An overview of the differences of different JAK inhibitors

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

atie

nts

with

Tra

nsfu

sion

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