R&D Meeting
February 22, 2024

Cautionary Notes
Forecasts and other forward-looking statements included in this document are based on 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 competingproducts or generic 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 product and,( ⅶ ) currency exchange rate fluctuations and interest rate trend.

Information about pharmaceutical products (including products currently in development) included inthis document is not intended to constitute an advertisement of medical advice.
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AgendaIntroduction（13:00-13:10）
President, Representative Director, and CEO

Gyo Sagara

ONO-4578 Development Status（13:10-13:30）••

ONO-4578-01 Part C
ONO-4578-01 Part D
Corporate Officer /Deputy Executive Director, Clinical Development

Tatsuya Okamoto

Updates of Open Innovation and ONO-8250 Introduction（13:30-13:50）•••

Drug Discovery Strategy & Priority Areas
Updates of Open Innovation
ONO-8250 Introduction
Member of the Board of Directors, Senior Executive Officer /Executive Director, Discovery & Research

Toichi Takino

Q&A session（13:50-14:30）
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Change in Representative Directors
Details of the change in directors as of April 1, 2024

Name

New Role

Current Title

Gyo Sagara

Representative Director, Chairman of the Board
and Chief Exective Officer

Representative Director, President

Toichi Takino

Representative Director, President and Chief
Operating Officer

Director, Senior Executive Officer /Exective Director, Discovery and Research

Toshihiro Tsujinaka

Representative Director, Exective Vice President /Executive Directorr, Corporate Strategy & Planning/ Director, Sustainability Promotion

Director, Senior Executive Officer, Exective
Director, Corporate Strategy & Planning /Director, Sustainability Promotion

3 / 63

Future growth strategies - Aggressively invest in R & D for growth Investment allocation (FY 2022 to FY 2026)
Strategic
investment

R & D investment

600 billion yen
scale

R & D expenses(billion yen)

250
Billions yen

Leverages abundant R & D capabilities
Accelerate global business development

Investment
to increase
corporate
value

Shareholder
Returns109

95.3(Forecast)

FY 2022

FY 2023

FY 2024

FY 2025

FY 2026

OpdivoFiling/approval・Opdivo

2 Approval・Opdivo

2 Approval

2 Approval(forecast) 5 Filing(forecast)
BRAFTOVI/MEKTOVI・Application for tirabrutinib in the US (forecast)

1 Approval(forecast) 1 Filing(forecast)

Pipeline
Stage transition

Alliance• Opdivo 3 cases• ONO-7018 P1 Start• ONO-2020 P1 Start• ONO-1110 P1 Start・Itrizumab, Exclusive Option andAsset Purchase Agreement
・Exercise option rights the drug
discovery collaboration agreementwith Fate
・12 Drug Discovery Alliance• ONO-2910 P2 Start• ONO-2808 P2 Start• ONO-4578 P2 Start• ONO-8250 P1 Start• ONO-4538HSC P1 Start

・9 Drug Discovery Alliance・Itrizumab
Decision to exercise options (Forecast)

As of Feb. 21, 2024

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ONO-4578 Development Status

ONO-4578
CompoundONO-4578（In-house, Small molecule）

Mechanism Prostagrandin receptor (EP4) antagonist
Formulation Tablet
Phase2：GC*（JP・KR・TW）

Phase1：Colorectal cancer*, Pancreatic cancer*,Stage

NSCLC*, Hormone receptor-positive, HER2-negative

breast cancer（JP）（* : Combination with OPD）
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ONO-4578 Mechanism of Action▪ Prostaglandin E2 (PGE2) is produced
from arachidonic acid throughcyclooxygenase-2 (COX-2)▪ COX-2 is overexpressed in solidcancer1). PGE2 has been reported toinduce myeloid-derived suppressor
cells (MDSC) and M2 macrophages inthe tumor microenvironment throughone of its receptors, EP4, and suppress
activation of cytotoxic T cells2.
▪ ONO-4578, a novel selective EP4antagonist, is expected to have anantitumor effect by abolishing the tumor
immunosuppressive mechanism that
PGE2 constructs via EP4.

Tumor
Tumorcell
cell

OpdivoT-cell1) Bing L, et al. Cancer Cell Int; 2015:15:106
2) Yukinori T, et al. Front Immunol. 2020;11:324
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ONO-4578 Non-clinical data
Fig 1. Time course of median tumor volume in syngeneic mouse colorectal cancer MC38 tumor-bearing model
VehicleαPD-1
αPD-1+4578（0.1 mg/kg）
αPD-1+4578（0.3 mg/kg）
αPD-1+4578（1 mg/kg）
αPD-1+4578（3 mg/kg）▪ In syngeneic mouse tumor-bearing model,
ONO-4578 improved immunosuppressive
tumor microenvironment and showed
antitumor effects (Figs. 1 and 2).

▪ Furthermore, ONO-4578 enhanced its
antitumor effect by co-administration with
anti-mouse PD-1 antibody (αPD-1) (Fig. 1).
Fig 2. Effect of ONO-4578 on intra-tumoral immune cells in syngeneic mouse colorectal cancer MC38 tumor-bearing model

A：No. of mMDSC
B：No. of M2 macrophage
C：No. of dendritic cells
D：No. of CD8-positive T cells

AACR 2020: Poster #4443

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ONO-4578
2017

2018

Development stage
2019

2020

2021

Phase1（FIH）：Solid cancer★

2022

2023

2024

2025

2026

2027

Phase1b：GC, Colorectal cancer ★

ONO-4578-01

Phase1b ： Colorectal cancer ★
ONO-4578-02

Phase1b ： Rectal cancer NAC ★
ONO-4578-03

Phase1b ： Pancreatic cancer ★
ONO-4578-04

Phase1b ：NSCLC★
ONO-4578-05
Phase1b ： Hormone receptor-positive
HER2-negative breast cancer
ONO-4578-06

Phase2：GC ★
ONO-4578-08★Combination with OPD
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ONO-4578-01

Part C Results

Safety, efficacy, and biomarkers for ONO-4578 plus
nivolumab in unresectable advanced or recurrent
gastric or gastroesophageal cancer
Hidekazu Hirano1, Akihito Kawazoe2, Kensei Yamaguchi3, Tetsuya Hamaguchi4,
Yukiya Narita5, Shogen Boku6, Takashi Oshima7, Hiroki Hara8, Yasuo Hamamoto9,
Taito Esaki10, Kenji Ishido11
1

Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Japan; 2Gastroenterology and Gastrointestinal Oncology Department,
National Cancer Center Hospital East, Kashiwa, Japan; 3Gastroenterological Chemotherapy Dept., The Cancer Institute Hospital of JFCR, Koto-ku, Japan;
4Gastroenterological Oncology Dept., Saitama Medical University International Medical Center, Hidaka, Japan; 5Department of Clinical Oncology, Aichi Cancer
Center Hospital, Nagoya, Japan; 6Cancer Treatment Center, Kansai Medical University, Hirakata, Japan; 7Department of Gastrointestinal Surgery, Kanagawa Cancer
Center, Yokohama, Japan; 8Gastroenterology, Saitama Cancer Center, Ina, Japan; 9Cancer Center, Keio University School of Medicine, Shinjuku-ku, Japan;
10Clinical Research Department, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; 11Department of Gastroenterology, Kitasato University East
Hospital, Sagamihara, Japan

ESMO 2023: Poster #1546

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Methods
Study Design◼ Part C of the ONO-4578-01 phase 1 study (NCT03155061) was an open-label, uncontrolled study, conducted at
22 sites in Japan◼ Recruited patients were categorized into three parts (C1, C2, C3) on the basis of prior anti-PD-1/◼ PD-L1 therapy and UGT1A1 genotype (Figure 2)◼ All subgroups received 40 mg of ONO-4578 orally every day and 240 mg NIV intravenously every two weeks;
one cycle consisted of 4 weeks†Patients assessed to have a progressive disease on the first image evaluation after the latest anti-PD-(L)1

antibody therapy were excluded
ECOG, Eastern Cooperative Oncology Group; PD-(L)1, programmed death-1 or programmed death ligand-1

ESMO 2023: Poster #1546

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Efficacy Results
C1 (n=30)

C2 (n=30)

Objective Response Rate, % [90% CI]

10.0 [2.8–23.9]

16.7 [6.8–31.9]

Disease Control Rate, % [90% CI]

73.3 [57.0–86.0]

40.0 [25.0–56.6]

0 (0) [0.0–9.5]

0 (0) [0.0–9.5]

Partial Response

3 (10.0) [2.8–23.9]

5 (16.7) [6.8–31.9]

Stable Disease

19 (63.3) [46.7–77.9]

7 (23.3) [11.5–39.4]

Progressive Disease

7 (23.3)

18 (60.0)

Not Evaluable

1 (3.3)0 (0)Median, months [90% CI]

3.88 [2.79–4.17]

1.56 [1.41–2.76]

At 6 months, % [90% CI]

26.3 [13.7–40.8]

21.8 [10.7–35.4]

At 12 months, % [90% CI]

7.5 [1.9–18.6]

3.6 [0.5–13.0]

Median, months [90% CI]

16.13 [10.18–18.92]

5.49 [4.27–10.68]

At 6 months, % [90% CI]

93.3 [80.2–97.9]

46.7 [31.3–60.6]

At 12 months, % [90% CI]

62.6 [46.1–75.4]

30.0 [17.2–43.9]

Best Overall Response, n (%) [90% CI]
Complete Response

Progression-Free Survivala

Overall Survivala

90% confidence intervals (CI) on both sides were calculated using the Clopper-Pearson method
aAnalysis using Kaplan-Meier method

ESMO 2023: Poster #1546

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Efficacy Results
Waterfall Plot by Best Overall Response

ESMO 2023: Poster #1546

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Study schedule of ONO-4578-01 Part C (3rd or later line, GC)
Pre
Baseline

Treatment

Day1

6 weeks

12 weeks

X weeks

Post
End of treatment

ONO-4578 + Nivolumab

Efficacy
CT scanEvery 6 weeks

Biomarkers
Tumor

Blood

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Results of Biomarker Analysis
T-cell Gene Signature and M1/M2 Macrophage Gene Signature in Tumor Biopsies

Signature score was calculated as mean of log-transformed expression value BOR, best overall response;PD, progressive disease; PR, partial response; SD, stable disease
Scr, Screening period; C2D15, cycle 2 day 15

ESMO 2023: Poster #1546

15 / 63

Results of Biomarker Analysis◼ Baseline urine PGEM, the potential surrogate marker of tumor PGE2, was found to be higher in patients withpartial response or stable disease than in patients with progressive disease

Baseline Urine PGEM Levels

PD, progressive disease; PGEM, prostaglandin E2 metabolites; PR, partial response; SD, stable disease

ESMO 2023: Poster #1546

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Safety Results

ESMO 2023: Poster #1546

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ONO-4578-01

Part D Results

Safety And Efficacy Of ONO-4578 Plus Nivolumab
In Metastatic Colorectal Cancer
Akihito Kawazoe1, Atsuo Takashima2, Hiroshi Matsuoka3, Yasuo
Hamamoto4, Tatsuya Okuno5, Tetsuya Hamaguchi6, Kensei Yamaguchi7,
Eiji Oki8, Naotoshi Sugimoto9, Yasushi Tsuji10, Shogen Boku11, Tomohiro
Nishina121National Cancer Center Hospital East, Kashiwa, Japan; 2National Cancer Center Hospital, Chuo City, Japan; 3Fujita Health University,
Toyoake, Japan; 4Keio University School of Medicine, Tokyo, Japan; 5Osaka Rosai Hospital, Sakai-Shi Kita-Ku, Japan; 6Saitama Medical
University International Medical Center, Saitama, Japan; 7Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan;
8Kyushu University, Fukuoka, Japan; 9Osaka International Cancer Institute, Osaka, Japan; 10Tonan Hospital, Sapporo, Japan; 11Cancer
Treatment Center, Kansai Medical University Hospital, Hirakata, Japan; 12National Hospital Organization Shikoku Cancer Center, Matsuyama,Japan

ASCO-GI 2024: Poster #93

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METHODS
Study Design•Part D (CRC cohort) of the ONO-4578-01 phase 1 study (NCT03155061) was an open-label, uncontrolled study,
conducted at 12 sites in Japan•Key eligibility criteria were as follows
─ Age ≥20 years─ Unresectable and metastatic CRC that progressed on/after standard treatment or could not tolerate it─ ECOG performance status score of 0 or 1
•Patients with microsatellite-instability-high, deficient mismatch repair, or BRAF mutations (by local testing) were
excluded•All subgroups received 40 mg of ONO-4578 orally every day and 240 mg NIV intravenously every two weeks; one
cycle consisted of 4 weeks (28 days)•Study treatment was continued until any of the discontinuation criteria were met

Study Endpoints•Primary endpoint: Safety•Exploratory efficacy endpoints: Investigator-assessed overall response rate (ORR), disease control rate (DCR),
progression-free survival (PFS), and overall survival (OS)Study Assessments•Tumor diameters were measured at various time points using CT and/or MRI images•Antitumor effects are assessed using the same procedures throughout the study in accordance with the RECISTGuidelines version 1.1.

ASCO-GI 2024: Poster #93

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Efficacy Results
Best Overall Response (BOR)n (%)[90% CI]CR

0 (0.0)[0.0–5.7]

PR

2 (3.9)[0.7–11.8]

SD

18 (35.3)[24.2– 47.7]

PD

30 (58.8)NE

1 (2.0)ORR (CR+PR)

2 (3.9)[0.7–11.8]

DCR (CR+PR+SD)

20 (39.2)[27.7–51.7]

CR, complete response; DCR, disease control rate; NE, not evaluable; ORR, objective response rate;PD, progressive disease; PR, partial response; SD, stable disease

ASCO-GI 2024: Poster #93

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Efficacy Results

Spider Plot for Best Overall Response

Waterfall Plot by Best Overall Response

Treatment
ongoing

Best overall response follows RECIST guidelines version 1.1
PD, progressive disease; PR, partial response; SD, stable disease

ASCO-GI 2024: Poster #93

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Results of studies in colorectal cancer
試験

ORR, DCR（%）

PFS（month）

OS（month）

CORRECT, CRC 3L, P3 1)Regorafenib vs Placebo

ORR: 1.0 vs 0.4
DCR: 41 vs 15

Median: 1.9 vs 1.7
HR: 0.49

Median: 6.4 vs 5.0
HR: 0.77

RECOURSE, CRC 3L, P3 2)
TAS102 vs Placebo
Imblaze 370, CRC 3L, P3 3)
Atezolizumab+Cobimetinib vsRegorafenib
Imblaze 370, CRC 3L, P3 3)
Atezolizumab vs Regorafenib

ORR: 1.6 vs 0.4
DCR: 44 vs 16

Median: 2.0 vs 1.7
HR: 0.48

Median: 7.1 vs 5.3
HR: 0.68

ORR: 3 vs 2
DCR: 26 vs 34

Median:1.91 vs 2.00
HR: 1.25

Median:8.87 vs 8.51
HR: 1.00

ORR: 2 vs 2
DCR: 21 vs 34

Median:1.94 vs 2.00
HR: 1.39

Median:7.10 vs 8.51
HR: 1.19

LEAP 005, CRC 3L, P3 4)Pembrolizumab + Lenvatinib

ORR: 10.4
DCR: 63.1

Median: 3.8 vs 3.3
HR: 0.69

Median: 9.8 vs 9.3
HR: 0.83

CRC 3L, P2
Pembrolizumab + Favezelimab

ORR: 6.3 (All comer)
ORR: 11.1 (CPS≧1)
DCR: 25.4 (All comer)
DCR: 36.1 (CPS≧1)

Median:2.1(All comer)
Median: 2.2(CPS≧1)

Median: 8.3(All comer)
Median: 12.7
(CPS≧1)SUNLIGHT, CRC 3L, P3 6)
TAS102+Bev vs TAS102

ORR: 6.3 vs 0.9
DCR: 76.6 vs 47.0

Median: 5.6 vs 2.4
HR: 0.44

Median: 10.8 vs 7.5
HR: 0.61

7)

ORR: 1.5 vs 0
DCR: 55.5 vs 16.1

Median: 3.7 vs 1.8
HR: 0.321

Median: 7.4 vs 4.8
HR: 0.662

ORR: 3.9
DCR: 39.2

Median: 1.54

Median: 10.68

5)

FRESCO-2, CRC 4L, P3
Fruquintinib vs Placebo
CRC 3L or later, P1
Nivo+ONO-4578

8)

1)
2)
3)
4)
5)
6)
7)
8)
9)

Lancet. 2013 Jan 26;381(9863):303-12.
N Engl J Med 2015;372:1909-19.
Lancet Oncol. 2019 Jun;20(6):849-861.
ESMO 2023. Abstract LBA-5.
ESMO Open. 2022;7(6):100639
N Engl J Med 2023;388:1657-67.
ASCO GI 2023 Abstract 4.
Lancet. 2023;402(10395):41-53.
J Clin Oncol. 2024;42. Abstract 93.

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Efficacy Results
Subgroup Analysis by PD-L1 (CPS)PD-L1 CPS=0(n=22)

PD-L1 CPS≥1(n=25)

n (%)[90% CI]n (%)[90% CI]

ORR (CR+PR)

1 (4.5)[0.2–19.8]

1 (4.0)[0.2–17.6]

DCR (CR+PR+SD)

8 (36.4)[19.6–56.1]

12 (48.0)[30.5–65.9]

CPS, combined positive score; CR, Complete Response; DCR, Disease Control Rate; ORR, Objective Response Rate;
PD, Progressive Disease; PD-L1, programmed death ligand-1; PR, Partial Response; SD, Stable Disease

ASCO-GI 2024: Poster #93

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Efficacy Results
Duration of Treatment by PD-L1 Status•The proportion of patients continuing treatment for 6 months was 4.5% (1/22) in those with CPS of 0 vs 20% (5/25)
in those with CPS ≥1

PD-L1 CPS≥1

PD-L1 CPS=0
26
25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1

25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1

0

50

100

150

200

250

300

350

Duration of treatment in days

400

450

*

*

* Treatment ongoing

0

50

100

150

200

250

300

350

400

450

Duration of treatment in days

PD-L1, programmed death ligand-1; CPS, combined positive score

ASCO-GI 2024: Poster #93

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Efficacy Results
Kaplan-Meier Plot for Overall Survival, Overall and by PD-L1 Status

Overall survival rate (%)•The overall survival rate at 12 months was numerically better in those with CPS ≥1 (59.5%) than those with CPS of 0 (36.4%)•Specifically, median (90% CI) overall survival was 9.4 months (5.65–12.06) in those with CPS of 0 and NR (10.41–NR) in thosewith CPS ≥1

100
90
80
70
60
50
40
30
20
10
0

≥1

0
Total

Indeterminate+ Censored

0

2

4

6

8

10

12

14

16

(Months)
ASCO-GI 2024: Poster #93

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Safety Results

ASCO-GI 2024: Poster #93

26 / 63

Summary✓ The results were presented here, the domestic phase I study (ONO-4578-01,
Part C and Part D) of combination therapy with ONO-4578 and nivolumab inpatients with gastric cancer or colorectal cancer that was refractory or
intolerant to standard therapy. These are excerpts of the contents reported atacademic conferences.
✓ The results of the efficacy and BM analyses obtained in Part C suggested thecertainty of the ONO-4578 and nivolumab combination concept.
✓ ONO-4578 may contribute to the efficacy of PD-1 antibodies in colorectal
cancers in which the PD-1/PD-L1 antibody monotherapy is not effective.
✓ A global phase II study in 1L gastric cancer (ONO-4578-08, jRCT2031230389)
has been initiated based on the results of Part C and other clinical studies.
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Updates of Open Innovation and ONO-8250 Introduction

INDE X

１

Drug Discovery Strategy & Priority Areas

２

Updates of Open Innovation

３

ONO-8250 Introduction

29 / 63

01
Drug Discovery Strategy & Priority Areas

30 / 63

Drug Discovery Strategy
Promoting open innovation in multiple fields and aiming to create innovative new drugs that meet
medical needs
ONO focuses on the areas of oncology, immunology, neurology and specialties; all of which include diseases with high medical
needs. In each of these areas, we are working to strengthen our drug discovery capabilities by delving into the biology of humandisease with the aim of discovering new drugs that can satisfy medical needs. In particular, by actively promoting open
innovation, which is one of our strengths, we aim to create breakthrough new drugs with medical impact by not only utilizing avariety of cutting-edge technologies, such as informatics, robotics, and genome editing, but also selecting the optimal modality(therapeutic approach), including small molecule compounds, antibodies, and cells for the unique drug discovery seed. In
addition, we are working to improve the quality and speed of drug discovery research through the use of digital technology.

31 / 63

Priority Areas of Drug Discovery Research"developing original and innovative new drugs."

32 / 63

02
Updates of Open Innovation

33 / 63

Updates of Open Innovation (2021～)

NEW

NEW

explained at the R & D
Day on Feb 24th, 2023

34 / 63

Updates of Open Innovation (2021～)

Biologics

Seeds

Biologics

NEW
Biologics

Biologics

Biologics

Seeds

AI

AI

Biologics

Biologics

2023～
Open Innovation Updates

Biologics

NEW
Biologics

Seeds
Biologics

Seeds

explained at the R & D
Day on Feb 24th, 2023

AI
AI

Biologics

Discovery
Seeds

AI

10

5

4

Seeds

35 / 63

Discovery Technology and Therapeutic Modalities
Biologics collaborations
Tech & Seeds

Small Molecule

PeptideProtein & Antibody

Cell Therapy

AI

Oncology

ONO-8250
ONO-7018

ONO-4685

Immunology

Neurology

Vanderbilt Univ.
AI

Specialty
AI

AI

AI

AI
AI

Undisclosed

2023~
36 / 63

02
Updates of Open Innovation◆ Biologics Collaboration

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5 Key Features of Biologics Collaborations
1

Antibody Libraries

2

AI・Digital

3

Multispecific Abs

4

Advanced PJ Introduction

Multi-specific Macrophage Engager

Bifunctional Fusion Proteins

Macrophage modulating antibodies

5

Cancer Immunotherapy

Anti-GPCR Abs

Diversified Modalities
CAR-T Cell Therapy

Modified Cytokine

Bifunctional Fusion Proteins

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Drug Discovery Collaboration with Macomics to Develop Macrophagetargeting Antibody for the Treatment of Cancer（2023.03.23）

Type of cancer【Tumor-associated macrophage (TAM)】
Bladder

TAM：

BreastBowel

Macrophages represent the major population infiltrating
most human cancers.

StomachLung

Macrophage【ENIGMACTM Discovery Platform】

Creating antibody drug candidates against

novel macrophage targets

RNA seq of purified
TAM vs Resident
macrophages

Bioinformatic
filtering and target
identification

Luca Cassetta & Jeffrey W. Pollard
Nat Rev Drug Discov 17, 887-904 (2018)

Target validation
with iPSC-derived
macrophages

Antibody
drug candidate

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•.

Option and Collaboration Agreement with Numab toDevelop Multi-specific Antibody NM49 (2024.02.14)
Next-generation Plug & Play Novel Multispecific Therapeutic Platform
Various Multivalent Antibody Format Generation Technologies Based on Optimized Humanized scFv (Hu-Fv)
CDR

Ultra-high throughput antibody
discovery for high yield andaffinity rabbit antibody

Fusion of rabbit CDR
with human Fv

Humanized antibody Fv
fragments that recognize
specific targets

Various Multivalent
Antibody Format
From Numab website

Acquisition of an exclusive option to license Macrophage Engager NM49

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Ono Enters into a Drug Discovery Collaboration Agreement with Twist Bioscience
to Discover Novel Antibodies for Autoimmune Diseases（2023.08.31）【Library of Libraries】
an expansive collection of synthetic antibody libraries based on naturally occurring sequences

High probability of obtaining functional antibodies to targets
Twist will utilize the Twist Biopharma Solutions Library of Libraries to conduct research
activities to discover novel antibodies against therapeutic target(s) identified by Ono
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Ono Enters into a Drug Discovery Collaboration Agreement with Adimab
to Discover Novel Antibody Drugs in the Oncology Field（2023.09.27）【Adimab’s platform technology】
Yeast Library

Rich experiences of multi-specific antibodies

Adimab will discover novel therapeutic antibodies against multiple targets
selected by Ono and generate bispecific antibody product candidates
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Ono Enters into Collaboration Agreement with EME to Generate Novel
VHH Antibodies against Multiple Therapeutic Targets（2024.02.21）【What is VHH】
Camelid HcAb

【HTS Platform “The Month”】
it only takes approximately a month for
obtaining hit VHH to a drug target

VHH抗体が分かる絵

Front. Immunol., 21 August 2017 Sec.
Vaccines and Molecular Therapeutics Volume 8 - 2017

Feature of VHH•

small molecular weight (ca. 15kDa)•

binding to different types of epitopes
from conventional antibodies

EME generate novel VHH antibody drugs against multiple therapeutic targets selected by Ono,using EME’s proprietary humanized VHH screening platform “The Month”
43 / 63

A Collaboration and Option Agreement with Shattuck Labsfor Bifunctional Fusion Protein（2024.02.13）
Agonist Redirected Checkpoint (ARC) Platform
Target 1

Target 2
Fc Region◼ Shattuck Labs has proprietary technology for creating modified proteins, enabling thedevelopment of functional proteins for previously challenging therapeutic targets.
◼ Shattuck Labs has generated bifunctional fusion proteinsdemonstrating immunomodulatory effects in animal models and are expected to beeffective across a wide range of autoimmune and inflammatory diseases.

We will use“ARC 'ARC
Platform”
to todevelop
WeShattuck’s
will use Shattuck's
Platform'
develop Bifunctional Fusion Proteins for treating
autoimmune and inflammatory diseases.
https://www.shattucklabs.com/wp-content/uploads/2020/06/2018_SITC_TIM3.pdf (modified)

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02
Updates of Open Innovation◆ AI・Digital Collaboration

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Ono Enters into Collaboration Agreement with EVQLV to Generate Novel
Antibodies against Multiple Targets Utilizing EVQLV’s AI-powered Antibody
Design Engine for Development of Innovative Antibody Drugs（2023.12.19)【EVQLV Platform】
AI-powered Antibody Design Engine

The platform
designs and modifies antibodies
while retaining conformationaland functional integrity using AI

create novel antibody candidates
more promptly and effectively

EVQLV will generate therapeutic antibody designs using EVQLV’s
proprietary Artificial Intelligence (AI)-powered Antibody Design Engine

46 / 63

Ono Enters into a Drug Discovery Collaboration Agreement with MOLCURE to
Discover and Develop Innovative Antibody Drugs for Multiple Targets Utilizing
MOLCURE’s AI-driven Platform Technology（2023.03.23）

For more details, please refer to Molcure website (https://molcure.com/).

Utilize MOLCURE's proprietary AI-driven platform technology to discover andidentify antibodies or molecules for multiple targets of interest selected by Ono
47 / 63

Research Collaboration with Turbine to Identify and Validate Novel
Therapeutic Targets in Oncology (2023.10.24)【Simulated Cell Platform】
The virtual cells capture cancer
biology and are used for in silico
cell simulation.

Leveraging Turbine’s AI-driven cell simulation,
we are committed to identifying novel therapeutic targets in oncology.

48 / 63

Ono Enters into a Research Collaboration Agreement with
InveniAI to Identify Novel Therapeutic Targets（2024.02.19）
proprietary AI platform technology based on machine learning,【AlphaMeld】 InveniAI's
advanced natural language processing and large language models

Data Source（Big Data）

•
•
•
•
•
•
•

Ideal mode of pharmacotherapy
Disease severity
Gene ontology
Disease pathways
Proteinopathies
Standard of care
Emerging innovation

AI technology

Generate Testable Hypotheses
factoring in medical, scientific, strategic, and commercial considerations.

We will interactively use a data-driven approach toidentify new therapeutic targets and drug
discovery hypotheses across multiple indications. 49 / 63

Accelerating AI Drug Discovery with the Supercomputer 'Tokyo-1’(2024.02.01)

Vast amounts of genetic information data
Assessment of the value of proprietary seeds
Image analysis, video analysis, natural language
processing
supercomputer dedicated to drug discovery

Significantly reduce time and effort

Analysis of molecular structures and predictionof interactions
Creation of high-quality new drug candidates
The photo above shows a supercomputer
dedicated to drug discovery. It processes andanalyzes massive amounts of chemical data andbiochemical information at high speeds to identify
promising drug candidates.

Challenging the transformation of
the drug discovery process
50 / 63

02
Updates of Open Innovation◆ Strategic Investment by Ono Venture Investment◆ Research Grants by Foundations

51 / 63

Open Innovation That Supports Drug Discovery

https://www.ono-pharma.com/en/company/rd/open_innovation.html

52 / 63

Investment in the start-up Bio-Ventures
Company

Location

Notes

Bio-Venture for development of
Boston, MA,
new drugs for the treatment ofUSAfibrosis

Tokyo,
Japan

Bio-Venture for drug discovery
based on detailed protein
structure information by cryoelectron microscopy

Waltham,
MA, USA

Bio-Venture committed to thecreation and development ofnovel therapies for cancer
patients

Cambridge,
MA, USA

Bio-Venture for new gene
editing therapy with a unique
DNA/RNA degrading enzyme

Cambridge,
MA, USA

Bio-Venture for aiming to
reprogram autophagy toeliminate diseases that current
drugs have failed to target

Company

Location

Notes

South San
Francisco,
CA, USA

Bio-Venture for developing
innovative genetic medicines totransform the treatment of CNS
diseases

Cambridge,
MA, USA

Bio-Venture for leveraging its
proprietary cell to cell engine todevelop a pipeline of the CNS
therapeutics

Seattle,WA, USA

Bio-Venture for developing CD8
Treg modulators for thetreatment of autoimmune andinflammatory diseases

Waltham,
MA, USA

Bio-Venture for developing
phosphorylation-inducing
chimeric small molecule
medicines(PHICS) to treat arange of diseases

https://www.onoventure.com/news
53 / 63

Research Grants Through Foundations and Donated Courses
ONO Medical Research
Foundation (FY1988~)
The Foundation provides grants for research activities in
the field of lipid metabolism disorders and also aims topromote research and treatment in that field throughvarious projects, thereby contributing to the health andwelfare of the public. Since its establishment, theFoundation has provided research grants and researchencouragement grants every year.

"Ono Pharma Oncology,
Immunology, Neurology Research
Foundation“ (FY2022~)
Aims to contribute to the health of people around the world by
supporting cutting edge science and researchers leading toinnovative (breakthrough) research achievements in the oncology,
immunology and neurology areas in which high unmet medical
needs still remain.

ONO Pharma Foundation(FY2016~)
Aims to support principal investigators (PIs) who are scientists with creativeideas in specific scientific research areas. By providing research grants, theFoundation contributes to supporting innovations that lead to innovative
medical treatments of patients and promoting the research of young
researchers.

https://sustainability.ono-pharma.com/ja/themes/126
54 / 63

03
ONO-8250 Introduction

55 / 63

Strategic Collaboration with Fate Therapeutics to Develop iPSC-derived CAR-T （2018.09.18）
Exercise Option to HER2-targeted CAR-T Cell Product Candidate for Solid Tumor（2022.11.07）

1. Preference of killing activity on HER2-expressing tumor cells and optimal killing signaling to avoid T cell exhaustion

H2CasMab-2 CAR＋1xx
CXCR2

T-cell receptor（TCR）deletion

2. Improvement of migration into tumor tissues

7. Avoidance of GVH reaction

iPS Cellderived CARTONO-8250

CD38 deletion

IL7RF
3. Improvement of persistency

6. Enhanced effector cell metabolic fitness and persistence

TGFβR2-IL18R

hnCD16a4. Overcome of immune suppressive environment

5. Combination effect with other therapeutic antibody“Off the Shelf” iPSC-derived HER-2 CAR-T incorporate 7 Functional Edits
Please refer to Clinicaltrials.gov for information on the clinical trial of ONO-8250.

56 / 63https://clinicaltrials.gov/study/NCT06241456?term=FT825&checkSpell=false&rank=1

Novel binder incorporated into ONO-8250“The preclinical data for FT825 / ONO-8250 indicate a highly-differentiatedtherapeutic profile across a broad range of solid tumors, with the novel HER2targeted antigen binding domain demonstrating selective targeting ofcancer cells expressing HER2 including those with low expression. We are
excited to initiate the Phase 1 study in collaboration with Ono and assess thepotential to benefit patients with hard-to-treat advanced solid tumors whocurrently have limited treatment options.”

https://ir.fatetherapeutics.com/news-releases/news-release-details/fate-therapeutics-announces-initiation-phase-1-clinical-trial

The above description is referred from Tohoku University. For more
57 / 63
details, please visit the website (https://www.med.tohoku.ac.jp/5561/).

Preferential targeting of HER2 expressed on tumor rather than normal
cells is uniquely enabled by the novel H2CasMab-2 binder
HER2high tumor cells（SKOV3）VS

Trastuzumab
CAR-T

HER2+ normal cells（MCF10A）

H2CasMab-2
CAR-T

Cytotoxicity（％）

HER２high tumor cells（SKOV3）

HER2+ normal cells（MCF10A）
Trastuzumab
CAR-T

Trastuzumab
CAR-T

H2CasMab-2
CAR-T

Trastuzumab
CAR-T

H2CasMab-2
CAR-T

ONO-8250

Target cells

Time（h）

Time（h）

Time（h）
Hosking Ｍ, et al. SITC 2023 #268

ONO-8250 which expressed H2CasMab-2 based CAR showed preferential targeting of HER2
58 / 63
on tumor cells and not on normal cells

ONO-8250：Multiplex-engineered CAR T designed to address andovercome challenges currently faced by cell therapies in solid tumors
Resistance to TME Suppression（TGFbR-IL18）

Promote tumor trafficking（CXCR2）Multi-antigen Targeting（hnCD16a）
HER２Low EGFR HighPCA（PC3）HER２High tumor cells（SKOV3）

HER2Low EGFRHIGH±TGFb

ONO-8250

2:1 cells
CAR-T：Target= 3:1

Repeat challenge
Target cells once
every 2 to 3 days

ONO8250±

3:1 cells
CAR-T：Target= 3:1

Cetuximab

Cytotoxic assay

ONO-8250

TGFβ
suppression

ONO-8250＋Cetuximab
ONO-8250

Target cells

IL8 (ng/mL)

Cytotoxicity（%）

CAR iT cells

ONO-8250

Combo with Cetuximab

Resistance to TGF Suppression
Cytotoxicity（%）

Fold Specific migrationCXCR2 Expression Enables IL8(CXCL8) -specific migration

Time（h）

Target cells

Time（h）

Target cells

Time（h）
Hosking Ｍ, et al. SITC 2023 #268

The transgenic elements incorporated into ONO-8250 have successfully demonstrated their intended functionality.

59 / 63

ONO-8250：Robust HER2 Targeting Across a Wide Range of Antigen
Expression Density
HER２high OVCA（SKOV3）
Target cells

CAR-T : Target cells= 10:1

Target cells

Tine（h）

ONO-8250

Cytotoxicity（％）

VS

ONO-8250

Cytotoxicity（％）

ONO-8250

HER２Low PCA（PC3）Target cells

Time（h）
Hosking Ｍ, et al. SITC 2023 #268

ONO-8250 is capable of killing tumor cellswith a range of expression from HER2 high to HER2 low targets.
60 / 63

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

ONO-8250＋／－

HER2+ tumor

aHER2mAb

Tumor Volume（mm3）hnCD16aCombination effect with other therapeutic antibody

aHER2mAb

ONO-8250

ONO-8250＋aHER2mAb

Hosking Ｍ, et al. SITC 2022 #304

ONO-8250 showed anti-tumor effect in HER2+ tumor bearing model.
Combo with anti-HER2 mAb enhanced anti-tumor effect by hnCD16a activation
61 / 63

Discovery Technology and Therapeutic Modalities
Biologics collaborations
Tech & Seeds

Small Molecule

PeptideProtein & Antibody

Cell Therapy

AI

CancerONO-8250
ONO-7018

ONO-4685

Immunology

Vanderbilt Univ.

Neurology

AI

Specialty
AI

AI

AI

AI
AI

Undisclosed

2023~
62 / 63

Main Status of Development Pipelines
Therapy
Area

Oncology

Immunology

Neurology

Development
Code

Area

Phase

Target Indication

ONO-4578

Japan

I

Solid Tumor, Gastric Cancer, Pancreatic Cancer, Colorectal
cancer, non-small cell lung cancer, Hormone receptor-positive,
HER2-negative breast cancer

ONO-7475

Japan

I

Solid Tumor, EGFR mutation-positive non-small cell lung cancer

ONO-7914

Japan

I

Solid Tumor

ONO-4685

Japan
USA

I

T-cell lymphoma

ONO-8250

USA

I

Solid Tumor

ONO-7018

USA

I

Non-Hodgkin's lymphoma, Chronic lymphocytic leukemia

ONO-4685

Japan
EuropeI

Autoimmune diseases

ONO-2910

Japan

II

Diabetic polyneuropathy, Chemotherapy-induced peripheral
neuropathy

ONO-2808

USAII

multiple system atrophy

ONO-1110

Japan

I

Pain

ONO-2020

USA

I

Neurodegenerative disease
63 / 63

Dedicated to the Fight against Disease and Pain