2017/9/29

Current Status of Advanced
Therapy in Japan
Regulatory aspect and trends
GBC2017 Symposium in Seoul

Teruhide Yamaguchi
Kanazawa Institute of Technology (Japan)

New Act on Advanced Therapy‐ clinical research and clinical trail for development ofadvance therapy

12017/9/29

Current approved advance therapy in Japan
Cell therapy
Indication

Auto／
Allo

Company

Approved Approvedyear
condition

cultured epithelial
cells (JACE)

Severe burn

Auto

J‐TEC

2009

Cultured Cartilage(JACC)

traumatic
Auto
cartilage defects
andosteochondritis
dissecans

J‐TEC

2009

Mesenchymal stem
cells (Temcell)

GVHD

Allo

JCR

2015

Skeletal myoblast
sheet (HeartSheet)severe heart
failureAuto

Terumo2015

Conditional andtime‐limited
approval

Gene therapy
No gene therapy products is approved for market authorization in Japan.

Background for new legislations of cell and gene therapy
The Act on the Safety of Regenerative Medicine (including not only celltherapy but also gene therapy) (2013 published, 2014 adapted)
New legislation was needed to put regenerative medicine practices(e.g. cancer immunotherapies, cosmetic surgeries) under regulatory
control to enhance their safety.
The Pharmaceuticals and Medical Devices Act (PMD Act)
Revision of the Pharmaceutical Affairs Law (renamed)to accommodate cellular product characteristics

The Goal is to benefit the patientswith unmet medical needs22017/9/29

Guidelines for Advanced Therapy in Japan
Advance therapy products
under Pharmaceutical Affairs
Law (PAL)

Regulation of clinical Research
for advance therapy

For Cell Therapy Products
Guideline for ensuring quality and safety of
products from processed cell/tissues (2008)
For autologous cells (2008)
For allogeneic cells (2008)
For somatic stem cells (2012)
For iPS cells (2012)
For ES cells (2012)

Cell Therapy
Guideline for stem cell therapy clinicalresearch (published in 2013)
Gene Therapy
Guideline for gene therapy clinicalresearch (1995, revision 2015)

For Gene Therapy Products
Guideline for ensuring quality and safety ofgene therapy products (1995, revision 2013)
As the Act on the Safety of Regenerative Medicine, the regulation of advanced
therapy has changed dramatically

Regenerative Medical Regulation
Clinical Trial forMarket Authorization

Clinical Research
Governing Rule/Regulation• The Act on the Safety ofGenerative Medicine• Medical Care Act
108 clinical research protocols
had been approved under theformer legislation.
Under the new legislation, 73
new clinical research protocol
using stem cells have been
approved.

Governing Rule/Regulation• The Act on the Safety ofGenerative Medicine•

The Pharmaceuticals, Medical
Devices Act (PMD. Act)•

3 Products were approved, and 1
Product was conditionally approved
No gene therapy product have been
approved in Japan•

According to new ACT, the regenerative products(cell and gene therapy products) will be applied asconditional and time‐limited approval.

According to new ACT, all cell therapy (regenerative therapy) clinical protocol should be
evaluated by governmental committee or committee on accreditation for regenerative therapy

3

2017/9/29

Regenerative Medical Regulation
Clinical Trial forMarket Authorization
However, many regenerative therapy
protocolsGoverning
have beenRule/Regulation
conducted
without evaluation by government• The Act on the Safety ofor IRB.
Generative Medicine

Clinical Research
Governing Rule/Regulation• The Act on the Safety ofRegenerative Medicine• Medical Care Act
108 clinical research protocols
were approved under theformer legislation.

•

The Pharmaceuticals, Medical
Devices Act (PMD. Act)•

3 Products were approved, and 1
Product was conditionally approved
No gene therapy product have been
approved in Japan•

Under the new legislation, 73
new clinical research protocols
using stem cells have been
approved.

According to new ACT, the regenerative products(cell and gene therapy products) will be applied asconditional and time‐limited approval.

According to the new ACT, all cell therapy (regenerative therapy) clinical protocols should be
evaluated by governmental committee or committee on accreditation for regenerative therapy

Process for development of advance therapy
medicinal products【Process of advance therapy medicinal products】
Pharmaceutical Company and Academia
Pharmaceutical Company

MarketingPhase III

PMDA

Phase II

Phase I

Non‐clinical
study

Early
development

Review for 30 days

Submission of new
drug approval

Submit the clinical trial
protocol

Conditional andtime‐limited
approval

Academia
Non‐clinical
study

Early
development

The
Committee ofregenerative
therapy

ClinicalResearch

Designation of advancetherapy

Submission of cell and gene therapy
clinical research protocol

4

2017/9/29

Cell Therapy (Regenerative Therapy)

Many advanced therapy protocols have been
initiated as clinical researches in Japan• Muscle stem cell sheet (Heart Cell) and cultured
cartilage (JACC) have been originally developed asclinical research by academia.
• During clinical research and early clinical trails foradvance therapy, academia and company are
struggling to collaborate the development ofthese products.
• Enhancing translational research for cellular andgene therapy will provide useful seeds foradvance therapy.

5

2017/9/29

Current approved advance therapy in Japan
Cell therapy
Indication

cultured epithelial
cell (JACE)
Cultured Cartilage(JACC)

Company
Approve
Auto／
allo
year
In Japan many cell
Severe burn
Auto
J‐TEC are2009
therapy products
originally developed byacademia. These seeds
traumatic
Auto
J‐TECto2009
are translated
cartilage defects companies.
andosteochondritis
dissecans

Mesenchymal stem
cells (Temcell)

GVHD

Allo

JCR

2015

Skeletal myoblast
sheet (HeartSheet)severe heart
failureAuto

Terumo2015

Approved
condition

Conditional andtime‐limited
approval

Gene therapy
No gene therapy products is approved for market authorization in Japan.

Pathway for clinical research of advanced therapy using cellularand gene therapy

Ministry Health Labor Welfare
Committee of Review board for regenerative therapy
and advance therapy

Subcommittee for genetherapy clinical researchv
approval

Committee on accreditation forregenerative therapy using cells
including allogeneic cells, iPS
cells or recombinant cells

Submission of clinical research protocol

Academia or hospitalCommittee on accreditation
for regenerative therapy
using low–risk cells

62017/9/29

Key issues of quality and safety of cell therapy
products from standard and guidelines
•

•

•

•

AS the ingredient of cell therapy products is living cell, sterilization process
could not applied to these products. Therefore, it is very important toenhance the safety of cell therapy products to use raw materials free fromadventitious agents
Serum, growth factor, and/or blood‐fractionated protein should be adopted to“Standard on Biologically‐derived Raw Material and the Notification” which
describes the criteria for the origin of raw materials and how evaluate and test
the adventitious agents such virus or PrPsc.
Since the specification of cell therapy products may be un‐enough to evaluate
quality attributes of cell therapy product, the consistency should be ensured
by robust control of production process. (Quality and Safety Assurance of
Cell/Tissue Pharmaceuticals and Cell/Tissue‐derived Medical Devices)
Concerning to non‐clinical study of cell therapy, products, due to the species
difference between cell therapy product and animal, the useful andmeaningful data could not be always obtained, and then early phase study
should be carefully conducted in the case of un‐enough non‐clinical safety
data.

Safety issues for cell therapy products from iPS
and ES cells (concept paper for clinical research)• Gene stability during the establishment of iPS cells. ⇒ It is
desirable to analyze no‐mutation of cancer‐related gene
(Cosmic census + Shibata list) and chromosome.
• Tumorigenicity of final product produced manufactured from
iPS or ES cells and contamination of undifferentiated cells infinal product. ⇒ Either in vitro abnormal growth ability or invivo tumorigenicity test are strongly recommended, andcontamination of teratoma in final products should be
conducted.
• New technology including the SGN could be utilize to analyze
mutation and epigenome variation during the long‐term
culture.

7

2017/9/29

JACE Review Report by PMDA
JACE consists of autologous cultured keratinocytes, produced using Dr. Green's
technique, in which keratinocytes isolated from the patient’s own skin tissue are co‐cultured with irradiated 3T3‐J2 cells derived from mouse embryo as a feeder layer.
This product is indicated for use in patients with serious, extensive burns who do nothave sufficient donor skin available for autografting and is applied to the woundsurface of deep dermal (deep second‐degree) or full‐thickness (third‐degree) burns.
Enzyme‐Treatment
cultureskin
Feedersubculture

EnzymeConfluent‐celltreatment

Lifted cell‐sheet
Cell‐sheet

From J‐TEC

A multi‐center, open‐label,
uncontrolled clinical study was
conducted in 2 patients to confirm theefficacy and safety of the product inthe treatment of severe burns. As aresult, epithelialization of the wounds
treated with JACE was observed andthere were no particular safety
problems. However, due to the very
limited data obtained from the clinicalstudy, it is considered necessary to
impose the following conditions forapproval: surveys in all patientstreated with JACE

Approval for additional Indication of JACE;
Congenital giant pigmented nevus
To examine extensive burn wounds in 14 patients by using a
combination of autograft and cultured epithelial autografts
developed in Japan (JACE).

Hayashi et al: Changes in the Dermal Structure during cultured Epidermal
Autograft Engraftment Process. www.PRSGlobalOpen.com p.1‐7 (2016)8

2017/9/29

HeartSheet: Restoring Cardiac function with skeletal myoblast sheets[Classification] Human cellular/tissue‐based products 2 Human somatic stem cellprocessed products[Non‐proprietary name] Human (autologous) skeletal myoblast‐derived cell sheet[Brand name] HeartSheet[Conditions for approval]
1. The applicant is required to ensure that the product is used by physicians andsurgeons with adequate knowledge and experience in severe heart failure andthoracotomy at medical institutions with capacity for emergency response under asystem that ensures appropriate patient control through laboratory tests, etc.
2. The applicant is required to conduct an approval condition‐based post‐
marketing evaluation in all patients transplanted with the product during theperiod between the conditional and time‐limited approval and reapplication formarketing approval.
[Duration of approval] 5 years

Application topatient heart

Skeletal myoblast sheet

From Terumo Co.

Development of iPS cell‐derived cell therapy in Japan
From Kyoto Univ. CiRA Institute
iPS Cell Stock for Regenerative Medicine
The building of an iPS cell stock forregenerative medicine involves the collectionof cells from healthy donors with homozygous
HLA (human leukocyte antigen). The aim of
the stock is to hold iPS cells of guaranteed
quality which can be supplied quickly to
medical care institutions and research
institutions in Japan and overseas whenrequired. The project is being led by the
Medical Application Promoting Office, which ispart of the CiRA Research Support Division, in
collaboration with Facility for iPS Cell Therapy(FiT), a CiRA cell‐processing facility.

Patient
Expansiontransplant
Stock

Donor
iPS cellSkin cell
iPS stock cells for celltherapy

Supply qualified
iPS cells
Many type of
iPS cells

18

92017/9/29

Pilot safety study of iPSC‐based intervention
for wet‐type AMD•

This site provides an introduction to a pilot safety study on the transplantation of
autologous induced pluripotent stem cell (iPSC)‐derived retinal pigment
epithelium (RPE) cell sheets in patients with exudative (wet‐type) age‐related
macular degeneration (AMD).
Healthy eye

AMD

PRE
cells

From Riken InstituteFirst clinical research was conducted using RPE cell from autologous iPS cells.
Next clinical research will use RPE cells from allogeneic HLA‐homo iPS cells.
As there was potential risk for Genome mutations during not only establishment of
iPS cells but also manufacturing of RPE from iPS cell, whole genome analysis by NGS
and in vivo tumorigenicity test have been conducted according to the concept paper.

Gene therapy

102017/9/29

List of Gene Therapy Clinical Study Protocols Approved in Japan from 2012
Year of
Approval

Institute, Company

Target Disease2014

kyushu Univ. Hospital Intermittent claudication

2014

Jichi Medical Univ.

Parkinson's disease2014

Jichi Medical Univ.

Aromatic L‐amino acid
Decarboxylase deficiency

2014Tokyo Univ. Research
Glioblastoma
Hospital

Gene

Vector/ Methods

Fibroblast growth factor‐2
Sendai viral vector／in vivo
（FGF‐2)
Aromatic L‐amino acid
Adeno associated vector／
Decarboxylase (AADC)
in vivo (intra‐putamen）
Adeno associated vector
AADC
type‐2／in vivo (intra‐
striatum）*Oncolytic herpes simplex
β‐galactosidase (Lac‐Z) as avirusesG47Δ
markerin vivo (intra‐tumor）

Chronic arterial occlusion
Hepatocyte Growth Factor Plasmid vector／in vivo （Osaka Univ. Hospital (arteriosclerosis obliterans;
intra‐muscular）（HGF）
Buerger's disease）
REIC（Reduced Expression Adenoviral Type 5／
Okayama Univ.
Malignant pleuralin Immortalized Cells）
in vivo (intra‐thoracic、
Hospitalmesothelioma/Dickkopf‐3（Dkk‐3）
intra‐tumor）
Retroviral vector/ex vivo
Refractory B cell Non‐
CD19‐specific chimeric
Jichi Medical Univ.
(Peripheral blood
Hodgkin Lymphoma
antigen receptor(CAR)
mononuclear cell)*Oncolytic herpes simplex
Tokyo Univ. Research olfactory
β‐galactosidase (Lac‐Z) as avirusesG47Δ
Hospitalesthesioneuroblastoma
markerin vivo(intra‐tumor）*Oncolytic herpes simplex
Tokyo Univ. Research
β‐galactosidase (Lac‐Z) as
Glioblastoma
virusesG47Δ
Hospitala markerin vivo (intra‐tumor）

2014

2014

2014

2013

2013

List of Gene Therapy Clinical Study Protocols Approved in Japan from 2012
Year of
Approval

Institute, Company

Target Disease

Gene

Vector/ Methods

2013

Mie Univ. Hospital

Esophageal cancer

2012
++

Anges‐MG

primary lymphedema

2013

Mie Univ. + (multiple Acute myeloid leukemia
collaboration study, 4 (AML) myelodysplastic
syndrome
institution)

2012

Okayama Univ.
Hospitalcervicofacial・thoracic
malignant tumor－

Chiba Univ. Hospital

Malignant pleural
mesothelioma

MAGE‐A4 antigen specific T
Retroviral vector/ex vivo
cell receptor (TCR) α‐chain(syngeneic T cell）
and β‐chain
Hepatocyte Growth Factor Plasmid vector／
in vivo (intra‐muscular）（HGF）
WT1 antigen specific T cell
Retroviral vector/ex vivo
receptor α‐chain and β‐(Peripheral blood
chain. siRNA gene againstmononuclear cell)
TCR.
*Oncolytic Adenoviral Type‐
5, Telomelysin/in vivo
(intra‐tumor）
Adenoviral vector/ in vivo
NK4
(intra‐thoracic）

2012

National Center ofChild Health andDevelopment

X‐linked （X‐Chronic
granulomatous disease）

human cytochrome b heavy Retroviral vector/ex vivo （chain（CYBB）
Hematopoietic stem cell）

2012

Tokyo Univ. Hospital Prostate cancer

2012

kyushu Unuv. HospitalRetinitis pigmentos

2013

Chiba Univ. Hospital familial LCAT deficiency*Oncolytic herpes simplex
β‐galactosidase (Lac‐Z) as avirusesG47Δ
markerin vivo (intra‐tumor）
simian immunodeficiency
Pigment epithelium‐derived
viral vector (SIV)／ in vivo
factor（hPEDF）(subretinal injection）
Lecithin cholesterol
Retroviral vector／ ex vivo
acyltransderase（LCAT） (pre‐adipocyte）

11

2017/9/29

List of Gene Therapy Clinical Study Protocols Approved in Japan from 2012
Year of
Approval

Institute,Company

Target Disease

Gene

Vector/ Methods

Condition

2015

Novartis
PharmaDiffuse Large B cell
lymphoma（DLBCL）CART19 Cells

autologous T cell transfectedby Lentivirus vector(CTL019)

Phase II

2015

Novartis
PharmaAcute B cell
lymphoblast

CART19 Cells

autologous T cell transfectedby Lentivirus vector(CTL019)

Phase II

2015

Astellas Pharma

Malignantmelanoma

GM‐CSF

2015

Kagoshima Univ

Progressive solidcancer2015

kyorinMalignantPharmceuticals mesothelioma

2015
2012
2012

Mie University +Multi‐hospital Solid tumor
trialsprimary
Anges‐MG
lymphedema
Astellas pharma
Cytomegalovirus
Inc.

−

Oncolytic virus using HSV1（
talimogene laherparepvec）
Survivine‐promoter‐dependent
oncolytic adenovirus （Surv.m‐
CRA‐1）

Reduced Expression
in Immortalized
adenovirus vector（Ad5‐SGE‐
Cells）/Dickkopf‐3 REIC/Dkk‐3）／（Dkk‐3）
NY‐ESO‐1‐specific Retrovirus vector (MS3II‐
TCR‐expressed T‐cell NYES01‐siTCR)／ex vivo
autologous T cell、siTCR
Hepatocyte Growth
Plasmid vector／
Factor（HGF）
antigen ofcytomegalovirus (2 Plasmid vectorkind)Phase I
Phase I

Phase I/II

on going[Terminated][Terminated]

Red: These clinical trials had been started as clinical research. Many clinical research
will be expected to develop the clinical trial as a translational research.

Trend of gene therapy in Japan• Oncolytic virus therapy: many oncolytic virus protocols
have conducted as clinical research and clinical trial. Recently, OV
therapy are considered to induce not only tumor‐lysis but also
immune reaction against tumor as a bystander effect.

• CART and TCR‐CTL therapy: New trend of cancer
therapy using these genetically modified T‐cells are expected
to cutting edge therapy.

• New technology: Genome editing technologies are
expected as useful tools for repairing the abnormal gene, but
it is difficult to exclude modification of undesired gene by off‐target effects.

122017/9/29

Guideline for gene therapy• Guideline for gene therapy clinical research (revised
2015)• Guideline for ensuring safety and quality of genetherapy products (revised 2013, under revision)
ICH• ICH Considerations ‐ General Principles to Address Virus
and Vector Shedding• ICH Considerations ‐ Oncolytic Viruses• ICH Considerations ‐ Non‐Clinical testing for Inadvertent
Germline transmission of Gene Transfer Vectors
IPRF GTDG• Reflection paper: Biodistribution of gene therapy
products

Oncolytic virus (Oncolytic Immunotherapy)
Replication-competent virus and recombinant virus specific in tumor cells but notnormal cells; Cancer virus therapyCancer immunotherapy as a bystander effect of oncolytic virus
Conventional cancer gene therapy

Lysis only occurs in infected cells

Viral vector (non-replication)

Cancer viral therapy
Oncolytic (replication) virus (OV)

Normal cells

OV proliferate in infected cells and re-infect into
other cells, then cause the cancer immune
response

Cancer cells

Infected cells

132017/9/29

Development of oncolytic virus in Japan
Company/Univ

ClinicalResearch

Clinical
Trial

Name

Gene

Indication

Nagoya Univ

attenuated HSV-1;
HF-10 TBI- 1401

Recurrent Brest Cancer,
Recurrent Head and Neck
CancerMie Univ

attenuated HSV-1;
HF-10

Solid tumor

Tokyo Univ

Recom.HSV-; G47Δ

Prostate Cancer, Progressive
glioblastoma,

Okayama Univ

Recom. Adenovirus;
Telomelysin(OBP-301)hTERT Promotor

Head and Neck Cancer,
Lung Cancer, esophageal
neoplasm

Oncolysis
BioPharma

Recom. Adenovirus;
Telomelysin(OBP-301)hTERT Promotor

Progressive Solid Cancer

Takara Bio

attenuated HSV-1;
HF-10

Head and Neck Cancer,
Malignant Melanoma,

Tokyo Univ

Recom.HSV-; G47Δ

Progressive Glioblastoma

Kagoshima Univ

recom. Adenovirus;
Surv.m-CRP-1

Survivine Promoter

Astellas-Amgen
BioPharma

HSV1（talimogene
laherparepvec）

GM-CSF

osteosarcoma

Malignant Melanoma

CART cell and TCR‐CTL• Tumor‐specific cytotoxic T cell gene therapies are developed
not only by pharmaceutical company but also by academia.
• CART clinical trials (CTL019) are expected to become newtools to treat patients with intractable cancer, because of
their high response rate.
• During CART(CTL019) clinical trials, several severe adverse
effects were observed such as cytokine storm, cerebral
edema, or swelling of the brain• The sponsor should correspond these adverse effects during
the clinical studies.
Whereas from their high responsibility, CART cell therapy will be expected to provide
breakthrough therapy for many cancers, it should be very important to control thesevere adverse effects.

142017/9/29

New technology such as gene editing
have impact on regulation

Gene therapy clinical study using gene‐editing
technology （clinicaltrial.gov data 2017.3.15)
10
9
8
number

7
6
5
4
3

CRISPR/Cas9

2

TALEN/CRISPRCRISPR
TALEN
ZFN

1
0
2009 2010 2011 2012 2013 2014 2015 2016 2017
Year

15

2017/9/29

Comparison of gene‐editing gene therapy
with traditional gene therapy
Gene therapy using gene-editing

Traditional gene therapy

Chromosome Target gene (abnormal gene)

Chromosome Target gene (abnormal gene)

Gene transfer

Retro-, lentivirus

Out-ofChromosome
Target gene(abnormal gene)

Gene cutting by CRISPR/CAS9

AAV

Normal gene

Nonhomologous
repairＸ
Knock-outof abnormal
gene

Not‐target gene locus

 Gene addition or complement

Donor DNAhomologous
recombination

Repairing abnormal gene

 No change of abnormal gene

 Repair or knockout of abnormal/target gene（for congenital disease）

 Difficult to control the insertion site

 Repair the abnormal gene

➡Risk of insertional mutagenesis

 Control the insertion site of target gene

 Difficult to control the expression of transgene

 Control the expression of target gene

Ultimate gene therapy for congenital chromosomal diseases
Risk of off-target genome editing (off target mutagenesis)

Clinical protocol using gene‐editing in Clinicaltrial.gov
TargetFirst received

Phase 1Phase

Autologous T cells genetically modified at the CCR5 gene by ZFN SB‐728 for HIV

Title

Completed

ZFN

ex vivo (T cell)HIV

4‐Feb‐09

Phase 1

Phase I dose escalation study of autologous T cells genetically modified at the CCR5 gene by ZFNin HIV‐infected patients

Completed

ZFN

ex vivo (T cell)HIV

6‐Jan‐10Phase 1/2 Study of autologous T cells genetically modified at the CCR5 gene by ZFN in HIV‐infected subjects

Completed

ZFN

ex vivo (T cell)HIV

29‐Nov‐10

Phase 1/2 Dose escalation study of cyclophosphamide in HIV‐infected subjects on HAART receiving SB‐728‐T

ActiveZFN

ex vivo (T cell)HIV

1‐Mar‐12

ActiveZFN

ex vivo (T cell)HIV

22‐Aug‐14

Repeat doses of SB728mR‐T after cyclophosphamide conditioning in HIV infected subjects on

Phase 1/2 HAART

Status

MethodPhase 1

Safety study of ZFN CCR5‐modified hematopoietic stem/progenitor cells in HIV‐1 infectedpatients

Recruiting

ZFN

ex vivo (HSC)HIV

16‐Mar‐15

Phase 1

A Phase I Study of T‐Cells Genetically Modified at the CCR5 Gene by Zinc Finger Nucleases SB‐
728mR in HIV‐Infected Patients

Recruiting

ZFN

ex vivo (T cell)HIV

24‐Feb‐15

Phase 1

Ascending Dose Study of Genome Editing by ZFN Therapeutic SB‐FIX in Subjects With Severe
Hemophilia B
Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB‐318 in
Subjects With MPS I

Recruiting

ZFN

in vivo

Hemophilia B

24‐Feb‐16

Not yet recruiting

ZFN

in vivo

MPS‐I

29‐Feb‐16

Phase 1
Phase 1

Dose Escalation Study to Evaluate the Safety, Tolerability and Biological Activity of a Single Doseof UCART19 in Patients With Relapsed / Refractory (R/R) B‐cell Acute Lymphoblastic Leukemia(ALL) and Chronic Lymphocytic Leukemia (CLL) (CALM)

Recruiting

TALEN

ex vivo(T‐cell:UCART19)

cancer7‐Mar‐16

Phase 1

PD‐1 Knockout Engineered T Cells for Metastatic Non‐small Cell Lung Cancer

Recruiting

CRISPRex vivo(T cell)

cancer30‐May‐16

Phase 1

Study of Molecular‐targeted Therapy Using Zinc Finger Nuclease in Cervical Precancerous Lesions

Phase 1

Study of UCART19 in Pediatric Patients With Relapsed/Refractory B Acute Lymphoblastic
Leukemia (PALL)

Phase 1
Phase 1

Not yet recruiting

ZFN

in vivo

HPV

1‐Jun‐16

Recruiting

TALEN

ex vivo(T‐cell: UCART19)

cancer16‐Jun‐16

PD‐1 Knockout Engineered T Cells for Muscle‐invasive Bladder Cancer

Not yet recruiting

CRISPRex vivo(T cell)

cancer1‐Aug‐16

PD‐1 Knockout Engineered T Cells for Metastatic Renal Cell Carcinoma

Not yet recruiting

CRISPRex vivo(T cell)

cancer11‐Aug‐16

Phase 1

PD‐1 Knockout Engineered T Cells for Castration Resistant Prostate Cancer

Not yet recruiting

CRISPRex vivo(T cell)

cancer11‐Aug‐16

Phase 1

Ascending Dose Study of Genome Editing by the ZFN Therapeutic SB‐913 in Subjects With MPS II

Not yet recruiting

ZFN

in vivoMPS II

13‐Jan‐17

Phase 1

PD‐1 Knockout EBV‐CTLs for Advanced Stage Epstein‐Barr Virus (EBV) Associated Malignancies

Not yet recruiting

CRISPRex vivo(T cell)

cancer22‐Jan‐17

Phase 1

A Safety and Efficacy Study of TALEN and CRISPR/Cas9 in the Treatment of HPV‐related CervicalIntraepithelial Neoplasia

Not yet recruiting

TALEN,CRISPR

in vivocancer12‐Feb‐17

Red：Ongoing or Plan in 2015; Yellow：Ongoing Blue：Plan in 201716

2017/9/29

Gene editing of human fertilized eggs using
CRISPR/Cas9
 Gene editing for human fertilized eggs
（Protein Cell 2015, 6(5):363–372)
model study for the treatment of βtalathemia
cutting of β‐globulin gene and introduce the mutation
Cas9 mRNA, gRNA, GFP mRNA and oligo donor DNA were micro‐injected Gene editing for human fertilized eggs
(J. Assisted Reproduction and Genetics 2016, 33; 581–588)
knock‐out of CCR5 gene
Cas9 mRNA, gRNA and donor oligo DNA were micro‐injected Application of gene editing to fertilized human egg (Mol Genet
Genomics: published online March 2017)
βglobulin gene, G6PD gene
Cas9 protein、Oligo‐sgRNA and donor oligo DNA were micro‐injected.

Definitions of Somatic Cell Therapy andGene Therapy
 Definition of Gene Therapy
 Gene therapy is a medical intervention based on modification of the genetic materialof living cells (FDA)
 Gene therapy is a medical treatment based on administration of gene or gene‐transfected cells to patient (Japan)
 Gene therapy medicinal products generally consist of a vector or delivery
formulation/system 105 containing a genetic construct engineered to express a
specific therapeutic sequence or protein 106 responsible for the regulation, repair,
addition or deletion of a genetic sequence (EMA) (Many guideline make a definition of gene therapy as transduce of a recombinant
DNA materials to patients)

 Gene‐knockout or gene deletion can be conducted by gene editing
technology using protein or mRNA for CRISPR/CAS9 and guide RNA alone.
From current guidelines, it may be possible to decide these gene‐editing
treatment will be out‐of focus of gene therapy.
 Even though using protein or mRNA for CRISPR/CAS9, there is a risk to cause
genome editing of other than target gene by off‐target effect.

17

2017/9/29

In Japan, gene therapy guideline are now underrevision, and the revised guideline will be publishedby the end of 2017 or early 2018.
 In Japan, gene therapy guideline are now underrevision, and the revised guideline will be publishedby the end of 2017 or early 2018.
 The revised guideline will cover the cutting-edge
technology such as gene-editing.
 We believe EMA also is considering the revision of
their gene therapy guideline.
 It is desirable to harmonize how to deal with thegene-editing technology as gene therapy.

In future
MHLW provide new pathway to enhance the development of cutting‐edge‐therapy tolife‐threating diseases : Designation of “Sakigake” (like breakthrough therapy)

18

2017/9/29

Sakigake‐designation

Japan Revitalization Strategy Revised in 2014
‒ Japan’s challenge for the future ‒June 24th, 2014
Assessment Criteria

Section 2 Three Action Plans II. Strategic Market Creation Plan
Theme 1: Extending the nation’s “healthy life expectancy”(3) Specific new measures to be takenv) Others
2) Promoting world‐leading commercialization of innovative drugs and medical devices(“Strategy of SAKIGAKE as a Package”)

The Government will promote a package of measures, including the creation of a “priority
examination designation system” that would halve the approval examination period before
commercialization (from 12 months to 6 months) for drugs identified in the early clinical trial
phase as being likely to be remarkably effective. Through these measures, the Government
will aim to ensure that Japan leads the world in commercializing innovative drugs, medical
devices, regenerative medicine products, and other items targeting fatal diseases (includingorphan cancers, intractable diseases, and other serious conditions) for which effective
remedies do not currently exist.

Assignments on regenerative medical products
indication and treatment
Name of applicant
cultured MSC for neurological disorder
NIPRO Medical Co., Ltd.
/Sapporo Medical Univ.
and/or dysfunction due to spinal cord
injuryrestrictive replicative recombinant herpes Daiichi Sankyo Co., Ltd.
2016/ G47Δ(oncolytic
virus1‐ for malignant brain tumor/ Institute of Medical Sciences,2/10 virus)
University of Tokyo(Glioma)
Japan Regenerative
cultured heart stem cell for congenital
2016/ autologous heart
children heart disease (functional single Medicine Co., Ltd.
2/10 stem cell
/Okayama University
ventricular disease)
CLS2702C/D (cellcultured epithelial cell sheet for2016/
sheet derived from stricturestenosis derived from surgery for CellSeed Co.Ltd.
2/28
oral mucosa)
esophageal cancer
dopamine‐produce dopamine‐produce progenitor cells
2016/
Sumitomo Dainippon
progenitor celldifferentiated from allogeneic iPS cells for
2/28
Pharm. Kyoto Univ
derived from iPS cell Parkinson disease
allogeneic bone‐
cultured allogeneic bone‐marrow‐derived
2016/
MSC for the acute‐phase cerebral
marrow‐derived
Healios Co.Ltd.
2/28
infarction (after 18‐36h)
MSC

Date Name
STR01autologous
2016/bone‐marrow‐
2/10
derived MSC

Designation of SAKIGAKE (like breakthrough therapy)

19

2017/9/29

Image of Review Process for assessment on “Sakigake”【Review Process for New Drug】
Drug strategy
consultation
Non‐clinical

12 month

2 monthPhase I/II

ClinicalConsultation

Review for market
authorization

Phase III

Insurance
formedicalexpensesmarket①Priority consultation【Review Process
for Assessment
Products】
Drug strategy
consultation
Non‐clinical,
Clinical study

Assessment

Phase I/II

②Pre‐review

1
month

(ref)

③ Priority review④Partner for review

Review for market
authorization

Pre‐review
ClinicalConsultation

6 monthPhase III

Insurance
formedicalexpenses

Early marketing of
breakthroughmarketproducts※In some case, the sponsor
can submit the clinical data
after the submission.

【Priority Review】
Drug strategy
consultation
Non‐clinical,
Clinical study

9 month

2 monthPhase I/II

ClinicalConsultat
ion

Phase III

Review for market
authorization

Insurance
formedicalexpensesmarketSummary• Many advanced therapy products have been developed at first as
clinical research by academia in Japan.
• Cell and gene therapy clinical researches may play an important roleon translational research to bring up seeds for advanced therapy.
• New Act for regenerative therapy carries out to enhance the safety ofregenerative therapy and its rapid development.
• To develop oncolytic virus therapy and CART therapy, many clinicalstudies are ongoing and provide promising results. Gene‐editing
technology provide have a possibility of ultimate gene therapy, butthere are remaining risk as off‐target effects. Some gene editing
technology are covered by the definition of gene therapy. We are
now trying to revise the guideline to include these technology.
• Designation of “Sakigake” will be expected to progress a new therapyof advance therapy products for life‐treating diseases.

20