1
02
2020 8 25
•
•
•
•
2
1.
2.
3.
4.
•
3
4
1
Modalis Therapeutics CRISPR
: 4883
2016 1
2016 1 EdiGENE Inc.
2016 4
Modalis Therapeutics Inc.
CEO CRISPR-GNDM
2017 4
16-5 Y’s 4F 2017 12
2017 12
Modalis Therapeutics Inc.
(51 Moulton st. Cambridge MA) 2018 6
J-Startup
2019 1
CRISPR
2019 3
2019 3
2,549,200
Modalis Therapeutics Corporation
2019 8
27,200,000 EdiGENE Inc. Modalis Therapeutics Inc.
2
17 ( 2020 7 31 ) PhD 7 2019 9
[ ]4 [ ]13
2019 11 CRISPR-GNDM
Editas Medicine, Inc. CRISPR/Cas9
J-STARTUP 2018 2020 4
2020 8 : 4883
5
1
Modalis Therapeutics 6
next big thing
•
•
CRISPR
•
•
•
• 5 2
• 3
• 2 380
•
• 2019.12
•
6
1
CEO
• ( ) CEO, •
( ), •
( PwC Strategy &),
( )
•
MD PhD: SVP, Chief Technology Officer
• , • Medical Patent Research ( )
• )( )
• Joslin Diabetes Center( ), , ( )
MBA: SV, Chief Financial Officer
Joseph S. McCracken
• ( ), (CFO), • Roche , Genentech,
Argenes( ), , Sanofi-Aventis
•
( ( (
)
• • ( ), •
•
•
(
PRISM
BioLab (
7
1
GNDM GNDM
GMP
3 10
12 24
*
*
*
8
1
/ /
*1
/ / IND I II III
MDL-201
MDL-202
MDL-204
MDL-205
MDL-206
MDL-101 MDC1A*2
MDL-102
*1:
*2:MDC1A= A
9
10
2020 12
2020 12
337 1,100 644
298 750 487
204 550 303
94 200 183
38 350 157
29 300 146
26 250 140
0 0
9 1 9 MDL-202 MDL-206
1 9
0 0
1 0 2
11
0 2020 12 0
2020 12 0
0
3,874 3,104 770
3,857 2,735 1,122
63 856 793
― 798 798
B 3,938 3,961 23
91 84 7
4 7 3
B 95 92 3
B 3,842 3,868 26
B 3,938 3,961 23
97.6 97.7
• 2 1
• 9 A CRISPR/Cas9
12
2020 12 9
2020 12 9
3,857 304
814
0 2,735
1 1 1
0 9 9 9 0
2020
• 29
9
• 0 338
9 • 0 2 814
9 • 0 1
13
14
3 CRISPR-GNDM
CRISPR = CRISPR-GNDM
CRISPR-GNDM (Guide Nucleotide-Directed Modulation) platform
ON/OFF
gRNA
dCas9
( )
15
3 MDL-101
MDC1A( 1A )
LAMA2
• : 1 / 30,000*
• :
• :
• :
•
•
• : LAMA2
: Flores et al, Frontiers in Molecular Neuroscience vol 13 (2020) *Ophanet
16
3 MDL-101
LAMA2 LAMA1
LAMA2 LAMA1
LAMA1 LAMA2
Expression by tissue RNA Protein RNA Protein
: Human Protein Atlas Nature 2019
17
3 MDL-101
GNDM MDC1A
LAMA1 ON
CRISPR-GNDM-a targeting LAMA1
ON
RNA
LAMA1
dCas9
LAMA2
18
19
4
2,200
100
MDL-102
MDL-101
MDL-206
MDL-205
MDL-204
MDL-202
MDL-201
20
4
*
2019/12 2020/12 2021/12
MDL-201
2019 1Q
2021
MDL-202
2019 3Q 2021
MDL-204
2019 3Q
CNS
MDL-205
2019 4Q
CNS
MDL-206
2020 2Q
CNS
*
21
4
*
2019/12 2020/12 2021/12
MDL-101
MDC1A 2020 2022
( )
MDL-102
2021
CNS
MDL-103
2021
CNS
*
22
4 GNDM
GNDM
•
•
•
•
•
•
23
24
25
=
10,000* 7,000# 80%†
600
95%† ¶
C
A
D
B
4 ¶
: *21st Century Cure Act, #NIH GARD †innovation.org ¶GlobalGenes.org
Active therapeutics of 491 NME, 106 BLA, 17 cellular and gene therapy products @FDA as of 2019.7.22 Source from KEGG
26
2 ON/OFF
X Y Z
• 37
A
• 200
DNA
• 30 DNA
2
ON
B OFF
27
AAGTCAACTAGC
ON OFF
OFF ON
28
DNA DNA
AAGTCAACTAGC AAGTCATCTAGC
29
DNA
AAGTCAACTAGC AAGTCATCTAGC
AAGTCATCTAGC
DNA
30
Monogenic Diseases
Monogenic Diseases( )
Monogenic Disease
Monogenic Disease =1
1
2
3
5
6
4
31
TAM
(1989~ )
7,000
Cancer diseases
Monogenic diseases
3,500 Cardiovascular diseases
Infectious diseases
Others
Healthy volunt eers
11.7%
2,200 66.8%
Neurological diseases
Gene marking
Ocular diseases
Inflammatory diseases
: Discovery Medicine Modalis Tx : The Journal of Gene Medicine (2019) Modalis Tx
32
CRISPR-GNDM
GNDM
GTx
GNDM
3,500
520 /siRNA/ASO 1
Gain of
Malfunction A
GNDM
2,200
B
Loss of C
Function 780
Small 3.5kb Large
400
GNDM
: Discovery Medicine Modalis Tx
33
GTx
GTx PoP PoC
CRISPR-GNDM
preclinical
preclinical
PhI
(Proof of Mechanism)
PhI
PhIIa
(Proof of Principal)
PhIIb
(Proof of Concept)
: Nature Biotechnology volume 30, p596–599 (2012) Modalis Tx
34
GTx
GTx
GTx
Gene Therapy
US $ (mln)
CAGR 185.7%
16,000 14,906
14,000
14.9 Billion$
12,000
(2024 ) 10,062
10,000
8,000
5,820
6,000
4,000 3,060
2,000 1,371
27 444
0
2018 2019 2020 2021 2022 2023 2024
(DNA&RNA therapeutics) (Monoclonal antibody) (Small molecule chemistry)
US $ (mln) CAGR 31.7% US $ (mln) CAGR 8.5% US $ (mln) CAGR 5.3%
10.7 Billion$ 197.2 Billion$ 545.6 Billion$
12,000 (2024 ) 10,651
250,000 (2024 ) 600,000 (2024 ) 545,585
197,215
10,000 187,211 475,819 508,220
200,000 500,000
8,051
176,325 416,784 444,066
163,136 399,874
8,000 149,757 400,000 399,725
150,000 135,722
5,795 120,563
6,000 300,000
4,336 100,000
4,000 3,496 200,000
2,693
2,040
50,000 100,000
2,000
0
0 0
2018 2019 2020 2021 2022 2023 2024
2018 2019 2020 2021 2022 2023 2024 2018 2019 2020 2021 2022 2023 2024
: Evaluate Ltd 2019 8 CAGR 2018 2024 2019 2024
35
GTx M&A
GTx M&A
2018 2019 M&A /
/ /
AT132: X (XLMTM)
2019/12 AUDENTES Tx 3.0 billion$ AT845:
AT702, AT751, AT753: (DMD)
3.0 billion$ SPIRO-2101:
2019/10 ROIVANT ( ) SPIRO-2102:
(DMD)
VERTEX 2019/6 Exonics Tx 1.0 billion$ 1 (DM1)
MYO-101: 2E (LGMD 2E)
SAREPTA Tx 2019/3 Myonexus Tx 165 million$ MYO-102: 2D (LGMD 2D)
NSR-REP1:
Biogen 2019/3 Nightstar Tx 800 million$ NSR-RPGR: X (XLRP)
NSR-ABCA4:
SPK-9001: B
Roche 2019/2 Spark Tx 4.3 billion$ SPK-8011, SPK-8016: A
SPK-7001: ( )
AVXS-101 IT : SMA Type 2
NOVARTIS 2018/5 AveXis 8.7 billion$ AVXS-201: RTT
AVXS-301: ALS
: ModalisTx
36
CRISPR-GNDM
GNDM
gRNA
ON
OFF
gRNA dCas9
37
CRISPR
CRISPR
RNA
CRISPR
ZFN TALEN
RNA DNA
( )
ZFN TALEN gRNA
Cas9
DNA
( )
38
CRISPR
CRISPR
Google ( ) 3 (2005-2015)
100
90 iPS
80
iPS
70 RNAi Oct 2012s
Oct 2006
60
RNAi
50
40
CRISPR
30
20
US JPN
10% 7%
10 7%
23%
0
Ja 4
Ja 5
Ja 6
Ja 7
Ja 8
Ja 9
Ja 0
Ja 1
Ja 2
Ja 3
Ja 4
Ja 5
Ja 6
Ja 7
Ja 8
19
67%
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
n-
n-
n-
n-
n-
n-
n-
n-
n-
n-
n-
n-
n-
n-
n-
n-
Ja
86%
: Google Trends ModalisTx iPS CRISPR RNAi
: iPS 2012 10 100
39
CRISPR-GNDM
CRISPR-GNDM
AAV
+GNDM
U6 gRNA Cas9 pA
-GNDM
AAV
1 2 3 4
AAV GNDM
GNDM
40
Broad CRISPR
Allergan
abbvie
JUNO Tx
Bristol-Myers Squibb
CART
Beam Tx
Editas Medicine
MIT
GNDM IP
Modalis Tx
41
42
Modalis
:
43
+
+
* *
( )
44
CRISPR
4565 4587
( 1,301 6,276
4883
)
JCR
J TEC
DWTI
( )
Delta-Fly Pharma
GNI
HMT
6 Modalis Tx 6/15
1990
45
CRISPR 3
JUNO Tx CART 3 $25M
$747M
Editas Medicine Bristol-Myers Squibb
+ $22M + $700M
$1,484M
Allergan LCA10 $90M + MS
EDIT-US abbvie 5
$10M + $20M
+ $20M
+ $230.3M / 1 product $293.3M
CART + 15%
Intellia Tx NOVARTIS
$13M
& Novartis DDS 14
$1,099M $75M
NTLA-US Option for + $135M / 1 product
REGENERON 10 $260M
+ 10%
& Except some $50M @ IPO
$75M
VERTEX Option to 6 targets + $30M $525M
+ $420M MS / 1 target +
CRISPR Tx JV 50:50 & $70M
BAYER
BAYER CASEBIA $405M
$45M + $255M
$3,654M CASEBIA
CRSP-US CASEBIA CRISPR
$15M $20M when get IP
Modalis Tx 6/12 *
46
CRISPR
CRISPR
Dx Tx
Platformer
KSQ VERTEX
Intellia TX
$1.1B
Exonics ~$1B
Canonical
CRISPR Tx Tx
( = )
$3.9B ? CASEBIA TX
BAYER
Editas
$1.5B BlueRock
~$1B
Tx
SHERLOCK
Non-canonical BIOSCIENCES Beam Tx
( ) Mammoth $1.4B
Biosciences
6/3 B=Billion
47
DMD
DMD
2024 3,000
US $ (mln)
7,000 : 1/3,500-1/9,300 *
6,000
5,000
4,000
3,000
2,000
3,000
1,000
0
2018 2019 2020 2021 2022 2023 2024
SRP-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
Evaluate Ltd Modalis Tx 2019 8 *: Orphanet
2019 2024 DMD MDC1A MDC1A DMD 1/3~1/10
48
Appendix
49
A
50
DNA
( ) DNA( A) ( )
A
51
i
A d
2 strategies for gene therapy
1. Ex vivo 2. In vivo
A
d DNA
A
d
e
52
x e d
GNDM GTx e d
p n
( )p n n
- ZFN TALEN CRISPR CRISPR CRISPR
- i i
p
1
A
AAV/LNP AAV AAV AAV/LNP AAV/LNP AAV
(1 )
p ~3.5kb
AUDENTES Tx Editas Medicine
Spark Tx
Sangamo Tx Intellia Tx Beam Tx
AveXis
SAREPTA Tx CRISPR Tx
REGENXBIO
: ModalisTx
53
1/2
Page Word Explanation
1A α2 nLama2
P9 MDC1A
P15 gRNA RNA CRISPR-Cas n RNA
DNA Cas9 Cas9
P15 dCas9
P21 CNS Central nervous system e x
P33 GTx Gene Therapy n
P33 Gain of Malfunction
P33 Loss of function
21-23 n d RNA RNA n
P33 siRNA (mRNA) n p
Antisense oligo( ) d DNAA RNA
P33 ASO
siRNAi n p
54
2/2
Page Word Explanation
i i A A DNA p
P38 ZFN
d
i ZFN TAL effector TALE
P39 TALEN
d DNA
A A
P40 AAV n
n n A n
P48 Duchenne muscular dystrophy
A n p (
P51 e i
)Ax DNA
e A n A
P51 n
Ex vivo A A
P52 Ex vivo / In vivo In vivo x A
55