Benefits of JAK2 Inhibitor Therapy: Why Do They Work in

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Transcript Benefits of JAK2 Inhibitor Therapy: Why Do They Work in

Benefits of JAK2 Inhibitor Therapy: Why Do They Work in Patients With and Without JAK2 Mutation

Alessandro M. Vannucchi Section of Hematology, University of Florence, Italy

JAK2 V617F is the Commonest Mutation Causing Abnormal JAK/STAT Signaling in MPN

Survival Differentiation Proliferation Oncogenesis Vannucchi et al., CA Cancer J Clin. 2009; 59:171-91

A Myeloproliferative Disorder is Induced by JAK2 V617F in Mice

PV MF Zaleska, Plos One 2006;e18

JH7 JAK2 inhibitors are not specific for the JAK2 V617F mutation Binding to receptors Chaperoning Stabilising at membrane Inhibits basal activity Signaling through P transfer ATP site FERM SH2 PseudoKinase Kinase Kinase site JH6 JH5 JH4 JH3 JH2 JH1 Activation loop V617F

• JAK inhibitors target the ATP binding site of JAK2 at the tyrosine kinase domain and not the pseudokinase domain • Therefore, both mutated and wild-type JAK2 are inhibited by JAK2 inhibitors

V617

James et al. Nature 2005; 434: 1144-8 ; Baxter et al. Lancet 2005; 365: 1054-61; Levine et al. Cancer Cell 2005; 7:387-97; Kralovics et al. NEJM. 2005: 352:1779-90

Inhibition of PV Progenitor Erythroid Differentiation by the JAK2 Inhibitor TG101348

Geron I et al, Cancer Cell, 13; 2008 321 - 330

Effects of Treatment with Ruxolitinib in a JAK2 V617F-Driven Murine Model

Quintás-Cardama et al., Blood 2010;115:3109-3117.

JAK1 and JAK2, or JAK2 Only, Inhibitors

Drug JAK1 Other targets Ruxolitinib/INC424 TG101348/SAR302503 CYT387 CEP-701 AZD1480 SB1518 LY2784544 BMS911543

   none known FLT3, Ret JNK1, CDK2 FLT3, TrkA Aurora A, TrkA, FGFr1 FLT3 na Verstovsek et al. N Engl J Med. 2010; 363:1117-27. Pardanani et al. JCO. 2011; online Jan 10. Pardanani et al. ASH Abstract 2010; Blood 2010; 116:460. Santos et al. Blood. 2010; 115:1131-6.La Fave LM, Trends Pharm Sciences 2012; 33:564-582.

Do they work?

If yes, Why?

Do they work?

If yes, Why?

The Effects of Ruxolitinib on Spleen Size is Independent of JAK2 V617F Mutation 22.5

20.0

17.5

15.0

12.5

10.0

7.5

5.0

2.5

0 0 JAK mutation POSITIVE; N = 33 JAK mutation NEGATIVE; N = 6 56 112 168 224 Time on Therapy (days) 280 336

• In the Phase I/II study with TG101348/SAR302503, 8 of 59 pts were JAK2 wild-type • 3 of 4 pts who completed six cycles had >50% reduction of splenomegaly (CI per IWG-MRT) Verstovsek S et al. NEJM 2010; 363:1117-1127; Pardanani A et al, JCO 2011; 29:789-796

Effect of JAK2 V617F Mutation on the Proportion of Patients Obtaining a >35% Spleen reduction *

• No significant difference in response rates was observed between patients with the JAK2V617F mutation compared with those without the mutation, although the trend was towards a greater response rate in JAK2 V617F mutated * By MRI Harrison C et al, ASH 2011; 279

The Effects of Ruxolitinib on Symptomatic Control Is Independent of JAK2 V617F Mutation

Kiladjian JJ et al, ASCO 2012: 451A

The Impact of Ruxolitinib on Survival Is Independent of JAK2 V617F Mutation

Verstovsek S et al. ASH 2011, 378A

Do they work?

If yes, Why?

Similarly Activated Signaling Pathways in JAK2 V617F Mutated and Wild-type MPN Cells

Anand S et al. Blood 2011;118:1610-1621

Similar Inhibition of Signaling in JAK2 V617F and Wild-type patients with a Selective JAK2 inhibitor

Anand S et al. Blood 2011;118:1610-1621

A Cytokine Storm in PMF Patients

    JAK2 V617F correlated   

Fold-increased over controls

 Tefferi A et al, JCO 2011;29:1356-1363

The Significance of JAK1 and JAK2 Inhibition

Vannucchi AM, N Engl J Med. 2010; 363:1180-2.

Ruxolitinib-Induced Normalisation of Inflammatory Cytokines in Phase I/II Trial

Baseline, Patients with Myelofibrosis vs. Healthy Controls Patients with Myelofibrosis, Day 28 vs. Baseline This effect was observed regardless of JAK2 mutational status or MF subtype

Verstovsek et al. N Engl J Med. 2010; 363:1117-27.

Predicted Effects of JAK1 and JAK2 inhibition

JAK2 inhibitors are not specific for mutated protein

THUS they are effective regardless of the JAK2V617F mutated status

JAK2wt (± JAK1) inhibition affects a variety of cytokine signaling pathways Concurrent Inhibition of JAK2wt might result in anemia and thrombocytopenia Placebo BAT Ruxolitinib 19.2

Anemia 43.2

1.3

Thr’penia 12.9

31 Anemia 42

• A marked reduction of pro-inflammatory cytokines was coincident with improvement in constitutional symptoms

Thr’penia 7 8 % of patients Verstovsek S et al. N Engl J Med. 2010; 363:1117-27; Verstovsek S et al. NEJM 2012; 366:799-807; Harrison C et al. NEJM 2012; 366:787-98

Conclusions

• Abnormal JAK/STAT signaling is a common pathogenetic mechanism in MPN cells independent of the JAK2 mutational status • Current JAK2 inhibitors are not specific for the mutated protein, and target the wild-type JAK2 as well • JAK2 inhibitors are similarly effective in JAK2 mutated and wild type patients • Inhibition of wild-type JAK1 signaling contributes to the clinical efficacy of JAK1/JAK2 inhibitors