Regenerative Medicine for Cardiac

Failure: Hope vs Hype

Joshua M. Hare, M.D.
Louis Lemberg Professor
Senior Associate Dean
Chief Science Officer
Interdisciplinary Stem Cell Institute
The Miller School of Medicine, University of
Miami
January 27, 2020
 Disclosures

• Research Grants – Biocardia, Osiris

• UM Patent
• Consultant – Kardia, Vestion
• Equity – Kardia, Vestion, Heart Genomics,
Biscayne Pharma, Longeveron
From: Association Between Aging of the US Population and Heart Disease Mortality From 2011 to 2017
JAMA Cardiol. 2019;4(12):1280-1286. doi:10.1001/jamacardio.2019.4187

Total Mortality Rates and Number of Deaths, 2000 to 2017A, Heart disease. B, Coronary heart disease. C, Heart failure as
underlying cause. D, Heart failure as contributing cause. E, All other heart disease.

Copyright 2019 American Medical Association.

Date of download: 1/27/2020
All Rights Reserved.
 Heart Attack and Ventricular Remodeling
Placebo 3-months after injection MSC-treated 3-months after injection

Quevedo et al. PNAS 2009

 Its not just myogenesis:

1. Remove the scar tissue

2. Replace blood vessels
3. Modulate the immune system

Sadek and Olson. Toward the goal of human heart regeneration.

Cell Stem Cell 2019
 State of the Art 2020
• Approvals and clinical application by 2020
– 21st Century Cures Act / RMAT designation
• Continuous refinement based upon biology and clinical
data:
– Combination Cell Therapy (CCT – CONCERT-HF Trial, NHLBI)
– Cell and gene therapy
– Deployment of pluripotent cells, alone or in combination
• Approvals:
– Heart Sheet
– Allogeneic Bone Marrow Derived MSCs or MPCs
 An Important Issue is Personalized
Medicine
• Application of Personalized medicine for a more rationale
allocation of treatment strategies
– Ischemic vs. non-ischemic cardiomyopathy
– Patient prognosis
– Patient etiology
Intramyocardial Injection of Mesenchymal Precursor Cells and Successful Temporary Weaning From Left
Ventricular Assist Device Support in Patients With Advanced Heart Failure: A Randomized Clinical Trial

Yau et al. JAMA March 26, 2019

Yau et al. JAMA March 26, 2019
 MSC Mechanism of Action
• Anti-fibrotic effects
• Immunomodulation (allows for
allografting)
• Neovascularization
• Stimulation of endogenous repair
– Opportunity to augment this
therapeutic target

Bagno L et al. Mol Ther. 2018

Golpanian S et al. Physiologic Rev 2016
 Impact of MSCs on Scar Morphology
Karantalis Circ Res 2014 (NHLBI SCCT – PROMETHEUS STUDY)

Baseline 18 months

Endocardial Length
Scar Thickness

Epicardial Cap

Endocardial Length Scar Thickness Epicardial Cap

40 6 6
30 P=0.005 P<0.001
20 P=0.002 4 4

10 2 2

0 0 0
Baseline 18 months Baseline 18 months Baseline 18 months
TAC-HFT Trial – Scar Reduction and Regional
Function

*
*
** *** *
**
**
**

*p<0.05, **p<0.01, ***p<0.001 *p<0.05, **p<0.01

Heldman et al. JAMA 2014
Idiopathic Dilated Cardiomyopathy:
The POSEIDON-DCM Trial
(Hare et al. JACC 2017)
 Ejection Fraction (%)
32
Ejection Fraction (%)
24

16 *

-8

-16

1 Year
# Allo N=15
# Auto N=9

12-months
Allo: 8.0 units (p=0.004), Allo
Auto: 5.4 units (p=0.116) Auto * p ≤ 0.05 within group
Between groups (p=0.49)
 Cardiac Function
Baseline 12 Months

EF =19.22% EF =43.33%
EDV= 256.52ml EDV= 192.69ml
ESV= 207.21ml ESV= 109.20ml
SV=49.32ml SV=83.49ml
Long Axis Diameter= 93.79 mm Long Axis Diameter=91.95 mm
SI=0.59 SI=0.47
 POSEIDON DCM Super-Responders
Allo hMSCs Auto hMSCs

50

Ejection Fraction (%)

40

30

20

10

Baseline 1 Year Baseline 1 Year

Rieger et al. AHA Scientific Sessions 2017 Visit Hare JACC 2017;69(5)
 Percent Survi

Percent S

Perce
Genotype modifies 50
50 Log-rank (Mantel-Cox) p=0.01

Log-rank (Mantel-Cox) p=0.01

Responsiveness of Cardiac Log-rank (Mantel-Cox)

0
0 p=0.01 200
100
0Tim e (days) 100
0

200
Follow-up Time, Days
300
300
400300
400

Function
50 100 150 200 250 350 400
0 Follow-up Time, Days

N umber
V- 6 6 6 6 6 6 6* 5 5
0 100 200 300 400

a t ri s k
Tim e (days) V 50
US 20
100 20
150 20
200 20
250 20
300 20
350 18
400 17 16*
Follow-up
P V6+ Time,
68 Days

N umber
V- 6 68 68 68 6*6* 55 55 4 3

a t ri s k
*
Tim e (days) 50V U S 100 20 * Los t 20
150 Follow-up
200 20 250 20 300 20 350 20 400 18 17 16*

N umber
V- 6 6P V + 6 8 6 8 6 8 6 8 6* 6* 5 5 5 5 4 3

a t ri s k
60 V 16*
- VUS PV +
** VUS
PV+
20
8
20 t Follow-up
* Los

8
20
8
20
8
20
6*
20
5
18
5
17
4 3
V- VUS PV +
**
* Los t Follow-up

V- VUS PV +

40
EF%

20

+ 1 3 .6 % + 6 .5% -5 .9 %
( + 7 .8 % , + 2 0 .5 % ) ( + 0 .9 % , + 1 1 .1 % ) ( -1 2 .7 % ,+ 1 .0 )
0
Rieger. EBioMedicine 2019 Bas.1Y Bas.1Y Bas.1Y
 Genetic variation affect MACE
and Survival in response to
MSC delivery
100 100

Percent Survival
Percent MACE

Log-rank (Mantel-Cox) p=0.02

50 50
Log-rank (Mantel-Cox) p=0.01

0 0
0 100 200 300 400 0 100 200 300 400
Follow-up Time, Days Follow-up Time, Days
Time (days) 50 100 150 200 250 300 350 400 Tim e (days) 50 100 150 200 250 300 350 400
N umber

N umber
V- 6 6 6 6 6 6 6 6 6 V- 6 6 6 6 6 6 6* 5 5
a t ri s k

a t ri s k
VUS 20 20 20 19 18 18 17 14 12 VUS 20 20 20 20 20 20 18 17 16*
PV+ 8 8 7 6 4 4 4 4 4 PV+ 8 8 8 8 6* 5 5 4 3
* Los t Follow-up

V- VUS PV +
 Sample Size and Treatment Groups:
POSEIDON DCM II

• 136 subjects will be randomized into 3 groups

1. No genetic defect
2. Variants of uncertain significance (VUS)
3. Variants of certain significance (VS)
• Each subject will receive 10 injections, each of 0.5 ml
volume (cells or placebo)

19
 Organizational Structure: POSEIDON II

CDMRP

PRC Chair DSMB

Hare

PDCs Steering Committee P&P

Data Coordinating Center

Cell Processing QC
Lab
UTSPH Biorepository &
Univ of Miami
Core Labs

MD
Core

Texas Heart
U Louisville U Miami Stanford
Institute
Targeting Endogenous Regeneration
• Cardiomyocyte renewal
rates are 0.5 to 2% per
year in adult humans
• Renewal rates increase
following injury

Olaf Bergmann et al. Science 2009;324:98-102

 A

I
A

H
E
B
CMLC2v HP3 GATA4 DAPI

pRbser608 ARF HP3 DAPI

CCT
Placebo

cKit+ alone
hMSC alone

%RbSer-608+/ARF-negative CMs/HPF GATA4+/HP3+ CMs/cm3

E

F
B

C
Sample Size and Treatment Groups:
CONCERT-HF TRIAL
• 144 subjects will be randomized 1:1:1:1
• 36 subjects/group to 1 of 4 treatment groups:
1. Combo: Target dose is a mixture of 150 million MSCs
and 5 million CSCs
2. MSCs: Target dose is 150 million MSCs
3. CSCs: Target dose is 5 million CSCs
4. Placebo: Cell-free PlasmaLyte-A medium
• Run in phase (n=16)
• Each subject will receive 15 injections, each of 0.4 ml
volume (cells or placebo)
23
Organizational Structure: NHLBI Cardiovascular Cell Therapy Research Network
(CCTRN) CONCERT-HF Trial
NHLBI
Ebert
PRC Chair DSMB
Simari

PDCs Steering Committee P&P

Data Coordinating Center

Cell Processing QC
Lab
UTSPH Biorepository &
Univ of Miami Moyé Core Labs

RC MD RC MD
Core Core Core Core

Texas Heart Minneapolis

U Florida U Louisville U Miami Stanford Indiana U
Institute Heart Inst.
Staged surgical palliation for patients with
hypoplastic left heart syndrome

I Norwood II bidirectional III total cavopulmonary (Fontan)

Brody Wehman, and Sunjay Kaushal Circulation Research.

2015;116:566-569
Copyright © American Heart Association, Inc. All rights reserved.
Aging as a key risk factor: The Geroscience
Hypothesis

Afilalo et al. 2017 The Frailty-AVR Study. JACC.

 Results of CRATUS Trial
• Intravenous allogeneic MSCs have been
tested in a phase I and II clinical trial for
older individuals with frailty
– Increased 6MWT and SPPB
– Improved FEV1
– Improved MMS
– Reduced TNF-a levels

J Gerontology, 2017
CRATUS – Phase I and II data

J Gerontology 2017
 Its not just myogenesis:

1. Remove the scar tissue

2. Replace blood vessels
3. Modulate the immune system
Minimal
functional
data

Have been tested in non-human

Primates
Major Risk of Arrhythmias
One study showed
engraftement but no
functional improvement
Sadek and Olson. Toward the goal of human heart regeneration.
Cell Stem Cell 2019
 GHRH-R Marks a Majority of Human NKX2-5+
Cardiomyogenic Precursors
Co-localization of NKX2-5 and GHRH-R
Day-7 of Differentiation
Secondary abs only CTRL primary & secondary
GHRHR (Alexa 488)

9.6%
1.9% 0.0%
81.4%
94.2% 3.8%
7.9% 1.0%

NKX2-5 (Alexa 633)

Collaboration: Chatzistergos, Hare, and Schally

 Progress to the Clinic: Cell Therapy
• MSCs reduce scar tissue tissue by 30-50% and replace the tissue
with contractile myocardium
• Regeneration in the human/mammalian heart occurs at 0.5 to 2%
per year
• Most Important Concepts and Trials
– DREAM-HF – First fully enrolled phase 3 trial
– ELPIS – Congenital Heart Disease
– Cell Combination therapy (CCT) – CONCERT-HF
– Divergent effects in DCM vs ICM
– Concept of hyper-responders
– Treatment of frailty as a co-morbidity
– Serious GI bleeding in LVAD patients
• Personalized medicine approach to patients with
advanced heart failure can help allocate advanced
therapies, improve prediction of deterioration as well as
chance for recovery
Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine, Volume: 123, Issue: 9, Pages: 1030-1032, DOI:
Schulman, Khan and Hare. Circulation Research, 2018
(10.1161/CIRCRESAHA.118.310426)
Soffer Family Foundation,
Starr, Marcus