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
IC50
Ruxolitinib
demonstrated
>100-fold
selectivity against
a broad panel of
kinases
Ba/F3-EpoR-JAK2V617F
cell proliferation assay1
pJAK2/pSTAT5/pERK
(Ba/F3-JAK2V617F cells)1
127±17 nM
(mean±SD)
128–320 nM
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, Doubleblind, 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 48w
Status
Reached primary and
secondary end-point of
symptomatic
improvement by MSAF *
Reached primary endpoint
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
COMFORT-I and COMFORT-II
Comparison of Spleen Volume Reductions
40
P < .0001
Ruxolitinib
COMFORT-II At Week 48a
Change From Baseline, %
Change From Baseline, %
COMFORT-I At Week 24a
20
P < .0001
0
-20
35% decrease
-40
-60
Ruxolitinib
-80
COMFORT-I
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
Ruxolitinib Arm
aPrimary
endpoint;
bKey
secondary
endpoint.
COMFORT-II
Spleen progression criteria
≥ 25% inc from BL
≥ 25% inc from nadir
Percent Change From Baseline in Spleen Volume
by JAK2V617F Mutation Status
Change From Baseline, %
At Week 48a
Primary endpoint
Ruxolitinib
BAT
JAK2V617F positive (n = 75)
JAK2V617F negative (n = 22)
Unknown mutation status (n = 1)
JAK2V617F positive (n = 24)
JAK2V617F negative (n = 8)
Unknown mutation status (n = 2)
• 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
a
For patients with spleen volume assessments by MRI/CT at both baseline and week 48.
12
Harrison CN,. Blood (ASH) 2011:Abstract 279.
Total Symptom Score: Modified
MFSAF v2.0
•
uestions 1 to 6 comprise Total Symptom Score
•
uestion 7 queries inactivity, an impact of MF
0 (Absent) 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable)
•
dministered
1.During thedaily
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?
Mesa RA, et al. Leukemia Res. 2009;33:1199-1203.
8
Mean % Change in Individual Symptoms
Ruxolitinib
•
Worsening
n=100
n=124
Abdominal
discomfort
n=86
n=109
Pain under
left ribs
n=96
n=122
Early
satiety
n=90
n=103
Night
sweats
n=77
n=98
Itching
n=89
n=108
n=97
n=119
Improvement
Mean % Change From Baseline
 Placebo
Bone/muscle Inactivity
pain
For all individual symptoms above, comparisons between ruxolitinib- and placebotreated groups were highly statistically significant (P < 0.01)
9
Anemia and Thrombocytopenia
Worst Lab Value on Study*,†
Grade
1
n (%)
Grade
2
n (%)
Grade
3
n (%)
Grade
4
n (%)
Ruxolitinib (n = 146)
24 (16) 55 (38) 50 (34)
12 (8)
BAT (n = 70)
16 (23) 28 (40) 15 (21)
7 (10)
Ruxolitinib (n = 146)
46 (32) 41 (28)
9 (6)
3 (2)
BAT (n = 69)
11 (16)
3 (4)
2 (3)
Hemoglobin
Platelet count
•
•
•
4 (6)
*Occurring on the randomized treatment phase only.
†Percentage
is based
on baseline
total67%
n. BAT) had grade 1/2 anemia at baseline
The majority
of patients
(63%
ruxolitinib;
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
Diarrhea
Ruxolitinib (n = 146)
Nausea
All grades
Grades 3/4
BAT (n = 73)
Pain in extremity
Headache
Pruritus
All grades
Grades 3/4
No serious adverse effects on dose
interruption…….
12
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. 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
Durability of Spleen Volume Reduction
1.0
≥10% reduction
(n=90)
Probability
0.8
0.6
≥35% reduction
0.4
0.2
0
0
8
16
24
32
48
56
64
72
80
88
96
104
41
35
4
4
4
112
Weeks from Onset
No. at risk
90
40
84
75
72
63
57
52
47
43
• 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.
EORTC QLQ-C30 Over Time
Mean Change From Baseline
Global Health Status/QoL
Fatigue
20
10
15
5
10
0
5
-5
0
-10
-5
-15
-10
-20
-25
-15
BL
12
24
36
48
60
72
84
BL
96
12
24
36
Ruxolitinib
60
72
84
96
Placebo
Role Functioning
Mean Change From Baseline
48
Weeks
Weeks
Physical Functioning
15
15
10
10
5
5
0
-5
0
-10
-5
-15
-20
-10
BL
12
24
36
48
60
Weeks
Arrows indicate improvement.
72
84
96
BL
12
24
36
48
Weeks
60
72
84
96
Overall Survival: ITT Population
1.0
Survival Probability
0.8
Ruxolitinib
Placebo
0.6
HR=0.58 (95% CI: 0.36, 0.95); P=0.028
No. of deaths: Ruxolitinib=27; Placebo=41
0.4
Median follow up: 102 weeks
0.2
Age adjusted HR*=0.61 (95% CI: 0.37, 0.99); P=0.040
0
0
12
24
36
48
60
72
84
96
108
120
132
Weeks
No. at risk
Ruxolitinib
155
154
148
145
136
125
121
113
96
44
6
Placebo
154
148
142
133
117
111
102
95
74
32
7
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).
Mean Platelet Counts Over Time
• Platelet counts remain stable with longer-term therapy
Mean Percentage Change From
Baseline
10
Ruxolitinib
Placebo
0
-10
-20
-30
-40
-50
-60
BL
12
24
36
48
60
72
Weeks
Median platelet count at baseline: Ruxolitinib, 262.0×109/L; Placebo, 238.0×109/L.
84
96
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
Probability of Maintaining Spleen Response
Loss of response: no longer a ≥ 35% reduction that is also a > 25% increase over nadir.
1.0
0.9
Ruxolitinib
0.8
0.7
0.6
0.5
0.4
0.3
Ruxolitinib
0.2
No. of Patients
Events
Censored
0.1
70
18 (25.7%)
52 (74.3%)
BAT
1
0
1 (100%)
0.0
0
12
24
36
48
60
72
Weeks
• 58% of patients maintain a response at week 84
• The median duration of spleen response has not yet been reached
19
84
96
Draft Oral Presentation
Overall Survival
1.0
0.9
0.8
Probability
0.7
0.6
0.5
Ruxolitinib
0.4
BAT
Ruxolitinib
No. of Patients
146
73
Events
20 (13.7%) 16 (21.9%)
Censored
126 (86.3%) 57 (78.1%)
0.3
BAT
0.2
0.1
0.0
n=
146
73
136
61
127
51
116
49
109
45
30
11
0
0
0
24
48
72
96
120
144
Weeks
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
PET
PMF
PPV
JAK2 V617F Allele Burden (%)
80
60
40
20
0
0 6 12
24
48
72
Time (weeks)
84
96
• 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
Percentage of Responders in Each
Allele Burden Reduction Group
Responders (≥ 35% Spleen Volume Reduction at Week
48) by Absolute Allele Burden Reduction Status
%
%
%
%
%
%
%
%
N = 16
24
14
15
N=
9
23
8
13
•
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
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
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%
Verstovsek et al, ASH 2011 abstract 3851
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
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
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; 29:789-96. Pardanani et al. Blood 201; 116:206 (abstract)
YES, 50-57% CI
28
SAR302503 Phase III Study Design
Multinational, multicenter, double blind, placebo-controlled randomized study
- Intermediate-2 or High
risk Primary MF
-Post-Polycythemia Vera
Myelofibrosis
-Post-Essential
Thrombocythemia
Myelofibrosis
No Stratification factor
Randomization 1/1/1
RA
ND
O
M
I
Z
A
T
I
ON
75 pts
75 pts
75 pts
Q 4 weeks
SAR302503 500mg
Daily oral doses
End
of C6
Q 4 weeks
SAR302503 400mg
Daily oral doses
Q 4 weeks
Placebo
Daily oral doses
• 225 pts, Sites ~125, Recruitment: 9 months, 25 countries
• Safety data monitored by DMC (Q 6 months)
• Cross over possible
30
03/03/13
Cross
over 1/1
End of C6
or PD
EOT
SAR302503 Phase II Study Design: ARD12181
JAKARTA 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
Recent amendment changing discontinuation period from 30
days to 14 days
70 pts
- Intermediate or High risk
Primary MF
- Post-Polycythemia Vera
Myelofibrosis
Post-Essential
Thrombocythemia
Myelofibrosis according to
the 2008 World Health
Organization (WHO) criteria
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
32
Country participation
10 Countries – 50 Sites – 70 patients
•
•
Austria (AT)
Italy (IT)
2 sites (2 pts)
4 sites (4 pts)
Belgium (BE)
The Netherlands (NL)
3 sites (6 pts)
2 sites (11 pts)
Canada (CA)
Spain (SP)
1 site (2 pts)
3 sites (3 pts)
France (FR)
United Kingdom (UK)
6 sites (8 pts)
1 site (2 pts)
Germany (DE)
United States
7 sites (11 pts)
21 sites (21 pts)
26 Subjects Enrolled at 12 sites (6 Countries)
23 Subjects under treatment
Data cut off: December, 4
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 strategies
Class
Immunomodulators
mTOR inhibitors
Hypomethylating
agents
Molecule
In vitro
study
Clinical
trial
Selected References
Pomalidomide

Tefferi et al. JCO2009;27:4563-9.
Lenalidomide

Mesa et al. Blood 2010;116:4436-8
Everolimus


Guglielmelli et al . Blood
2011;118:2069-76
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


ABT-737

Lu et al. Blood.2010; 116:4284-7
PU-H71

Levine et al. JCI 2010; 120:3578-93
PEGASYS

Parikh et al. Clin Lymph Myel Leuk
2010; 10:285-9
Kiladjian et al Blood 2010; 112, 1746
Panobinostat & Ruxolitinib
Combo in mouse models
of JAK2V617F-driven
disease
Effects on bioluminescence
Baffert eta al Blood 2011, Abstract 798, ASH 201
Panobinostat & Ruxolitinib Combo in MF patients
Phase Ib design
37
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 fitter
Favourable effects upon cytokine storm and potential effects upon
GVHD
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