OncoTherapy Science, Inc.
R&D Day meeting
President & CEO, Masaharu Mori
Dec .18th, 20151

Our Mission

2Contents

１）Overview of Anti-cancer Market
２）Features and Management Policy３）Pipelines and Updates

４）R&D Updates
 Small Molecular Drugs
 Cancer Precision Medicines
 Antibody Drug3

Anti-cancer market with double digit growth
Anti-cancer market becomes 3 times bigger due to launch ofmolecular target drug blockbusters during last decade
Sales of anti-cancer market (Global)

Mil USD

90,000Less than 3 Mil. USD
3億ドル未満CAGR 11%80,00070,000

3～10億ドル3 ~ 10 Mil. USD(23 product)（32品目）

60,00050,000

10億ドル以上
Over 10 Mil. USD(23 product)（23品目）

40,00030,00020,00010,00002005
Source: Uto Brain 2015

2006

2007

2008

20092010

2011

2012

2013

2014
4

High Attention to Cancer Immunotherapy
Big success of immune checkpoint inhibitors attract attention
to cancer immunotherapy, with the advent of NGS* genome
analysisTargetNon specific

Specific（pin point）
Molecular target drug

Cancer Cell

Immunesystem

Cytotoxicchemotherapy- Small molecule- Antibody（Poisonous for bothcancer and healthy cells ）Presstheaccelera-torCancer Vaccine

ReleasethebrakeImmune checkpoint inhibitor＊NGS： Next Generation Sequencer

Non-specificimmunotherapy- Oncoantigen vaccine- Neoantigen vaccine- High efficacy on cancers with lots ofmutations, such as melanoma

Cancer genome analysis
by utilizing NGS（Immunopharmacogenomics）

5

Contents

１）Overview of Anti-cancer Market
２）Features and Management Policy３）Pipelines and Updates

４）R&D Updates
 Small Molecular Drugs
 Cancer Precision Medicines
 Antibody Drug

6

Platform Technologies→ Genome-based Drug Discovery
With our platform technologies, providing comprehensive gene
expression profile analyses and gene function analyses, we haveidentified suitable target genes to develop new anti-cancer medicines witha minimal risk of adverse events.

1. A large number of fresh clinical specimen (samples)- More than １０００ clinical samples （20～80 patients /cancer type)

2. Identified gene groups over-expressed in cancer cells- Laser Microbeam Microdissection (LMM) system- Our original cDNA microarray system
Gene expression database of cancer and normal cells

3. Validate the effect of selected genes on the growth or survivalof cancer cells- A gene function inhibiting experiment using the RNA interference technology

4. Examine expression in 31 normal organs- Absent or hardly detectable in any normal and important vital organs

7

Genome-based Drug Discovery andDevelopment of Novel Anti-Cancer Drugs
Small Molecule Drugs
Genomedata

Identificationof target genes

OTS167

OTS964 etc.

Phase I study in US.

Pre-clinical study.

Comprehensive gene
expression profile comparing
cancer and normal cells

Cancer Peptide Vaccines

Genomedata

Genomedata
GenomedataGenomedataOTSGC-A24 etc.
Clinical study in Japan and Asian countries.
Other peptide vaccines have been licensed out.

Antibody Drugs
OTSA101
Phase I study in France.
8

OTS’s R&D strategy•Create a series of innovative new drugs using our novel
platform technologies ⇒ Genome-based drug discovery•Small molecule drug: Gather good clinical data at global
clinical studies, while closely cooperating with top-tierresearchers in the University of Chicago and other renowned
research institutes in US.

•Cancer vaccine: Contribute to cancer immune therapy byconducting cancer peptide vaccines and newly launched
TCR analysis business.
•Antibody drug: Prepare for phase II study by completing
OTSA101phase I study in France.
9Management Policies and Strategies
１. Continue deep basic research Own research＋Collaboration with Univ. of Chicago etc.
２. Promote genome-based drug discovery
 Small molecule drug, Cancer peptide vaccine, Antibody
３. Promote development by well designed clinical studies
 Our own activity＋Partner pharmaceutical company
 Expansion of indication based on preclinical data
４. Facilitate licensing business with potential/existing partners
 Strategic communication＋Technical assistance Launch T/B cell receptor analysis business, develop
novel immune therapy
10Contents

１）Overview of Anti-cancer Market
２）Features and Management Policy３）Pipelines and Updates

４）R&D Updates
 Small Molecular Drugs
 Cancer Precision Medicines
 Antibody Drug

11

Pipelines （as of Dec., 2015）
Small Molecule
Cancer Vaccines
Antibodies

ProductTarget /Indication

OTS167MELK

OTS964 etc.

TOPK-First-in-class
identified
5 targets

S-588410 *Licensing-out
to Shionogi

EsophagealCancer(Licensing-outto Shionogi)

Bladder
CancerHead andneck Cancer(Licensing-outto Ono)

Hepatocellularcarcinoma(Licensing-outto Otsuka)

Colorectal
CancerOTSA101

SynovialSarcoma(Licensing-outto Kyowa Kirin)

Alzheimer

LeadBasic
Research Optimization

Preclinical

Phase I

Phase II

Note: Solid lline shows our hands-on R&D products（including development assistance for a licensing-out product, S-588410*）
Dotted line shows licensing-out products, being developed by other companies

Phase III12

Highlight of this year（June ~ Nov., 2015）
 Small molecular drug
 MELK Conducting phase I study of OTS167-IV in the University of Chicago. Additional
oral administration study of OTS167-PO was approved .（Jun., 2015）
 TOPK Publication from collaborative group in the Univ. of Chicago shows TOPK
inhibitor is effective to the FLT3-ITD mutated AML and FLT3 inhibitor-resistant
AML. （Oct., 2015）
 Acceptance of a proposal on our compound for NCL characterization program.
（Nov., 2015）
 SUV39H2
 Publication of our collaborator at the University of Chicago indicated that AML
could be a potential target disease of SUV39H2 inhibitor （Oct., 2015）

 Cancer-specific peptide vaccine
 Out- license to Shionogi S-588410（5 peptide vaccine cocktail）
 The completion of patient enrollment in Phase II clinical study in bladdercancer conducted by Shionogi & Co., Ltd.（Sep., 2015）

 Action for Cancer Precision Medicine
 TCR analysis service
 Launched our service for research institutes and pharmaceutical companies
mainly in the fields of oncology.(Sep., 2015)13

Contents

１）Overview of Anti-cancer Market
２）Features and Management Policy３）Pipelines and Updates

４）R&D Updates
 Small Molecular Drugs
 Cancer Precision Medicines Antibody Drug14

Clinical Study of OTS167(MELK inhibitor ）On-going Phase I Clinical study （Univ. of Chicago）
 Indication: Refractory advanced/metastatic solid tumors
 Route of Administration：
 On-going; Intravenous (IV) Additional; Oral administration（approved June, 2015）
 Objective: Primary endpoint: To determine safety and tolerability
 Secondary endpoint: To check pharmacokinetics ,such as blood
drug concentration, and to search and evaluation of biomarker

Develop clinical studies for leukemia and solid tumor
 Accelerate clinical development by choosing the mostsuitable area for clinical study globally.
15

New Anti-Cancer Drug Target: MELK

Highly expressed MELK contributes to maintain cancer
stem cell.
Self-renewalOTS167
CancerstemcellCancer cells

Cancercell

Cancercell

Chemotherapy resistantCancercell

Chemotherapy sensitive
MELK
 New Anti-cancer drug target.
 OTS167(MELK inhibitor) is effective to cancer stem cell which is one of thecause of the recurrence.
16

MELK Selectively Overexpressed in Various Cancer Cells
 MELK (maternal embryonic leucine zipper kinase) is highly and selectivelyoverexpressed in various human cancer cells.
 No or low expression in normal human organs except testis.
Expression of MELK (cDNA microarray)
Tumor type

Positive rate(%)
23 normal human organs

Non Small Cell LungCancer

100

Small Cell Lung Cancer

100

Bladder Cancer

100

Cholangiocellular
Carcinoma

100

Cervical Cancer

93

Lymphoma93

Northern blot analysis

Breast Cancer

91

Lin, et al., BCR (2007)

Prostate Cancer

86

ColorectalCancer

80

Osteosarcoma

78

CML

77

Expressed only in testis

Positive rate : % of cases where Tumor/Normal > 2(Data from collaborator (U Tokyo))17

OTS167 - MELK specific inhibitor OTS167 inhibition curve● High inhibition activity against MELK

100

・ IC50* = 1.1 nM
IC50 of approved kinase inhibitor
Erlotinib； Tarceva ®(CHUGAI PHARMA.) 2 nM (EGFR)
Sorafenib；Nexavar® （Bayer）
6 nM (c-Raf)Sunitinib； Sutent® （Pfizer）
9 nM (VEGFR-2)
Imatinib； Glivec®(Novartis)
25 nM (Bcr-Abl)% Inhibition

8060
40
20010-5 10-4 10-3 10-2 10-1 100 101 102 103 104 105 106
Concentration (nM)

*ＩＣ50； 50% inhibition concentration, low value means high activity● Selective and significant growth inhibition against cancer cells
IC50 =
IC50 =
IC50 =

8.9 nM
5.3 nM
3.3 nM

22Rv1
HT1197

IC50 =
5.2 nM
IC50 = 120.0 nM（lung cancer cell ；MELK positive）（breast cancer cell；MELK positive）（triple-negative breast cancer；
MELK positive）（prostatic carcinoma：MELK positive）（bladder cancer cell；MELK negative）

1.2
Relative cell number

A549
T47D
DU4475

1.0

DU4475

0.8
0.6
0.4
0.2
0.0
0.0001 0.001
0.01
0.1
Compound (mM)118

OTS167 in vivo: Tumor with MELK selectively suppressed
OTS167 shows significant MELK-dependent tumor growth
suppression in xenograft model by oral administration.
PC14 lung cancer(MELK low)

VehicleVehicleOTS167 10 mg/kg q.d.

1000

400

Significant
tumor growth
suppression

300
200

TGI 124%

10002468 10 12 14Days after initial treatment

Tumor volume (mm3)Tumor volume (mm3)500

A549 lung cancer(MELK high)

OTS167 10 mg/kg q.d.

800
600
400

TGI -17%

20002468 10 12Days after initial treatment

14Chung, et al., Oncotarget (2012)19

OTS167 in vivo: IV Administration
OTS167 has strong growth suppression with no severe adverse events,
compare to Paclitaxel.
Intravenous administration: once daily (A549 xenograft model)
Body weight

Tumor volume (mm3)

600
500

TGI=51%
400
300

TGI=91%

200

TGI=108%(p<0.01)100
024681012

Days after initial treatment

14

Relative body weight

Tumor volume (n = 6)

1.2
1.1
1
0.9
0.8
02

4

68

1012

Days after initial treatment
Vehicle q.d.
OTS167 1 mg/kg q.d.
OTS167 5 mg/kg q.d.
OTS167 10 mg/kg q.d.
Paclitaxel 24 mg/kg i.v. Day 0, 3, 7, 10
Paclitaxel 24 mg/kg i.v. Day 0, 1, 2, 3, 4

1420

OTS167 in vivo: Oral Administration
OTS167 is more effective for tumor growth suppression than
Paclitaxel with no severe side effects such as loss of body weight.
Oral administration: once or twice daily (A549 xenograft model)
Tumor volume (n = 6)

Body weight
1.2

400

TGI=95%300

TGI=98%200

TGI=124%

100024681012

Days after initial treatment

14TGI=126%(p<0.01)

Relative body weight

Tumor volume (mm3)

500

1.1
10.90.802468101214Days after initial treatment

Vehicle q.d.
OTS167 2.5 mg/kg b.i.d.
OTS167 5 mg/kg b.i.d.
OTS167 5 mg/kg q.d.
OTS167 10 mg/kg q.d.
Paclitaxel 24 mg/kg i.v. Day 0, 3, 7, 10Paclitaxel 24 mg/kg i.v. Day 0, 1, 2, 3, 421

New Anti-Cancer Drug Target: TOPKTOPK is involved in cancer cell cytokinesis during mitosis
TOPKEntry to Mitosis

OTS964etcp

Histone H3pTOPKpp

Mitosispp97p47Mitosis

TOPK

Exit to Mitosis

TOPK New Anti-cancer drug target.
 Several anti-cancer drugs which target mitosis are already approved, however
they inhibit normal cells, too. Whereas inhibition of TOPK is expected to lessadverse effect since its expression is limited to cancer.

8

TOPK Highly Expressed in Various Human Cancers
 TOPK is highly expressed in various human cancers, including lungand breast cancers.
 TOPK is not expressed in human vital organs.
Expression of TOPK (cDNA microarray)
Tumor type

Positive rate(%)

Bladder Cancer100%

Cholangiocellular
Carcinoma

100%

Lung Cancer

100%

Cervical Cancer

93%

Lymphoma

93%

Breast Cancer

91%

Prostate Cancer

86%

Colorectal Cancer

80%

Osteosarcoma

78%

CML

77%

Positive rate : % of cases where Tumor/Normal > 2(Data from collaborator (U Tokyo))

Breast cancer cell lines

Normal organs**MDA-MB-435 is reported to have been cross-contaminatedwith is the M14 melanoma line.
Northern blot analysis

Park, et al., Can Res (2006)

23

TOPK Expressed in AML as well.

AML cell lines

AML patients

Modified form Alachkar, et al., Oncotarget (2015)24OTS964 in vivo : Oral Administration
OTS964 shows significant anti-tumor effect

LU99（human lung cancer） xenograft model (N=6)
Once a day, 14 days, PO (orally), OTS964 100mg/kg

Tumor
volume
腫瘍の大きさBody weight
体重コントロール（対照群）
Control group

PO oncea day
OTS964 100 mg/kg 経口
1回/1日

2000

タキソール
0, 3,0,3,7,10
7, 10日I.V. day
Paclitaxel 24 mg/kg 静注

body weight
Relative
体重比33)
Tumor volume)
腫瘍の大きさ(mm(mmControl group
コントロール（対照群）

1500

1000500

PO oncea day
OTS964 100 mg/kg 経口
1回/1日

1.3

Paclitaxel 24 mg/kg 静注
I.V. day
タキソール
0, 3,0,3,7,10
7, 10日1.2
1.1
10.9007142128

Days
after initial treatment
治療開始からの経過日数

Complete regressionin all six mice.
Source： Sci Transl Med, Matsuo et al, 2014 , OTS internal document

07142128

Days
after initial treatment
治療開始からの経過日数

No severe side effects suchas loss of body weight.
25

Actions for Cancer Precision Medicine

1) Cancer immunotherapy and genome

2) Launch of TCR analysis service

3) Novel immunotherapy based on

genomic analysis; Precision Medicine

26Cancer Immunotherapy and Genome• It was reported about 20 years ago that the patients with hereditarycolon cancer caused by mutation of DNA repair gene have better
prognosis than those with common type of colon cancer.

⇒ From this relationship between cancer and gene mutation,
we can propose a hypothesis of effective cancer therapy.

http://yusukenakamura.hatenablog.com/entry/2015/02/15/131903

27

Actions for Cancer Precision Medicine
2) Launch of TCR analysis service
 After the first half of this fiscal year of preparation, we posted
revenues since this September.
 We promoted public awareness through conference presentation
and BioJapan luncheon seminar.
 We received orders from the researchers in the fields of oncology
as the first step.
 We will expand our business to the research in the other fields
and pharmaceutical companies.

3) Novel immunotherapy based on genome
analysis data; Precision Medicine

28

TCR analysis: solving issues of cancer immunotherapy
 Immunomonitoring
Establishment of “diagnostic marker (TCR analysis)” that reflects
the change of immune state effected by therapy.
➡Rapid and quantitative evaluation of therapy contributes
accurate judgment of continuation/cessation of treatment.
Before treatment After treatment

 Patient selection

Tumor
regression

Prediction of clinical efficacy• Detecting T cells in the tumor
before treatment→ Start cancer immunotherapy• Not detecting T cells in the tumor
before treatment→ Avoid cancer immunotherapy➡ Increase of response rate
Decision of the start of treatment

Tumor
progression

Antigen A-specific T cell
Antigen B-specific T cell
29

Novel Therapy based on Immunopharmacogenomics
Immunecheckpoint inhibitors are now under developing,and hereafter, therapy of activating immune system andenhancing the attack against tumor will become important.

30
Source： Bio Japan 2015 luncheon seminar by Professor Nakamura,University of Chicago

Clinical Development Status of OTSA101
 On-going phase I clinical trial for synovial sarcoma, in France Under the direction of Professor Jean-Yves BLAY (former President ofEuropean Organization for Research and Treatment of Cancer; EORTC) who
is global key opinion leader in sarcoma treatment.
 Financially supported by Cancéropôle Lyon Auvergne Rhône-Alpes=CLAR Designated as orphan drug for treatment of soft tissue
sarcoma by EMA(EU) and FDA(US) Seeking approval for synovial sarcoma in EU and US
 Based on phase I study result, design the next phase clinical trial, consultingwith EMA/FDA （designation of orphan drug）
 Consider next clinical trial as the pivotal study to evaluate the effectiveness of
OTSA101 and plan to application of NDA after the study Develop companion diagnostics and seek expansion ofapplication to another cancer type31

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was not created to solicit investors to buy or sell securities.
With the exception of historical facts, the contents of thisdocument are predictive statements. These statements are
based on management‘s assumptions and beliefs in light of theinformation currently available to it. The assumptions involverisks and uncertainties which may cause the actual results,
performance or achievements to be materially different fromany future results, performance or achievements expressed orimplied by the predictive statements.
Please be aware that decisions regarding investing are theresponsibility of users themselves.

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