#AHA16
Randomized Comparison of Allogeneic vs. Autologous Mesenchymal Stem Cells for Non-lschemic Dilated
Cardiomyopathy (POSEIDON-DCM Trial)
Joshua M Hare, Darcy L DiFede, Angela M Castellanos, Victoria Florea, Ana M Landin, Jill El-Khorazaty, Aisha Khan, Muzammil Mushtaq, Maureen H Lowery, John J Byrnes, Robert C Hendel, Mauricio G Cohen, Carlos E Alfonso, Krystalenia Valasaki, MarietsyV Pujol, Samuel Golpanian, Eduard Ghersin, Joel E Fishman, Pradip Pattany, Samirah
A Gomes, Cindy Delgado, Roberto Miki, Fouad Abuzeid, Mayra Vidro-Casiano , Courtney Premer, Audrey Medina, Valeria Porras, Konstantinos E Hatzistergos, Erica
Anderson, Adam Mendizabal, Raul Mitrani, Alan W Heldman
ISCI, University of Miami Miller School of Medicine / EMMES Corp.November 14, 2016
Funded by the NHLBI RO1 HL RO110737
Acknowledgements: Mark Martin, Doug Suehr, Jonathan Wong, Jim Taylor, BDS / NHLBI DSMB
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Background
• Non-ischemic dilated cardiomyopathy (NIDCM) is anincurable condition with significant genetic and immunologicunderpinning
• Mesenchymal Stem Cells (MSCs) are immunomodulatory /immunoprivileged, pro-regenerative cells that are safe andpromote reverse remodeling in ischemic CM
• POSEIDON-DCM is a randomized comparison of the safetyand efficacy of autologous vs. allogeneic bone marrow-derived hMSCs in NIDCM.
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Methods
• Phase I/II, randomized comparison of alllogeneic (Allo)and autologous (Auto) hMSCs with 12m follow-up
• Institution: University of Miami• Patients: 37 with LV dysfunction due to NIDCM – Dec 2011
to July 2015• Interventions: Allo or Auto MSCs were delivered by
transendocardial stem cell injection (TESI) into 10 LV sitesby NOGA Catheter System
www.clinicaltrials.gov #NCT01392625
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Study FlowChart57 Patients assessed for eligibility
20 Excluded:14 Did not meet inclusion criteria 4 Declined to participate2 Other reasons
37 Randomized 1:1
19 Randomized to receive allogeneic mesenchymal stem cell treatment
18 Randomized to receive autologous mesenchymal stem cell treatment
15 complete on year follow-up:3 withdrawn or lost to follow-up
12 completed one year follow-up:2 withdrawn or lost to follow-up2 deaths
18 Included in the primary analysis(30-day TE-SAEa)
16 Included in the primary analysis(30-day TE-SAEa)
18 Received treatment as randomized 1 Did not receive treatment as randomized:
1 death post randomization
16 Received treatment as randomized2 Did not receive treatment as randomized:
1 withdrew consent1 underwent AICD placement and could no longer be
injected
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Endpoints
SAFETY–30 Day safety–1 Year safety–FEV-1
EFFICACY–Major Adverse Cardiac Event–6 Minute walk test–Peak VO2–Minnesota Living with Heart Failure Questionnaire–NYHA Class–Cardiac Imaging for Global and Regional analysis–Endothelial function–Immunologic status
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Patient Characteristics by Cell TypeCell Type
Baseline Characteristics
Allo
(n=18)
Auto
(n=16)
Age at injection (years) 54.4 (±11.5) 57.4 (±11.0)
Gender
Male 14 (77.8%) 10 (62.5%)
Female 4 (22.2%) 6 (37.5%)
Years of NIDCM diagnosis before TESI 6.05 (±6.2) 6.93 (±7.3)
History of adriamycin chemotherapy 1 (5.5%) 2 (12.5%)
AICD or BIV/CRT 15 (83.3%) 14 (87.5%)
End Diastolic Diameter (cm) 7.2 (±1.3) 7.1 (±1.7)
History of Coronary Interventions 2 (11.1%) 1 (6.3%)
Previously Referred for AICD Placement 15 (83.3%) 14 (87.5%)
History of Atrial or Ventricular Arrhythmia 5 (27.8%) 1 (6.3%)
History of Hypertension 7 (38.9%) 3 (18.8%)
New York Heart Association Class
Class I - No Limitation 4 (22.2%) 6 (37.5%)
Class II - Slight Limitation of Physical Activity 9 (50.0%) 8 (50.0%)
Class III - Marked Limitation of Physical
Activity
5 (27.8%) 2 (12.5%)
History of Congestive Heart Failure 11 (61.1%) 7 (43.8%)
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SAFETY
Safety Summary Post-TESI Allo (n=18) Auto (n=16)
n % (95% CI) n % (95% CI) Day 30 Post-TESI
Incidence of AE 7 38.9% (20.8-64.7) 4 25.0% (10.2-53.7)
Incidence of SAE 2 11.1% (2.9-37.6) 1 6.3% (0.9-36.8) Incidence of TE-SAE 0 0.0% (0.0-18.5) 0 0.0% (0.0-20.6)
Incidence of MACE 0 0.0% (0.0-18.5) 0 0.0% (0.0-20.6) Day 180 Post-TESI
Incidence of AE 12 66.7% (45.5-86.3) 11 68.8% (46.4-88.6) Incidence of SAE 4 22.2% (9.0-48.9) 4 25.0% (10.2-53.7)
Incidence of MACE 1 5.6% (0.8-33.4) 3 18.8% (6.5-47.5)
Incidence of Death 0 0.0% (0.0-18.5) 1 6.3% (0.9-36.)
Day 365 Post-TESI
Incidence of AE 12 66.7% (45.5-86.3) 12 75.0% (52.8-92.2) Incidence of SAE 5 28.2% (12.8-55.1) 10 63.5% (40.8-85.7)
Incidence of MACE 3 20.3% (6.8-52.1)ϯ 9 57.1% (34.9-81.2)
Incidence of Death 0 0.0% (0.0-18.5) 2 12.5% (3.3-41.4)
1 P < 0.05 between groups
SAFETY
• 12-month all-cause re-hospitalizations • Allo: 28.2% (95% CI: 12.8, 55.1)
• Auto: 70.0% (95% CI: 47.0, 89.8)
• p=0.0447 (between groups)
• No ectopic tissue formation was observed in either group by whole body CT scan
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Ejection Fraction (%)
* p ≤ 0.05 within group12-monthsAllo: 8.0 units (p=0.004),Auto: 5.4 units (p=0.116) Between groups (p=0.49)
AlloAuto
-16
-8
0
8
16
24
32E
jec
tio
n F
rac
tio
n (
%)
1 Year# Allo
# Auto
N=15
N=9
*
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Cardiac FunctionBaseline 12 Months
EF =19.22% EDV= 256.52mlESV= 207.21ml SV=49.32mlLong Axis Diameter= 93.79 mmSI=0.59
EF =43.33% EDV= 192.69mlESV= 109.20ml SV=83.49mlLong Axis Diameter=91.95 mmSI=0.47
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ED Baseline ED 12 months
ES Baseline ES 12 months
EF: 31.2%EDV: 262.9mlESV: 180.8ml
EF: 48.1%EDV: 163.3mlESV: 84.7ml
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Minnesota Living with Heart Failure Questionnaire
∆ NYHA Class at 12-Months
12 months: Allo: 66.70% Auto: 27.3% Between groups: p=0.0527
Allo: p=0.002Auto: p=0.1719Between groups p=NS
AlloAuto
WorsenedNo ChangeImprovedNYHA Class Change from Baseline
Visit
Auto MSCsAllo MSCs
2M 3M 6M 12M2M 3M 6M 12M
0
20
40
60
80
100
Pe
rce
nt
of
Pa
tie
nts
WorsenedNo ChangeImproved
NYHA Class Change from Baseline
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Change from Baseline in EPC-CFU Change from Baseline in FMD
3 Months between group (p=0.0107) *
p<0.05 †p<0.01
Between groups (NS)
-6
-4
-2
0
2
4
6
8
10
12
14
16
EP
C-C
FU
(C
FU
)
3 Months# Allo
# Auto
N=12
N=11
*
3 Months
-6
-4
-2
0
2
4
6
8
FM
D (
%)
3 Months# Allo
# Auto
N=12
N=11
*
3 Months
AlloAuto
Endothelial Function(%)
#AHA16 -80
-70
-60
-50
-40
-30
-20
-10
0
Allo Auto %
Dif
fere
nc
e a
t 6
mo
nth
s R
ela
tive
to
Ba
se
lin
e
Serum TNF-a
* * †
* *
Baseline TNF-a11.3 pg/ml
Baseline TNF-a13.8 pg/ml
* p<0.0001 vs baseline† p<0.05 vs Allo
TNF-a Levels: Impact of MSC TESI
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Immunomodulatory effect of MSCs Allo Auto
Immune Biomarkers Baseline 6-months Baseline 6-months
Serum TNF-α (pg/ml) 13.5 ± 1.5 2.3 ± 0.2 **,ϯ 11.8 ± 0.9 4.8 ± 0.8**
%Early T-cell Activation
(CD3+, CD69+) 13.4 ± 4.4 7.9 ± 3.3** 13.3 ± 4.8 10.6 ± 5.4*
%Late/Chronic T-cell
activation (CD3+, CD25+)
8.9, IQR
(5.9, 10.4)
3.4, IQR
(3.0, 5.0)*
8.1, IQR
(5.2, 14.1)
4.4, IQR
(3.6, 11.1)
% Temra (CD3+,
CD45RA+,& CCR7-) 33.7 ± 7.6 17.9± 5.2**,ϯ 30.1 ± 10.8 21.3 ± 7.5**
%Late/Exhausted B-cells
(CD19+, CD27- & IgD-)
19.3, IQR
(17.9, 28.6)
14.7, IQR
(14.2, 17.3)**, ϯ
20.0, IQR
(17.7, 32.0)
15.5, IQR
(14.0, 19.0)*
%Switched Memory B-cells
(CD19+, CD27 high & IgD-) 10.0 ± 3.6 20.2 ± 3.1**, ϯϯ 9.6 ± 3.1 14.1 ± 4.5*
% B -ells expressing
Intracellular TNF-α 32.1 ± 7.3 20.4 ± 6.3** 28.2 ± 6.8 19.7 ± 4.8**
1 • indicates p ≤ 0.05 within group; **indicates p ≤ 0.001 within group• ϯ indicates between group p ≤ 0.05, ϯϯ indicates between group p ≤ 0.001.
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Immunologic Responses
Cell Type
cPRA Risk Allo (n=15) Auto (n=13)
No reaction to Low risk (0 - 20% cPRA)
Moderate risk (21 - 79% cPRA)
High risk (+80% cPRA)
10 (66.7%)
4 (26.7%)
1 (6.7%)
12 (92.3%) ϯ
1 (7.7%) ϯ
0 (0%)
ϯ indicates between group p ≤ 0.05
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Summary and Conclusions
• Thirty-day safety and tolerability was excellent in both groups
• One patient developed a high cPRA in the allogeneic MSC group
• Allo MSCs produced improvements in EF, 6 MWD, MLWHFQ, and reduced MACE and all-cause hospitalization
• Immunomodulation may contribute to the efficacy of allo hMSCs in NIDCM
• These data support the use of Allo MSC therapy in pivotal clinical trials for NIDCM
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