R&D Briefing
September 7, 2021

Cautionary Notes
Forecasts and other forward-looking statements included in this document are
based on information currently available and certain assumptions that theCompany deems reasonable.
Actual performance and other results may differ significantly due to variousfactors. 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 indevelopment) included in this document is not intended to constitute anadvertisement of medical advice.

1Compounds to be presented
CompoundMechanism

Target indication

StageONO-2910

Schwann celldifferentiation promoter

Diabeticpolyneuropathy

P2

ONO-2909

Prostaglandin receptor(DP1) antagonist

Narcolepsy

P1

ONO-2808

S1P5 receptor agonist

Neurodegenerativedisease

P1

ONO-4578

Prostaglandin receptor(EP4) antagonist

Solid tumor

P1

ONO-2017(cenobamate)

Voltage-gated sodium
currents inhibition/GABAA modulation

Epilepsy

Clinical Trial
preparation

2

ONO-2910
Schwann celldifferentiation promoter3

ONO-2910
CompoundONO-2910

CompanyOno

Mechanism Schwann cell differentiation promoter
Formulation TabletIndication

Stage

Diabetic polyneuropathy

Phase 2 (Japan)

4

ONO-2910 Mechanism of Action
Repair process of nerve fiber

Myelin sheath
Schwann cell

NucleusNormal nerve fiber

Differentiation(Myelination)

Nerve axon

Enhancement

Hyperglycemia

Demyelination・
axon degeneration

Dedifferentiation(Injury)

ONO-2910

Suppression

Myelindebris

Axonaldebris

Prepared based on J. Cell Biol. 2008; 181: 575–577

5ONO-2910 Pharmacological study result
Rat streptozotocin (STZ)induced model
Human Schwann cell
Enhancement of Schwann
cell differentiation

Nociception threshold（g）

12*60
N=6, MEAN±SE,＊ p<0.05 vs vehicle (Dunnett test)

50
40

*

30
20
100Vehicle

0.3

1310ONO-2910（μ mol/L）

Nociceptive threshold（g）

Schwann cell differentiation（MAG positive area/nucleus）

70

N=8, MEAN±SE$ p<0.05 vs Normal（t-test）# p<0.05 vs vehicle（t-test）＊ p<0.05 vs vehicle (Dunnett test)

Orally,once daily

*
*

*
*

9*
*

*

#*

6

#

#

$

3$〇 Normal
正常◆ Vehicle
媒体▲ Duloxetine 30mg/kg
ONO-2910■ 1 mg/kg■ 0.3 mg/kg■ 0.03 mg/kg■ 0.003 mg/kg■ 0.0003 mg/kg$00714212835

Days after STZ-induction （day）

ONO-2910 suppresses pain-related behavior by promoting Schwann cell differentiation.
6

Diabetic Polyneuropathy
Simplified
diagnostic
criteria

Prerequisite conditions (the following two must be met)
1. Diagnosed as diabetes
2. Neuropathies other than diabetic neuropathy can be excluded
Criteria (any two of the following three must be met)
1. Presence of symptoms considered to be due to diabetic polyneuropathy
2. Decrease or disappearance of bilateral ankle reflex
3. Decreased vibration sensations in bilateral medial malleoli
Note
Subjective symptoms of diabetic polyneuropathy are characterized as:
1. Bilateral
2. Paralysis, pain and paresthesia in the toe and sole
3. Not inclusive of upper limb symptoms alone
Findings of interest (diabetic neuropathy is to be confirmed if one of the following two
has been met, despite failure to meet the criteria described above)
1. Abnormal nerve conduction findings on one or more parameters (i.e., conduction
velocity, amplitude and latency) in two or more nerves
2. Presence of clinically apparent diabetic autonomic neuropathy(preferably to be confirmed by tests to assess autonomic nerve function)

Natural course

Autonomicdysfunction (such aslightheadedness)

Symptoms
Absence ofsubjectivesymptoms

Presence ofsubjectivesymptoms

Hyperesthesia(such as pain)

Japanese Clinical Practice Guideline for Diabetes 2019

Motor dysfunction(amyotrophy of lower leg,difficulty in walking etc.)
Positive symptoms(pain, paresthesia, numbness, etc.)

Negative symptoms, hypoesthesia(dependent on loss of sensory nerve fibers)
Presence of neurological disorder by simplified diagnostic criteria
for diabetic polyneuropathy

Progress

7

ONO-2909
Prostaglandin receptor (DP1) antagonist

8

ONO-2909
CompoundONO-2909

CompanyOnoMechanism

Prostaglandin receptor (DP1) antagonist

Formulation

TabletIndication

Narcolepsy

StagePhase 1 (Japan)

9

ONO-2909 Mechanism of Action
PGD2

ONO-2909
Adenosine

Dopamine

Activationof cerebral
cortexAdrenaline

Histamine

Sleep center
OrexinNeed forsleep

Wakefulness
power

Decreased wakefulness due toorexin nerve depletion(narcolepsy)

ONO-2909 suppresses sleep center activation and hypersomnia symptoms.
10DP antagonist (Pharmacological study result 1)
Effect on wake time in normal rats
DP antagonist was administered at 11:00 am, which corresponds to the sleep phase for rodents,
and the wake time was measured by the EEG from 11:00 to 17:00
N=6～14, mean ± SD
*p<0.05 vs vehicle（Dunnett test）

Wake time in 6 hours (min)
6時間中の覚醒時間（分）

250

*

200

**

*

150

100

5000.3131030100
DP antagonist（mg/kg）

DP antagonist prolonged wake time during rat sleep phase (light period).
11DP antagonist (Pharmacological study result 2)
Effect on wake time in sleep deprivation rats
Lighting-off＜Arousal＞
14:00＜Sleep＞20:00

EEG and EMG were analyzed for 3
hours after administration toOraladministration,Sleep deprivation
Start of EEG measurement Lightning determine sleep stage（6 hours）
8:00

N=9, mean ± SD, *p<0.05 vs non-sleep deprivation（t-test),#p<0.05 vs vehicle（Dunnett test）

Wake time 3 hours aftersleep deprivation (min.)

140

#120
100

*80
60
40
200

Non-sleep
deprivation

vehicle

0.3

13

DP
antagonist (mg/kg)
DP拮抗剤（mg/kg）

6-hrs sleep deprivation

DP antagonist prolonged wake time after sleep deprivation.
12

Narcolepsy
2 Major symptoms
Major symptoms ①： Hypersomnia
Falling asleep when unable
to remain awake

First-line：Modafinil

Major symptoms ②：Cataplexy (Type 1 only)
Feelings are high, and muscles
throughout the body become weak

Tricyclic antidepressants, Sodium Oxybate (US)Narcolepsy type1(Narcolepsy with cataplexy)

Narcolepsy type2(Narcolepsy without cataplexy)Orexin;hormones involved in maintaining awakening

Narcolepsy type1 patients are loss of thenerves producing and secreting orexin.

 Persistent excessive daytime sleepiness for at least 3 months
 Mean sleep latency (mean sleep onset) within 8 minutes
 SOREM (REM sleep that occurs within 15 minutes)
 History of cataplexy Orexin level in CSF ≤ 110 pg/mL
 Persistent excessive daytime sleepiness for at least 3 months
 Mean sleep latency (mean sleep onset) within 8 minutes
 SOREM (REM sleep that occurs within 15 minutes)
 No history of cataplexy No decrease orexin level in CSF

International Classification of Sleep Disorders, Third Edition, Central Disorders Hypersomnolence 2018; 97-106.

13

ONO-2808
S1P5 receptor agonist

14

ONO-2808
Compound ONO-2808
CompanyOnoMechanism S1P5 receptor agonist
Formulation Tablet
Indication

Neurodegenerative disease

StagePhase 1 (Europe/ Japan)

15

ONO-2808 Mechanism of Action
Normal⇒ Neurodegeneration
Astrocyte

Microglia

NeuronOligodendrocyte（OLG）

OLG（Myelin sheath）：p25α、OLG protein：Monomer α-Syn：Oligomer α-Syn

Prepared based on N. Stefanova and G.K.Wenning. Neuropathol Appl Neurobiol. 2016 Feb;42(1):20-32

Reduction ofaberrant α-Syn &accumulation：GCIAberrant α-Syn：Cytokine

Repair ofMyelin sheathONO-2808

OLG

α-Syn : α-Synuclein

・Aberrant α-Syn accumulation⇒ OLG loss, demyelination
Reduction ofaberrant α-Synaccumulation

Neuron・ Decreased supply of neurotrophic factors
from OLG
・ Aberrant α-Syn accumulation⇒ Neuronal loss, axon degeneration
16

S1P5 agonist (Pharmacological study result)
Effect in mouse experimental autoimmune encephalomyelitis (EAE) model
Day -102

529Vehicle, S1P5 agonist administration
Measurement of EAE clinical score
MOG+PTX PTX

MOG：Myelin oligodendrocyte glycoprotein
PTX：Pertussis Toxin

N=10, mean ±SD, *p<0.05 vs vehicle（Steel test） EAE clinical score: 0, normal; 1, limp tail; 2, paralysis of one limb;
3, complete paralysis of both hind limbs; 4, paralysis of all limbs; 5, moribund or death

EAE clinical score

4媒体
Vehicle340

S1P5作動薬
6 mg/kg
S1P5 agonist
6 mg/kg

Cumulative EAE clinical score

30

S1P5作動薬
3030
mg/kg
S1P5 agonist
mg/kg
2*20

110000510152025Days after induction

30Vehicle
媒体

630S1P5 agonist（mg/kg）

S1P5 agonist suppressed aggravation of EAE clinical score.
17

Main neurodegenerative disease and number ofpatients in the US1)
1 mil patients

Parkinson
disease

5.2 mil1)

Alzheimer's
dementia

Lewy bodydementia

1.4 mil2)

Multiplesystem
atrophy

7-16K3)

Neurodegenerative
disease

20K1)

Amyotrophic
lateralsclerosis

Multiplesclerosis

400K1)

1)：Thermo Fisher SCIENTIFIC Web https://www.thermofisher.com/blog/learning-at-the-bench/neuro_disease1/
2)：Lewvy Boday Dementia Association Web https://www.lbda.org/about-lbd/3)：The portal for rare diseases and orphan drugs web https://www.orpha.net/consor/cgi-bin/Disease.php?lng=EN18

ONO-4578
Prostaglandin receptor (EP4) antagonist

19

ONO-4578
CompoundONO-4578

CompanyOnoMechanism Prostaglandin receptor (EP4) antagonist
Formulation TabletIndication

StageSolid Cancer
Phase 1 (Japan)
Colorectal cancer, pancreatic cancer, Non-small celllung cancer, gastric cancer

20

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 thetumor immunosuppressive mechanismthat PGE2 constructs via EP4.

Tumor
Tumorcell
cellOpdivo

T-cell1) Bing L, et al. Cancer Cell Int; 2015:15:106
2) Yukinori T, et al. Front Immunol. 2020;11:324

21

ONO-4578 Non-clinical data Fig 1. Time course of median tumor volume
in syngeneic mouse colorectal cancer MC38
tumor-bearing model In syngeneic mouse tumor-bearing model,ONO-4578 improved immunosuppressive
tumor microenvironment and showed
antitumor effects (Figs. 1 and 2).

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）

 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 tumorbearing 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
22

ONO-4578 Clinical data
 In the ONO-4578-01 study in Japanesepatients with solid tumors, the tolerability
and safety of ONO-4578 alone (Part A)
and in combination with Opdivo (Part B)
were evaluated.
 In Part A and B, the maximum tolerated
dose (MTD) was not reached.
 CR and PR were not observed in 10 casesof Part A, and SD was observed in 3cases.
 In 21 cases of Part B, PR was observed in
1 case of small cell lung cancer andunconfirmed PR was observed in 1 caseof pancreatic cancer. In addition, SD wasobserved in 5 cases.

60 mg + 240 mg
40 mg + 240 mg
20 mg + 240 mg
10 mg + 240 mg
5 mg + 240 mg
2 mg + 240 mg
600 mg
400 mg
200 mg
100 mg
60 mg
30 mg

Part B（Dose escalation）
・ONO-4578, once daily, po
・Opdivo 240 mg, every 2weeks, iv

Part A（Dose escalation）・ONO-4578, once daily, poMain inclusion criteria:• Age: 20 years or above, ECOG PS 0 or 1
• Advanced or metastatic solid tumors Refractory or intolerant to standard
treatment or no standard treatment (Part A) Refractory or intolerant to standard
treatment except anti-PD-1 antibody or nostandard treatment (Part B)
 No previous treatment with immune
checkpoint inhibitors (Part B)

Cut-off date：February 5, 2020
ECOG PS, Eastern Cooperative Oncology Group Performance Status;
CR: Complete response PR: Partial response SD: Stable disease

ESMO 2020: # 50423

ONO-4578 Development stage
Type of cancer

Solid tumor

Clinical stage

Phase 1 (FIH)

Phase 1 b

Phase 2

Mono or combination withOpdivo
Dose escalation

Gastriccancer

Combination with Opdivo

Colorectal
cancerCombination with Opdivo

PancreaticcancerCombination with Opdivo

Non-small celllung cancer

Combination with Opdivo

24

ONO-2017（cenobamate）
Voltage-gated sodium currents inhibition/GABAA modulation

25

ONO-2017
CompoundONO-2017（Cenobamate）

Company

SK Biopharmaceuticals Co., Ltd.

Mechanism

Voltage-gated sodium currents inhibition/GABAA
modulation

Formulation TabletIndication

Stage

Epilepsy (Partial seizure, tonic-clonic seizure)US:
Launched by SK Life Science
Europe: Launched by Angelini Pharma
Japan: Under preparation for clinical trial

26

ONO-2017 Mechanism of Action
ONO-2017
Cenobamate
Lamictal®
Vimpat®

Fycompa®

NormalEpileptic seizure

Mechanism of action of antiepileptic drugs
Upper figure：Web https://www.credentials.jp/2019-02/expert-1902/
Lower figure： https://epilepsy-support.net/about.html

27

ONO-2017 Clinical Results
Partial seizure, Patients with poor seizure control,
Combined use with existing drugs
Treatment period: Dose-escalation period + 12 or 13 weeks maintenance period
Patients:

Adult epilepsy patients with partial seizures for which existing antiepileptic drugs are notfully effective

50% responder rate：
Percentage of cases in whom the number of partial seizure
improved by ≧50% compared to the observation period

Seizure free rate:
Percentage of cases in whom no partial seizure wasobserved during the maintenance period

25%

50%

Seizure free rate

50% responder rate

60%

40%
30%
20%
10%
0%

P

100mg 200mg

400mg

ONO-2017
Cenobamate
108-111 sujects/group20%
15%
10%5%0%Recommended
doseP

100mg 200mg

400mg

ONO-2017
Cenobamate
108-111 subjects/ group

Krauss GL, et al. Lancet Neurol. 2020 Jan;19(1):38-48
28

Epilepsy

・Lennox-Gastaut syndrome
・West Syndrome

Patients refractory to existing treatments: 20-30%● Partial (Focal) seizures: 130-190 K• Prepared based on materials for training of epilepsy for school.
● Tonic-clonic seizures: 20-30 K• Epidemiology of epilepsy. Epilepsy 2020.; 14: 7-10.
• JAMA Neurol, 2008; 75: 279-86.
• MHLW Study Report, Research on Pathology and Treatment of Intractable Epilepsy, 1991.
• Epilepsy Research. 2005; 23: 249-53.

29

Dedicated to the Fight against Disease and Pain