JAK inhibitors update from ASH

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JAK inhibitors update from ASH
Claire Harrison Guys and St Thomas
Hospitals London
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INCB18424 - Ruxolitinib a JAK 1 and 2 inhibitor
Structure and activity in biochemical and
cellular assays
Enzyme IC50 meanSD (nM), at 1 mM ATP1
JAK1 3.31.2
JAK2 2.81.2
JAK3 428243
TYK2 193.2
Ba/F3-EpoR-JAK2V617F cell proliferation assay1 pJAK2/pSTAT5/pERK (Ba/F3-JAK2V617F cells)1
IC50 12717 nM (meanSD) 128320 nM
Quintás-Cardama et al. Blood 2010115310917.
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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 11 21
Location USA, Australia, Canada Europe (9 countries)
Patient number 309 219
Primary-end point Reduction of spleen size gt35 by MRI or CT at 24-w Reduction of spleen size gt35 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. 2012366799-807
Harrison C et al. N Engl J Med. 2012366787-798
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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

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COMFORT-I and COMFORT-IIComparison of Spleen
Volume Reductions
COMFORT-II At Week 48a
COMFORT-I At Week 24a
P lt .0001
P lt .0001
Change From Baseline,
Change From Baseline,
35 decrease
Ruxolitinib
Ruxolitinib
Ruxolitinib Arm COMFORT-I COMFORT-II COMFORT-II
Ruxolitinib Arm Week 24 Week 24 Week 48
35 spleen vol. ?, n () 95 CI P value 65 (41.9)a (34.1, 50.1) lt 0.0001 46 (31.9)b (24.4, 40.2) lt 0.0001 41 (28.5)a (21.3, 36.6) lt .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 25 inc from nadir
aPrimary endpoint bKey secondary endpoint.
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Percent Change From Baseline in Spleen Volume by
JAK2V617F Mutation Status
At Week 48a
Change From Baseline,
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

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Harrison CN,. Blood (ASH) 2011Abstract 279.
a For patients with spleen volume assessments by
MRI/CT at both baseline and week 48.
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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?
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Mesa RA, et al. Leukemia Res. 2009331199-1203.
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Mean Change in Individual Symptoms

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

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Anemia and Thrombocytopenia
Worst Lab Value on Study, Worst Lab Value on Study, Worst Lab Value on Study, 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. Occurring on the randomized treatment phase only. Percentage is based on baseline total n. Occurring on the randomized treatment phase only. Percentage is based on baseline total n. Occurring on the randomized treatment phase only. Percentage is based on baseline total n. Occurring on the randomized treatment phase only. Percentage is based on baseline total n.

• 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

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Nonhematologic Adverse Events Regardless of Study
Drug Relationship ( 10 in Any Group) COMFORT-II
Ruxolitinib (n 146) All grades
Grades 3/4
Nausea
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No serious adverse effects on dose interruption.
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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
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.
Kantarjian11University 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,
MI12Emory 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,
NYCurrently at Division of Hematology and
Hematologic Malignancies and Huntsman Cancer
Institute, University of Utah, Salt Lake City, UT
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Durability of Spleen Volume Reduction
1.0
10 reduction (n90)
0.8
0.6
Probability
35 reduction
0.4
0.2
0
0
8
16
24
32
40
48
72
80
88
104
112
64
96
56
Weeks from Onset
No. at risk
84
75
72
63
57
52
47
41
35
4
90
4
4
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• 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
lt35 reduction and 25 increase from nadir. 10
reduction Time from first 35 reduction to lt10
reduction from baseline.
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EORTC QLQ-C30 Over Time
Physical Functioning
Role Functioning
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15
10
10
5
5
0
Mean Change From Baseline
-5
0
-10
-5
-15
-10
-20
Arrows indicate improvement.
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Overall Survival ITT Population
1.0
0.8
Ruxolitinib
Placebo
0.6
HR0.58 (95 CI 0.36, 0.95) P0.028
Survival Probability
No. of deaths Ruxolitinib27 Placebo41
0.4
Median follow up 102 weeks
0.2
Age adjusted HR0.61 (95 CI 0.37, 0.99)
P0.040
0
0
12
24
36
48
60
72
84
96
108
120
132
Weeks
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
2012366799-807 (median age ruxolitinib, 66
years placebo, 70 years Plt0.05).
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Mean Platelet Counts Over Time

• Platelet counts remain stable with longer-term
  therapy

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Ruxolitinib
Placebo
0
-10
-20
Mean Percentage Change From Baseline
-30
-40
-50
-60
Median platelet count at baseline Ruxolitinib,
262.0109/L Placebo, 238.0109/L.
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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 13Guys and St. Thomas NHS Foundation
Trust, London, UK
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Duration of Spleen Response
Loss of response no longer a 35 reduction
that is also a gt 25 increase over nadir.
1.0
0.9
Ruxolitinib
0.8
0.7
0.6
Probability of Maintaining Spleen Response
0.5
0.4
0.3
Ruxolitinib
BAT
0.2
No. of Patients Events Censored
70 18 (25.7) 52 (74.3)
1 0 1 (100)
0.1
0.0
0
12
24
36
48
60
72
84
96
Weeks

• 58 of patients maintain a response at week 84
• The median duration of spleen response has not
  yet been reached

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Overall Survival
1.0
0.9
0.8
0.7
0.6
Probability
0.5
0.4
0.3
0.2
n
0.1
146
136
30
109
127
116
0
73
61
11
45
51
49
0
0.0
0
24
120
96
48
72
144
Weeks

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

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Biological effects beyond spleen and symptoms?
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Subjects With 20 Absolute Allele Burden
Reduction at Week 48 or Week 72
PET
80
PMF
PPV
60
JAK2 V617F Allele Burden ()
40
20
0
0
6
12
24
48
72
84
96
Time (weeks)

• 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

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



Percentage of Responders in Each Allele Burden
Reduction Group

• 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 lt 10 reduction at
  both week 48 and week 72
• There were no responders in the BAT arm

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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

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Spleen Reduction by Palpation on Ruxolitinib
Implies Survival Advantage
Patients with a confirmed reduction gt50 of
spleen size had better survival than those with
lt25
Verstovsek et al, ASH 2011 abstract 3851
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Exploring different strategies for use of JAK
inhibitors

• Earlier disease?
• Other drugs?
• Combination strategies?

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Courtesy of Ruben Mesa
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Trials with Other JAK2 Inhibitors in MF
TG101348/SAR302503 CYT387
Study 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 CI
Fibrosis 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
Pardanani et al. JCO 2011 29789-96. Pardanani
et al. Blood 201 116206 (abstract)
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SAR302503 Phase III Study Design
Multinational, multicenter, double blind,
placebo-controlled randomized study
Q 4 weeks SAR302503 500mg Daily oral doses
RANDOMIZ A TION
75 pts

• - Intermediate-2 or High risk Primary MF
• Post-Polycythemia Vera Myelofibrosis
• Post-Essential Thrombocythemia Myelofibrosis

End of C6
Q 4 weeks SAR302503 400mg Daily oral doses
75 pts
Cross over 1/1
EOT
No Stratification factor Randomization 1/1/1
Q 4 weeks Placebo Daily oral doses
75 pts
End of C6 or PD

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

03/03/13
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SAR302503 Phase II Study Design ARD12181JAKARTA
2
Phase 2, single arm, multicenter, open-label study

• 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

Recent amendment changing discontinuation period
from 30 days to 14 days
70 pts

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

• 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

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Country participation
10 Countries 50 Sites 70 patients
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 States 21 sites (21 pts)

• 26 Subjects Enrolled at 12 sites (6 Countries)
• 23 Subjects under treatment 

Data cut off December, 4
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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

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Potential combination strategies
Class Molecule In vitro study Clinical trial Selected References
Immunomodulators Pomalidomide ? Tefferi et al. JCO2009274563-9.
Immunomodulators Lenalidomide ? Mesa et al. Blood 20101164436-8
mTOR inhibitors Everolimus ? ? Guglielmelli et al . Blood 20111182069-76
Hypomethylating agents Azacitidine ? ? Mesa et al. Leukemia 2009 23180-2
Hypomethylating agents Decitabine ? ? Danilov et al. BJH 2009 145131-2
Hypomethylating agents Givinostat ? ? Rambaldi et al. BJH 2010 150446-55
Hypomethylating agents Panobinostat ? ? De Angelo et al (ASH annual Meeting Abstract). 2010276
Hypomethylating agents Obatoclax mesylate ? ? Parikh et al. Clin Lymph Myel Leuk 2010 10285-9
Hypomethylating agents ABT-737 ? Lu et al. Blood.2010 1164284-7
Hypomethylating agents PU-H71 ? Levine et al. JCI 2010 1203578-93
Hypomethylating agents PEGASYS ? Kiladjian et al Blood 2010 112, 1746
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Panobinostat Ruxolitinib Combo in mouse models
of JAK2V617F-driven diseaseEffects on
bioluminescence
Baffert eta al Blood 2011, Abstract 798, ASH 201
Panobinostat Ruxolitinib Combo in MF
patientsPhase Ib design
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Combination with BMT??
- 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 fitterFavourable effects upon cytokine
storm and potential effects upon GVHD
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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

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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

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• 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

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