PEVONEDISTAT (TAK-924): A POTENTIAL NEW
TREATMENT FOR HR-MDS AND AML
Phil Rowlands, PhD
Head Oncology Therapeutic Area Unit
Takeda Pharmaceutical Company Limited
New York, NY
November 14, 2019
BUILDING ON THE TAKEDA ONCOLOGY FOUNDATION IN
HEMATOLOGIC MALIGNANCIES
Cell therapies
Next Generation Type I IFN
I/O Novel checkpoints
GROWING MDS/AML
LEADERSHIP Phase 3
POSITION IN pevonedistat
HEMATOLOGIC
MALIGNANCIES
Lymphoma Chronic Myeloid Leukemia
Improving Patient Outcomes
in Multiple Myeloma
79
HIGH RISK MYELODYSPLASTIC SYNDROME (HR-MDS) AND ACUTE
MYELOID LEUKEMIA (AML) HAVE LIMITED TREATMENT OPTIONS
CONTINUUM OF HR-MDS AND AML CLINICAL TREATMENT
BM failure → cytopenias Clinical treatment goals:
Blasts • Fatigue (anemia) Alleviate cytopenias
20% 30% • Infection (neutropenia) Improve patient quality of life
• Bleeding (thrombocytopenia) Improve survival
HR MDS AML
Low-Blast AML
Fit Younger Unfit Older
Fewer co-morbidities Unfit for intensive chemotherapy
• HR-MDS and AML are both rare bone marrow- Patients Better performance status Patients and/or stem cell transplant
related cancers that share foundational
biology, clinical features, and genetic Intensive Chemotherapy Chemotherapy
mutations* azacitidine
decitabine
Low dose ara-c
• Incidence highest in elderly (>70 years old) Targeted therapies
(AML only)
BCL2
• Overall survival several months to a few years, IDH1/2
depending on risk category Stem Cell Transplant FLT3
(Only curative treatment)
≤ 10% HR-MDS, ~45% AML
80
* 30% of HR-MDS patients progress to AML
CURRENT STANDARD OF CARE IS INADEQUATE FOR HR-MDS PATIENTS
MDS SURVIVAL BY PROGNOSTIC RISK
• No new treatments have been
approved for MDS in over a decade
Transplant ineligible patients
Survival (probability)
•
treated with first line therapy:
Median OS = 15mo; 2yr OS rate 35%
• Economic burden is substantial -
hospitalizations are common among
patients and many are transfusion
dependent
Time (months)
Schanz et al., J Clin Oncol. 2012, 30:820-829
Median survival ~6 months to 5 years
81
PEVONEDISTAT: A UNIQUE FIRST-IN-CLASS NAE INHIBITOR
• Pevonedistat is a small molecule
inhibitor of NAE (NEDD-8 activating
enzyme), a protein involved in the
ubiquitin-proteasome system
• NAE acts upstream of the
proteasome and catalyzes the first
step in the neddylation pathway
Amir T. Fathi Blood 2018;131:1391-1392
82
ENCOURAGING RESPONSES IN AML PATIENTS TREATED WITH
PEOVNEDISTAT + AZACITIDINE
60% ORR with a trend towards
improved survival in secondary AML
Response rates not influenced by AML
genetic risk or leukemia burden
Initial data drove interest to move to
registration
Ronan T Swords et al. Blood 2016;128:98
83
A PHASE 2 STUDY IN HR-MDS TO CONFIRM THE RISK / BENEFIT
PROFILE OBSERVED IN AML
Phase 2, Randomized, Open-label, Global, Multicenter Study
Comparing Pevonedistat Plus Azacitidine vs. Azacitidine in Patients
with Higher-Risk MDS, CMML, or Low-Blast AML
• Mature OS data will be
n = 117 available in November
Pevonedistat + Azacitidine
Randomization
Pevo: 20 mg/m2 on Days 1, 3, 5
Aza: 75 mg/m2 on Days 1-5 ,8, 9
• Data will be presented in
1:1 Repeat every 28 days
upcoming congress
Azacitidine
Aza: 75 mg/m2 on Days 1-5, 8, 9
• Potential approval in FY21*
Primary endpoint: Secondary endpoints:
OS EFS
ORR
84
* Projected approval date assumes filing on Phase 2 data
THE PHASE 3 PANTHER STUDY WAS INITIATED AT RISK TO
ACCELERATE DEVELOPMENT
Phase 3, Randomized controlled trial of Pevonedistat Plus Azacitidine
Versus Single-Agent Azacitidine as First-Line Treatment for Patients
with Higher risk-MDS/CMML, or Low-blast AML
n = 450
• Completed global enrollment
Pevonedistat + Azacitidine
10 months earlier than
Randomization
Pevo: 20 mg/m2 on Days 1, 3, 5
Aza: 75 mg/m2 Days 1-5 ,8, 9
originally projected*
1:1 Repeat every 28 days
Azacitidine • Indicative of demand for new
Aza: 75 mg/m2 Days 1-5, 8, 9
innovative therapies
Primary endpoint: Secondary endpoints:
EFS OS
* Closed to global enrollment; Open for extended enrollment in China 85
EXPANDING PATIENT-CENTRIC DEVELOPMENT OF PEVONEDISTAT
Continuum of disease
HR-MDS NEW STUDIES IN UNFIT AML
Ph2 (P2001) Ph3 (P3001)
Ph3 PEVOLAM Utilizing partnership
Potential
approval in FY21* pevo + aza vs. aza (PETHEMA) for
Currently enrolling patients efficient development
Ph2 (P2002) Combo
Unique MOA and
pevo + venetoclax + aza vs. biologic hypothesis to
venetoclax + aza support combination
Study will open in 2020
86
* Projected approval date assumes filing on Phase 2 data
SUMMARY
1 2 3
Unmet need in High- Pevonedistat is a The Ph2 HR-MDS trial
risk MDS and AML selective first-in-class has reached the
remain high with few inhibitor with updated OS endpoint
treatment options potential to be first data readout and the
new therapy in over PANTHER Ph3 trial
a decade for HR-MDS has completed global
enrollment
87
R&D DAY AGENDA – NEW YORK, NOVEMBER 14, 2019
TIME AGENDA
Welcome and Opening Remarks
12:30 – 12:35
Sheelagh Cawley-Knopf, Head R&D Global Portfolio Strategy
Takeda: A Global Values-Based, R&D-Driven Biopharmaceutical Leader
12:35 – 12:45
Christophe Weber, President & CEO Takeda
Translating Science into Highly Innovative, Life-changing Medicines
12:45 – 13:20
Andy Plump, President R&D
Oncology and Cell Therapies with Spotlight on CAR-NK
13:20 – 13:45
Chris Arendt, Head Oncology Drug Discovery Unit
Spotlight on Oncology Opportunities
13:45 – 14:05 • TAK-788 : Rachael Brake, Global Program Lead
• Pevonedistat : Phil Rowlands, Head Oncology Therapeutic Area Unit
14:05 – 14:20 Break
Rare Diseases & Gene Therapy
14:20 – 14:45
Dan Curran, Head Rare Disease Therapeutic Area Unit
Spotlight on Orexin2R agonists
14:45 – 15:00
Deborah Hartman, Global Program Lead
Therapeutic Area Focus in GI with Spotlight on Celiac Disease
15:00 – 15:20
Asit Parikh, Head GI Therapeutic Area Unit
15:20 – 16:00 Panel Q&A Session
16:00 Drinks reception
88
RARE DISEASES & GENE THERAPY
Dan Curran, MD
Head Rare Diseases Therapeutic Area Unit
Takeda Pharmaceutical Company Limited
New York, NY
November 14, 2019
RARE DISEASES: AN OPPORTUNITY TO TRANSFORM TREATMENT
HIGH UNMET NEED SCIENTIFIC AND REGULATORY ADVANCES
Diseases are genetic
7,000 Distinct rare diseases1 80% in origin
Recombinant
350 Transformative engineering & delivery
Patients worldwide
million therapies of proteins and nucleic
acids
Diseases have no FDA-approved ~90%2 Orphan drug approvals
95% treatment
benefited from
100%3 expedited review
1. Rare diseases defined by prevalence in line with regulatory agencies (US: <7 in 10,000, EU: < 5 in 10,000 and JPN: <4 in 10,000), Global Genes, NIH National Human Genome Research Institute; 2. Comprises four pathways in US:
Accelerated approval, breakthrough therapy designation, fast track designation, priority review designation; 3. Three pathways in JPN: Priority review, Sakigake designation and conditional approval, CIRS R&D Briefing 70, New drug 90
approvals in six major authorities 2009-2018
RARE DISEASE MARKET IS EXPECTED TO DOUBLE IN SIZE
GLOBAL ORPHAN DRUG1 SALES EXCLUDING ONCOLOGY2, USD BN
% share of global, branded Rx sales
7% 11% 17% • Orphan drugs expected to make
124 up ~17% of global branded Rx
sales by 2024
12%
• Growth driven by advances in new
CAGR
modalities and new indications
62
9% • Orphan cell and gene therapies
37 CAGR estimated at ~$20 bn by 2024, up
from ~$2bn in 2018
2012 2018 2024
91
1. Orphan drugs generally used as synonym for rare disease due to lack of uniform definition, including also non-rare, but neglected diseases lacking therapy (e.g., tropical infectious diseases); 2. EvaluatePharma (03 June 2019)
TAKEDA IS THE LEADER IN RARE DISEASES
PATIENT IMPACT SCIENCE & INNOVATION CAPABILITIES AND SCALE
• Foundation of >30 year history • Multiple opportunities for • Engagement with key
of leadership in rare diseases transformational therapies stakeholders within the
across therapeutic areas ecosystem e.g. patient groups,
• Leading portfolio of rare
regulators
disease therapies: 11 out of 14 • Emerging, cutting edge
global brands spanning platforms to drive high-impact • Pioneering regulatory pathways
Hematology, Metabolic, GI and pipeline
• Global footprint
Immunology
• Investments in technologies to
accelerate diagnosis
92
OUR STRATEGY IS TO TRANSFORM AND CURE RARE DISEASES
As the global leader in Rare Diseases, we aspire to provide
transformative and curative treatments to our patients
Transformative Curative
Programs with transformative Emerging early pipeline of AAV
potential in devastating gene therapies to redefine
disorders with limited or no treatment paradigm in
treatment options today monogenic rare diseases
93
WE ARE POSITIONED TO DELIVER NEAR-TERM & SUSTAINED GROWTH
WAVE 11 WAVE 22
TARGET CLINICAL-STAGE NMEs PLATFORMS
APPROVAL FY20 FY21 FY22 FY23 FY24 FY25 AND BEYOND
TAK-007
TAK-620 TAK-607
TAK-7883 TAK-924 TAK-164 CMV infect. in
TAK-252
Hematologic GI malignancies Solid tumors Complications of
TARGETED
2L NSCLC malignancies AML
transplant CELL THERAPY
prematurity5
INNATE NEXT-GEN
ONCOLOGY AND IMMUNE
ENGAGERS IMMUNE
CHECKPOINT
TAK-9243 TAK-788 TAK-573 TAK-981 MODULATION MODULATORS
HR-MDS 1L NSCLC R/R MM Multiple cancers
TAK-620 TAK-611 TAK-607 TAK-0794 TAK-754 TAK-755
CMV infect. in MLD (IT) Complications of MG, ITP HemA iTTP, SCD
Immunology
RARE Hematology
transplant prematurity5 GENE
TAK-755
THERAPY
DISEASES Metabolic
TAK-609 TAK-755 TAK-531 cTTP
Hunter CNS (IT) cTTP Hunter CNS
TAK-935 Orexin2R-ag TAK-341 Orexin2R-ag TAK-041
DEE (TAK-925/994) Parkinson’s Sleep Disorders CIAS NS OTHER
Narcolepsy T1 Disease GENE PLATFORMS
THERAPY RNA Modulation
NEUROSCIENCE TAK-418 TAK-653 TAK-831 Orexin2R-ag
Antibody Transport
Vehicle
Kabuki Syndrome TRD CIAS NS (TAK-925/994)
WVE-120101 WVE-120102
Narcolepsy T1
Huntington’s Huntington’s
Disease Disease
TAK-721 Kuma062 TAK-101 TAK-018 TAK-671
EoE Celiac Disease Celiac Disease Crohn’s Disease Acute
GASTRO- TAK-721 (post-op and ileitis) Pancreatitis GENE
THERAPY
MICROBIOME
CELL
THERAPY
ENTEROLOGY TAK-954 EoE
TAK-906 TAK-951
POGD Gastroparesis Nausea &
vomiting
TAK-003 TAK-214 TAK-426 TAK-021
VACCINES Dengue Vaccine Norovirus Zika Vaccine EV71 vaccine
Vaccine
1. Projected timing of approvals depending on data read-outs; some of these Wave 1 target approval dates assume accelerated approval; 2. Some Wave 2 assets could be Orphan potential in at least one indication
accelerated into Wave 1 if they have breakthrough data; 3. Projected approval date assumes filing on Phase 2 data; 4. TAK-079 to be developed in Rare Diseases indications 94
Estimated dates as of November 14, 2019
myasthenia gravis (MG) and immune thrombocytopenic purpura (ITP) (FPI projected in each indication in 2H FY19); 5. Currently in a non-pivotal Phase 2 study; planning
underway to include interim stage gates that can advance the program into a pivotal trial
POTENTIAL APPROVALS OF TRANSFORMATIVE THERAPIES
WAVE 11
Phase 3 Phase 3 Phase 3 Phase 2 Phase 2 Phase 1/2 Phase 2b
TAK-721 TAK-620 TAK-755 TAK-611 TAK-935 Orexin TAK-607
Eosinophilic Cytomegalovirus Congenital Metachromatic Developmental Narcolepsy Type 1 Complications of
Esophagitis (CMV) infection Thrombotic Leukodystrophy and Epileptic (NT1) Prematurity2
(EoE) in transplant Thrombocytopenic (MLD) Encephalopathies
Purpura (cTTP) (DEE)
TARGET APPROVAL POSSIBLE
WAVE 1
FY 2020 FY 2021 FY 2023 FY 2023 FY 2023 FY 2024 APPROVAL2
ADDRESSABLE POPULATION IN US/WW3,4
~150k/Under ~7 - 15k/ ~500/ ~350/ ~50k/ 70 - 140k/ ~25k/
evaluation ~25 - 45k 2 - 6k ~1 - 2k ~70 - 90k 300k – 1.2M ~80 - 90k
1. Projected timing of approvals depending on data read-outs; some Wave 1 target approval dates assume accelerated approval
2. Currently in a non-pivotal Phase 2 study; planning underway to include interim stage gates that can advance the program into a pivotal trial 95
3. Estimated number of patients projected to be eligible for treatment, in markets where the product is anticipated to be commercialized, subject to regulatory approval
4. For TAK-620 and TAK-607, the addressable population represents annual incidence
SELECTED TRANSFORMATIVE PROGRAMS
Potential first treatment of CMV infection in transplant patients in over 10 years.
TAK-620
Inhibitor of protein kinase UL97.
Potential best-in-class therapy for Thrombotic Thrombocytopenic Purpura (TTP).
TAK-755
Recombinant ADAMTS13.
Potential first pharmacologic therapy in >20 years to prevent complications of
TAK-607
prematurity. Recombinant IGF-1 growth factor.
96
TAK-620: POTENTIAL BEST IN CLASS TREATMENT FOR POST-
TRANSPLANT CMV INFECTION
BURDEN OF CMV INFECTION IN TRANSPLANT RECIPIENTS TAK-620: NOVEL MOA TARGETING PROTEIN KINASE UL97
CMV infection is the most common 1
post-transplant viral infection1
2
Affects >25% of transplants
4 5
CMV infection can be fatal2,3
Higher rates of graft failure: 2.3X and
mortality: 2.6X
3
Current therapies have significant toxicities
and resistance4,5,6,7 TAK-620
Existing therapies
3 Replication
3 Replication
Incidence of neutropenia >20% and renal 4 Maturation and encapsidation
toxicity >50% 5 Egress of viral capsids
1. Minerva Med. 2009 Dec; 100(6): 479-501; 2. Blood. 2016 May 19;127(20):2427-38; 3. Infect Chemother. 2013 Sep; 45(3): 260–271; 4. Antimicrob Agents Chemother. 2014 Jan; 58(1): 128–135;
97
5. Transplantation. 2016 Oct;100(10):e74-80;. 6. Clin Microbiol Infect. 2015 Dec;21(12):1121.e9-15; 7. Clin Transplant 2009: 23: 295–304
TAK-620: ADDRESSES UNMET NEED IN BOTH FIRST-LINE AND
RESISTANT / REFRACTORY SETTING
CMV Failure
Viremia First-Line: Newly First-Line Resistant/
Transplant treatment
diagnosed CMV Refractory (R/R) CMV
TAK-620: Ph 3 Study 303
Solid organ
~100K ~30K ~5K
transplant (SOT)
patients1,2:
TAK-620: Ph 3 Study 302
Hematopoietic Stem
Cell Transplants ~90K ~15K ~5K
(HSCT) patients1,2:
CMV 10K
NON-CMV 5K 98
1. Solid organ and allogeneic HSCT transplants in global major markets: US, Europe, Canada, Japan, China , Australia and Korea 2. UNOS Data 2018; CIBMR2017IRODaT Registry 2017, EBMT activity survey 2019 , Shire CMV Epi Study, Feb. 2018
TAK-620 DEMONSTRATED SIMILAR EFFICACY AND BETTER SAFETY
VERSUS SOC IN A PHASE 2 STUDY IN FIRST-LINE PATIENTS
DEMONSTRATED SIMILAR ANTI-VIRAL ACTIVITY TO NEUTROPENIA WAS TREATED WITH GROWTH FACTORS MORE
VALGANCICLOVIR (VGV) ACROSS ALL DOSES1 OFTEN IN THE VGV ARM (15%) VS. TAK-620 ARM (7%)2
TAK-620: TAK-620:
Dose 400, 800 or 1200 mg BID2 VGV Dose 400, 800 or 1200 mg BID VGV
(N=40) (N=40)
All Doses (N=119) All Doses (N=119)
Confirmed Neutropenia that
undetectable occurred or worsened
plasma CMV DNA 79% 67% during treatment 5% 18%
within 6 weeks through week 12
1. Confirmed undetectable CMV DNA in plasma was defined as two consecutive CMV DNA polymerase-chain-reaction assay values measure during treatment that were below the level of quantitation (i.e., <200 copies per millimeter
according to the central laboratory) separated by at least 5 days. For the primary analyses of confirmed undetectable CMV DNA within 3 weeks and 6 weeks, data were missing for 3 patients: 1 each in the 400-mg TAK-620 group, the
1200-mg TAK-620 group and the valganciclovir group 99
2. N Engl J Med 2019; 381:1136-47. Overall risk ratio (95% CI) relative to the Valganciclovir reference was 1.20 (0.95-1.51)
TAK-620: GRANTED BREAKTHROUGH DESIGNATION IN RESISTANT
OR REFRACTORY CMV INFECTION
Efficacy in seriously ill R/R CMV in SOT and HSCT recipients with
1 multiple risk factors predictive of poor outcomes
TAK-620 Dose: 400 mg, 800 mg, 1200 mg BID1
Primary efficacy endpoint All doses (Total N = 120) Historical outcomes: High (~50%) failure
Patients with confirmed undetectable rates / relapse rates3,4,5
80
plasma CMV DNA within 6 weeks in
(66.7%)
ITT2 population
Superior renal safety profile - did not result in treatment Renal impairment is the primary reason
2 discontinuations for discontinuation with SOC (Foscarnet,
Cidovir); nephrotoxicity is > 50%6
1. Clin Infect Dis. 2019 Apr 8;68(8):1255-1264; 2. ITT - Intent to treat; 3. Antimicrob Agents Chemother, 58, 128-35; 4. Mehta et al, 2016 American Transplant Congress, Meeting abstract C279; 5. J Heart Lung Transplant. 2019 Sep 10; 100
6. Transplantation. 2016 Oct; 100(10): e74–e80
TAK-620: TWO ONGOING PIVOTAL STUDIES; EXPECT FIRST
APPROVAL IN RESISTANT OR REFRACTORY CMV IN 2021
TAK-620 PHASE 3 STUDY 303 TAK-620 PHASE 3 STUDY 302
Resistant/Refractory CMV Patients with SOT or HSCT HSCT Recipients With First CMV Infection
2:1 Randomization 1:1 Randomization
TAK-620 400mg BID Investigator's choice TAK-620 400mg BID 900mg BID VGV
(N=234) (N=117) (N=275) (N=275)
Primary Endpoint: Viremia @ 8 wks of Rx Primary Endpoint: Viremia @ 8 wks of Rx
EXPECTED EXPECTED
2020 2021 2022 2021 2022
MILESTONES (FY) MILESTONES (FY)
2H 2020: 2021: 2022: 1H 2021: US Approval
Ph 3 Readout US Approval EU Approval Ph 3 Readout EU Approval
101
SELECTED TRANSFORMATIVE PROGRAMS
Potential first treatment of CMV infection in transplant patients in over 10 years.
TAK-620
Inhibitor of protein kinase UL97.
Potential best-in-class therapy for Thrombotic Thrombocytopenic Purpura (TTP).
TAK-755
Recombinant ADAMTS13.
Potential first pharmacologic therapy in >20 years to prevent complications of
TAK-607
prematurity. Recombinant IGF-1 growth factor.
102
CONGENITAL AND IMMUNE TTP HAVE SUBSTANTIAL MORTALITY
AND MORBIDITY BURDEN DUE TO INADEQUATE SOC
CONGENITAL TTP (cTTP)
• Sub-therapeutic dose with plasma infusions
• Patients still experience ischemic injury of brain,
kidneys and heart
• Poor long-term outcomes
IMMUNE TTP (iTTP)
• ~30% relapse rate with plasma exchange (PEX)
• New market entrant reduces relapse rate, but has ADDRESSABLE POPULATION
significant limitations3,4 (WW)1,2
– Enhanced risk of bleeding: cTTP 2,000 – 6,000
Gingival bleeding 18% vs. 1% placebo iTTP 5,000 – 18,000
Epistaxis 32% vs. 3% placebo
103
1. Global major markets: US, Europe, Canada, JPN, and Global Emerging Markets; 2. Haematologica September 2010 95: 1444-1447; 3. N Engl J Med 2019;380:335-46.; 4. N Engl J Med 2016; 374:511-522
TAK-755 DIRECTLY ADDRESSES UNDERLYING CAUSE OF TTP
TAK-755 REPLACES ADAMTS13, DEFICIENCY OF WHICH LEADS TO TTP
Platelet Von Willebrand Factor (VWF)
Normal ADAMTS13:
clotting Cleaves VWF multimers that mediate
cascade platelet aggregation and clotting
Blood vessel
ADAMTS13 deficiency:
TTP Formation of microthrombi due to
accumulation of large VWF multimers
104
TAK-755: POTENTIAL TRANSFORMATIVE THERAPY FOR TTP
TAK-755 PHASE I, OPEN-LABEL, DOSE TAK-755 PK PROFILE AND PD EFFECT ON
ESCALATION STUDY IN cTTP1 VWF CLEAVAGE AT 40 IU/KG
100% Mean FRETS ADAMTS13 Activity 100%
176 kDa VWF Cleavage Product
90% 90%
• Administered as a single dose
VWF Cleavage Product (%)
ADAMTS13 Activity2 (%)
80% 80%
in 15 cTTP patients TTP diagnosis requires
70% confirmation of 70%
60% ADAMTS13 activity <10% 60%
• TAK-755 was well tolerated 50% 50%
40% 40%
• No anti-ADAMTS13 30% 30%
antibodies detected 20% 20%
10% 10%
0% 0%
0 24 48 72 96 120 144 168 192 216 240 264 288
Time (hours)
105
1. Blood 2017; vol. 130, number 19, 2055-63; 2. Measured using FRETS (fluorescence resonance energy transfer)
TAK-755: ONGOING PHASE 3 CONGENITAL TTP STUDY
TAK-755 PHASE 3 PROPHYLAXIS STUDY
cTTP patients
(N = 26 – 42)
1:1 Randomization
• All patients roll over to a 6 month TAK-755
extension
TAK-755 40 IU/kg
SOC
Every other week1 • Phase 3 study has a cohort of acute cTTP
Tx duration: 6 months patients who receive TAK755. Patients are
eligible to enter the prophylaxis study upon
TAK-755 40 IU/kg completion of acute treatment
SOC
Every other week
Tx duration: 6 months
Primary Endpoint:
Incidence of acute TTP episodes
EXPECTED 2019 2021 2023 2025
MILESTONES (FY) 1H: Ph 3 initiated 2H: Ph 3 Readout US Approval EU Approval2
106
1. A single dose modification to 1x/week may be mandated based on clinical outcomes; 2. Plan to seek deferral of pediatric data requirement in EU for initial filing, which would enable possible approval in EU in 2023
TAK-755 IMMUNE TTP PHASE 2 STUDY DESIGN
Primary or relapse acute iTTP episode (N=30)
PEX Day 1
1:1:1 Randomization
Placebo TAK-755 Low dose TAK-755 High dose
+ + +
SOC SOC SOC
Remission Phase
Placebo or TAK-755
Primary endpoints: PK/PD
EXPECTED 2020 2021 2023 2025
MILESTONES (FY) 2H: Ph 2 Readout 2H: Ph 3 Start 2H: Ph3 Readout US/EU Approval 107
SELECTED TRANSFORMATIVE PROGRAMS
Potential first treatment of CMV infection in transplant patients in over 10 years.
TAK-620
Inhibitor of protein kinase UL97.
Potential best-in-class therapy for Thrombotic Thrombocytopenic Purpura (TTP).
TAK-755
Recombinant ADAMTS13.
Potential first pharmacologic therapy in >20 years to prevent complications of
TAK-607
prematurity. Recombinant IGF-1 growth factor.
108
EXTREMELY PREMATURE INFANTS EXPERIENCE CONSIDERABLE
MORBIDITY
~80,000-90,000 0 Therapies
Extremely preterm for prevention of
babies (<28 wks complications of
gestational age) born prematurity
WW2,3
~40% have lung ~$200,000
Morbidity (%) by birth year, US data1
complications hospitalization
100%
Bronchopulmonary dysplasia (BPD)
in addition to costs per infant 4
80% morbidities in brain,
Severe intraventricular hemorrhage (IVH)
60% eye that adversely impact
40% development and learning
20%
0%
1992 1996 2000 2004 2008 2012
109
1. Stoll B, JAMA, 2015;314(10): 1039–1051; 2. CDC; 3. UN data and published sources; 4. Mowitz M et al. Co-occurrence and Burden of Complications of Prematurity Among Extremely Preterm Infants in the US AAP 2017 Poster 76
TAK-607 REPLENISHES IGF-1, A FETAL GROWTH FACTOR THAT IS
DECREASED IN PRETERM INFANTS
TAK-607: IGF-1 / IGFBP-31 COMPLEX IGF-1 LEVELS ARE LOW IN PRETERM INFANTS2
• IGF-1 is an important fetal growth factor
supplied by the mother that is involved in the IGF-1 in normal in utero fetus
IGF-1 in preterm infants
development of multiple organs
Mean predicted value
Upper prediction interval (95th)
• IGF-1 is low or absent in premature infants
Lower prediction interval (5th)
born before 28 weeks2
• TAK-607 demonstrated beneficial effects in
lung development and brain vasculature in
preclinical models3,4
1. Recombinant insulin-like growth factor 1 (rIGF-1), IGFBP-3- IGF binding protein-3; 2. Hellstrom et al., Acta Pædiatrica 2016 105, pp. 576–586; 3. Seedorf G et al. EAPS. Geneva 2016 (manuscript in preparation)
110
4. Ley D et al. jENS 2019
TAK-607: PHASE 2 STUDY INFORMED DOSE AND
ENDPOINT SELECTION
ROP-2008-01: RANDOMIZED, CONTROLLED PHASE 2 STUDY OF TAK-607 TAK-607 IMPACTED BPD AND IVH2
• Pre-term infants with a gestational age (GA) <28 weeks (N = 120) 100 Standard of care
IGF-1/IGFBP-3
• Assessed outcomes in ITT and “evaluable” sets (40% patients 80
Number of infants %
who achieved target exposure of IGF-1 levels)1
(evaluable set2)
60 55%
• Primary endpoint: ROP not met
40
• Pre-specified secondary endpoints: Bronchopulmonary 29%
Dysplasia (BPD) was reduced and Intra-Ventricular 23%
20
Hemorrhage (IVH) showed a positive trend 8%
• Granted FDA fast-track designation 0
BPD (Moderate IVH (Grade 3-4)
and Severe)
1. Evaluable set: ≥70% IGF-1 measurements within targeted intrauterine range (28‒109 µg/L) AND ≥70% intended duration of treatment 111
2. Ley D, J Pediatrics, 2018
ROP – retinopathy of prematurity
TAK-607: FOOTPRINTS STUDY DESIGNED TO DEMONSTRATE
REDUCTION IN THE COMPLICATIONS OF PREMATURITY
Open label, 1:1:1 Randomization Treatment Post Treatment
(N = 200/arm) (2-7 wks based on GA) Follow-up period
TAK-607 250 μg/kg/24 h Rx: Day 1 Rx End: 29 wk + Primary endpoint:
continuous IV 6 d PMA 12 months corrected age
Premature
TAK-607 400 μg/kg/24 h
infants:
continuous IV
<28 weeks GA
Outpatient: Respiratory
Standard Neonatal Care morbidity assessments/week
Primary endpoint: Duration of supplemental oxygen use through 1 year corrected age1
EXPECTED 2019 2023
MILESTONES (FY) 1H: Ph 2b initiated 1H: Ph 2b Readout
112
1. Supplemental oxygen use defined by one of the following: a) Any fraction of inspired oxygen (FiO2) >21%, b) Non-invasive respiratory support delivered via a nasal interface (e.g., continuous positive airway pressure [CPAP], nasal
cannula, etc.), c) Invasive respiratory support (mechanical ventilation) via an endotracheal tube or tracheostomy
NME MILESTONES ACHIEVED IN FY19 AND LOOKING AHEAD TO
OTHER POTENTIAL MILESTONES1 THROUGH FY20
PIVOTAL STUDY STARTS, APPROVALS
MLD PEVONEDISTAT AML EoE
TAK-611
Ph 2 start2 TAK-924 Ph 3 start
TAK-721
Approval
cTTP 1L NSCLC Huntington’s Disease
TAK-755
Ph 3 start
TAK-788
Ph 3 start
mHTT ASO
Pivotal start
1H FY 2019 2H FY 2019 1H FY 2020 2H FY 2020
Narcolepsy PEVONEDISTAT HR-MDS 2L NSCLC
TAK-925
POC TAK-924 Ph 2 Overall Survival
TAK-788
Ph 2 Pivotal
TAK-620
R/R CMV SOT & HSCT
Ph 3 data
TAK-721
EoE
Ph 3 data (induction) TAK-007
Hem. Malignancies
POC
TAK-573
R/R MM, Solid Tumor
POC
TAK-755
iTTP
POC
Celiac Disease Hunter (IT) DEE
TAK-101
POC
TAK-609
Ph 3 data 2yr extension
TAK-935
POC
Huntington’s Disease Gastroparesis
mHTT ASO TAK-906
POC POC
EoE Nausea & Vomiting
TAK-721 TAK-951
Ph 3 data (maintenance) POC
Oncology
Rare Disease
Neuroscience
Gastroenterology
Denotes milestones that have been achieved.
KEY DATA READOUTS
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1. Potential key milestone dates as of November 14, 2019. The dates included herein are estimates based on current data and are subject to change
2. Potentially registration enabling
WE AIM TO PROVIDE CURATIVE THERAPY
As the global leader in Rare Diseases, we aspire to provide
transformative and curative treatments to our patients
Transformative Curative
Programs with transformative Emerging early pipeline of AAV
potential in devastating gene therapies to redefine
disorders with limited or no treatment paradigm in
treatment options today monogenic rare diseases
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BUILDING A WORLD CLASS GENE THERAPY ‘ENGINE’
TOP TIER GMP GENE THERAPY GENE THERAPY
MANUFACTURING AAV1 PLATFORM PIPELINE
TAKEDA THERAPEUTIC AREAS
Preclinical Clinical
Development Development
Liver expression
3+ Research NextGen TAK-748 TAK-754
• Strong capabilities Candidates Hem A Hem B Hem A
in liver expression
• Emerging
capabilities in CNS expression
CNS expression StrideBio StrideBio TAK-686
Research Friedreich Huntington’s
Candidate Ataxia Disease
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1. Adeno-Associated Virus
WE WILL APPLY OUR CELL THERAPY PLAYBOOK AND UNIFYING
CAPABILITIES TO BUILD A GENE THERAPY PIPELINE
Select Cell Therapy Cell To Gene Therapy
Partnerships/Acquisitions
Unifying Capabilities
• Viral expertise
• Manufacturing
Acquisition
2016 2017 2018 2019 2020 2021 2022+
Focus of Future Gene Therapy Partnerships
1. Enable re-dosing
Deliver protective Capsids to enhance
or regenerative biodistribution in
Gene Therapy factors to CNS
Platform hepatocytes 2. Lower dose and enhance biodistribution
Acquisition
AAV tool box and
manufacturing platform 3. Develop alternative gene delivery vehicles
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SUMMARY
1 2 3
Takeda has the We have a leading late We are building cutting -
capabilities, scale, and stage portfolio of edge capabilities in gene
innovative platforms to transformative programs therapy that aim to
extend our leadership in that will establish or deliver ‘cures’ in
Rare Diseases re-define the standard of monogenic rare diseases
care for highly
underserved patients
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R&D DAY AGENDA – NEW YORK, NOVEMBER 14, 2019
TIME AGENDA
Welcome and Opening Remarks
12:30 – 12:35
Sheelagh Cawley-Knopf, Head R&D Global Portfolio Strategy
Takeda: A Global Values-Based, R&D-Driven Biopharmaceutical Leader
12:35 – 12:45
Christophe Weber, President & CEO Takeda
Translating Science into Highly Innovative, Life-changing Medicines
12:45 – 13:20
Andy Plump, President R&D
Oncology and Cell Therapies with Spotlight on CAR-NK
13:20 – 13:45
Chris Arendt, Head Oncology Drug Discovery Unit
Spotlight on Oncology Opportunities
13:45 – 14:05 • TAK-788 : Rachael Brake, Global Program Lead
• Pevonedistat : Phil Rowlands, Head Oncology Therapeutic Area Unit
14:05 – 14:20 Break
Rare Diseases & Gene Therapy
14:20 – 14:45
Dan Curran, Head Rare Disease Therapeutic Area Unit
Spotlight on Orexin2R agonists
14:45 – 15:00
Deborah Hartman, Global Program Lead
Therapeutic Area Focus in GI with Spotlight on Celiac Disease
15:00 – 15:20
Asit Parikh, Head GI Therapeutic Area Unit
15:20 – 16:00 Panel Q&A Session
16:00 Drinks reception
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