Introduction of Taiho R&D · • Introduction of Products in Clinical Development –Introduction of three representative products •Futibatinib (TAS-120) •TAS3681 •TAS-115 •

|Taiho R&D Introduction| 2019/10/10 |1

Introduction of Taiho R&D

Oct. 10, 2019

Copyright © Taiho Pharmaceutical Co., Ltd.


Outline

< R&D Strategy (In-house Drug Discovery & External R&D Collaboration)>

• In-house Drug Discovery: Taiho’s Approach in the Oncology Arena– Evolution from “futraful (FT)” an oral antimetabolite

• FT → UFT → S-1 → Lonsurf →

– Molecular targeted drugs• Build, strengthen and expand a unique drug discovery platform

– Cysteinomix

• Introduction of Products in Clinical Development– Introduction of three representative products

• Futibatinib (TAS-120)• TAS3681• TAS-115

• External R&D Collaboration: Access to Innovative Drugs


R&D STRATEGY (IN-HOUSE DRUG DISCOVERY & EXTERNAL R&D COLLABORATION)



IN-HOUSE DRUG DISCOVERY: TAIHO’S APPROACH IN THE ONCOLOGY ARENA



Changing Era/Technology InnovationsFrom Cytotoxic Drugs to Molecular Targeted Drugs and Immuno-oncology Drugs

1940 1950 1960 1970 1980 1990 2000 2010 2020 2030

Cytotoxic Drugs 1940’s～

Molecular Targeted Drugs1990’s ～

HumanGenome

Immune-checkpoint

Immunotherapy1970’s ～

Monoclonal antibodies,Protein kinase inhibitorsEpigenetic agents

Non-specific immune stimulator Immune-checkpoint blockade

Cytokine therapy

Alkylating agents

“Drugs using the different growth rates between cancer cells and normal cells”

“Drugs targeting molecules which accelerate growth of cancer cells”

“Drugs using the built-in immune system to eliminate cancer cells”

Antimetabolites

Antitumor antibiotics

Plant alkaloids

Synthetic antitumor agents

Platinum antitumor agents

Taxanes

Topoisomerase inhibitors

Immuno-oncology Drugs2010 ～

Increase the power of immunity → Disrupting Immune Suppression

Advances in Drug Discovery

Technology


History of Anticancer Drug Development in Taiho in Japan

1974 Launched Futraful Capsule

1969 Licensed in Futraful

1984 Launched UFT Capsule

1999 Launched TS-1 Capsule

Battle to Develop Oral Anticancer Drugs：Maximizing the Antitumor Effect by combining the Chemical Modulators

2014 Launched Lonsurf Tablet

2010 Launched AloxiLaunched Abraxane

1970 1980 1990 2000 2010 2020

Introduction of Crucial Drugs for Japanese Cancer Patients

Improvement QOL of Cancer Patients: AloxiAnticancer drug approved in > 70 countries: Abraxane


Taiho’s Anticancer Drug Development History: Evolution from Oral Anti-metabolite Futraful

・Oral anticancer drug・Combination product

• Treatment switch from hospitalization to outpatient through oral administration

• Overcame difficulties of determining and proofing the combination ratio→ Other companies could not imitate.

Tegafur(5-FU prodrug)

High oral absorbability

Maximizing the Potential of 5-FU

TS-1

(1999~)

1st Gen

Futraful（1974～）





2nd Gen

UFT（1984～）

3rd Gen

TS-1（1999～）

Uracil(DPD inhibitor）Keeps high 5-FU

blood concentrationOteracil potassium(OPRT inhibitor)

Reduce GI toxicity

Gimeracil(DPD inhibitor）Keeps high 5-FU

blood concentration


Research and Development of Antimetabolites：Lonsurf

Futraful1974 launched

UFT

1984 launched

TS-1

1999 launched

Lonsurf

2014 launched in Japan

2015 launched in the USA

Cumulative Experience and Technologies in Antimetabolite Drug Discovery

+ Establishment of New Drug Discovery Platforms

Novel anticancer drug

Trifluridine

(FTD: thymidine analog)

metabolized through phosphorylation in cancer cells, then incorporated into DNA.

Tipiracil (TP inhibitor）keeps the plasma FTD levels high

Lonsurf combination tablet


Establishment of Platforms for Molecular Targeted Drug Discovery

1940 1950 1960 1970 1980 1990 2000 2010 2020 2030



HumanGenome

Immune-checkpoint




Cytokine therapy




Immuno-oncology Drugs 2010 ～



Technology

Cumulative Experience and Technology in Antimetabolites Drug Discovery + Molecular Targeted Drug Discovery Platforms


Cysteinomix Drug Discovery Platform

Covalent Binding Drug

Target Protein（Cysteinome）

• CysteinomeDruggable proteins that have reactive amino acid residues (ex. Cys) located inside or adjacent to the binding sites of small~medium-sized molecules

• Covalent Binding DrugsDrugs that specifically captures reactive amino acid residues (ex. Cys) by forming covalent bonds


Cysteinomix Drug Discovery Platform

MS Screening Assay

Target Cysteinome + covalent binder

Target Cyseinome

Identification of covalent binding adducts

• CysteinomixTaiho’s proprietary technology platform to identify drugs that specifically forms a covalent bond with the target cysteinome

Covalent binder library

Target cysteinome

Cysteine


Futibatinib：The World’s First Covalent FGFR Inhibitor

Futibatinib(TAS-120)

Cancer Discov. 2019;9:1064–79

L. Goyal et al.

Futibatinib conc.100nM

KinomeScan456 kinase

FGFR1, 2, 3, and 4 were specifically inhibited

Futibatinib was found to show potent and selective inhibition of FGFR1, 2, 3, and 4 by forming a covalent bond with the targeted Cys in FGFR1, 2, 3, and 4

→ Currently in Phase 2. Aims to achieve early approval

Figure 4B

FGFR: Fibroblast growth factor receptor


DEVELOPMENT PIPELINE



Development Pipeline (As of Jun. 30, 2019)

Oncology

Other Disease Area

TAS-118Antimetabolite (TS-1/Leukovorin)

GastricJPN, Asia

TAS-115Multi tyrosine kinase inhibitor

ProstateJPN

TAS-114dUTPase inhibitorNSCLCJPN, US, EU

TAS-116

HSP90 inhibitorGISTJPN

TAS-120

FGFR inhibitorCholangiocarcinomaJPN, US, EU

Pro-NETUNK1RAChemotherapy-induced Nausea & Vomiting

JPN In-licensed from Helsinn

ET-743DNA minor groove binderOvarianJPNIn-licensed from PharmaMar

TAS-117Allosteric Akt inhibitorSolid TumorJPN

TAS4464NAE inhibitorSolid Tumor, Hematological Cancer

JPN, US, EU

TAS3681Novel AR antagonistProstateUS, EU

TAS0728

Her2 inhibitorSolid TumorUS, EU

TAS6417/CLN-081

EGFR inhibitorOut-licensed to Cullinan Pearl

AB928 (JPN)A2AR/A2BR AntagonistIn-licensed from Arcus Biosciences

TAS-119Aurora A inhibitorSolid TumorUS, EU

RET inhibitor

Co-developmentwith Helsinn

TAS0313Peptide VaccineUrothelialJPN

TAC-302Neuroprotective AgentDetrusor low activity withOveractive Bladder

JPNIn-licensed from Meiji

TAS-303Selective NA Reuptake inhibitor

Stress Urinary Incontinence

JPN

TAS-205Prostaglandin D2 synthase inhibitorDuchenne Muscular Dystrophy

JPN

TAS5315

BTK inhibitorRheumatoid ArthritisJPN

TAS-115Multi tyrosine kinase inhibitorIdiopathic pulmonary fibrosis

JPN

Phase 1Pre-clinical Phase 2 Phase 3

Molecular targeted

Others

Molecular targeted

Supportive care

Cytotoxic


Introduction of Three Representative Products

TAS-120- Covalent FGFR inhibitor- Potential Best-in-class drug- Indications (under development) : Cholangiocarcinoma, Breast cancer, Gastric

cancer, and others

TAS3681- Pure AR antagonist with AR downregulating activity- Potential First-in-class drug- Indication (under development) : Castration resistant prostate cancer

TAS-115- Multi tyrosine kinase inhibitor- Potential Best-in-class drug- Indication (under development) : Idiopathic pulmonary fibrosis, Prostate cancer

and others


FUTIBATINIB（TAS-120）



Characteristics of FGFRs as Cancer Treatment Targets

FGFR genetic abnormalities in cancer FGF overexpression

Geneamplification

Active point mutation

Translocation

Many types of genetic abnormalities compared with other genes; Point mutation, Translocation, Gene amplification and Overexpression

FGFR genetic abnormalities found in many types of cancer; Cholangiocarcinoma(CCA), Breast cancer, Lung cancer, and Gastric cancer

Impact on the tumor microenvironment; Forms a unique tumor microenvironment through not only tumor cells but also fibroblasts, and is

attracting particular attention from the viewpoint of tumor immunity

Contribution in drug resistance mechanisms; Resistance mechanisms of various chemotherapeutic and immunotherapeutic drugs

(Expectations as a combination therapy partner)

FGF

FGF

FGF

FGF

FGF

FGF

FGF

FGF

FGF

Stroma（included fibroblast）

Tumor growth

FGFRfusion protein


Key Profiles of Futibatinib

FGFR fusion gene

Growth factor

Tumorgrowth

Tumorgrowth

Cancer cell

Inhibits all 4 family receptors (FGFR1-4); Expected to show effects in cancer types that does not respond to other drugs

The only covalently-binding FGFR inhibitor in clinical development stage

Expected to be effective in patients who have acquired resistance mutations to other drugs

Expected to have high antitumor activity with few side effects

Futibatinib


Futibatinib Demonstrates Meaningful Clinical Benefit in CCA Patients with FGFR2 Gene Fusions

Currently conducting Global Phase 2 study aiming early approval

ESMO World Congress on Gastrointestinal Cancer, 2018 Abstract O-001 F. Meric-Bernstam et al.

Response rate: 25％，Disease control rate: 78.6%Progression free survival: 7.4 month

Prior FGFR inhibitor

*


Overcoming Acquired Resistance in Patient with FGFR2 Gene Fusion

AACR Annual Meeting 2019, Abstract CT239, L. Goyal et al.

Recurrence 1 year after response to the FGFR inhibitor (BGJ398)

Response and stable disease on TAS-120 for over one year

At the time of recurrence, a resistance mutation appeared in the blood, but the clone disappeared after administration of TAS-120

Many more cases of response with TAS-120 after recurrence with other FGFR inhibitors.


Expansion to Other Types of Cancers as a Single Agent

ESMO 2017 Congress, Abstract 372 PD, Y. Kuboki et al.

In the Phase 1 study, multiple cases of tumor reduction in other cancer types (including gastric cancer) have been observed.

Currently planning multiple Phase 2 studies.


Futibatinib: Development Strategy for Combination Therapy

Recent studies have revealed that FGFRs plays many roles including tumor microenvironment and drug resistance. Taiho currently aims to achieve clinical efficacy in combination therapies.

Tumor microenvironment

FGFR inhibitors reduce the number of myeloid-derived suppressor cells (MDSC) via fibroblasts and attenuate tumor immune resistance.

Anticancer drug resistance

Fluvestrant

Inhibition

HR positivebreast cancer

K-Ras mutant lung cancer

MEK inhibitor

ERK inhibitor

FGFR

inhibition

Futibatinib

Resistance

Combination study of futibatinib with IO drugs planned.

Combination studies of futibatinib with various anticancer agents planned (ongoing, in part).

Cell Physiol Biochem. 2014;33:633-45 L. Liu et al.

ER responsive element

ERα ERαE2 E2

PI3K

AKT

RAS

RAF

MEK

ERKT cellCAF* Tumor

IO-drug(Anti-PD-1 etc.)

T-cell activation

inhibition

MDSC

Activates immunosuppressive

cells

Futibatinib

Cancer cells make an environment to escape the immune

system ！！

attack

*CAF: cancer-associated fibroblast

By combination with futibatinib,

IO-drug’s efficacy will increase！？

（Hypothesis）Resistance


TAS3681A NOVEL PURE AR ANTAGONIST WITH AR DOWNREGULATING ACTIVITY



AR Agents in Prostate Cancer Treatment Tree

Androgen deprivation therapy

Death

Local treatment

AdditionalHR therapy

LH-RH agonist/ antagonist

BicalutamideCabazitaxelDocetaxel

Chemotherapy

2nd gen AR agents

Tumorvolume

Time

Metastatic

Symptomatic

Castration Resistant Prostate Cancer (CRPC)

Non metastatic

Asymptomatic

Alpharadin

Death due to CRPC

Modified from EAU2012 P. Mulders et al.

ADT success

5-year survival rate of CRPC; Less than 15%

Denosumab, Zoledronic Acid

AbirateroneEnzalutamide

AbirateroneEnzalutamideDarolutamideApalutamide

mHSPC

M0 CRPC

CRPC: Castration resistant prostate cancer

mHSPC: metastatic hormone sensitiveProstate cancer


Urgent Issues on CRPC Treatment Cross resistance between Enzalutamide and Abiraterone

Compounds with the same MOA currently in development have the same issue

One of the main resistant mechanism of the two drugs is AR splicing variants such as AR-V7 which lacks the ligand biding domain

Eff

ecti

ve←

PS

A →

Non

eff

ecti

ve

Patients without AR-V7

Patients with AR-V7

PSA response to Abiraterone

Due to the lack of LBD, both drugs do not function against splicing variant ARs

N Engl J Med 2014;371:1028-38, E. S. Antonarakis et al.

PSA response rateAR-V7–positive patients 0% (95% CI, 0 to 26; 0 of 12 men)AR-V7–negative patients 53% (95% CI, 29 to 76; 10 of 19 men; P = 0.004)

PSA response rateAR-V7–positive patients 0% (95% CI, 0 to 46; 0 of 6 men)AR-V7–negative patients 68% (95% CI, 46 to 85; 17 of 25 men; P = 0.004)

Full length AR

AR-V7

NTD DBD LBD

NTD DBD

AR binding domain

DNAbinding domain

PSA response to Enzalutamide

Eff

ecti

ve←

PS

A →

Non

eff

ecti

ve


Key Profiles of TAS3681

TAS3681 has an AR antagonist activity comparable to enzalutamide,

In addition, it downregulates NOT only the full length AR but also the splicing variant ARs,

Which leads to efficacy in enzalutamide resistant models with AR-V7

Results are expressed as the mean ± SD (n = 3).

26th AACR-NCI-EORTC International Conference 2014, Abstract 315, K. Minamiguchi et al.ASCO Gastrointestinal Cancers Symposium 2017, Abstract 197, D. Kajiwara et al.

Cell growth

NTD DBD LBD

NTD DBD

Full length AR

AR-V7


TAS3681

• Currently under Phase 1 trial


TAS-115 (MULTI TYROSINE KINASE INHIBITOR)



Idiopathic Pulmonary Fibrosis（IPF）

Annual incidence and prevalence of IPF【Japan】

Approximately 14,000 pts

Annual incidence 2.23 patients/100KPrevalence 10.0 patients/100K

【US/EU】

Annual incidence 4.6-8.8 patients/100KPrevalence 14.0-27.9 patients/100K

Idiopathic pulmonary fibrosisA type of a Idiopathic Interstitial Pneumonia defined in the National Registry of Designated Intractable Diseases in Japan Poor prognostic, idiopathic lung disease. Irreversible honeycomb form as a result of severe fibrosis Dyspnea and progressive decline in respiratory function are known as the typical symptom

Lung diffusion capacity is also declined in IPF patients

IPF Lung

Dry cough：Dyspnea

Fibrosis

Treatment option for IPF is limited. Nintetanib is the only approved drug recommended in the International Treatment Guideline.

Median overall survival in IPF is reported as approximately 3 years after diagnosis.

Lung in healthy people

Eur Respir Rev. 2012; 21: 141-6. RM. du Bois

Am J Respir Crit Care Med 2014; 190: 773-9 M. Natsuizuka et al.

Chest 2010; 137: 129-37 ER. Fernández Pérez et al.Thorax 2006; 61: 980-5 J. Gribbin et al. Am J Respir Crit Care Med 2006; 174: 810-6 G. Raghu et al.


Key Profiles of TAS-115

Mechanism of action of TAS-115 Inhibition of Fibrosis in preclinical IPF model- Comparison with nintedanib

TAS-115

Nintedanib

Fib

rosi

s Score

Am J Respir Cell Mol Biol. 2019; 60: 478-487, K. Koyama et al.

VEGF PDGF

VEGFR* PDGFR**

Fibroblasts growth

Nintedanib

Growth signal inhibition

Growth signal

TAS-115 TAS-115

Nintedanib

* VEGFR: Vascular endothelial growth factor receptor** PDGFR: Platelet-derived growth factor receptor

Endothelial cells growth


-15

-10

-5

0

5

10

15

20

25

-30 -24 -18 -12 -6 0 6 12 18 24 30

N Cohort

P Cohort

U Cohort

Efficacy: Significant Suppression of FCV Decline in Phase 2 Study

Pre-TAS-115 treatment Remarkable responder

FVC；71.6%

FVC；75.1%

Forc

ed

vit

al cap

acit

y（

FV

C,

%)

TAS-115 treatment period

（Week）

After nintedanibAfter pirfenidonNo prior treatment

Data cut-off date is Jul 2, 2019

ERS International Congress 2019, Abstract PA1296, T. Ogura et al.


Safety: Adverse Events (≥5%) in Phase 2 Study

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%Severe (Grade 3 or more）

Moderate(Grade 2)

Mild (Grade 1)

As of Jun 30, 2019

Four treatment-related SAEs (pyrexia, interstitial lung disease, idiopathic pulmonary fibrosis and rash) were observed in four patients.The most commonly observed AE was skin rash, which was controllable following interruption or dose modification of TAS-115.

ERS International Congress 2019, Abstract PA1296, T. Ogura et al.

The commonly observed digestive symptoms (such as diarrhea and nausea) of nintedanib were much less frequent in TAS-115.


TAS-115：Future Plan

• Planning Phase 3 trial in IPF

• Planning clinical trials to confirm antitumor activity


EXTERNAL R&D COLLABORATION: ACCESS TO INNOVATIVE DRUGS



Further Actions to Discover and Develop Innovative Drugs

1940 1950 1960 1970 1980 1990 2000 2010 2020 2030



HumanGenome

Immune-checkpoint




Cytokine therapy




Immuno-oncology Drugs 2010 ～



Technology

In-house Drug Discovery Platforms

Launched Futraful

Launched UFT

Launched S-1

Launched Lonsurf

External Innovations


Access to Highly “Innovative” Drugs : A Multifaceted Approach

Access to Innovative Drugs through Venture Investment

Late

Early

REMIGESVENTURES

TAIHOVENTURES

Wide range of disease areas

Tsukuba Research Center

Mainly Oncology

Obtaining innovative technologies and innovative development concepts not available in-house.

Example) Types of Drugs Small Molecule Medium Sized Molecule Antibody Vaccine Cell Therapy

Example) Disease Area Oncology Immunology/Allergy

Urology

Cancer (Innovative Treatments)

Rare Diseases

Development StageBusiness

Development

Oncology, Immunology/Allergy, Urology

TAIHO INNOVATIONS Japan only+Healthcare

Oncology, Immunology/Allergy, Urology

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http://www.taihoventures.com/portfolio.html

Please visit Taiho Ventures, LLC’s Website

http://www.taihoventures.com/portfolio.html


Agreements with Arcus Biosciences, One of Taiho Ventures’ Portfolio

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Documents

Introduction of Taiho R&D · • Introduction of Products in Clinical Development –Introduction of three representative products •Futibatinib (TAS-120) •TAS3681 •TAS-115 •