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

1. 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

2. Dual Epigenetic TherapyDual Epigenetic Therapy
Lung Cancer
3rd / 4th Line NSCLC: Azacitidine + entinostatNCI
2

3. Oncogenic Mechanisms
DNA
GENETIC
Chromatin
EPIGENETIC
DNA
M i / l i
Replication
errors
O / l d h i
Enzyme modification errors
Mutations/translocations Open/closed chromatin
DNA sequence
altered
DNA sequence
not 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

4. Definitions
TERM 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.

5. BIOMARKERS in Hematology/Oncology
( l l )(partial list)
Biomarker INDICATION
BCR/ABL CML
ER/PR/HER2 Breast Cancer
/ALK PTCL/Lung
EGFR Lung
JAK2/CALR MPNJAK2/CALR MPN
BRAF Melanoma
KRAS CRC
HDACi ??

6. HDAC Inhibitor Classes
Class II HDAC’s
Class I HDAC’s
S O S d
NON‐HISTONE
proteins located in
h l (
HISTONES and
TRANSCRIPTION
FACTORS located
in the nucleus
HDAC1
HDAC2
HDAC3
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

7. Pan-HDAC Inhibition
HDAC depicts individual
deacetylases, e.g.
HDAC1, HDAC4,
HDAC6
Proteins
d l d b
HDAC6
HDAC HDAC
HDAC HDAC HDAC
modulated by
DACs
Histone α‐tubulin HSP90HIF‐1α
p53
Tumor suppressor
gene activity
Loss of tumor
suppressor function
Microtubule
depolymerization/
aggresome formation
VEGF
OncoproteinsDownstream
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

8. 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.

9. 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

10. 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.

11. 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.

12. Breakthrough Designated Oncology
Drug Company Stage Indication Mechanism
Ofatumumab Genmab/GSK Ph 3 /
d
Chronic lymphocytic leukemia Anti‐CD20
Drugs
approved
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 Boerhinger
Ingelheim
Ph 2/3 AML PLK inhibitor
Ingelheim
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

13. 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.

14. 14

15. 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 theg 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.

16. Biomarkers/Correlates/Pharmacodynamics
Lysine 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

17. HDACi in Breast Cancer Clinical Trials
Vorinostat Entinostat
Single Agent
P 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 Abs
Includes only currently enrolling trials on
clinical trials.gov

18. Breast Cancer

19. Metastatic Breast Cancer – Better Options Needed
In 2012 it is estimated that there will be:
1.3 million women diagnosed worldwide
465,000 deaths worldwide
Breast Cancer Subsets by
M l l Bi k
No gain in overall survival
in ER+ metastatic disease in 20 years
Molecular Biomarkers
ER / PgR Triple NegativeHer-2
Positive
~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

20. Entinostat Overcomes Hormone Resistance
Entinostat restores estrogen receptor sensitivity in vivo1, 2
2,000 Switch to exemestane
1 0 5 1 0 8 1 0
HER‐2
1 000
1,500
Volume(mm3)
Continue letrozole
Switch to entinostatControl
1.0 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 entinostat
Continue letrozole / add entinostat
MeanTumorV
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

21. Entinostat Restores ERα Expression
Entinostat + Letrozole Effective
in vivo in ER PR HER2 Tumors
Entinostat Induces Expression of ERα
and 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

22. 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 = 64A
N
D
O
M
Post-menopausal
women with
metastatic or locally
advanced ER+
Exemestane + placebo (EP)
N = 66
M
I
Z
E
hormone refractory
breast cancer
Syndax Pharmaceuticals ‐ Confidential

23. ENCORE 301 Baseline Patient Characteristics
EE
N=64
EP
N=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 (%)
Adjuvant
Advanced/ Metastatic
10 (16%)
54 (84%)
9 (14%)
57 (86%)
Sites of Metastases, n (%)
Bone 49 (77%) 47 (71%)Bone
Bone Only Disease
Lymph nodes
Visceral 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 Disease
Metastatic Disease
22 (34%)
22 (34%)
28 (42%)
21 (32%)
Geographic Region, n (%)
h iNorth America
Central Europe/Russia
42 ( 66%)
22 ( 34%)
43 ( 65%)
23 ( 35%)
Syndax Pharmaceuticals ‐ Confidential

24. 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 months
EP: 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

25. 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

26. 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

27. 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 category
81% of EE patients and 85% of EP patients confirmed to have received post study treatment
Syndax Pharmaceuticals ‐ Confidential

28. Favorable Side Effect Profile ENCORE
301
Adverse Event1
EE (N=63) EP (N=66)
Any G3 G4 Any G3 G4Any G3 G4 Any G3 G4
Fatigue 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

29. 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 action
We 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

30. 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 months
EE 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)
Probability
0.75 Hazard ratio 0.32 (95% CI: 0.13, 0.79)
Progression
0.25
0.50 Potential to benefit may be determined by
blood test within 1st two weeks of treatment 8.5 months
2.8 months
P
0.00
0 2 4 6 8 10 12 14 16 18
Months Ordentlich AACR‐NCI‐EORTC Molecular Targets 2011
1° data cut
Syndax Pharmaceuticals ‐ Confidential

31. Ph 3 Registration Study
ECOG 2112ECOG 2112

32. 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

33. 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
A
N
D
O
M
Advanced breast cancer
ER+/PR+, HER2-
Progression on prior
Exemestane + entinostat 5mg wkly
N ≈ 300
1
Refractory
setting
N=600M
I
Z
E
non-steroidal AI
Exemestane + placebo
N ≈ 300
1
N 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

34. THANK YOUTHANK YOU
• Organizers – MarcusevansOrganizers Marcusevans
• Audience
i h i i i h i l• Patients who participate in research trials
• QUESTIONS???