2020 8
•
•
•
•
2
1.
2.
3.
4.
5.
• Appendix
3
4
Modalis Therapeutics CRISPR
2016 1
2016 1 EdiGENE Inc.
2016 4
Modalis Therapeutics Inc.
CEO 2017 4
CRISPR-GNDM
16-5 Y’s 4F 2017 12
Modalis Therapeutics Inc. 2017 12
(51 Moulton st. Cambridge MA)
2018 6
J-Startup
CRISPR 2019 1
2019 3
1,300,000
2019 3
41.1 Modalis Therapeutics
Corporation
2019 8
EdiGENE Inc. Modalis Therapeutics Inc.
25,100,000 ( 2,903,200 )
2
2019 9
17 ( 2020 5 31 PhD 7
[ ]4 [ ]13 2019 11
CRISPR-GNDM
J-STARTUP 2018 Editas Medicine, Inc. CRISPR/Cas9
2020 4
5
Modalis Therapeutics 6
next big thing
•
•
CRISPR
•
•
•
• 5 2
• 3
• 2 380
•
• 2019.12
•
6
)
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
GNDM GNDM
GMP
3 10
12 24
*1
*2
*2
*1: P21
*2:
8
*
IND I II III
MDL-201 380
MDL-202
MDL-204
MDL-205
MDL-206
MDL-101 MDC1A
MDL-102
*:
9
10
2019
304
645 218
33 109
2016/12 2017/12 2018/12 2019/12
(
(
146
JP
65 4
18
0
2016/12 2017/12 2018/12 2019/12 1
46
US
1 13
141
10 )PhD7
213
)PhD2 6 )PhD7
)PhD5
2
2016/12 2017/12 2018/12 2019/12
11
( )
( ) 2018/12 2019/12 2020/12 1Q
1,214,738 3,874,974 3,703,938
1,205,143 3,857,235 3,682,880
A
757 48,954 51,763 VC
36% :
9,011 14,499 14,199
1,224,508 3,938,428 3,769,901
42%
22,728 95,885 45,446
50,000 1,300,000 1,300,000
1,371,735 2,621,735 2,621,735
O O
219,640 79,112 197,398
12%
1,202,094 3,842,623 3,724,336
1,201,779 3,842,542 3,724,455 2%
8%
1,224,508 3,938,428 3,769,901
( )
( ) 2018/12 2019/12 2020/12 1Q
65,297 644,500 13,000 10%
A
279,420 487,305 129,164
:
217,927 303,680 81,317
61,493 183,625 47,846 37%
214,123 157,194 116,164
VC
983 1,119 98 32%
250 11,962 858
213,390 146,351 116,924
213,390 146,351 116,924
O O 2%
O 4,518 5,823 1,362
11%
217,909 140,528 118,286 8%
217,909 140,528 118,286
12
13
=
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
14
2 ON/OFF
X Y Z
• 37
A
• 200
DNA
• 30 DNA
2
ON
B OFF
15
AAGTCAACTAGC
ON OFF
OFF ON
16
DNA DNA
AAGTCAACTAGC AAGTCATCTAGC
17
DNA
AAGTCAACTAGC AAGTCATCTAGC
AAGTCATCTAGC
DNA
18
Monogenic Diseases
Monogenic Diseases( )
Monogenic Disease
Monogenic Disease =1
1
2
3
5
6
4
19
TAM
(1989~ )
7,000
Cancer diseases
Monogenic diseases
3,500 Cardio vascular diseases
Infectious dise ases
Others
He althy volunt eers
11.7%
2,200 66.8%
Neurological diseases
Gene marking
Ocular diseases
Inflammat ory diseases
: Discovery Medicine Modalis Tx : The Journal of Gene Medicine (2019) Modalis Tx
20
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
21
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
200,000 176,325 500,000 444,066
8,051 416,784
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
3,496 200,000
4,000
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
22
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
23
CRISPR
CRISPR
RNA
CRISPR
ZFN TALEN
RNA DNA
( )
ZFN TALEN gRNA
Cas9
DNA
( )
24
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%
0 23%
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
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
67%
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
25
CRISPR-GNDM
CRISPR = CRISPR-GNDM
CRISPR-GNDM (Guide Nucleotide-Directed Modulation) platform
ON/OFF
gRNA
dCas9
( )
26
CRISPR-GNDM
CRISPR-GNDM
AAV
+GNDM
U6 gRNA Cas9 pA
-GNDM
AAV
1 2 3 4
AAV GNDM
GNDM
27
CRISPR-GNDM
GNDM
gRNA
ON
OFF
gRNA dCas9
28
MDL-101
MDC1A( 1A )
LAMA2
• : 1 / 30,000*
• :
• :
• :
•
•
• : LAMA2
: Flores et al, Frontiers in Molecular Neuroscience vol 13 (2020) *Ophanet
29
MDL-101
GNDM MDC1A
LAMA1 ON
CRISPR-GNDM-a targeting LAMA1
ON
RNA
LAMA1
dCas9
LAMA2
30
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
31
32
Modalis
e.g.
e.g.
:
33
+
+
* *
( )
34
Broad CRISPR
Allergan
abbvie
JUNO Tx
Bristol-Myers Squibb
CART
Beam Tx
Editas Medicine
MIT
GNDM IP
Modalis Tx
35
DMD
DMD
2024 3,000
: 1/3,500-1/9,300 *
US $ (mln)
7,000
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
36
CRISPR 3
JUNO Tx CART 3 $25M
+ $22M + $700M
$747M
Editas Medicine Bristol-Myers Squibb
$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
Option for
NTLA-US REGENERON + $135M / 1 product $260M
10
+ 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 *
37
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
38
39
2,200
100
MDL-102
MDL-101
MDL-206
380
MDL-205
MDL-204
MDL-202
MDL-201
40
*
2019/12 2020/12 2021/12
MDL-201
2019 1Q 2021
IND
380
MDL-202
2019 3Q 2021
IND
MDL-204
2019 3Q 2020
CNS
MDL-205
2019 4Q
CNS
MDL-206
2020 2Q
CNS
*
41
*
2019/12 2020/12 2021/12
MDL-101
MDC1A 2020 2022
( ) IND
MDL-102
2021
CNS
MDL-103
2021
CNS
*
42
GNDM
•
•
•
•
•
•
43
CRISPR
4565 4587
( 1,301 6,276
)
JCR
J TEC
DWTI
( )
Delta-Fly Pharma
GNI
HMT
6 Modalis Tx 6/15
1990
44
Appendix
45
Modalis
24
• 2022 1 US
•
•
46
47
DNA
( ) DNA( ) ( )
48
2 strategies for gene therapy
1. Ex vivo 2. In vivo
DNA
49
CRISPR-GNDM
GNDM GTx
( )
- ZFN TALEN CRISPR CRISPR CRISPR
-
1
AAV/LNP AAV AAV AAV/LNP AAV/LNP AAV
(1 )
~3.5kb
AUDENTES Tx Editas Medicine
Spark Tx
Sangamo Tx Intellia Tx Beam Tx
AveXis
SAREPTA Tx CRISPR Tx
REGENXBIO
: ModalisTx
50
1/2
Page Word Explanation
1A α2 Lama2
P9 MDC1A
P21 GTx Gene Therapy
DNA
P24 ZFN
ZFN TAL effector TALE
P24 TALEN
DNA
P24 gRNA RNA CRISPR-Cas RNA
DNA Cas9 Cas9
P26 dCas9
P27 AAV
P31 Gain of Malfunction
P31 Loss of function
51
2/2
Page Word Explanation
21-23 RNA RNA
P31 siRNA (mRNA)
Antisense oligo( ) DNA RNA
P31 ASO siRNA
P36 Duchenne muscular dystrophy
P41 CNS Central nervous system
(
P48 ) DNA
P48
Ex vivo
P49 Ex vivo / In vivo In vivo
52