 381: 13

14. BIOSOLVE-I study results 6-and 12-month late lumen loss (LLL)
6-month LLL
0.64 ± 0.50 mm
12-month LLL
0.52 ± 0.39 mm
LLL of the bare AMS in the PROGRESS study at 4-month: 1.08 ± 0.49 mm
Cumulative Frequency (%)
M Haude. et al. Lancet 2013; 381: 14

15. BIOSOLVE-I study results Vasomotion results at 6-month (N=26)
Relative Change in mean lumen diameter %
Proximal Segment
Scaffolded Segment
Distal Segment
±17.93%
9.34 ± 12.88%
± 20.30%
8.69 ±10.05%
±22.05%
9.66 ±9.33%
Mean ±SD
ACH
NTG
-80
-60
-40
-20 20 40 60
ACH concentration
Low: µg/mL
Medium: 3.6 µg/mL
High: 18 µg/mL
Nitro concentration
200 µg/mL
Acetylcholine (ACH): Presents the % change in mean lumen diameter between pre-and post-Acetylcholine (ACH) at the highest response
Nitroglycerine (NTG): Presents the % change in mean lumen diameter between post-ACH and Nitroglycerine

16. DREAMS Device Evolution Sirolimus + PLLA (BIOlute)
DREAMS 1st generation
(Drug Eluting AMS 3.0 )
DREAMS 2nd generation
(Drug Eluting AMS 3.5)
Paclitaxel + PLGA
Sirolimus + PLLA (BIOlute)
6-crown 2-link design, 150µm strut thickness
Optimized scaffold design for
Higher bending flexibility
Higher acute radial force
Slower absorption rate
Sirolimus drug elution & PLLA (ORSIRO BIOlute coating)
Tantalum radiopaque markers
120µm
150µm
90-Day Faxitron, porcine explant
90-Day Faxitron, porcine explant

17. Does magnesium degradation affects Sirolimus?
Pharmacokinetic study shows no significant difference between scaffold and control device made from 316L
Vessel wall Sirolimus concentration
Mean values
Residual Sirolimus load on scaffold
Magnesium scaffolds coated with a matrix of PLLA and Sirolimus were compared to a control device made from 316L of identical geometry and coating/drug
Implantation in coronary arteries of hybrid farm pigs for up to 90 days
Blood, scaffold and tissue surrounding scaffold were analyzed by HPLC:
Data on file at BIOTRONIK

18. DREAMS 2nd generation histology
1st generation 3x 3x
Add slide on micro-CT
DREAMS
2nd generation 3x 3x
Source: AccelLAB preclinical studies
Data on file at BIOTRONIK

19. Clinical Study BIOSOLVE-II
121 patients with de novo coronary artery stenosis
Study design
Prospective, multi-center FIM. Single de novo coronary artery lesions in up to two coronary arteries
Primary endpoints
In-segment late lumen 6-month
Coordinating Clinical Investigator
M.Haude, Lukaskrankenhaus GmbH, Neuss, Germany
First patient enrolled Oct 8, 2013
1 month Clinical FUP
6 month Clinical FUP
Angiographic FUP (mandatory)
IVUS / OCT (Subgroup only)
Vasomotion (if patient consents)
12 month Clinical FUP
Angiographic FUP (voluntary)
IVUS / OCT (Subgroup only)
Vasomotion (if patient consents)
2 year, Clinical FUP
3 year, Clinical FUP 19

20. BIOSOLVE-II Investigational Sites
Germany
Prof. Haude, Neuss (CCI)
Dr. Tölg, Bad Segeberg
Prof. Neumann, Bad Krozingen
Prof. Ince, Berlin
Switzerland
Prof. Kaiser, Basel Universitätsspital
Prof. Eeckhout, Lausanne CHUV
Belgium
Dr. Wijns, Aalst
The Netherlands
Prof. von Birgelen, Enschede
Denmark
Dr. Christiansen, Aarhus Universitets Hospital
Spain
Dr. Nieves Gonzalo Lopez, Hospital Clinico San Carlos, Madrid
Brazil
Dr. Abizaid, Instituto Dante Pazzanese de Cardiologia, Sao Paolo
Pedros, Lemos, MD, Instituto do Coração da Universidade de São Paulo- INCOR-FMUSP
Singapore
Prof. Lim Soo Teik, Singapore

21. 6month follow-up case presentation
Masterlayout
6month follow-up case presentation
of the first patient
Pre-procedure
Post-procedure
6mo FUP
First patient 6-month follow-up with OCT
(GER , Lukaskrankenhaus Neuss, Germany)
© BIOTRONIK

22. Summary
Magnesium offers an ideal balance between biocompatibility, mechanical performances and absorption
Not all Magnesium alloys are the same !
BIOTRONIK absorbable Mg program is most advanced:
- BIOSOLVE-I trial proved the safety of DREAMS 1st generation with Paclitaxel elution and improved efficacy compared to the bare AMS version
- BIOSOLVE-II study is evaluating the safety and performance of DREAMS 2nd with Sirolimus elution and improved scaffold design