24th Annual Cancer Progress ConferenceM h 5 6 2013 | C d N Y k March 11 – 13, 2013 | Barcelona, Spain
www.therapeuticinsight.comMarch 5 – 6, 2013 | Conrad New York
www.cancerprogressbyDH.com
Defined Health will also be participating in the following industry events:• US Japan Health Sciences Dialogue 2012 | November 27 - 28, 2012 - Philadelphia | http://dfndhlth.com/usjpn-hsd12• Current Trends in Biosimilars Development and Regulatory Pathways in the Global Marketplace 2012 | December 4 - 5,
2012 Philadelphia | http://dfndhlth com/CTBDRPGM 20122012 - Philadelphia | http://dfndhlth.com/CTBDRPGM-2012• ASH | December 8 - 11, 2012 - Atlanta | http://dfndhlth.com/ASH-2012• Life Sciences Summit | December 13 - December 14, 2012 - New York | http://dfndhlth.com/LSS-2012• JPM & Biotech Showcase | January 7 - 13, 2013 - San Francisco | http://dfndhlth.com/bts-2013 • BioEurope Spring 2013 | March 11 - 13 2013 - Barcelona | http://www ebdgroup com/bes/index php
BioEurope Spring 2013 | March 11 13, 2013 Barcelona | http://www.ebdgroup.com/bes/index.php
Defined Health’s Insight Series
Changing AML Outcomes via Personalized Medicine:Personalized Medicine: Transforming Cancer Management
i h G i I i hwith Genetic InsightMichael C Rice MS MBAMichael C. Rice, MS MBASenior Consultant
2012 Insight Series Webinar2012 Insight Series WebinarNovember 15, 2012Florham Park, New Jersey
The information in this report has been obtained from what are believed to beThe information in this report has been obtained from what are believed to be reliable 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 currentexpressions 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 Withoutonly 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 whole 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 lawthat this report may be disclosed where disclosure is required by law.
Changing AML Outcomes via Personalized Medicine: Transforming Cancer Management with Genetic Insight
♦ The oncology market is becoming increasingly complex as new molecularly targeted therapies gain prominence in treatment algorithmstargeted therapies gain prominence in treatment algorithms.
♦ At the same time, the combination of plummeting costs and increased speed f i l i h l bl d l i d di fof genetic analysis has nearly enabled real-time understanding of cancer on
the molecular level.
♦ In the not too distant future, oncologists will have access to an increasingly complex set of data enabling great insight into an individual’s cancer, making it possible to transition from empiric cancer management to one guided by p p g g ybiomarker tests and predictive algorithms.
♦ Recent progress in the hematological malignancies has been largely driven by♦ Recent progress in the hematological malignancies has been largely driven by drugs targeting long known biomarkers implicated in blood cancers; however, many blood cancers such as AML have been exceptionally difficult to treatto treat.
Changing AML Outcomes via Personalized Medicine: Transforming Cancer Management with Genetic Insight
♦ AML is now the most molecularly characterized cancer to confirm the prognostic significance of known mutations and to identify novel drivers ofprognostic significance of known mutations and to identify novel drivers of leukemogenesis as potential targets for the development of rationally designed therapies for AML.
♦ Indeed, academia, biotech, pharma and diagnostic providers are using biomarkers to both improve chemotherapy and to develop new classes of therapies inhibiting the molecular drivers of AML. However, the integration of clinical, cytogenetic and molecular data will be essential to translate research momentum into better outcomes for patients with AML.p
The oncology market is becoming increasingly complex gy g g y pas new molecularly targeted therapies gain prominence
in treatment algorithms.g
Cancer Accounts for Nearly One-Quarter of Deaths in the United States, Exceeded only by Heart Diseases
Defined Health adapted from Spear et al. TRENDS in Molecular Medicine Vol 7 No.5 May 2001
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 deadliestyear; lung, GI, prostate, breast and ovarian are the deadliest
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 continue as solids represent bulk of late stage pipeline.
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 on 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.
Higher Success Rates in Heme Malignancies Reflect Differences in the Underlying Biology Versus the Highly Heterogeneous Solid Tumors
Phase I to Market Transition Rates for Cancer
In addition, broad settings such as lymphoma actually include a diversity of indications each with their own unique treatment algorithm and regimens (NHL, HL, CLL, T-cell lymphomas [PTCL and CTCL], etc.) as well as situations where the same drug has multiple approvals (e.g., Rituxan for aggressive and indolent non-Hodgkin’s lymphomas such as follicular and DLBCL, respectively).
Defined Health; Deloitte Recap DEVELOPMENT optimizer™ Deloitte Recap, www.recap.com
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 translocations of ALK in NSCLC has rapidly translated into registration trials for Crizotinib, a g ,‘cMET turned-ALK’ inhibitor, based on tantalizing response rates in ALK-fusion-positive tumors (Phase I and II trial results).
♦ Lik i th d l t di f l ti BRAF i hibit♦ 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 this case BRAF mutations) had been established for malignant
lmelanoma. ♦ 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.
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 their pipeline
Biomarker stratified patient subsets i i l l it d b t t t
7965
1132
10000
No of biomarkers
No of drugs
increasingly exploited by new entrants to enhance efficacy
>80% of current oncology pipeline (Phase 1-Reg) includes a biomarker
252
114100
1000
g)
♦ Although the late stage (Phase 3+) solid tumor pipeline is nearly 6 times the number of assets than the hematological malignancies, the 10
100
proportion of biomarker driven programs is similar at ~25%.
♦ Consequently, in the next several years oncologists will need to incorporate into their
1oncologists will need to incorporate into their practices policies and procedures for identifying the appropriate patients for a wide variety of stratified therapies.
Biopharma company websites, Thomson Pharma Partnering; clinical trials.gov; GVK BIO
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 cancernearly 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 ydisruptive technology
♦ The once laborious and expensive method of DNA $3 Billion and 13 years sequencing has now become routine, comparatively inexpensive platform for discovery and
$ yto sequence the first
human genome
platform for discovery and diagnostics
♦ As throughput increases, costs decrease rapidly and p yclinical 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 instruments
Illumina HiSeq 2000 SBS RDT Bridge PCR 36–101 bp (SE, PE) ≤300 Gb 2.5–11 days Pro: Ultra high output, ease of useCon: 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
Illumina’s sequencing platform has become the dominant NGS 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 RocheCon: 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 cellCon: Shorter reads than other platforms, longer time to clonal template prep than Illumina
Life Technologies SBL emPCR 35 75 bp (SE PE) 155 Gb 2 7 days Same as 5500
a $6.7 billion hostile bid from Roche.
Ion Torrent (acquired by Life Technologies in 2010) technology measures the H+ ions released during base incorporation (rather
Life Technologies 5500XL (4hp)
SBL emPCR 35–75 bp (SE, PE) 155 Gb 2–7 days Same as 5500
Life Technologies Ion Torrent
SBS H+ emPCR 316+318 chip>100 bp (SE)
316– >100 Mb318– >1 Gb
2 h+ Pro: Label-free chemistry is cheap, fast, highly scalable, long reads Con: Homopolymer errors, no PE yet, laborious template preparation
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 consumables has made it a popular platform.
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.Pacific Biosciences’ core technology is known as Single-Molecule
Real-Time (SMRT), the first of the “third generation” platforms, which do not require amplification. PacBio RS promises long read-
*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
length. short run-time and low costs per run (~$100 vs ~$10,000 to $20,000)
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 lipid 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 Halcyon Molecular 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 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 measure hybridization via electrical conductance changes. Parallel processing of strands to generate complete genome sequences.
NobleGen DNA is converted (via ‘circular DNA conversion’) into ‘expanded synthetic representation’ (ESR) molecules that are tagged with Biosciences 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.
Reveo 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.
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 prepand minimal sample prep.
♦ Oxford Nanopore Technology (ONT), one of a number of companies vying to commercialize nanopore sequencing technology, is making headlines with its miniature MinION sequencer.
Oxford Nanopore introduces DNA 'strand sequencing' on the high-throughput GridION platform and presents MinION, a sequencer the size of a USB memory sticky17th 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 accessible
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 p q g q p p y g pdata 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 array 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 is expected to retail at less than $900.
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 sequencegenome sequence.
~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. q p g g
ENCODE investigators employ a variety of assays and methods to identify functional elements The discovery andfunctional elements. The discovery and annotation of gene elements is accomplished primarily by sequencing RNA from a diverse range of sources, comparative genomics, integrative bioinformatic methods and humanbioinformatic methods, and human curation. Regulatory elements are typically investigated through DNA hypersensitivity assays, assays of DNA methylation, and chromatin immunoprecipitation (ChIP) of proteinsimmunoprecipitation (ChIP) of proteins that interact with DNA, including modified histones and transcription factors, followed by sequencing (ChIP-Seq).
Functional Translation Outpaces the Clinical Evidence Needed to Inform Clinical Decisions Leading to Improve Patient Outcomes
Published GWA Reports, 2005 – 9/2011
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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 p g g ghas been largely driven by drugs targeting long known biomarkers implicated in blood cancers; p ;however, many blood cancers such as AML have
been exceptionally difficult to treat. p y
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.
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 cells.
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
Improvement in patient outcomes can be rapid with rationally designed transformative therapies, or incremental advances in treatment standards
90 CML
Then and Now: Age of Onset Compared to Overall Survival
607080
nset
Pre-Gleevec (2001)
405060
e Ag
e of
On
Pediatric
In 1947 Boston pathologist Sydney Farber began testing aminopterin, a folic acid mimic, as a potential cure for leukemia in
102030
Aver
age
ALL1960s
, pchildren. The majority of the children with ALL who were tested showed signs of improvement in their bone marrow, but none of them actually were cured.
Improvement in patient outcomes can be rapid with rationally designed transformative therapies, or incremental advances in treatment standards
90 CML
Then and Now: Age of Onset Compared to Overall Survival
In 1962 researchers Emil Freireich and Emil
60
70
80
nset
Pre-Gleevec (2001)In 1962, researchers Emil Freireich and Emil Frei used combination chemotherapy to attempt to cure leukemia. The tests were successful with some patients surviving long after the tests
As A Case for Personalized Antileukemic Therapy, APL is a Biomarker Identified Subpopulation Benefiting from ATRA/ATO-Based Regimens
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
15 22 (PML )ATRA (all-trans retinoic acid) and anthracycline-
based chemotherapy
Inductionon 15q22 (PML gene).
♦ 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
( )ATRA / ATO and low dose
chemotherapyConsolidation
(daunorubicin or idarubicin) plus ATRA. This treatment induces remission in about 80% to 90% of
patients. ♦ As with other subtypes of AML, patients with APL then receive post-
ATRA and anthracycline-based chemotherapy
Maintenance
remission treatment. Consolidation therapy usually consists of 2 or more courses of
an anthracycline, usually along with ATRA. Consolidation is followed by maintenance therapy with ATRA
Arsenic trioxide(ATO) /Salvage
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 remissions in patients with relapsed APL.
Arsenic trioxide(ATO) / Autologous BMT 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.
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
SEER database; scientific literature Median 5-year Survival Rate0% 20% 40% 60% 80% 100%
AML is now the most molecularly characterized cancerAML is now the most molecularly characterized cancer to confirm prognostic significance of known mutations
and to identify novel drivers of leukemogenesis asand to identify novel drivers of leukemogenesis as potential targets for the development of rationally
designed therapies for AMLdesigned therapies for AML.
AML is Mainly a Disease of Older Adults
♦ Acute myeloid leukemia (AML) is a life-threatening disease in which the cells that normally develop into neutrophils, basophils, eosinophils, and monocytes become cancerous and p p , p , p , yinfiltrates the bone marrow with rapid growth kinetics.
♦ 2012 US AML statistics: Estimated new cases in US: 13,780Estimated new cases in US: 13,780 Expected mortality: 10,200 90% of new cases in adults
A t di i 65 Average age at diagnosis >65 yrs
♦ The disproportionate impact of AML on the very old is evident in comparing the i id i th ti US l ti d iincidences 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 carcinogensdue to cumulative exposure to carcinogens, radiation and chemotherapy for other malignancies, and also to improved screening and surveillance.
American Cancer Society, www.cdc.gov; SEER; Medscape, Lancet JE, Willman CL, Bennett JM. Hematol Oncol Clin North Am. 2000;14:251-267.
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 Prognosis
M0 5 very early cells, or blasts Poor
M1 15 some maturing cells Averageg g
M2 25 mature cells with granules and "Auer rods" Good
M3 10called promyelocytic; many granules and Auer rods in mature looking cells. treated with ATRA and chemotherapy, sometimes arsenic trioxide
Excellentarsenic trioxide
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 V PM6 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 fragments in blood; also not white blood cell leukemia 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 th i i il f ll bt
American Cancer Society, www.cdc.govtherapy 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:♦ AML subclassification:
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 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 andIncreasing 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 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.
♦ According to clinicians cytogenetics and molecular y gcharacterization has become one of the most important prognostic indicators in the treatment d i idecision.
♦ The cytogenetic-risk classification summarized in the table is based
t di th t d i tlon studies that predominantly included younger AML patients, below 56 or 60 years of age.
♦ T b t t di l d♦ Two subsequent studies analyzed the prognostic significance for pretreatment cytogenetic findings in outcome of older AML patients, p ,a group whose outcome is generally worse than that of younger patients.
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.
♦ The three stages of standard treatment for AML are:
Initial Treatment• Remission Induction• Clinical Trial• Best Supportive care
1. Remission Induction therapy: Treatment should be sufficiently aggressive to achieve complete remission (CR= <5% blasts in bone
) b i l i i ff
Post Remission Therapy
marrow) because partial remission offers no substantial survival benefit.
2. Post-remission therapy: Post-remission therapy primarily consists of consolidative •Consolidationtherapy primarily consists of consolidative treatment with high dose chemotherapy.
3. Salvage Therapy: Following initial induction and consolidation treatment patients are
Salvage TherapyLong Term Remission / Cure
and consolidation treatment, patients are then treated with salvage therapy if they fail to achieve initial CR (primary refractory) of after disease recurrence (relapse) .
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.
i ( ) h d ll i l i d i h b i♦ 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 treatment.
♦ Disease tends to be more treatment resistant in older patients, (de novo, antecedent MDS, sAML) with dramatically worse outcomes than in younger adults.
♦ M t di h d th ti f b t ti ith th t f t d d “3 7” i d ti♦ 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 chemotherapy.
♦ 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 y g , gof only 5-10 months.
Patient Age(median CR)
% of patients
Cytogenetics BMT? Relapse rate
<60 (60-80%)
40% good No (consolidative chemo) 30%
40% Int/poor Yes 20%
20% Int/poor No (no donors, patient refusal, commorbidities)
However, Despite the Seemingly Low Benchmark, Many Agents Have Failed in AML
♦ Pfizer recently discontinued marketing Mylotarg (gemtuzumab ozogamicin), unable to provide survival benefit of its 13% CR rateto provide survival benefit of its 13% CR rate.
♦ Vion’s cloretazine/laromustine showed good CR rates but poor durability, and a relatively high treatment relater mortality rate.
♦ The pivotal ACCEDE trial testing Xanafide (Antisoma) in combination failed to meet its♦ The pivotal ACCEDE trial testing Xanafide (Antisoma) in combination failed to meet its primary endpoint of improved CR over AraC + daunorubicin in secondary AML.
♦ Sanofi’s Clofarabine – CLO+ara-C significantly improves ORR (47 vs. 23%) and EFS over SA ara-C in older adult pts (≥55 yrs) with R/R AML (CLASSIC 1, 320pts). However, these improvements did not translate into a survival benefit compared to ara-C alone.p p
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 near future. Sunesis’ Vosaroxin, currently in phase 3 for primary refractor
and relapsed AML, is designed to avoid resistance $500
$600
$700
mechanisms and broaden the therapeutic index of anthracyclines.
Clavis’ elacytarabine is designed to increase import of the toxic nucleoside into the nucleus in phase 3 for second $300
$400
$500
salvage. Cyclacel’s Sapacitabine is being tested in phase 3 trials
(SEAMLESS trials) for treatment-naïve and relapsed elderly AML patients, in 2012 Cyclacel announced a CR rate of 25% at $100
$200
$300
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 decade. Although FDA did not grant Eisai/Astex approval
$0
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2012
2013
2014
2015
2016
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2018
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.
AML Leads Sequencing Efforts – Although Translation is Needed, Early Data is Redefining Understanding of Cancer Progression
♦ In 2008, a team led by Dr. Timothy Ley became 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.
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.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 weremutated 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 relapse. Chemotherapy failed to eradicate the founding clone and DNA damage caused by cytotoxic chemotherapy may shape clonal evolution and resistance.
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, including 4 genes that have not been previously implicated in the MDSs or AML. p y p
♦ Progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations.
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 dose daunorubicin.
♦ Results demonstrated that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML.
Sapacitabine is being tested in treatment-naïve and relapsed elderly AML patients, demonstrating a CR rate of 25% at the highest dosing schedule (400 mg
Results from a P2 study in AML and MDS showed thatDevelopment
Pipeline
Tosedostat
Midostaurin
AZD 1152
Mylotarg
Arsenic trioxide
(APL)
Vorinostat
MLN 8237
LY 2181308
LOR 2040
Lestaurtinib
AZD 6244
BI 6727
Tipifarnib
Sorafenib
BI 811283
αCD123 mAM- CSL
αCD9 mAB- ARIUS
MDX 1338
rhH1 x
AST 487
MC-2001
Flt 3 Kyowa
Vidaza
DOT1L- Epizyme highest dosing schedule (400 mg sapacitabine bid for 3 consecutive days per week every 3 to 4 weeks).
MDS showed that, out of 38 AML pts treated with tosedostat, 3 achieved CR and 7
Ceplene
Obatoclax
Chemo-therapy
Kinase
Aldesleukin
Epigenetic
i
ImatinibCenersen
Voreloxin
BI 811283
BI 2536
ON 01910
Quizartinib
4SC-203Fusion toxin
mAB, ARCA
Flt-3 Kyowa
KRN 388D11-5908
MAT 102CX-6258
CPX
achieved CR and 7 achieved PR lasting 1-3 months.
AEG 35156
Cediranib
Immuno-therapy
InhibitorOmacetaxine
Lintuzumab
AS 1411
AVE 9633
Lintuzumab Ac-225
CAL 101
R 763
SB-559457
SHP-2, VUMC
VLIM-88
D11 5908
RNAi- AntigenProapoptotic
CPX
AT-406
CDC7 MSK-777Progress has been made in deciphering the molecular pathogenesis of AML which has led to the development of molecularly targeted kinase inhibitors of the signal transduction cascades (eg,FLT3, KIT, RAS).
Progress has been made in deciphering the molecular pathogenesis of AML which has led to the development of molecularly targeted kinase inhibitors of the signal transduction cascades (eg,FLT3, KIT, RAS).
SCT / Other Lenalidomide
GRNVAC1
Zosuquidar
SL 401
Lintuzumab Bi-213
Lintuzumab Ac 225
Tamibarotene
R 763
LC 1
CBFb InhibitorsFLT-3 Inhib
the signal transduction cascades (eg,FLT3, KIT, RAS).Such targeted approaches may transform specific segments of AML similar as Gleevec transformed CML; however, initial attempts have been met with futility.
the signal transduction cascades (eg,FLT3, KIT, RAS).Such targeted approaches may transform specific segments of AML similar as Gleevec transformed CML; however, initial attempts have been met with futility.
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♦ 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 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 studies.
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
Whole-Genome Interrogation in AML Uncovers Novel and Potentially Drug-able Epigenetic Targets
♦ A large number of the genetic alterations discovered in
Adapted from: Adv Hematol. Epub 2011 Jun 26
myeloid malignancies appear to be in genes whose function is known, or suspected, to be i l d i i ti l ti
Gain-of-functionalteration
loss-of-functionalteration
EZH2 mutationsinvolved in epigenetic regulation of gene transcription.
♦ In the last 3 years alone, i i h ff
IDH1/2 mutationsEZH2 mutations
TET2mutations
mutations in genes that affect DNA and/or histone lysine methylation – TET2, IDH1, IDH2, DNMT3a, and EZH2 – have all
IDH1/2 mutationsDNMT3A mutations
DNMT3a, and EZH2 have all been found in patients with MDSs and/or AML.
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
• Whole genome sequencing (WGS) study identifies Isocitrate dehydrogenase-1 ( ) d l f l d d
2009(IDH1) and IDH2 as novel genes frequently mutated in MDSs and AML.
• Gain of function mutations in IDH1/IDH2 identified in AML patients in subsequent studies; shown to result in hypermethylation cell phenotype and impaired hematopoietic differentiation.
2010-11 • 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.
• QIAGEN developing a test for mutations of IDH1 and IDH2 genes as a companion2012
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)histone H3 lysine 27 (H3K27) methyltransferase (HMT).
♦ Known to be overexpressed in several epithelial malignancies for some time, only in 2010 was it discovered that EZH2 may be mutated in hematopoietic malignancies.
♦ Industry has become rapidly engaged in the pursuit of novel small molecule inhibitors of♦ 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 cancer including leukemias, non-Hodgkin's lymphoma, and breast cancer.
Partnership with Leukemia & Lymphoma Society (Sept 2012).
In Jan 2012 entered into a broad
Partnered with Eisai (March 2011) around EZH2. Strategic alliance with GlaxoSmithKline (January
2011) to discover develop and market novel In Jan. 2012, entered into a broad epigenetic-based drug discovery collaborative agreement with Genentech in cancer and other diseases.
2011) to discover, develop, and market novel small molecule therapeutics targeting HMTs.
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 functionproteins to histones and thereby affect chromatin structure and function.
♦ 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 proteinssubset of the larger family of 47 bromodomain-containing proteins.
♦ The binding of BET protein bromodomains to chromatin regulates gene expression (including MYC-dependent transcription) and have linked BETs to different cancers i l di idli i l k i d ll iincluding midline carcinoma, leukemia and squamous cell carcinoma.
Partnership with Leukemia & Phase I trial of small Developing small molecule Lymphoma Society (Sept 2012) to identifying novel small molecule inhibitors of BETs for hematological malignancies.
molecule inhibitor— GSK 525762 in patients with NUT midline carcinoma .
bromodomain inhibitors for cancer and potentially inflammatory disorders.
Lead programs aimed at NUT midline carcinoma AML and multiple
In the not-too-distant future, oncologists will have access to an increasingly complex set of data enabling great insight into an individual’s cancer capable of transitioning from empiric
cancer management to one guided by biomarker tests and predictive algorithms.
However, the integration of clinical, cytogenetic and molecular data will be essential to translate research momentum into better outcomes for
patients with AML.
Today’s Therapeutic Decisions are Based on Few Inputs Other Than Clinical Presentation, Age, Co-morbidities and Limited Use of Lab Tests
Increase in Data Parameters for Clinical Decision Points Relative to Human Cognitive CapacityRelative to Human Cognitive Capacity
Defined Health Modified from Clayton M. Christensen and Jason Hwang.
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. p p
Several challenges exist to widespread implementation of molecular profiling to generate diagnostic and prognostic i f i b h h ll b
Testing in the future may be dominated by genomics-based molecular profiling, which may include real-time PCR assays, microarray analysis and next generation sequencing;
The current standard evaluation of AML samples includes morphologic evaluation, flow cytometric determination of cell lineage, cytogenetic and
information, but these challenges may be overcome soon, and molecular profiling may herald a new approach to testing in leukemia and, by extension, other cancers.
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
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
24th Annual Cancer Progress ConferenceM h 5 6 2013 | C d N Y k March 11 – 13, 2013 | Barcelona, Spain
www.therapeuticinsight.comMarch 5 – 6, 2013 | Conrad New York
www.cancerprogressbyDH.com
Defined Health will also be participating in the following industry events:• US Japan Health Sciences Dialogue 2012 | November 27 - 28, 2012 - Philadelphia | http://dfndhlth.com/usjpn-hsd12• Current Trends in Biosimilars Development and Regulatory Pathways in the Global Marketplace 2012 | December 4 - 5,
2012 Philadelphia | http://dfndhlth com/CTBDRPGM 20122012 - Philadelphia | http://dfndhlth.com/CTBDRPGM-2012• ASH | December 8 - 11, 2012 - Atlanta | http://dfndhlth.com/ASH-2012• Life Sciences Summit | December 13 - December 14, 2012 - New York | http://dfndhlth.com/LSS-2012• JPM & Biotech Showcase | January 7 - 13, 2013 - San Francisco | http://dfndhlth.com/bts-2013 • BioEurope Spring 2013 | March 11 - 13 2013 - Barcelona | http://www ebdgroup com/bes/index php
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