1. Ongoing clinical trials with JAK2 inhibitors in MF
Jason Gotlib, MD, MS
Associate Professor of Medicine (Hematology)
Stanford Cancer Institute
December 7, 2012

2. JAK Inhibitors in Clinical Use / Trials
Agent
Trial Name
Current Status
Ruxolitinib
COMFORT-I
COMFORT-II
FDA Approved
SAR302503
(formerly TG101348)
JAKARTA
Phase III
CYT387
Phase II
SB1518
CEP-701 LY
Phase I
BMS
NS0118

3. SAR302503
(formerly TG101348)

4. Phase I Trial with Phase 2 Expansion Cohort
Pardanani et. al. JCO 2011;29:

5. Spleen Responses to SAR302503
Gotlib et al, EHA, 2012

6. JASON
Pre-Trial
On treatment
JAK2 Inhibitor SAR302503

7. Symptom Responses to SAR302503
Fatigue
Early Satiety
Night Sweats
Pardanani et. al. JCO 2011;29:

8. Resolution of leukocytosis/thrombocytosis
SAR302503:
Resolution of leukocytosis/thrombocytosis
Gotlib et al, EHA, 2012

9. SAR302503: JAK2 V617F Allele Burden
Gotlib et al, EHA, 2012
©2011 MFMER |

10. SAR302503: Spleen and symptom responses defined by baseline platelets
Gotlib et al, EHA, 2012
©2011 MFMER |

11. SAR302503 Phase III Study Design
Multinational, multicenter, double blind, placebo-controlled randomized study
RANDOM I Z A T I ON
Q 4 weeks
SAR mg
Daily oral doses
Intermediate-2 or High risk
-Primary MF
Post-Polycythemia Vera Myelofibrosis
Post-Essential Thrombocythemia Myelofibrosis
75 pts
End
of C6
Q 4 weeks
SAR mg
Daily oral doses
75 pts
Cross over 1/1
EOT
Q 4 weeks
Placebo
Daily oral doses
75 pts
No Stratification factor
Randomization 1/1/1
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

12. SB1518
Pacritinib

13. Baseline spleen size (cm below left costal margin)
SB1518 Significantly Reduces Splenomegaly in MF patients as Measured by Physical Exam (Phase II N=34)
Baseline spleen size (cm below left costal margin)
≥ 16; ;
15 of 34 (44%) patients had response of ≥ 50%
Mesa et. al. EHA 2011 (a1022) Oral Sunday

14. Pacritinib: SB 1518
> 9 Months Sustained Improvement in MF-related Symptoms 3*
Only pts with baseline ≥4 (MFSAF)
(N) For paired values
* = No change in mean symptom score
Komrokji et. al. ASH 2011

15. Komrokji, ASH 2011
©2011 MFMER |

16. CYT387

17. Constitutional Symptoms Response at Six Months
Pardanani et. al. ASH 2011 17

18. CYT387: Maximal Change in Palpable Spleen Size*
(Core Study; n=142)
≥ 25% decrease from baseline: 87%
≥ 50% decrease from baseline: 49%
≥ 75% decrease from baseline: 25%
100% decrease from baseline: 16%
*ongoing
Pardanani et. al. ASH 2011 18

19. CYT387: Transfusion Independence Response
Response by Dose
150 mg QD (n=52)
300 mg QD (n=60)
150 mg BID (n=42)
Total1 (n=166)
Transfusion dependent at baseline (evaluable; n) 25 26 14 68
Median time on study (days)
251
245
141
250
Transfusion independence rate (12 weeks)*
48%
65%
43%2
54%
Transfusion independence rate (12 weeks & Hgb≥8g/dL)*
40%
62%
29%2
46%
1 Includes 100 mg QD (n=3), 200 mg QD (n=3), and 400 mg QD (n=6) doses 2 Not statistically significant vs. 300 mg QD
* ongoing
>25% of subjects not receiving transfusions while on study experienced at least a 1 g/dL increase in Hgb for ≥ 8 weeks
Pardanani et. al. ASH 2011

20. CYT387: Duration of Transfusion Response
Time to Response
Median
Min-Max
Time to confirmed response (12 wks & Hgb≥8 g/dL) (days) 84
84-293
Duration of transfusion-free period (12 wks & Hgb≥8 g/dL) (days)
not yet reached
82-506*
Pardanani et. al. ASH 2011

21. Comparing JAK2 Inhibitors Efficacy
Spleen MF
Symptoms
Anemia
JAK2
Burden + +
+/-
Ruxolitinib + +
+/-
SAR302503 + + + ?
CYT387 + + ?
SB1518 LY
NS-018
BMS
Phase I Testing

22. Comparing JAK2 Inhibitors Safety / Tolerability
DRUG
Non-Heme
Thrombocytopenia
Anemia
Other
Ruxolitinib
Bruising/HA/
Diarrhea
+++ ++
SAR302503
GI/LFTs/Lipase
++/+++
CYT387
Lipase/HA/Neuropathy -
1st Dose
Effect
SB1518 GI
+/++
-/+

23. One Mechanism of Disease Persistence In MF on JAK2 inhibitors
Ligand binding and
activation of JAK2
kinase results in STAT
dimerization and
cellular proliferation A C
Exposure to JAK2 inhibitor results in reactivation of JAK2 by JAK family members
JAK1 and TYK2 which
heterodimerize with JAK2
JAK2 inhibitor binds to the JAK2 kinase and reduces JAK-STAT pathway activation and cell proliferation B
Koppikar et al, Nature, 2012

24. FUTURE JAK INHIBITOR COMBINATIONS
IMiDs
HDAC
inhibitors
Hsp90
inhibitors
JAK 1/2
inhibitor
FUTURE JAK INHIBITOR COMBINATIONS
PI3K / AKT/
mTOR
inhibitors
Anti-
fibrotics
HedgeHog
Pathway
inhibitors

25. Koppikar et al, ASH, 2011

26. Koppikar et al, ASH, 2011

27. Baffert et al, ASH 2011

28. Summary
After approval of ruxolitinib, SAR302503, SB1518, and CTY387 represent lead JAK inhibitors in ongoing clinical development
Patient-specific MF symptoms, differences in toxicity profiles, and potential for reversion of anemia will guide selection of agents
Strategies for overcoming disease persistence/ disease ‘creep’
Combination of JAK inhibitors with novel drugs with different mechanisms of action
Next generation of JAK inhibitors in development

29. Acknowledgements Stanford Mayo Clinic (Rochester and Mayo)
Marie Nguyen
Ayalew Tefferi
Andrea Linder
Ruben Mesa
Hersh Kaur
Animesh Pardanani
Cheryl Langford
Cecelia Perkins
MD Anderson Cancer Center
Parveen Abidi
Srdan Verstovsek
Lawrence Okumoto
Ben Varasteh
IWG-MRT
MPN Foundation
Funding
Charles and Ann Johnson Foundation