An overview of the differences of
different JAK inhibitors
Alessandro M. Vannucchi
University 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.
Dysregulated Cytokine Expression in MF Patients
Verstovsek S et al. NEJM 2010; 363:1117-27
Abnormally Increased IL-8 and IL2R Plasma
Levels Are Prognostically Detrimental
All (n=127)
Int-1 (n=27)
Int-2 (n=70)
Treatment naive
(n=90)
Tefferi A et al. JCO 2011;29:1356-1363
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 VF
2260 wt
?
Reddy M et al. Exp Opin Ther targets 2012; 16:313-24
All JAK2 Inhibitors are Type I and are not Mutation
Specific
Efficacy of JAK2 Inhibitors: Summary
Spleen response*
Ruxolitinib
42% COMFORT-I
28.5% COMFORT-II
SAR302503
39% overall
45% MTD cohort
66% pts >6cycles
CYT387
50% overall
Symptoms
Y
Body weight gain
Y
No body weight gain
Y
*, >35% by MRI (ruxolitinib) or >50% by palpation (SAR & CYT)
CYT387: Transfusion Independence Response
150 mg QD
(n=52)
300 mg QD
(n=60)
150 mg BID
(n=42)
Total1
(n=166)
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%
Response by Dose (Core Study)
Transfusion dependent at baseline (evaluable)
•
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
Onset and Durability of Response (Core and Extension Study)
Time to confirmed response (12 weeks) (Core; days) 3
Duration of transfusion-free period (12 weeks) (Core and Extension; days) 3
•
Median
Min-Max
85
85-353
Not yet reached
85-988*
3 additional subjects achieved 12 week transfusion independence response during the Extension Study
1
Includes 100mg QD (n=3), 200mg QD (n=3), and 400mg QD (n=6) doses
Not statistically significant vs. 300mg QD
3 Data based on responders
* Ongoing as of November 2012
2
Pardanani A et al, ASH 2012
CYT387: Effects on Anemia
50%
Percentage of Patients Receiving RBC Transfusions in Prior 4 Weeks
% Patients with Transfusions
45%
40%
Week 0: 166 patients
Week 40: 125 patients
35%
30%
25%
20%
15%
10%
5%
0%
0
4
8
12
16
20
24
28
32
36
40
Weeks Post Day 1
Pardanani A et al, ASH 2012
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
Inhibition of Inflammatory Cytokines does not
Mediate Efficacy of SAR203505
Pardanani A et al, JCO 2011; 29:789-96
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
Toxicity of JAK2 Inhibitors: Summary
Courtesy, R. Mesa 2013
Verstovsek S, NEJM 2012; Talpaz M, ASH 2012; Komrojki B, ASH 2012; Pardanani A, Leukemia 2013
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