Transcript Nuove acquisizioni nel campo della mielofibrosi primaria

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