R&D Meeting 2021
October 15, 2021
Nippon Shinyaku Co., LTD.

What we aim forWork on R＆D with more speed

PLCM

In-housedevelopment

In-licensing
2

Acceleration of global development
Head Quarter（Japan）

NS Pharma, Inc.（U.S.）

Europe
China

Japan

U.S.

Beijing Representative Office

Led by viltolarsen, we will accelerate our
global development.

3

Recalled from FY 2019
6th Five-Year Medium-termManagement Plan presentationmaterial (partially fixed)

Pharmaceutical R&D strategy

Expand the range of drug discovery to create new value by adding newmodalities and technologies to our drug discovery platform where wecreated a small molecule drug Uptravi and a nucleic acid drug Viltepso.
New modalities in drug discovery
e.g. gene therapy
Nucleic acid DDS(Drug Delivery System)
technology

Small molecule
Nucleic acid
iPS cells, AI drug discovery
Increase in efficiency of small
molecule drug discovery

Pharmaceuticals
with new value

4Progress of products to be launched during the
6th Five-year Mid-term Management Plan
Progress of products planned for launch during the 6th Five-Year Mid-Term
Management Plan (FY2019 to FY2023)
In Japan and overseas

NS-065／NCNP-01（DMD）

In-house

In Japan and overseas

NS-089／NCNP-02（DMD）
OverseasNS-018（Myelofibrosis）
ZX008（Intractable epilepsy）

In-licensed

NS-73（SOS・Prevention）
NS-32（Iron deficiency anemia）

Investigator initiated clinical trial in progress by
National Center of Neuroloogy and Psychiatry

Preparation for global PⅡ trial

In JapanDomestic PⅢ trial in progress
In Japan

NS-73（SOS・Treatment）

Launch in Japan on May 2020
Launch in U.S. on August 2020

In Japan

In Japan

Launch in Japan on
September 2019
Termination of development

Submitted NDA on March 2021
in Japan

DMD: Duchenne muscular dystrophy
SOS: Sinusoidal obstruction syndrome5Progress of products to be launched during the
6th Five-year Mid-term Management Plan
NS-304（CTEPH）

In Japan

Launch in Japan on August 2021

PLCM

In JapanDomestic PⅢ trial in progress
by Janssen Pharmaceutical K.K.

In Japan

Preparing for next
verification trial

Macitentan（CTEPH）
NS-304（Arteriosclerosis obliterans）
In Japan

NS-17（Acute myeloid leukemia）

Launch in Japan on March 2021

The products scheduled for launch During the mid-term
management plan (FY2019 to FY2023), are generally on
track

CTEPH: Chronic thromboembolic pulmonary hypertension

6

Products added to pipeline after the start of
6th Five-year Mid-term Management Plan
NS-304（Pediatric PAH）

In JapanDomestic PⅡ trial in progress

New

In Japan

NS-229（Inflammatory diseases）

Domestic PⅠ trial in progress

In Japan

NS-401（BPDCN）

Preparing for clinical development

In addition to these products,
we will continue to expand our pipeline

PAH: Pulmonary arterial hypertension
BPDCN：Blastic plasmacytoid dendritic cell neoplasm

7

Progress of development
Nucleic acid products
Pre clinical trial

Clinical trial

LaunchExon 50 Skipping（DMD）

NS-065／NCNP-01
Exon 53 Skipping（DMD）

NS-065／NCNP-01
Exon 53 Skipping（DMD）

Exon 51 Skipping（DMD）

NS-089／NCNP-02
Exon 44 Skipping（DMD）

Exon 45 Skipping（DMD）

NS-035
Exon Trapping Inhibitor（Fukuyama congenital
muscular dystrophy）

Exon 55 Skipping（DMD）

Novel coronavirus
infection：Investigator initiated clinical trial

8

～To establish new technology platforms ～【Next generation modalities】【Existing modalities】

9

R&D organization and activities

R&D policy
As a slogan for our R＆D division, we aim for“The creation of new drugs to be used worldwide”.
We will strive to contribute to the society through creating
highly unique and distinctive drugs in the pharmaceuticalfield of intractable disease where small number of patientsare suffering and awaiting for new treatments. Our goal is
to create new drugs which becomes a ray of hope forpatients awaiting for new treatments.
In order to achieve this goal, we will proceed with three
approaches: in-house drug discovery, in-licensing, and
PLCM*.
*Product Life Cycle Management
Maximize product value by considering new indications, dosage forms, etc. forexisting and developed products.
11

R&D approachApproach towards drug discovery modalities
In addition to our two pillars of drug discovery modalities in our R＆D;
nucleic acid and small molecule, we will continue to work on newmodalities such as gene therapy, that are suitable for targeting certain
diseases.

Promote data-driven drug discovery
We will improve the quality and quantity of data and utilize internal andexternal big data to promote research and development not only based on
experience and intuition but also through data analysis using AI and IT, tospeed up and improve the probability of success.

Encourage open innovation
We will continue to cooperate with top-class research institutions andventure companies to develop research themes and collect information on
new technologies. In specific research areas, we aim to build strategic
networks with academia and ventures.
12

R&D organization
Discovery
research
Labs.

Exploratory Research Dept.
Pharmacokinetics and Safety
Assessment Dept.
CMC R&D Dept.
Discovery Research Laboratories
in Tsukuba

ClinicalDevelopment
Div.

Global Clinical Development Dept.

R＆D
Administration
Dept.
Intellectual
Property
Dept.
R＆D
Operation
Dept.

Clinical Development Dept.

Clinical Development Dept. Tokyo
Clinical Development Dept.
Data Science Dept.

NS Pharma
R&D
Division

PMS Clinical Research Dept.
13

R&D bases and in-house development
R&D expenditure (FY2020): 16.1 billion yen (13%of net sales)
Discovery ResearchLaboratories (Kyoto)

Research and development for drug
discovery in pursuit of high added
value
In addition to small molecule drug discovery
which we have cultivated over the years, we willcontinue to incorporate new technology related
to drug discovery and promote the creation of
new drugs which responds to the increase offunctional sophistication.

Discovery ResearchLaboratories in Tsukuba

Innovative and advanced R＆D
With our strengths in nucleic acid research, weare able to lead the field of nucleic acid drugs. In
addition, by developing next-generation nucleic
acid drugs, we will promote the development oftreatments for diseases that have been difficult
to cure with existing modalities.
14

Clinical development
Domestic development (As of August 10, 2021)
Development
Code No.
phase(Generic name)
LaunchP III

NDA filing

Mechanismof action

Therapeutic
field

Indications

Development

Co-development:
Intractable
NS-065 / NCNP-01
Exon 53
National Center
diseases/
Duchenne muscular dystrophy
Nippon Shinyaku(viltolarsen)
Skippingof Neurology andOrphan disease
PsychiatryCo-development:
Intractable
NS-304
Selective IP
Chronic thromboembolic
Janssendiseases/
Nippon Shinyaku(selexipag)
receptor agonist
pulmonary hypertension
Pharmaceutical
Orphan disease
K.K.

NDA filing

NS-32(ferric
derisomaltose)

Iron

Gynecology

Iron-deficiency anemia

P III

ZX008

Serotonin
agonistIntractablediseases/
Orphan disease

Dravet syndrome
Lennox-Gastaut syndrome

P II

NS-304(selexipag)

Selective IP
Cardiovascular
receptor agonist

Arteriosclerosis obliterans

P II

NS-304(selexipag)

Selective IP
receptor agonist

P II

OriginNS-304(selexipag)

Licensed-in from:Pharmaosmos
Nippon Shinyaku
A/S
Commercial
rights from:
Zogenix, Inc.

Zogenix, Inc.

Nippon Shinyaku Nippon Shinyaku

Orthopedics

Lumbar spinal canal stenosis Nippon Shinyaku Nippon Shinyaku

Selective IP
Cardiovascular
receptor agonist

Co-development:
Janssen
Nippon Shinyaku
Pharmaceutical
K.K.

Pediatric pulmonary arterial
hypertension

15

Clinical development
Domestic development (As of August 10, 2021)
Development
Code No.
phase(Generic name)Mechanismof action

Therapeutic
field

Indications

OriginDevelopment

NS-580mPGES-1
Inhibitor

Gynecology

Endometriosis

Nippon Shinyaku

NipponShinyaku

P I / II

NS-87

Liposomal
combination ofcytarabine anddaunorubicin

Hematologic
malignancies

Secondary acute myeloid
leukemia

Licensed-in from:Jazz
Pharmaceuticals
plc

NipponShinyakuPI

NS-229

JAK1 inhibitor

Inflammatory
diseases

Inflammatory diseases

Nippon Shinyaku

NipponShinyaku

Preparation
for P I

NS-917

DNA stand-breakby incorporating
itself into DNA

Hematologic
malignancies

Relapsed/refractory acute
myeloid leukemia

Licensed-in from:
Delta Fly Pharma

NipponShinyaku

Preparationfordevelopment

NS-401(tagraxofusp)

Targeting cancer
cells expressing
CD123

Hematologic Blastic plasmacytoid dendritic
malignancies
cell neoplasm

Licensed in from:The Menarini
Group

NipponShinyaku

P II

mPGES-1: membrane-associated prostaglandin E synthase-1

16

Clinical development
Overseas Development (As of August 10, 2021)
Development
Code No.
phase(Generic name)Mechanismof action

Therapeutic
field

OriginCo-development:
Intractable
National Center of
diseases/
Duchenne muscular dystrophy
Neurology andOrphan disease
Psychiatry

LaunchP III

NS-065 / NCNP-01(viltolarsen)

P III

NS-304(selexipag)

Selective IP
Cardiovascular
receptor agonist

Preparation
for P II

NS-018(ilginatinib)

JAK2 inhibitor

Exon 53
Skipping

Indications

Hematologic
malignancies

Development

NipponShinyaku

Chronic thromboembolic
pulmonary hypertension

Nippon Shinyaku

Licensed-out
to: Johnson &JohnsonMyelofibrosis

Nippon Shinyaku

NipponShinyaku

17

NS-018- Treatment for myelofibrosis Needs for new JAK inhibitors for patients with myelofibrosis (MF)
Survey of 25 U.S. hematologists
Q. Is a new JAK inhibitor needed forpatients with MF?

Q. What are the requirements desired
for future JAK inhibitors?

Greatly neededneededNecessity

16%

36%

Use if available

4%
May
usetoifuse
available
If
any,

36%

Will notnot useDo
use evenevenififavailable

present.
Not required

Unmet need for indications for patients with platelet
count of less than 50,000/μL
18

NS-018- Treatment for myelofibrosis Development
phase

Preparing overseas PII

OriginNippon Shinyaku

Mechanism ofaction

JAK2 inhibitor

Indications

Myelofibrosis

Dosage form

Tablet Potent and highly selective JAK2 inhibitor

FeatureDevelopment
strategy

 High efficacy and safety are expected for myelofibrosis
patients with low platelet count, for whom QOL
improvement can’t be obtained because no treatment isavailable
We will aim for 1st line treatment for myelofibrosis
patients with platelet count of less than 50,000/μL, which
is an unmet medical need, by utilizing the efficacy andsafety profile characteristic of this drug19

NS-580- Treatment for endometriosis By inhibiting mPGES-1 selectively, inhibits the
production of PGE₂

20

NS-580- Treatment for endometriosis Development phase

PII trial

OriginNippon Shinyaku

Mechanism ofactionMembrane-bound prostaglandin E
synthase-1 (mPGES-1) inhibition

Indications

Endometriosis

Dosage form

Oral agent

Feature Treatment for endometriosis without hormonal
effect and with possible analgesic potency
 It is expected to be safe and can be taken over along term21

NS-229- Treatment for inflammatory diseases Selective inhibitory effect on JAK1 compared to existing drugs

 The JAK family consist of four members (JAK1-3 and TYK2).
 JAK1 involves pathogenesis of inflammatory diseases through various
cytokine signals
 JAK1 inhibitors launched for rheumatoid arthritis and atopic dermatitis

NS-229NS-229NS-229NS-229Adapted from Clark JD et al., al. J Med Chem, 2014, 57 (12), 5023-5038.

22

NS-229- Treatment for inflammatory diseases Development phase

PI trial

OriginNippon Shinyaku

Mechanism ofactionJAK1 inhibition

Indications

Inflammatory diseases

Dosage form

Oral agent
 Potent and highly selective JAK1 inhibitor

FeatureDevelopment
strategy

 High efficacy and good safety profiles are expectedin the treatment of inflammatory diseases
Planning to develop in Japan and in the U.S. for P2
and beyond, targeting diseases that are not expected
to be sufficiently treated with existing JAK1 inhibitors
23

R&D progress innucleic acid drugHistory of research on
nucleic acid drugs
1980

1990

2000
2009

Application of DDS, Poly(I):Poly(C)

2020

2010
2013

2020

Research on nucleoside synthesis

DDS

Clinical trials of
NS-9

Nucleosidesynthesis

Developmentof the CEM
methodCommence
co-developmentwith NCNP*

Antisense nucleic acid
(Exon skip)

NS-065/NCNP-01(viltolarsen) LaunchedStart of investigator initiatedstudy for NS-065/NCNP-01*NCNP: National Center for Neurology andPsychiatry

25

Characteristics of nucleic acid drugs(1) Activates toward targets which were difficult toapproach with exisiting modalities
Direct linkage to genetic information(2) Highly selective
Precise targeting to the target gene sequence(3) Development requires expertness
Sequence design, nonclinical evaluation, clinical
trials, and mass production(4) Shortening drug discovery period
Improves the efficiency of new drug development
26

Treatment for
Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD)
・ Incidence: about 1/3,500 male births
・ Number of patients:
approximately 3,500-5,000/Japan・ Cause: dystrophin gene mutation
・ Progressive muscular atrophy
・ Onset around age 3 years
・ Difficult to walk at age 11-13
・ Respiratory failure in the 20s
Out of cell
Cell membrane
Dystrophin
Inside of cell

Actin

Adapted from H. Lodish et al., in Molecular Cell Biology, p999

28

Viltepso (viltolarsen: NS-065/NCNP-01)
Origin: Nippon Shinyaku
National Center of Neurology andPsychiatry (co-development)
Feature: Antisense nucleic acids with morpholino
oligomer structure High exon 53 skipping activity

 March 2020 manufacturing and marketing

PMO
Phosphorodiamidate
Morpholino Oligomer

approval obtained in Japan
August 2020 U.S. FDA approved(Dosage and administration: 80 mg/kg/weekly intravenous infusions)

FDA: Food and Drug Administration

29

Mechanism of antisense nucleic acid
- Block the target sequence DNA
TranscriptionmRNA

ACGTTGCATTGCAACGTA

Antisense nucleic acid

Antisense nucleic acids:
single-stranded nucleic
acid with 20-30 bases
Targets mRNA
Work inside of cell
Inhibits binding offunctional factors bybinding against target
sequences↓
Inhibits the work offunctional factors

By blocking sequences involved in recognition as exons, it
can be repressed from being taken into the mRNA.

Exon Skipping30

Principles of DMD exon skipping therapy
Dystrophin mRNA
Full
length51

52

53

The reading frame
doesn't fit.

Exon 52
Deletion

51

52

53

54

Full-length mRNA
54

Deletion of exon 52
Fit the reading frame mRNA
Exon 52
Deletion

51

Exon 53
Skip

Full-length
protein production

No protein
production

54

mRNA lacking
exons 52 and 53

Short butfunctional
proteinproduction

31

Overview of the viltolarsen clinical trials
2013

2014

2015

2016

2017

2018

2019

2020

2021

2022

(by NCNP*)

Phase I investigator-initiated clinical trial(Japan)
Dose: 1.25, 5, 20 mg/kg for 12 weeks
Phase 1/2 dose-ranging
study (Japan)
Dose: 40, 80 mg/kg for
24 weeksApplicationin Japan

Launchin Japan

Applicationin U.S.

Phase 2 dose-ranging study (North America)
Dose: 40, 80 mg/kg for 24 weeks

Launchin U.S.

(In progress)

Application in China

Phase 2 extension study (North America)~192 Week (up to 216 weeks in total)*National Center for Neurology and Psychiatry

Phase III Verification Trial (Global)
Dose: 80 mg/kg for 48 weeks(In progress)

32

From the presentation of
the PPMD Annual Meeting(23-26 June, 2021)

PPMD: Parent Project Muscular Dystrophy

Extension Study (Interim; ～109 week)
Time to Stand from the floor (change from baseline)

w: weekCalculation of TTSTAND velocity: rise/sec * P < 0.05; (P < 0.01; ± P ≤ 0.0001)

The viltolarsen-treated group showed significant improvement in time tostand from the floor compared with the natural history control group.
CINRG: Cooperative International Neuromuscular Research GroupDNHS: Duchenne Natural History Study
TTSTAND: Time To Stand
PPMD Annual Meeting (June 23-26, 2021)
34

Improvement

Improvement

Extension Study (Interim; ～109 week)
10m run/walk time (change from baseline)

w: weekCalculation of TTRW speed: meter/sec * P < 0.05; P < 0.01; P ± 0.0001

The viltolarsen-treated group showed significant improvement in time to
10m run/walk compared with the natural history control group.
TTRW: Time To Run/Walk
PPMD Annual Meeting (June 23-26, 2021)
35

Extension Study (Interim; ～109 week)
6-Minute Walk Test (change from baseline)

w: week*P<0.05.

The viltolarsen-treated group showed significant improvement inwalking distance compared with the natural history control group.

PPMD Annual Meeting (June 23-26, 2021)
36

Summary of the presentations at PPMD
Annual Meeting (June 23-26, 2021)• viltolarsen was well tolerated. All adverse events weremild or moderate.
• All 16 patients treated with viltolarsen showed significant
dystrophin expression by Western Blot.
• The exon skipping effect demonstrated by RT-PCR
method showed clear evidence for the exon 53 skip ofviltolarsen.
• Time to Stand from the floor, 10m run/walk and 6-MinuteWalk showed significant improvement in viltolarsentreated patients compared with CINRG natural history
data statistically.
・Time to Stand and 10m run/walk were improved
compared to baseline in viltolarsen-treated patients.

37

Phase III Confirmatory Trial (Global)
Design and evaluation items
Randomization

Screening
Day -21

Viltolarsen
80 mg/kg/week
N=37

First
day

Viltolarsen
80 mg/kg/week
N=74

Placebo
N=37

Week 1

Study population• DMD patients who can be treated withexon 53 skipping• 4 to 8 years• Ambulatory• Stable therapies of glucocorticoids
ClinicalTrials.gov: NCT04060199, NCT04768062

Week 48

Rollover study(RACER53-X)

Week 96

Primary endpoint• Change in time to stand from floor
Secondary endpoints• 10m run/walk time, 6-Minute Walk,
North Star Ambulatory Assessment,
Change in 4-step ascent/descent timeand hand-held dynamometer
38

DMD pipeline

DMD pipeline*Approval on August 12, 2020 in the United States(Priority Review), Approval on March 25, 2020 inJapan (Conditional Early Approval System) , application on June 25, 2021 in China (priority review)NS-owned DMD pipeline can cover approximately 40% of all DMD patients.
NCNP: National Center of Neurology and Psychiatry40

NS-089/NCNP-02
Development
phase

NCNP: Investigator initiated study in progress
NS: Preparing PII trial in Japan and U.S.

Mechanism ofactionExon 44 skipping

Feature High skipping activity with a new sequence
design method developed by NS High safety confirmed in pre-clinical Expect remarkable effect by increased
dystrophin protein expression in shorter time

Expect to become a treatment that can manage disease progression
for DMD Patients in lifetime
41

Treatment for
Fukuyama congenital
muscular dystrophyFukuyama congenital muscular dystrophy(FCMD)
Characteristics
・Congenital muscular dystrophy
・1,000-2,000 patients・Hereditary disease common in Japan・Muscle atrophy and CNS abnormalities
Symptoms
・Average age for sitting: 2 years
・Many patients are unable to walk and are more
serious than DMD.
・Average life expectancy: around 12 years
43Fukuyama congenital muscular dystrophy- Abnormalities in the causative gene (fukutin) -Extracellular matrix

Glycosylation modification

Arq Neuropsiquiatr.
2009 Jun; 67(1):144168

Dystrophin
FukutinAbnormalities
in the fukutin
gene

Abnormalfukutinprotein

α-DG withno glycosylation

Failure to
fix muscle
cells

Vulnerable
musclecells
44

Fukuyama congenital muscular dystrophy- Exon trapping inhibition Normal fukutin
splicing

Stop codon

8

Normal fukutin
protein

910

8 9 10NormalExon trapping

FCMD
splicing

Transposon

8

9

10
New exon11
FCMD

FCMD fukutin
protein

8 9

10

11

Error

The C-terminal 38 aminoacid is converted to theabnormal 129 amino acid.

Stop codon

Normalize splicing
Post-treatment
splicing
Post-treatment
fukutin protein

8

9

10
(Taniguchi-Ikeda et al. Nature 2011)

8 9 10NormalAntisense nucleic acid normalizes splicing.
→ Fukutin expression
45→ Improvement of pathology

Fukuyama congenital muscular dystrophy- Exon trapping inhibition • Multisequence antisense nucleic acid treatment suppressed aberrant
splicing in patient cells and model mice, produced normal fukutin
protein, and restored dystroglycan glycosylation. These results pave theway for the fundamental molecular targeted therapy of the FCMD.

• Through joint research with Kobe University and Nippon Shinyaku, wefound the antisense nucleic acid sequence NS-035, which shows strong
exon trapping inhibitory activity.
• A clinical trial at the University of Tokyo Hospital (principal investigator:
Prof. Tatsushi Toda) was initiated in August 2021.
Study

Study design

Intervention

Primary outcome

Phase 1 study

・Investigatorinitiated study
・Open label

・1.6, 6, 20, 40 mg/kg
・Intravenous administration once weekly for 12 weeks
・sample size: 12・5-10age

Safety-related
endpoints

https://jrct.niph.go.jp/latest-detail/jRCT2031210252
46

Exon trapping
Stop codon

8

9

10

8 9 10Exon trapping

8

9
New exon11

8 9 10 11

C-terminal 38 amino acids to
129 transposon amino acids

FCMD
Stop codon

Abnormal protein

Exon trapping:
The presence of a strong splice acceptor site within the inserted
retrotransposon, which results from the insertion of theretrotransposon, affects the splicing of the final protein-encoding
exon, resulting in abnormal splicing.
47

Fukuyama congenital muscular dystrophy- Exon trapping inhibition • In patients with FCMD, insertional mutations of the "moving gene"
SVA retrotransposon into the downstream region of the fukutin
gene have been observed.
• Exon trapping (a process in which a copy of a DNA fragment calleda retrotransposon is inserted at various sites in the same genome)
is not a rare phenomenon, and is estimated to occur at a frequency
of about 1 in 20 offspring.
• The splicing changes caused by SVA retrotransposons have also
been found in genes responsible for familial hypercholesterolemia
and dyslipidemia with SVA insertion mutations, and antisense
nucleic acid-mediated exon trapping inhibition may also be
effective in the treatment of these diseases.

48

Development of next-generation
antisense nucleic acids

Development of next-generation
antisense nucleic acids
We are working on the development of next generation
antisense nucleic acids using the following three methods.
Membrane-permeable
peptide linkage
Membrane-permeable peptide
likage enhances PMO
internalization.

Stereoselective synthesis
Stereoselective synthesis allows
the synthesis of stereochemicallypure and optimized modified
nucleic acids.

Novel sequence design
methodSequence design in which one
sequence has two target sequences
improves the activity and specificity
of antisense nucleic acids.

Next generation antisense nucleic acids can improve distribution,
efficacy (persistence, intensity), safety, and physical properties
compared to current antisense nucleic acids. This expands theapplication of nucleic acid drugs to other diseases.
50

Next-generation antisense nucleic acids- Membrane permeable peptide linkage PPMO in which CPP is bound to morpholino nucleic acid as
DDS technology to improve the dynamics of nucleic aciddrugs by enhanced cell membrane permeability
・improve the drug efficacy
・reduce the frequency of administration
PPMO (Peptide-conjugated phosphorodiamidate morpholino oligomer)

Phosphorodiamidate
morpholino oligomer(PMO)
Peptide (CPP*)*CPP (cell penetrating peptide):
A short peptide of 30 or fewer
amino acids with low cell
membrane permeability at low
concentrations.
51

Next-generation antisense nucleic acids- Stereoselective synthesis <Conventional>
Rp : Sp = ~ 1 : 1

Steric uncontrolled<Next Generation>

*

*

Rp

Sp

Create new added value by controlling the stereochemistry ofmorpholinonucleic acid (Phosphorodiamidate morpholino oligomer)
52

Next-generation antisense nucleic acids- Stereoselective synthesis <Conventional>

n-mer: a mixture of 2n-1 stereoisomers(21 mer: more than 1,000,000 isomers)<Next Generation>

Completely single nucleic acid(21mer: 1/ 1,000,000)
53

Next-generation antisense nucleic acids- Novel sequence design method Conventional: One sequence acts on one target.
Antisense nucleic acidmRNA

Novel method: One sequence acts on two targets.
Antisense nucleic acidmRNA
Improve the activity and specificity of antisense nucleic acids
by applying a novel sequence design method
54

Novel coronavirus infection- Nucleic acid drugs -Novel coronavirus infection- Nucleic acid drugs The types and structures of nucleic acids such as long-chain RNA andantisense nucleic acids (morpholino nucleic acids) will be studied to
select the nucleic acids that effectively kill the novel coronavirus.
The figure shows an example of the application of long-chain RNA.

Long-chain RNAs are cleaved within the cell to produce several
siRNAs targeting multiple sites on the viral RNA, killing all of thenovel coronavirus.
56

Novel coronavirus infection- Sequence screening of nucleic acid Step 1

Step 2

Step 3

Step 4• In vitro efficacy evaluation of uninfected experimental systems• In vitro efficacy evaluation of infection experiments✓✓• In vivo efficacy evaluation of infection experiments• In vitro and in vivo toxicity assessment

Final candidate decision
Step 3 and Step 4 are being implemented simultaneously,
and we will select final candidates.
57

Safe Harbor Statement• Materials and information provided during this presentation may contain so-called “forward-looking
statements.” These statements are based on current expectations, forecasts and assumptions thatare subject to risks and uncertainties which could cause actual outcomes and results to differ materiallyfrom these statements.
• Risks and uncertainties include general industry and market conditions, and general domestic andinternational economic conditions such as interest rate and currency exchange fluctuations. Risks anduncertainties particularly apply with respect to product-related forward-looking statements. Product risks
and uncertainties include, but are not limited to, technological advances and patents attained bycompetitors; challenges inherent in new product development, including completion or failure of clinical
trials; claims and concerns about product safety and efficacy; regulatory agency’s examination, obtaining
regulatory approvals; domestic and foreign social security reforms; trends toward healthcare cost
containment; and governmental laws and regulations affecting domestic and foreign operations.

• Also, for products that are approved, there are manufacturing and marketing risks and uncertainties, which
include, but are not limited to, inability to build production capacity to meet demand, unavailability of raw
materials, and competition with others.
• The Company disclaims any intention or obligation to update or revise any forward-looking statements
whether as a result of new information, future events or otherwise.
• This English presentation was translated from the original Japanese version.
In the event of any inconsistency between the statements in the two versions, the statements in theJapanese version shall prevail.