the importance of biomarkers in hematology/oncology drug development - steven fruchtman

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Biomarkers to Optimize Drug Development in Hematology Oncology Development in Hematology Oncology Steven M Fruchtman MD Steven M Fruchtman, MD CMO Spectrum and Syndax Pharmaceuticals (Formerly) Associate Professor of Medicine Mount Sinai Medical Center; New York l i i Evolution Summit May 8, 2014

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The Importance of Biomarkers in Hematology/Oncology Drug Development - Presentation by Steven Fruchtman, Former Chief Medical Officer, Syndax Pharmaceuticals, at the marcus evans Evolution Summit 2014 held in Palm Beach, FL May 7-9

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Page 1: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Biomarkers to Optimize Drug Development in Hematology OncologyDevelopment in Hematology Oncology

Steven M Fruchtman MDSteven M Fruchtman, MD

CMO Spectrum and Syndax Pharmaceuticals (Formerly)( y)

Associate Professor of Medicine

Mount Sinai Medical Center; New York

l i iEvolution Summit 

May 8, 2014

Page 2: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Dual Epigenetic TherapyDual Epigenetic Therapy

Lung Cancer

3rd / 4th Line NSCLC: Azacitidine + entinostatNCI

2

Page 3: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Oncogenic Mechanisms

DNA

GENETICChromatin

EPIGENETICDNA

M i / l i

Replicationerrors

O / l d h i

Enzyme modification errors

Mutations/translocations Open/closed chromatin

DNA sequence altered

DNA sequencenot altered

Altered DNA/mRNA/proteins

Altered mRNA/proteins

Transformed cells

Oncogenesis

Can be caused by:

• Modifications to histone proteins

• Modifications of DNA 

The contents of this slide are confidential and for internal training purposes only.   Not for distribution. 3

methylation

Page 4: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

DefinitionsTERM DEFINITIONTERM DEFINITION

1. Biological marker A characteristic that is objectively measured and evaluated  as an indicator of normal biologic or pathogenic processes or pharmacologic response to an 

intervention 

2. Clinical endpoint A characteristic or variable that reflects on a function or survival

3 Surrogate endpoint A biomarker intended to substitute for a3. Surrogate endpoint A biomarker intended to substitute for a clinical endpoint. An investigator uses epidemiological, therapeutic, pathophysiologic or other scientific evidence to select a surrogate endpoint that is expected to predict clinical benefit or harm

4 U f l bi k I f i k/b fi i h h i4. Useful biomarker Informs risk/benefit ratio when there is a decision to be made. Does so in a better/

faster/cheaper way than existing approaches.

Generally applicable: sample and technology must be available and accessible.

Page 5: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

BIOMARKERS in Hematology/Oncology( l l )(partial list)

Biomarker INDICATIONBCR/ABL                                             CMLER/PR/HER2                                       Breast Cancer

/ALK PTCL/LungEGFR LungJAK2/CALR MPNJAK2/CALR MPNBRAF   MelanomaKRAS CRC

HDACi ??

Page 6: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

HDAC Inhibitor Classes

Class II HDAC’sClass I HDAC’s

S O S d

NON‐HISTONE proteins located in h l (

HISTONES andTRANSCRIPTIONFACTORS located

in the nucleus

HDAC1

HDAC2HDAC3

HDAC4

the cytoplasm (e.g. HDAC6)

in the nucleus HDAC3

HDAC8

HDAC5

HDAC7

HDAC6

HDAC7HDAC7

HDAC9

HDAC10

HDAC7

The contents of this slide are confidential and for internal training purposes only. Not for distribution.6

Page 7: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Pan-HDAC InhibitionHDAC depicts individual deacetylases, e.g. HDAC1, HDAC4, HDAC6

Proteins d l d b

HDAC6

HDAC HDACHDAC HDAC HDAC

modulated by DACs

Histone α‐tubulin HSP90HIF‐1αp53

Tumor suppressor gene activity

Loss of tumor suppressor function

Microtubule depolymerization/ aggresome formation

VEGF Oncoproteins Downstream

effects

p53

Cell-cycle arrest Cell motility and Invasion

Cell proliferation and survival

Tumor effects

The contents of this slide are confidential and for internal training purposes only. Not for distribution.7

Apoptosis Angiogenesis

Page 8: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Mechanism of ActionMechanism of Action

Cell transformation from normal to cancerous requires shutdown of tumor suppressor genes. Belinostat restores aberrant cellular control inBelinostat restores aberrant cellular control in tumour cells by reactivation of tumor suppressor genes.

Page 9: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

HDACi in Clinical Development

Name Company Dev Status Formulation Lead Indication(s) Structure / Class

vorinostat  Merck Launched Oral / IV CTCL; B Cell Lymphomas Hydroxamic Acid / Pan

romidepsin Gloucester  NDA filed  IV PTCL; CTCL Cyclic Peptide / Pan

panobinostat  Novartis AG Phase II Oral / IV CTCL; CML; HL Hydroxamic Acid / Pan

belinostat  TopoTarget UK Ltd Phase II IV / Oral PTCL Hydroxamic Acid / Pan

entinostat Syndax Phase II  Oral Breast, NSCLC, HL Benzamide / Selective

givinostat Italfarmaco SpA Phase II  Oral HL Hydroxamic Acid / Pan

PCI‐24781 Pharmacyclics Phase II  Oral Sarcoma/NHL Hydroxamic Acid / Pan

CS 055 Huya / Chipscreen Phase I Oral CTCL; NHL Benzamide / SelectiveCS‐055 Huya / Chipscreen Phase I  Oral CTCL; NHL Benzamide / Selective

4SC‐201 4SC Phase I  Oral TBD Hydroxamic Acid / Pan

CHR‐2845 Chroma  Phase I  Oral TBD Pro‐Drug Hydroxamic Acid / Pan

JNJ‐26481585 J & J Phase I  Oral TBD Hydroxamic Acid / Pan

SB‐939 S*BIO Pte Ltd Phase I Oral TBD Hydroxamic Acid / Pan

Page 10: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Accelerating the Approval Process

• Fast track is the process to get important new drugs to the patient

earlier by facilitating the development and expediting the review of

cce e at g t e pp o a ocess

earlier by facilitating the development, and expediting the review of

drugs to treat serious diseases and fill an unmet medical need.

• Accelerated Approval allows earlier approval of drugs to treatAccelerated Approval allows earlier approval of drugs to treat

serious diseases that fill an unmet medical need based on a

surrogate endpoint provided that post marketing clinical trials verify

the anticipated clinical benefit.

• Priority Review is given to drugs offering major advances in

t t t id t t t h d t th i ttreatment, or provide a treatment where no adequate therapy exists

with the goal for completing FDA Review in 6 months.

Page 11: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Breakthrough Therapyea t oug e apy

• A novel category of “breakthrough drugs” was established by the FDA as part

of legislation that became law in July 2012of legislation that became law in July, 2012.

• Companies can request the agency designate their experimental treatments for

life threatening diseases as breakthrough therapies, which affords them advice

and guidance from the FDA staff to optimize development.

– Requests must identify the indication under study, provide evidence that the drug is

intended, alone or in combination, to treat a serious or life-threatening disease or

condition.

– Preliminary clinical evidence indicating that the drug may demonstrate substantial

improvement over existing therapies on 1 or more clinically significant endpoints,

such as substantial treatment effects observed early in clinical development, are

required.

• As of Dec 10 2012, the FDA received 7 breakthrough requests; 2 were granted, , g q ; g ,

1 denied and 4 are pending.

Page 12: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Breakthrough Designated Oncology 

Drug Company Stage Indication Mechanism

Ofatumumab Genmab/GSK Ph 3 / d

Chronic lymphocytic leukemia  Anti‐CD20

Drugsapproved

Ibrutinib Pharmacyclics / J&J

Ph 3 1. Chronic lymphocytic leukemia ,2. relapsed or refractory Mantle cell lymphoma (MCL)3. Waldenstrom's macroglobulinemia (WM). 

BTK inhibitor

Obinutuzumab Roche Ph 3 Chronic lymphocytic leukemia Anti‐CD20Obinutuzumab Roche Ph 3 Chronic lymphocytic leukemia Anti CD20

Palbociclib Pfizer Ph 2/3 Metastatic ER+ breast cancer CDK4/6 inhibitor

Volasertib BoerhingerIngelheim

Ph 2/3 AML PLK inhibitorIngelheim

Entinostat Syndax Ph 2/3 Metastatic ER+ breast cancer HDAC inhibitor

LDK378 Novartis Ph 2 ALK+ NSCLC ALK inhibitor

Al ti ib R h Ph 2 ALK NSCLC ALK i hibitAlectinib Roche Ph 2 ALK+ NSCLC ALK inhibitor

Lambrolizumab Merck Ph 1/2 Advanced melanoma Anti‐PD‐1

Daratumumab Genmab/J&J Ph 1/2 Multiple myeloma Anti‐CD38

Syndax Pharmaceuticals ‐ Confidential

Page 13: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Cost of Drug DevelopmentCost o ug e e op e t

• Over the past generation, the economics burden of drug development has grown substantially.

• It is estimated that the costs of developing an approved drug has

i d 10 f ld j i f $199 illi t $1 9 billionincreased 10-fold, jumping from $199 million to $1.9 billion since the 1970s!!!!

• The Office of Health Economics identified 4 key factors:The Office of Health Economics identified 4 key factors: 1. soaring out of pocket research costs

2. a success rate cut in half

3. a vastly longer time spent in the clinic

4. an increased cost of capital as regulatory demands grew alongside scientific complexity.

Page 14: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

14

Page 15: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Factors Contributing to Rising Costsacto s Co t but g to s g Costs

• The average time to acquire the data needed for an approval jumped from 6 to

13 513.5 years.

• High priced drugs listed in 2012 were: – Gattex for short bowel syndrome (>$200k per patient per year )

– Kalydeco for CF (>$200k per patient per year )

– Elelyso for Gaucher’s (>$200k per patient per year )

– Juxtapid for homozygous familial hypercholesterolemia (>$200k per patient per year )

– Soliris for PNH ($440,000/year.)

• In 2012, 10% of the approved drugs by the FDA cost more than a house, with a

44% increase in the number of such high priced rare disease drugs on the g p g

market.

• The cost of Zaltrap ($9600/week) decreased 50% after an article in NYT by

MSKCC physicians stated the drug would not be used due to cost.

Page 16: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Biomarkers/Correlates/PharmacodynamicsLysine acetylation

• Histone H3 and H4 lysine acetylation may be viewed as PD endpoint but has not correlated with efficacywith efficacy

• Most analysis done in PBMCs so may not reflect tumor activity/concentration• Unclear how lysine acetylation relates to various MOA, i.e. apoptosis requires higher doses

than histone hyperacetylation• Acetylation of specific proteins may provide insight into clinical responses i e HSP90 tubulin• Acetylation of specific proteins may provide insight into clinical responses, i.e. HSP90, tubulin,

p53, etc

Cell cycle / DNA damage markers• p21 induction a consistent marker of HDACi activity• γH2AX induction as marker of DNA damage effects (or attenuation of DNA repair)

HDAC expression• Histone and tubulin acetylation reduced in DCIS, IDC vs normal epithelium (Suzuki et al 2009

Clin Canc Res)Clin Canc Res)• Class 1 HDAC protein expression may be linked to tumor progression (reviewed Weichert

Canc Lett 2009)

Question still remains for whether HDAC expression levels or its inhibition correlate with response to HDACi

Overview Presentation5/14/2014 © 2009. Syndax. All rights reserved. 16

correlate with response to HDACi

Page 17: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

HDACi in Breast Cancer Clinical TrialsVorinostat Entinostat

Single AgentP i l

Combination• Pre-surgical• DCIS• Advanced breast cancer

Combination• w/ chemotherapy

Panobinostat

• w/ endocrine therapy

• w/ chemotherapy • w/ endocrine therapy• w/ TKIs• w/ monoclonal Abs

Single Agent• Advanced breast cancer (+/- HER2)

Combination• w/ monoclonal Abs

15 Trials Ongoing in Breast Cancer

Overview Presentation5/14/2014 © 2009. Syndax. All rights reserved. 17

w/ monoclonal AbsIncludes only currently enrolling trials on clinical trials.gov

Page 18: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Breast Cancer

Page 19: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Metastatic Breast Cancer – Better Options Needed

In 2012 it is estimated that there will be: 

1.3 million women diagnosed worldwide465,000 deaths worldwide

Breast Cancer Subsets byM l l Bi k

No gain in overall survival in ER+ metastatic disease in 20 years

Molecular Biomarkers

ER / PgR Triple NegativeHer-2Positive~70-77%

(ER‐, PR‐ and Her‐2‐)~15%

Positive~25-30%

Near‐term opportunity in ER+ hormone‐

Syndax Pharmaceuticals ‐ Confidential

refractory breast cancer ‐ overall program targets all subsets

Page 20: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Entinostat Overcomes Hormone Resistance

Entinostat restores estrogen receptor sensitivity in vivo1, 2

2,000 Switch to exemestane1 0 5 1 0 8 1 0

HER‐2

1 000

1,500

Vol

ume

(mm

3 )

Continue letrozole

Switch to entinostatControl1.0 5.1 0.8 1.0

1.0 3.2 0.3 0.7

p‐HER‐2

1.0 3.2 0.8 0.9

p‐c‐Raf

500

1,000

Switch to exemestane / add entinostatContinue letrozole / add entinostatM

ean

Tum

or V ER

1.0 0.1 0.9 0.4

Protein expression  levels from tumors From xenograft AI  

00

Switch to exemestane / add entinostat

Weeks

resistant model,  Sabnis et al.1

1Sabnis et al Mol Canc Therap 2013 (accepted)Humanized mouse xenograft ER+ breast cancer model designed to study aromatase inhibitors (N=10 per group)

Syndax Pharmaceuticals ‐ Confidential

Page 21: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Entinostat Restores ERα Expression

Entinostat + Letrozole Effective in vivo in ER PR HER2 Tumors

Entinostat Induces Expression of ERαand Aromatase in ER Tumors in vivo

Entinostat + Aromatase Inhibitor Effective in vivo in ERα- model

Control

Entinostat (E) 2.5mg/kg/day po*

Letrozole (L) 10ug/day sc*

in vivo in ERα-, PR-, HER2- Tumorsand Aromatase in ERα- Tumors in vivo

Entinostat + Letrozole*

*Androstenedione added to treatment groups

at 100ug/day sc

Entinostat + Letrozole Effective in vivo in ERα-/PR-/HER2- Tumors

Sabnis et al 2008 ENDO

Overview Presentation5/14/2014 © 2009. Syndax. All rights reserved. 21

Entinostat + Letrozole Effective in vivo in ERα-/PR-/HER2- Tumors

Page 22: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

ENCORE 301 – Rigorous Ph 2 Study ENCORE 301

• Randomized, double-blind, placebo-controlled• Multi-center international study to ensure Ph 3-like populationMulti center, international study to ensure Ph 3 like population• Endpoints include: Progression-Free Survival, Overall Survival• Biomarker in subset: Protein lysine acetylation in blood cells

Exemestane + entinostat (EE) PO 5 mg weeklyR O 5 g ee y

N = 64ANDOM

Post-menopausal women with

metastatic or locally advanced ER+

Exemestane + placebo (EP)N = 66

MIZE

hormone refractory breast cancer

Syndax Pharmaceuticals ‐ Confidential

Page 23: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

ENCORE 301 Baseline Patient Characteristics

EEN=64

EPN=66

Median Age (range) 63 (37 – 85) 62 (37 – 88)

ECOG Performance Status , n (%)0 1

40 (63%)24 (38%)

50 (76%)16 (24%)

S i f AI P i (%)Setting of AI Progression, n (%)AdjuvantAdvanced/ Metastatic

10 (16%)54 (84%)

9 (14%)57 (86%)

Sites of Metastases, n (%)Bone 49 (77%) 47 (71%)BoneBone Only DiseaseLymph nodesVisceral Involvement

49 (77%)13 (20%)30 (47%)34 (53%)

47 (71%)11 (17%)32 (48%)44 (67%)

Measurable Disease, n (%) 52 (81%) 54 (82%), ( ) ( ) ( )Prior Chemotherapy, n (%)

Adjuvant DiseaseMetastatic Disease

22 (34%)22 (34%)

28 (42%)21 (32%)

Geographic Region, n (%)h iNorth America

Central Europe/Russia42 ( 66%)22 ( 34%)

43 ( 65%)23 ( 35%)

Syndax Pharmaceuticals ‐ Confidential

Page 24: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Positive Phase 2 POC: PFS and OS ENCORE 301

EE: median PFS 4 3 months

PFS ‐ Intent‐to‐treat population OS ‐ Intent‐to‐treat population

EE: median PFS 4.3 monthsEP: median PFS 2.3 months

Hazard ratio 0.73 (95% CI: 0.50, 1.07)P=0.055 (1‐sided)

EE:  median OS 28.1 months

EP:  median OS 19.8 months

Hazard Ratio 0.59 (95% CI: 0.36, 0.97)P=0.04 (2‐sided) ; P=0.02 (1‐sided)

Yardley et al. JCO

Syndax Pharmaceuticals ‐ Confidential

Page 25: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Consistent PFS Benefit Across All Subsets ENCORE 301

1 AI iti ( i d i t ) d fi d CR PR SD > 6 th d i t t t ith i (l t) AI f ABC

Syndax Pharmaceuticals ‐ Confidential

1 AI‐sensitive (acquired resistance) defined as CR, PR or SD > 6 months during treatment with prior (last) AI for ABC. All other patients, including all those who received the AI as adjuvant therapy, defined as AI‐resistant (primary resistance). 

Feb ‘12  data cut

Page 26: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Consistent Survival Benefit Across All Subsets ENCORE 301

1 AI iti ( i d i t ) d fi d CR PR SD > 6 th d i t t t ith i (l t) AI f ABC

Feb ‘12  data cut

1 AI‐sensitive (acquired resistance) defined as CR, PR or SD > 6 months during treatment with prior (last) AI for ABC. All other patients, including all those who received the AI as adjuvant therapy, defined as AI‐resistant (primary resistance). 

Syndax Pharmaceuticals ‐ Confidential

Page 27: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Post Study Treatment Well Balanced ENCORE 301

First Subsequent Therapy All Subsequent Therapies

Post Study Treatment Therapy

EE EP

Chemotherapy 48% 43%

Post Study Treatment Therapy

EE EP

Chemotherapy 66% 71%py

Hormone therapy 37% 35%

Bisphosphonates 2% 0%

py

Hormone therapy 47% 45%

Bisphosphonates 5% 2%

Radiation 6% 5%

Surgery 0% 2%

Other 0% 6%

Radiation 16% 8%

Surgery 0% 2%

Other 6% 11%Other 0% 6% Other 6% 11%

*Patients may be counted under more than one category81% of EE patients and 85% of EP patients confirmed to have received post study treatment

Syndax Pharmaceuticals ‐ Confidential

Page 28: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Favorable Side Effect Profile ENCORE 301

Adverse Event1EE (N=63) EP (N=66)

Any G3 G4 Any G3 G4Any G3 G4 Any G3 G4Fatigue 29 ( 46%) 7  11%  1   2%  17 ( 26%) 2   3%  ‐

Nausea 25 ( 40%) 3   5%  ‐ 10 ( 15%) 1   2%  ‐

Neutropenia2, 3 16 ( 25%) 7  11%  1 2%  0 (  0%) ‐ ‐

Oedema peripheral 13 ( 21%) ‐ ‐ 3 (  5%) ‐ ‐

Vomiting 13 ( 21%)  3   5%  ‐ 3 (  5%) ‐ ‐

Anemia2 12 ( 19%) 1   2%  ‐ 8 ( 12%) 1   2%  1   2% 

Dyspnoea 12 ( 19%) 2   3%  ‐ 7 ( 11%) ‐ ‐

Weight decreased 11 ( 17%) ‐ ‐ 12 ( 18%) ‐ ‐

Thrombocytopenia2 11 ( 17%) ‐ ‐ 4 (  6%) ‐ 1   2% 

Diarrhoea 10 ( 16%) ‐ ‐ 8 ( 12%) 1   2%  ‐

Pain 10 ( 16%)  1   2%  ‐ 4 (  6%) 1   2%  ‐

Back pain 9 ( 14%) ‐ ‐ 11 ( 17%) 1   2%  ‐

Arthralgia 7 ( 11%) 1   2%  ‐ 11 ( 17%) ‐ ‐

Constipation 6 ( 10%) ‐ ‐ 10 ( 15%) 1   2%  ‐

1 Occurring in >15% in either Group ; Safety Population; Treatment‐emergent Adverse Events, regardless of treatment‐attribution. 2 Composed of combined MedDRA preferred terms.3   None of these 8 grade 3/4 patients experienced febrile neutropenia or associated infections during the time of the neutropenia. 1 patient with non‐measurable bone‐only disease given a myeloid growth factor for neutrophil support; patient had history of neutropenia & growth factor usage

Syndax Pharmaceuticals ‐ Confidential

1° data cut

Page 29: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

ENCORE 301 Pharmacodynamic Analysis ENCORE 301

HDACi induce hyperacetylation of lysines on histones and a number of other proteins as their mechanism of actionof other proteins as their mechanism of actionWe hypothesized that HDACi-induced hyperacetylation will be associated with lower risk of disease progression

Cycle 1

Exemestane daily

Cycle 1

D22 D28D1 

Entinostat Entinostat Entinostat Entinostat

C1D0 P C1D8 7 d

D8 D15

C1D15 7 dC1D0 Pre‐treatment baseline

C1D2 4‐36hrs 

C1D8 ~7 days after previous entinostat

C1D15 ~7 days after previous entinostat

after entinostat

Syndax Pharmaceuticals ‐ Confidential

Page 30: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Patient Enrichment Strategy Identified ENCORE 301

Hyperacetylation associated with prolonged PFS in entinostat treated patients

EE HA-: median PFS 2.76 months

EE HA+: median PFS 8.55 months

1.00 EE HA+ (n=13) : median PFS 8.5 monthsEE HA‐ (n=14) : median PFS 2.8 months

Kaplan-Meier Estimates of PFS by Acetylation at Day 15 (n=27)

Hazard ratio 0.317 (95% CI: 0.127, 0.787)

Pro

babi

lity

0.75 Hazard ratio 0.32 (95% CI: 0.13, 0.79)

Pro

gres

sion

0.25

0.50 Potential to benefit may be determined by blood test within 1st two weeks of treatment 8.5 months

2.8 monthsP

0.000 2 4 6 8 10 12 14 16 18

Months Ordentlich AACR‐NCI‐EORTC Molecular Targets 20111° data cut

Syndax Pharmaceuticals ‐ Confidential

Page 31: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Ph 3 Registration StudyECOG 2112ECOG 2112

Page 32: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

Clinical Development Plan in ER+ MBC

• Ph 3 E2112 – to start Q1 2014– Conducted by ECOG-ACRIN Cancer Research Group

(ECOG) and sponsored by the Division of Cancer Treatment and Diagnosis National Cancer Institute (NCI)Treatment and Diagnosis, National Cancer Institute (NCI).

– Incorporates FDA input on patient population, statistics, design• Syndax applying for SPA

– Randomized, 600 pts in hormone refractory ER+ post-menopausal metastatic breast cancermenopausal metastatic breast cancer

– Endpoints: Co-primary PFS and/or OS– 1st data in Q4 2016 – PFS

Syndax Pharmaceuticals ‐ Confidential

Page 33: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

ECOG E2112 – Ph 3 Study Design E2112

A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Patients with Hormone Receptor‐Positive Metastatic Breast Cancer

R Exemestane + entinostat 5mg wkly

p

ANDOM

Advanced breast cancer ER+/PR+, HER2-

Progression on prior

Exemestane + entinostat 5mg wkly N  ≈ 300

1Refractory settingN=600M

IZE

non-steroidal AIExemestane + placebo 

N ≈ 300

1N 600

Co‐1° Endpoints: PFS (in first 360 patients) and/or OS (N=600) Other 2° Endpoints: ORR, Safety

Biomarkers: Protein lysine acetylation; molecular and genomic tumor characterizationBiomarkers: Protein lysine acetylation; molecular and genomic tumor characterization

Syndax Pharmaceuticals ‐ Confidential

Page 34: The Importance of Biomarkers in Hematology/Oncology Drug Development - Steven Fruchtman

THANK YOUTHANK YOU

• Organizers – MarcusevansOrganizers  Marcusevans

• Audience

i h i i i h i l• Patients who participate in research trials

• QUESTIONS???