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An overview of the differences of different JAK inhibitors
Alessandro M. VannucchiUniversity of Florence, Italy
JAK2 Signaling Abnormalities in MPN
JAKs are Involved in Multiple Cytokine Signaling
Vannucchi AM, N Engl J Med. 2010; 363:1180-2.
Verstovsek S et al. NEJM 2010; 363:1117-27
Dysregulated Cytokine Expression in MF Patients
Tefferi A et al. JCO 2011;29:1356-1363
All (n=127)
Treatment naive (n=90)
Int-1 (n=27)
Int-2 (n=70)
Abnormally Increased IL-8 and IL2R Plasma Levels Are Prognostically Detrimental
Reddy M et al. Exp Opin Ther targets 2012; 16:313-24
A portfolio of JAK2 inhibitors
Reddy M et al. Exp Opin Ther targets 2012; 16:313-24
A portfolio of JAK2 inhibitors
JAK1 JAK2 JAK3 TYK2
Ruxolitinib 2.7 4.5 322 X
SAR302503 103 3 996 ----
CYT387 11 18 155 ?
SB1518 1276 22 1392
Ly2784544 550 VF2260 wt
?
All JAK2 Inhibitors are Type I and are not Mutation Specific
Efficacy of JAK2 Inhibitors: Summary
Spleen response* Symptoms
Ruxolitinib 42% COMFORT-I28.5% COMFORT-II
YBody weight gain
SAR302503 39% overall45% MTD cohort66% pts >6cycles
YNo body weight gain
CYT387 50% overall Y
*, >35% by MRI (ruxolitinib) or >50% by palpation (SAR & CYT)
Response by Dose (Core Study) 150 mg QD(n=52)
300 mg QD(n=60)
150 mg BID(n=42)
Total1
(n=166)
Transfusion dependent at baseline (evaluable) 24 28 14 68
Transfusion independence rate (12 wks) 63% 75% 57%2 68%
Minimum 2 g/dL increase in hemoglobin level (8 wks) 11% 8% 14% 13%
IWG-MRT anemia response rate 48% 55% 36% 48%
CYT387: Transfusion Independence Response
• Of the transfusion dependent patients who did not achieve a full transfusion independence response, 23% achieved at least a 50% reduction in transfusion requirement in any 3-month period
1 Includes 100mg QD (n=3), 200mg QD (n=3), and 400mg QD (n=6) doses2 Not statistically significant vs. 300mg QD3 Data based on responders* Ongoing as of November 2012
Onset and Durability of Response (Core and Extension Study) Median Min-Max
Time to confirmed response (12 weeks) (Core; days) 3 85 85-353
Duration of transfusion-free period (12 weeks) (Core and Extension; days) 3 Not yet reached 85-988*
• 3 additional subjects achieved 12 week transfusion independence response during the Extension Study
Pardanani A et al, ASH 2012
CYT387: Effects on Anemia
0 4 8 12 16 20 24 28 32 36 400%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Weeks Post Day 1
% P
ati
en
ts w
ith
Tra
ns
fus
ion
s Week 0: 166 patientsWeek 40: 125 patients
Pardanani A et al, ASH 2012
Percentage of Patients Receiving RBC Transfusions in Prior 4 Weeks
Vannucchi AM et al, ASH 2012
Effect of TG101348/SAR302503 therapy on JAK2 V617F allele burden
Pardanani A et al. JCO 2011;29:789-796
Ruxolitinib Induced Inhibition of Inflammatory Cytokines
Verstovsek S et al. NEJM 2010; 363:1117-27
Pardanani A et al, JCO 2011; 29:789-96
Inhibition of Inflammatory Cytokines does not Mediate Efficacy of SAR203505
CYT387: cytokine changes
……….. Our data suggests a cytokine-mediated effect; a majority of
patients had treatment-related decrease in circulating IL-1β and IL-1RA
levels, which were the only two cytokines associated with
transfusion-independence response. Similarly, spleen response was
correlated with treatment-associated decreases in a number of
cytokines. Overall, these data implicate down-regulation of circulating
inflammatory cytokines, further confirmed by gene expression
analysis, as the major mechanism for CYT387’s clinical activity in MF.
Pardanani A et al, Leukemia 2013
Verstovsek S, NEJM 2012; Talpaz M, ASH 2012; Komrojki B, ASH 2012; Pardanani A, Leukemia 2013
Courtesy, R. Mesa 2013
Toxicity of JAK2 Inhibitors: Summary
Conclusions
• A portfolio of different JAK2/(1) inhibitors is available in addition to ruxolitinib
• There is no clear difference in efficacy against splenomegaly and symptoms
• Different JAK2 inhibitors may have different activity against inflammatory cytokines
• CYT387 may have unique effects on anemia• Modest activity against JAK2V617F allele burden• Overlapping hematologic toxicity