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