Defined Health is pleased to presentknowledgebase.definedhealth.net/wp-content/uploads/2013...Defined Health’s Insight Series Ch iChanging AML OtOutcomes via Personalized Medicine:

Defined Health is pleased to present:

BioEurope Spring | March 11 – 13, 2013Barcelona, Spain

www.therapeuticinsight.com

24th Annual Cancer Progress ConferenceMarch 5 – 6, 2013 | Conrad New York

www.cancerprogressbyDH.com

Defined Health will also be participating in the following industry events:

AACR Annual Meeting 2013 | April 6 - 10, 2013 - Washington, DC | http://dfndhlth.com/AACR-2013Current Trends in Biosimilars Development and Regulatory Pathways in the Global

Marketplace 2012 | April 8 - 9, 2013 - Philadelphia | http://dfndhlth.com/CTBDRPGM-2012BIO International Convention | April 22 - 25, 2013 - Chicago | http://dfndhlth.com/BIO-2013

Cancer Immunotherapy Consortium, Entering the Era of Combination Therapies: Practical

AML Insight Briefing© Defined Health, February 2013

Cancer Immunotherapy Consortium, Entering the Era of Combination Therapies: Practical Implementation | April 25 - 27, 2013 - Washington, DC. | http://dfndhlth.com/CIC-2013

Defined Health’s Insight Series

Ch i AML O t iChanging AML Outcomes via Personalized Medicine: Transforming Cancer Management with Genetic InsightgMichael C. Rice, MS MBASenior Consultant

2013 Insight Series WebinarFebruary 27, 2013Florham Park, New Jersey

The information in this report has been obtained from what are believed to be reliable sources and has been verified whenever possible Nevertheless we cannotreliable sources and has been verified whenever possible. Nevertheless, we cannot guarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Defined Health, and though current as of the date of this report, are subject to change. The opinions and information set forth herein are expressed solely for the benefit of only the addressee for the purpose(s) for which the report was ordered. Without the prior written consent of Defined Health, this report may not be relied on in h l i f h b h i id dwhole or in part for any other purpose or by any other person or entity, provided

that this report may be disclosed where disclosure is required by law.

© D fi d H l h 2013© Defined Health, 2013

Page 3AML Insight Briefing© Defined Health, February 2013

The oncology market is becoming increasingly complex as new molecularly targeted therapies gain prominence

in treatment algorithms.

The Oncology Specialty Market is Predicted to Soon Outgrow the Largest PCP‐Driven Pharmaceutical Markets

140

WW Revenue By Major Therapeutic Categories

100

120 Oncology

Anti‐Infectives

CNS

C di l$B

60

80

Cardiovascular

Blood

Musculoskeletal

Endocrine

wide Sales $

40

60 Respiratory

Genito‐Urinary

Gastro‐Intestinal

Sensory Organs

Worldw

0

20

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

Various

Dermatology

Other Rx & OTC Pharma


EvaluatePharma

Targeted Biologic and Cytostatic Agents Will Drive Growth While Cytotoxics Have Become Largely Genericized

35

WW Revenue By Major Oncology Drug Category

25

30Alkaloids

Alkylating agentsmAbs

$B

20

25Antimetabolites

Monoclonal Antibodies

Cytotoxic antibiotics

AntiangiogenicSmall MoleculeCytostaticsw

ide Sales $

10

15Antiangiogenic

Cytostatics

Hormone therapies

Platinum compounds

Oth ti

y

Multi‐targeted TKIs

Worldw

0

5

Other anticancer

Unclassified

g


EvaluatePharma

1986 1989 1992 1995 1998 2001 2004 2007 2010 2013 2016

Hem/Onc Has Been a Pioneer in the FDA Approval of Drugs for Biomarker Identified Patient Segments

♦ 22 FDA approved oncology drugs for biomarker identified patient segments

>50% approved for heme, although blood cancers represent only 10% of cancer cases

Less for solid tumors, but new approvals have accelerated in recent years. Momentum expected to , pp y pcontinue as solids represent bulk of late stage pipeline.

HerceptinHer2/neu( )

Faslodex

ErbituxEGFR(CRC)(Breast) ER

(Breast) VectibixEGFR(CRC)

TykerbHer2/neu(Breast)

GleevecC‐Kit(GIST)

Erbitux, VectibixKRAS(CRC)

ZelborafBRAF

(CRC)XalkoriALK

(NSCLC)HerceptinHer2/neu(Gastric) Perjeta

StivargaKRAS, EGFR

(CRC)

RituxanCD20(NHL)

BexxarCD20(NHL)

TrisenoxPML‐RARa

(PML)ZevalinCD20(NHL)

GleevecBcr‐Abl(CML)

SprycelBcr‐Abl Tasigna

(Melanoma)(Gastric) PerjetaHer2/neu(Breast)

Mylotarg (NHL) (CML) (CML) Bcr‐Abl(CML)

GleevecPDGFR,

FIP1L1‐PDGFRa(ALL, MDS/MPD,

HES/CEL, ASM, DFSP)

AdcetrisCD30(HL) Bosulif

Bcr‐Abl(CML)

MarqiboBcr‐Abl(ALL)

MylotargCD33(AML) Mylotarg

Withdrawn(AML)


http://www.centerwatch.com/drug‐information/fda‐approvals/; Thomson Pharma Partnering

Blood Cancers Comprise A Significant Share of Top 10 Oncology Blockbusters ‐ Forecasted to Exceed $15B by 2018

2018 Top 10 Cancer Drugs ($41.3B)

Top Ten Oncology Blockbusters are Expected to Grow 26% Over the Next Five Years

Product Company Class Patent Expiry Revenue 2018 ($B)

Avastin Roche VEGF MAbs 2018 $7.6

Revlimid Celgene IMID 2026 $6.7

Rituxan Roche CD20 MAbs 2018 $6.3

Herceptin Roche HER2 MAbs 2019 $5.6

Perjeta Roche HER2 MAbs ‐‐ $3 0Perjeta Roche HER2 MAbs $3.0

Xtandi Astellas AR Inhibitor 2027 $2.9

Afinitor Novartis MTOR Inhibitor 2019 $2.8

T i N ti Abl/ Kit I hibit 2023 $2 5Tasigna Novartis Abl/c‐Kit Inhibitor 2023 $2.5

Sprycel BMS Abl/SRC/c‐Kit Inhibitor 2020 $2.0

Alimta Eli Lilly Antimetabolites 2017 $1.9


Evaluate Pharma

Hematological Malignancies Represent Only 9.5% of Newly Diagnosed Cancer Cases and Deaths Each Year

♦ Solid tumors represent >90% of 1.6M new cancer cases diagnosed in the US each year; lung, GI, prostate, breast and ovarian are the deadliest

250 000

300,000

350,000

New Cases

150,000

200,000

250,000 New Cases

Deaths

0

50,000

100,000

0


American Cancer Society

Although Blood Cancers Represent Only 1/10 of Cancer Cases, Hem/Onc Contributes About 25% of Overall Oncology Drug Revenues

ALL HL

WW Revenue of HemeMalignancies

♦ The total cancer market was about $80B in 2011

MDS$1,277M

7%

ALL$857M5%

$22M0.1%

AML$19M0.1%

♦ The Hem/Onc market was ~$20B in 2011 led by drug sales in Myeloma, CML and NHL

♦ Market Growth through 2018 is expected to

MM$5,211M27%

CLL$1,473M

8%

♦ Market Growth through 2018 is expected to maintain at 8% driven by novel mechanisms in new indications

♦ Leading drug classes such as the abl kinase

CML

NHL$5,038M26%

♦ Leading drug classes such as the abl kinaseinhibitor, Gleevec (Novartis) and the proteasomeinhibitor, Velcade (Takeda/J&J) face genericization

♦ Biosimilars to Rituxan (Genentech) threaten$5,185M27%

♦ Biosimilars to Rituxan (Genentech) threaten emerging markets and potentially Europe; while impact to the US market remains unseen


EvaluatePharma, Defined Health analysis

Targeted Therapies Addressing Unmet Needs of Blood Cancer Patients Expected to Drive Continued Market Growth

♦ The WW heme malignancy market is estimated at $20B and is anticipated to approach $30B in the next several years.

Hematologic MalignanciesWorldwide Sales & Forecasted Sales ($B)

$6

$2

$25

$30

Cytotoxics

♦ Drug sales of targeted cytostatics and antineoplastic mABs are expected to drive growth

$6

$2

$15

$20Antineoplastic mAbs

♦ Targeted therapies typically have more attractive profiles than cytotoxics

$21

$6

$10

$15

Small Molecule Cytostatics

♦ Novel mechanisms and follow‐ons to existing drug classes initially launched for refractory disease

$11

$0

$5

2011 2018

♦ New entrants likely to supplant market leaders and gain new indications based improved product profiles aligned with unmet needs


EvaluatePharma

2011 2018

Solid Tumors Dominate the Early Oncology Pipeline. However, Hem/Oncand Hematology Products are More Evenly Distributed in Pipeline

♦ Although there are roughly 8 times the number of agents in development for solid tumors than for blood cancers in early stage, relatively few are bridging the Phase II “Valley of Death.”

♦ Novel agents for blood cancers appear more rationally based and developers use less of a “shots g pp y pon goal” clinical strategy.

♦ One trend to note: The number of programs pursuing “Big 5” tumors has decreased in recent years; more promising programs are using biomarkers to identify likely responder segments.

611

500

600

700

Solid Tumors

Heme/Onc

370

209300

400

500 Heme/Onc

Hematology

117

30

209

84 8735

849

24 37 17 7 27

0

100

200


ADIS R&D Insight, Thomson Pharma Partnering

Phase I Phase II Phase III Registered Marketed

Higher Success Rates in Heme Malignancies May Reflect Differences in the Underlying Biology Versus the Highly Heterogeneous Solid Tumors

In addition, broad settings such l h ll i l d

Phase I to Market Transition Rates for Cancer

as lymphoma actually include a diversity of indications each with their own unique treatment algorithm and regimens (NHL, HL, CLL, T‐cell lymphomas [PTCL , , y p [and CTCL], etc.) as well as situations where the same drug has multiple approvals (e.g., Rituxan for aggressive and indolent non Hodgkin’sindolent non‐Hodgkin s lymphomas such as follicular and DLBCL, respectively).


Defined Health; Deloitte Recap DEVELOPMENT optimizer™ Deloitte Recap, www.recap.com

FDA Approval Of “Personalized” Cancer Drugs Changing Clinical Practice

♦ Majority of oncology franchises publicly stated intent to include a biomarker into the product development strategy for all assets entering 796510000their pipeline

Biomarker stratified patient subsets increasingly exploited by new entrants to enhance efficacy

11321000

No of biomarkers

No of drugs

>80% of current oncology pipeline (Phase 1‐Reg) includes a biomarker

♦ Although the late stage (Phase 3+) solid tumor pipeline is nearly 6 times the number of assets

252

114100

pipeline is nearly 6 times the number of assets than the hematological malignancies, the proportion of biomarker driven programs is similar at ~25%.

♦ Consequently in the next several years

10

♦ Consequently, in the next several years oncologists will need to incorporate into their practices policies and procedures for identifying the appropriate patients for a wide variety of stratified therapies.

1

Cancer AML


y p

Biopharma company websites, Thomson Pharma Partnering; clinical trials.gov; GVK BIO

Cancer Genetics is Accelerating the Time from ‘Driver Mutation Discovery’ to ‘Clinical Proof of Concept’ and the Approval of New Drugs

♦ Gleevec received FDA approval long after the discovery of the Philadelphia chromosome mutation and hyperactive BCR‐ABL protein in CML.

♦ By contrast the more recent discovery of♦ By contrast, the more recent discovery of translocations of ALK in NSCLC has rapidly translated into registration trials for Crizotinib, a ‘cMET turned‐ALK’ inhibitor, based on tantalizing response rates in ALK‐fusion‐positive tumors (Phase I and II trial results).

♦ Likewise, the development paradigm for selective BRAF inhibitors, as exemplified by PLX4032, underlines the much faster pace of translation (8 years, compared with Gleevec or Herceptin) once the driver status (in h ) h d b bl h d f lthis case BRAF mutations) had been established for malignant melanoma.

♦ Such accelerated development times are enabled by the broader body of knowledge of cancer biology and mechanisms of actions that have been generated in the cancer field.


volume 17 | number 3 | march 2011 nature medicine

g

At the same time, the combination of plummetingAt the same time, the combination of plummeting costs and increased speed of genetic analysis has nearly enabled real‐time understanding of cancer

on the molecular level.

Commoditization of Genomic Technologies is Now Making Routine Whole Genome Sequencing Feasible

Sanger PAGE Gel

SangerCapillary

MPSSMicroarray

Solid Phase Nanopore?

♦ The pace of biologic information accelerated by disruptive technology

♦ The once laborious and expensive method of DNA sequencing has now become routine,

$3 Billion and 13 years to sequence the first human genome

comparatively inexpensive platform for discovery and diagnostics

♦ As throughput increases, g p ,costs decrease rapidly and clinical use expands


Next‐Gen Sequencing Platforms are Positioning to Address the Needs of Research and Diagnostic Markets

Company/ Platform Sequencing Amplification Read length Max. Output Run time Pros/Cons

Roche 454 GS FLX+ SBS Pyro emPCR 700 bp* (SE, PE) 700 Mb 10–23 h Pro: Long reads, short run timeCon: High Mb cost, homopolymer errors

Roche 454 GS Jr SBS Pyro emPCR 400 bp* (SE, PE) 35 Mb 10 h Same as GS FLX+ Con: Lowest output of small scale instrumentsIllumina’s sequencing platform has become the dominant NGS t h l Th kfl i l th f b id lifi tiIllumina HiSeq 2000 SBS RDT Bridge PCR 36–101 bp (SE, PE) ≤300 Gb 2.5–11 days Pro: Ultra high output, ease of use

Con: No run scalability like SOLiD 5500

Illumina MiSeq SBS RDT Bridge PCR 36–151 bp (SE, PE) >1 Gb 4–27 h Pro: Proven chemistry, fully automated workflowCon: Unproven instrument

Life Technologies 5500

SBL emPCR 35–75 bp (SE, PE) 77 Gb 2–7 days Pro: Ultra high output, scalable runs allow sequencing on part flow cell

technology. The workflow involves the use of bridge amplification to clonally amplify the fragments that are then sequenced using

sequencing‐by‐synthesis (SBS) chemistry. Illumina recently rejected a $6.7 billion hostile bid from Roche.

5500 flow cellCon: Shorter reads than other platforms, longer time to clonal template prep than Illumina

Life Technologies 5500XL (4hp)

SBL emPCR 35–75 bp (SE, PE) 155 Gb 2–7 days Same as 5500

Life Technologies I T t

SBS H+ emPCR 316+318 chip100 b (SE)

316– >100 Mb318 1 Gb

2 h+ Pro: Label‐free chemistry is cheap, fast, highly scalable, long d

Ion Torrent (acquired by Life Technologies in 2010) technology measures the H+ ions released during base incorporation (rather

than fluorescence or chemiluminescence), which has allowed rapid expansion of output (~10‐fold every 6M). Rapid pace of

improvement, along with fast runs (~2 hours) and inexpensive Ion Torrent >100 bp (SE) 318– >1 Gb reads Con: Homopolymer errors, no PE yet, laborious template preparation

PacBio RS Incorp. none 2,750 bp 40Mb 30 min Pro: cost per run is substantially lower than that of the market leaders (~$100 vs ~$10,000 to $20,000)Can: cost per base is substantially higher.

p , g ( ) pconsumables has made it a popular platform.

Pacific Biosciences’ core technology is known as Single‐Molecule Real‐Time (SMRT), the first of the “third generation” platforms,

*Mode read length: the individual fragment read length is variable SBS = Sequencing‐bysynthesis; Pyro = Pyrosequencing; RDT = reverse dye terminator chemistry; H+ = Hydrogen ion

Real Time (SMRT), the first of the third generation platforms, which do not require amplification. PacBio RS promises long read‐length. short run‐time and low costs per run (~$100 vs ~$10,000 to

$20,000)


Blueseq.com; Company Reports; Analyst Reports; Clin Biochem Rev. 2011 November; 32(4): 177–195.

Mode read length: the individual fragment read length is variable. SBS = Sequencing bysynthesis; Pyro = Pyrosequencing; RDT = reverse dye terminator chemistry; H+ = Hydrogen ion detection; SBL = Sequencing‐by‐ligation; emPCR = emulsion PCR; SE = Single‐end read; PE = Paired‐end read; Mb = Megabases; Gb = Gigabases; bp = base pairs.

Emerging Technologies Aggressively Focused on Improved Throughput and Cost Reduction

Company Description

Electron Optica EM‐based sequencer in development that should be capable of directly reading sequence without requiring labeled or modified nucleotides, eliminating need for upfront sample prep. Absence of radiation damage should yield relatively low error rates.

Genia Nanopore sequencing with analog‐to‐digital sensors on integrated circuits, to facilitate increased sensitivity, dynamic creation of the li id bil ith d i d d t ti t l h t hi d i dlipid bilayer with one pore per sensor, and independent active control over each sensor to achieve desired accuracy.

GnuBIO Sequencing‐by‐hybridization (SBH) within nanodrops. Capable of high pass coverage of large gene panels (<100 genes of 1kb each). A run covering a 20 gene panel is expected to cost <$35 and take less than 2 hours. Projected list price of <$50k.

Halcyon Molecular EM‐based system will work by stretching out long individual molecules of DNA (up to 150kb) and staining them with contrast agents which will allow for the determination of individual bases with an electron microscope. Unclear how much progress has been made.

IBM/Roche(454) Developing “DNA Transistor”, a solid state nanopore which will use alternating layers of metal and dielectric material to control the f h h h h l ill i h l d l h b dIBM/Roche(454) rate of passage through the nanopore. Technology still in the early stages and no actual sequence has been generated.

LaserGen Combines National Instruments hardware with their ‘Lightning Terminator’ chemistry, a photocleavable technology compatible with standard DNA polymerases that could achieve improved accuracy and longer reads.

Lightspeed Genomics

Sub‐pixel optical technology (“Synthetic Aperture Optics”) to achieve higher resolution optics that should allow increase throughput, reduce feature size by 4X, and reduce reagent use by 16X relative to sequencers that rely on standard optics technology.

NABsys Solid state nanopore single molecule sequencer in which DNA is partially hybridized and threaded through a nanopore which can NABsys measure hybridization via electrical conductance changes. Parallel processing of strands to generate complete genome sequences.NobleGen Biosciences

DNA is converted (via ‘circular DNA conversion’) into ‘expanded synthetic representation’ (ESR) molecules that are tagged with quenched beacons through hybridization that are stripped and unquenched when passed through emission detecting nanopores.

Oxford Nanopore Technologies

GridION system involves single molecule sequencing and detection via passage through protein‐based or solid‐state nanopores. MinION is a miniature disposable single molecule sequencer that can deliver real time experimental data output via USB connection. OmniMoRA will use atomic force microscopy to measure the vibrational characteristics of individual bases on DNA molecules that haveReveo OmniMoRA will use atomic force microscopy to measure the vibrational characteristics of individual bases on DNA molecules that have been stretched and immobilized on a surface. Goal is error‐free complete genome coverage at low cost.

Starlight (Life Technologies)

Single molecule sequencing technology combined with FRET‐based detection. Owned by Life Technologies, whose current focus is on the Ion Torrent and SOLiD technologies (little if any active development on Starlight).

Stratos Genomics Nanopore‐based single molecule sequencer which converts DNA into an expanded molecule (‘xpandomer’) via polymerase‐mediatedincorporation of 4‐base oligos which contain reporter molecules that can be detected when threaded through a solid state nanopore.


ZS Genetics Single molecule sequencer which incorporates halogenated nucleotides (‘ZSG labels’) that can be detected by TEM.

Blueseq.com; Company Reports; Analyst Reports

Next‐Gen Sequencing Making Real‐Time Point of Care Genetic Analysis Feasible

♦ Oxford Nanopore Technology’s MinION Is a Sequencer the Size of a USB Memory Stick that could potentially provides the high read‐lengths with low error rates and minimal sample prep.

♦ Oxford Nanopore Technology (ONT) one of a number of companies vying to

Oxford Nanopore introduces DNA 'strand sequencing' on the high‐

♦ Oxford Nanopore Technology (ONT), one of a number of companies vying to commercialize nanopore sequencing technology, is making headlines with its miniature MinION sequencer.

p q g gthroughput GridION platform and presents MinION, a sequencer the size of a USB memory stick17th February 2012New generation of sequencing technology uses nanopores to deliver ultra long read length single molecule sequence data, at competitive accuracy, on scalable electronic GridION platform. Miniaturized version of technology, MinION, will make nanoporesequencing universally accessibleq g y

17 February 2012, Oxford, UK/FL, US. Oxford Nanopore Technologies Ltd. today presented for the first time DNA sequence data using its novel nanopore 'strand sequencing' technique and proprietary high performance electronic devices GridION and MinION. These data were presented by Clive G Brown, Chief Technology Officer, who outlined the Company's pathway to a commercial product with highly disruptive features including ultra long read lengths, high throughput on electronic systems and real‐time sequencing results.

Oxford Nanopore intends to commercialize GridION and MinION directly to customers within 2012.Oxford Nanopore's GridION system consists of scalable instruments (nodes) used with consumable cartridges that contain proprietary

hi f l i i E h G idION d d id i i i i ll d i d d li f Gb f darray chips for multi‐nanopore sensing. Each GridION node and cartridge is initially designed to deliver tens of Gb of sequence data per 24 hour period, with the user choosing whether to run for minutes or days according to the experiment.

Oxford Nanopore will introduce a new model of versatile pricing schemes designed to deliver a price per base that is as competitive as other leading systems at launch. Further substantial pricing improvements are expected with future development to the technology, in particular with increases in nanopore processing speed and higher density electronic sensor chips.Oxford Nanopore has also miniaturized these devices to develop the MinION; a disposable DNA sequencing device the size of a USB memory stick whose low cost, portability and ease of use are designed to make DNA sequencing universally accessible. A single MinION i t d t t il t l th $900


Blueseq.com; Company Reports; Analyst Reports

is expected to retail at less than $900.

Next‐Gen Sequencing Enabling Rapid Progress Toward Molecular Understanding of Numerous Cancer Types

47 Cancer Genome Projects Ongoing


http://icgc.org/

Encode Indicates that Gene Regulation is Far More Complex Than Previously Believed

♦ ENCODE, the Encyclopedia of DNA Elements, is a project funded by the NHGRI to identify all regions of transcription, transcription factor association, chromatin structure and histone modification in the human genome sequence.

20% f di DNA i th h i f ti l i l ti i ~20% of noncoding DNA in the human genome is functional in regulating gene expression 60% is transcribed with no known function. 90% of SNPs in sequences that are associated with various diseases fall outside of protein coding regions.

ENCODE investigators employ a variety of assays and methods to identify functional elements. The discovery and annotation of gene elements is accomplished primarily by sequencing RNA f di fRNA from a diverse range of sources, comparative genomics, integrative bioinformatic methods, and human curation. Regulatory elements are typically investigated through DNA hypersensitivity assays, assays of DNA methylation, and chromatin immunoprecipitation (ChIP) of proteins that interact with DNA, including modified histones and transcription factors, followed by sequencing (ChIP‐Seq).


http://www.nature.com/encode/#/threads

Without Clinical Translation, Researchers are Up to Their Eyeballs in Biologically Interesting but Clinically Useless Information


Functional Translation Outpaces the Clinical Evidence Needed to Inform Clinical Decisions Leading to Improve Patient Outcomes

1000

Published GWA Reports, 2005 – 9/20111068

600

700

800

900

1000

f Pub

licat

ions

100

200

300

400

500

Tota

l Num

bero

f

02005 2006 2007 2008 2009 2010 2011

Calendar Quarter

Genomewide Associations Reported through September 2011: Circles indicate the chromosomal location of over 800 single‐nucleotide polymorphisms (SNPs) significantly associated (P<5x10?8) with a disease or trait and reported in the literature (904 studies published through September 2011 yielded the associations depicted). Each disease type or trait is coded by color


Hindorff LA, MacArthur J (European Bioinformatics Institute), Morales J (European Bioinformatics Institute), Junkins HA, Hall PN, Klemm AK, and Manolio TA. A Catalog of Published Genome‐Wide Association Studies. Available at: www.genome.gov/gwastudies. Accessed [date of access].

Recent progress in the hematological malignancies has been largely driven by drugs targeting longhas been largely driven by drugs targeting long known biomarkers implicated in blood cancers; however, many blood cancers such as AML havehowever, many blood cancers such as AML have

been exceptionally difficult to treat.

Hematological Malignancies are Defined as Types of Cancer that Affect Blood, Bone Marrow and Lymph Nodes

♦ Hematological malignancies may derive from either of the two major blood cell lineages: myeloid and lymphoid cell lines.

Th l h id ll li The lymphoid cell lineage produces B, T, NK and plasma cells.

Cancers deriving from this lineage include lymphomas, lymphocytic leukemias and also myelomas.

The myeloid cell line normally produces granulocytes, erythrocytes, thrombocytes, macrophages and mast cellsmacrophages and mast cells.

AML, MDSs and MPDs are myeloid in origin.


Defined Health, modified from WHO Classification 2008, Hematology Am Soc Hematol Educ Program. 2009:523‐31.

Hematological Malignancies Represent a Broad Spectrum of Diseases, Each with Diverse Outcomes

Comparison of Diseases by Survival Rate, Age of Onset & Incidence

NHL CLLMM NHL CLL

CML

t

AML

MPD

Age of Onse

MDS

HL

ALL

Average A

58,000

4 300

Incidence

ALL4,300


SEER database; scientific literature. Incidence is indicated by the size of the sphere.Median 5‐year Survival Rate

Outcomes in Blood Cancers Have Been Transformed Through Both Trial and Error and Rationally Designed Transformative Therapies

• Pediatric ALL incrementally advanced through trial and error• CML transformation in the past decade based on 1 biomarker, the Philadelphia Chromosome• Serendipitously, APL outcomes dramatically improved identifying molecular drivers of disease

80

90CML

Then and Now: Age of Onset Compared to Overall Survival

CML

50

60

70

80

of Onset

Pre‐Gleevec (2001) Post‐Gleevec

APLATO&ATRA

30

40

50

verage Age o

PediatricALL1960s

Trial and error incremental advancement

APL1980s

Today

0

10

20

0% 20% 40% 60% 80% 100%

Av

1960sPediatric

ALLToday


SEER database; scientific literature Median 5‐year Survival Rate0% 20% 40% 60% 80% 100%

AML is now the most molecularly characterized cancer to confirm prognostic significance of known mutations and to identify novel drivers of leukemogenesis as

l f h d l f llpotential targets for the development of rationally designed therapies for AML.

AML is Mainly a Disease of Older Adults

♦ Acute myeloid leukemia (AML) is a life‐threatening disease in which hematopoietic progenitor cells committed to the myeloid lineage that normally develop into neutrophils, basophils, eosinophils, and monocytes become cancerous and infiltrates the bone marrow with rapid p , y pgrowth kinetics.

♦ 2012 US AML statistics:

Estimated new cases in US: 13,780

Expected mortality: 10,200

90% of new cases in adults

Average age at diagnosis >65 yrs♦ The disproportionate impact of AML on the

very old is evident in comparing the incidences in the entire US population and in people older than 75: 2.6 vs.16 per 100,000.

♦ The greater incidence in older adults may be due to cumulative exposure to carcinogens, radiation and chemotherapy for other malignancies, and also to improved screening


American Cancer Society, www.cdc.gov; SEER; Medscape, Lancet JE, Willman CL, Bennett JM. Hematol Oncol Clin North Am. 2000;14:251‐267.

malignancies, and also to improved screening and surveillance.

AML is a Group of Related, Yet Distinct, Myeloid Neoplastic Disorderswith Divergent Outcomes

♦ FAB divides AML into subtypes, M0 through M7, based on the type of cell from which the leukemia developed and maturity based on microscopy after routine staining.

Sub classification % Diagnosed AML Characteristics PrognosisSub‐classification % Diagnosed AML Characteristics Prognosis

M0 5 very early cells, or blasts Poor

M1 15 some maturing cells Average

M2 25 mature cells with granules and "Auer rods" Good

M3 10called promyelocytic (APL); many granules and Auer rods in mature looking cells. treated with ATRA and chemotherapy, sometimes arsenic trioxide

Excellent

M4 25 called myelomonocytic; cells are mature Average to Excellent

M5 5 called monocytic because of cell appearance Very Poor

M6 5 called erythroid or DiGuglielmo’s syndrome; this is why not all AMLs are white blood cell diseases Very Poor

M7 10 called megakaryoblastic; lots of megakaryocyte f t i bl d l t hit bl d ll l k i Poor

♦ WHO classification incorporates genetics and clinical features of AML in an attempt to define entities that are biologically homogeneous and that have prognostic and therapeutic relevance.

♦ Each criterion has prognostic and treatment implications but, for practical purposes, antileukemic

fragments in blood; also not white blood cell leukemia


American Cancer Society, www.cdc.gov

p g p , p p p ,therapy is similar for all subtypes.

AML Prognosis Has Progressed from Clinical Criteria and Cytology…

Historically the most important prognostic indicators to base treatment decision include:♦ AML subclassification:

Diff t t f th b d d th lik l f th di d i b Different types of therapy may be used and the likely course of the disease and prognosis may be different.

Leukemias that express the progenitor cell antigen CD34 and/or the P‐glycoprotein (MDR1 gene product).

♦ Age and general health of Patient:

Increasing age is an adverse factor because older patients more frequently have a prior AHD and also co‐morbid medical conditions that compromise the ability to give full doses of chemotherapy.

Clinicians consider age 55 65 a general cut off when considering aggressive high dose Clinicians consider age 55‐65 a general cut‐off when considering aggressive, high‐dose chemotherapeutic treatment.

♦ Prior antecedent hematologic disorder (AHD):

An AHD such as myelodysplastic syndrome (MDS) is associated with a poor outcome to therapy.

♦ Prior Treatment:

High‐doses of anthracyclines, in particular, is important when assessing risk of cumulative dosing toxicities.

Treatment induced secondary AML


American Cancer Society, www.cdc.gov

Treatment‐induced secondary AML.

… To Cytogenetic Stratification

♦ According to clinicians cytogenetics and molecular characterization has become one of the most important prognostic indicators in the treatment decision.

♦ Th t ti i k l ifi ti♦ The cytogenetic‐risk classification summarized in the table is based on studies that predominantly included younger AML patients, b l 56 60 fbelow 56 or 60 years of age.

♦ Two subsequent studies analyzed the prognostic significance for pretreatment cytogenetic findings p y g gin outcome of older AML patients, a group whose outcome is generally worse than that of younger patients.


y g p

Krzysztof Mrózek and Clara D. Bloomfield, Hematology 2006

… To Molecularly Defined Risk Assessment

♦ Patients with a normal marrow karyotype are the largest cytogenetic subset of AML and are classified in the intermediate prognostic category, but not all patients benefited equally from these high dose chemotherapy.

♦ The likely reason for such variable response is the striking molecular heterogeneity of cytogenetically normal AML patients.


Krzysztof Mrózek and Clara D. Bloomfield, Hematology 2006

Molecular Heterogeneity of AML Translating Into Useful Prognostic Information

Heterogeneity of Cytogenetically Normal AML


BLOOD, 21 JANUARY 2010 VOLUME 115, NUMBE,March 22, 2012; n engl j med 366;12, p 1079 R 3

However, AML Treatment Has Not Changed Much In Over 30 Years

Diagnosis / Workup(Morphology, Immunophenotype, Cytogenetics, molecular markers, Cli i l i ( S)

♦ The treatment of patients with AML ranges from standard therapy, to investigational approaches, to palliative care.

Clinical Presentation (age, PS)

Initial Treatment• Remission Induction

pp , p

♦ The three stages of standard treatment for AML are:

1. Remission Induction therapy: Treatment h ld b ff l h

Remission Induction• Clinical Trial• Best Supportive care

should be sufficiently aggressive to achieve complete remission (CR= <5% blasts in bone marrow) because partial remission offers no substantial survival benefit.

Post Remission Therapy•Consolidation

2. Post‐remission therapy: Post‐remission therapy primarily consists of consolidative treatment with high dose chemotherapy.

3 Salvage Therapy: Following initial induction

Salvage TherapyLong Term Remission / Cure

3. Salvage Therapy: Following initial induction and consolidation treatment, patients are then treated with salvage therapy if they fail to achieve initial CR (primary refractory) of after disease recurrence (relapse)


Remission / Cureafter disease recurrence (relapse) .

As A Case for Personalized Antileukemic Therapy, APL is a Biomarker Identified Subpopulation Benefiting from ATRA/ATO‐Based Regimens

ATRA (all trans retinoicI d i

Acute promyelocytic leukemia (APL)

♦ APL is a subtype of AML (M3) in which the retinoic acid receptor alpha (RARα) gene on 17q12 fuses with a nuclear regulatory factor on 15q22 (PML gene). APL h iti it t t t t ith ll t ti i id (ATRAATRA (all‐trans retinoic

acid) and anthracycline‐based chemotherapy

ATRA / ATO and low dose

Induction

Consolidation

♦ APL has a sensitivity to treatment with all‐trans retinoic acid (ATRA, tretinoin), which acts as a differentiating agent. Initial treatment usually involves an anthracycline

(daunorubicin or idarubicin) plus ATRA. This treatment induces remission in about 80% to 90% of

chemotherapy

ATRA and anthracycline‐

Consolidation

M i

patients. ♦ As with other subtypes of AML, patients with APL then receive post‐

remission treatment. Consolidation therapy usually consists of 2 or more courses of

an anthracycline usually along with ATRAATRA and anthracycline‐based chemotherapy

Maintenance an anthracycline, usually along with ATRA. Consolidation is followed by maintenance therapy with ATRA

for at least a year. ♦ Arsenic trioxide, an agent with both differentiation‐inducing and

apoptosis‐inducing properties against APL cells, is used to re‐induce

Arsenic trioxide(ATO) / Autologous BMT

Salvage remissions in patients with relapsed APL. Clinical complete remissions have been reported in 85% of

patients induced with arsenic trioxide, with a median time to clinical complete remission of 59 days.

♦ About 70 90% of patients with APL are cured with treatment


DH primary research; http://www.cancer.gov/cancertopics/pdq/treatment/adultAML/healthprofessional/allpages

♦ About 70‐90% of patients with APL are cured with treatment.

AML Remains Among Highest Unmet Need Cancer Treatment Segments

90

Comparison of Leukemias by Survival Rate, Age of Onset & Incidence

Acute Myeloid Leukemia

Chronic Myeloid Leukemia

60

70

80

gnosis

MyelodysplasticSyndromes

Acute Lymphocytic

Chronic Lymphocytic Leukemia

Acute MonocyticLeukemia

40

50

60

e Ag

e of Diag

Acute Lymphocytic Leukemia (Pediatric)

Leukemia (Adult)

10

20

30

Average

0

10

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

5 S i l

* Bubble size proportionate to new incidence


5 year Survival

AML Remains Among Highest Unmet Need Cancer Treatment Segments

♦ ~75% of adult AML patients fit enough for chemotherapy (“7+3” regimen comprised of cytarabine with an anthracycline) achieve complete remission (CR); however, only 20 – 30% of patients achieve long‐term disease‐free survival.

♦ Younger patients (<60yr) then to respond well to aggressively induction therapy, but AML more common in older patients (>60yr) who are more likely to have comorbidities that can limit treatmentolder patients (>60yr) who are more likely to have comorbidities that can limit treatment.

♦ Disease tends to be more treatment resistant in older patients, (de novo, antecedent MDS, sAML) with dramatically worse outcomes than in younger adults.

♦ Many studies have compared the option of best supportive care with that of a standard “3 + 7” induction regimen for older patients with AML which show trends toward improved survival when patients received chemotherapychemotherapy.

♦ However, it is important to be reminded of a sobering statistic—older patients with AML, usually defined in clinical trials as above 55 or 60 years of age, have a median time from treatment with 3 + 7 regimens to death of only 5‐10 months.

Patient Age % of Cytogenetics BMT? Relapse ratePatient Age(median CR)

% of patients

Cytogenetics BMT? Relapse rate

<60 (60‐80%)

40% good No (consolidative chemo) 30%

40% Int/poor Yes 20%

20% I t/ N ( d ti t f l 60%20% Int/poor No (no donors, patient refusal, commorbidities)

60%

>60yr (50‐60%)

20% Int/poor Yes (non‐myeloablative) 30%

80% All types No 80%

/ ( )


>70yr (<10%)

100% All types No N/A (BSC)

However, Despite the Seemingly Low Benchmark, Many Agents Have Failed in AML Across Multiple Subsets

Trial Design

Product MOA 1st Line Relapsed /Refractory Elderly Comparator Commentary on Discontinuation

re Reg Laromustine

VionAlkylatingAgent

Historical:Single‐arm,monotherapy

• FDA rejected NDA, requesting RCT Ph 3 trial demonstrating survival benefit

Historical:

Pr ClofarabineGenzyme

Nucleoside Analog

Historical:Single‐arm,monotherapy

• FDA rejected submission, requested RCT Ph 3 trial

OblimersenGenta

Bcl‐2 inhibitor RCT: Dauno +

AraC +/‐ agent • Failed to meet OS endpoint

ase 3 Lintuzumab

Seattle Genetics

CD33 antigen inhibitor RCT: LoDAc +/‐

agent• Failed to meet OS endpoint• Ph2b registration study

DNA Historical:

Pha Troxacitabine

SGX/Eli Lilly

DNA synthesis inhibitor

Historical: Single‐arm,monotherapy

• Poor efficacy – Response rates

AmonafideAntisoma

DNA topo‐isomerasei hibit

RCT: AraC + agent vs. • Failed to meet CR endpoint

• Secondary AML patients


Antisoma inhibitor Dauno + AraC Secondary AML patients

Sources: 1) Adis; 2) IDDB ; Note: Analysis limited to studies post‐2005 in Phase 2b or higher, for which discontinuation in AML was discernibly related to trial outcomes in AML

Near Term Advancement in AML Treatment is Likely to be Incremental

WW AML Revenue ($US Millions)♦ Several other products designed to improve upon chemotherapy have progressed to late stage development for which physicians are optimistic to have access to in the

f$700

near future. Sunesis’ Vosaroxin, currently in phase 3 for primary refractor

and relapsed AML, is designed to avoid resistance mechanisms and broaden the therapeutic index of anthracyclines.

$400

$500

$600

y Clavis’ elacytarabine is designed to increase import of the

toxic nucleoside into the nucleus in phase 3 for second salvage.

Cyclacel’s Sapacitabine is being tested in phase 3 trials (SEAMLESS t i l ) f t t t ï d l d ld l

$200

$300

$400

(SEAMLESS trials) for treatment‐naïve and relapsed elderly AML patients, in 2012 Cyclacel announced a CR rate of 25% at the highest dosing schedule (400 mg sapacitabine bid for 3 consecutive days per week every 3 to 4 weeks).

♦ Dacogen (decitabine) first new approval in AML in over a $0

$100

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018g ( ) pp

decade. Although FDA did not grant Eisai/Astex approval earlier this year, J&J/Astex recently received EMA approval based on Phase 3 DACO‐016 trial results showing 7.7 months median overall survival in patients taking decitabinecompared to 5 0 months for standard treatment

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

Mylotarg PKC412 QuizartinibRubida Tamibarotene TrisenoxVosaroxin Dacogen


EvaluatePharma

compared to 5.0 months for standard treatment.

Indeed, academia, biotech, pharma and diagnostic providers are using biomarkers to both improveproviders are using biomarkers to both improve chemotherapy and to develop new classes of

therapies inhibiting the molecular drivers of AML.

Therapies in Development for AML Represent Nearly 1/5 of the Pipeline for Heme Cancers

Number of Agents In Clinical Development (P1‐Reg) For Hematological Malignancies

NHL

HL3%

CML5% ALL

6%

g g

NHL26%

AML18%

6%

OTHER MYELOID10%

CLL

18%

(Total= 400)

10%MM19%

13%


ADIS R&D Insight, Thomson Pharma Partnering

AML Has Comparably the Broadest Pipeline Among Blood Cancers by MOA

♦ Development Stage Agents, Discovery To Registration By Indication & Rolled‐up Mechanism

Indication / MOA Protein Enzyme Biological factor Peptide Immune

system Cell

physiologyMacro‐molecule

Growth substance

Nucleic acid nucleoside Cell Carbohydrate

metabolism

Signal trans‐duction

Alkylating agents

Photo‐sensitisers

Anti ‐metabolites

Genetic process

Inorganic chemical

Ionising agents

Acute lymphoblastic leukemia 2 8 1 2 1 1 3 1 1

Acute myeloid leukemia 18 25 11 9 4 7 2 2 10 1 1 2 2 1 1

Acute nonlymphocytic leuk. 1

B cell lymphoma 1 4 1 1 1 1 1

Chronic lymphocytic leukemia 11 13 11 6 7 5 3 1 4 2 1 1

Chronic myeloid leukemia 5 6 5 5 4 2 1 1Chronic myeloid leukemia 5 6 5 5 4 2 1 1

Cutaneous T cell lymphoma 2 6 2 1 1 2 1 1

Diffuse large B cell lymphoma 4 13 7 3 4 1 1 1 3 2 1 1

Follicular lymphoma 3 6 4 2 3 2 1 1

Giant lymph node hyperplasia 1 1 1

Hairy cell leukemia 1 1 1 1Key

# Dev. AgentsHodgkin's disease 2 4 1 1 1 1 1 1

Leukemia 2 4 2 2 1

Lymphoma 3 1 1 2 1 1 1

Lymphoproliferative disorders 1 1 1 1

Mantle‐cell lymphoma 3 11 3 1 5 3 1 1 1 2 1

M lti l l 19 17 14 10 5 8 4 3 3 2 4 2 2 1

g01

2 ‐ 55 ‐ 1010 ‐ 2020‐50>50Multiple myeloma 19 17 14 10 5 8 4 3 3 2 4 2 2 1

Myelodysplastic syndromes 5 11 3 3 3 3 2 4 1

Non‐Hodgkin's lymphoma 13 13 12 5 9 5 6 1 3 3 1 1 1 1 1

Peripheral T‐cell lymphoma 1 5 1 1 1 1 1

T cell lymphoma 2 2 2 1 1

T cell prolymphocytic leukemia 1 2 1 1 1 1

>50


ADIS R&D Insight

Waldenstrom's 2 3 2 1 1 1

Novel clinical stage agents pursuing different MoAs and AML patient settings

Phase 3Phase 3Phase 2Phase 2Phase 1Phase 1Chemotherapy

Vosaroxin

Epigenetic ElacytarabineQuizartinib

Crenolanib

Rigosertib

AT 9283

SL 401

MDX 1338

RG 7536

Tosedostat

Immuno‐therapy

Kinase Inhibitor

Other

Selumetinib

Proapoptotic

LOR 2040

Ponatinib

Idelalisib

ENMD 2076

AZ 1208

MK 8242

SL 401

AVE 9633

DCPrime Vac

ALT 801

CNDO 109

Lintuzumab Ac‐225

ElesclomolTriciribine

CA1PDFP 10917

PR 104

BP 100‐1‐01

CWP 232291PLX 3397

Relapsed / Refractory

Temozolomide

CPX‐351

Arsenic trioxideOmacetaxine SapacitabineLestaurtinib

LenalidomideLintuzumab Bi‐213

VolasertibBI 811283 VidazaGanetespib

LiriilimumabSGI‐110

Treosulfan

BelinostatBirinapant

KX2 391 PRI 724

PF 4449913

RG 7112

Non‐Candidates for Induction CT

Imatinib

OCV 501AEG 35156

Midostaurin

Imatinib

GRNVAC1

Sorafenib

GVAX (postHSCT)

WT1‐A10+AS01B ASCI

131‐I‐anti‐CD45Induction CT orConsolidation

Trials in Multiple (or Plerixafor PracinostatAKN 028

Rebastinib

p.DOM‐WT1‐126 Vorinostat

Panobinostat


Sources: 1) ADIS; 2) IDDB; 3) ClinicalTrials.gov; 4) DH analysis

undefined) Settings BL 8040RebastinibrhH1.3

VAL‐1000Panobinostat



Vosaroxin


Crenolanib

Rigosertib

AT 9283

SL 401

MDX 1338

RG 7536

Tosedostat

Immuno‐therapy

Kinase Inhibitor

Other

Selumetinib

Proapoptotic

LOR 2040

Ponatinib

Idelalisib

ENMD 2076

AZ 1208

MK 8242

SL 401

AVE 9633

DCPrime Vac

ALT 801

CNDO 109Results from a P2 study in AML and MDS showed that, out of 38 AML pts treated

Progress has been made in deciphering the molecular pathogenesis of AML which has led to the development of molecularly targeted kinase inhibitors of the signalLintuzumab Ac‐225


CA1PDFP 10917

PR 104

BP 100‐1‐01

CWP 232291PLX 3397


out of 38 AML pts treated with tosedostat, 3 achieved CR and 7 achieved PR lasting 1‐3 months.

targeted kinase inhibitors of the signal transduction cascades (eg,FLT3, KIT, RAS).Such targeted approaches may transform specific segments of AML similar as l f d h l

Temozolomide

CPX‐351





Treosulfan


KX2 391 PRI 724

PF 4449913

RG 7112


Imatinib

Sapacitabine is being tested in treatment‐naïve and relapsed elderly AML patients

Gleevec transformed CML; however, initial attempts have been met with futility.

OCV 501AEG 35156

Midostaurin

Imatinib

GRNVAC1

Sorafenib

GVAX (postHSCT)




Rebastinib


Panobinostat

naïve and relapsed elderly AML patients, demonstrating a CR rate of 25% at the highest dosing schedule (400 mg sapacitabine bid for 3 consecutive days per week every 3 to 4 weeks)




VAL‐1000Panobinostatper week every 3 to 4 weeks).



Vosaroxin


Crenolanib

Rigosertib

AT 9283

SL 401

MDX 1338

RG 7536

B‐Cell Vaccines: Rapid di ki ti i AML

Tosedostat

Immuno‐therapy

Kinase Inhibitor

Other

Selumetinib

Proapoptotic

LOR 2040

Ponatinib

Idelalisib

ENMD 2076

AZ 1208

MK 8242

SL 401

AVE 9633

DCPrime Vac

ALT 801

CNDO 109

Proapoptotic Agents are promising; however, development may have been challenged by technology employed

disease kinetics in AML represents a challenge for therapeutic vaccine creation, administration and eliciting a meaningful response. However may have a role inLintuzumab Ac‐225


CA1PDFP 10917

PR 104

BP 100‐1‐01

CWP 232291PLX 3397


(oligonucleotides) in early agents rather than target.

However, may have a role in maintaining durable remissions.

Temozolomide

CPX‐351





Treosulfan


KX2 391 PRI 724

PF 4449913

RG 7112


Imatinib

Agents that target Stem Cell Mobilization and Self Renewal are among the most promising emerging therapies in AML, but lack

OCV 501AEG 35156

Midostaurin

Imatinib

GRNVAC1

Sorafenib

GVAX (postHSCT)




Rebastinib


Panobinostat

validation:




VAL‐1000Panobinostat

AML Leads Sequencing Efforts – Although Translation is Needed, Early Data is Redefining Understanding of Cancer Progression

♦ In 2008, a team led by Dr. Timothy Leybecame the first to sequence an entire cancer genome using a patient’s own cancerous cells. The cancer they chose to sequence first was AML.

♦ Today hundreds of AML genomes have been sequenced (between TGI and other WGS initiatives) that are mapping genetic mutations impacting the etiology, prognosis, responsiveness to therapy and progression of AML.


http://genome.wustl.edu/projects/cancer_genomics

Basic Research: Acceleration of Peer Reviewed Publications in AML by Funding Basic and Translational Research

AML Publication History

s 1400

1600

1800

Since 2008, Rapid increase in publications ti bi k (i l di WGS)

Publications

1000

1200

1400 on prognostic biomarkers (including WGS), disease pathways therapeutic targets and experimental molecules targeting

Num

ber o

f P

400

600

800

N

0

200

1974 1979 1984 1989 1994 1999 2004 2009


NCBI PubmedYear

2012 Appears to be a Pivotal Year for AML in the Age of Genomics: Understanding Mutations Driving AML Relapse

Seminal publications on findings from AML and MDS whole genome sequencing efforts provide context for applying data toward improving patient management:

“Clonal evolution in relapsed acute myeloid leukaemia revealed by whole‐genome sequencing.” Ding L, et. al.p y y g q g g ,

Investigation of the mutational spectrum associated with relapse by comparing de novo AML with relapse genomes using deep sequencing. Results provided clonal evolution patterns precisely at relapse and discovered novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML. Two major clonal evolution patterns were observed: (1) the founding clone in the primary tumor gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy gained additional mutations and expanded at relapsesubclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. Chemotherapy failed to eradicate the founding clone and DNA damage caused by cytotoxic chemotherapy may shape clonal evolution and resistance.


Nature. 2012 Jan 11;481(7382):506‐10

2012 Appears to be a Pivotal Year for AML in the Age of Genomics: Understanding Mutations Driving Progression from MDS

♦ Seminal publications on findings from AML and MDS whole genome sequencing efforts provide context for applying data toward improving patient management:

“Clonal Architecture of Secondary Acute Myeloid Leukemia”, Matthew J. Walter, et. al.

♦ Profile of the genetic changes that underlie progression from the MDSs to secondary AML. The secondary‐AML samples contained mutations in 11 recurrently mutated genes, i l di 4 h h bincluding 4 genes that have not been previously implicated in the MDSs or AML.

♦ Progression to acute leukemia was defined by the persistence of an antecedent founding p gclone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations.


March 22, 2012; NEJM 366;12, p 1090

Genomics is Improving AML Prognostication and Treatment Strategies

♦ Seminal publications on findings from AML and MDS whole genome sequencing efforts provide context for applying data toward improving patient management:

“Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia”

♦ Investigated the prognostic value of recently identified somatic mutations in the context of a phase 3 trial comparing outcomes for patients treated with standard dose and high d d bi idose daunorubicin.

♦ Results demonstrated that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high‐p p gdose induction chemotherapy in patients with AML.


March 22, 2012; n engl j med 366;12, p 1079

Translating Genomic Analyses Into Drug Programs: Academics and Industry, with Support from Government and Philanthropy

Mutated Gene Development Projects


FLT3 (ITD TKD) 42 PHF6 0Recent genome‐wide analyses

FLT3 (ITD, TKD) 42 PHF6 0

NPM1 0 KRAS 3

DNMT3A 1 PTEN 1

NRAS 11 TP53 21

in patients with a variety of myeloid malignancies not only validated known markers, but has led to the rapid discovery

NRAS 11 TP53 21

CEBPA 0 HRAS 1

TET2 0 EZH2 5

WT1 11 CDH23 0

of a series of recurrent genetic alterations, leading to:• New programs pursuing the prognostic and therapeutic

i l f l i i WT1 11 CDH23 0

IDH2 4 PTPN11 0

IDH1 3 SMC3 0

KIT 41 STAG2 0

potential of novel epigenetic targets (e.g., DNMT3A, IDH1/2, MLL, EZH2 and RAS).

• Renewed interest in kinaseinhibitors given recent clinical

RUNX1 0 U2AF1 0

MLL‐PTD 7 UMODL1 0

ASXL1 0 ZSWIM4 0

inhibitors, given recent clinical responses with next generation inhibitors (FLT3, KIT, RAS).


However, Observed Mutations Need to be Vetted to Differentiate Drivers vs. Passengers in Disease Progression and Potential Therapeutic Targets

Model for evolution of genetic changes in acute myeloid leukemia

♦ A hypothetical model in which nonpathogenic somatic mutations (1–3) acquired over the lifespan of a stem cell are propagated in the malignant clone after it acquires a critical initiatinglifespan of a stem cell are propagated in the malignant clone after it acquires a critical initiating mutation (4). Mutation 5 is a progression mutation that cooperates with the AML‐initiating mutation 4 to contribute to AML development. Other mutations (represented by 6 and 7) do not cooperate with the AML‐initiating mutation 4, and do not contribute to AML development. These subclones are lost or fail to expand to the limit of detection by sequencing studiesThese subclones are lost, or fail to expand to the limit of detection by sequencing studies.

AML A l id l k i HSC H i i ll


AML: Acute myeloid leukemia; HSC: Hematopoietic stem cell.

From:Walter MJ, Graubert TA, DiPersio JF, Mardis ER, Wilson RK, Ley TJ Next‐generation sequencing of cancer genomes: back to the future. Per Med 2009 Nov 1;6(6):653

Large number of variants in myeloid malignancies appear to be in genes whose function is involved in epigenetic regulation of gene transcription

Histone methyltransferases (HMTs) are enzymes that catalyze the addition of

The discovery of the first histonedemethylase (HDM) fundamentally

Readers are proteins that bind to specific recognition domains typicallyenzymes that catalyze the addition of

methyl marks to histone proteins. These types of chemical modifications to histones impact chromatin architecture and the regulation of

demethylase (HDM) fundamentally changed the understanding of the reversibility of histone methylation. There are two families of HDMs –amine oxidases and hydroxylases –

specific recognition domains, typically methyl or acetyl marks, on chromatin in a highly regulated manner. These chromatin‐binding events result in the modulation of chromatin architecture,

gene expression. Aberrant activity of HMTs is implicated in a host of human diseases, including oncology, inflammation, infection, metabolism, and neurology

and both are implicated in human diseases, including cancer, inflammation, and metabolic disease.

which impacts gene expression and are ultimately implicated in key cellular processes such as cell cycle progression, cytokine signaling, and viral integration


http://www.constellationpharma.com/research‐development/

and neurology. viral integration

Progress For Epigenetic Inhibitors as Cancer Therapies


Epigenetic Inhibitors as Cancer Therapies

Several Early‐Stage Biomarker‐Driven Drug Development Programs Pursuing AML


TargetingAML


TargetingAML

FLT3 (ITD, TKD) 42 P2 PHF6 0

NPM1 0 KRAS 3

DNMT3A 1 PTEN 1

NRAS 11 TP53 21 P1

CEBPA 0 HRAS 1

TET2 0 EZH2 5 PC

WT1 11 P2 CDH23 0WT1 11 P2 CDH23 0

IDH2 4 PC PTPN11 0

IDH1 3 PC SMC3 0

KIT 41 STAG2 0

Com

mon in AKIT 41 STAG2 0

RUNX1 0 U2AF1 0

MLL‐PTD 7 P1 (Dot1L) UMODL1 0

ASXL1 0 ZSWIM4 0

AM

L and MD

S


ASXL1 0 ZSWIM4 0

S

Whole‐Genome Interrogation in AML Uncovers Novel and Potentially Drug‐able Epigenetic Targets

♦ In the last 3 years alone, mutations in genes that affect

Adapted from: Adv Hematol. Epub 2011 Jun 26

Gain‐of‐function loss‐of‐functiongDNA and/or histone lysine methylation:

TET2, IDH1, IDH2, DNMT3 d EZH2 h

IDH1/2mutations

alterationloss‐of‐function

alteration

EZH2mutations

TET2DNMT3a, and EZH2 – have all been found in patients with MDSs and/or AML.

DNMT3A

mutations

IDH1/2mutations mutations

Specific histone and DNA posttranslational modifications shown to be associated with mutations in epigenetic modifiers in hematologic malignancies


Rapid Translation from WGS to Therapeutic Program in AML Isocitrate dehydrogenase‐1 (IDH1) and IDH2

2009

• Whole genome sequencing (WGS) study identifies Isocitrate dehydrogenase‐1 (IDH1) and IDH2 as novel genes frequently mutated in MDSs and AML.

2009

• Gain of function mutations in IDH1/IDH2 identified in AML patients in subsequent

2010‐11

studies; shown to result in hypermethylation cell phenotype and impaired hematopoietic differentiation.

• Agios Pharmaceuticals awarded US Gov’t grants for development of company's cancer metabolism therapeutics, including IDH inhibitors.

• Agios enters strategic collaboration with Celgene involving IDH1.

2012• QIAGEN developing a test for mutations of IDH1 and IDH2 genes as a companion diagnostic for use with certain drug therapies for cancer.


Additional Epigenetic‐Targeting Therapeutic Initiatives Sparked by WGS

♦ EZH2 (enhancer of zeste homolog 2) is a highly conserved enzyme which serves as a histone H3 lysine 27 (H3K27) methyltransferase (HMT).K t b d i l ith li l li i f ti l i 2010♦ Known to be overexpressed in several epithelial malignancies for some time, only in 2010 was it discovered that EZH2may be mutated in hematopoietic malignancies.

♦ Industry has become rapidly engaged in the pursuit of novel small‐molecule inhibitors of HMTs, including EZH2, in a bid to identify potential therapeutics for multiple forms of , g , y p p pcancer including leukemias, non‐Hodgkin's lymphoma, and breast cancer.

Partnership with Leukemia & Lymphoma Society (Sept 2012).

Partnered with Eisai (March 2011) around EZH2.

Strategic alliance with GSK (January 2011) to In Jan. 2012, entered into a broad

epigenetic‐based drug discovery collaborative agreement with Genentech in cancer and other diseases.

discover, develop, and market novel small molecule therapeutics targeting HMTs.

Funding from The Leukemia & Lymphoma Society

Epizyme Eisai and Roche to Develop EZH2


Epizyme, Eisai and Roche to Develop EZH2 Companion Diagnostic (2013)

Rapid Translation from WGS to Therapeutic Program in MLL genetically defined acute leukemias

• Whole genome sequencing (WGS) studies identify DOT1L – a histone H3 methyltransferase – mutations associated with acute leukemias.

• Mixed lineage leukemia (MLL) patients identified by the presence of a chromosomal translocation (MLL‐translocation) that directs DOT1L activity to unusual gene

2009‐locations, leading to up‐regulation of oncogenic gene products that drive leukemia cell proliferation

• Epizyme initiates program to design small molecule DOT1L inhibitors to selectively target and kill MLL cells while sparing cells that do not contain the MLL‐translocation.

• Epizyme and Celgene form a strategic partnership to discover, develop and commercialize personalised therapeutics based on small molecule HMT inhibitors, with focus on Epizyme’s DOT1L inhibitors.

2012

• Phase I clinical trial of first DOT1L inhibitor ‐ EPZ 5676 – initiated late 2012 to evaluate the agent in patients with advanced haematological malignancies, including an assessment of the preliminary efficacy of EPZ 5676 in a cohort of patients with MLL.

• Epizyme will retain all US rights to the programs and receives a $US90 million upfrontEpizyme will retain all US rights to the programs and receives a $US90 million upfront payment, with potential to earn > $160M in milestone payments and up to double‐digit royalty payments on ex‐US sales for each HMT inhibitor licensed by Celgene


Chromatin “Readers” also Generating Significant Interest in Hematological Malignancies and Elsewhere…

♦ Bromodomains are acetyl‐lysine binding pockets that target bromodomain‐containing proteins to histones and thereby affect chromatin structure and function.h (b d i d i l) i f l l l d♦ The BET (bromodomain and extra‐terminal) proteins are four closely related bromodomain‐containing proteins (BRD2, BRD3, BRD4, and BRDT) which constitute a subset of the larger family of 47 bromodomain‐containing proteins.

♦ The binding of BET protein bromodomains to chromatin regulates gene expression♦ The binding of BET protein bromodomains to chromatin regulates gene expression (including MYC‐dependent transcription) and have linked BETs to different cancers including midline carcinoma, leukemia and squamous cell carcinoma.

Partnership with Leukemia & Lymphoma Society (Sept 2012) to identifying novel small molecule inhibitors of BETs for hematological malignancies

Phase I trial of small molecule inhibitor— GSK 525762 in patients with NUT midline carcinoma .

Developing small molecule bromodomain inhibitors for cancer and potentially inflammatory disorders.

Lead programs aimed at NUT midline


hematological malignancies. carcinoma, AML and multiple myeloma.

h d f l llIn the not‐too‐distant future, oncologists will have access to an increasingly complex set of data enabling great insight into an individual’sdata enabling great insight into an individual s cancer capable of transitioning from empiric

cancer management to one guided by biomarker g g ytests and predictive algorithms.

However, the integration of clinical, cytogenetic and molecular data will be essential to translate research momentum into better outcomes forresearch momentum into better outcomes for

patients with AML.

Current Clinical Evaluation of Acute Myeloid Leukemia and Potential Future Testing.Current Clinical Evaluation of Acute Myeloid Leukemia and Potential Future Testing

♦ In the future prognostication in myeloid cancers may rely on the analysis of many genes with clinical relevance and a patient's germline may be investigated simultaneously with the disease, enabling an assessment of inherited predispositions.

Several challenges exist to widespread implementation of molecular profiling to

Testing in the future may be dominated by genomics‐based molecular profiling, which may

The current standard evaluation of AML samples includes morphologic evaluation flow cytometric

generate diagnostic and prognostic information, but these challenges may be overcome soon, and molecular profiling may herald a new approach to testing in leukemia and, by extension, other

g p g, yinclude real‐time PCR assays, microarray analysis, and next‐generation sequencing; together, these tests have the capacity to define the gene‐expression signature of the leukemia and thereby determine the cell lineage of the disease, as well as to identify common chromosomal rearrangements and gene

includes morphologic evaluation, flow cytometric determination of cell lineage, cytogenetic and fluorescence in situ hybridization (FISH) studies to delineate recurrent chromosomal rearrangements, and molecular testing for expression of chromosomal fusion transcripts and the presence of mutations in FLT3 NPM1 and


Godley LA. N Engl J Med 2012;366:1152‐1153.

cancers.chromosomal rearrangements and gene mutations.

the presence of mutations in FLT3, NPM1, and CEBPA.

Healthcare Complexity is Increasing the Value of Precision Medicine

More Complex Patterns of Care

New technologies

Tx algorithms more complex

Therapeutic

Tx algorithms more complex

PhysicianDiagnostic

Growing Medical Need

Disease burden risingIncreasing aging

Competitive Pressure Increasing

Number of drug i i

Payer

Patient

g g gpopulation that can afford treatment

companies, emerging MOAs, genericization

Cost Constraints

Payer adopting pricing controls


Defined Health

Thank YouThank You

Defined Health is pleased to present:

BioEurope Spring | March 11 – 13, 2013Barcelona, Spain

www.therapeuticinsight.com

24th Annual Cancer Progress ConferenceMarch 5 – 6, 2013 | Conrad New York

www.cancerprogressbyDH.com

Defined Health will also be participating in the following industry events:

AACR Annual Meeting 2013 | April 6 - 10, 2013 - Washington, DC | http://dfndhlth.com/AACR-2013Current Trends in Biosimilars Development and Regulatory Pathways in the Global

Marketplace 2012 | April 8 - 9, 2013 - Philadelphia | http://dfndhlth.com/CTBDRPGM-2012BIO International Convention | April 22 - 25, 2013 - Chicago | http://dfndhlth.com/BIO-2013

Cancer Immunotherapy Consortium, Entering the Era of Combination Therapies: Practical


Cancer Immunotherapy Consortium, Entering the Era of Combination Therapies: Practical Implementation | April 25 - 27, 2013 - Washington, DC. | http://dfndhlth.com/CIC-2013

Changing AML Outcomes via Personalized Medicine: Transforming Cancer Management with Genetic Insighta s o g Ca ce a age e t t Ge et c s g t

Co-Moderators:• Rick Winneker, PhD, Senior Vice President, Research, Leukemia &

Lymphoma Society__Lymphoma Society • Mike Rice, Senior Consultant, Defined Health

Panelists: • Brian J Druker MD Director OHSU Knight Cancer Institute JELD WEN• Brian J. Druker, MD, Director, OHSU Knight Cancer Institute, JELD-WEN __Chair of Leukemia Research, Oregon Health & Science University,__Investigator, Howard Hughes Medical Institute• Eric Hedrick, MD, Chief Medical Officer, Epizyme, Inc. • Omar Abdel-Wahab MD Assistant Member Memorial Sloan Kettering• Omar Abdel-Wahab, MD, Assistant Member, Memorial Sloan Kettering __Cancer Center • Nicholas J. Sarlis, MD, PhD, Vice President & Head, Medical Affairs, __Incyte Corporation • Scott Biller PhD Chief Scientific Officer Agios• Scott Biller, PhD, Chief Scientific Officer, Agios

Pharmaceuticals


Documents

Defined Health is pleased to presentknowledgebase.definedhealth.net/wp-content/uploads/2013...Defined Health’s Insight Series Ch iChanging AML OtOutcomes via Personalized Medicine: