|Taiho R&D Introduction| 2019/10/10 |1
Introduction of Taiho R&D
Oct. 10, 2019
Copyright © Taiho Pharmaceutical Co., Ltd.
|Taiho R&D Introduction| 2019/10/10 |2
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
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R&D STRATEGY (IN-HOUSE DRUG DISCOVERY & EXTERNAL R&D COLLABORATION)
Copyright © Taiho Pharmaceutical Co., Ltd.
|Taiho R&D Introduction| 2019/10/10 |4
IN-HOUSE DRUG DISCOVERY: TAIHO’S APPROACH IN THE ONCOLOGY ARENA
Copyright © Taiho Pharmaceutical Co., Ltd.
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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
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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
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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~)
Tegafur(5-FU prodrug)
High oral absorbability
Tegafur(5-FU prodrug)
High oral absorbability
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
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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
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Establishment of Platforms for Molecular Targeted Drug Discovery
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
“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”
Immuno-oncology Drugs 2010 ~
Increase the power of immunity → Disrupting Immune Suppression
Advances in Drug Discovery
Technology
Cumulative Experience and Technology in Antimetabolites Drug Discovery + Molecular Targeted Drug Discovery Platforms
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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
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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
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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
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DEVELOPMENT PIPELINE
Copyright © Taiho Pharmaceutical Co., Ltd.
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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
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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
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FUTIBATINIB(TAS-120)
Copyright © Taiho Pharmaceutical Co., Ltd.
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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
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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
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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
*
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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.
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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.
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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
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TAS3681A NOVEL PURE AR ANTAGONIST WITH AR DOWNREGULATING ACTIVITY
Copyright © Taiho Pharmaceutical Co., Ltd.
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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
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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
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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
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TAS3681
• Currently under Phase 1 trial
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TAS-115 (MULTI TYROSINE KINASE INHIBITOR)
Copyright © Taiho Pharmaceutical Co., Ltd.
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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.
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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
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-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.
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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.
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TAS-115:Future Plan
• Planning Phase 3 trial in IPF
• Planning clinical trials to confirm antitumor activity
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EXTERNAL R&D COLLABORATION: ACCESS TO INNOVATIVE DRUGS
Copyright © Taiho Pharmaceutical Co., Ltd.
|Taiho R&D Introduction| 2019/10/10 |36
Further Actions to Discover and Develop Innovative 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
“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”
Immuno-oncology Drugs 2010 ~
Increase the power of immunity → Disrupting Immune Suppression
Advances in Drug Discovery
Technology
In-house Drug Discovery Platforms
Launched Futraful
Launched UFT
Launched S-1
Launched Lonsurf
External Innovations
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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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Taiho Ventures’ Portfolio Companies
http://www.taihoventures.com/portfolio.html
Please visit Taiho Ventures, LLC’s Website
|Taiho R&D Introduction| 2019/10/10 |39
Agreements with Arcus Biosciences, One of Taiho Ventures’ Portfolio
https://www.taiho.co.jp/en/release/2018/20180713.html
https://www.taiho.co.jp/en/release/2017/20170920.html