JAK inhibitors update from ASH

Claire Harrison

Guy’s and St Thomas’ Hospitals

London

INCB18424 - Ruxolitinib – a JAK 1 and 2 inhibitor

Structure and activity in biochemical and cellular assays

Enzyme IC50 mean±SD (nM),at 1 mM ATP1

JAK1 3.3±1.2

JAK2 2.8±1.2

JAK3 428±243

TYK2 19±3.2

Ba/F3-EpoR-JAK2V617F cell proliferation assay1

pJAK2/pSTAT5/pERK (Ba/F3-JAK2V617F cells)1

IC50

127±17 nM (mean±SD) 128–320 nM

Ruxolitinib demonstrated >100-fold selectivity against a broad panel of kinases

Quintás-Cardama et al. Blood 2010;115:3109–17.

COMFORT: Phase 3 trials with ruxolitinib (INCB018424)

COntrolled MyeloFibrosis study with ORal JAK inhibitor Therapy

COMFORT- 1 COMFORT- 2

Design Randomized, Double-blind, Placebo-controlled

Randomized, compared to best-available therapy

Random 1:1 2:1

Location USA, Australia, Canada Europe (9 countries)

Patient number 309 219

Primary-end point

Reduction of spleen size >35% by MRI or CT at 24-w

Reduction of spleen size >35% by MRI or CT at 48-w

Status Reached primary and secondary end-point of symptomatic improvement by MSAF *

Reached primary end-point

Verstovsek S N Engl J Med. 2012;366:799-807; Harrison C et al. N Engl J Med. 2012;366:787-798

COMFORT-I Primary Endpoint: % of Patients With ≥35% Decrease in Spleen Volume at Week 24

• Patients who discontinued prior to week 24 or crossed over prior to week 24 were counted as non-responders

5

Ruxolitinib Arm

COMFORT-I COMFORT-II

Week 24 Week 24 Week 48

≥ 35% spleen vol. ↓, n (%) 95% CI P value

65 (41.9)a

(34.1, 50.1)< 0.0001

46 (31.9)b

(24.4, 40.2)< 0.0001

41 (28.5)a

(21.3, 36.6)< .0001

Percentage spleen vol. ↓, mean (SD) Median

–31.6 (18.9)–33.0

–29.2 (19.5)–27.5

–30.1 (22.1)–28.3

Spleen progression criteria ≥ 25% inc from BL ≥ 25% inc from nadir

aPrimary endpoint; bKey secondary endpoint.

40

20

0

-20

-40

-60

-80

Ruxolitinib

COMFORT-II At Week 48a

P < .0001

Chan

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Bas

elin

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COMFORT-I At Week 24a

P < .0001

Ruxolitinib

COMFORT-I and COMFORT-IIComparison of Spleen Volume Reductions

35% decrease

Chan

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rom

Bas

elin

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Percent Change From Baseline in Spleen Volume by JAK2V617F Mutation Status

At Week 48a

JAK2V617F positive (n = 75)Ruxolitinib

JAK2V617F negative (n = 22)Unknown mutation status (n = 1)

BATJAK2V617F positive (n = 24)JAK2V617F negative (n = 8)Unknown mutation status (n = 2)

Primary endpoint

• At week 48, the vast majority of patients receiving ruxolitinib experienced spleen volume reductions, including JAK2V617F-positive (88% [66/75]) and JAK2V617F-negative (91% [20/22]) patients

Chan

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12a For patients with spleen volume assessments by MRI/CT at both baseline and week 48. Harrison CN,. Blood (ASH) 2011:Abstract 279.

Total Symptom Score: Modified MFSAF v2.0

•Questions 1 to 6 comprise Total Symptom Score

•Question 7 queries inactivity, an impact of MF

•Administered daily

0 (Absent) 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)

1.During the past 24 hours, how severe were your worst night sweats (or feeling hot or flushed) due to MF?

2. During the past 24 hours, how severe was your worst itchiness due to MF?

3. During the past 24 hours, how severe was your worst abdominal discomfort (feel uncomfortable, pressure or bloating) due to MF?

4. During the past 24 hours, how severe was your worst pain under the ribs on the left side due to MF?

5. During the past 24 hours, what was the worst feeling of fullness (early satiety) you had after beginning to eat due to MF

6. During the past 24 hours, how severe was your worst bone or muscle pain due to MF (diffuse non-joint or arthritis pain)?

7. During the past 24 hours, what was the worst degree of inactivity (including work and social activities) you had due to MF?

8Mesa RA, et al. Leukemia Res. 2009;33:1199-1203.

9

Mean % Change in Individual Symptoms

• For all individual symptoms above, comparisons between ruxolitinib- and placebo-treated groups were highly statistically significant (P < 0.01)

Ruxolitinib

Placebo

Abdominaldiscomfort

InactivityPain underleft ribs

Earlysatiety

Nightsweats

Itching Bone/musclepain

n=100 n=86 n=96 n=90 n=77 n=89 n=97

n=124 n=109 n=122 n=103 n=98 n=108 n=119

Mea

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Bas

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Wo

rsen

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Imp

rove

me

nt

Worst Lab Value on Study*,†

Grade 1

n (%)

Grade 2

n (%)

Grade 3

n (%)

Grade 4

n (%)

Hemoglobin

Ruxolitinib (n = 146) 24 (16) 55 (38) 50 (34) 12 (8)

BAT (n = 70) 16 (23) 28 (40) 15 (21) 7 (10)

Platelet count

Ruxolitinib (n = 146) 46 (32) 41 (28) 9 (6) 3 (2)

BAT (n = 69) 11 (16) 4 (6) 3 (4) 2 (3)*Occurring on the randomized treatment phase only.†Percentage is based on baseline total n.

Anemia and Thrombocytopenia

• The majority of patients (63% ruxolitinib; 67% BAT) had grade 1/2 anemia at baseline • In both arms, all patients who entered the study had grade 0-1 thrombocytopenia at baseline• Discontinuations: 1 patient in each arm due to thrombocytopenia and 1 patient due to anemia

on the ruxolitinib arm

Nonhematologic Adverse Events Regardless of Study Drug Relationship (≥ 10% in Any Group) COMFORT-II

Ruxolitinib (n = 146) All grades Grades 3/4

BAT (n = 73) All grades Grades 3/4

Nausea

Diarrhea

Pain in extremity

Headache

Pruritus

12

No serious adverse effects on dose interruption…….

Srdan Verstovsek1, Ruben A. Mesa2, Jason Gotlib3, Richard S. Levy, Vikas Gupta5, John F. DiPersio6, John V. Catalano7, Michael W.N. Deininger8*, Carole B. Miller9, Richard T. Silver10, Moshe Talpaz11,

Elliott F. Winton12, Jimmie H. Harvey Jr.13, Murat O. Arcasoy14, Elizabeth O. Hexner15, Roger M. Lyons16, Ronald Paquette17, Azra Raza18, Kris Vaddi4, Susan Erickson-Viitanen4,

William Sun4, Victor Sandor4 and Hagop M. Kantarjian1

1University of Texas MD Anderson Cancer Center, Houston, TX; 2Mayo Clinic, Scottsdale, AZ; 3Stanford Cancer Institute, Stanford, CA; 4Incyte Corporation, Wilmington, DE; 5Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada;

6Washington University School of Medicine, St. Louis, MO; 7Frankston Hospital and Department of Clinical Haematology, Monash University, Frankston, Australia; 8Oregon Health & Science University, Portland, OR; 9Saint Agnes Cancer Institute, Baltimore, MD; 10Weill Cornell Medical Center, New York, NY; 11University of Michigan, Comprehensive Cancer Center, Ann

Arbor, MI;12Emory University School of Medicine, Atlanta, GA; 13Birmingham Hematology and Oncology, Birmingham, AL; 14Duke University Health System, Durham, NC; 15Abramson Cancer Center at The University of Pennsylvania, Philadelphia, PA;

16Cancer Care Centers of South Texas/US Oncology, San Antonio, TX; 17UCLA Division of Hematology/Oncology, Los Angeles, CA; 18Columbia Presbyterian Medical Center, New York, NY

*Currently at Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT

Long-Term Outcome of Ruxolitinib Treatment in Patients With Myelofibrosis:

Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall

Survival Advantage in COMFORT-I

Durability of Spleen Volume Reduction

• 90/155 (58%) had a 35% reduction at any time point during the study

• 64% maintained a ≥35% reduction for at least 2 years

≥35% reduction: Time from first 35% reduction to <35% reduction and 25% increase from nadir.

≥10% reduction: Time from first 35% reduction to <10% reduction from baseline.

≥10% reduction (n=90)

≥35% reduction

1.0

0.8

0.6

0.4

0.2

00 8 16 24 32 40 48 72 80 88 104 112

Pro

bab

ilit

y

Weeks from Onset

9656 64

84 75 72 63 57 52 47 41 35 4

No. at risk

90 4 443

EORTC QLQ-C30 Over Time

Ruxolitinib Placebo

Global Health Status/QoL

Me

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Fro

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BL 12 24 36 48 60 72 84 96

Weeks

20

10

0

-5

-10

-15

15

5

Physical Functioning

10

-10

15

-5

0

5

BL 12 24 36 48 60 72 9684Weeks

Fatigue

BL 12 24 36 48 60 72 84 96

10

0

-10

-15

-20

-25

5

-5

Weeks

Arrows indicate improvement.

Role Functioning

15

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10

-10

0

-20BL 12 24 36 48 60 72 9684

Weeks

5

-5

-15

Overall Survival: ITT Population

Note: For this unplanned analysis, P-values are descriptive and nominally significant.*Age was the only baseline characteristic that differed significantly between treatment groups as reported in Verstovsek S, et al. N Engl J Med

2012;366:799-807 (median age: ruxolitinib, 66 years; placebo, 70 years; P<0.05).

Placebo

Ruxolitinib

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84 96 108 120 132

Su

rviv

al P

rob

abil

ity

Weeks

148 142 133 117 111 102 95 74 32 7Placebo

154 148 145 136 125 121 113 96 44 6Ruxolitinib

No. at risk

154

155

HR=0.58 (95% CI: 0.36, 0.95); P=0.028

Age adjusted HR*=0.61 (95% CI: 0.37, 0.99); P=0.040

No. of deaths: Ruxolitinib=27; Placebo=41

Median follow up: 102 weeks

• Platelet counts remain stable with longer-term therapy

Mea

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10

-10

-30

-40

-60

0

-20

BL 12 24 36 48 60 72 84 96

Weeks

-50

Ruxolitinib Placebo

Median platelet count at baseline: Ruxolitinib, 262.0×109/L; Placebo, 238.0×109/L.

Mean Platelet Counts Over Time

Long-Term Efficacy, Safety, and Survival Findings From COMFORT-II, a Phase 3 Study Comparing Ruxolitinib With Best Available Therapy for the Treatment of Myelofibrosis

Francisco Cervantes,1 Jean-Jacques Kiladjian,2 Dietger Niederwieser,3 Andres Sirulnik,4 Viktoriya Stalbovskaya,5 Mari McQuitty,4 Deborah S. Hunter,6 Richard S.

Levy,6 Francesco Passamonti,7 Tiziano Barbui,8 Giovanni Barosi,9 Heinz Gisslinger,10 Alessandro M. Vannucchi,11 Laurent Knoops,12 Claire N. Harrison13

1Hospital Clínic, IDIBAPS, Barcelona, Spain; 2Hôpital Saint-Louis et Université Paris Diderot, Paris, France; 3University of Leipzig, Leipzig, Germany; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA;

5Novartis Pharma AG, Basel, Switzerland; 6Incyte Corporation, Wilmington, DE, USA; 7Ospedale di Circolo e Fondazione Macchi, Varese, Italy; 8A.O. Ospedali Riuniti di Bergamo, Bergamo, Italy; 9IRCCS Policlinico San

Matteo Foundation, Pavia, Italy; 10Medical University of Vienna, Vienna, Austria; 11University of Florence, Florence, Italy; 12Cliniques Universitaires Saint-Luc and de Duve Institute, Université catholique de Louvain,

Brussels, Belgium; 13Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

Draft Oral Presentation

Duration of Spleen Response

19

Loss of response: no longer a ≥ 35% reduction that is also a > 25% increase over nadir.

• 58% of patients maintain a response at week 84

• The median duration of spleen response has not yet been reached

1.0

Pro

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Weeks

0 12 24 36 48 60 72 84 96

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Ruxolitinib

No. of PatientsEventsCensored

7018 (25.7%)52 (74.3%)

10

1 (100%)

Ruxolitinib BAT

Draft Oral Presentation

1.0

Pro

ba

bil

ity

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Weeks0 24 1209648 72 144

BAT

Ruxolitinib

Overall Survival

14673

136 30109127 116 061 114551 49 0

n =

No. of PatientsEventsCensored

14620 (13.7%)

126 (86.3%)

7316 (21.9%)57 (78.1%)

Ruxolitinib BAT

20

• Suggests a relative reduction in the risk of death with ruxolitinib compared with BAT (HR = 0.51; 95% CI: 0.26-0.99)

Biological effects beyond spleen and symptoms?

Subjects With ≥ 20% Absolute Allele Burden Reduction at Week 48 or Week 72

• Among patients who achieved a ≥ 20% reduction in allele burden, 39% had PMF, 39% had PPV-MF, and 22% had PET-MF

– This distribution was similar to that of the overall study population

0 6 12 24 48 72 84 96

0

20

40

60

80

JA

K2

V6

17

F A

lle

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urd

en

(%

)

Time (weeks)

PET

PMF

PPV

Responders (≥ 35% Spleen Volume Reduction at Week 48) by Absolute Allele Burden Reduction Status

N = 16 24 14 9 2315 8 13N =

%

%%

%

%

%

%

%

• In the ruxolitinib arm, a higher proportion of patients with a ≥ 20% allele burden reduction achieved a ≥ 35% reduction in spleen volume compared with those with a < 10% reduction at both week 48 and week 72

• There were no responders in the BAT arm

Per

cent

age

of R

espo

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Eac

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Bur

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Red

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roup

Phase 3 COMFORT studies • First phase 3 studies in MF• Highly significant reduction of spleen volume

and resolution of disabling symptoms• Median duration of response NOT reached• BOTH studies demonstrate survival

advantage

• Effective regardless of JAK V617F status

• Anaemia and thrombocytopenia occur but no increase in grade 4

• No new safety features including no AEs related to discontinuation after 2 year update

Verstovsek et al, ASH 2011 abstract 3851

Spleen Reduction by Palpation on Ruxolitinib Implies Survival Advantage

Patients with a confirmed reduction >50% of spleen size had better survival than those with <25%

Exploring different strategies for use of JAK inhibitors

• Earlier disease?

• Other drugs?

• Combination strategies?

Courtesy of Ruben Mesa

Trials with Other JAK2 Inhibitors in MF

Pardanani et al. JCO 2011; 29:789-96. Pardanani et al. Blood 201; 116:206 (abstract) 28

TG101348/SAR302503 CYT387Study characteristics Phase I, dose escalation Phase I/II, dose escalation

Patients, N 59 60

MTD 680 mg/d, G3 elevated amylase 300 mg/d, G3 elevated lipase, headache

Spleen reduction , CI 45% 47-53%

Constitutional symptoms YES YES

Leukocytosis, Thrombocytosis YES, 72%

V617F allele burden YES, 39-45%Anaemia response NO YES, 50-57% CIFibrosis response YES ?G3/4 haematological toxicity Anaemia 35%, thrombocytopenia

24%, neutropenia 10%Thrombocytopenia 25%

Side effects, non-haematological Nausea, vomiting (G3, 3%) Modest. “First-dose effect" with grade 1 light-headedness and hypotension

03/03/1330

SAR302503 Phase III Study Design

Multinational, multicenter, double blind, placebo-controlled randomized study

No Stratification factorRandomization 1/1/1

RANDOMI

Z A TI

ON

Q 4 weeksSAR302503 500mgDaily oral doses

Q 4 weeksSAR302503 500mgDaily oral doses

75 pts

75 pts

- Intermediate-2 or High risk Primary MF

-Post-Polycythemia Vera Myelofibrosis

-Post-Essential Thrombocythemia

Myelofibrosis

- Intermediate-2 or High risk Primary MF

-Post-Polycythemia Vera Myelofibrosis

-Post-Essential Thrombocythemia

Myelofibrosis

Cross Cross over 1/1over 1/1 EOT

75 pts Q 4 weeksSAR302503 400mgDaily oral doses

Q 4 weeksSAR302503 400mgDaily oral doses

Q 4 weeksPlaceboDaily oral doses

Q 4 weeksPlaceboDaily oral doses

End of C6 End of C6 or PDor PD

End End of C6 of C6

• 225 pts, Sites ~125, Recruitment: 9 months, 25 countries• Safety data monitored by DMC (Q 6 months)• Cross over possible

SAR302503 Phase II Study Design: ARD12181JAKARTA 2

32

Phase 2, single arm, multicenter, open-label study

Dose regimen • SAR302503 once daily, • Starting dose: 400mg/day • Continuously in 28-day cycles• Titration allowed: 200mg, 300mg, 400mg, 500mg or 600mg

Dose regimen • SAR302503 once daily, • Starting dose: 400mg/day • Continuously in 28-day cycles• Titration allowed: 200mg, 300mg, 400mg, 500mg or 600mg

- Subjects who previously received Ruxolitinib

treatment for PMF or Post-PV MF or Post-ET MF or PV

or ET for at least 14 days and discontinued the treatment for at least 14 days prior to

study entry

- Intermediate or High risk Primary MF

- Post-Polycythemia Vera Myelofibrosis

Post-Essential Thrombocythemia

Myelofibrosis according to the 2008 World Health

Organization (WHO) criteria

- Subjects who previously received Ruxolitinib

treatment for PMF or Post-PV MF or Post-ET MF or PV

or ET for at least 14 days and discontinued the treatment for at least 14 days prior to

study entry

- Intermediate or High risk Primary MF

- Post-Polycythemia Vera Myelofibrosis

Post-Essential Thrombocythemia

Myelofibrosis according to the 2008 World Health

Organization (WHO) criteria

70 pts

• Primary endpoint: • % of patients who achieve ≥35% reduction in spleen volume from baseline at C6 EOC by MRI/CT.

• Secondary endpoint:• - % of subjects with a ≥50% reduction from baseline to the end of Cycle 6 in the total symptom

score using the modified MFSAF• Safety, PK/PD, JAK2V617F allele burden, JAK-STAT and other signaling pathways, OS

Recent amendment changing discontinuation period from 30 days to 14 days

Country participation

Austria (AT)2 sites (2 pts)

Italy (IT)4 sites (4 pts)

Belgium (BE)3 sites (6 pts)

The Netherlands (NL)2 sites (11 pts)

Canada (CA)1 site (2 pts)

Spain (SP)3 sites (3 pts)

France (FR)6 sites (8 pts)

United Kingdom (UK)1 site (2 pts)

Germany (DE)7 sites (11 pts)

United States21 sites (21 pts)

10 Countries – 50 Sites – 70 patients

Data cut off: December, 4

• 26 Subjects Enrolled at 12 sites (6 Countries)

• 23 Subjects under treatment 

Exploring different strategies for use of JAK inhibitors

• Earlier disease? • Other drugs?

• Combination strategies?Rationale

•To reduce unwanted side effects (anaemia, thrombocytopenia) without compromising response

•To increase or broaden the benefits seen with JAK inhibitors

Potential combination strategiesClass Molecule

In vitro study

Clinical trial

Selected References

ImmunomodulatorsPomalidomide Tefferi et al. JCO2009;27:4563-9.

Lenalidomide Mesa et al. Blood 2010;116:4436-8

mTOR inhibitors Everolimus Guglielmelli et al . Blood 2011;118:2069-76

Hypomethylating agents

Azacitidine Mesa et al. Leukemia 2009; 23:180-2

Decitabine Danilov et al. BJH 2009; 145:131-2

Givinostat Rambaldi et al. BJH 2010; 150:446-55

Panobinostat De Angelo et al (ASH annual Meeting Abstract). 2010;276

Obatoclax mesylate

Parikh et al. Clin Lymph Myel Leuk 2010; 10:285-9

ABT-737 Lu et al. Blood.2010; 116:4284-7

PU-H71 Levine et al. JCI 2010; 120:3578-93

PEGASYS Kiladjian et al Blood 2010; 112, 1746

Panobinostat & Ruxolitinib Combo in MF patientsPhase Ib design

37

Panobinostat & Ruxolitinib Combo in mouse models of JAK2V617F-driven diseaseEffects on bioluminescence

Baffert eta al Blood 2011, Abstract 798, ASH 201

- Splenomegaly is a negative risk factor for survival after Allo-BMT

- Significant improvement in performance status rapid onset no major problem with drug withdrawal i.e. patients are fitter

Favourable effects upon cytokine storm and potential effects upon GVHD

Combination with BMT??

Current MPN Trials in the UK

Academic -open• PT-1 amended

– Low risk– Intermediate risk closed expect results next year

• MAJIC for HC resistant PV and ET• PEGASYS vs HC for newly diagnosed ET or PV

Unfunded but in process• JAKi pre-BMT• SAR302503 + HDAC• Ruxolitinib + azacytadine in sAML

Trials• SAR302503

JAKARTA phase 3 –------ Closed UK highest recruiter

In ET/PV phase 2; 8 sites selected just reopening

JAKARTA-2 in MF resistant of intolerant to ruxolitinib

• Pacritinib SB1518 – PERSIST 1 and 2

Vs placebo in MF no lower limited for platelets count prior ruxolitinib allowed.

• ?? CYT 387 phase III

In Myelofibrosis

• Phase 1 ruxolitinib MF low platelets

• Phase 1 ruxolitinib PLUS panobinostat Phase 1 ruxolitinib PLUS PI3 kinase inhibitor

• Phase 1 ruxolitinib PLUS smoothened inhibitor

• To come smoothened inhibitor alone