Keynote Address

Giulio Draetta, PhD, MD, Professor, Genomic Medicine Director, Institute for Applied Cancer Science, MD Anderson Cancer Center

Waterfall plot of best percent change in target lesions from baseline for 133* patients on the basis of investigator assessment *Excludes patients with early death before re-imaging, non-measurable non-target disease, or indeterminate r...

Camidge et al., Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study The Lancet Oncology Volume 13, Issue 10 2012 1011 - 1019

When something works you notice it!!

ACADEMIA

Clinical Trials

Current “Ecosystem” Challenges

INDUSTRY

Drugs, Diagnostics, Technologies

Discovery

ACADEMIA

Basic Discoveries

This is shrinking!

3

Percentage entering next stage

0

10

20

30

40

50

60

70

80

90

100

Entering Phase 1 Entering Phase 2 Entering Phase 3 Entering preregistration

Targeted therapy

Chemotherapy

Other

B. Pagliara, MedNous, 2011

Analysis conducted on 529 new chemical or biological entities that entered clinical trials between November 2004 and November 2005, followed through April 2011

Barriers to overall progress in cancer treatment

• Limited insights into factors driving cancer • Elemental knowledge of the cancer genome • Poor understanding of the target’s “biology”

– In what context (genetic, micro-environmental, host and macro-environmental) is the target rate-limiting?

• Lack of insight on appropriate combinations – Tumor will find a way to bypass a single-point intervention – Co-extinction is required to shut down a complex highly-redundant

network • Challenged cancer drug development ecosystem

5

Cancer signaling is not linear…. It is a highly inter-connected and redundant network

• Greater than 90% of cancer drugs fail approval • E ven approved ones are not s ubs tantially effective and provide benefit

only in a s ubs et of patients

New era of cancer genomics

OLD NEW

100

1,000

10,000

100,000

1,000,000

Sep-

01

Sep-

02

Sep-

03

Sep-

04

Sep-

05

Sep-

06

Sep-

07

Sep-

08

Sep-

09

Sep-

10

NHGRI Large-Scale Sequencing Program: Cumulative Sequence Production (Gb)

~5 million bases (2000) ~250 billion bases (CURRENT) Per week:

Comprehensive analysis

Common standards

Public data release

Coordination & comparison

International Cancer Genome Consortium Projects 38 project teams in 13 jurisdictions 16,000 tumor genomes in 5 years

Massively parallel sequencing enables comprehensive genome characterization

Meyerson, Getz and Gabriel. NRG 2011

Translate cancer genome into actionable drug development endpoints

11

Need to functionalize the cancer genome

• Hundreds of candidates

• Drivers vs. passengers

• Context-specificity

• Deep biology to inform on mechanism of action

Analysis

Insight

Function

Cancer Genomics

The genome will inform the right targets and the right patients for the right drugs, ONLY when interpreted in context of the biology

Barriers to overall progress in cancer treatment

• Limited insights into factors driving cancer • Elemental knowledge of the cancer genome • Poor understanding of the target’s “biology”

– In what context (genetic, micro-environmental, host and macro-environmental) is the target rate-limiting?

• Lack of insight on appropriate combinations – Tumor will find a way to bypass a single-point intervention – Co-extinction is required to shut down a complex highly-redundant network

• Challenged cancer drug development ecosystem

12

Primary Tumor-Derived Cells Primary Engineered Cell Lines

ORF Libraries shRNA Libraries

In vivo Tumorigenicity

Metastasis

Anchorage Independent

growth

Invasion Migration

Proliferation Apoptosis

Cancer Phenotypes in the Context of Resistant Disease

Drug Resistance

Functional interrogation of cancer genomes

13 Tim Heffernan

Primary Melanocyte hTERT, p53DD, R24C, BRAFV600E

Focused “Driver Kinase” Lib. 110 WT Human

Kinases

Genetically-defined Tumor Target Cells

Orthotopic Injection Library of GEOIs

Multiple in vivo hits in JNK-pathway Clinical path hypothesis

Phenotype: in vivo tumorigenicity

Tumor Latency - Control: 28 weeks - Drivers: 10 -18 weeks

Proof of concept: In vivo screen to identify kinases that cooperate with BRAF to accelerate melanoma growth

14 T Heffernan, L Chin

Context-Specific Screens

Target Cell

Omics-profiled

Tumor-initiating cells

Drug Resistant (e.g. post-neoadjuvant

TNBC)

Latency and penetrance

accurately defined

Candidate libraries

Wild-type and mutant cDNAs

Barcoded shRNA libraries

Quality controlled

Host

Host genetic background

defined

Syngeneic transplant possible

Immune system impact

T Heffernan, A Carugo, A Viale, N Sanchez, PG Pettazzoni

Leverage patient-derived glioma stem cells for in vivo GOF and LOF studies

16

GSC255: Latency ~5wks GSC248: Latency ~30wks

In vivo LOF Pooled shRNA screen to identify genes essential for GSC survival

In vivo GOF Pooled ORF screen to identify GEOIs that accelerate tumorigenesis

Output: Novel, context specific targets for GBM

Resource example: Access to patient-derived PDAC xenografts and cell lines

SOP: Specimen removed from patient and implanted in mouse within 30 mins. Genomic characterization of human PDAC samples Similar resources for multiple other tumor types Jason Fleming

After 2 weeks

mm3

+KRas -KRas

KRas* expressing Tumor

EE 20X EE 20X

Tumor after Kras* extinction

in vivo tumor regression after Kras* extinction

A Viale

Ald+

CD133

CD133

+KR

as*

-KR

as* A

ld+

Tumor cells surviving KRas* extinction are all triple positive

IHC

40X αCD44 αCD133

Remaining tumor cells express stem cell markers

A Viale

αBrdU αCD44 20X

BrdU incorporation 48hs after KRas* reactivation

Upon KRas*re-expression residual cells enter massively into cell cycle and tumors relapse

A Viale

- DOX

- DOX

+ DOX

+ DOX

Her2 AXL EGFR 4650

3551

PDGFRα

VEGFR1

A Viale, PG Pettazzoni

Identification of RTK possibly involved in survival in the absence of Kras*

Genetic network modeling informs combined MEK and CDK4/6 inhibition in N-Ras melanoma

Kwong, Chin et al. (2012) Nature Medicine Clinical trials initiated

Barriers to overall progress in cancer treatment

• Limited insights into factors driving cancer • Elemental knowledge of the cancer genome • Poor understanding of the target’s “biology”

– In what context (genetic, micro-environmental, host and macro-environmental) is the target rate-limiting?

• Lack of insight on appropriate combinations – Tumor will find a way to bypass a single-point intervention – Co-extinction is required to shut down a complex highly-redundant

network • Challenged cancer drug development ecosystem

23

Make a deal before it’s too late!

Phase III Phase II Phase I IND Clinical Candidate

Drug discovery Target

Academia > Biotech Biotech > Pharma Pharma Research > Pharma Development Start company > Sell Company VCs > IPOs

Oncology Drug Development: gap between Academy and Industry

25

Academia Industry

Culture

Creativity

Personal Eminence

Perseverance

Risky projects, long term commitment

Publication driven culture

Culture

Focus

Team work

Flexibility

Risk mitigation, quick Go-NoGo decision

Product & patent driven culture

Oncology Drug Development: gap between Academy and Industry

26

Academia Industry

Culture Aberration

Creativity Science for Science’s sake

Personal Eminence Personalities crash, redundant efforts

Perseverance Miss opportunities

Risky projects, long term committment

Unrealistic objectives, unpredictable timeline

Publication driven culture Data bias, publish “best” results

Culture Aberration

Focus Don’t see the forest for the trees

Team work Attitude >>> Aptitude, no speak-up

Flexibility Lack of biology insight

Risk mitigation, quick Go-NoGo decision

Herd mentality, shifting strategies

Product & patent driven culture

Drug bias, lack of vision

Oncology Drug Development: gap between Academy and Industry

27

Academia Industry

Physiology

Creativity

Personal Eminence

Perseverance

Risky projects, long term committment

Publication driven culture

Physiology

Focus

Team work

Flexibility

Risk mitigation, quick Go-NoGo decision

Product & patent driven culture

Improvements in translational research will be determinant for success

Basic Research

“The sky is the limit”

Reductionist approach

Hypothesis generation:

preliminary evidence

Translational Research

Focused on confirming (or refuting) initial observations

High stringency, clinical pathological

validation, seek impact in preclinical

models

Clinical Research

Seeks evidence of clinical activity in cancer patients

Need to be transparent around potential for disease

improvement

Cytotoxic vs. targeted agents – both validated therapies – different paradigms

Conventional cytotoxic agent Targeted agents

Proven modality: e. g. childhood ALL, testicular cancer

Proven curative modality: e. g. CML,

Undefined molecular target in most cases

Primary target defined

Broad anti-proliferative activity Anti-tumor activity limited to specific genetic context

DNA damage, e.g. alkylating and intercalating agents

No evidence of DNA damage or other “permanent” damage

Mutagenic in in vitro and in vivo tests No evidence of mutagenic activity

Narrow therapeutic window Higher therapeutic window

Testing in healthy volunteers considered unethical

Testing in healthy volunteers possible

Administer at maximum-tolerated dose Administer at biologically effective dose

Cytotoxic vs. targeted agents – both validated therapies – different paradigms

Conventional cytotoxic agent Targeted agents

Proven modality: e. g. childhood ALL, testicular cancer

Proven modality: e. g. CML, BRAFm melanoma, EGFRm NSCLC

Undefined molecular target Primary target defined

Broad anti-proliferative activity Anti-tumor activity limited to specific genetic context

DNA damage, e.g. alkylating and intercalating agents

No evidence of DNA damage or other “permanent” damage

Mutagenic in in vitro and in vivo tests No evidence of mutagenic activity

Narrow therapeutic window Higher therapeutic window

Testing in healthy volunteers considered unethical

Testing in healthy volunteers possible

Administer at maximum-tolerated dose Administer at biologically effective dose

Clinical development of targeted agents needed shift in paradigm

Dose escalation in Phase I (unselected

patients)

If active in any indication, move

forward to Phase II

If activity confirmed in Phase II, move

forward to randomized study

Classic cytotoxic paradigm

Dose escalation in Phase I while

monitoring omics profile

If active, move

forward to Phase

II

If activity confirmed in Phase II, move

forward to randomized study

Classic cytotoxic paradigm won’t work with molecular targeted agents, e.g. early EGFRi trials

Proof of biology (PD) and clinical

signal in target

population

Where will improvements come from

• Eliminate “cytotoxic” development culture when dealing with targeted therapies • Should be able to utilize healthy volunteers for PK and PD analysis in early Phase I • Avoid subjecting patients to useless treatments • Access to early stage patients rather than late stage disease • Mandatory patient biopsies

Pharmacokinetics, biodistribution, safety adequate for testing in

healthy volunteers

High quality agents (small molecules,

antibodies, vaccines, other)

Tumor genetic fingerprinting at time of

treatment Patient stratification Tailored combination

strategies

Improved understanding of

disease state at time of treatment (molecular and

physiopathology)

Early proof of biology and activity response

read-out (imaging, others)

Allows trial interruption and

potential to evaluate alternative

The MD Anderson Moon Shot Initiative

“By applying today’s knowledge and game-changing technologies, MD Anderson’s Moon Shots Program will dramatically accelerate improved survival in the next five to ten years, beyond the 1% to 2% annual declines in cancer mortality that we’ve seen in the past decade. The expertise and team science behind our selected cancer moon shots also will lay the foundation for ultimate cure of these diseases in the years to follow.” Ronald DePinho, M.D., MD Anderson president

Cancer Prevention and Early Detection

Prevention Early Detection Treatment

NO

W

Prevention Early Detection Treatment

FUTU

RE

How to drive a comprehensive plan of attack

– Prevention – Early detection: imaging, tissue markers – Diagnostics: integrate genomic profiling into clinical practice – Drug discovery expertise

• Internal effort justification: need to have internal expertise to better integrate with the external world – importance of scouting and triaging

• Small molecules • Biologics and immunotherapeutics

– Clinical development • Evaluating therapies of true potential

– Early access to new, high quality treatments • Streamlining regulatory reviews and operations • Imaging and other modalities to monitor response • Immuno-monitoring

The Initial Moon Shots at MD Anderson

Acute myeloid leukemia and myelodysplastic syndrome

Breast and ovarian cancers – two cancers with a shared genetic pathway

Chronic lymphocytic leukemia

Lung cancer

Melanoma

Prostate cancer

Current state of scientific knowledge Strength and breadth of the MD Anderson team Potential for measurable near-term success Potential for cure in long term

37

Moon Shot Project

Cancer Control and

Early Detection

Genomics and Proteomics

Immune-Monitoring Checkpoints

Big-Data Analytics

Drug Discovery and

Diagnostics Development

Co-Clinical Trial Center

Discovery Science by the Moon Shot Projects Enabled by Moon Shot Platforms

Institute for Applied Cancer Science

• Singular focus on the rapid discovery of new drugs that are clinically relevant: small molecules and biotherapeutics

• Operational since January 2012: currently 60 scientists; will grow to 75 at full capacity

• More than 200 years’ collective industry drug discovery experience

• Thorough evaluation of more than 50 potential programs: 3 inaugural programs and several in exploratory pipeline

– Disease relevance – Ease of therapeutic attack – Defined clinical trial path

Center for Co-Clinical Trials • Preclinical research arm of MD Anderson’s

Translational Research Continuum

• Disease modeling in appropriate genetic and pathophysiological contexts, focusing on understanding the biological and genotypic context in which drug targets are rate-limiting

• Promote biomarker-driven single agent and combination trials that leverage the concept of mechanistic co-extinction in appropriately selected tumor (patient) subpopulations

• Imaging infrastructure to monitor response in preclinical models

• Foster close collaboration between preclinical and clinical scientists during the very early phases of drug development to ensure quick translation of preclinical data into “smart” clinical trials

40

C Toniatti, T Heffernan

From cancer genome to clinical trials: disease genetics and pathophysiology drive response

Biomarker Driven Clinical Trials

Identify genetic alterations

Correlate to prognosis

Dx hypothesis

Rx hypothesis

Models reflect genetic alterations

Before and after treatment profiling

Patients selection based on genetic alterations

Single agent and combinations

PK/PD relationships

Imaging-aided trials

Single agent and combinations

PK/PD relationships

Imaging-aided trials

Before and after treatment profiling

Efficacy in Preclinical Models

Biomarker Driven -Responder Hypothesis

Drug Discovery

Candidate Target

New Target Hypothesis

Genomic analysis

Clinical information

and data

Treatment Decisions

& Response

Assessment

Patient Consent, Biospecimen Collection, QC, Banking , Biomolecule Processing

Omics & Research Data Big Data Platform

TCGA/ICGC Pubmed Patent db Social media Other

Longitudinal Patient Data Warehouse

Massive Data Analytics Massive Data Analytics

Watson Solutions

Research & Operations

Adaptive Learning in Cancer Care

Lynda Chin, Andy Futreal

Develop minimal Assay funnel

POC Cmpds (Selectivity)

Stringent/broad Loss of function studies

Comprehensive Target Validation

Context-specific Gain of function studies

Go/No-Go

Cmpd Efficacy Study in vivo

Lead Optimization

Clinical pathological validation

Prec

linic

al C

andi

date

Basic

and

tran

slatio

nal r

esea

rch

in a

cade

mia

Clinical Path

Human Relevance; clinical path hypothesis

Pharmacological Target Validation

Biomarker discovery Biomarker dev

Relevant MOA to define biomarkers for target engagement; pathway modulation; efficacy, etc.

Assays in human

Parallel and integrated target and drug discovery biology

Cancer Biology

Drug Discovery

Clinical Research

Drug Discovery Project at IACS – Metabolic target

44

nM cellular activity 3 Patents filed 08/12 Multiple chemotypes In vivo PoC in 3 models

On-track to select clinical candidate in 2H13

Treatment Period

Working with MDACC physician scientists to translate findings into clinical impact

Explored opportunities with eleven disease centers

Robust responses in patient samples for specific indication

Establishing PK/PD/Efficacy relationship

Potential phase 1b population identified

Comprehensive understanding of MOA

Fully enabled research operating plan

Identified tumors dependent on pathway

Exploring additional synthetic lethality opportunities

Right target, right drug, right patients

Selection of targets

• Unbiased target selection based on disease relevance

Quality of compounds identified

• Critical assessment

• Wait for right compound to be developed

• Implement industry standard stage gate - optimized for:

• Potency and cellular activity

• lack of off-target activity/ancillary pharmacology

• benign safety/toxicity profile

• pharmacokinetics, tissue distribution, efflux

• understand dosing regimes and exposure required for maximal efficacy

• appropriate physicochemical characteristics and formulation

46

Rapalog

mTOR ATP competitive Inhibitors

Protein translation is critical for malignant transformation

V Giuliani, T Heffernan

Protein synthesis is required for PI3K-AKT dependent transformation

47

Increased cap-dependent translation is required for AKT-induced lymphoma

Hsieh et al. Cancer Cell 2010

V Giuliani, T Heffernan

EIF4E knockdown inhibits growth in vitro and in vivo

48

eIF4E KD induces apoptosis IV dosing of eIF4E ASO inhibits xenograft growth

KD of eIF4E expression with antisense oligos inhibits expression of eIF4E-regulated proteins

Graff et al. JCI 2007

V Giuliani, T Heffernan

49

Targeting cap-dependent translation through inhibition of MNK1/2

MNK inhibitors

V Giuliani, T Heffernan

Comprehensive summary of in vitro MNK inhibition studies

MNK activity is not required for growth of PI3K-mut cell lines.

MNKi + Rapamycin 2D Proliferation Assay

MNKi + AZD-8055 2D Proliferation Assay

MNKi 3D Methylcellulose assay

MNKi 2D Proliferation Assay

Cell biochemical assay (Meso Scale)

Cell biochemistry

V Giuliani, T Heffernan

Proprietary and Confidential 51

pHAGE-dsRED-IRES-GFP (in house)

MNK inhibition does not reduce protein translation

CAP Dependent

CAP Independent

DMSO

MNK inhibitor

• MNK inhibition failed to decrease CAP-dependent translation

Analysis by Harmony (blue Hoechst; Green GFP; Red dsRED)

24h

MASCIA

From disconnected sequential process to fully integrated approach: only at MD Anderson!

Cancer Biology

Drug Discovery

Clinical Research

Clinical Trials

Drug Discovery

Cancer Biology

Providing access to technology vs. project financing?

European Lead Factory opens for business

Who is going to lead and integrate projects?

Not convinced this is the best option

Highlights The Karyopharm Story – born October 2010!

• Karyopharm is the leader in the science and chemistry of SINE – Selective Inhibitors of Nuclear Export – for cancer, inflammation, viral, and other proliferative disorders

• A family of closely related, oral SINEs show potent and selective anti-cancer

and anti-inflammatory activities in multiple preclinical models • KPT-330 oral SINE Phase 1 human clinical trials in solid tumors and

hematologic malignancies initiated in June 2012 – proceeding well

• KPT-335 oral SINE in Phase 1 dogs with non-Hodgkin’s lymphoma with clear activity and good tolerability – pivotal study start November 2012

• KPT-355 oral SINE for inflammatory disorders and viral infections in

preclinical development with potential for 2013 IND with partnership

Sharon Shacham, PhD, MBA – Founder, Chief Scientific Officer, Head of R&D, SAB Co-Chairman Former Sr. Vice President of Drug Development, Epix Pharmaceuticals Founding scientist, Predix Pharmaceuticals Led discovery and development from target identification through development of NCEs across multiple therapeutic areas to proof of concept studies in human (PhIIb)

Michael Kauffman, MD, PhD – Co-Founder, Chief Executive Officer and Board Member Former Chief Medical Officer, Onyx Pharmaceuticals Inc (ONXX), Proteolix Inc. Former VP, Clinical (Millenium): Led clinical development team leading to accelerated approval of Velcade® Former CEO, Epix Pharmaceuticals and Predix Pharmaceuticals - raising >$215M in 5 years Director, Zalicus (ZLCS) and former Chairman, Proteolix Inc.

Ron DePinho, M.D. – Co-Founder and Oncology Advisor President, MD Anderson Cancer Center Member, National Academy of Sciences and Institute of Medicine Former Director, Belfer Institute for Applied Cancer Science at the Dana-Farber Cancer Institute Founder & Director: Aveo Pharmaceuticals, Eden Therapeutics, and Metamark Genetics, Inc.

Mansoor Raza Mirza, M.D. – Board Member and Clinical Oncology Advisor Chief Oncologist at the Department of Oncology, Rigshospitalet, Copenhagen University Hospital National representative in the European Network of Gynecologic Oncology Trials (ENGOT) and in the Gynecologic Cancer Inter-Group (GCIG) Director: Metamark Genetics, Inc. Giulio Draetta, MD PhD – Co-Founder, Chairman of SAB and Oncology Advisor Director, Applied Cancer Genetics, MD Anderson Cancer Center Former Chief Research Business Development Officer, Dana Farber Cancer Institute; Formerly head of oncology drug discovery at Pharmacia and Merck. Scientific Advisor: Epitherapeutics, Daiichi-Sankyo, Genzyme. Former Advisor: Mitotix, Inc.

Leadership Team People

Nuclear Export Machinery

KPT-330 SINE Forces Nuclear Retention and Increases Levels of Many TSPs

DMSO

KPT- 330

p53 pRB PP2A p21 IκB p27

KPT-330 on U2OS osteosarcoma for 4-24 hours @ 1 µM (~400 ng/mL)

Forced Nuclear Retention & Activation by Blocking Nuclear Export

CRM1 Inhibition

Solid Tumor Patient 1 (3 mg/m2): p53

Solid Tumor Patient 1 (3 mg/m2): IκB (Cellular Inhibitor of NF-κB)

Summary Summary

• KPT-SINE, CRM1 Antagonists, irreversibly block the nuclear export of multiple tumor suppressor & growth regulatory proteins countering multiple oncogenic signals across a variety of tumor types

• SINE show selective tumoricidal toxicity

– Potent killing of CLL, lymphoma, MM, acute leukemia, pancreatic, HCC, and other malignant cells

– Minimal effects on normal cells which have an intact genome

• SINE are well tolerated in vivo, with oral bioavailability

– Main toxicity is weight loss (0-15%) at doses highly active across multiple xenograft experiments in mice and in dogs; mitigated with high caloric foods; No significant effects on clinical chemistry or hematologic parameters (except reticulocyte counts) at anti-cancer doses in several species

• KPT-335 oral shows clear activity in dogs with spontaneous NHL at well tolerated doses with planned FDA CVM approval in 2H 2014

• KTP-330 oral up to 12 mg/m2 well tolerated to date with clear biomarker effects, stable long-term disease control in both solid and heme malignancies, nuclear localization of tumor suppressor proteins in human K-ras colon cancer; dose escalation progressing well

Institute for Applied Cancer Science: Building team science to conquer cancer!

61

Keynote Address

Giulio Draetta, PhD, MD, Professor, Genomic Medicine Director, Institute for Applied Cancer Science, MD Anderson Cancer Center