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Stem cell sheets therapy for patients with cardiomyopathy Yoshiki Sawa Osaka University Department of Cardiovascular Surgery

Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

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Page 1: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Stem cell sheets therapy for patients with cardiomyopathy

Yoshiki Sawa

Osaka University

Department of Cardiovascular Surgery

Page 2: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Medications

DevicesOperation

LVAS

HTX

Strategy for Heart Failure

Regenerative therapy is desired in the World

Page 3: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Stem cell therapy for heart failure

Bone Marrow(RepairAMI)

Endothelial progenitor cell

Skeletal muscle cell(MagicTrial)

Mesenchymal stem cell

Cardiac stem cell (SCIPIO Trial)

No protocol can be commercially available.

Page 4: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Peace-Keeping Design, Osaka University

The culture surface grafted with N-isopropylacrylamide(temperature-responsive polymer) NIPAAm

<32℃37℃Hydrophobic hydrophilic

⇒ cell attachment ⇒ cell detachment

A tissue engineered myocardial regeneration using temperature-responsive culture dish

enzymaticproteolysis (Trypsin)

reducing temperature

lost of almost transplanted cells (80~90%)

myocardial damage by injection needle

limited therapeutic area by local delivery

Page 5: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Tissue engineered cardiac graft

Page 6: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Indications: End stage of DCM patients under LVAS who indicate heart transplantation

Endpoint: to clarify its safety and feasibility

Secondary endpoints: evaluate cardiac function

Case number:6

Study periods:2years

Safety and Feasibility study of regenerative therapy with myoblast sheets

Page 7: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

051015

Administration because of Heart Failure

0 5

Myoblast im

plantation

Administration by Heart Failure 1.12 → 0.34 event/year(p<0.01 Wilcoxon signed –rank test)

Cardiac event0.75 → 0.28 event/pt・year

系列4 系列3

系列2 系列1

NYHASeverity of Heart Failure

pre 6M 1 year

3.2±0.6 2.2±1.1* 2.0±0.9*

Page 8: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

植込型VADSVR

Clinical Outcomes

100%@ 1year82.5%@ 3years

HTX on waiting list (Status 2)

Cell sheetSHM

Predictable survival curve

Survival Curve of severe heart failure patients receiving myoblast sheets implantation

Page 9: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Translational Research of autologous myoblast sheet therapy for severe heart failure patients

Project start

Rat ICM mdel(Transplantation 2005)

Rat model for ICM(JTCS2005,JTCS 2009)

DCM hamstere(JTCS 2006)

Canine model for DCM(JTCS 2007)

Pig model for ICM(Transplantation 2010)

Pre-Clinical study

Basic Research

Clinical Study

Small animal study

Clinical study

(Tissue Eng. 2001)

Clinical trial for approval (Terumo)2012

2007

2004

2002

2000

Page 10: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Abroad

Number of Heart Failure Patients introduced to Osaka University Hospital

in 2014

Page 11: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

再生医療の国際医療貢献

International collaboration and contribution in regenerative therapy with Saudi Arabia

Page 12: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

My second visit with ourPrime minister Mr.Abe

Page 13: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Regenerative therapy in Heart failure patient from Qatar

Before operation

After operation

Page 14: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Dept. Global and Innovativel Medicine, Osaka Univ.

Page 15: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

The human resources development for Regenerative medicine

Heart

Eye

Bone

LVAS + Myoblast Sheet Transplantation

<32℃37℃Hydrophobic Hydrophilic

Temperature-responsive Culture Surface

N-isopropylacrylamide”

Myoblast sheet for Cardiomyopathy by Prof. SawaMSC

new bone

①benign bone tumor with large bone defect

②bone marrowharvesting ③primary culture

(MSC expansion)

④MSC integration to NEOBONE®

differentiationculture for 2 wks

⑤cultured bone (final product)

⑥transplantation of cultured bone

Bone Tissue Engineering Integrating Novel Ceramic Scaffoldand Mesenchymal Stem Cells by Prof. Yoshikawa

Oral Mucosal Epithelium sheet for Corneal Reconstruction by Prof. Nishida

iPED

Page 16: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

2 Cardiac cell sheets show synchronized beating with heart

Connexin43(+)

タンパク発現維持

Page 17: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Heart failure patients iPS cells

Somatic cell

iPS derived cardiac cellsiPS derived cell sheet

Myocardial regeneration therapy using iPS derived cell sheets

Oct3/4 Sox2

Klf4 (c-Myc)

Page 18: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Control iPS cell sheet

0

10

20

30

40

50

60

P=0.0001

EF

n.s. P=0.0003

Baseline 4weeks 8weeks

First POC of iPS cell for heart failure in the world

Surface mapping

Skeletal myoblast iPS derived CMS

Page 19: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)
Page 20: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)
Page 21: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Brentuximab vedotin (AdcetrisTM ) might eliminate immature iPS cell completely.

Brentuximab vedotin (ADCETRIS™)0, 5, 25 mg/ml

72 h, 96 hhiPSCs-derived cardiomyocyte

Brentuximab vedotin reduced the number of undifferentiated cells

* :P<0.01vs. 72 h, 0 mg/ml

** :P<0.01vs. 96 h, 0 mg/ml

% of undifferentiated cell

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

1 2 3 4 5 6

% o

f u

nd

iffe

ren

tiat

ed c

ell

(%)

0 5 25 mg/ml0 5 2572 h 96 h

* ***

**

N. S.

† :P<0.05vs. 96 h, 5 mg/ml

qRT-PCR ; the expression level of Lin28= the percent of undifferentiated cell

Tumoriogenesis =4/5 (Control)

0/8(Adcertis)

(ADCETRIS™)

Page 22: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Protocol of differentiation from iPS cells into cardiac myocyte

Ff-l 01cell

Ff-l 01cell Ff-l 14cell

Ff-l 14cell

CiRA(Kyoto Univ.) has shipped us GMP-grade iPS cell For clinical use

Page 23: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

【New Pathway for Regenerative Medical Products】

New Regulation for Regenerative Medical Products under PMDA Act since November 2014

Clinical Trial(confirmation of efficacy and safety)

ApprovalClinical

Research

On Market(further confirmationof efficacy and safety)

PMS with Registry of All Patients

Conditional /time-limited

marketing authorization

Clinical Research

On Market

On Market

Clinical Trial(predict likely efficacy

and confirm safety)

Re-A

pp

roval

< Drawback of traditional PAL approval system > Long-term data collection and evaluation in clinical trials is not suitable for cellular/tissue-based products

because of non-uniform quality reflecting individual heterogeneity of autologous donor patients

Ensuring the safety of patients with post-marketing registry

【Standard Pathway of Approval for Drugs and Regenerative Medicinal Products】

Leading to Earlier Access to patients and Earlier Reimbursement

Page 24: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Nature Medicine STEM CELL ACTION AWARD to JSRM

Invitation by USA Ambassador Ms. Kennedy

Japan is now expected its regulation and scientific activity of Regenerative therapy from the world

Page 25: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

25

Roadmap of Industrialization of Regenerative therapy

Autologous cellSkinBone

Cornea

Neuron

Heart

Retina

Liver

Kidney

Mar

ket

Siz

e

Years2015

iPS cell, cell sheet technology and new regulation are the breakthrough for new era in regenerative therapy

Allogenic cell

Cartilage

Clinical application

Industrialization

Page 26: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Partnership Which partnership we can do?

We can collaborate each other in the

field of new medical technologies.

We can promote human resource development including medical

students.

Page 27: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)

Heart failure patients received regenerative therapy in Osaka University Hospital

Thank you for your attention !

Page 28: Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical Research On Market On Market Clinical Trial (predict likely efficacy and confirm safety)