Defined Health’s Insight Series Htl WhitSHematology White ...knowledgebase.definedhealth.net/wp-content/uploads...Revlimid Celgene IMID 2026 $5.5 Alimta Eli Lilly Antimetabolites

Defined Health’s Insight SeriesH t l Whit SHematology White Space: Multipotent Franchise Opportunity

Q i t Ni h ?or Quiescent Niche?

Michael C Rice MS MBAMichael C. Rice, MS MBASenior Consultant

2011 Insight Series WebinarJuly 25, 2011Florham Park, New Jersey

Defined Health's Therapeutic Insight will be a featuredDefined Health s Therapeutic Insight will be a featured track at these 2011 and 2012 EBD conferences:

Page 2Hem/Onc Insight Briefing© Defined Health, July 2011

The information in this report has been obtained from what are believed to be reliable sourcesThe 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 current as of the date of this report, are subject to changeto 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 whole or in part for any other

b h i id d h hi b di l d hpurpose or by any other person or entity, provided that this report may be disclosed where disclosure is required by law.

© Defined Health 2011© Defined Health, 2011


Hematology White Space: Multipotent Franchise Opportunityor Quiescent Niche?• I t th h ti l i d t h i d i t t i l i lt• In recent years, the pharmaceutical industry has increased investment in oncology specialty

franchises as traditional PCP markets became increasingly challenging in an outcomes driven healthcare system.

• The $75B oncology market has been an attractive area of development as theThe $75B oncology market has been an attractive area of development as the understanding of the science of neoplastic pathways and biomarkers has converged with innovative small molecule and biologic platforms to produce promising anti-cancer therapies.

• Pharma’s development and commercial strategy have been focused on the prevalent solid tumor markets and medical oncology practices that comprise nearly 90% of new cancer diagnoses and deaths annually.

• However, the solid tumor space has become intensely competitive, and drug developers have become increasingly interested in hematology as a “white space” area, wheresignificant need remains and standards of care are poorly established.

• B k h h h i h f d h f i i h bl d• Breakthrough therapies have transformed the management of patients with blood cancers and created blockbuster markets which have grown to represent 4 of the 10 top oncology revenue producers.

• M&A and alliances for products treating hematological malignancies have risen in numberM&A and alliances for products treating hematological malignancies have risen in number and value in the past years; however, aside from Novartis and Roche, buyers are largely Biotech and midcap Specialty Pharma rather than Large Pharma oncology franchises, despite the apparent strategic fit.

Hematological Malignancies

Al f d i h i dAlso referred in the industry as:

“Non-Core Tumor Types”“Blood Cancers”“Liquid Tumors”“Niche Cancers”

“Orphan Oncology”“Whit S O l ”“White Space Oncology”

“Outside the Big Five”“New Markets”New Markets

“Neglected Diseases”


Niche? Blood Cancers Comprise Half of the Oncology Top 10 Blockbusters - Forecasted to Exceed $20B by 2016

2016 Top 10 Cancer Drugs ($42.7B)

Product Company Class Patent Expiry Revenue2016 ($M)2016 ($M)

Avastin Roche VEGF MAbs 2018 $7.8

Rituxan Roche CD20 MAbs 2018 $7.7

Herceptin Roche HER2 MAbs 2019 $6 5Herceptin Roche HER2 MAbs 2019 $6.5

Revlimid Celgene IMID 2026 $5.5

Alimta Eli Lilly Antimetabolites 2017 $3.0

bi S/ k KG A G Ab 2018 $2 8Erbitux BMS/ Merck KGaA EGFR MAbs 2018 $2.8

Provenge Dendreon Immunotherapy 2017 $2.6

Gleevec/Glevic Novartis Abl/c-Kit Inhibitor 2015 $2.3

Tasigna Novartis Abl/c-Kit Inhibitor 2023 $2.3

Velcade JNJ/ Takeda Proteosome Inhibitor 2018 $2.2


As traditional PCP markets became increasingly challenging in an outcomes driven healthcare system in recent years, the pharmaceutical industry has increased

i t t i l i lt f hiinvestment in oncology specialty franchises.

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

♦ While numbers of prescriptions are growing, revenue growth is slowing ♦ In terms of share of the overall pharmaceutical market, CVD and Neurology are shrinking

compared to other therapeutic areas.

140Oncology

p p♦ Decline is largely driven by generic erosion of off-patent products

WW Revenue By Major Therapeutic Categories

80

100

120 Anti-Infectives

CNS

Cardiovascular

BloodSal

es $

B

40

60

80 Blood

Musculoskeletal

Endocrine

Respiratory

Genito UrinaryWor

ldw

ide

0

20

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

Genito-Urinary

Gastro-Intestinal

Sensory Organs

Various

W


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

EvaluatePharma

Cancer Accounts for Nearly One-Quarter of Deaths in the United States, Exceeded only by Heart Diseases


US Mortality Data 2007, NCHS, CDC 2010

And is Among the Most Expensive of Medical Conditions


Burrill & Company

Traditional Chemotherapeutics Have Pitiful Response Rates – Broad Clinical Evidence and Presentation Drive Empiric Treatment Decisions

Response Rate (%)

Medicine Today Is An Imperfect Art, Only 25 – 75% of Patients Respond

IncontinenceHypertension (ACEIs)

Heart Failure (β-Blockers)Oncology

Response Rate (%)

Migraine (Acute)Rheumatoid Arthritis

Migraine (Prophylaxis)Osteoporosis

HCVIncontinence

SchizophreniaCardiac Arrhythmia

AsthmaDiabetes

Migraine (Acute)

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

AnalgesicsStatins

Depression (SSRI)


Defined Health adapted from Spear et al. TRENDS in Molecular Medicine Vol 7 No.5 May 2001

While Cytotoxics Have Become Largely Genericized, Targeted Biologic and Cytostatic Agents Will Drive Growth for the Foreseeable Future

35

WW Revenue By Major Oncology Drug Category

25

30

Alkaloids

Alkylating agents

ales

$B

y j gy g g y

mAbs

15

20

Antimetabolites

Monoclonal Antibodies

Cytotoxic antibiotics

Antiangiogenicrldw

ide

Sa mAbs

Small MoleculeCytostatics

10

15cytostatics

Hormone therapies

Platinum compounds

Other anticancer

Wor

MultitargetedTKIs

0

5

Ot e a t ca ce

Unclassified


1986 1989 1992 1995 1998 2001 2004 2007 2010 2013 2016EvaluatePharma

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

2010 Top 10 Cancer Drugs ($33.8B)Product Company Class Patent

ExpiryRevenue2010 ($M)

2016 Top 10 Cancer Drugs ($42.7B)Revenue2016 ($M)

Patent Expiry

Class Company Product

Avastin Roche VEGF MAbs 2018 $6.2

Rituxan Roche CD20 MAbs 2018 $6.1

Herceptin Roche HER2 MAbs 2019 $5.2

$7.8 2018 VEGF MAbs Roche Avastin

$7.7 2018 CD20 MAbs Roche Rituxan

$6.5 2019 HER2 MAbs Roche Herceptin

Gleevec Novartis Abl/c-KitInhibitor

2015 $4.3

Taxotere Sanofi Taxane 2010 $2.8

Revlimid Celgene IMID 2026 $2 3

$5.5 2026 IMID Celgene Revlimid

$3.0 2017 Antimetabolites Eli Lilly Alimta

$2.8 2018 EGFR MAbs BMS/ Merck

ErbituxRevlimid Celgene IMID 2026 $2.3

Alimta Eli Lilly Antimetabolites 2017 $2.2

Velcade JnJ/ Takeda

ProteosomeInhibitor

2018 $1.6

Merck KGaA

$2.6 2017 Immuno-therapy

Dendreon Provenge

$2 3 2015 Abl/ Kit N ti GlErbitux BMS/ Merck KGaA

EGFR MAbs 2018 $1.6

Arimidex Astra Hormone 2010 $1.5

$2.3 2015 Abl/c-KitInhibitor

Novartis Gleevec

$2.3 2023 Abl/c-KitInhibitor

Novartis Tasigna


Zeneca therapies $2.2 2018 ProteosomeInhibitor

JnJ/ Takeda

VelcadeEvaluatePharma

Cancer Drugs Constitute a Modest Component of Overall Pharma Sales for Leading Oncology Franchises (except Roche and CelGene)

50

Oncology/Overall Pharmaceutical Sales of Top 10 Oncology Franchises

354045

s $B

202530

Overall Sales

Sal

es

51015 Oncology sales

0


EvaluatePharma

Heme Oncology is Gaining Prominence in Leading Oncology Portfolios, Mostly Through Acquisitions

25

S lid T

15

20 Solid Tumors

Heme Oncology

s $B

5

10Sal

es

0

5


EvaluatePharma

The $75B oncology market has been an attractive area of development as understanding of the science of

neoplastic pathways and biomarkers has converged with innovative small molecule and biologic platforms to

d i i i h iproduce promising anti-cancer therapies.

In the Next Few Years, $89 Billion of Drug Revenues are at Risk of Generic Substitution


IMS Health: 2009 U.S. Pharmaceutical Market Trends: A Picture of Increasing Trends

Attempts to Replace Aging Drugs Have Been Expensive in Comparison to the Output Over the Last 2 Decades

$ billions

R&D Spending and Output


Parexel; Defined Health analysis; FDA website; Phrma.org website; Includes Pharma Domestic Spend

© Defined Health 2011

Pharma Now Sees Greater Commercial Risk vs. Scientific Risk in Pursuing Traditional Broad Label, Primary Care Markets

Scientific Risk Underserved Niche Indications

Biomarker ValidationsBiologics Platformsiologics Platforms

Commercial RiskMarket AccessRegulatory Risk

Generic Competition


Products Approved for Blood Cancers are Often Eligible for Orphan Designation

♦ During the years 2000 to 2010, 18 of the 38 therapeutic oncology drugs approved by the FDA were first indicated for blood cancers (47%)

i l i l f h h l d h d h

Year Drug Company 1st indication

2000Mylotarg(gemtuzumab) Wyeth CD33 positive AML

♦ Pivotal trials of these orphan oncology drugs had the following characteristics:

Smaller participant numbers (96 vs. 290 patients exposed to drug

2000 Trisenox (arsenic trioxide) Cell Thera APL2001 Campath (alemtuzumab ) Berlex Labs B-cell CLL2001 Gleevec; (imatinib) Novartis CML2002 Zevalin (ibritumomab) IDEC Pharma NHL

2003 B (t it b) C iCD20 positive, Relapsed f lli l NHL Were less likely to be randomized (30% vs 80%)

Orphan trials were less likely to be double-blind (4% vs. 33%).

Primary study outcomes with orphan trials more

2003 Bexxar (tositumomab) Corixa follicular NHL2003 Velcade (bortezomib) Millennium Pharma 3rd-line MM2004 Clolar (clofarabine) Genzyme Relapsed Pediatric ALL

2004 Vidaza (azacitidine) Pharmion CorpMDS subtypes including refractory and CMML

2005 Revlimid (lenalidomide) Celgene; low- and int-1-risk MDSlikely to assess disease response (68% vs 27%) rather than overall survival (8% vs. 27%)

However, more treated patients had serious adverse events in such trials (48% vs. 36%).

2005 Revlimid (lenalidomide) Celgene; low- and int-1-risk MDS

2005 Arranon (nelarabine) GlaxoSmithKlineT-cell ALL and T-cell lymphoblastic lymphoma

2006 Zolinza (vorinostat) Merck & Co CTCL

2006 Sprycel (dasatinib); Bristol-Myers Squibb imatinib-resistant CML

♦ All 18 received FDA orphan designation and/or designation as orphan medicinal products by the EMA; while only 5 of 20 solid tumor oncology products received orphan designation.

2006 Dacogen (decitabine) MGI Pharma Int-2 and high risk MDS2007 Tasigna (nilotinib) Novartis imatinib-resistant CML2008 Treanda (bendamustine) Cephalon Relapsed CLL2009 Arzerra (ofatumumab) GlaxoSmithKline Campath refractory CLL2009 Istodax (romidepsin) Gloucester Pharma CTCL


2009 Istodax (romidepsin) Gloucester Pharma CTCL2009 Folotyn (pralatrexate) Allos Therapeutics PTCL

FDA.gov, Leukemia &Lymphoma Society, Defined Health analysis

Oncology is the Poster Child for Biomarker Driven Drug Development: Understanding of Neoplastic Pathways has Outpaced Translation


Nature Reviews Drug Discovery, Altshuler, David, How the pace of new insights in genetic variation affects the need for evidence; Institute of Medicine Annual Meeting, October 8, 2007

Biomarkers: St. Jude, Washington University Launch Genome Project for Childhood Cancers - Blood Cancers Lead the Wayy

Researchers at St. Jude Children’s Research Hospital and the Washington University School of Medicine in St. Louis have launched the Pediatric Cancer Genome Project to sequence the genomes of at least 600 children with cancer over the next 3 years. The collaboration marks the first time that whole-genome sequencing will be used on a large scale to discover genetic changes driving pediatric cancers. “This is the largest and most powerful single initiative in the 50-year history of St. Jude,” the research hospital’s director, Dr. William E. Evans, said at a press briefing announcing the project yesterday. “DNA is being sequenced as we speak,” he added. S J d h i f bi l i l l d li i l i f i f hild h h b d h i h 1970 Th ll iSt. Jude has a repository of biological samples and clinical information from children who have been treated there since the 1970s. The collection represents a treasure trove of information about cancer, and it can now be scrutinized using the latest genomic technologies at a cost that continues to decline substantially over time. “This is a new era for pediatric cancers,” NIH Director Dr. Francis Collins said at the briefing. “The study represents an opportunity to discover all the ways that a good cell in an innocent child goes wrong.”

The project—estimated to cost $65 million and funded by St. Jude—aims to discover the genetic origins of pediatric cancers while creating knowledge that can be used to improve the care of young people with these rare diseases. Early results could reveal new uses for available drugs, and, over the long term, lead to targeted agents for these cancers, the researchers said. New genetic signatures for classifying and treating patients are also anticipated. Knowing that a child has a subtype with a poor prognosis would allow physicians to select aggressive treatments early in the course of the disease. Similarly, doctors could safely withhold treatments from a patient who has a p y gg y y, y pbetter prognosis, based on a genetic profile.

Another genome effort in pediatric cancer is the NCI-supported childhood cancer TARGET initiative, which includes St. Jude investigators as well as other childhood cancer researchers. The initial discoveries from this project are being translated to the clinic through an early stage clinical trial that is in development for a newly described type of acute lymphoblastic leukemianewly described type of acute lymphoblastic leukemia.What distinguishes the new project from past efforts, said Dr. Richard Wilson, director of the Genome Center at Washington University, is that this one will be “all whole-genomes all the time.” Most genome studies have been limited to sets of genes or genetic markers because of the costs of sequencing DNA. Those costs have now fallen to below $100,000 for a tumor-normal combination, and the sequencing can be done in about a week, Dr. Wilson said. “There is a sense of urgency to make progress here, and it has now become affordable,” said Dr. Evans. “We see this effort as a marathon, and the first 3 years are really just the beginning. I am certain there will be lots of unanswered questions at the end of this period, and there will be much more work to be d ”


done.” —Edward R. Winstead, Jan 26, 2010

Biologic Platforms: Cancer Has Been the Leading Indication for Novel Antibody Technologies – Blood Cancers Lead the Way

1908: Paul Ehrlich envisions antitoxins (antibodies) as ”magic bullets” that could selectively

2000: Mylotarg(Gemtuzumab ozogamicin, humanized anti-CD33 + calicheamicin) approved for relapsed AML in US

2001: Campath (alemtuzumab, humanized anti-CD52) approved for CLL in US.

2003: Bexxar (tositumomab,

2010: Genentech submits BLA to FDA for T-DM1 (trastuzumab + emtansine) for refractory HER2+ y

deliver toxins to pathogens.

1975: Kohler and Milstein describe generation of murine

Ab

1995: Panorex(edrecolomab, murine anti-EpCAM) approved for post-

p(later withdrawn).

( ,murine anti-CD20 + 131I) approved for refractory NHL in US.

2006: Vectibix( i b h

ymetastatic breast cancer.

1908 1975 1988 1996 1998 2000 2002 2004 2006 2008 2010

mAbs. operative CRC in Germany (later withdrawn).

(panitumumab, human anti-EGFR) approved for metastatic CRC in US.

1908 1975 1988 1996 1998 2000 2002 2004 2006 2008 2010

1988: First chimeric(mouse-human) antibodies described.

1998: Herceptin(trastuzumab, humanized anti-HER2) d f

2009: Arzerra (ofatumumab, human anti-CD20) approved for refractory CLL in US.2009: SGN-35 (brentuximab vedotin, anti-

1997: Rituxan (rituximab, chimeric anti-CD20) approved for relapsed/refractory NHL in US.

HER2) approved for HER2+ metastatic breast cancer in US.

2002: Zevalin (ibritumomab tiuxetan, 2004: Avastin (bevacizumab, humanized anti-VEGF) approved for metastatic CRC in US

CD30 + monomethyl auristatin E) awarded fast-track status for refractory HL by FDA.


murine anti-CD20 + 90Y) approved for relapsed/refractory NHL in US.

2004: Erbitux (cetuximab, chimeric anti-EGFR) approved for metastatic CRC in US.

Oncology is Not Immune to Patent Expiry and Generic Substitution –Blood Cancers Less Effected by Near Term Genericization

♦ Nearly $17 B of oncology drugs face patent expiry and generic substitution in the next 3 years.

Total Annual Oncology Sales From Products Expected To Lose Exclusivity y

♦ Total revenue generated by sales of mature oncology products are expected to decrease from $14B in 2009 to less than $8B in 2014.

d d d l f l d

14,000

16,000

Solid

p yThrough 2014

♦ Products indicated primarily for solid tumors which a largely small molecule cytotoxics and TKIs are the main source of lost revenues.

♦ Conventional small molecule drugs are 8,000

10,000

12,000Solid

Heme

expected to have the largest impact as long as the regulatory route of biosimilars remains stringent.

♦ Accordingly revenues from mature products 2,000

4,000

6,000

♦ Accordingly, revenues from mature products for blood cancers are expected to have a prolonged rate of decline since they are more often biologic therapies and protected by orphan drug laws

0

,

2009 2010 2011 2012 2013 2014


orphan drug laws.

EvaluatePharma, Defined Health analysis

But Generic Cancer Drugs are in Short Supply

Oncologists lament growing drug shortagesJune 8, 2011 — 11:17am ET | By Tracy Staton

Low margins on generic cancer drugs are fueling ongoing shortages, doctors said as the annual American Society of Clinical Oncology meeting wrapped up this week. Oncologists are forced to cast about for alternative therapies--or even to delay treatment when alternatives aren't available. And the scarce meds aren't little-used niche drugs, but common chemotherapies that often are the foundations for modern combination treatments."These are not old-fashioned drugs," Dana-Farber Cancer Institute's Robert Mayer told Reuters. "They remain incredibly important drugs which serve as the backbone for treating many of the most common and treatable cancers."The hard-to-obtain drugs include cisplatin, used to treat testicular, bladder, ovarian and lung cancers; doxorubicin, used against lymphoma, multiple myeloma, leukemia and other forms of the disease;doxorubicin, used against lymphoma, multiple myeloma, leukemia and other forms of the disease; cytarabine, a leukemia drug; and leucovorin for colorectal and head-and-neck cancers. They're made by a variety of companies, including Teva Pharmaceutical Industries and Hospira.Drug shortages have been a growing problem recently, as manufacturing problems, regulatory woes and competitive pressures have interfered with the supply of these and other drugs. Some drugmakers blame the FDA maintaining the agency doesn't have the resources to quickly inspect plants after problems arethe FDA, maintaining the agency doesn t have the resources to quickly inspect plants after problems are fixed to allow drug production to resume. But economics are also important: Cheap drugs may be good for patients and payers, but low margins can give drugmakers little incentive--and little breathing room--to fix manufacturing or other problems when they arise. "We don't see an end in sight," ASCO President Michael Link said.


www.fiercepharma.com June 8, 2011

Biosimilars Not a Near Term Threat in Therapeutic Oncology: Recent FDA Guidance Portends Heightening Investment and Burden of Proof for Biosimilars

FDA outlines steep hurdles, early fees for first-gen biosimilarsDemonstrating once again that developing biosimilars will be neither cheap nor easy, the FDA says that it plans to charge the same user fees for a biosimilar application as it does any other new biologic that

it A d it' l i i th h l i th d l tcomes its way. And it's planning on assessing those charges early on in the development process, as regulators and developers blaze a regulatory trail with the first generation of pioneering projects.Reviewing these biosimilar programs, says the agency in a new proposal, will be "comparably complex, technically demanding, and resource-intensive" as a brand drug. And the agency says that as this new pathway opens up for developers its services will be needed well before the marketing application hits its d k A l Th Hill h FDA h $150 000 d i d l ddesk. As a result, reports The Hill, the FDA expects to charge $150,000 a year during development and then subtract the total from the final tally for an approval."Given that the approval pathway for biosimilar and interchangeable biological products is new," notes the agency, "FDA services are most critical for continued and successful development of biosimilar and interchangeable biological products during the investigational stage prior to submission of a marketing

l "application."The proposal makes clear that drug companies are already clamoring for insight on product development, and will likely continue to pose a blizzard of questions early on. And the FDA faces a tough challenge getting up to speed quickly. "For example, characterizing biological products for the purpose of determining biosimilarity or interchangeability is challenging because the molecules of biological products tend to be much larger and have a far more complex spatial structure than small-molecule drugs."Separately, the FDA's Janet Woodcock told a conference that a full set of biosimilar guidelines will be out later this year. And human testing, she adds, will not be required for all of them."It depends on how confident you can be of the absolute sameness to the innovator product," Woodcock said "There's a spectrum some will get much closer than others in your ability to characterize them "


said. There s a spectrum ... some will get much closer than others in your ability to characterize them.

First Word Plus May 2011

FDA is Twiddling its Thumbs Waiting for Biosimilar Applications

No FDA biosimilars applications filedPublished on Thursday, June 2, 2011

FDA has not received any applications to market a biosimilar version ofFDA has not received any applications to market a biosimilar version of an approved biologic drug, Kimberly Rawlings, deputy director of the Office of Communications at the Center for Drug Evaluation and Research told BioCentury Thursday. The agency had previously declined to respond to inquiries about biosimilar applications Thedeclined to respond to inquiries about biosimilar applications. The new biosimilars pathway has been officially open since the Patient Protection and Affordable Care Act was signed into law in March 2010. FDA has held 14 pre-IND meetings for proposed biosimilardevelopment programs. It also has received eight pre-IND or IND applications, Amy Rosenberg, director of CDER's Office of Biotechnology Products, said at a public meeting on May 31. FDA plans to publish multiple biosimilars guidance documents, p p p g ,including at least one before the end of 2011, Rachel Behrman, associate director for medical policy in FDA's Center for Drug Evaluation and Research, said in May on BioCentury This Week, BioCentury's public affairs television program.


y p p g

BioCentury Published on Thursday, June 2, 2011

Pharma’s development and commercial strategy has been focused on the prevalent solid tumor markets that

comprise nearly 90% of new cancer diagnoses and deaths annually.

Solid Tumors Represent >90% Of 1.6 Million New Cancer Cases Diagnosed in the US Each Year; Lung, GI, Prostate, Breast and Ovarian are Deadliest

♦ Hematological malignancies represent 9.5% of newly diagnosed cases and deaths each year

350000

200000250000300000350000

New Cases

Deaths

50000100000150000200000

050000


American Cancer Society

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 is that the number of programs pursuing “Big 5” tumors has decreased in recent years; more promising programs are using biomarkers to identify likely responder segmentssegments.

611

500

600

700

370

209

300

400

500

Solid Tumors 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

Lack of Translation of Preclinical Efficacy in First-in-Man Studies Plagues Early Oncology Research

♦ Lack of efficacy and safety issues are the predominant causes of early stage failure.

♦ In oncology lack of translation of antitumor

Oncology Attrition Rates

♦ In oncology, lack of translation of antitumor efficacy demonstrated in preclinical models into early clinical efficacy is the leading reason for discontinuation.

f f l♦ Unforeseen toxicities are more frequently seen when testing novel targets compared to validated targets.

♦ Furthermore, although there are numerous Phase II failures: 2008–2010.commercial and organizational reasons for discontinued development projects, inadequate product profiles unable to achieve benchmark target product profile

The 108 failures are divided according to reason for failure when reported (87 drugs)

(TPP) is less common in oncology, but is a challenging value proposition for follow-on targeted therapies in a data driven oncology market.


Nature Reviews Drug Discovery 10, 328-329 (May 2011), Deloitte Recap

The Oncology Pipeline Has Become More Targeted and Less Focused on “Big Five” Tumors

Understanding of Neoplastic Pathways Has Led To More Rationally Based NMEs

Competition In Common Tumors Has Increased Programs In Niche Cancers

Cell surface

Share of Pipeline

Breast

Share of Late-Stage Pipeline

receptor

DNA repair

Broad Acting

Prostate

Non "BigGrowth factor

Broad Acting

Lung

Non- Big-Five"

Angiogenesis

Proliferation Cell

Signalling

Colorectal

Gastric



Monoclonal Antibodies Dominate Oncology Biologics Pipeline

♦ The Oncology biologic pipeline represents a strong emphasis (62% of programs) on validated technologies (mAbs, mAb conjugates and recombinant proteins), with significant activity in novel platforms. p

Oncology Biologics in Development by Technology

Antisense137

RecombinantTransgenic

2137

Vaccines253

Cell therapyOther

93

282

Cell therapy40

93

Gene therapy43

mAb559

mAb Conjugates

91


EvaluatePharma, development pipeline includes Research through Phase 3

91

Rationally Based Targeted Therapies May Be Improving Attrition Rates in Oncology

♦ “Targeted” agents, specifically TKIs, appear to have an edge over “non-targeted” agents.


Nature Reviews Drug Discovery, Vol. 8, Number 1, pp. 15-6, Jan 2009

Accelerated Approval Mechanism is Often Employed in Registration of Oncology Drugs; However…

Utilization of FDA Approval Mechanisms For Oncology Drugs Compared To Other Therapy Areas

♦ Since 1992, the FDA has granted accelerated approval to 47 new indications for 35 cancer drugs

d i th h lf th (26 i di ti )and, in more than half the cases (26 indications), further trials have confirmed the benefits of the drugs and regular approval was granted.

♦ Among these 26 indications, the average time b t l t d d l lbetween accelerated and regular approval was 4.7 years. But it took more than 7 years to complete confirmatory trials for 5 indications (some took 12.6 and 9.7 years), report the authors.

F h 14 l d l ill d♦ Furthermore, 14 accelerated approvals still do not have completed confirmatory trials; one of these agents has been on the market for 10.5 years, and 3 have been on the market for more than 5 years.

l d d h b d d f ll l♦ Only 3 drugs to date have been denied full regular approval because subsequent trials did not confirm a benefit. Notably, 2 of these — amifostine and gemtuzumab ozogamicin — were on the market for 10 years before being withdrawn


N Engl J Med. 2011;364:1087-1089, J Natl Cancer Inst. Published online March 21, 2011., Deloitte Recap

10 years before being withdrawn.

…But Not Always… Even Long After Approval!

Pfizer Withdraws Drug After Deaths, No Proven Benefit By Catherine Larkin

June 21 (Bloomberg) -- Pfizer Inc. will withdraw its blood cancer drug Mylotarg after 10 years on the U.S. market because studies didn’t prove it works and the treatment was linked to deaths from liver and lung complications.Mylotarg for relapsed acute myeloid leukemia is the first medicine to be pulled off the market that was cleared through the FoodMylotarg, for relapsed acute myeloid leukemia, is the first medicine to be pulled off the market that was cleared through the Food and Drug Administration’s accelerated approval program, the agency said today in a statement. Pfizer volunteered to halt sales after trial results raised safety concerns “and the drug failed to demonstrate clinical benefit,” the FDA said.Mylotarg was approved in 2000 based on preliminary data showing improved remission rates, with a requirement for more complete trials to prove it extended survival. Wyeth, which sold Mylotarg before being purchased by Pfizer in October, didn’t start mandated follow-up research until 2004 and didn’t provide results until this year.“Accelerated approval still has a place in the approval process but it’s also more important that we learn over the years that the whole development plan be set up well in advance,” said Robert Kane, acting deputy director for safety in the FDA’s Division of Hematology Products, in a phone interview today. “The trials should be planned and if possible under way when the sponsor submits the application.”Wyeth began a required study designed to confirm Mylotarg’s benefits in 2004, four years after it won the conditional marketing clearance The test was stopped early when patients didn’t show any benefit on treatment and four times as many deaths wereclearance. The test was stopped early when patients didn t show any benefit on treatment and four times as many deaths were possibly attributed to the drug.‘Disappointed’ in Results“We are disappointed that the study did not confirm the clinical benefit of Mylotarg,” said Mace Rothenberg, Pfizer’s head of oncology development.Pfizer will withdraw the drug from the U S market Oct 15 to allow time to assess current studies and planned individual treatmentsPfizer will withdraw the drug from the U.S. market Oct. 15 to allow time to assess current studies and planned individual treatments, he said. Patients and researchers who want to continue using it after that time must file an investigational new drug application with the FDA. Sales of Mylotarg were $8.8 million in the first quarter, the company said.“We have to label the drug for investigational purposes,” Rothenberg said today in a phone interview. “There’s a lot of processes to work back from saying we need this much time.”Pfizer fell 11 cents, or less than 1 percent, to $15.10 at 4 p.m. in New York Stock Exchange composite trading. The stock dropped 17

t thi d ith 8 8 t d li i th 11 b St d d & P ’ 500 Ph ti l I d


percent this year, compared with an 8.8 percent decline in the 11-member Standard & Poor’s 500 Pharmaceuticals Index.

Therapies for Blood Cancers Appear to Demand Higher Pricing

♦ Recently approved drugs for blood cancers were priced at >2 times the price per treatment for the solid tumor agents introduced during the same period. For oncology drugs launched in the last 3 years, the average annual treatment costs for blood

cancers was $61K vs. $21K for solid tumors Treatment cost of the solid tumor agents was in a narrow band of $19K to $30K whereas the

blood cancers ranged much more widely: $37k to $98K.$100,000

A l C t f Th F R tl

$50,000 $60,000 $70,000 $80,000 $90,000

,Annual Cost of Therapy For Recently

Approved Oncology DrugsBlood Cancers Solid Tumors

$0 $10,000 $20,000 $30,000 $40,000


Leukemia & Lymphoma Society, Compass Strategic Consulting, DH analysis

Pricing and Performance


ONCOLOGY BUSINESS REVIEW • WWW.ONCBIZ.COM • MARCH 2010

However, the solid tumor space has become intensely , p ycompetitive and drug developers have become

increasingly interested in hematology as a “white space” area where standards of care are poorly

established and significant needs remain.

Oncology Pipeline Coverage is Both Broad and Deep –Novel Mechanisms and Rarer Tumors Have More “White Space”

♦ Development Stage Agents, Discovery To Registration By Indication & Rolled-up MechanismIndication Protein

modulatorsEnzyme

modulators

Biological factor

modulators

Peptide modulators

Immune system

modulators

Cell physiology modulators

Macro-molecule

modulators

Growth substance

modulators

Nucleic acid nucleoside modulators

Cell modulators

Carbohydrate metabolism modulators

Hormone modulators

Signal transduction

pathway modulators

Alkylatingagents

Vascular disrupting

agents

Undefined mechanism

Photo-sensitisers

Anti -metabolites

Genetic process

modulators

Inorganic chemical

modulators

Ionisingagents

Biological transport

modulators

Neuro -transmitter modulators

Lipid modulators

Acute lymphoblastic leukaemia 2 8 1 2 1 1 3 1 1

Acute myeloid leukaemia 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

Hem

atol

ogic

alM

alig

nanc

ies

B cell lymphomaChronic lymphocytic leukaemia 11 13 11 6 7 5 3 1 4 2 1 1

Chronic myeloid leukaemia 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 leukaemia 1 1 1 1

Hodgkin's disease 2 4 1 1 1 1 1 1

Leukaemia 2 4 2 2 1 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

Multiple myeloma 19 17 14 10 5 8 4 3 3 2 4 2 2 1H M Multiple 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 leukaemia 1 2 1 1 1 1

Waldenstrom's 2 3 2 1 1 1

Adrenocortical carcinoma 1 1 1 1

Anal cancer 1 1 1 1 1

Anaplastic astrocytoma 4 2 2 2 1 1 1

Biliary cancer 5 5 1 1 1 1 1 1 1

Bladder cancer 12 8 4 3 2 2 4 3 1 1 1 1 1 1 1 1

Brain cancer 7 7 3 3 1 2 1 1 1 1

B

d Tu

mor

s

Breast cancer 76 57 23 16 13 14 16 7 9 4 3 7 1 2 3 1 2 1

Cervical cancer 6 4 3 3 8 1 1 1

Chondrosarcoma 2 1 1 1 1

Colorectal cancer 41 38 23 18 14 2 1 6 4 1 1 5 2 1 1 2 1 1 1 1 1 2

Esophageal cancer 12 4 6 5 3 4 1 1 2 1

Eye neoplasms 1 1 1 1 1

Fallopian tube cancer 6 3 3 3 1 2 3 1 1

Gastric cancer 22 15 9 8 4 4 6 2 1 2 1 4 1 2

GIST 13 11 7 5 1 1 1 1 3 1

Glioma 8 7 5 4 2 4 1 3 1 2 3 1

Head and neck cancer 15 15 7 7 5 3 2 1 2 2 3 1 1 1 2

Liver cancer 26 24 16 13 10 4 2 6 3 1 2 1 1 2 1 1 1

Lung cancer 2 2 3 1

# Dev. Agents0

Solid Malignant melanoma 29 22 15 11 26 6 6 5 1 5 1 4 1 1 1 1 1

Mesothelioma 3 7 2 1 1 1 1 2 1

Nasopharyngeal cancer 2 2 2 2 1 1 1

Neuroblastoma 2 1 1 2

Neuroendocrine tumours 9 3 5 5 1 1 1 1 1 1

Neurofibromatoses 2 1 2 2 1

Non-small cell lung cancer 81 64 32 24 16 17 20 8 6 1 5 4 2 5 2 1 1 2 1 1

Osteosarcoma 1 1 1 1 1 1 1 1

Ovarian cancer 34 32 16 10 7 10 10 7 8 3 6 4 3 1 1

Pancreatic cancer 32 19 13 9 14 6 7 7 3 5 2 3 5 2 1 1

Peritoneal cancer 7 3 3 3 1 2 3 2 1 1

Prostate cancer 59 36 19 21 15 11 15 7 7 6 6 11 2 2 1 1 1 1 1 1

Renal cancer 21 20 11 8 11 2 6 2 5 1 1 1

01

2 - 55 - 10

10 - 2020-50>50


ADIS R&D Insight

Small cell lung cancer 11 12 7 4 1 7 2 1 3 1 1 1 1

Soft tissue sarcoma 11 6 6 5 3 3 2 1 2 1 2 2 1

Thyroid cancer 8 9 6 2 1 1 3 1 1 1 1 2

While One-Quarter of the Pipeline for Heme Cancers is for NHL (the most prevalent), a Significant Portion is for Rare Cancers (Myeloma, AML, MDS…)( y , , )

Number of Agents In Clinical Development (P1-reg) For Hematological Malignancies

NHL

HL3%

CML5% ALL

6%

g g

NHL26%

AML

3% 6%

OTHER MYELOID10%CLL

18%

10%MM19%

13%

(Total= 400)



The Number of Clinical Stage Products Appears Disproportionate to the Number of Affected Patients

Comparison of Agents (P1-Reg) in development to Incidence

100

120

60,000

70,000

Incidence Number of Agents

Comparison of Agents (P1 Reg) in development to Incidence

elop

men

t

60

80

30 000

40,000

50,000

ents

In D

eve

se In

cide

nce

20

40

10,000

20,000

30,000

umbe

r of A

ge

Dise

as

00NHL OTHER

MYELOIDMM CLL AML HL CML ALL

Nu


SEER, ADIS R&D Insight, Thomson Pharma Partnering

However, That May Be Justified by Unmet Needs in Terms of Mortality

Comparison of Development Stage Agents Compared to a Composite Factor of Incidence and

120100,000

Incidence/5-year Survival pmen

t

al

Compared to a Composite Factor of Incidence and Outcomes (Incidence/5-year Survival)

60

80

100

60,000

80,000/ y

Agents in Development

ts In

Dev

elop

year

Sur

viva

20

40

60

20,000

40,000

ber o

f Age

nt

ncid

ence

/5-y

00NHL MM AML Other

MyeloidCLL HL ALL CML

Num

bIn


SEER, ADIS R&D Insight, Thomson Pharma Partnering

NIH to Fill the Translational Gap?

We have seen a deluge of new discoveries in the last few years on the molecular basis ofDisease However despite increasing investments by the private sector there has been aDisease…However, despite increasing investments by the private sector, there has been a downturn in the number of approved new molecular entities over the last few years…So, we have this paradox: we have a great opportunity to develop truly new therapeutic approaches, but are undergoing a real constriction of the pipeline. One solution is to come up with a non-traditional way of fostering drug development through increased NIH involvement


way of fostering drug development — through increased NIH involvement.Nature Publishers

In Addressing Patient Needs, the Government and Non-Profit Funding Aims to Fill Translational Gaps

CS

Funding Allocation For Hematological Malignancies: NCI vs LLS Budgets

NCI Programs ($586 MM, 2008)

LLS Programs ($72 MM, 2010)


Leukemia & Lymphoma Society grant database, NCI grant funding search: http://fundedresearch.cancer.gov/

Non-profits are Proactively Investing in Pipeline Agents Aligned With the Unmet Needs of Blood Cancers

♦ Founded in 1949, The Leukemia & Lymphoma Society (LLS) has b idi t f di tbeen providing grant funding to leading academic investigators and providing CORE grants in the pursuit of curing leukemia, lymphoma and myeloma.

♦ Today, LLS is taking a more proactive role in advancing promising therapies bypromising therapies by supporting translational research towards clinical results.

♦ Furthermore, LLS has been engaging partnerships with biotech to accelerate therapies through all stages of clinical development.


Personal communication, J. DeGennaro, PhD | Executive Vice President, Chief Mission Officer

p

Non-profits are Proactively Investing in Pipeline Agents Aligned With the Unmet Needs of Blood Cancers

♦ Found in 1998, Multiple Myeloma Research Foundation (MMRF) pledges to pursue innovative means to accelerate the development of next-generation multiple myeloma treatments. MMRF’s portfolio includes investments in discovery,includes investments in discovery, translation and phase I and II clinical trials.

♦ Run like a for-profit business, MMRF touts its business model as an end-to-end solution to accelerate drug development which works by bridging drug discovery gaps andbridging drug discovery gaps and more importantly, by developing business solutions that inject speed and efficiency into every step along the drug development pathway


the drug development pathway. DH secondary research; MMRF website

Notable Initiatives: Multiple Myeloma Research Consortium (MMRC)

♦ MMRF’s founder Kathy Giusti realized early on that a key factor slowing development of new myeloma drugs is lack of collaboration between researchers at different academic institutions. In 2002, she assembled MMRC, a consortium of scientists who would be required to submit their research proposals to a steering committee for approval and to publish their resultstheir research proposals to a steering committee for approval, and to publish their results jointly. In exchange, the scientists would receive access to a tissue bank of myeloma blood cells and bone marrow, as well as administrative and organizational support for lab tests and clinical trials.

♦ The consortium’s steering committee, composed of three myeloma researchers from member institutions, advises on which experimental drugs to test in clinical trials, and MMRF’s team of scientists, recruited from pharmaceutical companies, evaluates the committee’s decisions.

5

At MMRC metrics andAt MMRC, metrics and rewards systems are implemented to improve processes and enforce accountability.


y

DH secondary research; MMRF website

Notable Initiatives: Multiple Myeloma Research Consortium (MMRC)

♦ To date, this unique collaborative model, now comprised of 15 academic research centers has advanced 21 clinical trials with industry partners, including Novartis, Celgene, Merck, and Proteolix. Recent trials conducted through the MMRC were opened an average of 30 to 40 percent faster than the industry standardpercent faster than the industry standard.

1


DH secondary research; MMRF website

Breakthrough therapies have not only transformed the management of patients with blood cancers, but have created blockbuster markets which have

t t 4 f th 10 t lgrown to represent 4 of the 10 top oncology revenue producers.

Mid 1800s: First Medical Descriptions of Blood Cancers

Reed-Sternberg cell

Molecular Understanding of Disease Improved Outcomes for Patients with Hematological Malignancies

Immunophenotyping Karyotype& Molecular Analysis (2000s)

Cellular Morphology (1920)

Clinical Presentation

(1900s)

Patient Symptoms (1800s)

Chronic Leukemia

Over 40 subtypesAcute Myelogenous LeukemiaAcute Promyelocytic LeukemiaAcute Lymphoblastic LeukemiaChronic Myelogenous Leukemia

Whit Bl d

Leukemia

Myelolproliferative DisordersMyelodysplastic SyndromesMixed MPD/MDSAssociated subtypesAcute Leukemia

White Blood Disease

LymphomaIndolent

Lymphoma

Over 50 subtypesMature B-Cell LymphomaMature T-Cell LymphomaImmature Precursor LymphomasHodgkin’s Lymphoma

Aggressive Lymphoma

g y pBurkitt’s LymphomaMantle Cell LymphomaFollicular LymphomaHairy Cell LeukemiaCutaneous T-Cell Lymphoma


WHO Classification; SEER 2009

Peripheral T-Cell Lymphoma

Today 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.

2008 WHO Classification System Includes Molecular Markers to Define Over 140 Types of Blood Cancers

WHO Defined Lymphomas


WHO

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 O

nse

MDS

HL

ALL

Aver

age

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

Improvement in patient outcomes can be rapid with rationally designed transformative therapies, or incremental advances in treatment standards

Then and Now: Age of Onset Compared to Overall Survival

708090 CML

Pre-Gleevec (2001)


506070

ge o

f Ons

et

In 1947 Boston pathologist Sydney Farber began testing aminopterin a folic acid

203040

Aver

age

Ag PediatricALL

1960s

began testing aminopterin, a folic acid mimic, as a potential cure for leukemia in children. The majority of the children with ALL who were tested showed signs of improvement in their bone marrow,

010

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

but none of them actually were cured.


SEER database; scientific literature Median 5-year Survival Rate

Improving Patient Outcomes in Childhood Leukemia



70

80

90 CMLPre-Gleevec (2001)


In 1962, researchers Emil Freireich and Emil Frei used combination chemotherapy to attempt to cure leukemia The tests were

50

60

70

ge o

f Ons

et

di i

attempt to cure leukemia. The tests were successful with some patients surviving long after the tests.

20

30

40

Aver

age

Ag PediatricALL

Today

PediatricALL

1960s Trial and error incremental advancement

0

10

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



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



70

80

90 CMLPre-Gleevec (2001)


50

60

70

ge o

f Ons

et

The management of CML , a myeloproliferativeThe management of CML , a myeloproliferativeneoplasm (~5,000 new diagnoses each year in

20

30

40

Aver

age

Ag

biomarker, the Philadelphia Chromosome.

p ( , g ythe US) has gone through a radical transformation in the past decade based on 1 biomarker, the Philadelphia Chromosome.

0

10

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



One Biomarker Transforms Patient Outcomes in CML

♦ Ph1 Chromosome(BCR-ABL) is causative for CML and confirms diagnosis .♦ CML was the first human cancer to be associated with a consistent chromosomal abnormality, the

Philadelphia chromosome (Ph1), which is a balanced reciprocal translocation involving the long p ( ), p g garms of chromosomes 9 and 22.

♦ This translocation results in the production of the hydrid BCR-ABL fusion oncogene, which has constitutively active tyrosine kinase activity that is essential for its transforming capability.

h d f f d b h f h h f h♦ The diagnosis of CML is confirmed by the presence of Ph1, the BCR-ABL fusion gene or the BCR-ABL fusion mRNA by conventional cytogenetics, fluorescence in situ hybridization (FISH) analysis, or reverse transcription polymerase chain reaction (RT-PCR), respectively.

Philadelphia Chromosome BCR-ABL Fusion Gene BCR-ABL mRNAPhiladelphia Chromosome BCR ABL Fusion Gene BCR ABL mRNA


Defined Health primary research; Besa, EC and Woermann, U., 2006; Chronic Myelogenous Leukemia. Emedicine. http://www.emedicince.com

CML was the First Malignancy for Which a Drug was Rationally Designed to Yield an Effective Targeted Molecular Therapy



70

80

90 CMLPost-Gleevec

CMLPre-Gleevec (2001)


50

60

70

ge o

f Ons

et

Long-term follow up studies on patients t t d ith i ti ib h

Imatinib was first approved in 2001 as a first-line treatment for patients with

20

30

40

Aver

age

Ag treated with imatinib have demonstrated that:

• 93% of patients have no disease progression after 7 years (PFS at 7 years is 81%)

treatment for patients with CML, and the long-term outcomes with front-line Imatinib treatment have been paradigm shifting.

0

10

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

y )• Overall Survival at 7 years is 86%



R&D Activity: Publications in CML Fueled by Basic/Translational Research Discoveries and Clinical Data

CML

500 published

IRIS study long-term data publishedDasatinib

Nilotinibapproved by

1845: CML described

350

400

450

BCR-ABL found to cause CML in

the FDAapproved by

the FDAthe FDA

approved by the FDA

IRIS study data first published

250

300

350

er o

f Ref

eren

ces

t(9 22)

to cause CML in mice

the FDA

Imatinibapproved by

the FDAFirst TKIs reported

100

150

200

Num

be

Ph chromosomeid ifi d

t(9:22) translocation

identified

p

BCR-ABL fusion gene discovered Imatinib Imatinib

d

0

50

19481950195219541956195819601962196419661968197019721974197619781980198219841986198819901992199419961998200020022004200620082010

identified tested in CML patients


pubmed.gov

Year

Oncology Example: Biomarkers Further Refine Treatment for Refractory CML Patients♦ Shortly after the development and launch of imatinib in CML, the genetic mechanisms of

Gleevec resistance (mutations in the ABL kinase domain and ATP-binding region) were characterized. Translation of this research into clinical results was rapid in the d l t f d ti ib f ll d b il ti ibdevelopment of dasatinib followed by nilotinib.

♦ With the advances of imatinib, dasatinib and nilotinib, treatment approaches for CML have been completely rewritten and continue to evolve.

fi d H l h i h


Defined Health primary research; O’Hare, T. 2008. Clinical Cancer Research, 14:7971-7974

Second-Generation CML Drugs are More Effective Than Imatinib –May Move to Front-line Despite Availability of Generic Imatinib

Medscape Medical News from the: American Society of Hematology (ASH) 52nd Annual MeetingFollow-up Results Favor Dasatinib Over Imatinib as CML Front-Line Therapy

December 13, 2010 (Orlando, Florida) — The newer drug dasatinib (Sprycel; Bristol-Myers S ibb) ti t d t t i ffi d ith i ti ib (Gl

The CML market is expected to exceed $6BSquibb) continues to demonstrate superior efficacy compared with imatinib (Gleevec;

Novartis Oncology) in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP).The 18-month follow-up data from the Dasatinib versus Imatinib Study in Treatment-Naive CML Patients (DASISION) supports the potential use of dasatinib as first-line treatment for patients with CML-CP. The findings were presented here at the American Society of Hematology 52nd Annual Meeting.

to exceed $6B

"Dasatinib 100 mg once daily continues to demonstrate superior efficacy compared with imatinib, with higher and faster rates of complete cytogenetic response and major molecular response," said study author Neil Shah, MD, PhD, an assistant professor at the University of California–San Francisco. "The longer follow-up continues to support the use of dasatinib as first-line therapy in newly diagnosed chronic phase patients."Based on the predictive value of early complete cytogenetic response, we anticipate that further follow-up may demonstrate better long-term outcomes for patients receiving dasatinib rather than imatinib " he concludeddasatinib, rather than imatinib, he concluded.Earlier 12-month results from the phase 3 DASISION study were presented at the American Society of Clinical Oncology 2010 Annual Meeting and published simultaneously in the New England Journal of Medicine. As reported by Medscape Medical News at that time, the results showed that complete cytogenic and major molecular responses were higher in the dasatinib group than in the imatinib group, and both responses were obtained significantly faster.P i t th l t d bl t h l l i th d ti ibProgression to the accelerated or blast phase was also lower in the dasatinib group, occurring in 5 patients in the dasatinib group (1.9%, all blastic phase) and 9 patients in the imatinib group (3.5%, all blastic phase).As a result of these data, the US Food and Drug Administration approved an expanded indication for dasatinib as a first-line therapy for CML-CP. Dasatinib was initially approved for patients with CML-CP who had developed resistance or were intolerant to prior therapy, including imatinib.


Medscape; EvaluatePharma

What’s in the Pipeline?


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

AML is Mainly a Disease of the Older Adults AML

♦ In 2010 there will be an estimated 12,800 new cases of AML and 9,000 deaths in the US.♦ The disease is more common in adults (90% of new cases) than in children, with the average

age at diagnosis being more than 65 years. Elderly patients (>60 years old) represent about g g g y y p ( y ) p2/3 of all diagnoses. Children and adults of any age can develop AML (~1 in 5 children with leukemia has AML). Diagnostic procedures and treatment of children and adults are similar.

However, all major population subgroups show the same, rapidly increasing incidence with age. The disproportionate impact of AML ondisproportionate impact of AML on the elderly 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 the elderly may be due to greater cumulative exposure to carcinogens and to the effects of radiation and chemotherapy for other malignancies, and also to improved screening and surveillance.

than 75: 2.6 vs 16 per 100,000.


American Cancer Society, www.cdc.gov; SEERMedscape, Lancet JE, Willman CL, Bennett JM. Acute myelogenous leukemia and aging: clinical interactions. Hematol Oncol Clin North Am. 2000;14:251-267

also to improved screening and surveillance.

AML is Treated With Intent to Cure AML

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

Remission Induction Therapy

Post-Remission Therapy

♦ In the US, the two stages of standard treatment for AML are:

1. Remission Induction Therapy: Treatment should be sufficiently aggressive to achieve

Cure Relapse

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

i i h i iSalvage Therapy

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

3. Salvage Therapy: Following initial induction and consolidation treatment, patients are then treated with salvage therapy after relapse.


Defined Health analysis based on KOL research

Treatment of AML in Older Adults Remains a Tremendous Challenge

AML

♦ Standard approaches to treatment have resulted in PFS in only a small minority of patients with AML over the age of 60.

♦ 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 y y g ,treatment with 3 + 7 regimens to death of only 5-10 months.


Wendy Stock, Hematology 2006

AML Clinical Research and Development Activity AML

PreclinicalPreclinical Phase 2Phase 2Phase 1Phase 1 Phase 3Phase 3 Registration / Registration / Launched

Temozolomide Clofarabine Mylotarg

VosaroxinSapacitabineAnnamycin liposome

rh Histone H1 3AML vaccineCOTI

AML Development Pipeline Midostaurin

CPX-354

Dacogen

Arsenic trioxideVorinostat

p

Panobinostat

MLN 8237

Belinostat

ARRY 520KW 2449

rh Histone H1.3

BI 6727

Elacytarabine

Ti if ib

SAR 103168

IMC EB10

IPH 2101MRx-102

AC 220- Ambitvaccine - Juvaris

αCD123 mAM- CSL

αCD9 mAB- ARIUSAST 487

miRNA - Mirna Vidaza

C l

Tosedostat

OblimersenAZD 1152

Chemo-therapy

MLN 8237

LY 2181308

LOR 2040Lestaurtinib

Imatinib

AZD 6244

Tipifarnib

Sorafenib

BI 811283

BI 2536

ON 01910

4SC-203Fusion toxin

mAB, ARCA

MDX 1338

rhH1 x

MC-2001

Flt-3 Kyowa

KRN 388

CX-6258

Ceplene

AEG 35156

Obatoclax

Cediranib

Immuno-

Kinase Inhibitor

AldesleukinEpigenetic

Omacetaxine

Cenersen

AS 1411

Voreloxin

Lintuzumab Bi 213

AVE 9633

Lintuzumab Ac-225CAL 101

AC 220SB-559457

SHP-2, VUMC

KRN 388

D11-5908

RNAi- Antigen

MAT 102

Proapoptotic

CPX

therapy

SCT / OtherLintuzumab

Lenalidomide

GRNVAC1

Zosuquidar

SL 401

Lintuzumab Bi-213

Tasisulam

Tamibarotene

AC 220

R 763

LC 1

VLIM-88

AT-401

CBFb Inhibitors

XIAP InhibFLT-3 Inhib


ADIS R&D Insight, Thomson Pharma Partnering, Defined Health analysis

Chemotherapies in AML (Anthracycline and Nucleoside Analogs) – More Tolerable and/or Avoid Drug Resistance

AML


Temozolomide

SapacitabineAnnamycin liposome


Clofarabine

Vosaroxin

Mylotarg

AML Development Pipeline

CPX-354

Vorinostat

p

Panobinostat

MLN 8237

Belinostat

ARRY 520KW 2449

rh Histone H1.3

BI 6727

Ti if ib

SAR 103168

IMC EB10

IPH 2101MRx-102


αCD123 mAM- CSL


miRNA - Mirna

Midostaurin

Dacogen

Arsenic trioxide

Elacytarabine

VidazaCLO+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). In a small P1/2

d dAZD 1152

Chemo-therapy

MLN 8237

Lestaurtinib

Imatinib

AZD 6244

Tipifarnib

Sorafenib

BI 811283

BI 2536

ON 01910

4SC-203Fusion toxin

mAB, ARCA

MDX 1338

rhH1 x

MC-2001

Flt-3 Kyowa

KRN 388

CX-6258

C l

Tosedostat

Oblimersen

LY 2181308

LOR 2040

( y ) / ( , p )However, these improvements did not translate into a survival benefit compared to ara-C alone.

study, Median overall survival was three-fold that of historical control.

AEG 35156

Obatoclax

Cediranib

Immuno-

Kinase Inhibitor

Epigenetic

Omacetaxine

Cenersen

AS 1411

Voreloxin

Lintuzumab Bi 213

AVE 9633


AC 220SB-559457

SHP-2, VUMC

KRN 388

D11-5908

RNAi- Antigen

MAT 102

Proapoptotic

CPX

Ceplene

AldesleukinSunesis is running a PIII, VALOR, a 450 pt. adaptive trial of vosaroxin or placebo in combination with cytarabine

therapy


Lenalidomide

GRNVAC1

Zosuquidar

SL 401

Lintuzumab Bi-213

Tasisulam

Tamibarotene

AC 220

R 763

LC 1

VLIM-88

AT-401

CBFb Inhibitors


for patients with first relapsed or refractory



Epigenetic Mechanisms Such as Methylation and Acetylation are Impacting the Management of AML

AML


Temozolomide

SapacitabineAnnamycin liposome


Clofarabine

Vosaroxin

MylotargSapacitabine is being tested in treatment-naïve and relapsed elderly AML patients,


CPX-354

Vorinostat

p

Panobinostat

MLN 8237

Belinostat

ARRY 520KW 2449

rh Histone H1.3

BI 6727

Ti if ib

SAR 103168

IMC EB10

IPH 2101MRx-102


αCD123 mAM- CSL


miRNA - Mirna

Midostaurin

Dacogen

Arsenic trioxide

Elacytarabine

Vidaza

p y p ,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).

AZD 1152

Chemo-therapy

MLN 8237

Lestaurtinib

Imatinib

AZD 6244

Tipifarnib

Sorafenib

BI 811283

BI 2536

ON 01910

4SC-203Fusion toxin

mAB, ARCA

MDX 1338

rhH1 x

MC-2001

Flt-3 Kyowa

KRN 388

CX-6258

C l

Tosedostat

Oblimersen

LY 2181308

LOR 2040

In a maintenance study (pts randomized to receive decitabine or continue chemotherapy/observation), 7 of 8

i h d i bi d 9 f

p y )

AEG 35156

Obatoclax

Cediranib

Immuno-

Kinase Inhibitor

Epigenetic

Omacetaxine

Cenersen

AS 1411

Voreloxin

Lintuzumab Bi 213

AVE 9633


AC 220SB-559457

SHP-2, VUMC

KRN 388

D11-5908

RNAi- Antigen

MAT 102

Proapoptotic

CPX

Ceplene

Aldesleukin

In a study of 113 elderly pts (86% unfit for IC), median OS for azacitidine-treated

patients on the decitabine arm and 9 of 11 patients on the control arm remained in remission.

therapy


Lenalidomide

GRNVAC1

Zosuquidar

SL 401

Lintuzumab Bi-213

Tasisulam

Tamibarotene

AC 220

R 763

LC 1

VLIM-88

AT-401

CBFb Inhibitors


for azacitidine treated patients was 24.5 months compared with 16.0 months for CCR-treated patients, and 2-year OS rates were 50% and


2 year OS rates were 50% and 16%, respectively.


Targeted Approaches Promise to Transform AML –Initial Efforts Unsuccessful So Far

AML


Temozolomide Clofarabine



Mylotarg


Midostaurin

CPX-354

Oblimersen

Dacogen


p

Panobinostat

MLN 8237

Belinostat

ARRY 520KW 2449

rh Histone H1.3

BI 6727

Elacytarabine

Ti if ib

SAR 103168

IMC EB10

IPH 2101MRx-102


αCD123 mAM- CSL


miRNA - Mirna

Ceplene

Tosedostat

Oblimersen

AZD 1152

Chemo-therapy

MLN 8237LY 2181308

LOR 2040

Lestaurtinib

Imatinib

AZD 6244

Tipifarnib

Sorafenib

BI 811283

BI 2536

ON 01910

4SC-203Fusion toxin

mAB, ARCA

MDX 1338

rhH1 x

MC-2001

Flt-3 Kyowa

KRN 388

CX-6258

AEG 35156

Obatoclax

Cediranib

Immuno-

Kinase Inhibitor


Omacetaxine

Cenersen

AS 1411

Voreloxin

Lintuzumab Bi 213

AVE 9633


AC 220SB-559457

SHP-2, VUMC

KRN 388

D11-5908

RNAi- Antigen

MAT 102

Proapoptotic

CPXProgress has been made in deciphering the molecular pathogenesis of AML which has led to the development oftherapy


Lenalidomide

GRNVAC1

Zosuquidar

SL 401

Lintuzumab Bi-213

Tasisulam

Tamibarotene

AC 220

R 763

LC 1

VLIM-88

AT-401

CBFb Inhibitors


which has led to the development of molecularly targeted kinase inhibitors of the signal transduction cascades (eg,FLT3, KIT, RAS).

Results from a P2 study in AML and MDS showed that, out of 38 AML pts treated with tosedostat, 3 achieved CR and 7 achieved PR lasting 1-3


7 achieved PR lasting 1 3 months.


Disruptive Technologies Such as Therapeutic Vaccines and Therapies Directed at Leukemic Stem Cells May Impact AML

AML


Temozolomide Clofarabine


rh Histone H1 3AML vaccineCOTIB-Cell Vaccines: Rapid

disease kinetics in AMLMylotarg


Midostaurin

CPX-354

Oblimersen

Dacogen


p

Panobinostat

MLN 8237

Belinostat

ARRY 520KW 2449

rh Histone H1.3

BI 6727

Elacytarabine

Ti if ib

SAR 103168

IMC EB10

IPH 2101MRx-102


αCD123 mAM- CSL


miRNA - Mirna

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

Ceplene

Tosedostat

Oblimersen

AZD 1152

Chemo-therapy

MLN 8237LY 2181308

LOR 2040

Lestaurtinib

Imatinib

AZD 6244

Tipifarnib

Sorafenib

BI 811283

BI 2536

ON 01910

4SC-203Fusion toxin

mAB, ARCA

MDX 1338

rhH1 x

MC-2001

Flt-3 Kyowa

KRN 388

CX-6258 Agents that target Stem Cell Mobilization and Self Renewal are

However, may have a role in maintaining durable remissions.

AEG 35156

Obatoclax

Cediranib

Immuno-

Kinase Inhibitor


Omacetaxine

Cenersen

AS 1411

Voreloxin

Lintuzumab Bi 213

AVE 9633


AC 220SB-559457

SHP-2, VUMC

KRN 388

D11-5908

RNAi- Antigen

MAT 102

Proapoptotic

CPX

Mobilization and Self Renewal are among the most promising emerging therapies in AML, but lack validation:

therapy


Lenalidomide

GRNVAC1

Zosuquidar

SL 401

Lintuzumab Bi-213

Tasisulam

Tamibarotene

AC 220

R 763

LC 1

VLIM-88

AT-401

CBFb Inhibitors




Myeloproliferative DisordersOverlaps and Transitions Between the Disorders

MPD

♦ The clinical features of these conditions are distinguishable, but can also overlap.

h h l♦ In some patients with chronic myelogenous leukemia (CML), the presenting clinical picture may be very similar to that of essential thromocythemia (ET).

♦ A minority of patients who present with ET will develop an increased red cell mass and, therefore, polycythemia vera (PV) over time.

♦ Almost all patients with CML will eventually♦ Almost all patients with CML will eventually transform to acute leukemia (AL), whereas only a tiny fraction of patients with PV or ET will do so unless they are put at greater risk by therapy with radiation or alkylating agentstherapy with radiation or alkylating agents.

♦ A significant minority of patients with PV, ET, or CML will develop the clinical picture of primary myelofibrosis (MF). Arrows indicate transitions that may occur, with

frequencies suggested by the thickness of the arrows


Murphy S, Iland HJ. Thrombocytosis. In: Losalzo J, Schafer AI, editors. Thrombosis and hemorrhage. Cambridge MA: Blackwell; 1994. p. 597–612

frequencies suggested by the thickness of the arrows.

Myeloproliferative DisordersJAK2V617F Mutation

MPD

♦ In 2005, PV, ET, and MF were shown to be caused, in some cases, by mutations that activate JAK2.

♦ JAK2 (Janus Kinase 2) is a cytoplasmic tyrosine kinase♦ JAK2 (Janus Kinase 2) is a cytoplasmic tyrosine kinase involved in cytokine receptor signaling and plays a crucial role in normal hematopoiesis. JAK proteins relay signals to the nucleus by activating the STAT (signal transducers and activators of transcription) family of transcription factorsfamily of transcription factors.

♦ A single point mutation in the JH2 pseudokinase domain of the JAK2 gene results in a valine to phenylalanine substitution at amino acid 617 (V617F).

♦ Th JAK2V617F i t t ti d 12 t ti lt i tit ti ti ti f JAK2 d♦ The JAK2V617F point mutation and exon-12 mutations result in constitutive activation of JAK2, and are widely used diagnostic markers for Philadelphia chromosome-negative MPDs.

♦ The identification of the JAK2V617F mutation has provided important insight into the pathogenesis of PV, ET, and MF, but many important questions still remain regarding the pathogenesis of these neoplasms and the ultimate role of JAK2. Further understanding of the contribution of a single p g gdisease allele to the development of 3 related, but clinicopathologically distinct, myeloid disorders remains as a high unmet need expressed by our KOL interviews.

♦ JAK2 is now a therapeutic candidate for molecularly targeted therapies. The lead JAK2 inhibitor (INCB-18424, Incyte/Novartis) is currently in Phase 3 for myelofibrosis. In addition, there are four other JAK2 inhibitors in development in Phase 2 and a multitude earlier in development


Curr Med Chem. 2005;12(16):1819-28; Am J Physiol Renal Physiol. 2006 Apr;290(4); Nat Clin Pract Oncol. 2005 Jun;2(6):315-24; stemcell.com

other JAK2 inhibitors in development in Phase 2, and a multitude earlier in development.

Myeloproliferative DisordersPublications

MPD

450

500

Essential Thromboc themia

350

400

450 Essential ThrombocythemiaMyelofibrosisPolycythemia vera

Identification of JAK2 mutation in

2005

200

250

300

100

150

200

0

50

1954 1959 1964 1969 1974 1979 1984 1989 1994 1999 2004 2009


pubmed.gov

Myeloproliferative DisordersOccurrence of JAK2V617F Mutation in PV, ET and MF Varies

MPD

♦ Most, if not all patients with PV and a significant number of patients with ET and MF are JAK2V617F positive, and the mutation likely arises in the hematopoietic stem cell compartmentcompartment.

♦ JAK2-positive thrombocythemia and polycythemia have overlapping phenotypes in the chronic phase and can progress to an accelerated phase, which is manifested as myelofibrosis or other complications. Leukemic transformation can also occur.

♦ While the structure of Janus kinases are dissimilar to the abl tyrosine kinase (the kinase fusion partner of BCR-ABL), the validation of imatinib’s efficacy as a cytosolic tyrosine kinase inhibitor in CML provides a persuasive example for the creation of a novel therapeutic targeting JAK2.

Annual NewMPD Disorder Annual New Cases (US) Median survival JAK2 mutation

Polycythemia Vera 6,000 Untreated 6-18 monthsTreated 10-20+ years 90 - 95%

Essential Thrombocytemia 6,000 at 5 years 74-93%, at 10 years 61-

84% (similar to normal) 50 – 70%

Idiopathic l f b ~2,500 3-7 years; leukemic

f 40 – 50%


Myelofibrosis 2,500 transformation occurs in 10-25% 40 50%

Ross and Wernig, Hematology 2006

Myeloproliferative DisordersMolecular Abnormalities

MPD

♦ Information concerning molecular abnormalities of MPDs has been limited until 2005 when the JAK2V617F mutation was discovered. Some additional mutations have since been identified, but there is still in a lot to learn regarding their role in the MPDs, especially in light of the fact that over 50% of ET and MF patients are g g , p y g pnegative for the JAK2V617F mutation.

♦ Recent studies support the existence of other mutations, such as W515L in the MPL gene found in V617F negative MF patients, and the JAK2 Exon 12 mutation which all meet centrally at the level of the native JAK2. One of the more recent discoveries in the field is the TET2 mutation identified in 2009.

TET2 Mutations And Their Clinical Correlates In PV, ET And MFLeukemia. 2009 May;23(5):905-11; Tefferi A, et al.; Dept Med, Mayo Clinic, Rochester, MN

High-throughput DNA sequence analysis was used to screen for TET2 mutations in bone marrow-derived DNA from 239 patientsHigh throughput DNA sequence analysis was used to screen for TET2 mutations in bone marrow derived DNA from 239 patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). Thirty-two mutations (19 frameshift, 10 nonsense, 3 missense; mostly involving exons 4 and 12) were identified for an overall mutational frequency of approximately 13%. Specific diagnoses included polycythemia vera (PV; n=89), essential thrombocythemia (ET; n=57), primary myelofibrosis (PMF; n=60), post-PV MF (n=14), post-ET MF (n=7) and blast phase PV/ET/MF (n=12); the corresponding mutational frequencies were approximately 16, 5, 17, 14, 14 and 17% (P=0.50). Mutant TET2 was detected in approximately 17 and approximately 7% of JAK2V617F-positive and -negative cases, respectively (P=0.04). However, this apparent clustering of the two mutations was accounted for by an independent association between mutant TET2 and advanced age; mutational frequency was approximately 23% in patients > or =60 years old versus approximately 4% in younger patients (P<0.0001). The presence of mutant TET2 did not affect survival, leukemic transformation or thrombosis in either PV or PMF; a correlation with hemoglobin <10 g per 100 ml in PMF was noted (P=0.05). We conclude that TET2 mutations occur in both JAK2V617F-positive and -negative MPN, are more prevalent in older

ti t di l i il f i MPN b t i d di t d h ld li it d ti l


patients, display similar frequencies across MPN subcategories and disease stages, and hold limited prognostic relevance.

Polycythemia VeraTreatment Algorithm

MPD - PV

Diagnosis of PV Anti-platelet therapy (e.g. aspirin) is given in a large percentage of patients ( ~ 60%). This reduces thrombotic risk.

Young, low risk patient Older, high risk patient

Patient younger than 65, few co-morbidities, no previous thrombotic events

Patient older than 65, existing co-morbidities, especially cardiovascular, one or more previous thrombotic events

Phlebotomy and HydroxyUrea

Many clinicians prefer phlebotomy in

HydroxyUreaPhlebotomy

In most patients, hydroxyurea adequately controls the short-term vascular events butHydroxyUreayounger patients because of the

potential for hydroxyurea to facilitate leukemogenesis

L d IFN

controls the short-term vascular events, but does not address ongoing symptoms such as night sweats, pruritis, and fatigue

Alt ti T t t I ti ibLow dose-IFN

Because of the concern for potential leukemogenicity of hydroxyurea, some clinicians recommend interferon alfa as the drug of choice

Alternative treatments can include anagrelide, radiophosphorus, development compounds or off-label drugs. Anagrelide can control platelet count, but does not show a decrease in thrombosis in PV. Radiophosphorus only used in patients with

Alternative Treatments Imatinib


for young people (<40 years old). short life expectancies intolerant to other therapies.

Blood. 2006 Apr 15;107(8):3339-41; Mayo Clin Proc, 2005 80:947-958; Defined Health Primary Research

Emerging Therapies for MPDs MPD

Phase 2Phase 2Phase 1Phase 1 Phase 3Phase 3 Registration / Registration / Launched

XL 019 - USKinase/Intracellular

Drugs Used for PV and ET

PreclinicalPreclinical

Multi-kinase inhibitorsTargeGen

CYT387 – US

PolycythemiaVera

Lestaurtinib -USCephalonJAK2, FLT3 inhibitor

ExelixisJAK-2 inhibitorTarceva (erlotinib) -USOSI, Univ OKEGFR inhibitorGleevec (imatinib)NVS, MDACC; Multi-t t d ki i hib

Drugs Used for PV and ET

• Hydroxyurea (ribonucleotide reductase)• Gleevec• Interferon alpha• Anagrelide (PDE3 inhib)

TargeGenExelixisS*BIOAbbott

JAK2 inhibitorsSGX PharmaceuticalsDicepheraRigel

INCB 18424 – US, EUIncyte Novartis

YM BioscisncesJAK2 inhibitor

Anagrelide & hydroxyurea

Agrylin(anagrelide)ShiVera

Development Pipeline

PomalidomideCelgene; TNF IL 1b

Sprycel (dasatinib) -USBMS, MDACC; Multi-targeted kinase inhib

Immunotherapy

targeted kinase inhibRigelAstexAstraZenecaSuperGenIncyte (JAK1/JAK2)

TAK-901 -USMillennium; Aurora B kinase cell cycle inhib

Incyte, NovartisJAK-2 inhibitor

hydroxyureaShire; PDE 3 inhib, platelet aggregation inh

ShirePlatelet aggregation inhibitor, PDE3 inhib

Interferon-alpha - USAmarillo BioscienceImmunomodulator

Celgene; TNF, IL-1b inhibitor, IL-10 stim

JAK2 inhibitor+

Pegasys (IFN-alpha2a)MDACC, Roche

Aurora B kinase cell cycle inhib

PNP inhibitor

Givinostat (ITF2357) EUItalfarmacoHDAC inhibitor

Immunomodulator

TNF inhibitor, IL-1binhibitor, IL-10 stim

Multi-targeted kinase inhibitor

EGFR inhibitor Epigenetics

Forodesine (BCX-

,Immunomodulator

Metabolic Poisons-Nucleoside analogs


HDAC inhibitor

Forodesine (BCX1777)BioCrystPNP inhibitor

clinicaltrials.gov, ADIS R&D Insight, Thomson Pharma IDdb, Primary Research


Emerging Therapies For MPDs MPD

Myelofibrosis

Phase 2Phase 2Phase 1Phase 1 Phase 3Phase 3 Registration / Launched

Kinase/Intracellular

Preclinical

Preclinical

INCB 18424 – US/EUCYT387 – USYM Bi i

XL 019 - USE li i

AZD1480A t Z

Multi-kinaseinhibitorsDevelopment

PipelineTAK-901 -USMillennium; Aurora B kinase cell cycle inhib

Sprycel (dasatinib) - USBMS, MDACC; Multi-

INCB 18424 US/EUIncyte, NovartisJAK-2 inhibitor


TG101348TargeGen; JAK2, FLT3, Ret inhibitor

SB1518S*Bio

ExelixisJAK-2 inhibitor

AstraZenecaJAK2 inhibitor


inhibitorsTargeGenExelixisS*BIOAbbott

JAK2 inhibitorsSGX PharmaDicephera

Sources: ADIS R&D Insight, Thomson Pharma Partnering, DefinedHealth analysis

Immunotherapy

, ;targeted kinase inhib

Pomalidomide

S BioJak2 inhibitor

Lenalidomide (Revlimid)

Gleevec (imatinib)NVS, MDACC; Multi-targeted kinase inhib

AT9283Astex Therap; Multi-targeted kinase inhib

mTOR inhibitor

Bcl-2 inhibitor

PDGF/VEGR inhib

DNA methyl-transferase inh

DicepheraRigelAstexAstraZenecaSuperGenIncyte (JAK1/2)

JAK2 inhibitor+

EGFR inhibitor

EpigeneticsAurora B kinase cell cycle inhib

PNP inhibitor

PomalidomideCelgene; TNF, IL-1b inhibitor, IL-10 stim

PanobinostatNovartisHDAC inhibitor

Azacitidine (Vidaza)Celgene, MDACCDNA methyltransferase

Lenalidomide (Revlimid)Celgene, MDACCThalidomide der

HDAC inhibitor

Immunomodulator

TNF inhibitor+


EGFR inhibitor

Forodesine (BCX-1777)

Cell Cycle

Vatalanib Obatoclax

EverolimusMDACC, NovartismTOR inhibitor

Ridaforolimus (DX)AriadmTOR inhibitor

Others including Metabolic Poisons-Nucleoside analogs, Tumor Invasion & Metastasis, and Apoptosis Inducers


HDAC inhibitor

Anti-thrombotic

Forodesine (BCX 1777)BioCrystPNP inhibitor

VatalanibNovartis, MDACCPDGF/VEGF inhibitor

ObatoclaxGemin XBcl-2 inhibitor

clinicaltrials.gov, ADIS R&D Insight, Thomson Pharma IDdb, Primary Research

Emerging Therapies for MPDs MPD

Myelofibrosis

Phase 2Phase 2Phase 1Phase 1 Phase 3Phase 3 Registration / Launched

Kinase/Intracellular

Preclinical

Preclinical

INCB 18424 – US/EUCYT387 – USYM Bi i

XL 019 - USE li i

AZD1480A t Z

Multi-kinaseinhibitorsDevelopment

PipelineTAK-901 -USMillennium; Aurora B kinase cell cycle inhib

Sprycel (dasatinib) - USBMS, MDACC; Multi-

INCB 18424 US/EUIncyte, NovartisJAK-2 inhibitor


TG101348TargeGen; JAK2, FLT3, Ret inhibitor

SB1518S*Bio

ExelixisJAK-2 inhibitor

AstraZenecaJAK2 inhibitor


inhibitorsTargeGenExelixisS*BIOAbbott

JAK2 inhibitorsSGX PharmaDicephera

Immunotherapy

, ;targeted kinase inhib

Pomalidomide

S BioJak2 inhibitor

Lenalidomide (Revlimid)

Gleevec (imatinib)NVS, MDACC; Multi-targeted kinase inhib

AT9283Astex Therap; Multi-targeted kinase inhib

mTOR inhibitor

Bcl-2 inhibitor

PDGF/VEGR inhib

DNA methyl-transferase inh

DicepheraRigelAstexAstraZenecaSuperGenIncyte (JAK1/2)

• Incyte submitted an NDA for its lead investigational compound, ruxolitinib (INCB18424), to the FDA. Incyte is seeking US marketing

JAK2 inhibitor+

EGFR inhibitor

EpigeneticsAurora B kinase cell cycle inhib

PNP inhibitor

PomalidomideCelgene; TNF, IL-1b inhibitor, IL-10 stim

PanobinostatNovartisHDAC inhibitor

Azacitidine (Vidaza)Celgene, MDACCDNA methyltransferase

Lenalidomide (Revlimid)Celgene, MDACCThalidomide der

y g gapproval of ruxolitinib for the treatment of myelofibrosis (MF), a potentially life-threatening blood cancer for which there are currently no approved therapies in the US.Th NDA i l d l f b h

S*BIO said plans to advance SB1518 for th t t t f l fib i (MF) t

TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical

HDAC inhibitor

Immunomodulator

TNF inhibitor+


EGFR inhibitor

Forodesine (BCX-1777)

Cell Cycle

Vatalanib Obatoclax

EverolimusMDACC, NovartismTOR inhibitor

Ridaforolimus (DX)AriadmTOR inhibitor

Others including Metabolic Poisons-Nucleoside analogs, Tumor Invasion & Metastasis, and Apoptosis Inducers

• The NDA includes results from both COMFORT-I and COMFORT-II pivotal trials.

• Data from both studies were presented at the ASCO 2011 American annual meeting

the treatment of myelofibrosis (MF) to pivotal Phase III trials later this year. The company said data from Phase II trials of SB1518 indicated promising clinical efficacy and good tolerability. Onyx recently returned rights

benefit in patients with myelofibrosis.


HDAC inhibitor

Anti-thrombotic

Forodesine (BCX 1777)BioCrystPNP inhibitor

VatalanibNovartis, MDACCPDGF/VEGF inhibitor

ObatoclaxGemin XBcl-2 inhibitor

clinicaltrials.gov, ADIS R&D Insight, Thomson Pharma IDdb, Primary Research.

American annual meetingOnyx recently returned rights.


M&A d lli d t f t tiM&A and alliances on products for treating hematological malignancies have risen in number and value in the past years; however aside from Novartisvalue in the past years; however, aside from Novartis and Roche, buyers are still dominated by Biotech and midcap Specialty Pharma rather than large Pharma

oncology franchises, despite the apparent strategic fit for Pharma.

2010 Oncology Deal Value Trended Lower

30 40

Oncology Deals, Upfront Payments Oncology Deals, Total Potential Value

20

25

30

35

15

20

>$50M

$26-50M20

25

>$50M

$26-50M

10

$1-25M

10

15 $1-25M

0

5

0

5


EvaluatePharma

Highlighted Recent Deal Activity for Hematological Products

Alliance License / Acq

Asset / Class Indication (Phase)

Upfront Total Notes

Onyx/ Proteolix

Acq Carfilzomib, Proteasomeinhibitors

Multiple myeloma(Preregistration) $267M $535M

Proteolix to receive $40M as development milestone payable in 2010 + up to $535M on regulatory approvals in US & Europeinhibitors regulatory approvals in US & Europe

Celgene/ Gloucester

Acq IstodaxHDAC Inhibitor

Cutaneous T cell lymphoma(Marketed)

$340M $340M Celgene licensed Istodax from Astellas. Will receive additional milestones up to $300M.

Gil d/ A CAL 101 CLL (P2) $375M $600M Eli ibl f $225M i il t tGilead/ Calistoga

Acq CAL-101PI3K inhibitors

CLL (P2) $375M $600M Eligible for $225M in milestone payments.

Novartis/ Incyte

Ex-US License

INC424 JAK-2 inhibitor

Myelofibrosis(Registered)

$150M $210M Eligible for additional payments of up to approximately $1.1bn in milestones. Eligible for tiered, double-digit royalty on ex-US sales.

Sanofi / Targegen

Acq TG101348JAK-2 inhibitor

Myelofibrosis(P2)

$75M $560M Additional payments tied to reaching development goals may bring the total purchase price to $560 million.

Takeda / S l

Ex-USd

brentuximabd ti CD30

Hodgkin's disease (P i t ti )

$60M $290M SG gets progress and sales milestones in dditi t ti d d bl di it lti tSeattle

Geneticsand Canada License

vedotin ; CD30mAb plus tubulin inhibitor

(Preregistration)

NHL(Preregistration)

addition to tiered double-digit royalties on net sales in Takeda‘s territories. Milestones could total more than $230 M. SG and Takeda will jointly fund WW development costs .

AMAG/ Acq Folotyn( )

Peripheral T-Cell $268 Allos stockholders will get 0.1282 Amag


Allos (pralatrexate); antimetabolite

Lymphoma (Marketed)

million shares for each share of Allos. Amagshareholders own 61% of combined company.

EvaluatePharma

What are the opportunities and challenges inWhat are the opportunities and challenges in hematological malignancies for your franchise?

Defined Health's Therapeutic Insight will be a featuredDefined Health s Therapeutic Insight will be a featured track at these 2011 and 2012 EBD conferences:


Documents

Defined Health’s Insight Series Htl WhitSHematology White ...knowledgebase.definedhealth.net/wp-content/uploads...Revlimid Celgene IMID 2026 $5.5 Alimta Eli Lilly Antimetabolites