INTRAMYOCARDIAL INJECTION OFMESENCHYMAL PRECURSOR CELLS INLEFT VENTRICULAR ASSIST DEVICE

RECIPIENTS:THE LVAD MPC-II TRIAL

Francis D. Pagani & Terrence Yauon behalf of the CTSN Investigators

BACKGROUND LVAD therapy improves myocardial function, but few explants LVAD associated with myocardial and systemic inflammation & AEs

o Mucosal bleeding in 30-70% MPCs respond to inflammatory signals by releasing immunomodulatory factors Can immunomodulation by MPCs augment cardiac recovery and reduce AEs? Prior exploratory trial of intramyocardial injection of 25M allogeneic MPCs in LVAD pts

o Signal of potential efficacy (temporary weaning)o No safety concernso Signal of major bleeding reduction, mostly GI

OBJECTIVE AND TARGET POPULATION

Adults with advanced HFo Ischemico Non-ischemic

Scheduled for implantation of an FDA- or HC-approved LVAD foro BTTo DT

Percutaneous LVAD or BV support Planned ablation or aortic valve

intervention Recent CT surgery or prior cardiac Tx LV reduction surgery or cardiomyoplasty >10% anti-HLA antibody titers with known

specificity to MPC-donor HLA antigens Prior cell therapy for cardiac repair

Inclusion Criteria Exclusion Criteria

Objective : To assess whether one-time injections of high dose MPCs into the native myocardium of LVAD recipients is safe and improves cardiac recovery

TRIAL DESIGNAssessed for eligibility

(n=637)

Randomized(N=159)

MPC (150M)(N=106)

Sham Control(N=53)

Excluded (N=478)• Did not meet inclusion criteria (N=276)• Refused to participate (N=150)• Other (N=52)

• Withdrew (N=0)• Death (N=10)• Transplant (N=8)

Primary Endpoint Analysis• Excluded (N=1)

• Withdrew (N=2)• Death (N=6)• Transplant (N=6)

Primary Endpoint Analysis• Excluded (N=1)

Allocation

Follow-upat 6 Months

Analysisat 6 Months

2:1

PRIMARY ENDPOINTS

Primary Efficacy EndpointProportion of successful temporary weans (≥30 minutes) from full to minimal LVAD support out of 3planned assessments at 2, 4, and 6 months after randomization

Primary Safety EndpointIncidence of study intervention-related adverse events, including infectious myocarditis, myocardialrupture, neoplasm, hypersensitivity reaction and immune sensitization

Patients Tolerating Wean on Minimal Support

LVAD to Full

Support

Prior to Wean

Comprehensive Echo

15 Min

Comprehensive Echo

20 Min (±10)

6-Min Walk

Post 6-Min Walk

Comprehensive Echo

All Patients

LVAD to Full Support

SECONDARY ENDPOINTS

Echocardiographic assessment at full support and at time of wean Incidence and rate of serious GI bleeding events and/or epistaxis Serious adverse events Hospitalizations

Survival Sensitization to MPC donor-specific HLA antigens Time to heart transplant

Month 6

Month 12

MPC (N=106) Control (N=53)Age, mean (SD), y 55.5 (12.3) 56.9 (11.7)Male sex, No. (%) 94 (88.7) 47 (88.7)LVEF, mean (SD), % 17.3 (5.9) 16.2 (6.0)Cardiac Index, mean (SD), I/min/m2 2.1 (0.6) 2.0 (0.5)Etiology of Heart Failure, No. (%)

Ischemic 43 (40.6) 27 (50.9)Non-ischemic 63 (59.4) 26 (49.1)

INTERMACS Profile, No. (%)1-3 83 (78.3) 46 (86.8)4-7 23 (21.7) 7 (13.2)

NYHA Class IV, No. (%) 75 (70.8) 41 (77.4)LVAD Indication, No. (%)

Bridge-to-Transplant 66 (62.3) 34 (64.2)Destination Therapy 40 (37.7) 19 (35.8)

Device Implanted, No. (%)HeartMate-II 39 (36.8) 19 (35.8)HVAD 67 (63.2) 34 (64.2)

BASELINE CHARACTERISTICS

SUCCESSFUL TEMPORARY WEANS FROM LVAD SUPPORT

59%

66%62%

58%

53%

62%

0

10

20

30

40

50

60

70

Month 2 Month 4 Month 6Pr

opor

tion

of S

ucce

ssfu

l W

eans

Average proportion of successful temporary weans:o 61% in MPC vs. 58% in controlo RR=1.08 (95% CI 0.83-1.41;

p=0.55)

Posterior probability that MPC increased likelihood of successful weaning: o 69% (<80% pre-defined threshold)

MPCControl

EXPLORATORY SUBGROUP ANALYSES

Interaction of Rx and pre-determined subgroups on wean success rate over 6 months

PRIMARY SAFETY ENDPOINT & SENSITIZATION

No patients developed a primary safety stopping event

Allosensitization to Class I HLA antigenso 26% MPC vs 9.4% Control o Between-group difference: 16.5% (95% CI: 5 to 28%)

Allosensitization to Class II HLA antigenso Similar in control and MPC patients at all time points

TIME TO HEART TRANSPLANT & SURVIVAL

MUCOSAL BLEEDING AT 6 MONTHS

MPC (n = 106) Control (n = 53) P-valueEvent Rate

(100-Pt-Months)Event Rate

(100-Pt-Months)3.8 15.9 <0.001

Rate of GI/Epistaxis Bleeding

78.7

32.4

3

6.6

3

10.2

5.3

3.3

70.9

24.7

5.4

7.7

3.5

9.1

3.6

4.4

All serious AEs

Any bleeding

Ventricular arrhythmias

All arrhythmias

Major device malfunction

Major infections

Right heart failure

Neurological dysfunction MPC Control

Rate

per

100

pt-

mon

ths

SERIOUS AES & HOSPITALIZATIONS AT 6 MONTHS

0.75

0.21

0.68

0.07

All hospitalizations

GI Bleeding

Rate

per

100

pt-

mon

ths

Hospitalizations

LIMITATIONS

High rate of pump thrombosis reduced number of evaluable wean attempts

Enrolled heterogeneous study population o Ischemic/non-ischemic HF, BTT/DT, 2 types of deviceso Increased variability may have reduced likelihood of detecting Rx effect

Although all bleeding events & transfusions were adjudicated, we did not routinely collect INR, platelets, and anticoagulation regimens

CONCLUSIONS

MPCs did not increase rate of cardiac recovery in LVAD-supported patients. However, in exploratory sub-group analysis, a positive signal in ischemic HFo May affect patient selection in future cardiac recovery trials

Overall serious AEs & hospitalization rates similar. Higher rate of allosensitization to Class I HLA antigens in MPCo Time to transplant similar

Clinically meaningful decrease in rate of mucosal bleedingo If substantiated in future trials, may lead to new therapeutic approach

STUDY INFRASTRUCTURE Network Chairs (Weisel, O’Gara, Rose) Coordinating Center, InCHOIR, Mount Sinai (Gelijns, Moskowitz, Bagiella, Mancini, Lala) NIH (Miller, Taddei-Peters, Jeffries, Moy)

o Duke University (Milano)o University of Michigan (Pagani)o Stanford University (Woo)o Toronto General Hospital (Yau)o University of Pennsylvania (Acker)o University of Utah (Selzman)o Cleveland Clinic Foundation (Soltesz)o University of Virginia (Kern)o Hôpital Laval (Charbonneau)o Mayo Clinic (Maltais)

o Montefiore – Einstein (Goldstein)o Lutheran Hospital (Ladowski)o University of Pittsburgh (Kormos)o Baylor Research Institute (Lima)o Ohio State University (Whitson)o Columbia University (Naka)o University of Maryland (Griffith)o University of Southern California (Bowdish)o University of Wisconsin (Kohmoto)

ACKNOWLEDGEMENTS

This trial was supported by a cooperative agreement (U01-HL088942) funded by NHLBI and NINDS, of the National Institutes of Health (NIH), and the Canadian Institutes for Health Research (CIHR)

Mesoblast provided MPCs and cryoprotective medium

We would like to thank the patients, their families, doctors, nurses and research personnel for participating in this trial

LVEF CHANGES OVER 6 MONTHS

LVEF on full LVAD support LVEF after 15 min of LVAD weaning (on min. support)