changing aml outcomes via personalized …...changing aml outcomes via personalized medicine:...

Changing AML Outcomes via Personalized Medicine: Transforming Cancer Management with Genetic Insight Co-Moderators: • Rick Winneker, PhD, Senior Vice President, Research, Leukemia & __Lymphoma Society • Mike Rice, Senior Consultant, Defined Health Panelists: • Brian J. Druker, MD, Director, OHSU Knight Cancer Institute, JELD-WEN __Chair of Leukemia Research, Oregon Health & Science University, __Investigator, Howard Hughes Medical Institute • Eric Hedrick, MD, Chief Medical Officer, Epizyme, Inc. • Omar Abdel-Wahab, MD, Assistant Member, Memorial Sloan Kettering __Cancer Center • Nicholas J. Sarlis, MD, PhD, Vice President & Head, Medical Affairs, __Incyte Corporation • Scott Biller, PhD, Chief Scientific Officer, Agios Pharmaceuticals

AML Insight Briefing © Defined Health, February 2013

AML Remains Among Highest Unmet Need Across Blood Cancers (and solid tumors)

♦ Acute myeloid leukemia (AML) is a life-threatening disease in which hematopoietic progenitor cells committed to the myeloid lineage become cancerous.

♦ This year, nearly 15,000 people will be diagnosed with AML in the US – causing >10,000 deaths. ♦ 90% of new cases in adults with an average age at diagnosis >65 yrs


AML Prognosis Involves Characteristics of The Patient and The Disease

American Cancer Society, www.cdc.gov

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

• 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.

• Morphology, immunophenotype, cytogenetics and clinical features. • Leukemias that express the progenitor cell antigen CD34 and/or the P-glycoprotein (MDR1 gene product).

♦ Age and general health of Patient: • Increasing age is an adverse factor because older patients more frequently have a prior AHD and also co-morbid

medical conditions that compromise the ability to give full doses of chemotherapy. • Clinicians consider age 55-65 a general cut-off when considering aggressive, high-dose chemotherapeutic

treatment. ♦ Prior antecedent hematologic disorder (AHD):

• An AHD such as myelodysplastic syndrome (MDS) is associated with a poor outcome to therapy. ♦ Prior Treatment:

• High-doses of anthracyclines, in particular, is important when assessing risk of cumulative dosing toxicities. • Treatment-induced secondary AML.

♦ Genetics: • The WHO classification incorporates more recent discoveries regarding the 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 therapy is similar for all subtypes.


Heterogeneity of AML Translating Into Useful Prognostic Information

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

Heterogeneity of Cytogenetically Normal AML


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

Diagnosis / Workup (Morphology, Immunophenotype, Cytogenetics, molecular markers,

Clinical Presentation (age, PS)

Initial Treatment • Remission Induction • Clinical Trial • Best Supportive care

Post Remission Therapy •Consolidation

Salvage Therapy Long Term Remission / Cure

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

♦ The three stages of standard treatment for AML are:

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

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 if they fail to achieve initial CR (primary refractory) of after disease recurrence (relapse) .


SOC Provides Meager Benefit to Majority Affected by AML: The Old

♦ ~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.

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

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

60%

>60yr (50-60%)

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

80% All types No 80%

>70yr (<10%)

100% All types

No N/A (BSC)


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

Trial Design

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

Pre

Reg Laromustine

Vion Alkylating Agent

Historical: Single-arm, monotherapy

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

Clofarabine Genzyme

Nucleoside Analog


• FDA rejected submission, requested RCT Ph 3 trial

Phas

e 3

Oblimersen Genta

Bcl-2 inhibitor RCT: Dauno +

AraC +/- agent • Failed to meet OS endpoint

Lintuzumab Seattle Genetics

CD33 antigen inhibitor RCT: LoDAc +/-

agent • Failed to meet OS endpoint • Ph2b registration study

Troxacitabine SGX/Eli Lilly

DNA synthesis inhibitor


• Poor efficacy – Response rates

Amonafide Antisoma

DNA topo-isomerase inhibitor

RCT: AraC + agent vs. Dauno + AraC

• Failed to meet CR endpoint • Secondary AML patients

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


Accordingly, AML Drug Market is Almost Nonexistent: Near-term Advancement in Treatment is Likely to be Incremental

EvaluatePharma

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 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 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 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 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 decitabine compared to 5.0 months for standard treatment.

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Mylotarg PKC412 Quizartinib Rubida Tamibarotene Trisenox Vosaroxin Dacogen


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

ADIS R&D Insight, Thomson Pharma Partnering

(Total= 400)

NHL 26%

OTHER MYELOID 10% MM

19%

CLL 13%

AML 18%

HL 3%

CML 5% ALL

6%

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


Phase 3 Phase 2

Novel clinical stage agents pursuing different MoAs and AML patient settings

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

Phase 1

Tosedostat

Temozolomide

CPX-351

Chemotherapy

Immuno-therapy

Kinase Inhibitor

Other

Vosaroxin

Epigenetic

Arsenic trioxide Omacetaxine Sapacitabine Lestaurtinib

Lenalidomide

Selumetinib

Lintuzumab Bi-213

Volasertib

Elacytarabine

BI 811283

Lintuzumab Ac-225

Quizartinib

Proapoptotic

Vidaza Ganetespib

Crenolanib

Liriilimumab

LOR 2040

SGI-110

Treosulfan

Belinostat Birinapant

Elesclomol

KX2 391

Triciribine CA1P

DFP 10917

PR 104

PRI 724

Rigosertib

AT 9283

Ponatinib

Idelalisib

ENMD 2076

AZ 1208

BP 100-1-01

CWP 232291

MK 8242

PF 4449913

RG 7112

SL 401

AVE 9633

PLX 3397

DCPrime Vac

ALT 801

CNDO 109

MDX 1338

RG 7536

Relapsed / Refractory

Non-Candidates for Induction CT

OCV 501 AEG 35156

Midostaurin

Imatinib

GRNVAC1

Sorafenib

GVAX (postHSCT)

WT1-A10+AS01B ASCI

131-I-anti-CD45 Induction CT or Consolidation

Trials in Multiple (or undefined) Settings

Plerixafor Pracinostat AKN 028

BL 8040 Rebastinib

p.DOM-WT1-126

rhH1.3 VAL-1000

Vorinostat

Panobinostat


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.

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

http://www.cancer.gov/�

http://cancergenome.nih.gov/�

http://genome.wustl.edu/�


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.

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


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

Mutated Gene Development Projects

Mutated Gene Development Projects

FLT3 (ITD, TKD) 42 PHF6 0

NPM1 0 KRAS 3

DNMT3A 1 PTEN 1

NRAS 11 TP53 21

CEBPA 0 HRAS 1

TET2 0 EZH2 5

WT1 11 CDH23 0

IDH2 4 PTPN11 0

IDH1 3 SMC3 0

KIT 41 STAG2 0

RUNX1 0 U2AF1 0

MLL-PTD 7 UMODL1 0

ASXL1 0 ZSWIM4 0

Recent genome-wide analyses in patients with a variety of myeloid malignancies not only validated known markers, but has led to the rapid discovery of a series of recurrent genetic alterations, leading to: • New programs pursuing the

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

• Renewed interest in kinase inhibitors, given recent clinical responses with next generation inhibitors (FLT3, KIT, RAS).


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

Model for evolution of genetic changes in acute myeloid leukemia ♦ A hypothetical model in which nonpathogenic somatic mutations (1–3) acquired over the

lifespan of a stem cell are propagated in the malignant clone after it acquires a critical 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.

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

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


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

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

Histone methyltransferases (HMTs) are enzymes that catalyze the addition of methyl marks to histone proteins. These types of chemical modifications to histones impact chromatin architecture and the regulation of gene expression. Aberrant activity of HMTs is implicated in a host of human diseases, including oncology, inflammation, infection, metabolism, and neurology.

The discovery of the first histone demethylase (HDM) fundamentally changed the understanding of the reversibility of histone methylation. There are two families of HDMs – amine oxidases and hydroxylases – and both are implicated in human diseases, including cancer, inflammation, and metabolic disease.

Readers are proteins that bind to specific recognition domains, typically methyl or acetyl marks, on chromatin in a highly regulated manner. These chromatin-binding events result in the modulation of chromatin architecture, which impacts gene expression and are ultimately implicated in key cellular processes such as cell cycle progression, cytokine signaling, and viral integration


Progress For Epigenetic Inhibitors as Cancer Therapies

Epigenetic Inhibitors as Cancer Therapies

Discussion Points • Why is AML a good model to employ personalized cancer care? What lessons have been

learned? What obstacles need to be overcome? What are the short term goals and the long term goals?

• What is the state of the art in changing AML outcomes via genetic evidence? – What progress is being made on functional analysis to get beyond AML “genomics” and

move towards useful information that can be applied in the clinic? • What new information has come out from AML whole genome sequencing and genetic

association studies? Preclinical models? Epigenetic modifiers (TET2, IDH1/2, ASXL1, etc.) – What implications does it have on the use of currently utilized AML therapies? How it

impacting care? • What are the specific implications of HMT alterations (DOT1L) to different subsets of AML?

– What does it take to translate this new science into clinically useful diagnostics and therapies?

• How do you develop a drug in these small niche malignancies and also provide a commercially viable product? What are the regulatory and commercial challenges?

• What are the specific implications of cancer metabolism IDH1/2 gain of function mutations? – Patient selection at the molecular level for clinical trials

• What might the future of AML management look like? How we get beyond the dogma of “7+3” after 35 years even if the target is molecularly defined?

• How can innovation be encouraged and how is collaboration between academics and industry being used to address these barriers?

changing aml outcomes via personalized …...changing aml outcomes via personalized medicine:...

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