Development Forum
Presentation to Analysts
November 21, 2013
Tokyo, Japan

Jeffrey S. Humphrey, M.D.
President, Chief Medical Officer
Kyowa Hakko Kirin Pharma, Inc.
Princeton, NJ

Forward-looking statements
This document contains certain forward-looking statements relating to suchitems as the company’s (including its domestic and overseas subsidiaries)
forecasts, targets and plans. These forward-looking statements are based upon
information available to the company at the present time and upon reasonableassumptions made by the company in making its forecasts, but actual results inpractice may differ substantially due to uncertain factors.
These uncertain factors include, but are not limited to, potential risks
associated with the pharmaceutical industry’s domestic and international
operating environment, intellectual property risks, the risk of adverse reactions
to pharmaceutical products, legal risks, risks arising from productmanufacturing deficiencies, risks due to fluctuations in the market prices of raw
materials, fuel and products, as well as exchange rate and financial market
volatility.
This document contains information on pharmaceutical products (including
products under development), but its contents should not be construed as
promotion, advertising or as a medical recommendation
2

Agenda

Session 1
One Drug Development Organization – The Future
Session 2
Current US FDA stance on characterization of risk andbenefit, and use of global data3

Striving to Become a Global Specialty Pharma

Leap to GSP・Maximizebusiness in Japan・Integrated two
companies
・Transferred Foodbusiness

・Divested petro-chemicals
・Acquired ProStrakan
・Entered Biosimilars
・Reorganized production
・Transferred alcohol /livestock businesses

・Promote productdevelopment in US/EU

・Improve revenue & profitabilityof Bio-Chemicals

STEP 1

Integrate strengths

2008~2009

・Launch three products
originated from KHK in US/EU
KW-0761/KW-6002/KRN23
・Materialize global
Biosimilar business・Expand BioChemicals
business

STEP 2

Select and concentrate

2010~2012

STEP 3

Strive toward GSP

STEP 4

Realize our GSP model

2013~2015*GSP = Global Specialty Pharma

44Striving to Become a Global Specialty Pharma
Development Strategy
・Establish ODDO for global development US/EU
・Promote Product Development in US/EU

EuropeOne Drug
Development
Organization

America●PSK

KHK HQ●●Asia
ODDO = One Drug Development Organization
KKP = Kyowa Hakko Kirin Pharma, Inc.
PSK = ProStrakan
KHK = Kyowa Hakko Kirin, Co.

●
●

●

5

KKP

Formation of ODDO*Striving to Become a Global Specialty Pharma
September 2012

One Drug Development Organization
Chartered from KKP and PSK (ODDO)
April 2012
HQ Development
Committee Meetings
First Held in English

April 2013

American appointed
KKP/ODDO President

Establish Culture; Improve Process and Communication; Define Roles; Recruit Talent;
Develop Skills; Create Transparency; Develop Strategy
May

Jun

Jul

Aug

Sep

Oct

Nov

Dec

Jan

Feb

2012

Mar

Apr

May

Jun

Jul

Aug

Sep

Oct

Nov

2013

Jul 2012
First EU PTCL Patient
KW-0761-007

Dec 2012
First US CTCL Patient
KW-0761-010

Aug 2012
First US ATL Patient
KW-0761-009*ODDO = One Drug Development Organization

Sep 2013
KRN23 Collaboration
with Ultragenyx

Feb 2013
First EU ATL Patient
KW-0761-009

6

Oct 2013
First EU CTCL Patient
KW-0761-010

Nov 2013
First US Parkinson's Patient
Expected KW-6002-014

ODDO
One Drug Development OrganizationMissionODDO will design and conduct efficient, effective andcompliant drug development in Europe and the US to build
KHK Global Specialty Pharmaceutical businesses, bringing new
medicines to patients

Major goals
Form one drug development organization in Europe and US
with growth driven by KHK’s innovative pipeline File KW-0761, KW-6002 and KRN23 for approvals
 Support and build the business in Europe and the US


7

ODDO
KHK Drug Development in Europe and the US
President

QA/DS

Operations

Biometrics

Drug
Development

Planning

Regulatory

MedicalSciences

Quality
Assurance

ClinicalOperations

Statistics

Dev. Team
Leaders

Project
Management

Regulatory
Affairs

Study
Physicians

Drug
SafetyChemistry,
Manufacturing
and Controls

DataManagement

ClinicalPharmacology

Contracts

Regulatory
Operations

Strategy
Physicians

MedicalWriting

Non-Clinical

Admin.
office: Staffed by KKP (US) and PSK (EU) personnel: Staffed by KKP (US) personnel only
8

Innovative Pipeline for Europe and US
Compound

MOA a

Therapeutic
Area

Stage

Remark

KW-0761(Poteligeo®)

Anti-CCR4 HumanizedMab

Oncology

Ph III

ATL, CTCL, PTCL

KW-6002(Nouriast®)

Adenosine A2A
Receptor Antagonist

Neurology

Ph III

Parkinson’s Disease

KRN23 bAnti-FGF23
Fully Human Mab

OthersPh II

X-Linked Hypophosphatemia

KW-2478

Hsp90 inhibitor

Oncology

Ph II

Multiple Myeloma

BIW-8962

Anti-GM2 HumanizedMab

Oncology

Ph I/IISCLC

KHK4083

Immunomodulator

Immunology

Ph I

Autoimmune disease

KHK2804 b

Anti-tumor specificglycoprotein
humanized Mab

Oncology

Ph I

Solid Tumorsa Mechanism of Actionb KRN23 is partnered with Ultragenyx; KHK2804 is partnered with Teva Pharmaceutical Industries Ltd.

9

Innovative Pipeline for Europe and US
Research*

Preclinical*

Phase 1

Phase 2

KW-0761

KW-0761 (ATL)

BIW-8962

KW-0761 (PTCL)KHK2804**

KW-2478

KHK4083

KRN23**

Phase 3

Oncology
Immunology
Nephrology

Not
disclosed

CNS* Research and Preclinical candidates not yet disclosed
10** KRN23 is partnered with Ultragenyx; KHK2804 is partnered with Teva Pharmaceutical Industries Ltd.

KW-0761 (CTCL)
KW-6002

Making the Leap to Global Specialty Pharma

KW-0761
Defucosylated, humanized monoclonal antibody to C-C Chemokine
Receptor 4 (CCR4)
 Approved in Japan as Poteligeo® for relapsed or refractory CCR4-positive
Acute T-cell Leukemia-lymphoma (ATL)

KW-6002
Small-molecule inhibitor of adenosine A2A receptor
 Approved in Japan as Nouriast® for Parkinson’s disease




KRN23


Fully human monoclonal antibody to Fibroblast Growth Factor 23 (FGF23)

11

KW-0761

Defucosylated, Humanized Monoclonal Antibody to CCR4
Approved as Poteligeo® in Japan for relapsed or refractory CCR4-positive
Adult T-cell Leukemia-lymphoma (ATL)

KW-0761

CCR4
C-C chemokine receptor 4
N-terminal
Extracellulardomains

FucoseAsn297
Potelligent® technology

CCR4 is normally expressed on T-cells (Treg and Th2).
CCR4 is abnormally expressed on tumor cells in ATL.

Shinkawa et al, J Biol Chem 2003;278:3466Ishii et al, Clin Cancer Res 2010;16:1520

12

Sugiyama et al, PNAS 2013; 10:1073
Ishida et al, Clin Cancer Res 2003;9:3625
Jones et al., Blood 2000; 96:685
Imai et al., Int. Immunol 1999, 11:81

KW-0761: Global Development
Development Phase
RegionIndication
ATL

Japan

Pilot
(P1/2a)Pivotal(P2b/3)

BLA/MAA
submission

BLA/MAA
approval

0761-0501

0761-002

April 2011

March 2012

0761-003

July 2013

0761-004

July 2013(relapsed)(NCT00355472)(NCT00920790)

ATL

in combination
with mLSG15(NCT01173887)(1st-line)
T/NK cell lymphoma(relapsed)(NCT01192984)

ATL(relapsed/refractory)

GlobalCTCL(relapsed/refractory)

PTCL(relapsed/refractory)

0761-009

USA, Europe

0761-010

USA, Europe(NCT01626664)

KW-0761-001/002(NCT00888927)(NCT01226472)

0761-007(NCT01611142)(NCT01728805)

Europe

ATL: Adult T-cell Leukemia-Lymphoma, CTCL: cutaneous T-cell Lymphomas, PTCL: Peripheral T-Cell Lymphoma,
BLA: Biologics License Applications, MAA: Marketing authorization application13

KW-0761-009
Phase II Trial for ATL
Population:
Subjects with Adult T-cell Leukemia-Lymphoma (ATL) who are relapsed or
refractory after at least one prior systemic therapy regimen

Study Design:
Open-label, 2:1 randomized, global Phase II trial to evaluate safety andefficacy of KW-0761 or chemotherapy (investigator’s choice of pralatrexate,
GemOx or DHAP)

Primary Endpoint:
Overall Response Rate
2
Approximately 70
relapsed or refractory
ATL patients

Randomization
1

ClinicalTrials.gov Identifier: NCT01626664

KW-0761 group14

chemotherapy group

KW-0761-010
Phase III Trial for Cutaneous T Cell Lymphoma
Population:
Subjects with mycosis fungoides (MF) or Sézary syndrome (SS) who haveprogressed following at least one prior course of systemic therapy

Study Design:
Open-label, randomized, global phase III trial to evaluate safety and efficacy of
KW-0761 versus vorinostat

Primary Endpoint:
Progression free survival
1
Approximately 317
previously treated MF
or SS patients

KW-0761 group

Randomization
1

ClinicalTrials.gov Identifier: NCT01728805
15*Cutaneous T-cell Lymphoma includes mycosis fungoides and Sézary syndrome

vorinostat group

KW-0761 SummaryKW-0761 has been approved in Japan as Poteligeo®
and is currently in development in Europe and the
US for PTCL, ATL and CTCL
KW-0761 may have uses in other tumors due toeffects on the immune system20

KW-6002
Small-molecule inhibitor of adenosine A2A receptor
Approved in Japan as Nouriast® for Parkinson’s disease
First in Class Parkinson’s Disease treatment

Reduces average “OFF” time in Parkinson’s patients receiving treatment
with L-DOPA who are experiencing wearing off phenomenon
40mg daily dose improves motor capacity* during “ON” timeEnd-of-dose wearing off, Peak-dose dyskinesia, and ON-OFF phenomena:*UPDRS part Ⅲ

21

Dose

Dose

Dose

Blood Concentration

Therapeutic Concentration

KW-6002-014: Phase III Trial for Parkinson’s disease
Population:
Moderate to severe Parkinson's disease patients with motor fluctuations anddyskinesia on levodopa combination therapy

Study Design:
12-week, double-blind, placebo-controlled, randomized, multicenter study toevaluate efficacy and safety of istradefylline 20 and 40 mg/d versus placebo

Primary Endpoint:
Change from Baseline in total hours per day spent in the OFF state.

Approximately 609
Moderate to severe
Parkinson’s disease
patients

KW-6002 40 mg groupplacebo group

Observation period: 2weeks prior to randomization
ClinicalTrials.gov Identifier: NCT01968031

KW-6002 20 mg group

Randomization

0
22

12

(weeks)Careful Attention to Data Quality;
Efforts to Reduce Placebo EffectEnsuring Quality of Site and Investigator
All Sites and Staff must have 2 years of experience in Parkinson’s research
 “ON/OFF” time scores entered by the site will be monitored during the trial and indicate theneed for any additional site training

Ensuring Quality of Patient-reported Data
During screening, patients will be trained on how to score “ON/OFF” time and must completean “ON/OFF” self-rating (Hauser diary) During screening, scores recorded by the site staff and the patient must agree
 An electronic pen will record the time a score is entered by patients. Scoring times will bemonitored during the trial and indicate the need for additional patient training.
Reducing Placebo Effect
Site personnel will be trained in tactics to minimize the placebo effect Site personnel will be trained and certified on how to score “ON/OFF” time One-third of patients will be randomized to placebo alone

23

KW-6002-014
Special Protocol Agreement from FDA

FDA agreed that the design and planned analysis of the study
adequately address the objectives necessary to support a
regulatory submission
Dosing of first patient expected November 201324

KW-6002 Summary

KW-6002 has been approved in Japan as Nouriast® and iscurrently in development in the US for Parkinson’s disease
with motor fluctuations and dyskinesia on levodopa
combination therapy
The phase III trial is a multinational study and being conductedwith special efforts to ensure data quality and reduce theplacebo effect
The trial is being conducted under a SPA agreement with FDA*SPA: Special Protocol Assessment25

KRN23
Fully Human Monoclonal Antibody to FGF23
KHK is collaborating with Ultragenyx
to develop and commercialize KRN23

Aiming to launch clinical trials for pediatric XLH* in 2014
Ultragenyx Pharmaceutical Inc.
Established in 2010, specializing in therapeutic drug development
for rare metabolism-related hereditary diseases
CEO and President: Emil D. Kakkis, M.D., Ph.D.
Details of collaboration• Parties to collaborate on development and commercialization in USA, Canada, and EU- Ultragenyx to lead development efforts in the XLH indication.
- Parties to share development costs• Parties to share commercial responsibilities and profits in USA and Canada• Kyowa Hakko Kirin responsible for commercialization in the EU• Ultragenyx responsible for development and commercialization in Mexico, Central & South America* X-linked hypophosphatemia (XLH) - a syndrome due to excessive concentrations of FGF23 in the blood associated with excessive loss of phosphate in theurine leading to hypophosphatemia and resulting in a rare disease characterized by poor bone growth and mineralization.

26

KRN23-US-02
Phase I trial for Adult XLH
Population:
Adults with X-Linked Hypophosphatemia

Study Design:
Multicenter, phase I, double-blind, randomized, placebo-controlled, single-dose(Intravenous and Subcutaneous), dose-escalation study of KRN23 versus Placebo

Endpoints:
Safety, tolerability, pharmacokinetics, and pharmacodynamics (TmP/GFR*,
serum phosphorus, 1,25(OH)2D**)
Abstract of main results 1 awarded “The Most Distinguished Clinical Research Abstract”
by American Society for Bone and Mineral Research (ASBMR) at 2013 meeting

1 Carpenter, et al ; A First-In-Human, Randomized, Double-blind, Placebo-Controlled, Single Dose Study of a

Humanized Monoclonal Anti-FGF23 Antibody (KRN23) in X-linked Hypophosphatemia.
* TmP/GFR: renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate.
TmP/GFR is an indication of the ability of the kidney to retain phosphate.
** 1,25(OH)2D: 1,25 dihydroxy vitamin D

ClinicalTrials.gov Identifier: NCT00830674

29

Safety Data

Treatment Emergent Adverse Events
KRN23 (24/29) > placebo (4/9)
 Most common were:Intravenous administration: nausea (24%); headache (18%)
 Subcutaneous administration: elevated serum amylase and back pain (17%)
 Most were mildNo Serious Adverse Events, Deaths, or Adverse Events leading to withdrawal
 No significant changes in vital signs, renal u/s, ECGs, or biochemical values
 No hypersensitivity/infusion reactions
Maximum tolerated single dose not reachedNo anti-KRN23 antibody detected30

T. Carpenter, et al. Oral Presentation #1048, 2013 ASBMR, Baltimore, MD

KRN23 SummaryKRN23 is partnered with Ultragenyx for development inpediatric and adult X-Linked Hypophosphatemia
Single-dose phase I trial showed dose-dependent increases inserum phosphorus and 1,25 dihydroxy Vitamin D
Results from multiple dose trials will be presented at ascientific forum in the future33

Session 1 Summary

ODDO represents a rapid integration of KHK assets
to enhance infrastructure and expertise for drug
development in US and Europe
KHK has an innovative pipeline based on rigorous
science
KW-0761, KW-6002 and KRN23 are enabling KHK’sleap to Global Specialty Pharmaceutical Company

34

Agenda

Session 1
One Drug Development Organization – The Future
Session 2
Current US FDA stance on characterization of risk andbenefit, and use of global data

35

FDA’s Directive

Ensure that drugs approved for marketing are safeand effective for intended use

FDA decisions are based on assessment of Benefit
and Risk
Decisions are patient-focused Decisions must be consistent with applicable guidelines andpolicies

36

FDA’s Benefit-Risk Framework**FDA Publication: Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making; Draft PDUFA V
Implementation Plan - February 2013
• http://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm329758.pdf
37

Decision Factors
Severity of unmet medical need
Benefits-risks of other available therapies
Efficacy results of clinical trials:• Clinical meaning of endpoints• Size of treatment effect• Appropriate analysis of
subpopulations
Safety results of clinical trials:• Type, severity and reversibilityof adverse events• Adequacy of safety database• Potential for problems in postmarket setting that may be ofconcern

What efforts ensure drug is directed topatients for whom risk is acceptable?
• Recommended labeling language
What efforts mitigate safety concerns?
• Risk Evaluation and Mitigation Strategy(REMS) programs• Post-marketing surveillance38For Each Decision Factor, FDA considers…


Evidence

Trial data

Conclusions


Uncertainties
Identify sources of uncertainty,
such as lack of data, conflicting
outcomes, and marginal results Define assumptions about how
uncertainties may impact
outcome for patients in the
post-marketing setting

Conclusions are based oninterpretation of evidence,
opinions , uncertainties andassumptions







ReasonsGiven the uncertainties, will results
apply to patients who will receive thedrug after approval?

39

Basis for conclusions

Summary of Benefit-Risk Assessment
Explains rationale for the final regulatory decision, including
important judgments that contributed to the decision









States key evidence and uncertainties
Accounts for current understanding of disease condition and alternative therapies,
against which benefit-risk is weighed
Explains rationale for labeling, risk management requirements, and other postmarketing requirements
Notes differences of opinion in scientific and clinical judgment and explains how
differences were resolved or taken into account in the final decision

Experts and companies may disagree with FDA’s decisionbecause of differences of opinion or interpretation of data40

FDA’s Benefit-Risk FrameworkStaged implementation
2014
 FDA will publish available Benefit-Risk Assessments
 FDA will use new format for all initial NDA/BLAs for new drugs
 2016 FDA will use new format for supplemental NDA/BLAsThis enhanced transparency may make future FDA approval
decisions more predictable

41

Global Clinical Trials to Support
New Drug Applications

Global Clinical Trials


FDA Concern - More data are coming from countries outside the US
FDA inspections have not found significant differences between US and non-US sites in thequality of trial conduct
 However, there are many potential differences in populations and medical practice

FDA allows a marketing application based on non-US data if:
The trials are adequate and well-controlled Conducted by investigators of recognized competence Conducted in compliance with Good Clinical Practices
 Submission includes all documentation expected for a US trial
 Data are applicable to US population and US medical practiceSubset analyses by region

Khin NA, Yang P, Hung HM, et. al.. Regulatory and scientific issues regarding use of foreign data in support of new drug
applications in the United States: an FDA perspective. Clin Pharmacol Ther. 2013 Aug;94(2):230-42.
44Global Clinical Trials

Global Trials allow exploratory comparisons of subset
data from different regions

Differences between regions in observed response inevitably occur
as a result of chance differences among patient subsets



It is rarely possible to determine whether observed differences arereal unless they are large, but even fairly large differences may
occur by chance

45Planning Global Trials for Quality

Identify activities important to
final quality








Activities that, if done incorrectly, would
decrease trial’s ability to reach reliableconclusions or reduce subject safety

Carefully select investigators withqualifications, training andresources necessary for the trial
Monitor Early

Identify critical risks to those
activitiesManage these critical risksFor example,

Use precise definitions, similar
treatment standards, similarconcomitant medications, similar
treatment assessmentsPower global trial conservatively

46

Consider supplemental central
monitoring
Identify errors early to allow earlycorrective and preventive actions
Identify missing data, variations in
protocol implementation early
Pay attention to prevent errors
previously identified as criticalOrphan Drug versus
Breakthrough Therapy

FDA Designations
Orphan Drug

Breakthrough Therapy

Requirement
Drug intended to treat a rare diseaseor condition (i.e., affecting fewer
than 200,000 people in the US)

Requirement

Drug intended to treat a serious conditionPreliminary clinical evidence indicates thatthe drug may demonstrate substantial
improvement over existing therapies



Incentives

Tax credits up to 50% of trial costs

Incentives

Same benefits of fast track designation

Waiver of PDUFA User Fees (~$2M)



7-year marketing exclusivity

Assistance from Office of Orphan
Product Development andopportunity for special grants



48



Frequent interactions with review teamPossible early submission of certain elements of NDAEligible for priority review

Also: intensive guidance on an efficient
drug development program, including
involvement of FDA senior managers

どうも 有難う 御座います
Thank You Very Much

END

52

Breakthrough Therapy
Fast Track

BreakthroughAccelerated

Priority Review

Reference

FD&C Act, §506(b)FD&C Act, §506(a)21CFR314, sub H
21CFR601, sub E
FD&C Act, §506(c)PDUFA 1992

Qualifying
Criteria•Treat serious condition•Unmet medical need

•Treat serious condition•Substantial improvementof clinically significant
endpoint over available
therapy•Treat serious condition•Advantage overavailable therapies•Effect on surrogate
endpoint•Treat serious condition•Provide significant
improvement in safety oreffectiveness

When toSubmit•With/after IND•Before pre-BLA
meeting•With/after IND•Before EOP2 meeting

Discuss with review
divisionWith BLA, NDA orefficacy supplement

Timeline for
Response

Within 60 calendar days

Within 60 calendar days

Within 60 calendar days

Within 60 calendar days

Features•Actions to expedite
development + review•Rolling review•Fast track features•Guidance•FDA Sr. Mgrs involved

Approval based onsurrogate endpoint

Shorter clock for review(6 months)

Additional
Considerations•Can be withdrawn if
criteria no longer met

Can be withdrawn if
criteria no longer met•Early submission of
Promotional Material•Post approval studies toconfirm approval•Can be withdrawn

Assigned at time of BLA,NDA or efficacy
supplement

53