Why do we need new drugs in PV and ET?

BCSH Guidelines: Hydroxycarbamide 1st Line PV ET

Limitations of Hydroxycarbamide in PV and ET Poor control of symptoms Resistance: Failure to normalise blood counts Fails to normalise vascular risks Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

Limitations of Hydroxycarbamide in PV and ET Poor control of symptoms Resistance: Failure to normalise blood counts Fails to normalise vascular risks Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

Symptomatic burden prevalent across all MPN Mesa R. et. al. Cancer 2007;109:68-76

Systemic symptoms: pruritus Efficacy Among 1,953 PV patients from 10 studies, 42% (31%-69%) reported pruritus Reportedly associated with significant impairment of QoL in 19/44 (43%) of the patients in one study Agent JAK2 inhibitors mTOR inhibitor HDAC inhibitors Interferon Paroxetine/Fluoxetine H1-H2 blockers Anti-allergic Myelosuppression Phlebotomy Saini KS et al., Eur J Clin Inv 2010; 40:828-34

Limitations of Hydroxycarbamide in PV and ET Poor control of symptoms Resistance: Failure to normalise blood counts Fails to normalise vascular risks Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

Resistance in 11%; Intolerance 13%

Limitations of Hydroxycarbamide in PV and ET Poor control of symptoms Resistance: Failure to normalise blood counts Fails to normalise vascular risks Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

184 of 3411 (5%) developed side effects 167 mucocutaneous 16 fever 1 pneumonitis Am J Hematology, 2012

Intolerance to HU 3,411 MPN pts 1 Side Effects 184 pts (5%) * No Side Effect 2,831 pts Pneumonitis 1 pt Fever 16 pts (8.5%) Mucosal/cutaneous 167 pts (91%) * 11% in PT-12 12% in 3 1 Antonioli E et al., Am J Hematol 2012, In press; 2 Harrison c et al, NEJM 2005; 353:33-45; 3 Hernandez-Boluda JC et al, BJH 2010; 152:81-8

Limitations of Hydroxycarbamide in PV and ET Paucity of randomised trials in PV Poor control of symptoms Resistance: Failure to normalise blood counts Fails to normalise vascular risks Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

Risk factors for transformation in PV Marchioli et al, JCO, 2005

Choice of second line treatments Relax treatment targets Erythropoietin to help control anaemia in selected patients Anagrelide Interferon standard pegylated Alkylating agents P32 Investigatory agents Combination treatment Transplant Very little prospective trial data on which to base decisions Use non leukaemogenic agents where possible

Cortelazzo, 1995

Interferon: Non-leukaemogenic

Forthcoming MPD RC PEGASYS studies Phase 2 168 JAK2V617F +ve ET/PV patients HU resistant/refractory and 20 patients with splanchnic vein thrombosis Phase 3 612 JAK2V617F +ve ET/PV patients diagnosed within 3 years of trial entry Randomised between PEGASYS + aspirin and HU + aspirin

Current status of experimental therapies HDAC inhibitors – panobinostat, givinostat, vorinostat JAK 2 inhibitors

Durable Responses with the JAK1/JAK2 Inhibitor, INCB018424, in Patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory or Intolerant to Hydroxyurea (HU) Srdan Verstovsek1, Francesco Passamonti2, Alessandro Rambaldi3, Giovanni Barosi4, Peter Rosen5, Richard Levy6, Edward Bradley6, William Garrett6, Kris Vaddi6, Nancy Contel6, Victor Sandor6, Reid Huber6, Lee Schacter7, Elisa Rumi2, Elisabetta Gattoni4, Elisabetta Antonioli8, Lisa Pieri8, Mario Cazzola2, Hagop Kantarjian1, Tiziano Barbui3, Alessandro M. Vannucchi8 2010 Annual Meeting of the American Society of Hematology December 6, 2010 1Department of Leukemia, University of Texas MD Anderson Cancer Research Center, Houston,Tx, 2Division of Hematology, University of Pavia, Fondazione Istituto di Ricovero e Cura a Carattere, Scientifico Policlinico San Matteo, Pavia, Italy, 3Division of Hematology, Ospedali Riuniti, Bergamo, Italy, 4Unit of Clinical Epidemiology and Center for the Study of Myelofibrosis, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia, Italy,5 Tower Cancer Research Foundation, Beverly Hills, Ca,6Incyte Corporation, Wilmington, De, 7Pfizer Corporation, New York,,8Section of Hematology, Deparment of Critical Care, University of Florence, Italy

Phase II Study of INC424 in Patients with Advanced ET and PV Eligibility Criteria: Refractory or intolerant to hydroxyurea (HU) or HU contraindicated PV: Hct > 45% OR phlebotomy 2 times in last 6 months, with at least one phlebotomy in last 3 months ET: Platelets > 650 x 109/L unless on therapy Polycythemia vera (N=34) 10 mg BID (n=7) 25 mg BID (n=8) 50 mg QD (n=7) 10 mg BID (n=12) Part 1 Part 2 Essential Thrombocythemia (N=39) 10 mg BID (n=8) 25 mg BID (n=8) 50 mg QD (n=8) 25 mg BID (n=15) Part 1 Part 2 Srdan Verstovsek et at ASH, December 6, 2010

PV Results: Splenomegaly and WBC 80% of patients with palpable splenomegaly (n=25) achieved ≥ 50% reduction as of the last follow-up (68% achieved complete resolution of palpable splenomegaly) Leukocytosis (>15x109/L) was present in 15 patients at baseline: 73% normalized WBC as of the last follow-up visit Srdan Verstovsek et at ASH, December 6, 2010

PV Results: Platelet Counts and symptoms Mean Symptom Severity Scores Pruritus Bone Pain Thrombocytosis (>600 x109/L) was present in 13 patients at baseline: platelets normalized in 69% as of the last follow-up visit Night Sweats Srdan Verstovsek et at ASH, December 6, 2010

PV Response Response Criteria - European LeukemiaNet1 CR: Hct < 45% without phlebotomy, platelet count < 400,000, WBC < 10,000, normal spleen, no disease-related symptoms (pruritus, headache, microvascular disturbances) PR: Hct < 45% OR response in > 3 of the other criteria 97% overall response 50% CR 47% PR (spleen measured by palpation) 1Barosi et al., Blood 113:4829-4833, 2009

PV – ASH 2012 update 97% OR; 79% OR at 48 weeks, maintained in 74% at week 144

Platelet Count Reduction in ET 49% achieved normal platelet counts and 79% achieved <600,000 or a ≥50% reduction as of last follow-up visit 13 of 14 subjects with baseline platelet counts >1,000,000 have achieved a greater than 50% reduction

ET Response Response Criteria - European LeukemiaNet1 CR: Platelet count < 400 x109/L, WBC < 10 x109/L, normal spleen, no disease-related symptoms (pruritus, headache, microvascular disturbances) PR: Platelet count < 600 x109/L OR decrease > 50% from baseline 90% overall response 26% CR 64% PR 1Barosi et al., Blood 113:4829-4833, 2009

MAJ   C A RandoMised study of best Available therapy versus JAK Inhibition in patients with high risk Polycythaemia Vera or Essential Thrombocythaemia who are resistant or intolerant to HydroxyCarbamide TAP

Trial Schema 1:1 Randomisation Ruxolitinib Best Available Therapy PV: N = 90 patients per arm. ET: N = 55 patients per arm Patients stratified by disease type Ruxolitinib PV patients - 10 mg twice daily ET patients – 25mg twice daily Commence within 1 week of randomisation Best Available Therapy Commence within 1 week of randomisation BAT - any active agent but not solely venesection or supportive care Complete or Partial Response Continue Ruxolitinb and Follow-up for 5 years total FU minimum 2 monthly No response observed at 1 Year Continue Follow-up for 5 years Frequency at Investigators discretion Screening Patients with Polycythaemia vera or Essential Thrombocythaemia who are resistant to or intolerant of hydroxycarbamide Response assessed by European LeukemiaNet criteria within 1 year Change therapy

Summary Hydroxycarbamide is a well established and highly effective first line treatment for patients with ET and PV Patients who “fail” hydroxyurea treatment are at high risk of disease related complications Second line therapies are suboptimal and there is an unmet need for new agents for these hydroxycarbamide resistant patients Experimental therapy with JAK2i, pegylated interferon or HDACi show promise in these patients

Questions?