targeting ras and mds: rigosertib taking aim at important targets-steven fruchtman, onconova...

Rigosertib: Mechanism of Action & Clinical

Development

Steven Fruchtman, M.D.

Chief Medical Officer

May 8,2017

Evolution Summit

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

Bone Marrow Anatomy

hematopoietic bone marrow

4

Bone Marrow Aspiration

5

Bone Marrow Smears

6

Bone Marrow Biopsy

Bone marrow biopsy needle

(Yamshidi)

Revised IPSS

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

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

(%

)

http://www.clinicaloptions.com/oncology

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. 9 April, 2017 Confidential

Pg. 10 April, 2017

Understanding RAS Signaling and Targeting

the “Untargetable”

Confidential

Pg. 11 April, 2017

Discovery of Rigosertib as a RAS Mimetic

Confidential

Pg. 12 April, 2017

Rigosertib Mechanism of Action

PLK1

Aurora A

Mitosis

MEK

ERK

Transcription

PI3K

Akt

Cell growth Survival Metabolism

Receptor

Tyrosine

Kinase

RAS

PI3K

Akt

Cell growth Survival Metabolism

Growth

Factor

Receptor

Tyrosine

Kinase

RAS

Growth

Factor

RAS RAS

PLK1

Aurora A

Mitosis

MEK

ERK

Transcription

+ Rigosertib + Rigosertib

Confidential

Pg. 13 April, 2017

Rigosertib Binds to Multiple RAS Effector RBDs

CRAF

BRAF

ARAF

RAS

CRAF

BRAF

ARAF

PI3K

PI3Kβ

PI3Kγ

PI3Kδ

RALGDS

Confidential

Pg. 14 April, 2017

Rigosertib Does Not Affect In Vitro RAF Kinase Activity

ARAF BRAF CRAF

GW5074 is a Raf

inhibitor Confidential

Pg. 15 April, 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

Pg. 16 April, 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


Rigosertib Inhibits Tumor Growth and Signaling in Xenografts of Human Cancer

615222730

Daysoftreatment

HCT-116 (CRC)

A549 (adeno alveolar)

Tumor growth

inhibition is

associated with

reduced RAF and

AKT signaling

Pediatric Investigational Plan

An Abridged Story

of JMML


Juvenile Myelomonocytic Leukemia (JMML)


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


Myeloid Progeny Hypersensitivity


RAS-MAPK Pathway and Gene Mutations Contributing to JMML

Clinical Trials in Adult MDS


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 Goldberg Cogle

34,101

IMS

Estimated Annual MDS Incidence


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.


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

Pro

po

rtio

n S

urv

ivin

g

CCR AZA

Difference: 9.4 months

24.4 months

15 months

50.8%

26.2%

Fenaux et al. Lancet Oncology 2010


MDS after hypomethylating agent-based therapy: urgent need to develop novel approaches


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

Con

ce

ntr

atio

n (

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


Single-agent IV Rigosertib for 2nd-line HR-MDS

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. 30 March 2017


ONTIME Trial: ITT Subgroups Correlated with Better Survival Benefit - ITT

Subgroup

Rigosertib BSC

HR (95% CI) p-value N 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


Effect of acquisition of Flt3 or Ras mutations in MDS

Time (Months)

Pro

ba

bili

ty o

f T

ran

sfo

rma

tio

n-f

ree

Su

rviv

al

0 20 40 60 80 100 120 140

0.0

0.2

0.4

0.6

0.8

1.0

Non-FLT3/RASFLT3/RAS

Koichi Takahashi


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)


INSPIRE Update

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. 35 March 2017

*9 cycles within 12 months of starting treatment


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


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.


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


ORAL RIGOSERTIB AND AZACITIDINE


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:


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


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


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


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


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


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

QUESTIONS???????

Pg. 48 Month, 2017

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

targeting ras and mds: rigosertib taking aim at important targets-steven fruchtman, onconova...

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