Development Forum
2014
Kyowa Hakko Kirin Co., Ltd.
October 2, 2014
2014年10月2
Agenda
Topic
p 1. R&D framework for implementation
p
of category
g y strategy
gy
Managing Executive Officer, Vice President, Head, R&D Division
Yoichi Sato
Topic 2. Kyowa Hakko Kirin’s potential in cancer immunotherapy
Director, Oncology R&D Unit, R&D Division
Masamichi Koike
Q&A session
2
Topic 1.R&D framework for implementation of
category
g y strategy
gy
3
FY2013-2015 Medium-term business plan progress
Steady progress towards becoming GSP* under three basic strategies.
1.
Further strengthen competitiveness in Japan through our category-based strategy
Strengthened category-based strategy function:
Reorganization of R&D Division
Strengthen category product capabilities:
Oncology: Application for expansion of indications for anti-CCR4 antibody KW-0761
p
gy Approval
pp
of renal anemia treatment NESP® for p
pediatric p
patients
Nephrology:
®
Nephrology: Launch of Onglyza tablets for Type 2 Diabetes
Central nervous system: Launched NOURIAST®, an antiparkinsonian agent
2 Expand our business base in the U.S.,
2.
U S EU and Asia and aim to become a global
specialty pharmaceutical company
Global development through ODDO**
Progress with late-stage development of KW-0761 in Europe and the U.S.
Began Phase 3 studies on KW-6002 in Europe and the U.S.
Developed KRN23 with Ultragenyx, announced sales partnership
3. Strengthen the revenue base of our Bio-Chemicals business
Expansion
E
i off overseas production
d ti facilities,
f iliti
progress with
ith iinitiatives
iti ti
tto consolidate
lid t
domestic production facilities
*Global Specialty Pharmaceutical Company
**One Drug Development Organization
4
Purpose of R&D Division reorganization
Advance Kyowa Hakko Kirin’s category-based strategy,
one of the fundamental strategies of the medium-term plan
plan,
and enhance the productivity of R&D activities
The internal and external environment is rapidly changing
[Industry]
Decline in success rates of new drug R&D
[Policy]
Strengthening of medical cost curtailment policies
following increase in national medical expenditure
[Internal]
Weakening of early stage product pipeline
Essential tasks
•Conduct drug discovery based on understanding the unmet needs of healthcare
providers
•Maximize the value of new drugs and existing drugs and further enhance category
strengths
•Enhance
Enhance pipeline and speed up
p R&D
⇒ Create an organizational framework to win against tough competition
5
Consolidation and reorganization of research and
development divisions
【Essential Points】
1. Integrate operations of drug discovery research, project management of development
products and value creation research of launched products in each Category-based
R&D Unit
2. Speed up R&D through close collaboration between Category-based Units and R&D
Core Functions Units
3. Enhancing drug discovery and preclinical research through open innovation style
utilizing external opportunities
R&D Planning Department
Open Innovation Department
Fuji Research Park
Tokyo Research Park
C
Category-based
R&D
& Units**
R&D Division
(Nephrology, Oncology,
Immunology & Allergy and CNS)
Research Functions Unit
Translational Research Unit
Development Functions Unit
R&D Planning &
Administration
Arm
Category-based
R&D Arm
Collaboration
R&D Core
Functions Arm
6
Project (theme) management framework
Each category R&D project will be led by that category’s R&D unit
Functions Units will collaborate on these projects and allocate resources based on
function and specialization
Research Functions
Unit
Nephrology
R&D Unit
Translational Research
(TR)
Unit
Development
Functions
Unit
Project A
Project B
Project C
Project D
Oncology
O
l
R&D
Unit
P j
Project
E
Project F
Project G
Project H
Project J
Immunology &
gy
Allergy
R&D Unit
CNS
R&D Unit
j
Project
K
Project L
Project M
Project N
7
Further strengthen competitiveness in Japan through
our category-based strategy
Implement PPM* in each category from R&D to S&M
Realize sustainable growth while enhancing productivity
Nephrology
(Including diabetes/
hypertension)
Enhance presence in CKD
Immunology & Allergy
Enhance presence in
dermatology /otorhinology
・ Maintain high NESP® market share
・Expand REGPARA® market
・ Market penetration of Onglyza®
・ Accelerate development of
KHK4563, KHK4827
・ Address ALLELOCK ® /Patanol ®
competitor products
Oncology
Central
Nervous System
Enhance position in hematology
Enhance presence in cancer
supportt therapies
th
i
・Establish POTELIGEO ® brand
・Early launch of KRN125, KW-2246
・Accelerate ARQ 197 development
*PPM: Product Portfolio Management
Maximize synergy with
existing products
・ Market penetration of Apokyn ®
・Early launch of KW-6002
8
Progress of Overseas strategy
Europe/USA: Development/sales structure
Development in USA/Europe: Promotion of ODDO1) centering on KKP 2)
Develop robust sales structure for smooth transition to a global specialty
pharmaceutical company
Development in USA/Europe (KKP2))+PSK3)))
・Establish KKP1) as the central base for global development
・Make progress on development of in-house products
・Make progress on development of biosimilars in Europe
PSK
KKP
1) One Drug Development Organization
2) Kyowa Hakko Kirin Pharma, Inc.
3) ProStrakan, Inc.
Sales in USA/Europe (PSK3))
・Promote market penetration of existing PSK3) products
・Expand product portfolio through active licensing activities
・Build structure for KW
KW-0761
0761 market launch in the Americas
9
Drug discovery from open innovation
In order to search for high-quality drug discovery seeds, collaborations with outside partners are
shifting further upstream under the intensifying competitive circumstances. Kyowa Hakko Kirin will
concentrate on exploring early-stage collaboration opportunities and establish an Open Innovation
D
Department
t
t as an organization
i ti th
thatt flflexibly
ibl pursues di
diverse research
h alliances.
lli
Academia / different industries / venture companies
Bio-ventures / pharmaceutical companies
External
seeds
Internal
R&D
Research stage
Development stage
Utilization of external seeds for drug discovery
Integration of own technology and external technology
Product licensing and collaboration
Application, Launch
Co-promotion partnerships
The Business Development Department will continue to oversee these stages
Roles of Open Innovation Department
[Opportunity exploration]
Identify and assess external opportunities
Propose alliance opportunities to research laboratories
[Contract administration]
Negotiate contracts with partners
Promote industry-academia partnering programs and other initiatives
[Alli
[Alliance
management]
t]
M i t i alliances
Maintain
lli
with
ith external
t
l partners
t
(The Business Development Department will take responsibility for future contract negotiations of commercial terms)
10
KHK4563
Structure / MoA
Anti-IL-5Rα
A
ti IL 5R humanized
h
i d MAb with
ith enhanced
h
d ADCC using
i POTELLIGENT®
technology
(1) Antibody binding
(2) Recognition by the effector cells
(3) Target cell killing
R
Remarks
k
(3)
Development Area: Asia
Generic name: benralizumab
Origin: in-House
Potential competitors: anti-IL-5 (mepolizumab, reslizumab)
License-out
Effector cell
(NK, MF, etc)
Fc receptor
(2)
KHK4563
(1)
IL-5Rα subunit
Target cell
(eosinophil)
AstraZeneca/MedImmune s global Phase 3 program in patients with asthma
AstraZeneca/MedImmune’s
(Windward Program) started in October 2013
 KHK is collaborating with AstraZeneca/MedImmune in Japan and South Korea
 Phase 2b st
study
d res
results
lts have
ha e been shared at the American Thoracic Societ
Society (ATS) and
European Respiratory Society (ERS) meetings in 2014

11
Asthma and KHK4563 (benralizumab)
 Asthma is a chronic inflammatory disease of the airways characterized by
recurrent episodes of wheezing,
wheezing shortness of breath and coughing
 According to the Global Initiative for Asthma (GINA), 300 million people
worldwide are suffering from asthma, 5 to 10% of which are severe
asthmatics whose day-to-day activities or quality of life are deteriorated by
the disease
 Approximately 40 to 60% of severe asthmatics have eosinophilia
 Higher blood eosinophil count is often associated with higher risk of
asthma exacerbation
 Phase 2b study1 of benralizumab with severe asthmatics inadequately
controlled on ICS/LABA therapies showed
a. Reduction in asthma exacerbations
b. Improvement in FEV1
c. Improvement
p
in ACQ-6 score
1. Data presented at ATS 2014
12
Phase 2b results of KHK4563 (benralizumab)
Reduction in asthma exacerbation rates (AER)
AER by baseline eosinophil cut-off point (mITT population)
I the
In
th pre-specified
ifi d subgroup
b
analysis,
l i b
benralizumab
li
b produced
d
d greater
t
improvements, as baseline blood eosinophil counts increased
American Thoracic Society 2014 Poster
Poster, May 2014
RR, rate reduction, relative to placebo; mITT, modified intent-to-treat
*P<0.169 vs placebo is statistically significant
13
KHK4563 (benralizumab): summary
 An anti-IL-5Rα antibody with robust eosinophil depletion with potential
best-in-class asthma efficacy
 Potential to transform disease management by targeting asthma subsets
distinct from current therapies (eosinophilic asthma)
 Possibility to offer tailoring therapies in combination with simple
hematology test to selectively identify patients with high likelihood to
respond ii.e.
respond,
e elevated blood eosinophils
 Global Phase 3 asthma program (Windward Program) is ongoing in
collaboration
ll b ti with
ith A
Astrazeneca/MedImmune
t
/M dI
 Accelerated timelines: first anticipated submission in 2016
14
KRN23
Structure / Mechanism of action
Anti FGF23 fully human IgG1 monoclonal antibody
Anti-FGF23
Acts primarily in the kidneys, binding exclusively to and inhibiting the action of Fibroblast
growth factor （FGF） 23, a hormone that reduces serum phosphorus and 1.25 dihydroxy
Vitamin D concentrations in the kidneys
kidneys.
Indication
Currently
C
tl iin d
development
l
t ffor th
the ttreatment
t
t off X-linked
X li k d Hypophosphatemia(XLH),
H
h
h t i (XLH) a fform off
rickets and osteomalacia that impairs bone growth and maintenance as a result of low
phosphorus associated with elevated FGF23
XLH is a rare disease occurring in one in 20,000 people.
There are approximately 12,000 adult patients and 3,000
pediatric patients in the US and in each of the five major
countries of the EU
EU.
Current treatment with oral phosphorus drugs and vitamin D
preparations have insufficient effect on growth, and
p
p
problems exist such as compliance
and adverse reactions
(diarrhea, hyperparathyroidism, and ectopic calcification.
In severe cases, osteotomy is performed to straighten bones
and promote growth.
Phase 1/2 study targeting adult XLH completed in the US
and Canada
* In Japan, there are 5,000 adult patients and 1,000 pediatric patients
Isao Saikawa Orthopedic surgery & Traumatology 39; 1340-43, 1991.
Ali Al Kaissi, Swiss Med Wkly. 2013,
15
Current development
Collaboration
Entered into collaboration and licensing agreement with U.S. company Ultragenyx for the
development and commercialization of KRN23 for the US, Canada, and EU (press release
issued in September 2013)
Development costs will be shared by both companies and clinical trials in the US and EU will
be conducted by Ultragenyx
Joint sales in US and Canada. Kyowa Hakko Kirin will be responsible for sales in EU
Clinical development
EU & US: Initiation of phase 2 clinical trial targeting pediatric XLH patients1)
Objective: Safety and efficacy during multiple doses
Enrollment: 30
Locations: U.S., UK, The Netherlands, France
Asia: Start of phase 1 clinical trial targeting adult XLH patients2)
Objective: Safety and efficacy in single dose
Subjects: 15
Locations: Japan, Korea
1) Clinical Trials. Gov Identifier : NCT02163577
2) Clinical Trials. Gov Identifier : NCT02181764
16
Future plans in Europe and U.S.
Pediatric XLH development（agreements with FDA on phase 3 clinical trial)
 Blinded radiographic assessments of changes in bone abnormalities and changes
in growth may be used as primary endpoint measures
 Phase 3 study in pediatric patients could not be open-label
 Recommendation for inclusion of a standard care control arm for comparison on a
non-inferiority basis
 Final studyy design
g to be determined once sufficient study
y data are available and
after further consultation with the FDA
Adult
development
Ad lt XLH de
elopment
 Scheduled to initiate late-stage phase 2 clinical trial in 2015
17
APPENDIX
18
Acceleration of drug discoveries
Acceleration of drug discoveries
• Discovery
y of new drugs
g for unmet needs
• Improvement of R&D success rates through
collaboration with medical institutions
Antibodies
Small molecules
Oligonucleotides
Translational Research
Open Innovation
Biotechnology
Passion & Integrity
g y
Infinite pursuit of cutting-edge scientific progress
Technology platform,
platform a key strength
Researchers’ integrity and passion towards drug discovery
19
Global network-based drug discovery research
Japan
Generation of candidate
products using platform
technologies including
antibody
San Diego
• Concept verification using
clinical samples
• Access to cutting-edge
scientific research progress
• Promoting open
innovation
F
Focus
on translational
t
l ti
l research
h
Academia-industry
y alliances
Singapore
Bench to bedside by
using bioimaging
technology
20
Core strategy 1. Strengthen business in Japan:
Background of category-based strategy
To win in an increasingly challenging external environment
Increase in new
drug creation
hurdles
Complexity of information
and high level of expertise
d
demanded
d db
by medical
di l ffrontt
To become a global specialty
pharmaceutical company
p
p y
Further restriction
of medical
expenses
Strengthen competitiveness
in focused categories
Emergence of new
medical technologies
Change
g from competition
p
on
scale to era requiring intelligence,
network and internal and external
collaboration
Change from competition by
individual item to competition
by comprehensive strengths
21
Open innovation
Pipelines
Academia
 KW-0761
Univ. of Tokyo, Nagoya City Univ.
 KRN23
Univ. of Tokyo
 KHK4563
Univ of Tokyo
Univ.
 KHK2898
Kyorin Univ., Kitasato Univ., Osaka Univ.
 KHK4083
La Jolla Institute (LJI)
 ASKP1240
LJI
 LIGHT
LJI
Venture
 CEP-37250/KHK2804 Arana（TEVA）
22
KHK4563 (benralizumab): Phase 3 development plan
AstraZeneca/MedImmune’s Global Phase 3 asthma program (Windward Program)
Two pivotal studies: CALIMA and SIROCCO
 Severe asthma uncontrolled on ICS/LABA therapies
 A range of blood eosinophil levels to fully characterize which
patients may respond best to therapy
 Primary endpoint: reduction in rate of exacerbations
 Secondary endpoints: lung function (FEV1) and symptoms (ACQ)
Phase 3
ongoing and
on track
to complete by
Q1 2016
Q
0 6
 Doses and control groups: 30 mg q4wk, 30 mg q8wk, placebo
 Treatment period: CALIMA (56 weeks), SIROCCO (48 weeks)
Kyowa Hakko Kirin is participating in Windward Program
 CALIMA as the In-Country Caretaker in Japan
 SIROCCO
S OCCO as the IND Holder in South
S
Korea
Phase 1 / 2 study targeting adult XLH patients
INT-001/002
Target: Adult XLH patients
Design: A multiple-dose Phase 1/2 study with escalating doses
Objective: Safety and efficacy during multiple doses
Dosage and administration: KRN23 (0.05, 0.1, 0.3, 0.6, 1.0 mg/kg SC), 28 day intervals/50 weeks (12
administrations)
Subjects: 28
INT-001 study
INT-002 study
2.5 <P < 3.5 mg/dL 44.4% - 81.8%
3 5 < P < 4.5
3.5
4 5 mg/dL 4.5%
4 5% - 16.7%
16 7%
Carpenter TO , 2014 American Society of Bone and Mineral Research
During each dosing cycle of the extension study (INT
(INT-002),
002) peak serum phosphorous
concentrations (Pi) in more than half of subjects reached target range. Also serum Pi
did not exceed the upper limit of normal (4.5mg/dL) in any subjects.
24
Phase 2 study targeting XLH in pediatric patients
UX023-CL201
Study name
Clinical trial of KRN23 in Pediatric Subjects with X-linked Hypophosphatemia
Phase
Phase 2
Target
Pediatric X-Linked Hypophosphatemic Rickets（5 - 12 year olds）
Primary
p
endpoint
Dosage and
administration
Changes in serum phosphorus concentration, incidence of adverse event
Cohort 1：KRN23
Cohort 2：KRN23
Cohort 3：KRN23
mg/kg Q2W,
mg/kg Q2W,
mg/kg Q2W,
Subjects
30
Locations
U.S., UK, The Netherlands, France
Study
yp
period
mg/kg Q4W
mg/kg Q4W
mg/kg Q4W
June 2014 – May
y 2016
Clinical Trials. Gov Identifier : NCT02163577
25
Phase 1 study targeting adult XLH patients
KRN23-001
Study
y name
Phase 1 Clinical Trial of KRN23 with X-linked Hypophosphatemic Rickets/Osteomalacia in
Ad lt Subjects
Adult
S bjects
Phase
Phase 1
Target
Adult X
X-linked
linked Hypophosphatemic Rickets/Osteomalacia
Primary
endpoint
Incidence of adverse event
Dosage
Cohort 1: KRN23 0.3 mg/kg SC single-dose
Cohort 2: KRN23 0.6 mg/kg SC single-dose
Cohort 3: KRN23 1.0 mg/kg SC single-dose
Subjects
15
Locations
Japan, Korea
Period of study
July 2014 – December 2015
Clinical Trials. Gov Identifier : NCT02181764
26