2020 8

2

•

•

•

•

3

1.

2.

3.

4.

5.

• Appendix

4

Modalis Therapeutics CRISPR

5

2016 1

CEO

16-5 Y’s 4F

Modalis Therapeutics Inc. (51 Moulton st. Cambridge MA)

CRISPR

1,300,000

41.1

25,100,000 ( 2,903,200 )

17 ( 2020 5 31 PhD 7[ ]4 [ ]13

J-STARTUP 2018

2016 1

2016 4 EdiGENE Inc.Modalis Therapeutics Inc.

2017 4 CRISPR-GNDM

2017 12

2017 12

2018 6 J-Startup

2019 1

2019 3

2019 3

2019 8

Modalis Therapeutics Corporation

EdiGENE Inc. Modalis Therapeutics Inc.

2019 9 2

2019 11 CRISPR-GNDM

2020 4 Editas Medicine, Inc. CRISPR/Cas9

Modalis Therapeutics 6

6

next big thing••

CRISPR

••

• 3• 2 380

•• 2019.12

•• 5 2

•

)

7

• ••

• ( ),

•PRISM

BioLab

CEO

• ( ) CEO, ( ) , ( PwC Strategy &),

( ) •

••

MD PhD: SVP, Chief Technology Officer

• ,

• Joslin Diabetes Center( ),

• Medical Patent Research ( )• ) ( )

, ( )

MBA: SV, Chief Financial Officer

• ( ), ()(CFO), Argenes( ), ,

•

Joseph S. McCracken• Roche , Genentech,

Sanofi-Aventis

8

*1: P21*2:

GNDM GNDMGMP

12 24 3 10

*2

*2

*1

9

MDL-201

MDL-202

MDL-204

MDL-205

MDL-206

*I II IIIIND

MDL-101

MDL-102

MDC1A

*:

380

10

0 1865

645

46

141

213

146

2016/12 2017/12 2018/12 2019/12

2

6

10131

1

4

2016/12 2017/12 2018/12 2019/12

2019

11

US

)PhD7

(JP

)PhD5)PhD7)PhD2

33 109

218

304

2016/12 2017/12 2018/12 2019/12

(

12

( ) 2018/12 2019/12 2020/12 1Q1,214,738 3,874,974 3,703,9381,205,143 3,857,235 3,682,880

757 48,954 51,7639,011 14,499 14,199

1,224,508 3,938,428 3,769,90122,728 95,885 45,44650,000 1,300,000 1,300,000

1,371,735 2,621,735 2,621,735219,640 79,112 197,398

1,202,094 3,842,623 3,724,3361,201,779 3,842,542 3,724,4551,224,508 3,938,428 3,769,901

( ) 2018/12 2019/12 2020/12 1Q65,297 644,500 13,000

279,420 487,305 129,164217,927 303,680 81,317

61,493 183,625 47,846214,123 157,194 116,164

983 1,119 98250 11,962 858

213,390 146,351 116,924213,390 146,351 116,924

O 4,518 5,823 1,362217,909 140,528 118,286217,909 140,528 118,286

( )

( )

A

:

42%

2%8%

O O12%

VC36%

A

:

37%

2%

8%

O O11%

VC32%

10%

13

=10,000* 7,000# 80%†

14

A B C D95%† ¶

600

4 ¶

: *21st Century Cure Act, #NIH GARD †innovation.org ¶GlobalGenes.orgActive therapeutics of 491 NME, 106 BLA, 17 cellular and gene therapy products @FDA as of 2019.7.22 Source from KEGG

2 ON/OFF

15

A

B

X Y Z• 37

• 200

DNA

• 30 DNA2

ONOFF

16

AAGTCAACTAGC

ON OFF

OFF ON

DNA DNA

17

AAGTCAACTAGC AAGTCATCTAGC

DNA

18

AAGTCAACTAGC AAGTCATCTAGC

AAGTCATCTAGC

DNA

Monogenic Diseases( )Monogenic Disease

19

Monogenic Disease =1

1

2

3

4

5

6

Monogenic Diseases

20

7,000

3,500

2,200

(1989~ )

: Discovery Medicine Modalis Tx

TAM

: The Journal of Gene Medicine (2019) Modalis Tx

66.8%11.7%

Cancer diseases

Monogenic diseases

Cardiovascular diseases

Infectious diseases

Others

Healthy volunteers

Neurological diseases

Gene marking

Ocular diseases

Inflammatory diseases

GTx PoP PoC

21

(Proof of Mechanism)

(Proof of Principal)

(Proof of Concept)

PhIIb

PhIIa

PhI

pre

clinic

al

CRISPR-GNDM

pre

clinic

al PhI

: Nature Biotechnology volume 30, p596–599 (2012) Modalis Tx

GTx

GTxGTx

22

: Evaluate Ltd 2019 8 CAGR 2018 2024 2019 2024

27 4441,371

3,060

5,820

10,062

14,906

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

2018 2019 2020 2021 2022 2023 2024

CAGR 185.7%14.9 Billion$

(2024 )

2,0402,693

3,4964,336

5,795

8,051

10,651

0

2,000

4,000

6,000

8,000

10,000

12,000

2018 2019 2020 2021 2022 2023 2024

120,563135,722

149,757163,136

176,325187,211

197,215

0

50,000

100,000

150,000

200,000

250,000

2018 2019 2020 2021 2022 2023 2024

399,725399,874

416,784 444,066475,819 508,220

545,585

0

100,000

200,000

300,000

400,000

500,000

600,000

2018 2019 2020 2021 2022 2023 2024

CAGR 31.7%10.7 Billion$

(2024 )

CAGR 8.5%197.2 Billion$

(2024 )

CAGR 5.3%545.6 Billion$

(2024 )

US $ (mln)

US $ (mln) US $ (mln) US $ (mln)

Gene Therapy

(DNA&RNA therapeutics) (Monoclonal antibody) (Small molecule chemistry)

GTx

GTx M&A2018 2019 M&A /

23

/ /

2019/12 3.0 billion$AT132: X (XLMTM)AT845:AT702, AT751, AT753: (DMD)

2019/10 3.0 billion$( )SPIRO-2101: SPIRO-2102:

2019/6 1.0 billion$ (DMD)1 (DM1)

2019/3 165 million$ MYO-101: 2E (LGMD 2E)MYO-102: 2D (LGMD 2D)

2019/3 800 million$NSR-REP1: NSR-RPGR: X (XLRP)NSR-ABCA4:

2019/2 4.3 billion$SPK-9001: BSPK-8011, SPK-8016: A SPK-7001: ( )

2018/5 8.7 billion$ AVXS-101 IT : SMA Type 2AVXS-201: RTTAVXS-301: ALS

: ModalisTx

GTx M&A

VERTEX

SAREPTA Tx

Biogen

Roche

NOVARTIS

AUDENTES Tx

ROIVANT

Exonics Tx

Myonexus Tx

Nightstar Tx

Spark Tx

AveXis

CRISPRRNA

24

CRISPR

ZFN TALENCas9

gRNA

ZFN TALEN

RNA DNA( )

CRISPR

DNA( )

0

10

20

30

40

50

60

70

80

90

100

Jan-

04

Jan-

05

Jan-

06

Jan-

07

Jan-

08

Jan-

09

Jan-

10

Jan-

11

Jan-

12

Jan-

13

Jan-

14

Jan-

15

Jan-

16

Jan-

17

Jan-

18

Jan-

19

CRISPR

25

RNAi

iPS

CRISPR

67%

23%

10%

86%

7%7% JPNUS

RNAi Oct 2006

iPS Oct 2012s

Google ( ) 3 (2005-2015)

CRISPR

: Google Trends ModalisTx: iPS 2012 10 100

iPS CRISPR RNAi

CRISPR = CRISPR-GNDM

26

CRISPR-GNDM (Guide Nucleotide-Directed Modulation) platform

dCas9( )

ON/OFFgRNA

CRISPR-GNDM

CRISPR-GNDMAAV

27

1 2 3

AAV

AAV GNDM

4

U6 Cas9gRNA pA

+GNDM

-GNDM

GNDM

CRISPR-GNDM

GNDMgRNA

28

gRNA

ON

OFF

dCas9

CRISPR-GNDM

• : 1 / 30,000*• : • : • :

••

• : LAMA2

MDC1A( 1A )LAMA2

: Flores et al, Frontiers in Molecular Neuroscience vol 13 (2020) *Ophanet

MDL-101

29

GNDM MDC1ALAMA1 ON

dCas9

CRISPR-GNDM-a targeting LAMA1

RNA

LAMA2

MDL-101

ON

LAMA1

30

Small 3.5kb Large

780

520 /siRNA/ASO

GNDMGTx

31

A

B

C

Gain ofMalfunction

Loss ofFunction

400

: Discovery Medicine Modalis Tx

GNDM

3,500

GNDM2,200

GNDM

1

CRISPR-GNDM

32

Modalis

33

e.g.

e.g.

:

34

+

+**

( )

Broad CRISPR

CART

Modalis Tx

GNDM IP

35

Editas Medicine

MIT

Allerganabbvie

JUNO TxBristol-Myers Squibb

Beam Tx

DMD2024 3,000

36

Evaluate Ltd Modalis Tx 2019 8 *: Orphanet2019 2024 DMD MDC1A MDC1A DMD 1/3~1/10

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

2018 2019 2020 2021 2022 2023 2024SRP-9001 (AVII) Raxone (SANTH) Exondys 51 (AVII)Golodirsen (AVII) Vamorolone (SANTH) Casimersen (AVII)Translarna (PTC Therapeutics) Suvodirsen (WAVE Life Sciences) Edasalonexent (Catabasis Pharmaceuticals)NS-065 (NIPSH) Other

US $ (mln)

3,000

DMD

: 1/3,500-1/9,300 *

$1,484MEDIT-US

CART 3 $25M+ $22M + $700M

LCA105

$90M + MS

$1,099MNTLA-US

CART

$10M + $20M+ $20M+ $230.3M / 1 product+ 15%$13M

& Novartis DDS 14

Option for10& Except some

$75M+ $135M / 1 product+ 10%$50M @ IPO

$3,654MCRSP-US

Option to 6 targets$75M+ $30M+ $420M MS / 1 target +

JV 50:50 & $70M

BAYER CASEBIA$45M + $255M

CASEBIA CRISPR$15M $20M when get IP

CRISPR 3

37

$747M

$293.3M

$260M

$525M

$405M

Modalis Tx 6/12 *

Editas Medicine

Intellia Tx

CRISPR Tx

JUNO TxBristol-Myers Squibb

Allerganabbvie

NOVARTIS

REGENERON

VERTEX

BAYER

CASEBIA

CRISPR

38

6/3 B=Billion

Canonical( = )

Non-canonical( )

$3.9B

$1.5B

$1.4B

$1.1B~$1B

~$1B

?

Dx Platformer Tx

CRISPR

Intellia TX

CRISPR Tx

Editas

Beam Tx

KSQ

ExonicsTx

CASEBIA TX

BlueRockTx

VERTEX

BAYER

SHERLOCK BIOSCIENCES

Mammoth Biosciences

39

40

MDL-201

MDL-202

MDL-101

MDL-102

MDL-204

2,200

MDL-205

100

MDL-206380

*

41

*

MDL-201

MDL-202

MDL-204

MDL-205

2019/12 2020/12 2021/12

2019 1Q 2021

IND

2019 3Q 2021

IND

2019 3Q 2020

2019 4Q

CNS

CNS

MDL-206

CNS2020 2Q

380

*

42

*

MDL-101

MDL-102

2019/12 2020/12 2021/12

2020 2022

IND

2021

MDC1A( )

CNS

CNS

2021

MDL-103

GNDM

••

••

••

43

CRISPR

()

( )

44

6 Modalis Tx 6/151990

45876,276

45651,301

HMT

DWTI

Delta-Fly Pharma

GNI

JCR

J TEC

Appendix

45

Modalis24

46

• 2022 1 US

•

•

47

DNA( ) DNA( ) ( )

48

49

2 strategies for gene therapy1. Ex vivo 2. In vivo

DNA

( )

- ZFN TALEN CRISPR CRISPR CRISPR

-

1

AAV/LNP AAV AAV AAV/LNP AAV/LNP AAV

(1 )

~3.5kb

GNDM GTx

50

: ModalisTx

CRISPR-GNDM

AUDENTES TxSpark Tx

AveXisSAREPTA Tx

REGENXBIO

Sangamo TxEditas Medicine

Intellia Tx

CRISPR Tx

Beam Tx

1/2

51

Page Word Explanation

P9 MDC1A1A α2 Lama2

P21 GTx Gene Therapy

P24 ZFNDNA

P24 TALENZFN TAL effector TALE

DNA

P24 gRNA RNA CRISPR-Cas RNA

P26 dCas9DNA Cas9 Cas9

P27 AAV

P31 Gain of Malfunction

P31 Loss of function

2/2

52

Page Word Explanation

P31 siRNA 21-23 RNA RNA(mRNA)

P31 ASO Antisense oligo( ) DNA RNAsiRNA

P36 Duchenne muscular dystrophy

P41 CNS Central nervous system

P48 () DNA

P48

P49 Ex vivo / In vivo Ex vivoIn vivo