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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15 complete on year follow-up:3 withdrawn or lost to follow-up

12 completed one year follow-up:2 withdrawn or lost to follow-up2 deaths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