Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in

primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential

thrombocythemia-myelofibrosis (PET-MF)Ruben A. Mesa,1 Miklos Egyed,2 Anita Szoke,3 Aleksandr Suvorov,4 Andrew Perkins,5

Jiri Mayer,6 Peter Ganly,7 Eric Jourdan,8 Harry C. Schouten,9 Patrizia Tosi,10 Charles Michael Farber,11 Pierre Zachee,12 Christof Scheid,13 James P. Dean,14

Paul Cernohous,14 Jyoti Nangalia,15 Jean-Jacques Kiladjian,16 Alessandro M. Vannucchi,17 Adam Mead,18 Claire N. Harrison19

1Mayo Clinic, Scottsdale, AZ; 2Kaposi Mor Teaching Hospital, Kaposvar, Hungary; 3lbert Szent-Györgyi Clinical Center, Universisty of Szeged, Szeged, Hungary; 4First Republican Clinical Hospital of Udmurtia, Izhevsk, Russia; 5ICON Cancer Care, Brisbane, Australia; 6University Hospital Brno, Brno,

Czech Republic; 7Christchurch Hospital, Christchurch, New Zealand; 8Centre Hospitalier Universitaire de Nîmes, Nîmes, France; 9University Hosp Maastricht, Maastricht, Netherlands; 10Ospedale "Infermi", Rimini, Rimini, Italy; 11Morristown Memorial Hospital, Carol G. Simon

Cancer Center, Morristown, NJ; 12ZNA Stuivenberg, Antwerp, Belgium; 13University of Cologne, Cologne, Germany; 14CTI BioPharma Corp., Seattle, WA; 15Cambridge Institute for Medical Research, Cambridge, United Kingdom; 16Hôpital Saint-Louis and Paris Diderot University, Paris, France;

17University of Florence, Florence, Italy; 18Oxford University Hospitals, Oxford, United Kingdom; 19Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom

Disclosures

• Employment – No relationships to disclose

• Leadership – No relationships to disclose

• Stock and other ownership interests – No relationships to disclose

• Honoraria – Novartis Healthcare A/S

• Consulting or advisory role – No relationships to disclose

• Speakers’ bureau – No relationships to disclose

• Research funding – CTI, Incyte, Gilead, Promedior, Genentech, Pharmessentia, Pfizer

• Patents, royalties, and other intellectual property – No relationships to disclose

• Expert testimony – No relationships to disclose

• Travel, accommodations and expenses – No relationships to disclose

• Other relationship – No relationships to disclose

Background

• Myelofibrosis is a rare hematologic malignancy, the symptoms of which have a substantial negative impact on both patient quality of life and overall survival1-3

• As early as 1 year from the time of diagnosis, the incidence of disease-related thrombocytopenia, anemia, and RBC transfusion requirements increase dramatically4

• Thrombocytopenia is a prognostic factor for shorter overall survival and risk of leukemic transformation5

• Current treatments have not demonstrated the ability to simultaneously improve splenomegaly, symptoms, and cytopenias in myelofibrosis patients

RBC, red blood cell.

1. Tefferi A, et al. Blood. 2013;122:1395-1398. 2. Mesa RA, et al. Cancer. 2007;109:68-76. 3. Geyer HL, et al. Blood. 2014;124:3529-3537. 4. Tefferi A, et al. Mayo Clin Proc. 2012;87:25-33. 5. Gangat N, et al. J Clin Oncol. 2010;29:392-397.

Kinase IC50 (nM)

JAK1 1280

JAK2wt 6.0

JAK2V617F 9.4

JAK3 18.3

TYK2 27.0

FLT3-ITD 13.4

FLT3D835Y 4.7

CSF1R 39.5

IRAK1 13.6

Pacritinib A Selective JAK2/FLT3 Inhibitor

Not associated with clinically significant treatment-emergent anemia or thrombocytopenia in clinical studies1

CSF1R, colony stimulating factor 1 receptor; FLT, FMS-like tyrosine kinase; IC50, half-maximal inhibitory concentration; IRAK1, interleukin-1 receptor–associated kinase; ITD, internal tandem duplication; JAK, Janus kinase; TYK, tyrosine kinase.

1. William AD, et al. J Med Chem. 2011;54:4638-465. 2. Hart S, et al. Leukemia. 2011;25:1751-1759.

PERSIST-1Study Design

• Stratification at randomization: platelet count, risk category, and region• Study endpoints

• Primary: proportion of patients achieving a ≥35% reduction in spleen volume (by MRI/CT) from baseline to Week 24

• Secondary: proportion of patients with ≥50% reduction in TSS from baseline to Week 24 on the Myeloproliferative Neoplasm Symptom Assessment Form

CT, computed tomography; Hgb, hemoglobin JAK, Janus kinase; MRI, magnetic resonance imaging; PET-MF, post-essential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; R, randomized; TSS, total symptom score.

Key Eligibility Criteria

PMF, PET-MF, or PPV-MF

Intermediate- or high-risk disease

Palpable spleen ≥5 cm

No exclusion for baseline platelet levels; stratified for platelet counts <100,000/µL and <50,000/µL

No exclusion for baseline Hgb levels

No prior treatment with JAK2 inhibitors

Best Available Therapy (BAT)a

excluding ruxolitinib

Pacritinib 400 mg qd

a Cross-over from BAT allowed after progression or after Week 24 assessment

R(2:1)

N=327

a As of data cut off: Jan 17, 2015. BAT, best available therapy; ITT, intent-to-treat; PAC, pacritinib.

Patient Dispositiona

Median Follow-up: 8.4 months (Range, 0.1-22.2)

PAC (ITT)n=220

BAT (ITT)n=107

Randomized 2:1

PAC (Safety)n=220

BAT (Safety)n=106

Discontinued: n=98 (92%)Adverse event: n=3 (3%)Patient withdrawal: n=3 (3%)Investigator decision: n=78 (73%)Progressive disease: n=12 (11%)Death: n=1 (1%)Non-compliance: n=1 (1%)

Discontinued: n=96 (44%)Adverse event: n=32 (15%)Patient withdrawal: n=28 (13%)Investigator decision: n=16 (7%)Progressive disease: n=10 (5%)Death: n=3 (1%)Other: n=7 (3%)

Ongoingn=9 (8%)

Ongoingn=124 (56%)

Crossed over to PACn=85 (79%)

Baseline Characteristics

a Derived from central laboratory data; b n=219 for PAC, n=106 for BAT; c n=218 for PAC, n=107 for BAT.BAT, best available therapy; CT, computed tomography; ECOG PS, Eastern Cooperative Oncology Group performance status; Int, intermediate; IPSS, International Prognostic Scoring System; JAK, Janus kinase; MF, myelofibrosis; MRI, magnetic resonance imaging; PAC, pacritinib.

Characteristic PAC(n=220)

BAT(n=107)

Median age, years (range) 67 (23-87) 65 (37-84)≥65 years, n (%) 135 (61) 55 (51)

Male, n (%) 125 (57) 60 (56)ECOG PS, n (%)

0-1 191 (87) 96 (90)2-3 29 (13) 11 (10)

MF diagnosis, n (%)Primary MF 144 (65) 59 (55)Post-polycythemia vera MF 48 (22) 33 (31)Post-essential thrombocythemia MF 27 (12) 15 (14)

IPSS score, n (%)a

Int-1 30 (14) 18 (17)Int-2 76 (35) 35 (33)High 106 (48) 51 (48)

Median spleen length by physical exam, cm (range)b 12 (4-33) 12 (4-30)Median spleen volume by MRI/CT, cm3 (range)c 2223 (472-7948) 2367 (436-5404)JAK2V617F positive, n (%) 154 (70) 92 (86)

Baseline CharacteristicsHematology

BAT, best available therapy; BM, bone marrow; Hgb, hemoglobin; MF, myelofibrosis; PAC, pacritinib.

Characteristic PAC(n=220)

BAT(n=107)

BM biopsy completed, n (%) 219 (100) 107 (100)Reticulin and collagen fibrosis staging

MF 0-1 32 (15) 18 (17)MF 2-3 180 (82) 83 (78)Missing 7 (3) 6 (6)

Peripheral blasts, n (%)<1% 78 (35) 44 (41)≥1% 94 (43) 38 (36)

<5% 159 (72) 74 (69)≥5% 13 (6) 8 (7)Missing 48 (22) 25 (23)

White blood cell count, n (%)≤25 ×109/L 177 (80) 80 (75)>25 ×109/L 43 (20) 26 (24)

Hemoglobin, n (%)<10 g/dL 84 (38) 47 (44)≥10 g/dL 136 (62) 59 (55)

Platelet count, n (%)<50,000/μL 35 (16) 16 (15)≥50,000 to <100,000/μL 37 (17) 18 (17)≥100,000/μL 148 (67) 73 (68)

BAT Treatment

WHO Drug Term, n (%)BAT

(n=107)WHO Drug Term, n (%)

BAT(n=107)

Watch and wait (no active Tx) 27 (25.5)

Hydroxycarbamide 59 (55.7) Anagrelide 1 (0.9)

Prednisone 7 (6.6) Azacitidine 1 (0.9)

Interferon alfa 6 (5.7) Epoetin alfa 1 (0.9)

Thalidomide 6 (5.7) Epoetin theta 1 (0.9)

Danazol 4 (3.8) Everolimus 1 (0.9)

Prednisolone 4 (3.8) Lenalidomide 1 (0.9)

Busulfan 2 (1.9) Mercaptopurine 1 (0.9)

Cytarabine 2 (1.9) Methotrexate 1 (0.9)

Peginterferon alfa-2a 2 (1.9) Vincristine 1 (0.9)

BAT, best available therapy; Tx, treatment.

Spleen Volume Reduction ≥35%At Week 24 as Assessed by MRI/CT

a Evaluable Population: patients had both baseline and Week 24 spleen assessment by MRI or CT; n=168 for PAC and n=85 for BAT.BAT, best available therapy; CT, computed tomography; ITT, intent to treat; MRI, magnetic resonance imaging; PAC, pacritinib.

• ITT population: 19.1% vs 4.7%, PAC vs BAT (p=0.0003)

• Evaluablea population: 25.0% vs 5.9%, PAC vs BAT (p=0.0001)C

han

ge

Fro

m B

asel

ine,

%

35% decrease

Patientsa

60

01020304050

-10-20-30-40-50-60-70-80-90

-100

PAC (n=168) BAT (n=85)

Spleen Volume Reduction ≥35%Patients With Baseline Thrombocytopenia

a Patients had both baseline and Week 24 spleen assessment by MRI or CT; n=168 for PAC and n=85 for BAT.

BAT, best available therapy; CT, computed tomography; ITT, intent to treat; MRI, magnetic resonance imaging; PAC, pacritinib.

ITT Evaluablea

0%

10%

20%

30%

40%

22.9%

16.7%

33.3%

23.5%

0% 0% 0% 0%

Pat

ien

ts

p=0.0451

p=0.0370

p=0.0086

p=0.0072

PAC BAT

<50,000/μL <100,000/μL <50,000/μL <100,000/μL

Correlation of SVR With OS By TreatmentLandmark Analysis at Week 24

a Reference to < 10% SVR as assessed by MRI/CT.

BAT, best available therapy; CT, computed tomography; MRI, magnetic resonance imaging; NA, not applicable; OS, overall survival; SVR, spleen volume reduction.

SVR Hazard Ratio (95% CI)a p-value

Pacritinib

≥10% to <20% (n=37) 0.15 (0.02, 1.18) 0.071

≥20% (n=98) 0.26 (0.09, 0.76) 0.014

BAT

≥10% to <20% (n=5) 2.31 (0.50, 10.81) 0.287

≥20% (n=11) NA NA

a TSS and TSS 2.0 combined; b n=220 for PAC and n=107 for BAT.

BAT, best available therapy; ITT, intent to treat; PAC, pacritinib; TSS, total symptom score.

Patients Achieving ≥50% Reduction in TSSa

At Week 24 (ITT Populationb)

Series10%

5%

10%

15%

20%

25%

30%

0.245

0.2

0.25 0.243

0.065 0.0630.088

0.055

Pat

ien

ts

All Patients

Platelet Subgroup

<50,000/μL <100,000/μL ≥100,000/μL

p<0.0001

p=0.4086

p=0.0677 p=0.0004PAC BAT

a TSS and TSS 2.0 combined; b Patients had both baseline and Week 24 TSS value; n=132 for PAC and n=71 for BAT.BAT, best available therapy; PAC, pacritinib; TSS, total symptom score.

Patients Achieving ≥50% Reduction in TSSa

At Week 24 (Evaluable Populationb)

Series10%5%

10%15%20%25%30%35%40%45%50%

0.409

0.318

0.419 0.404

0.099 0.1110.167

0.075

Pat

ien

ts

All Patients

p<0.0001

p=0.3791

p=0.0790 p<0.0001PAC BAT

Platelet Subgroup

<50,000/μL <100,000/μL ≥100,000/μL

Patients Achieving ≥50% Reduction in TSSReduction Over Time (Evaluable Populationa)

a Patients had both baseline and the corresponding post-baseline TSS value.BAT, best available therapy; ITT, intent to treat; TSS, total symptom score.

Weeks

50

45

40

35

30

25

20

15

10

5

0

Pat

ien

ts w

ith

≥50

% R

edu

ctio

n i

n

Tota

l S

ymp

tom

Sco

re,

%

PACBAT

1 4 8 12 16 20 24

Mean % Change in Body Weight Over Time

BAT, best available therapy; PAC, pacritinib.

4 8 12 16 20 24 36

-0.5

0

0.5

1

1.5

2

2.5

PAC BAT

Mea

n C

ha

ng

e F

rom

Bas

eli

ne

, %

Baseline Weeks

Series1-20

0

20

40

60

80

100

Weeks

Me

an

% C

ha

ng

e i

n H

gb

(±

SE

M)

Hemoglobin Over TimeBy Central Laboratory

BAT, best available therapy; BL, baseline; Hgb, hemoglobin; SEM, standard error of the mean.

Mean % Change in Hgb (± SEM) Mean Hgb (g/dL) (± SEM)

Safety Population Patients With Baseline Hgb <10 g/dL

Mea

n H

gb

(g

/dL

) (±

SE

M)

Weeks

10

9.5

9

8

8.5

PACBAT

PACBAT

BL 3 4 8 12 16 20 24 BL 3 4 8 12 16 20 24

Platelets Over TimeBy Central Laboratory

a Based on linear regression using mixed model.BAT, best available therapy; BL, baseline; PAC, pacritinib; SEM, standard error of the mean.

Mean Platelets×109/L (± SEM)Mean % Change Platelets (± SEM)

Safety Population Patients With Baseline Platelets <50,000/μL

Mea

n %

Ch

ang

e P

late

lets

(±

SE

M)

Weeks

100

80

60

-20

40

20

0

PACBAT

Mea

n P

late

lets

×10

9 /L

(±

SE

M)

Weeks

60

50

40

0

30

20

10

PACBAT

p=0.0034a

p=0.1927a

BL 3 4 8 12 16 20 24 BL 3 4 8 12 16 20 24

RBC Transfusion Independence

a ≥ 6units/90 days.BAT, best available therapy; PAC, pacritinib; RBC, red blood cell.

• At baseline, 15.9% PAC and 14.0% BAT patients were RBC transfusion dependent, per Gale criteriaa

Series10%

5%

10%

15%

20%

25%

30%25.7%

0%

PACBAT

p=0.043P

atie

nts

Patients Achieving Transfusion Independence

Most Common Adverse EventsWithin 24 Weeks (by Investigator)

AE, adverse event; BAT, best available therapy; PAC, pacritinib.

All Grades Grade 3 Grade 4

Adverse Event, n (%) PAC(n=220)

BAT(n=106)

PAC(n=220)

BAT(n=106)

PAC(n=220)

BAT(n=106)

Non-hematologic (>10%)

Diarrhea 117 (53.2)

13 (12.3) 11 (5.0) 0 0 0

Nausea 59 (26.8)

7 (6.6) 2 (0.9) 0 0 0

Vomiting 35 (15.9)

6 (5.7) 2 (0.9) 0 0 0

Peripheral edema 16 (7.3) 12 (11.3) 1 (0.5) 1 (0.9) 0 0

Pyrexia 11 (5.0) 11 (10.4) 4 (1.8) 1 (0.9) 0 0

Hematologic (>2%)

Anemia 49 (22.3) 21 (19.8) 32 (14.5) 13 (12.3) 5 (2.3)  3 (2.8)

Thrombocytopenia 37 (16.8) 14 (13.2) 12 (5.5) 7 (6.6) 14 (6.4) 3 (2.8)

Neutropenia 8 (3.6) 2 (1.9) 1 (0.5) 1 (0.9) 4 (1.8) 1 (0.9)

• 10% of patients in the PAC arm had dose reductions due to AE (3% diarrhea; 2% anemia)

Side Effects of InterestGastrointestinal

• Majority of cases occur within the first 2 weeks

• Benefit (SVR, TSS) preserved irrespective of any gastrointestinal side effects

• More frequent in patients aged >65 years and patients with platelets <100,000/μL  

• Diarrhea resolves in a little over 1 week irrespective of grade with antimotility agents

• Diarrhea resulted in discontinuation or  dose interruption (average 1 week) in only 3 and 13 patients, respectively

SVR, spleen volume reduction; TSS, total symptom score.

Conclusions

MPN, myeloproliferative neoplasm; RBC, red blood cell; TSS, total symptom score.

• Significantly greater proportion of patients with ≥35% reduction of spleen volume, regardless of baseline platelet count (p=0.0003)

• Significant treatment effect (p<0.05) in highest-risk subset (baseline platelets <50,000/μL)

• Significant reduction in TSS (p<0.0001)

• Significantly higher proportion of patients became RBC transfusion independent (p<0.05)

• Patients with baseline platelets <50,000/μL had mean increase in platelet counts of 35% by Week 24

• Based on preliminary data, pacritinib may be disease modifying and warrants combination studies with other potentially disease-modifying agents in MPNs

PERSIST-2Study Design

CT, computed tomography; JAK, Janus kinase; MRI, magnetic resonance imaging; TSS, total symptom score.

Status: reached agreement with FDA on SPA October 2013

Sites: North America, Europe, Russia, and Oceania

Anticipated patient accrual: ~ 300

Principal investigator: Srdan Verstovseka Crossover from BAT allowed after progression or assessment of the primary endpoint.

b BAT may include ruxolitinib at the approved dose for platelet count

Co-Primary Endpoints

% of patients achieving

≥35% reduction in

spleen volume from baseline

to Week 24 (MRI/CT)

Patients achieving ≥50%

reduction in TSS from

baseline to Week 24

Best available therapy (BAT)b

Pacritinib400 mg qd

Pacritinib200 mg bid

Eligibility Criteria

Patients with platelet counts ≤ 100,000/µL,

prior/current JAK2 therapy allowed

1:1:1

Randomizationa

N=300

Acknowledgments

• We would like to thank all the patients, investigators, and personnel who contributed to this study

• Medical editorial assistance funded by CTI Biopharma Corporation was provided by Nexus Global Group Science, LLC