Presentation delivered by Dr Steven M. Fruchtman, Chief Medical Officer, Onconova Therapeutics at the marcus evans Evolution Summit Spring 2017 held at the Ritz-Carlton Coconut Grove, FL, May 8-10.

1. Rigosertib:
Mechanism of Action & Clinical
Development
Steven Fruchtman, M.D.
Chief Medical Officer
May 8,2017
Evolution Summit

2. Definition of MDS
Myelodysplastic syndromes (MDS) are a
complex group of hematologic malignancies,
occurring predominantly in older patients,
characterized by ineffective hematopoiesis
leading to peripheral blood cytopenias, and a
high risk of progression to acute myeloid
leukemia (AML).

3. 3
Bone Marrow Anatomy
hematopoietic bone marrow

4. 4
Bone Marrow Aspiration

5. 5
Bone Marrow Smears

6. 6
Bone Marrow Biopsy
Bone marrow biopsy needle
(Yamshidi)

7. Revised IPSS
Greenberg et al. Blood 2012;120:2454-65

8. Bejar R, et al. ASH 2015. Abstract 907. Reproduced with permission.
IWG-PM: OS by Number of
Mutations
• In 1996 pts with OS data:
• 17 genes sequenced
• ASXL1, CBL,
DNMT3A, ETV6,
EZH2, IDH1, IDH2,
JAK2, KRAS, NPM1,
NRAS, RUNX1,
SF3B1, SRSF2,
TET2, TP53, U2AF1
Slide credit: clinicaloptions.com
Yrs
0 2 4 6 8 10 12 14
0
20
40
60
80
100 0 (n = 377)
1 (n = 595)
2 (n = 460)
3 (n = 210)
4 (n = 125)
5/6/7 (n = 22)
SF3B1 only (n = 207)
Number of Mutated Genes
OS(%)

9. RAS in Oncology
• Three RAS genes (KRAS, NRAS, HRAS)
• Cancer-associated RAS genes
characterized by single base missense
mutations
• Wild type RAS, through aberrant
signaling pathways, plays key role in
neoplastic transformation and
proliferation
• Mutations of RAS and signaling
pathways that activate wild type RAS
present in myelodysplastic syndromes
(MDS)
Pg. 9April, 2017 Confidential

10. Pg. 10April, 2017
Understanding RAS
Signaling and Targeting
the “Untargetable”
Confidential

11. Pg. 11April, 2017
Discovery of Rigosertib as a RAS Mimetic
Confidential

12. Pg. 12April, 2017
Rigosertib Mechanism of Action
PLK1
Aurora A
Mitosis
MEK
ERK
Transcription
PI3K
Akt
Cell growthSurvival Metabolism
Receptor
Tyrosine
Kinase
RAS
PI3K
Akt
Cell growthSurvival Metabolism
Growth
Factor
Receptor
Tyrosine
Kinase
RAS
Growth
Factor
RAS RAS
PLK1
Aurora A
Mitosis
MEK
ERK
Transcription
+ Rigosertib + Rigosertib
Confidential

13. Pg. 13April, 2017
Rigosertib Binds to Multiple RAS Effector RBDs
CRAF
BRAF
ARAF
RAS
CRAF
BRAF
ARAF
PI3K
PI3Kβ
PI3Kγ
PI3Kδ
RALGDS
Confidential

14. Pg. 14April, 2017
Rigosertib Does Not Affect In
Vitro RAF Kinase Activity
ARAF BRAF CRAF
GW5074 is a Raf
inhibitor
Confidential

15. Pg. 15April, 2017
Rigosertib Binds to RBD of RAF Kinases In Vitro
Kinase
Domain
RAS-Binding
Domain
GST-RBD
Biotin RGS-Biotin RGS-Biotin RGS-Biotin
25 uM 50 uM 100 uM
GST-Kinase
Domain
Biotin RGS-Biotin RGS-Biotin RGS-Biotin
25 uM 50 uM 100 uM
Confidential

16. Pg. 16April, 2017
Secondary/Tertiary Structural Similarity of RBDs
Despite Lack of Extensive Sequence Homology
RAF/Ral-GDS/PI3K
Crystal Structures
Superimposed
Yellow: Hydrophobic Core; Cyan: Conserved Charged Amino Acids
Red: Conserved Hydrophobic AA; Green: Conserved Aromatic AA
Sequence Alignment of RA and RB Domains
NMR Structures of 10 RBDs
Superimposed
Confidential

17. Pg. 17April, 2017 Confidential
Rigosertib Inhibits Tumor Growth and
Signaling in Xenografts of Human Cancer
6 15 22 27 30
Days of treatment
HCT-116 (CRC)
A549 (adeno alveolar)
Tumor growth
inhibition is
associated with
reduced RAF and
AKT signaling

18. Pediatric
Investigational Plan
An Abridged Story
of JMML

19. Pg. 19April, 2017 Confidential
Juvenile Myelomonocytic Leukemia
(JMML)

20. Pg. 20April, 2017 Confidential
Overview
• Unique disorder of infancy caused by proliferation of
monocytes/granulocytes; infiltrates the spleen/liver,
intestines and lungs
• 2% of pediatric hematologic malignancies (in the US
about 50 new cases per year)
• Presents with fever, thrombocytopenia, failure to
thrive, and splenomegaly
• Fatal; allogeneic stem cell transplant only curative
approach

21. Pg. 21April, 2017 Confidential
Myeloid Progeny Hypersensitivity

22. Pg. 22April, 2017 Confidential
RAS-MAPK Pathway and Gene
Mutations Contributing to JMML

23. Clinical Trials in
Adult MDS

24. Pg. 24April, 2017 Confidential
MDS Epidemiology
• Disease affects bone marrow function
and can transform into leukemia
• MDS is predominantly disease of the
elderly
• Classified as high- or low-risk
disease based on likelihood of
progressing to acute myeloid
leukemia (AML)
• Distinct opportunities in lower-risk
and higher-risk patients
• IMS Identified 34,101 newly diagnosed
patients in the U.S. (MAT June 2012)
• ~47% of the MDS diagnosed
patients, mostly low-risk category;
growth factors, transfusion
support, or not treated
• Incidence of MDS and treated patients
are growing
• Treatment penetration (HMAs,
Revlimid) is ~14%; great unmet
need
Sources: Goldberg SL, Chen E, Corral M, Buo A, Mody-Patel N, Pecora AL, Incidence
and Clinical Complications of Myelodysplastic Syndromes Among US Medicare
Beneficiaries; J Clin Oncol 2010 (28):2847-52, IMS Patient Diagnoses Study 2012
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
45,000
50,000
15,089
45,000
30,100
SEER/
NAACCR
GoldbergCogle
34,101
IMS
Estimated Annual MDS Incidence

25. Pg. 25April, 2017 Confidential
Natural history of MDS after
incorporation of HMAs
Prodrome
ICUS, CHIP
LR-MDS HR-MDS
AML
HMA failure
?
HMA failure
AML-like?
?
Untreated
HMA?
lenalidomide
Untreated
HMA
AML-like
SCT
HMA lower risk failure survival: 14-17 months
HMA higher risk failure survival: 4-6 months
Jabbour. Cancer 2015; Jabbour. Cancer 2010; Steensma Blood 2015.

26. Pg. 26April, 2017 Confidential
Overall Survival: Azacitidine vs CCR
ITT Population Log-Rank p=0.0001
HR = 0.58 [95% CI: 0.43, 0.77]
Deaths: AZA = 82, CCR = 113
0 5 10 15 20 25 30 35 40
Time (months) from Randomization
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
ProportionSurviving
CCR
AZA
Difference: 9.4 months
24.4 months
15 months
50.8%
26.2%
Fenaux et al. Lancet Oncology 2010

27. Pg. 27April, 2017 Confidential
MDS after hypomethylating agent-
based therapy: urgent need to develop
novel approaches

28. Pg. 28April, 2017 Confidential
Two Rigosertib Formulations
• IV (Phase 3 INSPIRE ongoing)
• Continuous infusion using a
portable pump
• >500 patients treated in trials
• Lead indication 2nd-line HR-
MDS
• Oral (Phase 2 enrolled)
• Bioavailability ~35%
• >200 patients treated
• Combination with azacitidine
for HR-MDS and AML
0
1000
2000
3000
4000
5000
0 4 8
Concentration(ng/mL)
Time (hr)
Plasma Levels of Rigosertib from a Bioavailability
Study
24 Hr Inf 800 mg/m2 Oral-560 mg Fasted
Oral-560 mg Fed

29. Pg. 29April, 2017 Confidential
Single-agent IV Rigosertib for 2nd-line
HR-MDS

30. Data from ONTIME paper* published in Lancet Oncology
ITT for ONTIME Trial Subpopulation for INSPIRE Trial (ONTIME subset)
299 Patients 116 Patients
*Guillermo Garcia-Manero, Pierre Fenaux, Aref Al-Kali, Maria R Baer, Mikkael A Sekeres, Gail J Roboz, et al. Rigosertib versus best supportive care
for patients with higher-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, Phase 3 trial;
The Lancet Oncology 2016 (17): 496–508
ITT OS analysis of ONTIME – HR= 0.87; NS survival benefit
ITT OS of proposed INSPIRE population – HR = 0.48; P = 0.0008
PATIENT POPULATION FOR PHASE 3 INSPIRE TRIAL
Pg. 30March 2017

31. Pg. 31April, 2017 Confidential
ONTIME Trial: ITT Subgroups Correlated
with Better Survival Benefit - ITT
Subgroup
Rigosertib BSC
HR (95% CI) p-valueN Median (mos) N Median (mos)
Monosomy 7 16 5.6 13 2.8
0.24
(0.09-0.66)
0.003
Trisomy 8 22 9.5 8 4.5
0.34
(0.12-0.95)
0.035
Del 7q 17 5.0 3 2.7
0.38
(0.10-1.48)
0.14
Very high risk
per IPSS-R
93 7.6 41 3.2
0.56
(0.37-0.84)
0.005

32. Pg. 32April, 2017 Confidential
Effect of acquisition of Flt3 or Ras
mutations in MDS
Time (Months)
ProbabilityofTransformation-freeSurvival
0 20 40 60 80 100 120 140
0.00.20.40.60.81.0
Non-FLT3/RAS
FLT3/RAS
Koichi Takahashi

33. Pg. 33April, 2017 Confidential
Safety of Single-agent IV Rigosertib in MDS
MedDRA Preferred Term
All
Grades
Grade
1
Grade
2
Grade
3
Grade
4
Grade
5
Any treatment-related AE 238 (67) 55 (15) 70 (20) 71 (20) 37 (10) 5 (1)
Nausea 64 (18) 51 (14) 10 (3) 3 (1) 0 0
Fatigue 63 (18) 18 (5) 38 (11) 6 (2) 1 (<1) 0
Diarrhoea 51 (14) 37 (10) 10 (3) 4 (1) 0 0
Constipation 40 (11) 32 (9) 7 (2) 1 (<1) 0 0
Anaemia 25 (7) 1 (<1) 4 (1) 18 (5) 1 (<1) 1 (<1)
Vomiting 24 (7) 17 (5) 5 (1) 2 (1) 0 0
Dysuria 20 (6) 14 (4) 3 (1) 3 (1) 0 0
Abdominal pain 19 (5) 14 (4) 4 (1) 1 (<1) 0 0
Treatment-related Adverse Events Reported in ≥5% of Patients with MDS
Treated with IV Rigosertib as Monotherapy (N=355)

34. Pg. 34April, 2017 Confidential
INSPIRE Update

35.  Statistical analysis: two analyses planned
 Power 0.80; Target HR < 0.625; (reduce mortality by > 37.5%)
  for ITT = 0.04;  for IPSS-R VHR = 0.01
 Trial can succeed in two ways: ITT population or IPSS-R Very High Risk
 Genomic sequencing of patient samples
Commentary on new trial in recent publication: Emilio P Alessandrino, Matteo G Della Porta. Novel
trial designs for high-risk myelodysplastic syndromes; The Lancet Oncology 2016 (17): 410–412
Post-HMA HR-MDS (N=225)
Key Eligibility Criteria:
- Failed HMA < 9 cycles* DoT
- < 82 years of age
- Last HMA within 6 months
Randomization
2:1
IV rigosertib
+
BSC
N = 150
Overall Survival
- Interim analysis (88
events)
- Intent-to-treat analysis
(176 events)
Follow-up
Physician’s
Choice
+
BSC
N = 75
INSPIRE: GLOBAL PHASE 3 TRIAL
Pg. 35March 2017
*9 cycles within 12 months of starting treatment

36. Pg. 36April, 2017 Confidential
INSPIRE Trial Progress
Goals:
• 19 countries
• 174 sites
• 225 randomized patients
Status:
• 160 Sites Initiated Globally
• 19 countries open
• 4 countries upcoming
• Belgium, Sweden, Switzerland,
The Netherlands
• DMSC Meeting Oct 31, 2016 –
Continue Study
Japan: Phase 3
Participation
by SymBio
Interim analysis planned for H2-2017

37. Pg. 37April, 2017 Confidential
Global INSPIRE Trial Progress
225 patients; 174 selected sites in 19 countries on 4 continents
1. USA* 37
2. Japan* 31
3. Spain* 12
4. Israel 10
5. France* 9
6. Germany* 8
7. Italy* 9
8. U.K. 5
9. Australia* 5
10. Canada* 6
11. Poland* 6
12. Belgium 5
13. Czech Rep.* 5
14. Ireland 4
15. Sweden 4
16. Croatia* 4
17. Austria* 3
18. Netherlands 2
19. Switzerland 2
Country Sites
As of Dec 1, 2016
*Patients enrolled in these countries
The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the U.S. Food and
Drug Administration and European Medicines Agency and derives from findings of the ONTIME Phase 3 trial. Our
partner SymBio is enrolling in Japan after discussions with the PMDA.

38. Pg. 38April, 2017 Confidential
Data Analysis for INSPIRE Trial
• Primary endpoint is overall survival
• Entire trial (ITT) after 176 events have occurred
• If the ITT analysis is negative, a second analysis of IPSS-R VHR subgroup is permitted
• Interim analysis planned
• ITT analysis after 88 events
• Adaptive design as a part of Statistical Analysis Plan for HA Review
• Secondary analysis includes
• By region of enrollment (U.S., EU, ROW)
• Karyotypes
First Patient Q4-2015
Interim Analysis H2-2017
Full Enrollment H2-2017-
1Q2018
Top-line Data H1-2018
Timeline for Global Trial Conducted in 19 Countries on 4 Continents

39. Pg. 39April, 2017 Confidential
ORAL RIGOSERTIB AND AZACITIDINE

40. Pg. 40April, 2017 Confidential
Oral Rigosertib + Azacitidine for HMA
Naïve HR- MDS
• Efficacy of single-agent DNMT+ inhibitors (HMAs) is limited
◦ Low CR and PR rates (7-20%)
◦ Limited median duration of response (Cr + PR 3.2 months*)
 More recent literature suggests improving efficacy**
• Combination with other agents is warranted
◦ Combinations should not add burdensome toxicities
 Minimize hematuria
• DNMT inhibition in combination with novel mechanisms
may improve response rates and duration of benefit
*Fenaux et al ; Lancet Oncology 2009; 10; 223.
**Aziz Nazha for MDS Consortium; haematologica 2016; 101:e225; letter to the editor
+DNA Methyl Transferase inhibitors are also known as Hypomethylating Agents (HMAs)
In Higher-risk MDS patients:

41. Pg. 41April, 2017 Confidential
Epigenetic and Growth Factor Pathway Mutations
Synergize Inducing Leukemic Transformation
(LR-MDS) (HR-MDS)
Adapted from Papaemmanuil et al., 2013 Blood
= Ras pathway
activation
Preclinical/clinical evidence suggest combination of epigenetic therapy plus growth factor
signaling inhibitor could be effective in curbing MDS pathogenesis
AML Animal Model
Temporal Order of Gene Mutations in 107 MDS Patients
Lu et al., 2016 Cancer Cell

42. Pg. 42April, 2017 Confidential
Pre-clinical Background
• Combination of rigosertib with AZA produced an increase of 1.7- to
2.9-fold in cytotoxicity (p<0.05) in HL-60 cells*
• Interaction resulted in a synergistic effect with combination indexes
between 0.3 and 0.75
• U.S. patent issued for combination based on pre-clinical data
• Sequence of administration influenced degree of cytotoxicity;
rigosertib priming offered optimal results
• These pre-clinical results provided rationale for combining agents in
a Phase 1/2 study in MDS and AML patients with optimal sequence
*Skidan I, Zinzar S, Holland J, Silverman. Toxicology of a novel small molecule ON01910Na on human bone marrow and leukemic cells in vitro.
AACR Meeting Abstracts, Apr 2006:309

43. Pg. 43April, 2017 Confidential
Rigosertib + Azacitidine Combination
• Phase 1 combination was well tolerated with
evidence of efficacy in patients with MDS*
• Azacitidine given one week per month (full
dose and administrative scheme per label)
• Rigosertib given 3 of 4 weeks (at
recommended Phase 2 dosing of 560/280 mg
BID – dose optimization study underway)
• Adverse event profile of combination similar
to single-agent azacitidine (per label)
*Navada S, Garcia-Manero G, Wilhelm F, et al. A phase I/II study of the combination of oral rigosertib
and azacitidine in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). ASH
2014; Abstract 3252.
Week 1
Oral
Rigosertib
Only
Week 4
No Treatment
Week 2
Oral Rigosertib
+
Azacitidine
(75 mg/m2)
Week 3
Oral
Rigosertib
Only

44. Pg. 44April, 2017 Confidential
Rigosertib + Azacitidine
Updated Phase 2 Data ASH 2016*
• ORR of 85% in 20 HMA naïve patients
• ORR of 62% in 13 patients who progressed/failed prior HMA
• Median DoR for CR is 8.0 months; median time to best response is 3.3 cycles
Response Assessment per 2006 IWG Criteria
Patient Characteristics Eval (n=33) HMA Naïve (n=20) HMA Failure** (n=13)
Complete Remission (CR %) 8 (24%) 7 (35%) 1 (8%)
Overall Response Rate (ORR %) 25 (76%) 17 (85%) 8 (62)
* Data shown as of data cut off Oct 1, 2016; response based on IWG 2006 criteria
**10 patients received previous therapy with azacitidine, 2 with decitabine and 1 with both HMAs;
prior HMA cycles ranged from 4-20
Navada S, et al. A phase 2 study of the combination of oral rigosertib and azacitidine in patients with myelodysplastic syndrome (MDS). ASH 2016

45. Pg. 45April, 2017 Confidential
Hematology Trends for Patient 101-006
Hemoglobin Platelets
Neutrophils • 12 cycles of AZA – stable disease
• RBC and platelet transfusions
• Blasts 7%
• Monosomy 7
• Runx-1
• AZA + RIG in 09-08 for 20+ months
• Complete remission
• RBC transfusion independent
• <5% blasts
• PB CR criteria

46. Pg. 47April, 2017 Confidential
Rigosertib Trial Timelines
First Patient Q4 2015 Interim Analysis H2 2017
Full Enrollment H2 18-1Q18 Top-line Data H1 2018
INSPIRE Global Trial
EOP2* Meeting Q3 2016 Trial Amendment 12/16
Phase 2 Data ASH 2016
Dose Optimization of Oral Rigosertib + Azacitidine
Start Amended 09-08 H1 17**
Optimal doublet dose Q4 17
*EOP2: End of Phase 2 meeting: completed in September 2016
**at risk if IRBs do not approve
Interim analysis H1 2019
FPI 4Q 2017
Pivotal Trial of Oral Rigosertib + Azacitidine
Full enrollment H2 2019
Topline data H2 2019

47. QUESTIONS???
????
Pg. 48Month, 2017

48. Why vote for me (Fruchtman; as in
fruit!!) to visit the Ritz for free?
• Why not; no other speaker has asked?
• I have 3 kids in college at the same time, and thus
can’t afford to take vacations?
• I stopped speaking before my allotted time so we
can go to the pool?
• I will give you free entry to tonight’s dinner?
Thank you for your kindness