1. Mitchell W. Krucoff MD, FACC
Combo: A Combination of Sirolimus-Eluting Biodegradable Polymer and Anti-CD34 Antibody Coated Stent
Mitchell W. Krucoff MD, FACC
Professor of Medicine / Cardiology
Duke University Medical Center
Director, Cardiovascular Devices Unit
Duke Clinical Research Institute

2. Disclosure of Conflicts
No personal stock, holdings or IP
No corporate revenue >$50k per annum
Research grants, consulting relationships:
Abbott Vascular
Acist Medical
Biosensors
Boston Scientific
Cook Medical
Cordis J&J
CSI
Medtronic
OrbusNeich
St. Jude Medical
Terumo

3. DES: Unmet medical needs & stent “healing”
Short DAPT:
High bleeding risk
Non-compliant
30 day vs 3 month
VLST & extended duration of DAPT
Thrombotic lesions (ACS, STEMI)

4. The COMBO Plus Dual Therapy Stent: Traditional DES with biological therapy
CD34 Antibodies
Enable active capture of EPC for fast endothelial coverage
Sirolimus & Polymer Matrix
Drug and bioabsorbable polymer matrix for control proliferation
Stent & Delivery System Highly conformable stent with excellent radial strength

5. CD34 antibodies capture circulating EPCs who mature into functional endothelium
Following implantation, the immobilized CD34 antibodies are exposed to the circulating blood
Circulating endothelial progenitor cells (EPC) are captures by antibody
EPCs attach and differentiate into mature endothelial cells; an important step in re-establishing healthy neointima

6. Stent Surface Coverage by SEM in Stented Porcine Coronary Arteries
Genous
3 Days
14 Days
CD34/Cypher
Cypher
Several years ago, when the risk of late stent thrombosis associated with drug eluting stents was brought to light, we were challenged to apply our “Pro-Healing” immobilized anti-CD34 antibody technology to commercial DES to see if we could influence their healing behavior.
In a series of published experiments in collaboration with CVPath and CRF, we applied the antibody treatment to commercial DES and then implanted them in porcine coronary arteries.
Here on the left, you can see that at three days follow up, the antibody coated stent had the best tissue coverage while the DES showed minimal tissue with spotty protein coverage, and the DES coated with antibody was intermediate. At 14 days as seen on the right, the effect is even more pronounced, where the antibody coated stent was completely covered with tissue, the DES very poorly covered still with predominant protein material and sparce cells, while the antibody DES was intermediate and well on the way to being completely covered.
Nakazawa G et al., JACC Cardiovasc Interv Jan;3(1):68-75.

7. Confirmation of Coverage in Rabbit Model
Percent Stent endothelialization (sEM) at 28 days
EES
p < 0.038
96.6%
78.5%
COMBO
Quantification of stent strut coverage (by sEM) showed a significantly improved endothelialization of the COMBO stent (96.6±3.5%) compared to the EES (78.5±16.8%; p=0.038)
Ellenbroek, G.H., et al., AsiaIntervention, (2): p

8. REMEDEE: FIM 183 pts 2:1 RCT Combo vs. Taxus Liberte
1o endpoint: 9 mos LLL
Haude M et al, JACC CV Int 6(4), 2013

9. Lesion Characteristics c/o Robbert J de Winter, MD PhD FESC
Multivessel disease (>1 vessel, >70%)
21.1%
Treated lesions (n=1511)
Left main
1.3%
LAD
50.6%
LCx
20.2%
RCA
26.1%
Bypass graft
1.8%
Number of vessels treated
One vessel PCI
89.5%
Multivessel PCI
10.5%
AHA/ACC lesion type A
16.4% B1
24.9% B2
37.5% C
21.1%
TIMI flow pre-procedure
14.5% 1
4.5% 2
9.8% 3
71.3%
50% }
One Year Results REMEDEE Registry TCT 2015

10. Putting the results into perspective: 1-year results of ‘All Comers’’
REMEDEE Registry
TWENTE
DUTCH PEERS
LEADERS
COMBO
Resolute
Xience V
Promus
BioMatrix
Cypher N
1000
697
694
906
905
857
850
TLF (%)
5.7
7.9
6.8
6.0
5.0
6.5
7.4
TV-MI (%)
0.7
4.6
2.0
1.0
5.8
Cardiac Death (%)
1.7
1.4
2.1
2.7
iTLR (%)
4.4
5.1
Definite ST (%)
0.5
0.6
0.0
0.3
Probable ST (%)
0.1
1.2
0.2
0.8
Source: P. Woudstra et al. J Am Coll Cardiol Intv. 2016; 9(11):

11. REMEDEE Registry Results
2-Year Clinical Results
D. Kalkman et al. Poster presentation 2016 TCT.

12. Pivotal DES registration data: Japan & USA 572 pts 1:1 RCT vs
Pivotal DES registration data: Japan & USA 572 pts 1:1 RCT vs. EES 1 year clinical & angio follow up
Includes MV CAD and non-STEMI ACS
FFR guided repeat revascularization
OCT subgroups: 6 month & 1 year strut coverage
Sites: Japan & USA
Trial Structure:
Sponsor: OrbusNeich
International Pis: Shigeru Saito & Mitch Krucoff
Japan & USA Pis: Shigeru Nakamura & Roxanna Mehran
Study Chair: David F. Kong
Coordinating Center: DCRI
Site Monitoring: CMIC (Japan) & DCRI (USA)
Angio Core Lab: CRF (Philippe Genereux)
OCT Core Lab: CRF (Akiko Maehara)
FFR Core Lab: Case Western (Hiram Bezerra)
Uchida T et al, Circulation Journal 2013

13. ClinicalTrials.gov identifier: NCT02073565
HARMONEE Study Design
Enrollment Completed
Study Objective To demonstrate the effectiveness of COMBO vs. Xience in the treatment of significant ischemic heart disease, including UA and NSTEMI patients
Primary Endpoint Ischemia & FFR driven TVF at 1 Year, where TVF defined as cardiac death, tv-MI, or ischemia- driven TVR
Principal Investigators Mitch Krucoff, MD, Duke UMC
Durham, NC, USA
Shigeru Saito, Shonan Kamakura General Hospital, Kamakura, Japan
ClinicalTrials.gov identifier: NCT

14. OCT Measurement Methodology: EPC Mechanistic Surrogate
Healthy tissue coverage:
Independent , blinded Core Laboratory (Akiko Maehara, CRF)
Per strut , per frame, and per patient analysis
Combo superiority to EES

15. Leaving “occulo-stenotic” PCI Behind for Pivotal Trials Physiologic & High Resolution Anatomic F/U
Fractional Flow Reserve (FFR):
All patients at 1 year
All “re-looks”
Independent core lab (Hiram Bezerra, Case Western)

16. COMBO Dual Therapy Stent Clinical Trial Program
Data available at TCT 2017
5-Year
completed
36-Month
completed
12-Month
completed
24-Month completed
Clinical FUP ongoing
Enrollment completed
Enrollment completed
Enrollment completed
Enrollment completed
6,000+
Patients planned in clinical trials
Primary endpoint completed
Enrollment completed

17. COMBO Stent: Conclusions
DES technology still evolving
Unmet needs:
Short DAPT for HBR pts
Site healing & very late ST (long DAPT)
Thrombotic (ACS) lesions
“Pro-healing” DES design might answer unmet needs for CAD patients
Next step: HARMONEE results in 2017!

18. Mitchell W. Krucoff MD, FACC
Combo: A Combination of Sirolimus-Eluting Biodegradable Polymer and Anti-CD34 Antibody Coated Stent
Mitchell W. Krucoff MD, FACC
Professor of Medicine / Cardiology
Duke University Medical Center
Director, Cardiovascular Devices Unit
Duke Clinical Research Institute