1. Cardiovascular Cell Therapy 2017: Hype or Hope?
Timothy D. Henry, MD
Director of Cardiology
Cedars-Sinai Heart Institute

2. DISCLOSURE
Baxter, Cytori, Aastrom, Capricor, Cardio3, NHLBI all for Cell Therapy trials

3. The Hope of Stem Cells

4. Too Much Hype!

5. Cardiovascular Disease Targets
Refractory angina
Acute myocardial infarction
Congestive heart failure
Ongoing ischemia
Previous MI
Nonischemic
Peripheral arterial disease
CLI
Claudication

6. Refractory Angina/Ischemia

7. Catheter-based Cell Transplantation
Biosense Webster Injection Catheter
No Needle Extension
Isolated cells were intramyocardially transplanted using an injection catheter. 27G needle at the tip of the catheter is extendable, and needle length is adjustable.
Usually, we adjust the needle length to 4 to 6 mm.
4-6mm Needle Extension

8. Phase II ACT34–CMI Study Design
Screening and Baseline Visits
Subject population (n=167)
21-80 yrs
CCS class III or IV Angina
Attempted “best” medical therapy
Non-candidate for Surgical/Perc. revasc.
Ischemia on SPECT
3-10 min. mod. Bruce protocol with angina or anginal equivalent at baseline
Cell Mobilization (GCSF 5mcg/kg/d x 5d)
Apheresis on Day 5
Randomization
1 x 10^5 CD34+ cells/kg
(n = 55)
Placebo
(n = 56)
5 x 10^5 CD34+ cells/kg
(n = 56)
Endomyocardial Mapping and Injection with NOGA
Isolex selected CD34+ cells / Placebo Rx
Follow-up Safety and Efficacy Assessments:
1 - 7 days, and 1, 3, 6, and 12 months; ETT at 3, 6, 12 months
MRI at 6 months, SPECT at 6 & 12 months

9. ACT-34 CMI: Reduction in Angina
Anginal Episodes per Week
Change from baseline at 6 months
P=0.04
Analysis of Variance (ANOVA)

10. ACT-34 CMI: Exercise Time Change from baseline at 6 months
Total ETT Time
Change from baseline at 6 months
p=0.013
Seconds

11. Major Adverse Cardiac Events (24 Months)
Control
1x105 CD34+cells/kg
5x105 CD34+cells/kg
p-value*
Death
7(12.5%)
1(1.8%)
2(3.6%)
0.081 MI
10 (17.9%)
9(16.4%)
6(10.7%)
0.587
Death, MI
15(26.8%)
10(18.2%)
0.096
Death, MI, ACS Hospitalization
17(30.4%)
8(14.3%)
0.101
Death, MI, ACS or Worse CHF Hospitalization
19(33.9%)
12(21.8%)
9(16.1%)
0.078
Pts with MACE events from start of mobilization thru 12 mo in injected pts; *= Fisher’s Exact Test 11 11 11 11

12. Angina Counts at 24 Months
Diff=5.3,
p=0.030

13. Refractory Angina Phase III RENEW Study Design
Screening and Baseline Visits
Randomization
Subject population
21-80 yrs
CCS class III or IV
Angina
Attempted “best” medical therapy
Non-candidate for
Surgical/Perc. revasc.
Ischemia on SPECT or
3-10 min. mod. Bruce protocol with angina or anginal equivalent at baseline
1 x 105 CD34+ cells/kg
(n = 200)
Active Control
(n = 100)
Unblinded Standard of Care
(n = 100)
Cell Mobilization (G-CSF 5 mg/kg/d x 4d)
Apheresis on Day 5
___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
Intramyocardial Mapping and Injection with NOGA
ISOLEX selected CD34+ cells / Placebo
Efficacy Assessments during 12 month follow-up: ETT, angina frequency, and QoL (SF-36)
Safety Assessments during 24 month follow-up: AEs, SAEs, MACE
Safety Assessments during 24 month follow-up: AEs, SAEs, MACE 13 13

14. RENEW: Primary Endpoint as Treated
MEAN
MEDIAN

15. RENEW: Angina Frequency
6 months Relative Risk
As Treated 0.63 P=0.05
ITT
0.58 P=0.02

16. RENEW Results: 2-Year MACE
Standard of Care
(n=28)
Active Control (n=28)
CD34+ Cell Txt (n=50)
Started Mobilization but Not Injected (n=6)
Patients with MACE
19 (67.9%)
12 (42.9%)
23 (46.0%)
2 (33.3%)
Death
2 (7.1%)
3 (10.7%)
2 (4.0%) MI
5 (10.0%)
Perforation
1* (16.7%)
Stroke -
CV hospitalization
18 (64.3%)
9 (32.1%)
21 (42.0%)
Ventricular arrhythmias
1 (3.6%)
1 (2.0%)
MACE <2 weeks
3 (6.0%)
MACE during follow-up

17. Treatment Effect (95% CI) (s) Treatment Effect (95% CI) (s)
CD34 Patient level Metanalysis: Total Exercise Time
ITT
Placebo (s)
CD34+ (s)
Treatment Effect (95% CI) (s)
p-value
Month 3
31.4 (16.0)
78.0 (12.1)
46.6 (13.0, 80.3)
0.007
Month 6
50.2 (18.5)
100.2 (13.6)
49.9 (10.0, 89.8)
0.014
Month 12
42.5 (20.7)
88.2 (14.7)
45.7 (0.2, 91.2)
0.049
As Txt
Placebo (s)
CD34+ (s)
Treatment Effect (95% CI) (s)
p-value
Month 3
28.1 (15.7)
80.5 (12.1)
52.5 (19.2, 85.7)
0.002
Month 6
48.8 (18.2)
101.8 (13.7)
52.9 (13.5, 92.4)
0.009
Month 12
39.5 (20.3)
90.5 (14.7)
50.9 (6,0, 95.9)
0.027
*Least squares mean change from baseline (SD)

18. OPPORTUNITY LOST!!!

19. PLoS One 2013 Jun 19;8(6):e64669

20. Mortality
PLoS One 2013 Jun 19;8(6):e64669

21. Martin-Rendon Meta-analysis
Angina Class
Angina Frequency
PLoS One 2013 Jun 19;8(6):e64669

22. Martin-Rendon Meta-analysis
Quality of Life
Exercise Time
LVEF
PLoS One 2013 Jun 19;8(6):e64669

23. CHF

24. Ischemic Heart Failure Progression vs Therapeutic Options
Novel approaches to fill
the gap
Therapy
Medical
Health status
+ CRT
Several novel approaches are being tested to fill this therapeutic gap. On one hand, there are novel devises tested for the specific subsets of heart failure patients.
On the other hand, a broad range of biologics including cellular interventions is being introduced.
So this is the positioning of the cell therapy in the current heart failure management.
LVAD → HTx
NYHA I NYHA II NYHA III NYHA IV
Bartunek J and Vanderheyden M (Eds): Translational Approaches to Heart Failure, Springer 2013

25. Mesenchymal Colony Forming Units
(CFU-F)
Patient ID
180
CFU Number per 106 BM Mononuclear Cells

26. MSC Growth Kinetics
Control
Cell Number (103)
Time (hours)

27. Strategies to Enhance Cell Therapy
Increase the number of cells (autologous)
Whole bone marrow (Harvest)
Selected cells (autologous)
Adipose derived cells (Cytori)
CD34+ cells (Baxter)
ALD-bright (Aldagen)
Expand and/or enhanced cells (autologous)
Aastrom Biosciences
C-Cure
MSC-HF
Corrected spelling of Caduseus.

28. C-CURE FIM Trial
The C-Cure trial demonstrates the feasibility and safety of cardiopoietic mesenchymal stem cells in patients with ischemic cardiomyopathy
Complementing standard of care, C-Cure therapy improved cardiac function and clinical performance
The favourable profile supports follow-up pivotal studies in a larger patient population
And we have heard earlier this morning the trial
In its totality, the C-Cure trial was important in establishing the first clinical experience and future leads for the ensuing trial at three levels: manufacturing, delivery and design and methodology;

29. Second Generation of Cell Therapy
to Ensure Cardiac Lineage Specification
Discovery
Translation
Application
Cell Therapy GF
Naïve MSC
Decoding natural
cardiopoiesis
Pre-clinical
assessment
GMP Scale-up
C-CURE trial
CP MSC
Lineage
specification
At the level of the cell product optimizaiton, let me reiterate that Andre Terzic and Atta Behfar.
By decoding natural cardiopoiesis derived a cardiogenic cocktail capable to prime consistently patient-derived mesenchymal stem cells into cardiac progeny.
In preclinical studies, these primed cardiopoietic stem cells demonstrated superior benefit as compared to their unprimed, naïve source.
This in tandem with GMP scale up and quality control was the basis for the C-Cure trial.
Nature Clin. Pract. 2006, 2007; J Ex Med 2007; Gen. Biol. 2008; Stem Cells, 2008, 2009; JMCC 2008; JACC 2010; Cell Transplant 2011

30. C-CURE International Program
Congestive Heart Failure
CArdiopoietic Regenerative Therapy (CHART-1) Trial
Efficacy and safety of bone marrow- derived mesenchymal cardiopoietic cells (CRBS-CQR-1) for treatment of chronic advanced ischemic heart failure
Prospective, multi-center, randomized, sham-controlled, double-blinded study
240 subjects: 2 arms
Standard of Care + cardiopoietic cells
Standard of Care + sham procedure
Based on this advances the Chart 1 trials
ClinicalTrials.gov Identifier NCT

31. Exploratory Analysis Primary Efficacy Outcome as a Function of Baseline LV EDV and Treatment Intensity ≤
<

32. Ixmyelocel-T: Expanded Multicellular Therapy
Two-Week Expansion Increases:
CD45+ CD14+ M2-like macrophages
CD90+ MSCs
Potential Mechanisms:
Anti-Inflammatory
Tissue Remodeling
Endothelial Protection
Angiogenesis

33. 75% fewer patients treated with ixmyelocel-T experienced a MACE
Phase 2a Results
IMPACT-DCM (n=39)
Catheter-DCM (n=22)
75% fewer patients treated with ixmyelocel-T experienced a MACE
(* p < 0.05)
MACE = cardiac death, cardiac arrest, MI, HF hospitalization, or major bleeding
Henry TD, et al. Circ Res 2014;115:

34. Lancet

35. ixCELL–DCM Eligibility
Inclusion Criteria
Age 30 to 86
NYHA Class III/IV heart failure
Diagnosis of ischemic cardiomyopathy
LVEF ≤35%
ICD in place
Heart failure hospitalization within 6 months or
BNP ≥400 pg/mL or NT-pro BNP ≥2000 pg/mL or
6 MWT ≤400 meters
Exclusion Criteria
MI, Stroke, TIA within 3 months
LV thrombus/ineligible for NOGA
PCI, CABG within 30 days
Status 1A or 1B on heart transplant list
Severe valvular disease
Malignancy within 12 months
CKD or creatinine clearance <15 mL/min
Hg <9 g/dL or HbA1c ≥9%

36. Randomization/Aspiration
Protocol
Ixmyelocel-T
12 Day ± 1 Expansion R
Randomization/Aspiration
Day -14
Injection
Day 1
Month 12
Data Analysis
Month 24
Safety Follow-up
Month 3
Month 6
Screening
Days -30 to -15
Placebo

37. Primary Endpoint: Modified ITT (n=114)
_____Primary Endpoint_____ Without IP Procedure Related Events
_____Sensitivity Endpoint_____ With IP Procedure Related Events
Placebo (N=55)
Ixmyelocel-T (N=59)
P-Valuea
0.0107
0.0082
Rate Ratio [95% CI]
0.59 [0.40, ]
0.58 [0.39, ]
Events/100 patient years
121.73
72.16
123.79
Patient years Exposed
48.5
55.4
Total Events 59 40 60
Distribution of Events by Patient, n (%)
27 (49.1)
36 (61.0)
26 (47.3)
>=1
28 (50.9)
23 (39.0)
29 (52.7) 1
11 (20.0)
13 (22.0)
12 (21.8) 2
4 ( 6.8) 3
2 ( 3.6)
5 ( 8.5) 4
1 ( 1.7) 5
1 ( 1.8)
0 ( 0.0) 7

38. LVEF and Volumes

39. Summary
Patients treated with ixmyelocel-T had a significant reduction in the primary endpoint on both per protocol and modified ITT analysis
37% to 41% reduction in cardiac events compared to placebo; similar to the Phase 2a clinical trials
Driven by a reduction in mortality and cardiac hospitalizations
Fewer patients with SAEs observed in the ixmyelocel-T group compared to the placebo group
No significant changes in LVEF or LV volumes, NYHA or 6-minute-walk

40. ALLogeneic heart STem cells to Achieve myocardial Regeneration
PIs: Tim Henry, Raj Makkar
Phase I/II study Post-MI EF: < 45%, IS > 15% (MRI)
Intracoronary infusion of allogeneic CDCs
Open-label Ph I (3 sites) followed by double-blind randomized placebo-controlled Ph II (20 sites)
Stratified patient recruitment (274 pts total)
30-90 days post MI (healing)
> 90 days post MI (chronic)
Primary efficacy enpoint: scar size
funded by NIH and CIRM grants to Capricor

41. Still not available at the florist yet….

42. We still need better Options!!
Will it be Cell Therapy??

44. Kaplan-Meier Analysis
MACE
Days
Comparison of Placebo vs. CD34+:
p=0.08
Death
Days
Comparison of Placebo vs. CD34+:
p=0.003
0.8
0.6
0.4
0.2
Probability of Event
Placebo
CD34+
SOC