taiho pharma r&dmajor progresses since “r&d meeting” on oct. 10, 2020 development...
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|Taiho R&D Introduction| 2020/09/29 |1
TAIHO PHARMA R&D
Sep. 29, 2020Taiho Pharmaceutical Co., Ltd.
Copyright © Taiho Pharmaceutical Co., Ltd.
|Taiho R&D Introduction| 2020/09/29 |2
Disclaimer
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• The IQVIA, Euromonitor and other reports described herein (the “Reports”) represent data, research opinions orviewpoints published as part of a syndicated subscription service and are not representations of fact. TheReports speak as of their original publication dates (and not as of the date of this material), and the opinionsexpressed in the Reports are subject to change without notice.
• This material contains information on pharmaceuticals (including compounds under development), but thisinformation is not intended to make any representations or advertisements regarding the efficacy oreffectiveness of these preparations nor provide medical advice of any kind.
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Agenda
R&D Activity SummaryMajor Progresses since “R&D Meeting” on Oct. 10, 2019Development PipelineOpen Innovation and Venture Investment
Development Pipeline UpdatesFutibatinib(TAS-120)TAS-115
Drug Discovery Research Updates Expansion of Cysteinomix (from Kinases to RAS Drug Discovery) Brain Metastasis Drug Discovery (Partnering with MD Anderson Cancer Center)
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Agenda
R&D Activity SummaryMajor Progresses since “R&D Meeting” on Oct. 10, 2019Development PipelineOpen Innovation and Venture Investment
Development Pipeline UpdatesFutibatinib(TAS-120)TAS-115
Drug Discovery Research Updates Expansion of Cysteinomix (from Kinases to RAS Drug Discovery) Brain Metastasis Drug Discovery (Partnering with MD Anderson Cancer Center)
|Taiho R&D Introduction| 2020/09/29 |5
Taiho Pharma R&D: Major Progresses since last R&D Meeting
Basic research
collaboration
Small molecules against several drug targets including KRAS
Initiate collaboration with Astex and MSD Jan. 6, 2020News Release
In-license Zimberelimab(AB122; anti-PD-1 antibody)
Obtain development and commercialization rights of an anti-PD-1 antibody, AB122 in Japan and certain other territories in Asia (excluding China) from Arcus Biosciences
Feb. 27, 2020News Release
Basicresearch
collaborationBrain metastasis drug discovery Partner with MD Anderson Cancer Center Sep. 24, 2020
News Release
Clinical development
Futibatinib(TAS-120; FGFR inhibitor)
Publish the result of interim analysis of a Phase 2 study in patients with intrahepatic cholangiocarcinoma
ASCO2020Oral Presentation
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Strategic Oncology Collaboration Targeting KRAS OncogeneNews Release
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Research Collaboration with MD Anderson Cancer CenterTaiho Pharma News Releaseon Sep. 24, 2020
2015~
Covalent BindersCysteinomix
2010~
SBDD/FBDD2009~
Kinase Inhibitors2009~
Natural Product2014~
UFT TS-1 Lonsurf
ClinicalApproved
Nucleic Acids1993~
DNA-encoded Library
2016~
Brain MetastasisBrain Cancer
2017~
TAS-114
Technology Enabled Drug Discovery in Taiho
TAS0728TAS-120 TAS5315 TAS6417
TAS3681
TAS1440
TAS-116
TAS-117
TAS-119
TAS-115
RAS2012~2019~
8
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Development Pipeline (As of Jun. 30, 2020)
TAS-115Multi tyrosine kinase inhibitorProstate Cancer etc.JPN
TAS-114dUTPase/DPD inhibitorNSCLCJPN, US, EU
TAS-116HSP90 inhibitorGIST etc.JPN
TAS-120FGFR inhibitoriCCA, Breast Cancer etc.JPN, US, EU
Pro-NETUNK1RAChemotherapy-induced Nausea & VomitingJPN In-licensed from Helsinn
ET-743DNA minor groove binderOvarian CancerJPNIn-licensed from PharmaMar
TAS-117Allosteric AKT inhibitorSolid TumorJPN
TAS3681Novel AR antagonistProstate CancerUS, EU
TAS6417/CLN-081EGFR inhibitorOut-licensed to Cullinan Pearl
TAS-119
TAC-302Neuroprotective AgentDetrusor low activityOveractive BladderJPNIn-licensed from Meiji
TAS-303Selective NA Re-uptake inhibitorStress Urinary IncontinenceJPN
TAS-205Prostaglandin D2 synthase inhibitorDuchenne Muscular DystrophyJPN
TAS5315BTK inhibitorRheumatoid ArthritisJPN
TAS-115Multi tyrosine kinase inhibitorIdiopathic pulmonary fibrosisJPN
Phase 1 Phase 2 Phase 3
Molecular targeting
Others
Molecular targeting
Supportive care
Cytotoxic
Oncology
Other Disease Area
TAS1440LSD1 inhibitorAMLUS
Immunooncology
TAS0313Peptide VaccineUrothelial CancerJPN
TAS0728Her2 inhibitorSolid TumorUS, EU
AB928A2AR/A2BR AntagonistIn-licensed from Arcus Biosciences
AB122PD-1 inhibitorIn-licensed from Arcus Biosciences
Aurora A inhibitorOut-licensed to VITRAC Therapeutics
Preparing Clinical Development in Japan/Asia (ex. China)
TAS0953/HM06
Co-developmentwith Helsinn
RET inhibitor
Pre-clinical
IND
Out-licensed to VITRAC Therapeutics
Stage up to Phase 1Developing by Astex
Stage up to Phase 1 Developing byCullinan Pearl
Acquired development and commercialization rights
Started Breast Cancer study
TAS-118Development discontinued
Update from Jun. 30, 2019
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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 Stage Business Development
Oncology, Immunology/Allergy, Urology
TAIHO INNOVATIONSOncology, Immunology/Allergy,
Urology
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Taiho Ventures’ Portfolio Companies
Immuno-Oncology
Checkpoint inhibitor TCR-T cell therapy T-cell engager TME immune stimulant
(RCUS) (NXTC) (HARP)
Oncology
RNA epigenetics Cancer resistance DNA damage response Oncogenic driver
Microbiome
As of Aug. 31, 2020
(ORIC)Spin-out TAS6417 to
Cullinan Pearlto accelerate its clinical
development
Taiho Ventures will have a first right to negotiate for an exclusive license
related to the new oncology programs
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Arcus Biosciences Anti-PD-1 antibody Zimberelimab (AB122): Obtained Rights to Develop and Commercialize in Japan and Certain Other Territories in Asia
Obtain development and commercialization rights of an Adenosine Receptor Antagonist
Preparing clinical development in Japan/Asia
Obtain development and commercialization rights of an anti-PD-1 antibody
Preparing clinical development in Japan/Asia
Taiho Pharma News Releaseon Feb. 27, 2020
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Agenda
R&D Activity SummaryMajor Progresses since “R&D Meeting” on Oct. 10, 2019Development PipelineOpen Innovation and Venture Investment
Development Pipeline UpdatesFutibatinib(TAS-120)TAS-115
Drug Discovery Research Updates Expansion of Cysteinomix (from Kinases to RAS Drug Discovery) Brain Metastasis Drug Discovery (Partnering with MD Anderson Cancer Center)
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Clinical Pipeline Update
Futibatinib (TAS-120)- Covalent FGFR inhibitor- Potential Best-in-class drug- Indications (under development) : Intrahepatic
cholangiocarcinoma, Breast cancer, Gastric cancer, and others
TAS-115- Multi tyrosine kinase inhibitor- Potential Best-in-class drug- Indications (under development) : Idiopathic pulmonary fibrosis,
Osteosarcoma, and others
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FUTIBATINIB(TAS-120)
Copyright © Taiho Pharmaceutical Co., Ltd.
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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 typesthat does not respond to other drugs
The only covalently-binding FGFR inhibitor inclinical development stage
Expected to be effective in patients whohave acquired resistance mutations to otherdrugs
Expected to have high antitumor activitywith few side effects
Futibatinib
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Overcoming Acquired Resistance in Patients 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 futibatinibfor over one year
At the time of recurrence, a resistance mutation appeared in the blood, but the clone disappeared after administration of futibatinib
Many more cases of response with futibatinib after recurrence with other FGFR inhibitors.
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Futibatinib Demonstrates Meaningful Clinical Benefit in iCCA Patients with FGFR2 Gene Fusions
Completed enrollment of Global Phase 2 study aiming early approval.Currently Planning Phase 3 study for 1st line iCCA.
ASCO Annual Meeting 2020, Abstract 108 Lipika Goyal et al.
• Response rate:37.3%,Disease control rate:82.1%• Progression-free survival (median): 7.2 months
iCCA: intrahepatic cholangiocarcinoma
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Futibatinib: Adverse Events
ASCO Annual Meeting 2020, Abstract 108 Lipika Goyal et al.
MedDRA (v18.1) preferred termAll patients (N=67), n (%)
Grade 1 Grade 2 Grade 3 TotalPatients with at least one AE 6 (9.0) 23 (34.3) 38 (56.7) 67 (100)Hyperphosphatemia 4 (6.0) 32 (47.8) 18 (26.9) 54 (80.6)Diarrhea 18 (26.9) 7 (10.4) 0 25 (37.3)Dry mouth 19 (28.4) 3 (4.5) 0 22 (32.8)Alopecia 15 (22.4) 5 (7.5) 0 20 (29.9)Dry skin 13 (19.4) 5 (7.5) 0 18 (26.9)Fatigue 10 (14.9) 2 (3.0) 4 (6.0) 16 (23.9)Aspartate aminotransferase increased 6 (9.0) 1 (1.5) 6 (9.0) 13 (19.4)Dry eye 10 (14.9) 2 (3.0) 1 (1.5) 13 (19.4)Dysgeusia 9 (13.4) 4 (6.0) 0 13 (19.4)Alanine aminotransferase increased 3 (4.5) 5 (7.5) 4 (6.0) 12 (17.9)Constipation 8 (11.9) 4 (6.0) 0 12 (17.9)Palmar-plantar erythrodysesthesiasyndrome 4 (6.0) 7 (10.4) 1 (1.5) 12 (17.9)
Nail disorder 8 (11.9) 3 (4.5) 0 11 (16.4)Stomatitis 6 (9.0) 3 (4.5) 2 (3.0) 11 (16.4)
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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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Tumor Agnostic Phase 2 Study is Ongoing
Cohort AAdvanced/metastatic solid tumors with FGFR1–4rearrangements* (n=60)
Cohort BAdvanced/metastatic gastric or GEJ cancer with FGFR2 amplification (n=35)
Cohort CMLN with FGFR1 rearrangements (n=20)
Futibatinib
20 mg QD orally in 28-day cycles
https://clinicaltrials.gov/ct2/show/NCT04189445
Primary endpointCohort A, B:Objective response rateCohort C:Complete response rate
GEJ: Gastroesophageal junctionMLN: Myeloid or lymphoid neoplasms* Brain tumors and iCCA are excluded.
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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
FluvestrantInhibition
HR positivebreast cancer
K-Ras mutant lungcancer
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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Futibatinib (TAS-120):Ongoing Studies of Combination Therapy
• TAS-120 monotherapy/TAS-120+fulvestrant– Phase 2 study for FGFR mutated Breast Cancer
• TAS-120+pembrolizumab– Phase 1 study for FGFR mutated Solid Tumor
• TAS-117+TAS-120– Phase 1/2 study for FGFR mutated Solid Tumor
(NCT04024436)
(JapicCTI-195063)
(JapicCTI-194864)
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TAS-115(PAMUFETINIB) (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 ptsAnnual 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 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. Nintedanib and pirfenidone are 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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【IPF】 Efficacy: Significant Suppression of FVC Decline in Phase 2 Study
FVC;71.6%
FVC;75.1%
We are currently planning a Phase 3 study.American Thoracic Society 2020 International Conference. Abstract 4547, Arai N et al.
N=45
(週)
ERS International Congress 2019, Abstract PA1296, T. Ogura et al.
Pre-TAS-115 treatment TAS-115 treatment period
- After nintedanib- After pirfenidon- No prior treatment
Remarkable responder
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Phase 3 Study of TAS-115 in Patients with Osteosarcoma has Started
Treatments for unresectable / metastatic osteosarcoma are limited and medical needs are high.
J Orthop Sci. 2017;22:755-64 Ogura K et al.
TAS-115 has a unique kinase inhibition spectrum and high antitumor activity against osteosarcoma and bone metastasis.
Efficacy of TAS-115 for OsteosarcomaOsteosarcoma
• Bone sarcomas include osteosarcoma,chondrosarcoma, Ewing's sarcoma, and giantcell tumor of bone.
• The annual incidence of osteosarcoma inJapan is said to be 200 to 300. Many casesoccur in teens to 20s.
FEBS Open Bio. 2020;10:767-779. Yasuda N et al.
Control
TAS-115 50mg/kg
TAS-115 200mg/kg
day14day7 day21
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Phase 1 Study of TAS-115 in Patients with Osteosarcoma (20 cases)
In some cases, the treatment period with TAS-115 is longer than that of the previous treatment. We have started a Phase 3 study.
Naka N et al., The 2nd Annual Meeting of Japanese Association of Sarcoma Treatment and Research 2019, P3-3
Data cut-off date is Aug 19, 2018
Pre-TAS-115 treatment TAS-115 treatment period
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Phase 3 Study DesignR cohort
P cohort
≧15 years old Osteosarcoma Refractory or intolerance to MAP regimen or
similar ones Unable curative resection due to metastatic
lesion Primary lesion has been removed
completely
R
TAS-115
Placebo
target sample size:60
7-15 years old Osteosarcoma Refractory or intolerance to MAP regimen or
similar ones Unable curative resection due to metastatic
lesion Body weight is over 30 kg
TAS-115
TAS-115PD
JapicCTI-205335MAP: Methotrexate+Doxorubicin+CisplatinPD: Progressive Disease
Primary endpoint:Progression-free survival based on blinded central radiological review, Overall survivalExpected duration of study:June 2020 - June 2023
target sample size:6
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Agenda
R&D Activity SummaryMajor Progresses since “R&D Meeting” on Oct. 10, 2019Development PipelineOpen Innovation and Venture Investment
Development Pipeline UpdatesFutibatinib(TAS-120)TAS-115
Drug Discovery Research Updates Expansion of Cysteinomix (from Kinases to RAS Drug Discovery) Brain Metastasis Drug Discovery (Partnering with MD Anderson Cancer Center)
2015~SBDD/FBDD
2009~
Kinase Inhibitors2009~
Natural Product2014~
UFT TS-1 Lonsurf
ClinicalApproved
Nucleic Acids1993~
DNA-encoded Library
2016~
Brain MetastasisBrain Cancer
2017~
TAS-114
Technology Enabled Drug Discovery in Taiho
TAS0728TAS5315 TAS6417
TAS3681
TAS1440
TAS-116
TAS-117
TAS-119
TAS-115
RAS2012~2019~
Covalent BindersCysteinomix
2010~TAS-120
31
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Expansion of Cysteinomix~from Kinases to RAS Drug Discovery~
Copyright © Taiho Pharmaceutical Co., Ltd.
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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 to medium-sized molecules
• Covalent Binding DrugsDrugs that specifically capture reactive amino acid residues (ex. Cys) by forming covalent bonds
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MS Screening Assay
Target Cysteinome + covalent binder
Target CyseinomeIdentification of covalent binding adducts
• CysteinomixTaiho’s proprietary technology platform to identify drugs that specifically form a covalent bond with the target cysteinome
Covalent binder library
Target cysteinome
Cysteine
Cysteinomix Drug Discovery Platform
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Futibatinib:The World’s First Covalent FGFR Inhibitor
Futibatinib(TAS-120)
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 and aim to achieve early approval.
Figure 4B
FGFR: Fibroblast growth factor receptor
Cancer Discov. 2019;9:1064–79L. Goyal et al.
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Cysteinomix Drug Discovery Platform
• Cysteinome Identification PlatformProprietary technology for genome-wide screening of druggable Cysteinome
Cysteinome
Target Cysteinome
Genome Wide Search of Targetable Cysteinome
Experimentally Validate the Reactivity of Teget Cysin Cysteinome
Proc. Natl Acad. Sci. USA 2014; 111: 8895-8900. John C Hunter et al.
Drug Discov Today. 2018; 23: 727-735. Zheng Zhao et al.Nat Rev Drug Discov. 2012; 11: 384-400. Cheryl H Arrowsmith et al.
Disease related geneome(Kinome, Epigenome, GTPase family etc.)
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Cysteinomix Drug Discovery Targeting Small GTPase Family• Small GTPase family (160)• Protein kinase family (518)
The 188 kinases and 217 locations are shown in different colors and symbols
188518
29160
Proc. Natl Acad. Sci. USA 2014; 111: 8895-8900. John C Hunter et al.Drug Discov Today. 2018; 23: 727-735. Zheng Zhao et al.
Cysteinome Cysteinome
FGFR (TAS-120)
BTK (TAS5315)
EGFR exon20 (TAS6417)
HER2 (TAS0728)
KRAS G12C
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Drug Discovery Targeting RAS Oncogene
Mutant RAS driven cancers are high unmet medical needsFrequently mutated in deadly cancers (lung, pancreatic, colon, etc.)Remained as undruggable targets despite 30 years challengesInvolved in highly complicated intracellular protein-protein interactions
Normal Cancer
Nat Rev Cancer 2018, 18, 767–777. Li, S., Balmain, A. & Counter, C.M
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Oncogenic KRAS Mutations Are Highly Valuable Targets
Pancreatic
Colorectal
Adenocarcinoma
KRAS G12 mutation
Incidence of KRAS Mutations in Three Human Cancers
Percentages of KRAS mutations that are in codon 12 by tissue type for pancreatic, colorectal and lung adenocarcinoma
Nat Rev Drug Discov 2018; 19: 533–552. Amanda R. Moore et al.
Cancer Cell. 2014; 25: 272-281. Andrew G. Stephen et al.
HN CH C
CH2
O
SHCysteine
KRAS G12C
HN CH C
CH2
O
CO OAspartic acid
KRAS G12D KRAS G12V
HN CH C
CH
O
CH3H3CValine
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Cysteinomix Screening of KRAS G12C Covalent Binders
KRAS G12C(Cancer Cell)Target Cysteinome
KRAS G12C – Compound X
KRAS wild-type (Normal Cell)Off target
Discovery of covalent bindingKRAS modulators
High speed MS binding assay
Covalent binder library
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Strategic Oncology Collaboration Targeting KRAS Oncogene
41
News Release
2015~
Covalent BindersCysteinomix
2010~
SBDD/FBDD2009~
Kinase Inhibitors2009~
Natural Product2014~
UFT TS-1 Lonsurf
ClinicalApproved
Nucleic Acids1993~
DNA-encoded Library
2016~
Brain MetastasisBrain Cancer
2017~
TAS-114
Technology Enabled Drug Discovery in Taiho
TAS0728TAS-120 TAS5315 TAS6417
TAS3681
TAS1440
TAS-116
TAS-117
TAS-119
TAS-115
RAS2012~2019~
42
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Brain Metastasis and Brain Cancers
Copyright © Taiho Pharmaceutical Co., Ltd.
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Primary Site Occupancy(%)
Lung Cancer 50-60%Breast Cancer 20-30%
Melanoma 5-10%Gastric, Esophageal,
Prostate, Ovarian CancerIn total5-10%
Advance in Cancer Therapy Leads to Increased Brain Metastasis
Frequency of brain metastasis according to primary site
Newly diagnosed cases of brain metastases
US:200,000 patients/yearJapan:~80,000 patients/year
OA Mol Oncol. 2013;1(1) A Bollig-Fischer et al. NCCN Guidelines Version 3.2020 (Central Nervous System Cancers)Practical Guidelines for Neuro-Oncology 2019, The Japan Society for Neuro-Oncology
Metastatic Brain Tumor Brain CancersNewly diagnosed cases
US:23,890 patients/year
Prognosis and Treatment(Glioblastoma )• Glioblastoma is an almost incurable
disease with a median survival of14.6 months, even in patients whocan be treated with standardtreatment.
• Treatment for glioblastoma islimited to temozolomide andbevacizumab.
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Our Strategy to Tackle Brain Metastasis
Pioneering Basic and Clinical Brain Metastasis Research
Research Collaboration withMD Anderson Cancer Center
Drug Discovery PlatformsTargeting Brain Metastasis
Discovery BrainPenetrant Compounds
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Research Collaboration with MD Anderson Cancer Center
Taiho Pharma News Releaseon Sep. 24, 2020