FY 2023
R&D Meeting
December 12, 2023
Nippon Shinyaku Co., Ltd.

Introduction

R&D approach
Pursuing originality on a global scale
Providing the world with quality pharmaceuticals
to address diseases with unmet treatment needs

In-house drug
discovery

Introduction

PLCM

Fundamental technologies

Open
InnovationDX(AI-based drug
discovery)

Small molecule drugs, nucleic acid drugs,
new drug discovery modalities
PLCM: Product life cycle management<How to promote global expansion>••

Our own marketing: Disease areas where the number of patients is very small andthe number of medical facilities to which we provide
information is relatively limited
Collaboration with partner companies: Disease areas where the estimated number ofpatients is above a certain level3

Toward our sustainable growth
We will establish new growth drivers
to overcome Uptravi’s patent cliff and grow sustainably.
Other newproducts

・NS-87・ZX008・NS-018
・NS-580
・NS-229
・NS-401etc.

In addition to nucleic acid drugs and a cell therapy for DMD, we believe that othernew products will be driving force behind our sustainable growth.
4

R&D activities

Update of DMD pipelines

Progress of the DMD pipeline
Stage

Targetexon

Proportionof patients% of DMD

NS-065/
NCNP-01

Exon
53

8%

Around the spring of
FY2024P3 data presentation

NS-089/
NCNP-02

Exon
44

6%

FPI: FY2023
LPO: FY2025

NS-050/
NCNP-03

Exon
50

4%

FPI: FY2023
LPO: FY2026

NS-051/
NCNP-04

Exon
51

13%

FPI: FY2023
LPO: TBD

Exon 45
Skipping

Exon
45

8%

TBD

Exon 55
Skipping

Exon
55

2%

TBD

CAP-1002

-

-

PPMO

TBD

TBD

TBD

Gene
therapy

-

-

TBD

Item

Schedule
Research

Preclinical

Ph1

Ph2

Ph3

LaunchGlobal Ph3 / Launch (US, JP)

Preparation for Ph2 (US, JP)

Prep. for Ph1/2 (US, JP)

Futility analysis End of2023
Topline data End of 2024

FPI: First Patient In, LPO: Last Patient Out7

NS-089/NCNP-02 exon 44 skipping therapy

Schematic diagram of the mechanism of action of
NS-089/NCNP-02
Induce exon 44 skips with NS-089/NCNP-02 in patients with DMD
with exon 45 deletion and restore slightly shortened dystrophin
expressionNew highly active sequence search method thatis a patent application technology

World’s first sequence-linked dual-targeting
antisense nucleic acid drug targeting two distantnucleotide sequences



Induction of dystrophin protein expression inmuscle cells derived from DMD patients

Paper Exon 44 skipping in Duchenne muscular dystrophy: NS-089/NCNP-02, a dual-targeting antisense oligonucleotide
Author Naoki Watanabe, Yuichiro Tone, Tetsuya Nagata, Satoru Masuda, Takashi Saito, Norio Motohashi, Kazuchika Takagaki, Yoshitsugu Aoki and Shin'ichi Takeda
Journal Molecular Therapy Nucleic Acids

8

Investigator-initiated trial of NS-089/NCNP-02
Dystrophin protein expression levels

Dystrophin protein% change (SD)
40mg/kg(n=3)

10.27 (1.88)

80mg/kg(n=3)

15.79 (6.44)

Mean (%)

13.03 (5.21)
ClinicalTrials.gov identifier NCT4129294

 In 6 patients treated (24 weeks), significant increases in exon skipping efficiency
and dystrophin protein were observed. In addition, safety and tolerability weregood.

 In Part 2 (dose-finding period), there was a tendency to maintain and improve
motor function.
 Since this study had a small number of subjects (n=6) and did not include a placebo
control group, the efficacy of this drug, including the maintenance of motor function,
should be further investigated.
9

NS-089/NCNP-02 exon 44 skipping therapy
Orphan Drug, Rare Pediatric Disease, and Breakthrough Therapy
designations from the U.S. FDA; currently preparing for global P2 study10NS-050/NCNP-03 exon 50 skipping therapy
FDA and PMDA have agreed to the planned Phase Ⅰ/Ⅱ study of
NS-050/NCNP-03. Global Phase 1/2 study is in preparation.

11

CAP-1002 Cell Therapy
 Cardiosphere-derived cell therapeutic.
 Exosomes (extracellular vesicles) released from this drug are expected to reduce
oxidative stress, inflammation, fibrosis, and increase cellular energy and myocyte
generation, resulting in slowing the decline of skeletal muscle and cardiac function in
DMD.
 In the P2 study (HOPE-2 study), efficacy on upper limb function (PUL) and cardiac
function was confirmed, and in the OLE study, it was confirmed that the effects lasted
for a long time.
 Currently, the phase 3 trial (HOPE-3) is underway. Protocol amendment was submitted
in August 2023.

CAP-1002

Leukocyte⇒ Immunomodulation

Fibroblasts⇒ Anti-fibrotic

Vessels⇒ Angiogenic

ExosomeProgenitor
cells⇒ Regenerative

Myocytes⇒ Anti-apoptotic
Proliferative

WMS,October
2023

12

CAP-1002 Amendment of the protocol for the HOPE-3 trial
・2023/Q4 interim analysis
・2024/Q4 Top line data

12 months

Cohort A
ongoingThe
investigational
drug isMade in LA

CAP-1002

1:1
randomn=~58

Placebo

12 months
open label study

2025
BLA submission

CAP-1002

Cohort B
The
investigational
drug isMade in San
Diego

•
•

Target number of subjects ：44
After the initial BLA approval,
apply for Prior-Approval supplement

 The investigational product is being manufactured at a facility in Los Angeles, but in
preparation for its commercial release, Capricor established an additional facility in San
Diego.
 The HOPE-3 trial was divided into two cohorts: Cohort A (manufactured in Los Angeles)
and Cohort B (manufactured in San Diego).
 The trial design and schedule until the Biological License Application (BLA) submission
were agreed upon in a Type B meeting with the FDA.
13

CAP-1002 HOPE-2-OLE study
HOPE-2
study

Gap
Phase

CAP-1002
vs. PlaceboOfftreatment

Open Label（OLE）Phase

OLE Month12

All patients
received CAP-1002

OLE(Original
Placebo) Group

Original
Placebo Group

Original
CAP-1002 GroupOLE
Month24

OLE(Original
CAP-1002) GroupEnd
HOPE-2

Original
Placebo GroupOLE Baseline↑
Baseline↑End
HOPE-2

↑
↑
↑
OLE
OLE
OLE
Baseline Month12 Month24↑

Baseline

Administration period
・HOPE-2 study: CAP-1002 or placebo administered 4 times every 3 months
・Gap Phase : untreated period
・OLE Phase: CAP-1002 administered every 3 months for 2 yearsModified from WMS, October 2023
The linear mixed model uses all available data.

In the HOPE-2-OLE study, the average decrease in PUL 2.0 after 24 months of treatment with CAP1002 was 2.8 points, while an average decrease of 7.7 points was observed in placebo group untreatedfor 24 months.
Patients who received CAP-1002 treatment showed 64% reduction in disease progression.
14

CAP-1002 Press release for Interim Futility Analysis

excerpt from press release of Capricor Therapeutics, 11th Decemnber 2023
15

Positioning in the three DMD treatments

We are working to expand treatment options with various modalities to ensure that more patients
receive the best treatment depending on the genetic background and stage of the disease.
16

Pipelines other than DMD

R&D pipeline (other than DMD)
Stage

Code No.
(Generic name)

Therapeutic field

Indications

OriginDevelopment

Schedule

NDA filing

NS-87(daunorubicin / cytarabine)

hematologic
malignancies

high-risk acute myeloid leukemia

Licensed - in from
Jazz Pharmaceuticals plc

Nippon Shinyaku

FY2023 application
FY2023 expected to be approved

NDA filing

ZX008(fenfluramine hydrochloride)

intractable disease・orphan disease

Lennox-Gastaut syndrome

Sales Alliance: UCB(Former Zogenix Corporation)

Distribution partnership: UCB S.A.
FY2023 application(former : Zogenix, Inc.)
FY2023 expected to be approved

P III

ZX008
(fenfluramine hydrochloride)

intractable disease・orphan disease

CDKL5 deficiency disorder

Sales Alliance: UCB(Former Zogenix Corporation)

Distribution partnership: UCB S.A.
(former : Zogenix, Inc.)

FY2025 Completion of the study

P III

GA101
(obinutuzumab)

intractable disease・orphan diseaselupus nephritis

Licensed - in from
Chugai Pharmaceutical Co., Ltd.

Co - development:
Chugai Pharmaceutical Co., Ltd.

Expansion of indications:from 2026 onward

P III

GA101
(obinutuzumab)

intractable disease・orphan disease

pediatric nephrotic syndrome

Licensed - in from
Chugai Pharmaceutical Co., Ltd.

Co - development:
Chugai Pharmaceutical Co., Ltd.

Expansion of indications:from 2026 onward

P III

GA101
(obinutuzumab)

intractable disease・orphan disease

extra renal lupus

Licensed - in from
Chugai Pharmaceutical Co., Ltd.

Co - development:
Chugai Pharmaceutical Co., Ltd.

Expansion of indications:from 2026 onward

P II

NS-018(ilginatinib)

hematologic
malignancies

myelofibrosis

Nippon Shinyaku

Nippon Shinyaku

LPO: FY2024 (TBD)

P II

NS-304(selexipag)

cardiovasculararteriosclerosis obliterans

Nippon Shinyaku

Nippon Shinyaku

FY2024 completion of the study

P II

NS-304(selexipag)

intractable disease・orphan disease

pediatric pulmonary arterial hypertension

Nippon Shinyaku

Co - development:
Janssen Pharmaceutical K.K.

FY2025 completion of the study

P II

NS-580gynecology

endometriosis

Nippon Shinyaku

Nippon Shinyaku

FY2023 completion of the study

P II

NS-580urological diseases

chronic prostatitis/chronic pelvic pain syndrome

Nippon Shinyaku

Nippon Shinyaku

FY2024 completion of the study

Preparation
for P II

NS-229intractable disease・orphan disease

Eosinophilic granulomatosis with polyangiitis

Nippon Shinyaku

Nippon Shinyaku

FY2025 completion of the study

P I / II

NS-401(tagraxofusp)

hematologic
malignancies

blastic plasmacytoid dendritic cell neoplasm

Licensed - in fromThe Menarini Group

Nippon Shinyaku

FY2026 completion of the studyPI

NS-917(radgocitabine)

hematologic
malignancies

relapsed/refractory acute myeloid leukemia

Licensed - in from
Delta-Fly Pharma, Inc.

Nippon Shinyaku

FY2025 completion of the studyPI

NS-161

inflammatory
diseases

inflammatory diseases

Nippon Shinyaku

Nippon Shinyaku

FY2023 completion of the studyPI

NS-025

urological diseases

urological diseases

Nippon Shinyaku

Nippon Shinyaku

FY2023 completion of the studyPI

NS-863

cardiovascularcardiovascular diseases

Nippon Shinyaku

Nippon Shinyaku

FY2024 completion of the study18

NS-87 high-risk Acute Myeloid Leukemia treatment
Planned trade nameVYXEOS

Active ingredient

Cytarabine and daunorubicin

Composition• Containing cytarabine 100 mg anddaunorubicin 44 mg in 1 vial (molar ratioof cytarabine to daunorubicin 5:1)
• Encapsulated in nanoscale dual-structured
liposomes of diametric 100nm

NDA submission

June 2023

Cytarabine

Daunorubicin

JAZZ HP Mechanism of Delivery
https://vyxeospro.com/mechanism-of-delivery
19

High-risk Acute Myeloid Leukemia
high-risk Acute Myeloid Leukemia
Defined as therapy-related acute myeloid leukemia (tAML) or AML
with myelodysplasia-related changes (AML-MRC)
Patient group
Approximately half of all AML patients* can be high-risk AML,
among which 7+3 therapy (cytarabine, anthracycline combination)is currently used primarily in intensive chemotherapy-indicatedpatients. NS-87 may be used to treat this patient-group.
Overseas P3 study of NS-87 showed significant extension of overall
survival compared with 7+3 therapy.
*There is no accurate statistics about the patients of AML. However, 14,000 people per year are
diagnosed with leukemia. (Reference: Cancer Statistics)

20

Characteristics of NS-87
 Liposomal formulation of cytarabine and daunorubicin in a 5:1 molarratio It reaches the bone marrow as liposomes and remains for a longtime.
 After the drug is taken up into leukemic cells in the bone-marrow,cytarabine and daunorubicin are released to exert their antitumor
effects.
Reach and remainin the bone marrowBonemarrow

Uptake by leukemic cells

Release of active ingredientsin cells

Leukemia
Cell
NormalCell

NucleusBloodvesselJAZZ-HP Mechanism of Delivery
https://vyxeospro.com/mechanism-of-delivery

21

Time and duration of NS-87
NS-87 vs 7+3 therapy (overseas P3 study)
NS-87
Intravenous administration
for 90 minutes

DAY 3

Intravenous administration
for 90 minutes

DAY 5

Intravenous administration
for 90 minutes

DAY 1
DAY 2
DAY 3

DAY 4
DAY 5

7-day continuous
intravenous infusion

Inductiontherapy(1 cycle)

DAY 1

7+3 therapy (5+2)
15-minute infusion
15-minute infusion
15-minute infusion

DAY 6
DAY 7

Inductiontherapy(1-2 cycles)

Postremission
therapy

Intravenous administration
for 90 minutes

DAY 3

Intravenous administration
for 90 minutes

DAY 1
DAY 2
DAY 3

15-minute infusion

5 days(2 cycles, as needed)

JAZZ-HP VYXEOS preparation and administration
https://vyxeospro.com/dosing-ordering/preparation

DAY 1

15-minute infusion

DAY 4
DAY 5

DAY 1

DAY 1
DAY 2

DAY 3

Intravenous administration
for 90 minutes

DAY 3

15-minute infusion

5 daysIntravenous administration
for 90 minutes

15-minute infusion

DAY 4

DAY 5
22

NS-87 Oversea P3 study
Subjects: Untreated high-risk AML 309 aged 60-75 years
Control group: 7 + 3 therapy (AraC 100 mg/m2 + DNR 60 mg/m2)
NS-87(n=153)7+3 therapy(n=156)overall survival(median)

9.56 months

5.95 months

1-year survival
rates

41.5 %

27.6 %[Primary: overall survival(OS)]Survival rate

Hazard ratio

0.69
Log rank p=0.003

NS-87

7 + 3 therapy

NS-87
7+3
Time since randomisation (months)

J Clin Oncol. 2018 Sep
10;36(26):2684-2692

23

NS-87 Summary of P1/2 studies
DesignSingle-arm, open-label

Study Objectives

To investigate the pharmacokinetics, safety, andefficacy of NS-87 in patients with high-risk AML.

Study patient
populations

High-risk AML

Period of registration August 2019 - October 2021

 We conducted a phase 1/2 study in Japan. Based on the
results of a phase 1/2 study and P3 studies, we applied for
application for approval in June 2023.
 Orphan drug designation obtained.

24

NS-580 Endometriosis Treatment
Stage

PIIb study

Developmentform

In-house development

Mechanism ofactionmicrosomal prostaglandin E synthase-1(mPGES-1) inhibition

Indications

Endometriosis

Dosage form

Oral drug Non-hormonal endometriosis
treatment with analgesic effect andanti-proliferative effectCharacteristics
 Possible long-term use with few side
effects25

NS-580 Endometriosis
Chronic inflammatory disease in which endometrial tissue
engrafts outside the uterus and proliferates and bleeds
repeatedly according to menstruation
NS-580Endometriosis

Ovary

Fallopian tube
Perimetrium
Myometrium

Endomerium
Chocolate cyst
vaginaMenstrual pelvic pain
Chronic pelvic pain
Defecation pain
Dyspareunia

Endometriosis
https://seiritsu.jp/

The figure published by the Japanese Obstetrics and Gynecology HP was partially modified

Endometriosis affects approximately 10% women of
reproductive age and significantly reduces women's QOL.
26

NS-580 Mechanisms of Action
mPGES-1 inhibitor, NS-580 selectively inhibits PGE2 productionarachidonic acid
COX
PGH2

NSAIDsInhibition of all prostaglandins→ ・Side effect・Weak effect on endometriotic lesion

NS-580 mPGES-1
Selective Inhibition of PGE2
→ ・Favorable safety profile
・Strong effect on endometriotic
leisionPGE2

Inflammation
pain

Several prostaglandins such as PGI2

Several physiological actions(anti-proliferative effect on
endometriosis cells)
27

Action point of each drug in Endometriosis

Hormonal treatment

Menstruation

Engraftment

Endometriotic
LesionProliferation

Since NS-580 selectively inhibits
PGE2 production by inhibiting
mPGES-1, it can be expected not
only to have analgesic and antiinflammatory effects but also to
inhibit the growth of theendometriotic lesion.

NSAIDsEndometriotic
LesionInflamation

Endometriotic
LesionPain

Endometriotic
LesionNS-58028

NS-580 P2a study (Endometriosis)
Study design

Randomized, double-blind, multicentre, placebocontrolled, parallel group comparison

Endpoint

Change in pain VAS (Visual analog scale)score

Dosage andOral, once daily
Administration Dose: placebo, 100 mg, 300 mg/timeTarget sample
size

150 (100 mg : 300 mg : placebo = 2:2:1)

The analgesic effect of NS-580 was confirmed in Phase 2a study.

29

NS-580 P2b study (Endometriosis)
Study design

Randomized, double-blind, multicentre, placebo-controlled,parallel group comparison

Endpoint

Change in pain VAS score

Dosage andAdministrati
on

Oral, twice daily
Dose: placebo, 50 mg, 100 mg, 150 mg/timeTargetsample size

372 (50 mg : 100 mg : 150 mg : placebo=1:1:1:1)

Screening(about 2months)

Vic

V1

Treatment period（24 weeks）

Follow-up(2 weeks)

IC(Enrollment)

Randomization

NS-580 150mg b.i.d

93

NS-580 100mg b.i.d

93

NS-580 50mg b.i.d

93

Placebo93

Target Sample size
Total 372

rescue medication（analgesic ex: NSAIDs）
30

NS-580 Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Development
stage

P2a study

Developmentform

In-house development

Membrane-bound prostaglandin E
Mechanism ofsynthase-1
action(mPGES-1) inhibition
Indications

Chronic prostatitis/chronic pelvic pain
syndrome(CP/CPPS)

Dosage form

Oral drug

31

CP/CPPS
Psychiatric symptoms

Dysuria
・Pollakiuria
・Decreased urination etc.

Peritoneum

UreterRectum・Anxiety・Stress
・QOL decreased

Pubic symphysis
Urinary
bladder

Seminal vesicle
Ejaculatory duct

Prostate

Sexual dysfunction

Inflammation

external urethral sphincter

Areas of pain and discomfort
urethraVas deferens
Epididymis
TestisStandardized Urological Chemistry 8th Edition; Medical Shoin; P.18; 2010 Modified

Peripelvic and periurogenital pain persists for 3 of 6 months.
It is defined as the one with voiding and sexual dysfunction,and the etiology has not been clarified.
Number of patientsJapan: Approximately 2 million potential patients (5% of adult males)
Approximately 0.6 million patients were diagnosed
Overseas: About 4% of the male population
32

Treatment for CP/CPPS and Product-concept of NS-580

NSAIDsAntimicrobial
agent

NS-580Pain improvement

Alpha blocker
PDE 5 inhibitors
Improvement ofvoiding symptoms

Improvementof QOL

Plant preparation(Cernilton)
Fewer side effects
Long-term safety

Product concept

Highly safe treatment for CP/CPPS that can be expected to control
pain in the long term33

NS-229 eosinophilic granulomatosis with polyangiitis


EGPA (eosinophilic granulomatosis withpolyangiitis)
Rare and intractable diseases of unknown
cause designated as intractable diseases inJanuary 2015.



Characteristics of the clinical course:
Severe asthma with eosinophilia andallergic rhinitis (eosinophilic sinusitis)
preceded by several years. Subsequently, amarked increase in peripheral blood
eosinophils causes eosinophilic
inflammation of various organs of the bodyand granulomatous necrotizing vasculitis ofsmall to medium-sized vessels.



Number of specified medical expense
beneficiary certificate holders(designated intractable diseases):
5,839 (as of the end of FY2021)*Refer to the number of specific medical
expense beneficiary certificate holders at Japan Intractable
Disease Information Center.

34

NS-229 eosinophilic granulomatosis with polyangiitis
Diagnosis of EGPA

Remission induction treatment

SevereNon severe

GC ± immunosuppressantsGC alone
Inadequate
effectGC+IVCY
Inadequate
response/relapse
Concomitant MEP

GC: glucocorticoid
IVCY: intravenous cyclophosphamide
MEP: mepolizumab
MTX: methotrexate
AZA: Azathioprine

Maintenance of remission

GC (+MTX, AZA, MEP)
Partially modified from ANCA-related vasculitis practice guideline 2023

 In the treatment of EGPA, glucocorticoids are basically used to induce andmaintain remission.
 NS-229 is assumed to be widely available in patients with EGPA, replacing
glucocorticoids, by inhibiting symptom-related signaling of EGPA.
35

NS-229 eosinophilic granulomatosis with polyangiitis

 In EGPA, inflammatory cells, such as T cells, B cells, and eosinophils, areactivated and lead to tissue damage.
 NS-229 has potent inhibitory effects on JAK1.
 Through inhibition of JAK1, it suppresses various cytokine signaling,
suppresses activation of T cells, B cells, eosinophils, and other cells, andleads to improvement of disease status.
 NS-229 is a selective inhibitor of JAK1, and its selectivity reduces the effects
of JAK2 inhibition on the hematopoietic system.
36

NS-229 eosinophilic granulomatosis with polyangiitis
Study

A Double-Blind, Randomized, Placebo-Controlled Phase II Study to
Evaluate the Efficacy and Safety of NS-229 in EGPA Patients

DesignNS-229 and placebo are compared.
At baseline, approximately 45 subjects will be randomly assigned toreceive NS-229 or placebo.

Primary efficacy endpoint

Percentage of subjects in remission (OGC 4.0)* at Week 28

Primary safety endpoint

Confirmation of adverse events and adverse drug reactions

Secondary efficacy
endpoints

Percentage of subjects in remission (OGC 7.5)* at Week 28
Time to relapse/worsening

Number of subjects

Approximately 45 patients

Treatment period

28 weeks*(OGC X): A score of 0 on the BVAS, which assesses vasculitis activity, and the amount of oral glucocorticoids
administered is less than or equal to X mg/day.

37

Accelerating drug discovery～To exceed the target of launching more than one product per year～

Open Innovation: Innovation Research Partnering (IRP)
We established Innovation Research Partnering (IRP) in Boston area of the United States,
where the heart of an ecosystem consisted by various players such as world-classuniversities, research institutions and bio-venture companies.

Building where IRP office is locatedAn event in IRP office

IRP will increase our access to the seeds of the world's most advanced drug discovery
technologies and efficiently search for partner opportunities.
We believe that this will lead to accelerate and diversify in-house drug discovery research.
39

AI for drug discovery
Disease selection

Searchformolecular
targetAI gathers huge amount of data andanalyzes information

Identification
andoptimization of
hit compounds

Identification
andoptimization oflead compounds

AI discovers hit compounds ~ AI optimizes lead compounds
AI predicts safety ~ AI predicts PK

Clinical
TrialsAI discovers clinical site
AI measures and diagnoses

 In particular, the use of AI for chemical synthesis,
safety, and pharmacodynamicsis is increasing.
 AI is applied to existing R&D pipeline.

(Problem) In order to launch more than one product per
year, refinement and high efficiency of drug discovery
process and rapid development are required. Therefore,
cooperation through IT adoption in view of the entire
process is necessary.

We are developing an integrated system that collects and provides a hugeamount of drug discovery information from research to clinical trials.
40

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.

Nippon Shinyaku Co., Ltd.
R&D Meeting
December 12, 2023

Presentation
Nakai: I am Nakai, President of Nippon Shinyaku Co., Ltd.
Thank you very much for joining our R&D meeting today.
Today, I would like to start from a brief introduction of the meeting. Then, Takagaki, Director of Research andDevelopment Division, will explain R&D efforts into DMD and non-DMD pipelines and efforts to accelerate
drug discovery.

First, I would like to explain Nippon Shinyaku’s approach to R&D approach.
In the pharmaceutical business, we will provide valuable pharmaceuticals in areas and fields where treatment
needs have yet to be met to realize our management philosophy of Helping People Lead Healthier, HappierLives.
To this end, we need to enhance our development pipeline through the three pillars of in-house drug
discovery, Introduction, and product lifecycle management or PLCM, using our own fundamental technologies.
We will further accelerate R&D by combining these three pillars with open innovation and DX.

In addition, since the number of patients with intractable and rare diseases, which is one of the areas we arefocusing on, is relatively small, we believe that promoting global expansion will enable us to achievesustainable growth.
We look not only at the domestic market but also at the global market to deliver needed drugs in an optimal
way to patients around the world.
Regarding our global expansion concept, we are considering strategies with a view to in-house sales in the
global market for disease areas where the number of patients is very small, and the number of medical
facilities providing information is relatively limited.
On the other hand, if the disease area is above a certain level of the estimated number of patients, we will
give priority to partnering with companies that have a broad sales network.

The patent for Uptravi, which is currently our driving force, is scheduled to expire in October 2026 in the US
and in April 2027 in other regions including Japan.
We need to actively promote R&D and establish new growth drivers in order to overcome this patent cliff andto achieve our sustainable growth.
In addition to the nucleic acid drugs such as NS-089, NS-050, and NS-051, and the cell therapy product CAP1002, which are targeted for DMD, we are also expanding our non-DMD product lineup. We believe that theseproducts will be the ones that drive our growth.

Next, Takagaki will explain the details about DMD and non-DMD pipeline as well as our efforts in accelerationof our drug discovery. Thank you.
Takagaki: I am Takagaki, Director, Research and Development Division.
I would like to explain our R&D efforts.

First, I would like to talk about the DMD update.
This table shows the progress of the DMD pipeline. The main progress made this fiscal year will be describedon the slides that follow.

First, I would like to introduce NS-089/NCNP-02, DMD’s development items.
Like Viltepso, which is already approved, the mechanism of action of NS-089/NCNP-02 is to restore slightly
shortened dystrophin expression by exon skipping.
The mechanism is the same, but unlike ordinary antisense nucleic acids that have sequences that bind to asingle target, NS-089/NCNP-02 is a sequence-linked dual-targeting antisense nucleic acid that targets two
distant nucleotide sequences.
Sequences that bind to each of the two targets in two locations are designed, linked, and created.
As shown in the graph on the right, mixing each of the two sequences has no activity, but by linking the two
into a single sequence, strong activity is achieved.

I would like to explain the results of the investigator-initiated clinical trial for NS-089/NCNP-02.
The investigator-initiated clinical trial is divided into part one and part two. Safety and tolerability wereconfirmed at doses of 40 mg/kg and 80 mg/kg in part two while doses were titrated up in part one.
The upper left graph shows the results of the muscle biopsy after part two. As for the amount of change indystrophin protein, the 40 mg/kg group showed an average of 10.27%, and the 80 mg/kg group showed anaverage of 15.79%, an increase in expression from baseline was observed.
The safety and tolerability of the drug during this administration period were good.
Since this study had only six subjects and did not include placebo control group, we believe that the efficacyof this drug should be further investigated.

The last slide of NS-089/NCNP-02 is about the study design of the next phase of the Japan-US Phase II study.
The study design for NS-089/NCNP-02 is planned as shown in the figure based on the results of theinvestigator-initiated clinical trial in Japan.
The study design of the Japan-US Phase II consists of part one and part two.
In part one, the maximum tolerated dose will be obtained by gradually increasing the dose from 40 mg/kg, 60
mg/kg, and 80 mg/kg. In part two, efficacy will be confirmed by administering the maximum tolerated dosein part one once a week for 24 weeks.
Based on the results of the investigator-initiated clinical trial, we are planning a Japan-US Phase II study for
NS-089/NCNP-02. At the same time, in the US, we have filed various applications and received orphan drug
designation, rare pediatric disease designation, and breakthrough therapy designation.
Breakthrough therapy designation is for drugs that have demonstrated meaningful preliminary clinicalevidence compared to existing therapies for serious diseases. NS-089/NCNP-02 is the first in our DMD pipeline
to be designated.
NS-089/NCNP-02 is currently preparing for Phase II study.

Next, I would like to explain about NS-050/NCNP-03.
We are preparing for the global Phase I / II study, which will be a first-in-human study.
The design consists of part one and part two.
In part one, the dose is titrated in six steps from 1.95 mg/kg to 80 mg/kg to obtain the maximum tolerated
dose. In part two, the dose is administered once a week for 24 weeks at the maximum tolerated dose in partone to confirm efficacy.

Next, I would like to explain about CAP-1002.
CAP-1002 is a cardiosphere-derived cell therapeutic.
Exosomes or extracellular vesicles released from CAP-1002 act on various cells to reduce oxidative stress,
inflammation, fibrosis, and increase myocyte generation and angiogenesis, etc., resulting in slowing thedecline of skeletal muscle and cardiac function.
In the Phase II study, HOPE-2, efficacy on upper limb function and cardiac function was confirmed. In the OLE
study, it was confirmed that the effects lasted for a long time.
A Phase III study, HOPE-3, is currently underway, and Capricor has revised the protocol in August 2023.

This is the content of the protocol amendment for the HOPE-3 trial.
The investigational product is being manufactured at a facility in Los Angeles, but in preparation for its
commercial release, Capricor established an additional facility in San Diego.
Since the investigational product made in San Diego also needs to be tested in humans, the HOPE-3 trial was
divided into two cohorts, the study with the original investigational product manufactured in Los Angeles as
Cohort A, and the study with the investigational product manufactured in San Diego as Cohort B.
For Cohort A, after a 12-month placebo-controlled randomized controlled trial will be followed by a 12-monthopen trial. An interim analysis will be performed in 2023/Q4, topline data will be obtained in 2024/Q4, and a
BLA application will be filed in 2025. Later, I will explain about the results of the interim analysis, released lastnight in the US.
For Cohort B, Capricor plans to apply for Prior-Approval supplement after the completion of the study andobtain marketing approval for this formulation as well.
Regarding these study designs and timelines for BLA submissions, Capricor agreed with the FDA at a Type B
meeting.

Results from the HOPE-2 trial and the two-year OLE study were presented by Capricor in a poster presentation
at the World Muscle Society in October.
The figure on the left shows the upper limb function, PUL.
In the HOPE-2 study, CAP-1002 or placebo was administered for one year, followed by an untreated gap period,
and then an open-label extension study allowed for two years of CAP-1002 administration took place.
Regardless of treatment during the HOPE-2 study, the decline in upper limb function during the OLE period
was similar with decrease by 2.8 points for two years.
The figure on the right indicates the change in upper limb function from baseline in the OLE study with blue
and light blue lines, and the change in upper limb function from baseline to no treatment for two years in the
HOPE-2 study with red lines. The decline in upper limb function after 24 months of treatment with CAP-1002
in HOPE-2-OLE was 2.8%, regardless of treatment during the HOPE-2 study.
In contrast, HOPE-2 placebo patients who did not receive treatment for 24 months experienced an average
decrease by 7.7 points.
These results indicate that patients treated with CAP-1002 had a 64% reduction in disease progression.

The interim analysis of CAP-1002 was released by Capricor on December 11, 2023.
The interim analysis results the continuation of Phase III HOPE-3 trial of CAP-1002. Based on the results, wewill make a milestone payment to Capricor.
As I explained earlier, the enrollment has been completed for Cohort A, and topline data will be disclosed by
December 2024.
For Cohort B, enrollment has begun.

I would like to explain about positioning in the DMD treatments.
Nucleic acid drug, cell therapy, and gene therapy have their own advantages and disadvantages. We believethat the best treatment can be achieved by combining them based on patient’s genetic background, medical
condition, and timing.
In the opinion of a US clinician specializing in muscle and a basic researcher of muscle, since muscle
regeneration at an early age is active due to the abundance of stem cells in the patient’s muscle and theexpression of the DMD gene is high, patients eligible for exon skipping therapy are treated with nucleic aciddrugs to produce a little short but functioning. It is desirable to express dystrophin protein to prevent muscle
breakdown and maintain muscle mass.
Gene therapy has been received accelerated approval in the US, and it is currently available for patients aged
four to five years, and clinical trial results have not clearly demonstrated efficacy in patients aged six to sevenyears. Although there is a possibility that the subject may overlap with exon skipping therapy, effects of genetherapy are theoretically difficult to sustain over a long period of time. At this time, we believe that exonskipping drugs with long-term motor function data will be the preferred choice.
However, since exon skipping drugs need to be administered weekly, while gene therapy is administered only
once, gene therapy may be chosen at the ages four to five for the convenience of treatment.
As I mentioned earlier, even if a patient undergoes gene therapy, the patient will return to exon skipping
therapy when the effect of the therapy diminishes, or if the symptoms have progressed to the point of non-

ambulant, the patient will choose cell (exosome) therapy. Therefore, we believe that exon skipping drugs andgene therapy will coexist without competition.
As I explained earlier, as for cell therapy, clinical trials are underway for patients who have difficulty walking.
Since evidence has been obtained so far that cell therapy contributes to upper limb motor function, we expectthat cell therapy will be widely used for non-ambulant patients. The Company targets DMD by offering a rangeof therapeutic agents in multiple modalities. We will work to ensure that as many patients as possible receive
optimal treatment according to their various genetic backgrounds and disease progression.

Next, I would like to discuss our pipeline for future growth other than DMD.

Here is our R&D pipeline other than DMD.
I would like to introduce some of the development items in these pipelines indicated in red.

First, let me explain about the NS-87.
NS-87, with the planned trade name VYXEOS, is a liposomal formulation containing cytarabine anddaunorubicin, both of which are conventionally used in the treatment of leukemia.
The application was filed in June 2023.

The planned indicaton for NS-87 are therapy-related acute myeloid leukemia or AML with myelodysplasiarelated changes, which are considered to be poor prognosis among AML. These are referred to as high-risk
AML.
Approximately half of all AML patients can be high-risk AML, and NS-87 is used in intensive chemotherapyindicated patients.
Although 7+3 therapy is currently used primarily in this patient group, NS-87 showed significant extension of
overall survival compared with 7+3 therapy in clinical trials.

NS-87 is liposome formulation of cytarabine and daunorubicin in a 5:1 molar ratio with the highest antitumor
efficacy. NS-87 is known to reach the bone marrow as liposome form and remain for a long time.
After the drug is taken up into leukemic cells in the bone-marrow, cytarabine and daunorubicin are released
to exert their antitumor effects.

7+3 therapy requires continuous intravenous infusion for five to seven days, whereas NS-87 is effective after
90 minutes of intravenous infusion over three or five days.
NS-87 enables to reduce the burden of treatment for both patients and healthcare professionals.

The results of the overseas Phase III study are shown here.
The patients included 309 cases of untreated high-risk AML patients aged 60 to 75 years.
Overall survival with NS-87 was 9.56 months, compared to 5.95 months with 7+3 therapy, significantly
prolonging overall survival.

A summary of the NS-87 domestic Phase I/ II study is shown here.
The design was a single-arm, open-label study, and the objective of the trial was to investigate thepharmacokinetics, safety, and efficacy of NS-87 in patients with high-risk AML.
Based on the results of the Phase I/II study in Japan and the overseas Phase III study conducted by Jazz
Pharmaceuticals, we filed an application for manufacturing and marketing approval in June 2023.
The drug has already been designated as an Orphan Drug and is expected to be approved in March 2024,
based on a review period of approximately 9 months.

Next, I would like to introduce NS-580.
NS-580 is being developed for endometriosis and is currently undergoing a Phase IIb study in Japan. A
microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor is discovered and developed in-house.

Endometriosis, for which NS-580 is indicated, is a chronic inflammatory disease in which endometrial tissue
engrafts outside the uterus and continues to proliferate and bleed during the menstrual cycle.
Pain and sterility are the primary symptoms and significantly reduce women’s quality of life.

NS-580 inhibits only the production of inflammation- and pain-inducing PGE2 by blocking mPGES-1, theenzyme responsible for the final step in PGE2 production. It does not inhibit other prostaglandins and is
expected to be highly safe and effective for endometriosis lesions.

This slide shows the point of action of each drug on the pathogenesis of endometriosis. By selectively
inhibiting PGE2, NS-580 is expected to have analgesic and anti-inflammatory effects as well as inhibit thegrowth of the endometriotic lesion.
We expect it to act differently from existing hormonal treatment and NSAIDs.

Phase IIa study was conducted in Japan. Pain associated with endometriosis was evaluated using VAS
score. The target number of cases is 150, 60 cases in each of the two actual drug groups with different doses
and 30 cases on placebo group. The results confirmed the analgesic effect of NS-580.

Based on the results of the Phase IIa study, Phase IIb study is currently underway.
As in the Phase IIa study, pain associated with endometriosis is evaluated by VAS score.
NS-580 with three different doses and a placebo groups.
The target number of cases is 372, and case inclusion has already been completed.
We expect NS-580 to answer the needs of endometriosis patients by acting differently from existing hormonal
treatment and NSAIDs.

NS-580 is also being developed for chronic prostatitis/chronic pelvic pain syndrome. The domestic Phase IIa
study is currently underway.

Chronic prostatitis/chronic pelvic pain syndrome is defined as peripelvic and periurogenital pain that persists
for three out of six months. It is associated with urinary and sexual dysfunction, with no clear etiology.
The number of potential patients in Japan is approximately two million, and there are similar ratio of patientsoverseas.

This slide shows the current status of CP/CPPS treatment and product concept of NS-580.
Currently, drugs are selected for each symptom, with NSAIDs and antibacterial agents used for pain relief andalpha blockers and PDE5 inhibitors for urinary symptoms. In addition, the only approved drug, Cernilton, is asafe drug, but new drugs are needed.
NS-580 is expected to become a new treatment option for CP/CPPS with a highly safe treatment and control
pain in the long term.

I would like to explain about NS-229.
NS-229 will be developed for a disease called eosinophilic granulomatosis with polyangiitis, EGPA.
First, I will continue with a description of EGPA.
EGPA is a rare and intractable disease of unknown cause that was designated as an intractable disease inJapan in January 2015.
The figure on the left shows the symptoms that develop in EGPA patients. Symptoms of asthma and allergic
rhinitis precede the onset of the disease, followed by systemic eosinophilic inflammation and vasculitis.
As of the end of FY2021, there were 5,839 EGPA patients receiving specific medical expenses in Japan.
Considering that not all patients are receiving such expenses, we believe that there are probably morepatients than this number in reality.

The ANCA-related vasculitis practice guideline was published in 2023 for the treatment of EGPA. The figureshown here is the basis for the treatment plan.
Treatment is divided into the remission induction phase and the remission maintenance phase. During
remission induction, patients are treated with glucocorticoids alone or in combination with glucocorticoids
and immunosuppressants or mepolizumab.
Once remission is achieved, glucocorticoid monotherapy is used to prolong and maintain the remission period.
Alternatively, glucocorticoids are used in combination with methotrexate, azathioprine, or mepolizumab.
At this time, it is very important to keep glucocorticoid doses low in order to avoid the side effects caused byprolonged administration of glucocorticoids. NS-229 aims to be a drug that reduces glucocorticoid doses andcontrols disease activity while replacing its drug effects.

Next, I will discuss the mechanism of action of NS-229.
EGPA is an abbreviation for eosinophilic granulomatosis with polyangiitis, but its symptoms develop with theactivation of not only eosinophils but also other inflammatory cells such as T cells and B cells, leading tovarious types of tissue injury.
NS-229 has potent JAK1 inhibitory activity and suppresses activation of eosinophils, T cells, and B cells by
inhibiting various cytokine signaling through JAK1 inhibition, leading to improvement of disease conditions.

I will talk about the Phase II study for NS-229.
The Phase II study will be a double-blind, randomized, placebo-controlled trial. The 45 patients will be divided
into the NS-229 group and placebo group.
This current study will confirm the safety of NS-229 while confirming that the patient is in remission with areduced dose of glucocorticoids at the time of the last dose as efficacy.
This examination is currently under preparation.

Finally, I would like to introduce our efforts to expand our pipelines I have explained so far.
Currently, we have set a goal of launching an average of at least one new product per year. As President Nakai
mentioned at the beginning of this presentation, we believe that we must exceed this goal in order to continue
to grow in the future. To achieve this, it is necessary to expand our pipeline, shorten the R&D period, andaccelerate drug discovery.

The nucleic acid drug Viltepso, which was launched in Japan and the US in 2020, is the fruit of more than 30
years of nucleic acid research at our company.
However, we cannot take so long to acquire new drug discovery modalities or to advance in-house drug
discovery in the future. Therefore, we are considering shortening development time by acquiring superior
external technologies.
Accordingly, we established Innovation Research Partnering in Boston area in January 2023. We aim toincrease opportunities for co-creation with world-class scientists through open innovation, to build a diverse
R&D portfolio, and to accelerate research.

Next, I would like to explain our use of AI in drug discovery.
The arrows at the top indicate the drug discovery process.
We are using AI in the identification and optimization of the framed compounds and in the prediction of theirsafety and pharmacokinetics, applying it to existing R&D items as well.
For example, when AI is used in the synthesis stage of a compound, AI predicts the steric structure of thetarget. The AI will be able to generate the structure of the compound to be bound to it, which is expected toshorten the period of time and discover more active compounds.
Currently, we are in the process of applying AI in each step of drug discovery. To further accelerate our R&D,
we are developing an integrated system that collects and provides a huge amount of drug discovery
information from research to clinical trials.
In the past, during the initial disease selection and molecular target search phase, researchers conducted
literature searches to select targets, and at the same time, it was too time-consuming and difficult toinvestigate and consider the evaluation of the targets in clinical trials.
If there is an integrated system, AI will take over the labor of searching for such information, making it possible
to draft new themes based on the search and clinical evaluation in a short period of time.
We will accelerate drug discovery through these efforts.

This is all. Thank you very much.

FY 2023 R&D Meeting Q&A (Summary)

Held on December 12, 2023
NO

Questions

Answers

1

I have a question about partnering and in-house development. In today's presentation, NS-580 and NS-229 are

In basic terms, we are planning to collaborate with a partner company to expand NS-580 globally. The market size of

topics, and I think that you will collaborate with a partner company to promote the global expansion of NS-580.

NS-229 is not so large. If disease areas of each product are not same, different sales teams are required. However, we

Other than that, will you promote products indicated for hematological and rare diseases with a partner company?

can leverage our sales basis such as market access, therefore, we are planning to promote the global expansion of NS229 through our own marketing.

2

Are you planning to promote global expansion of NS-018 through your own marketing?

Since NS-018 targets relatively small market of myelofibrosis, we are considering our own marketing.

3

Please tell us when your gene therapy proceeds to pre-clinical.

Unlike small molecules, it is difficult to define the beginning of the preclinical stage in gene therapy. We consider
preclinical to be the phase in which we initiate safety testing by establishing product specifications similar to those ofcommercial products, and we anticipate that this phase will take more than two years..

4

This is a question about the pipeline table on slide p.7. The blue arrow of PPMO is shorter than those of exon 45

This table does not provide a direct indication of the timing of clinical trials, but it shows the current progress. We

skipping and exon 55 skipping, so it appears that the PPMO cannot be developed unless all the others arewould like to develop PPMO as quickly as possible.

developed. However, considering a competitive situation, should PPMO of Viltepso, exon 45 skipping, and exon
51 skipping be developed faster despite some risks?
5

Regarding the development of PPMO, has the nucleic acid sequence been designed?

Yes, it has.

6

Is it possible to develop both conventional morpholino oligomer and PPMO at the same time?

We would like to simultaneously develop both of them as far as the budget allows.
There are competitors, so we would like to strategically invest our management resources. We are still in the process ofassessing a bold investment in PPMO. I will make a decision to proceed with the development of PPMO according to
the situation.

7

Do you mean that you are still not in the position to intensively invest your management resources in the

You are right.

development of PPMO?
8

According to the presentation material, NS-089 has been designated as a breakthrough therapy in the U.S. Has
the information been released?

1

We have already issued the press release in July 2023.

9

Regarding the study design of NS-089, I understand that LPO will be in FY2025. Is there any plan to publish theSince muscle biopsy will not be done after part 1, the only result that will come out after part 1 is maximum tolerable

results in part 1 earlier? If so, will it be published within 12 months?

dose. That is not enough to make a presentation, so we would like to confirm the dystrophin expression level with thelast muscle biopsy after P2 study is completed. Then we will unveil the results.

10

Regarding slide page 9, the data of NS-089 that shows amount change in dystrophin in patient muscle, is there

The baseline of patients amenable to exon 53 skipping was originally close to zero. Therefore, we achieved 5% of

any concern that significant difference will not be observed due to the high baseline? The concept of this drug is

dystrophin protein expression in the study for Viltepso. It is said that patients amenable to exon 44 skipping may not

to achieve 4 or 5% of dystrophin protein expression, which is the same level as the Becker type and a certain levelneed medication because of the high baseline, but their symptoms progress slowly as they age. The patient organizationof motor function can be maintained in such a case. I think that significant difference of motor function cannot

in the U.S. has previously asked our U.S. subsidiary to develop exon 44 skipping therapy. The child of the representing

be observed, if the baseline is high. I would like to hear your opinion about this.

of the patient organization that made the request is a patient amenable to exon 44 skipping, so it cannot be said that
there is no need for exon 44 skipping therapy.

11

There was data in the article of NS-089 that nucleic acid might be distributed to cardiac muscle. However, theThe permeability of morpholino oligomer into cardiac muscle is not different between NS-089 and Viltepso. However,baseline of dystrophin protein expression of patients amenable to Exon 44 skipping is above a certain level. So I

NS-089 has higher activity than Viltepso, so it can be expected for NS-089 to be more effective. We do not know how

think that NS-089 would not be effective in animal experiments unless its dose was substantially increased. Does

much dystrophin expression in cardiac muscle is effective because the structure of skeletal and cardiac muscle are

NS-089 with a new sequence design method have higher activity than Viltepso, though NS-089 is morpholino

different. There are no data on the efficacy of dystrophin protein expression in cardiac muscle.

oligomer that do not basically affect cardiac muscle?
12

Can't you assume that dystrophin protein is expressed much longer if exon skipping is administered continuously

I would like to expect such an effect, but now there is no evidence.

because the cardiac muscle has no turnover?
13

Regarding the HOPE-3 study of CAP-1002, is it correct that if the study is worth continuing is judged in interim

Whether it is meaningless or acceptable to continue with this trial is judged in the futility analysis. The results indicate

futility analysis and how much CAP-1002 is effective was not observed?

that there is no safety concern and regarding the efficacy, it is not a situation to suspend the study.

14

Will the milestone for the result of the interim futility analysis of HOPE-3 trial be recorded on P/L?

It will be recorded on BS this fiscal year.

15

Will the results of the HOPE-3 study of CAP-1002 be approved if the results at the same level as HOPE-2 study

The difference between HOPE-3 study and HOPE-2 study is the number of patients and that of HOPE-3 study is moreare confirmed?

than that of HOPE-2 study. We think that CAP-1002 can be approved if the results of HOPE-3 study are similar to thatof HOPE-2 study. We know that Capricor Therapeutics has had frequent contact with FDA.

16

Do you have any information beyond the press release about the interim futility analysis of CAP-1002? Capricor

We don't have further information than the press release. We have heard that they have requested a meeting with FDA

Therapeutics is going to have a meeting with FDA in the first quarter of next year. Do they have confidence about

to further discuss opportunities for accelerated approval pathways, but we have no information on the probability of

expedited approval of CAP-1002?

expedited approval.

2

17

I have a question about CAP-1002. Is the equivalence of products manufactured in Los Angeles and San Diego

We understand that Los Angeles and San Diego sites can manufacture similar products. However, CAP-1002 is aevaluated in accordance with the specifications?

biologic drug and the equivalence must be confirmed in clinical trials. Therefore, cohort B is underway in conjunction
with cohort A.

18

19

One of the secondary endpoints of the HOPE-3 study of CAP-1002 is change in cardiac muscle function and

Because of the cardiosphere-derived exosomes, we expect an effect on cardiac muscle. If the change in cardiac muscle

structure. Although the primary endpoint is important for approval, it is likely that cardiac muscle function andfunction and structure in the secondary endpoints can be proved, it is expected to have a positive effect on the factors

structure are also commercially important. What is the commercial impact of secondary endpoints?

that determine the lifespan of DMD patients because DMD patients tend to die due to the decline in cardiac function.

In the Q&A section of IR meeting for the 2Q, we heard that one of the payers has a policy of reimbursement for

We have told our U.S. subsidiaries to pay close attention, but we have not yet confirmed the actual examples.

Viltepso after using gene therapy. Have you confirmed the example of reimbursement after the IR meeting inNovember?
20

Although I don’t know whether it is related to NS-580, you have recently published a patent stating that

Chemotherapy other than hematologic cancer is not our target areas. We would like to develop it if we can collaborate

prostaglandins are effective in combining tumor immunity. How committed are you to developing this?

effectively with other companies.

What level of efficacy and safety was achieved in the P2a study of NS-580 for endometriosis? Based on the

It is hard to explain the details, but the analgesic effect of NS-580 was confirmed in P2a study. We will determine themechanism, I think that the short-term effect is weak, but the long-term effect becomes gradually stronger because

potential of NS-580 by the twice-daily administration based on the results of the P2a study. There are patients who

it inhibits the growth of the endometriotic lesion. Although it is not a comparative study with other drugs, what

hesitate to use hormonal treatments due to the side effects and some people in Japan who are reluctant to use hormonal

sort of positioning is likely to be expected from the efficacy and safety data? Why is the number of administrations

treatments themselves. Therefore, regarding to the position of NS-580, it is assumed that NS-580 will be used by thosechanged to twice-daily in the P2b study?

kind of patients. We would like to carefully review the positioning according to the results.

22

Is NS-580 mechanistically available in combination with hormone therapy or NSAIDs?

We assume that NS-580 will be used separately from them basically.

23

Is NS-229 similar to Avacopan? In addition, are the target patient group and the positioning of NS-229 similar to

Since the mechanism of action of NS-229 is different from that of Avacopan, we expect different effects. Avacopan isthose of Avacopan?

not indicated for EGPA but other ANCA-related diseases, so they are not in competition.

21

3