R&D Meeting

February 24, 2023

0/49

Cautionary Notes
Forecasts and other forward-looking statements included in this document are basedon information currently available and certain assumptions that the Company deems
reasonable.
Actual performance and other results may differ significantly due to various factors.
Such factors include, but are not limited to:(ⅰ) failures in new product development(ⅱ) changes in general economic conditions due to reform of medical insurance
system(ⅲ) failures in obtaining the expected results due to effects of competing products orgeneric drugs(ⅳ) infringements of the Company’s intellectual property rights by third parties(ⅴ) stagnation of product supply from the delay in production due to natural
disasters, fires and so on(ⅵ) onset of new side effect of post-licensure medical productand,( ⅶ ) currency exchange rate fluctuations and interest rate trend.

Information about pharmaceutical products (including products currently in development) includedin this document is not intended to constitute an advertisement of medical advice.

1/49

AgendaResearch and Development Strategy of ONO
President, Representative Director, and Chief Executive Officer

Gyo Sagara

Drug Discovery Strategy & Alliance Updates

Senior Executive Officer, Executive Director of Discovery and Research

Toichi Takino

Itolizumab (Anti-CD6 antibody)

Executive Officer, Executive Director of Clinical Development

Kiyoaki Idemitsu
Q&A

2/49

Research and Development Strategy of ONO

President, Representative Director, and Chief Executive Officer
Gyo Sagara

3/49

Investment strategy over the next 5 years
Aggressive R&D investment
Sources of cash
（2022-2026）

to overcome patent cliff and further growth

Allocation of Investments（2022-2026）

R&D

Newly generated cash

¥600B

Priority investments inoncology, immunology,
neurology, and specialty areas

Strategic investments

Strategic investment to strengthen
the drug discovery business, expand
business areas, and strengthen
the corporate infrastructure

Shareholder return

Stable dividends distribution andflexibly considering stock
repurchases share buybacks¥ 250B

Funds on hand

Capacity to invest to
further increase
corporate value

Multiple M&As for drug discovery
and technology ventures

4/49

Global pipeline expansion
Global development（medium to long term）
VELEXBRU（BTK inhibitor / PCNSL

ONO-4578 （EP4 antagonist / Solid tumor, Gastric cancer, etc）
Oncology

ONO-7475 （Axl / Mer inhibitor / Acute leukemia, etc）
ONO-4685 （PD-1×CD3 bispecific antibody / T cell Lymphoma）
ONO-7018 （MALT1 inhibitor ／ hematologic lymphoid tumor ）ONO-2808 （S1P5 receptor agonist / Neurodegenerative disease）

Neurology

ONO-2910 （Schwann cell differentiation promoter / Diabetic polyneuropathy）
ONO-2020 （Epigenetic Regulation／Neurodegenerative disease）
ONO-1110 （Endocannabinoid regulation／Pain）

Immunology
Specialty

ONO-4685 （ PD-1×CD3 bispecific antibody / T cell Lymphoma ）ONO-7684 （FXIa inhibitor / Thrombosis）
Itolizumab

In house

In-licensed candidates for global development
5/49

Drug Discovery Strategy & Alliance Updates
Senior Executive Officer/Executive Director
Discovery & Research
Toichi Takino

6/49Corporate Philosophy” Dedicated to the Fight against Disease and Pain”

7/49

Focused Areas of Drug Discovery Research

8/49

Drug Discovery Strategy「Open Innovation」×「Technology」
allows us create unique & innovative new drugs

9/49

Drug Discovery Strategy「Open Innovation」×「Technology」
allows us create unique & innovative new drugs「Open Innovation」×「Technology」
10/49

Recent Updates of Discovery Alliances (2021～)

Jan

Sponsorship
Agreement

Feb

Mar

Mar

Apr

Anti-GPCR
Antibodies

Autoimmune
DiseasesJan

DNA Damage
Response

CancerFeb

Modified
Cytokine

Autoimmune
Diseases

Cancer

Jun

Mar

Aug

Large-scale
Transcriptome
Analysis

undisclosed

Nov

Antibody/Imm
uno-Oncology

CancerNov

Target Protein
Degradation

CNS

Dec

TargetIdentification

CNS

Aug

Aug

Dec

Jan

Varderbilt
Univ.

Ion Channel

CNS

11/49

Our Focus on Drug Discovery Platform and Modalities
Technology
Platform

Small Molecule2021

Peptide Protein/Antibody

2023

2022

Oncology

Immunology
expanded in

Neurology

Expanding
Biologics

2023

2022

2023

2021
Others2022

2022

Specialty

2022

2021

Vanderbilt Univ.

2022

Cell
Therapy

2021

2021

2022

2021

2021

2021
2022
12/49

Drug Discovery Strategy「Open Innovation」×「Technology」
allows us create unique & innovative new drugs

13/49

Drug Discovery Strategy「Open Innovation」×「Technology」
allows us create unique & innovative new drugs

Exploratory of the original drug discovery seeds
14/49

Sponsorship Agreements with LabCentral and MBC BioLabs（2021.02.26）“Investment to the start-up Biotech companies”
2021～

San Francisco
2021～

BostonAccess to the latest information andexploration of future collaborators
Weatherwax Biotechnologies

https://labcentral.org/news-events/press-releases/ono-entered-https://mbcbiolabs.com/ono-golden-ticket/ono-golden-ticket-2022-winner/ sponsorship-agreements-with-labcentral-and-mbc-biolabs

15/49

Joins the University of California Drug Discovery Consortium（2021.03.16）

 Access to undiscovered top scientists
 Explore collaboration opportunities based on unverified

and unpublished ideas
 Bridging academia's drug discovery seeds to pharma
UC 8
Universities

Research Plan

Funding

16/49

Collaborative research with knowledge palette to build a datadriven new drug discovery platform using large-scaletranscriptome analysis technology （2022.08.10）
Treatment with many different compounds
Perturbations such as inhibition of gene function

Mapping
Database
Elucidation of new
target moleculesand mechanisms

Human cells

Large-scale transcriptome analysis

Artificial intelligence（AI）
Large-scale scientific computation
Quartz-Seq2：Technology that enables comprehensive
gene expression profiles with highprecision（Mereu, et al. Nature Biotecnology, 2020）

Cells

Gene Expression Big Data ofProfiling
Cells

https://www.knowledge-palette.com/technology.php

Elucidation of new target molecules and mechanisms in a data-driven mannerby making large-scale database on the effects of existing drugs, gene knochout, etc.
on human cells
17/49

Multi Target R&D Collaboration Agreement with PrecisionLife
to identify novel therapeutic targets in CNS disorders（2022.12.14）

Target Patient

Bioinformatics Analysis

Identification of Therapeutic
Targets and Biomarkers

Disease-related Genes inTarget Patients

Patient Dataset

Unique Combinatorial
Analytics Platform

Validation Study

Identification of Novel Therapeutic Targets and Patient Stratification Biomarkers through
Unique Combinatorial Analytics Platform to Datasets of Treatment-resistant Patients
18/49

Acquisition of Multiple Research-Stage Oncology Programsfrom KSQ Therapeutics（2023.01.25）

Acquisition of multiple research-stage DNA damage response programs
identified by KSQ’s CRISPRomics® platform technology
19/49

Drug Discovery Strategy「Open Innovation」×「Technology」
allows us create unique & innovative new drugs

Utilization of Therapeutic Modalities
20/49

Alliances on Multispecific Antibodies

OmniRat®, OmniMouse® and OmniFlic®

Biclonics® technology platform
Holland2014～

Highly flexible multispecific format, MATCH
Switzerland
2017～

The US
2016～

LassoGraft Technology®
Japan
2021～

21/49

ONO-4685：PD-1×CD3 Bispecific Antibody• PD-1×CD3 Bispecific Antibody generated by Biclonics®
Discovery Platform

PD-1 arm

CD3 arm

T cell lymphoma （USA, Phase 1）
Autoimmune Diseases（Japan・EU, Phase1）
Suppression of activated T cell
Cytotoxicity on activated T cells
T cellCD3

PD-1

PD-1 expressing cell
（Activated T cell）
PD-1

CD3

Activation
T cellSuppression

Cytolysis

22/49

Antibody Discovering Partnership for Immuno-oncology with
MEMO Therapeutics（2022.11.01）

B cells(Entire repertoire)

Entire repertoire
library

Repertoire
copied in HEKHigh throughput
Functional Screening

Maximizing antibody repertoire against target antigens
Therapeutic Antibody for Immuno-oncology
Antibody discovery by microfluidic single-cell molecular cloning and screening
technologies (Dropzylla®) at unprecedented speed, efficiency, and sensitivity.
23/49

Antibody Drug Discovery Collaboration with Neurimmune AG
in the Field of Neurodegenerative Diseases（2022.01.17）
Healthy ElderDonors

Non-ClinicalStudies

Candidate
Antibodies

Creating Selective High Affinity Antibodies Using the Reverse Translational Medicine™
Technology Platform Based on Immune Responses to
Disease-related Proteins in Healthy Elderly

24/49

Research Collaboration with Monash University in the
Autoimmune and Inflammatory Diseases（2023.01.13）

 Monash University’s sophisticated technologies for
antibody discovery which enables the creation oftherapeutic antibodies using monoclonal antibodies
against two GPCRs traditionally hard to target.

 We expect to increase the efficiency of finding new
drug candidates that fulfil unmet medical needs in
autoimmune and inflammatory diseases.
Biochem Pharmacol. 2013 Jan 15; 85 (2): 147-52

25/49

Strategic Collaboration with Fate Therapeutics to Develop
iPSC-derived CAR-T（2018.09.18）
Exercise Option to HER2-targeted CAR T-Cell ProductCandidate for Solid Tumors（2022.11.07）
Appropriate activation signal to escape exhaustion

HER2CAR＋1xx
CXCR2

T-cell receptor (TCR） deletion

Improvement of migration into tumor tissues

Avoidance of GVH reaction

CD38 deletion

iPSCDerived CARTONO-8250

Resistant to pretreatment by
CD38 mAb

IL7RF

Improvement of viability

TGFβR2-IL18R
hnCD16aOvercome of immune suppressive environment

Combination effect with other therapeutic antibody“Off the Shelf” iPSC-derived HER2-CAR-T armed with seven Functional Edits
26/49

ONO-8250：Anti-tumor effect on HER2+ tumor bearing model

ONO-8250＋／－

HER2+ tumor

αHER2mAb

hnCD16aTumor Volume (mm3)Combination effect with other therapeutic antibody

αHER2mAb

ONO-8250

ONO-8250+αHER2mAb

VehicleONO-8250 showed anti-tumor effect in HER2+ tumor bearing model.
Combo with anti HER2mAb enhanced anti-tumor effect by hnCD16a activation
Hosking Ｍ, et al. SITC 2022 #304

27/49

Collaboration and Option Agreement with Cue Biopharma for
CUE-401, a Bispecific Protein （2023.02.22）
CUE-401
IL-2 moiety

Tregs induced by CUE-401
 Diversity：Generated from vastly diverse T cells
 Phenotype：Regulatory phenotype can be achieved and sustained Disease impact：Conversion of pathogenic T cells into Tregs is an

TGF-β
moietyattractive strategy for immune re-set
 Application：Broad applications in numerous autoimmune
diseases
Treg
Effector T cell

NormalAutoimmune disease

Treg treatment

Efficient induction of Tregs from diverse repertoire is expected to restore the balanceof immune cells to help patients suffering from autoimmune and inflammatory diseases.
https://cuebiopharma.gcs-web.com/node/8111/html revised

28/49

License agreement with PeptiDream Inc. on automatedPeptide Discovery Platform System (2021.03.01)
Characteristics of Specialty Cyclicpeptide Drug Discovery
Smallmolecule

Specialty Cyclic
peptide（Middle molecule）

Antibody（Largemolecule)

MW

<500

500 - 2000

150000Specificity

Low

High

High

Oral administration

Available

AvailableNotavailable

Intracellulartargets

Available

Available

Difficult

Off-target toxicity

Low - mid

Low

Low

Cost of goods

Low

Low

High

RSC Chem. Biol., 2022, 3, 7-17

Expansion of modality options suitable for tough targets by utilizing the original Peptide
Discovery Platform System (PDPS)
29/49

Drug Discovery Collaboration with Captor Therapeutics to
Develop Protein Degraders for Treatment of
Neurodegenerative Diseases（2022.11.14）
Undruggable Proteins*
Degradation

Druggable Proteins
Functional Inhibition

Target Protein Degraders

Receptor Antagonists
Enzyme Inhibitors*70-80% of all proteins

E3 ligase
Target Proteins withdeep binding pocket

Target Protein
DegraderE3 Ubiquitin
LigaseTarget Proteins withshallow binding pocket

TargetProteinComplexTargetProteinProteasome

Ubiquitination

Poly-Ubiquitination

Degradation

Békés, et al., Nature Rev Drug Dis, 2022, modified

Creating Degrader Drug Candidates using Unique OptigradeTM TPD Platform in
Neurodegenerative diseases
30/49

Drug Discovery Strategy「Open Innovation」×「Technology」
allows us create unique & innovative new drugs

Digital/AI/Robotics
31/49

Collaboration agreement with Iktos to discover and develop
a novel small molecule using AI technology.（2022.03.30）(2017.12.19～)

Auto-synthesis

AI design・MPO

Auto-analysis

DesignMake

Analysis

Test

Autotesting

AＩ design・automation enables major productivity gains in
upstream pharmaceutical research
32/49Collaboration agreement with Curreio to access to structual
analysis technology using Cryo EM.（2022.05.23）「Visualization of interaction mode between target protein and compound」
X-ray analysis
soluble proteins
Kinase/protease2005～

X-ray analysis
Membren proteins
GPCR
2011～

CryoEM
Target X
2022～

Array Biopharma
Evotec A.G.

Receptos

Curreio

Acccessing super computing system
for using cutting-edge AI technology

33/49

Making full use of Human disease modeling

iPS cell technology

Humanoid robot×Digital technology
2020. 08 -Joint research（Academia）
Japan6・Overseas10
Alliance（Biotech venture/CRO)
Japan and Overseas8（2023.03）

Drug discovery research based on human disease biology through active
utilization of human disease iPS cell technology
34/49

Creation of PET for Bioimaging of Abnormal Protein "αsynuclein" in the Neurodegenerative Disease（2022.08.31）
α-synuclein accumulation(Multiple System Atrophy)
Ref.： Tokyo Medical Research Institute Neuropathology Database

Captures α-synuclein accumulation
Co-Development of Radiopharmaceuticals

Inject radioactive drug

Multiple
System Atrophy

Ref.：Movement Disorder. 2022. 37:2159-2161.

High
A-synuclein accumulation

Healthy

Low

PET（ positron emission tomography ）Successful Imaging of Brain α-Synuclein
Application of the PET to clinical development for neurodegenerative diseases
is expected.
35/49

Drug Discovery Strategy「Open Innovation」×「Technology」
allows us create unique & innovative new drugs

Create unique and innovative new drugs
36/49

Promotion System to Support Open Innovation
Driven Drug Discovery
Ono Pharma
Foundation

Discovery Research Alliance &Business Development

Ono Venture Investment, Inc.

37/49

Investment to the start-up Bio-Venture
Start-up

OutlineCambridge,
MA, USA• Bio-Venture for development of new drugs for thetreatment of fibrosis

Tokyo,
Japan• Bio-venture for drug discovery based on detailed
protein structure information by cryo-electron
microscopy

Waltham,
MA, USA• Bio-Venture Committed to the Creation andDevelopment of Novel Therapies for Cancer Patients

Cambridge,
MA, USA• Bio-Venture for New Gene Editing Therapy with a
Unique DNA/RNA Degrading Enzyme• Established based on the achievements of the Broad
Institute and Harvard University

Cambridge,
MA, USA• Bio-Venture for Development of New Therapeutic
Drugs through Targeted Degradation by Autophagy

https://www.onoventure.com/news
38/49

Research Grant Activities by the Ono Pharma
Foundation in the United States
Ono Pharma Breakthrough Science Initiative Awards Program：is the embodiment of the Foundation’s commitment to focus on and accelerate
researcher-driven open innovation by supporting high-risk and high-reward science
research projects which have potential to lead to science discoveries/solutions and,possibly, based on further research, to breakthrough treatments for patients.

SCIENTIFIC ADVISORY BOARD• STUART L. SCHREIBER, PH.D.（Chair）• DAVID COREY, PH.D.（Vice Chair）• BENJAMIN CRAVATT, PH.D.（Secretary）• CAROLYN R. BERTOZZI, PH.D.
• MASAD J. DAMHA, PH.D., F.C.I.C.
https://www.onofound.org/about/Prof. Carolyn R. Bertozzi
Stanford University
2022 Nobel Prize Winner
in Chemistry
39/49

Itolizumab(Anti-CD6 antibody)
Executive Officer/Executive Director
Clinical Development
Kiyoaki Idemitsu

40/49

Itolizumab
Ono and Equillium Announce Exclusive Option and Asset Purchase Agreement for
the Development and Commercialization of Itolizumab（5 Dec, 2022）
Partner

Equillium, Inc（CA, USA）

CompoundName

Itolizumab

Mechanism

Anti-CD6 antibody

Characteristics

Highly safe FIC drug that change T-cell status to treat autoimmune
diseases
Acute graft-versus-host disease* (aGvHD) ：Phase 3

Indications
and stages

Lupus nephritis ：P1b study

Formulationi.v.(aGvHD) ／ s.ｃ.(Lupus nephritis )Rightsacquisition
regionUS/Canada/Australia/New Zealand,（Biocon／CIM** reserve rights in all other Region）••

aGvHD： Complications after hematopoietic stem cell transplantation,a treatment for hematologic cancer
CIM：Centro de Inmunologia Molecular

41

41/49

CD6 Drives Pathogenic T Cell Activity & Trafficking
Co-stimulation=

Activation

Proliferation

Differentiation/Survival

Suppression ofregulatory pathways

Trafficking

42

42/49

Itolizumab inhibits pathogenic T Cell Activity & Trafficking
Co-stimulation=

Activation

Proliferation

Differentiation/Survival

Trafficking

Itolizumab

Restoration ofregulatory
pathways
43/49

aGvHD treatment guideline in the US
aGvHD：Complications After Hematopoietic Stem Cell Transplantation, a Treatment for Hematologic Cancer

aGvHD

4,500

【Abbreviations】
ATG： Antithymocyte globulin, CSP： Cyclosporine, MMF： Mycophenolate mofetil,mPSL： Methylprednisolone, MTX： Methotrexate, TAC： Tacrolimus

Approx.
patients in the US
Conditioning
regimen
High-dose
chemotherapy

Allogeneic
hematopoietic stem celltransplantation
Donar to Patient≤ 100 days after transplantation

GVHD予防aGvHDApprox.50%

CSP／MTX／TAC＋MMF
Abatacept*

Skin disorder
Liver disorder
Gastrointestinal
disorderGrade I
Grade
II
Grade
III
Grade
IV

1st line

2nd line

Follow up

Ruxolitinib

Steroids

JAK inhibitor

mPSL→PSL＋
Itolizumab

ATG、MMF
anti-TNF agents,
daclizumab（anti CD25
antibody）etc.

＊ Abatacept（Orencia）has been approved for prophylaxis of acute GVHD in the US in Dec. 2021

44/49

Phase 1b study - EQUATE study
Evaluate the clinical activity and safety of
Itolizumab on top of steroids, as 1st line treatment foraGvHD
mPSL, i.v., ~2mg/kg  prednisolone, p.o., （i.v.p.o.［Dose tapering］）
Steroids

Itolizumab

D1

D15

D29

D43

D57

0.4 , 0.8 , 1.6 mg/kg, q2w, i.v.

• Scoring of skin, liver, and gastrointestinal symptoms were
evaluated
at D15 and D29.
• CR (Complete Response) : Disappearance of all symptoms.
45/49

High Response Rates to Itolizumab + Steroids
Itolizumab treatment (≤3 days of steroids)

Day 15

急性GvHD Response

100%
80%
60%

75%
25%

20%
0%

50%

100%
20%

69%

50%

20%

65%
13%

21%

4%

80%
50%

38%

(N=13)

64%

5%

0.4 mg/kg 0.8 mg/kg 1.6 mg/kg
(N=4)

80%

77%
23%

23%
8%

40%

Day 29

(N=5)

50%

TOTAL
TOTAL
(N=22)(N=22)CR

VGPR

CR, complete response
ORR, overall response rate (PR+VGPR+CR)
PR, partial response
VGPR, very good partial response

43%

60%

0.4 mg/kg 0.8 mg/kg 1.6 mg/kg
(N=4)
PR

ORR

(N=14)

(N=5)

48%

TOTAL
TOTAL
(N=23)(N=23)ASTCT & CIBMTR, 2023

[per Martin 2009 Consensus criteria]

46/49

Phase 3 Study for aGvHD（EQUATOR study）

Grade III-IV
patients &Grade II
patients withlower GI
Concomitant
within 72 hours
of high-dose
corticosteroids(2 mg/kg)

Itolizumab:
IV 1.6 mg/kg loading dose followed by 0.8 mg/kg Q2W x 6 doses (n=100)

R

Steroid tapering recommendation

Placebo:(n=100)
Day
1

Day
15

Day
29

Day
43

Day
57

Day
71

Day
85

Dosing Schedule: patients followed out to Day 365

 Primary Outcome：Complete Response Rate at Day 29
 Secondary Outcome：Durability of Complete Response
Rate from Day 29 through Day 99（Interim DSMC Review @ 100 patients）

47/49

P1b Study for Lupus Nephritis （EQUALISE study）
Evaluate the efficacy and safety of Itolizumab as an addon to Steroids + Mycophenolate mofetil
Target Class III/IV(with V) on
renal biopsy
 UPCR > 1 g/g

Steroids Tapering to ≤10mg/d@10weeks

Mycophenolate mofetil (MMF)：2～3g/day
Efficacy
assessment

Itolizumab：1.6mg/kg, q2w

24w

28w

Follow
up

36w

Complete Renal Response UPCR：≤0.5 g/g(urine protein/creatinine ratio)

 eGFR：Not less than 20% below baseline(estimated glomerular filtration rate)

48/49

P1b Study for Lupus Nephritis
Cut off：2022/09/02※ CR : ≧ 50% UPCR reduction + <0.5g/g
PR : ≧ 50% reduction UPCR

UPCR reduction in all cases（Urine protein／Creatinine ratio）

CR ≧ 50% UPCR reduction + <0.5g/g
CR ≧ 50% UPCR reduction + 0.5-0.7g/g

PR ≧ 50% reduction UPCRNo Response < 50% reduction or worsening UPCR

49/49

Dedicated to the Fight against Disease and Pain