1. How Many Inhibitors for JAK2?
Francisco Cervantes
Hematology Department, Hospital Clínic, University of Barcelona, Spain
Prague, May 2014 1

2. JAK2 Inhibitors in Myelofibrosis
ATP-competitive inhibitors targeting both wild-type and JAK2V617F in vitro
Agent Other targets Phase
Ruxolitinib JAK Approved
SAR FLT3, Ret III (filed)
SB1518 (pacritinib) FLT III
CYT JAK1, JNK1, TYK2, CDK III
CEP FLT3, TrkA II
AZD JAK1, JAK II LY NA II
NS Src I
BMS I

3. Ruxolitinib and Spleen Volume Reduction
COMFORT-I
(week 24)
COMFORT-II
(week 48)
28.5%
P <
41.9%
P <
0.7%
Response: >35% reduction of spleen volume by MRI/CT
A 35% spleen volume reduction by MRI  52% reduction in spleen length by palpation
It occurred at a median of 12 weeks from treatment start
Verstovsek S et al., NEJM 2012; 366:799-07
Harrison C et al., NEJM 2012; 366:787-98

4. Impact on Disease Symptoms and QoL
COMFORT-I
(week 24)
COMFORT-II
(week 48)
Worsening
Improvement
Global health status/QoL
Role functioning
Mean change from baseline 15 10 5 -5
-10
9.1
3.4
9.9
-5.4
Ruxolitinib
BAT
% of Patients
Weeks 24 60 50 40 30 20 10 2 4 6 8 12 14 16 18 22
ruxolitinib
placebo
Ruxolitinib
Placebo
% w Response 46 5
p<0.0001, Chi-square test
Response: % of patients with >50% reduction in MSAF Total Symptom Score
Change in EORTC QLQ-C30 scores at week
48 compared with baseline
Verstovsek S et al., NEJM 2012; 366:799-07
Harrison C et al., NEJM 2012; 366:787-98

5. Overall Survival (ITT Population)
COMFORT-I
(2 year-follow-up)
COMFORT-II
(3 year-follow-up)
Verstovsek S et al., Haematologica 2013; 98:
Cervantes F et al., Blood 2013; 122:

6. Why more JAK inhibitors?
Substantial ruxolitinib drop rate
Better control of the anemia
Deeper disease modifying effect

7. Why more JAK inhibitors?
Substantial ruxolitinib drop rate
Better control of the anemia
Deeper disease modifying effect

8. COMFORT-I: Spleen Volume Reduction
Primary Analysis1 (median follow-up ~7 months)* 80 60 40
-80
Change From Baseline (%)
Individual Patients
-20 20
-40
-60
35% Decrease
Ruxolitinib (n=154)
Placebo (n=153)
-100
Updated Analysis† (median follow-up ~24 months)* 80 60 40
-80
Change From Baseline (%)
Individual Patients
-20 20
-40
-60
Ruxolitinib (n=154)
Crossover (n=111)
-100
35% Decrease
The majority of ruxolitinib-treated patients maintained a spleen volume reduction
The majority of crossover patients experienced spleen volume reduction relative to original baseline (median follow up: 60 weeks)
*Median follow up for patients originally randomized to ruxolitinib. †Change from baseline to last available spleen volume measurement.
1. Verstovsek S et al., NEJM 2012; 366:799-07

9. COMFORT-II: Percent change from baseline in spleen volume
% change from baseline at week 48 60 40 20
-20
-40
-60
-80
Primary endpoint
Ruxolitinib
BAT 80
P <
At week 48
Ruxolitinib
BAT
↓ Spleen volume
132 (97%)
35 (56%)
↑ Spleen volume
4 (3%)
28 (44%)
Best response at any time on study
Harrison C et al., NEJM 2012; 366:787-98

10. Duration of Spleen Response to Ruxolitinib
COMFORT-I
(2 year-follow-up)
COMFORT-II
(3 year-follow-up)
Verstovsek S et al., Haematologica 2013; 98:
Cervantes F et al., Blood 2013; 122:

11. COMFORT-II Patient Disposition (median FU, 151 wk)
Ruxolitinib
(n = 146)
BAT
(n = 73)
Ruxolitinib after cross-over from BAT (n = 45)
Ongoing
66 (45.2)
22 (48.9)
Discontinued
80 (54.8)
28 (38.4)
23 (51.1)
Crossed over –
45 (61.6)
After qualifying progression event
26 (35.6)
After protocol amendment 5
13 (17.8)
Othera
6 (8.2)
Primary reason for discontinuation
Adverse event(s)
24 (16.4)
5 (6.8)
6 (13.3)
Consent withdrawn
9 (6.2)
9 (12.3)
Protocol deviation
2 (1.4)
5 (11.1)
Disease progression
22 (15.1)
4 (5.5)
Non-compliance with study medication
3 (2.1)
1 (2.2)
Non-compliance with study procedures
1 (1.4)
Unsatisfactory therapeutic effect
5 (3.4)
Otherb
15 (10.3)
4 (8.9)
a 6 patients crossed over from BAT to ruxolitinib prior to the protocol amendment 5 without experiencing qualifying progression events (5 patients discontinued due to the protocol deviation and one patient discontinued due to other reason).
b Other reasons for discontinuation included patients who underwent stem cell transplantation.
Cervantes F et al., Blood 2013; 122:
Cervantes F et al., Blood 2013; 122:

12. Fedratinib (SAR302503) Phase I Study in MF Main Results (n= 59)
Feature Response & toxicity
Spleen %*
Constitutional symptoms %
Anemia response No
JAK2 allelic burden reduction %
Grade 3-4 anemia %
Grade 3-4 thrombocytopenia %
Non-hematologic toxicity G-I symptoms
* IWG-MRT criteria
Pardanani A et al., JCO 2011; 29:789-96

13. By baseline platelet count (×109/L)
Fedratinib in Ruxolitinib Resistance/Intolerance Spleen response at end of cycle 3 (n= 20)
By baseline platelet count (×109/L)
Proportion of patients with ≥35% reduction in spleen volume at end of Cycle 3 (%) 43 43 40 39 33
6/14
2/6
8/20b
3/7
5/13
RUX resistanta
RUX
intolerant
Overall
<100
≥100
Overall
Spleen response (≥35% reduction in spleen volume from baseline) was the primary endpoint for this interim analysis
aAs reported by the investigator
b7 patients not evaluable: no post-baseline MRI/CT scan (n=5); no baseline MRI/CT scan (n=1); MRI/CT scan outside time window end of cycle 3 assessment (n=1).
Harrison C et al., ASH 2013

14. Change in spleen volume from baseline at EOC3 (%)
Fedratinib in Ruxolitinib Resistance/Intolerance Spleen volume changes in individual pts at end of cycle 3 30 20 10
–10
Change in spleen volume from baseline at EOC3 (%)
–20
–30
–35%
–40
RUX resistanta (n=14)
–50
RUX intolerant (n=6)
–60
–70
Data are shown for the 20 patients with evaluable spleen volume assessment at the end of Cycle 3
Harrison C et al., ASH 2013

15. Fedratinib Safety Issues
Cases consistent with Wernicke’s encephalopathy have been reported in patients participating in fedratinib trials.
Following a thorough risk-benefit analysis, the risk to patient safety was considered to outweigh the benefit that fedratinib would bring to patients.
All clinical trials involving fedratinib have been halted, and fedratinib treatment discontinued in patients enrolled in ongoing trials.

16. Momelotinib (CYT387) Phase I/II Study Spleen Response
Number of Subjects (%)
Total enrollment
166 (100%)
Baseline spleen size > 5 cm at baseline
148 (89%)
≥ 50% reduction in splenomegaly that lasts
≥ 8 weeks for splenomegaly ≥ 10 cm at
baseline: A (A/148)
52 (35%)
Resolution of splenomegaly that lasts ≥ 8
weeks for splenomegaly > 5 and < 10 cm:
B (B/148)
6 (4%)
Spleen Response: A + B
58 (39%)
Pardanani A et al., ASH 2013

17. Momelotinib After Failure to Other JAK Inhibitors (n= 27)
Pardanani A et al., ASH 2013

18. Phase 2 Study of Pacritinib in MF Spleen Response
Komrojki et al., ASH 2013

19. Why more JAK inhibitors?
Substantial ruxolitinib drop rate
Better control of the anemia
Deeper disease modifying effect

20. Clinical Manifestations
of Myelofibrosis
Anemia
Thrombosis
Symptomatic
splenomegaly
Constitutional
symptoms
Extramedul.
hemopoiesis
Bone pain
Infection
Bleeding
Pruritus

21. Ruxolitinib Phase I/II Study in MF. Main Efficacy Results (n= 153)
Disease feature Response
Spleen shrinkage, overall %
> 50% %
Constitutional symptoms %
Leukocytosis response %
Anemia response %
Reduction JAK2 allelic burden Scarce
Verstovsek S et al., NEJM 2010; 363:

22. Laboratory Data: Hemoglobin Levels Over Time
COMFORT-II
Laboratory Data: Hemoglobin Levels Over Time
12.0
Baseline
11.0
10.0
10 g/dL
9.0
8.0
n =
Ruxolitinib
146
127
121
101
101 96 90 78 71 64 61 59 49 50 22
BAT 73 59 53 37 31 29 19 10 6 1
In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 weeks of treatment and then recovered to levels similar to those in the BAT arm and remained > 10 g/dL from week 24 onward (> 151 weeks)
Note: Only scheduled visits are included; ruxolitinib includes both the randomized and extension phases; BAT includes randomized phase only and not assessments after crossover.

23. Momelotinib (CYT387) Phase I/II Study Anemia Response
Number of Subjects (%)
Transfusion dependent at baseline
72 (43%)
Achieved transfusion independence on study
that lasts ≥ 12 weeks: C (C/72)
49 (68%)
Transfusion independent with Hgb < 10 g/dL at baseline
39 (24%)
Rise in Hb ≥ 2 g/dL on study that lasts ≥ 12
weeks: D (D/39)
10 (26%)
Anemia Response: C + D
59 (53%)
Transfusion dependence at baseline is defined as ≥ 2 units of RBC transfusions in the 30 days prior to C1/D1 and/or identified as transfusion dependent in medical history
Pardanani A et al., ASH 2013

24. Momelotinib (CYT387) Phase I/II Study Duration of Anemia Response
1.0
 Event
 Censored
0.9
Number of events (%): 18 (30.5)
Number of censored (%): 41 (69.5)
Median (days) (95% CI): 1,042 (514, NE)
0.8
0.7
0.6
Probability
0.5
0.4
0.3
0.2
0.1
200
400
600
800
1000
Duration of anemia response (days)
Pardanani A et al., ASH 2013

25. Phase 2 Study of Pacritinib in MF Evolution of Hb Values
Komrojki et al., ASH 2013

26. Why more JAK inhibitors?
Substantial ruxolitinib drop rate
Better control of the anemia
Deeper disease modifying effect

27. Survival Prolongation with Ruxolitinib
Passamonti F et al., Blood 2014 (Epub ahead of print)

28. Change in BM Fibrosis Over Time with Ruxolitinib and BAT*
48 mo
60 mo
Rux
BAT
Rux
BAT
Rux
BAT
Rux
BAT
Rux
BAT
Rux
BAT
75%
76%
75%
56%
46%
36%
32%
26%
25%
22% 3% 2% 3%
Odds Ratio [95% CI]** for worsening BM fibrosis at 48 mo
Odds Ratio [95% CI]** for worsening BM fibrosis at 60 mo
Rux [0.03 – 0.50]
Rux [0.01 – 0.34]***
* Compilation of data - not a formal comparison ** Logistic regression method *** Last available grade from 54, 60, or 66 mo
Kvasnicka HM, et al., 2013 ASH abs 4055

29. COMFORT-II: JAK2 V617F Allele Burden Reductions at Week 48 and Week 72
More patients in the ruxolitinib arm had ≥ 10% allele burden reductions compared with BAT at week 48 (42% [29/69] vs 9% [2/22]) and at week 72 (40% [21/53] vs 0%)
Vannucchi AM et al., EHA 2013 29

30. Momelotinib (CYT387) Phase I/II Study in MF Main Results (n= 166)*
Feature Response & toxicity
Spleen % §
Constitutional symptoms %
Anemia %*
Transfusion-dependent pts %
JAK2 allelic burden reduction Scarce
Grade 3-4 thrombocytopenia %
Non-hematologic toxicity Unfrequent
* Median follow-up: 16.9 months
§ IWG-MRT criteria
Pardanani A et al., ASH 2012

31. Efficacy of JAK Inhibitors in Myelofibrosis
Spleen MF
Sympt.
Anemia
Survival effect
JAK2 + + + ?
Ruxolitinib
NEJM 2012 ; Blood 2013 + + ? ?
SAR302503
JCO 2011 + ? + ?
SB1518
EHA 2011 + + + ? ?
CYT387
ASH 2012 + +
CEP-701
AZD1480
LY a4807
NS-018 a4106
BMS a4112
Phase I/II Testing 31

32. A More Selective JAK Inhibitor for Myelofibrosis?
Pros
- Higher effect on JAK2 allele burden
- Less hematological toxicity
- Less potential for long-term immunosuppression
Loss of the off-target effects of ruxolitinib (constitutional
symptoms, splenomegaly…)
- Lack of efficacy in JAK2-negative patients?
Cons

33. Conclusions
Despite the success of ruxolitinib in MF, in the mid term more than half of the patients discontinue due to resistance or intolerance.
There are indications that a proportion of these patients can respond to other JAK inhibitors.
Newer drugs of this class effective for the anemia of MF are necessary.
A deeper disease modifying effect of JAK inhibition would also be desirable.