Arizona, USA

©2011 MFMER | 3133089-1

Ruben A. Mesa, MDProfessor & Chairman, Division of Hematology & Medical Oncology

Deputy Director, Mayo Clinic Cancer CenterMayo Clinic – Arizona, USA

Myeloproliferative NeoplasmsHematology Highlights

Las Vegas, NV, USA – February 27, 2014, 2014

Myeloproliferative NeoplasmsHematology Highlights 2014

•Burden and Biology of MPNs

•JAK2 Inhibition in 2014

•JAK2 Inhibition and beyond

The Natural History of MPNs

Polycythemia Vera

Early/ Pre-fibrotic Primary

Myelofibrosis

Classic Primary MFPost ET/PV MF

MPN Blast Phase

WHO 2008Essential

Thrombocythemia

Diagnosis

©2011 MFMER | 3133089-4

Within ER - chaperone ensuring quality control of glycoprotein folding - calcium homeostasis

Outside ER - found in cytoplasmic, cell surface and extracellular compartments - roles in: proliferation apoptosis phagocytosis immunogenic cell death

Calreticulin (CALR)

CALR mutations in JAK2 negative ET and MF

Burden of ET/PV

MicrovascularSymptoms

MacrovascularRisk

MPN Associate

dSymptom

s

Burden of Myelofibrosis

Anemia/Cytopenis

Splenomegaly

MF AssociatedSymptoms

Et & PV AssociatedSymptoms

Myelofibrosis and Cytopenias (N=364)

©2011 MFMER | 3133089-8

Emanuel et. al. JCO 2012

PLT > 15070%

PLT = 100-14910%

PLT = 50-9911%

PLT < 509%

N.B.• Varying times• NL Hg

• Men 13.5 g/dL• Women 12 g/dL

Hb - Normal25%

Hb 10g/dL - Normal

33%Hb <10g/dL-Tx Dep18%

Tx Dep24%

WBC ≥ Normal90%

WBC < Normal10%

Myelofibrosis and Splenomegaly

©2011 MFMER | 3133089-9

89%

11%Splenomegaly

Not Enlarged

64%

36%Splenomegaly

Not Enlarged

Cervantes et. al.Blood 2009(N=1054 PMF)

Emanuel et. al.JCO 2012(N=329 MF)

Why does Splenomegaly Matter in MF?

• Mechanical discomfort• Pain• Possible splenic

infarction• Early satiety adding to

cachexia• Splenic sequestration

and exacerbation of cytopenias

• May delay engraftment in setting of allogeneic stem cell transplant

Quartile 1 (Q1): 0-24% Quartile 2 (Q2): 25-49%Quartile 3 (Q3): 50-74% Quartile 4 (Q4): 75-100% Percentile MPN-SAF TSS

Q1TSS <8

Q2TSS 8 -17

Q3TSS 18 - 31

Q4TSS >32

Parameter P value of Comparison

Age 0.24

Gender F>M <0.001

MPN Diagnosis <0.001

Subtype of MF 0.86

IPSET (ET Risk) 0.18

PV Risk (PV) 0.30

DIPSS (MF Risk) <0.001

MPN Symptom Burden by Quartiles1858 MPN-SAF Respondents

ET (N=775)

PV (N=654)

MF (N=423)

Q1 – 30% Q2 – 26% Q3 – 24% Q4 – 20%

Q1 – 17% Q2 – 21% Q3 – 26% Q4 – 36%

Q1 – 25% Q2 – 23% Q3 – 26% Q4 – 26%

New Response Criteria for MPNs

ET2 PV2 MF1

Complete response Partial response Clinical improvement Stable disease No response Relapse

Other responses Molecular Molecular Cytogenetic andmolecular

1. Tefferi A et al. Blood. 2013;122:1395-1398. 2. Barosi G et al. Blood. 2013;121:4778-4781.

New Response Criteria for MF: Complete Response1

EMH: extramedullary hematopoiesis1. Tefferi A et al. Blood. 2013;122:1395-1398.

Bone marrow: Age-adjusted normocellularity;<5% blasts; ≤Grade 1 MF; and

Peripheral blood: Hemoglobin ≥ 100 g/L and <UNL; Neutrophils ≥ 1 x 109/L and <UNL; Platelets ≥ 100 x 109/L and <UNL; <2% immature myeloid cells; and

Clinical: Resolution of disease symptoms Spleen and liver not palpable No evidence of EMH

Required criteria: for all response categories, benefit must last for ≥12 wks to qualify as a response

New Response Criteria for MF: Other Categories1

1. Tefferi A et al. Blood. 2013;122:1395-1398.

Clinical improvement

Achievement of anemia, spleen, or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia

Anemia response

Transfusion-independent pts: a ≥20 g/L increase in Hb level

Transfusion-dependent pts: becoming transfusion independent

Spleen response

Baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable, OR

Baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by ≥50%

Baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for spleen response

Symptoms response A ≥50% reduction in the MPN-SAF TSS

CI: clinical improvement; LCM: left costal margin.

Myeloproliferative NeoplasmsHematology Highlights 2014

•Burden and Biology of MPNs

•JAK2 Inhibition in 2014

•JAK2 Inhibition and beyond

JAK Inhibitors and Status of DevelopmentMyelofibrosis as lead indications

AZD1280

XL019

CEP 701

Fedratininb (SAR302503)

INCB039110 (JAK1)

NS-018

BMS-911543

LY2784544

Momelotinib (CYT387)

Pacritinib (SB1518)

Ruxolitinib (FDA Approved)

0 1 2 3 4©2011 MFMER | 3133089-16

No Longer in DevelopmentFor MPNs

* Now Testing in PV

*

*

*

*

Patient Disposition – 3 Year FU Comfort I

Ruxolitinib (n = 155)

Placebo

Placebo(n = 151)

Placebo Ruxolitinib

(n=111)

Median exposure, weeks 145 37 105

Still on treatment, n (%) 77 (49.7) 0 57 (51.4)

Crossed over, n (%) 111 (73.5)

Discontinued, n (%) 78 (50.3) 40 (26.5) 54 (48.6)

Primary reasons for discontinuation, n (%)*

Death 15 (19.2) 7 (17.5) 11 (20.4)

Adverse event 15 (19.2) 9 (22.5) 8 (14.8)

Consent withdrawn 12 (15.4) 7 (17.5) 11 (20.4)

Disease progression 18 (23.1) 13 (32.5) 15 (27.8)

• All patients originally randomized to placebo crossed over or discontinued within 3 months of the primary analysis

• Median time to crossover: 41.1 weeks

17* Percentages are calculated based on the number of patients who discontinued within the respective treatment group.

ASH 2013

Mean Daily Dose of Ruxolitinib Over Time

18

• Approximately 70% of patients had dose adjustments during the first 12 weeks of therapy

• By week 24, patients originally randomized to RUX 15 mg BID and 20 mg BID were titrated to a mean dose of ~10 mg BID and 15-20 mg BID, respectively

25

20

15

10

5

0

Mea

n D

aily

Do

se

(mg

, B

ID)

± S

EM

0 8 16 24 32 72 104 136 14448 88 1206456 96 12840 80 112Weeks

20 mg BID starting dose15 mg BID starting dose

98 6220 mg BID

49 2015 mg BID

Number of patients

100

55

77 69

33 26

73

30

93

35

ASH 2013

Series1

-60

-50

-40

-30

-20

-10

0

10

Series1

-60

-50

-40

-30

-20

-10

0

10

Percentage Change in Spleen Size

19

• Mean reductions in spleen volume and palpable spleen length with ruxolitinib were stable over time

Ruxolitinib Placebo

Weeks

Mea

n P

erce

nta

ge

Ch

ang

e fr

om

Bas

elin

e

148 139 120 107 100 84 132 107 3573n =

12 24 48 72 96 120 144 12 24 48

Weeks12 24 48 72 96 120 1444 8 12 24 484 8

Ruxolitinib Placebo

153 152 150 141 130 110 102n = 147 141 136 109 4790 79

Mea

n P

erce

nta

ge

Ch

ang

e fr

om

Bas

elin

e

Spleen Volume Spleen Length

ASH 2013

Improvements in EORTC QLQ-C30 Over Time

Arrows indicate improvementRUX PBO

Global Health Status/QoL

Mea

n C

han

ge

Fro

m B

asel

ine

0 12 24 36 48 72 96 120 144Weeks

20

10

0

-5

-15

15

5

-10

60 84 108 132

Fatigue

Mea

n C

han

ge

Fro

m B

asel

ine

0 12 24 36 48 72 96

Weeks

10

0

-10

-15

-25

-35

5

-5

-20

-30

60 84 120 144108 132

Physical Functioning

Mea

n C

han

ge

Fro

m B

asel

ine

Weeks

15

5

-5

-10

10

0

0 12 24 36 48 72 9660 84 120 144108 132

Role Functioning

Mea

n C

han

ge

Fro

m B

asel

ine

Weeks

25

10

0

-5

-15

-25

15

5

-10

-20

20

0 12 24 36 48 72 9660 84 120 144108 13220

ASH 2013

Overall Survival

*By week 80, all patients originally randomized to placebo discontinued or crossed over to ruxolitinib therapy 21

153 144 129 114 105Placebo 154 149 134 119 107 100 92 85 8 0100 95 88 79 3882 68 28

155 148 143 131 124 115 111 108 1 0Ruxolitinib

Number of patients at risk

155 153 145 137 125 122 112 111 101 45106 84 19

Randomized to Placebo Ruxolitinib

Randomized to Ruxolitinib

1.0

0.8

0.6

0.4

0.2

00 8 24 40 56 72 88 104 120 136 168 176

Pro

bab

ilit

y

Weeks16 32 48 64 80 96 112 128 152144 160

4 22 54 88 99 100 100 100 100 10013 35 73 97 100 100 100 100 100100 100 100

HR=0.69 (95% CI: 0.46, 1.03); P=0.067

No. of deaths: Ruxolitinib=42; Placebo=54

Median follow-up: 149 weeks

Percent of at-risk placebo who crossed over or discontinued

*

• Overall survival favored patients originally randomized to ruxolitinib compared with patients originally randomized to placebo

ASH 2013

Overall Survival: Rank-Preserving Structural Failure Time (RPSFT) Analysis

1.0

0.8

0.6

0.4

0.2

00 8 24 40 56 72 88 104 120 136 168 176

Pro

bab

ilit

y

Weeks16 32 48 64 80 96 112 128 152144 160

HR=0.36 (95% CI: 0.204, 1.035)

Placebo Ruxolitinib

Ruxolitinib

Placebo-RPSFT

22

• RPSFT is a recognized method to estimate HR after adjusting for crossover1-5

• Hazard ratio of 0.36 is consistent with the hypothesis that ITT analysis underestimates the survival benefit of ruxolitinib relative to “true placebo”

(1) Robins J, Tsiatis A. Commun Stat Theory Methods. 1991;20:2609-31; (2) Demetri GD, et al. Clin Cancer Res. 2012;18:3170-79; (3) National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance 179. http://guidance.nice.org.uk/TA179. Issued September 23, 2009; (4) Sternberg CN, et al. Eur J Cancer. 2013;49:1287-96; (5) National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance 215. http://guidance.nice.org.uk/TA215/Guidance/pdf/English. Issued February 2011.

ASH 2013

Mean Platelet Count and Hemoglobin Level Over Time

Platelet Count Hemoglobin

23

85

90

95

100

105

110

115

0 12 24 36 48 60 72 84 96 108 120 132 144

WeeksM

ea

n H

em

og

lob

in (

g/L

)120

170

220

270

320

0 12 24 36 48 60 72 84 96 108 120 132 144

Weeks

Me

an

Pla

tele

ts (

x1

09/L

)

128 82PBO

144 136 112 107 100 88RUX

Number of patients

151

155

112 37

143 124 110 104 94 79

132 83

145 136 113 107 100 88

151

155

113 37

143 124 110 104 94 79

Number of patients

370Ruxolitinib Placebo Ruxolitinib Placebo

ASH 2013

Incidence of New Onset All Grade Non-hematologic Adverse Events Regardless of Causality

24

Incidence (%)Ruxolitinib

0–<12 months (n=155)

12–<24 months (n=130)

24–<36 months (n=103)

≥36 months(n=82)

Fatigue 29.0 15.2 15.3 7.7

Diarrhea 27.8 6.7 10.8 3.9

Ecchymosis 21.2 10.4 5.7 0

Peripheral edema 21.3 8.4 12.6 0

Dyspnea 19.2 10.2 2.9 3.3

Dizziness 18.1 10.4 3.0 3.5

Pain in extremity 18.0 6.2 4.2 3.3

Headache 16.6 5.1 2.7 0

Nausea 16.6 6.8 5.1 5.9

Constipation 14.5 8.6 10.1 9.0

Abdominal pain 13.8 5.7 3.6 0

Insomnia 13.8 5.7 3.7 0

Vomiting 13.7 2.8 2.4 5.5

Pyrexia 13.5 7.3 8.5 2.9

Cough 13.1 13.3 4.0 6.0

Arthralgia 11.8 5.8 6.6 6.3

Upper respiratory tract infection

7.7 11.1 4.0 3.2

• There was no change in the rate, distribution, or severity of nonhematologic adverse events in the ruxolitinib group with longer-term treatment; most nonhematologic adverse events were grade 1 or 2

Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the beginning of the interval minus half of the censored patients during the time interval). Adverse event is included if the incidence was >10% at any yearly interval.

ASH 2013

Incidence of New Onset Grade 3 or 4 Non-hematologic Adverse Events Regardless of Causality

25

Incidence (%)

Ruxolitinib

0–<12 months (n=155)

12–<24 months (n=130)

24–<36 months (n=103)

≥36 months(n=82)

Fatigue 6.2 0.9 3.3 0

Pneumonia 5.6 3.6 3.5 0

Abdominal pain 4.2 0 3.2 0

Arthralgia 2.1 0 0 0

Diarrhea 2.1 0 0 0

Dyspnea 2.1 0.9 2.2 2.5

Pain in extremity 2.1 0 1.1 0

Hyperuricemia 1.4 0.9 0 2.5

Fall 1.4 0.9 0 0

GI hemorrhage 1.4 0.9 0 0

Septic shock 1.4 0 0 0

Muscular weakness 1.4 0 1.1 0

Hypoxia 1.4 0 2.2 0

Sepsis 0.7 1.7 2.2 0

Epistaxis 0.7 1.7 0 0

Renal failure acute 0.7 0.9 2.2 2.4

Abdominal pain upper 0.7 0 2.2 0

Myocardial infarction 0 0.9 0 4.8

Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the beginning of the interval minus half of the censored patients during the time interval).Adverse event is included if the incidence was ≥2 patients at any yearly interval.

ASH 2013

BM Morphology in a Ruxolitinib-Treated Patient: A Case Demonstrating Improvement on Ruxolitinib

26

Baseline BiopsyGrade 3

24 MoPost Ruxolitinib

Grade 2

48 MoPost Ruxolitinib

Grade 0

Kvasnicka HM, et al. ASCO. 2013 (abstr 7030). Permission to use images from Kvasnicka, HM

ASH 2013

Dynamics of BM Changes Following Ruxolitinib Treatment at 48 Mo

27

Kvasnicka, et al. ASH 2013. Abstract 4055.ASH 2013

JAK1 & 2 Inhibitors in MPNs – Efficacy Summary – As of ASH 2013

Myelofibrosis PolycythemiaVera

EssentialThrombocythemia

Spleen Const.Sympt.

Anemia Survival Counts

Const.Sympt.

VascEvents

Counts

Const.Sympt.

VascEvents

Ruxolitinib - Approved P III P III P III P III P II P II P II P II P II P II

SAR302503 – PH III JAKARTA (HOLD)

P III P III P II P III

Pacritinib-PIII Ongoing (Persist MF)

P II P II P II

CYT387 P II P II P II

LY2784544 P I P I

NS-018

BMS-911543 PH II PH II

INCB039110 (JAK1 Alone)

P I P I PI

CEP701 P II P II P II P II P II P II©2011 MFMER | 3133089-28

NotReported

Yet

Yes No

Occasional Ongoing Trials

JAK1 & 2 Inhibitors in MPN – Toxicity ASH 2013Hematological

ToxicitiesGastrointestinal/ Renal

ToxicitiesNeurological

Toxicities

Anemia ANC

PLT

Nausea Diarr-hea

LFTsOr CR

Lipase

Head-ache

Dizzy NeuroP/Parathia

Ruxolitinib - Approved

23% 7% 11% 2% 0.6%

SAR302503 – PIII Ongoing (MF)

41% 6% 11% 0% 5% 1% W. E.% ?

Pacritinib-PIII Ongoing (MF)

6% 0% 18% 6%

CYT387PII Ongoing (MF)

10% 2% 20% 1%

INCB039110 (JAK1) – PI/II MF

28% 27% 10%

BMS 911543 3% 10% 10% 0% 0% 0% 0%

LY2784544 3% 0% 3% 8% Renal

©2011 MFMER | 3133089-29

<10%11-

20%21-

30%31-

40%41-

50%51-

60%61-

70%71-

80%81-

90%91-

100%

Toxicity Color – Represents All Grades ( Grade ¾ Toxicity - Percentage in Table Above)

Myeloproliferative NeoplasmsHematology Highlights 2014

•Burden and Biology of MPNs

•JAK2 Inhibition in 2014

•JAK2 Inhibition and beyond

MPNs – Plateau vs. Decline

©2011 MFMER | 3133089-31

ET – Possible PlateauAsymptomatic ThrombocytosisNo Vascular Events

ET – Possible Plateau 2Symptomatic ThrombocytosisSinus Venous Thrombosis

Time

Clinical Status

PV – Possible Plateau 2Symptomatic ErythrocytosisNo Vascular Events

Post PV MF6 Months worsening Fatigue10 kg weight lossMassive spleen

MF on Successful JAK2 RxImproving WeightDecreased SpleenImproved Survival

MPNs – Cumulative Benefits

©2011 MFMER | 3133089-32Time

Clinical Status

Improved Symptom Burden

Improved Spleen Burden

Improved SurvivalRuxolitinib

MPNs – Cumulative BenefitsSingle Agent Trials JAK2 InhibitorsCompared to Ruxo

©2011 MFMER | 3133089-33Time

Clinical Status

Improved Symptom Burden

Improved Spleen Burden

Improved Survival

? Other Benefit-Less cytopenias-Improved activity

STUDY (JAK2/FLT3 Inhibitor) NS-018 (PH I/II)NCT01423851

STUDY (JAK2/FLT3 Inhibitor)Pacritinib (SB1518) (PH III vs. BAT)

NCT01773187

STUDY (JAK2 Inhibitor – Also ET and PV) LY2784544 (PH I/II)

NCT01520220

STUDY (JAK2/JAK1 Inhibitor)Momelotinib (CYT387) (PH III vs. Ruxo)

NCT001969838

MPNs – Cumulative BenefitsRuxolitinib + drug X for Anemia

©2011 MFMER | 3133089-34Time

Clinical Status

Improved Symptom Burden

Improved Spleen Burden

Improved Survival

Improved Anemia Burden

STUDY COMBINATION (JAK2 PLUS Androgen)Ruxolitinib Plus Danazol

Mayo Clinic (AZ) and Mt. Sinai Trial: NCT01732445

STUDY COMBINATION(JAK2 PLUS Hypomethylation)

Ruxolitinib Plus AzacitidineMDACC Trial: NCT01787487

STUDY COMBINATION (JAK2 PLUS IMID)Ruxolitinib Plus Lenalidomide

NCT01375140

STUDY COMBINATION (JAK2 PLUS IMID)Ruxolitinib Plus PomalidomideGermany (ULM): NCT01644110

MPNs – Cumulative BenefitsRuxolitinib + drug X for Deeper Marrow Changes Impact

Clinical Status

Improved Symptom Burden

Improved Spleen Burden

Improved Survival

Improved Marrow Dysfunction

STUDY COMBINATION (JAK2 PLUS HDAC Inhibitors)Ruxolitinib Plus Panobinostat

Mt. Sinai Trial: NCT01693601UK Trial: NCT01433445

STUDY COMBINATION (JAK2 PLUS LOXL2 Inhibitors)

Ruxolitinib Plus GS-6624NCT01369498

STUDY COMBINATION (JAK2 PLUS rhPTX-2 (Anti-fibrosing))

Ruxolitinib Plus PRM -151Opening Soon

STUDY COMBINATION (JAK2 PLUS PI3 Kinase Inhibitor)

Ruxolitinib Plus BKM120NCT01730248

STUDY COMBINATION (JAK2 PLUS Hedgehog Inhibitor)

Ruxolitinib Plus LDE225NCT01787552

MPNs – Cumulative BenefitsSingle Agent Trials Alternate Targets

Time

Clinical Status

Improved Symptom Burden

Improved Spleen Burden

Improved Survival

? Other Benefit-Less cytopenias-Improved activity

STUDY (Interferons)Peg Interferon α2b in “Early” MF

Cornell Lead: NCT01758588

STUDY (Activin - ActRIIA-IgG1Fc) Sotatercept (ACE 011)MDACC: NCT01712308

STUDY (Telomerase Inhibitor)Imetelstat (GRN163L)

Mayo Clinic (Rochester): NCT01731951

STUDY (JAK1 Inhibitor) INCB039110 (PH II)

NCT01633372

Imetelstat: A Telomerase Inhibitor

imetelstat binds to RNA template preventing maintenance of telomeres

Telomerase enzyme:• Reverse transcriptase comprised of an RNA component (hTR) and

a reverse transcriptase catalytic protein subunit (hTERT)

• Binds to the 3’ strand of DNA and adds TTAGGG nucleotide repeats to offset the loss of telomeric DNA occurring with each replication cycle

• Not active in somatic cells; transiently upregulated in normal hematopoietic progenitor cells to support controlled proliferation

• Highly upregulated in malignant progenitor cells, enabling continued and uncontrolled proliferation

Imetelstat:

• Proprietary: 13-mer thio-phosphoramidate oligonucleotide complementary to hTR, with covalently-bound lipid tail to increase cell permeability/tissue distribution

• Long half-life in bone marrow, spleen, liver (estimated human t½ = 41 hr with doses 7.5 – 11.7 mg/kg);

• Potent competitive inhibitor of telomerase: IC50 = 0.5-10 nM (cell-free)

• Target: malignant progenitor cell proliferation

(hTR)

– 37 –

(hTERT)

Tefferi et. al. ASH 2013

Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosis

– 10 –

Geron’s independent efficacy analysis of the first 22 MF patients enrolled in the study

Tefferi et. al. ASH 2013

Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosis

– 10 –

Geron’s independent efficacy analysis of the first 22 MF patients enrolled in the study

Tefferi et. al. ASH 2013

100 mg BID 200 mg BID 600 mg QD-20

0

20

5.0

-14.1

-9.9

Change in Spleen Volume at Week 12 by Dose Cohort

40

Per

cen

tag

e C

han

ge

Fro

m

Bas

elin

e at

Wee

k 12

n=7

n=9

*Only patients with baseline and week 12 data were included.

Median % Change in Spleen Volume*

n=38

INCB039910 ASH 2013- Mascarenhas et. al

Improvement in TSS at Week 12 by Dose Cohort

100 mg BID 200 mg BID 600 mg QD0

10

20

30

40

50

60

22.2

34.9

50.0

41

Per

cen

tag

e o

f P

atie

nts

Per

cen

tag

e C

han

ge

Fro

m

Bas

elin

e at

Wee

k 12

n=9 n=43

*Patients who discontinued prior to the week 12 visit were considered nonresponders; 20%-33% of patients in each group discontinued prior to week 12.†Only patients with baseline and week 12 data were included.

≥50% Reduction in TSS*100 mg BID 200 mg BID 600 mg QD

-100

-80

-60

-40

-20

0

-28.5

-45.8

-76.8

Median % Change in TSS†

n=10

n=6 n=34 n=8

INCB039910 ASH 2013- Mascarenhas et. al

Mean Hemoglobin Levels Over Time by Dose Cohort

0 2 4 6 8 10 129.0

9.5

10.0

10.5

11.0

11.5

12.0

12.5

13.0

42

0 2 4 6 8 10 129.0

9.5

10.0

10.5

11.0

11.5

12.0

12.5

13.0

Weeks Weeks

Mea

n (

±SE

M)

Hem

og

lob

in (

g/d

L)

Mea

n (

±SE

M)

Hem

og

lob

in (

g/d

L)

10 10 9 8 8 6 6 100 mg BID45 45 45 41 43 39 37 200 mg BID29 21 10 9 10 9 9 600 mg QD

7 7 7 6 6 4 424 24 24 22 23 21 2219 15 6 6 6 5 6

n, patients

Patients entering the study without transfusion requirements*

All Patients

*Receipt of 2 or more units of red blood cell product transfusions in the 12 weeks prior to day 1.

100 mg BID 200 mg BID 600 mg QD

100 mg BID200 mg BID600 mg QD

n, patients

INCB039910 ASH 2013- Mascarenhas et. al

MPNs – Cumulative BenefitsDifficult PV-ET

Clinical Status

Improved Symptom Burden

Improved Spleen Burden

Improved Survival

Improved Marrow Dysfunction

STUDY COMBINATION (PV)Ruxolitinib Vs. Hydroxyurea (RELIEF)

NCT01632904

STUDY (ET and PV) MPD-RC 112 Peg Inf a2a vs. Hydroxyurea (PH III)

NCT01259856

STUDY (ET and PV) MPD-RC 111 Peg Inf a2a AFTER Hydroxyurea

(PH III)NCT01259856

STUDY (PV) AOP Peg Inf a2a vs Hydroxyurea (PH III)

NCT01230775

FUTURE STUDY COMBINATIONJAK2 Inhibitor Plus PEG INF a 2a/b

Improved Vascular Event Risk (?PV)

Patient Goals & Input

Improving Symptom Burden/HR QOL

“Balancing” Spleen/ Cytoses/ Cytopenias

Extending Life

CURE

©2011 MFMER | 3133089-44

Individualizing MPN Pharmacotherapy

©2011 MFMER | 3133089-46

Acknowledgements Argentina Ana Clara Kneese, MDFederico Sackmann, MD Australia David M Ross  MBBS, PhDCecily Forsyth John Seymour, MBBS, PhD Karen Hall, MD Kate Burbury MD Tam Constantine, MD Canada Lynda Foltz, MDVikas Gupta, MD China Hsin-An Hou, MD Huan-Chau Lin, MD Hung Chang, MDMing-Shen Dai, MD Yuan-Bin Yu, MD Yung-Chen Su, MD Zhijian Xiao, MD Denmark Christen Lykkegaard Andersen, MD Hans Hasselbalch, MDFrance  Brigitte Dupriez, MD Jean-Jacques Kiladjian, MD Jean-Loup Demory MDMagali Demilly, PhD Germany Heike L. Pahl, PhD

Ireland

Mary Francis McMullen, MDIsraelMartin Ellis, MD Italy Alessandro M. Vannucchi, MD Francesco Passamonti, MD Giovanni Barosi, MD Tiziano Barbui, MD Netherlands Harry Schouten, MD, PhD Jan Jacques Michiels, MDKarin Klauke, MDPeter te Boekhorst, MD Sonja Zweegman, MD PhD Stephanie Slot, MD Suzan Commandeur, MD New Zealand Hilary Blacklock, MD Panama Francis Guerra, MDSingapore  Wee Joo Chng, MB ChB Spain  Ana Kerguelen Fuentes, MD Carlos Besses, MD Francisco Cervantes, MD Dolores Fernandez-Casados

Sweden  Andreasson Bjorn, MD

Elisabeth Ejerblad, MD Gunnar Birgegard, MD Jan Samuelsson, MD Johanna Ablesson, MD Peter Johansson, MD UK Anthony Green, MD Claire N. Harrison, MD Deepti Radia, MD Uruguay Pablo Muxi, MD USAAlison Moliterno, MD Brady Stein, MD MHS Casey O'ConnellCatriona Jamieson Daniel Rubin, ND Elizabth Hexner Hala Simm Jason Gotlib, MD Jeff Sloan, PhD Jessica Altman, MD Joseph Prchal, MD Kimberly Hickman Martin Tallman, MD Mike Boxer, MD   Olatoyosi Odenike, MD Robert Silver, MD Ross Levine, MD Soo Jin Kim Srdan Verstovsek, MD