Durable Responses with the JAK1/JAK2 p Inhibitor, INCB018424, in Patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory or Intolerant to Hydroxyurea (HU) Srdan Verstovsek 1 , Francesco Passamonti 2 , Alessandro Rambaldi 3 , Giovanni Barosi 4 , Peter Rosen 5 , Richard Levy 6 , Edward Bradley 6 , William Garrett 6 , Kris Vaddi 6 , Nancy Contel 6 , Victor Sandor 6 , Reid Huber 6 , Lee Schacter 7 , Elisa Rumi 2 , Elisabetta Gattoni 4 , Elisabetta Antonioli 8 , Lisa Pieri 8 , Mario Cazzola 2 , Hagop Kantarjian 1 , Tiziano Barbui 3 , Alessandro M. Vannucchi 8 2010 Annual Meeting of the American Society of Hematology g y gy December 6, 2010 1 Department of Leukemia, University of Texas MD Anderson Cancer Research Center, Houston,Tx, 2 Division of Hematology, University of Pavia, Fondazione Istituto di Ricovero e Cura a Carattere, Scientifico Policlinico San Matteo, Pavia, Italy, 3 Division of Hematology, Ospedali Riuniti, Bergamo, , , y, gy, p , g , Italy, 4 Unit 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, 6 Incyte Corporation, Wilmington, De, 7 Pfizer Corporation, New York,, 8 Section of 1 Hematology, Deparment of Critical Care, University of Florence, Italy
ET and PV � ET and PV, with MF, represent the 3 ‘classic’ BCR-ABL-negative MPNs – ET is characterized by megakaryocyte hyperplasia and persistent thrombocytosis; PV by clonal proliferation of erythroid, myeloid, and megakaryocyte cell lineages – Both are associated with increased risk of thrombosis and progression to MF or AML � Normalization of platelet counts in ET and Hct % in PV are primary treatment goals – Rx also needed for symptomatic splenomegaly and debilitating symptoms that arise with disease progression � Therapeutic options are limited for ET and PV patients refractory or intolerant to hydroxyurea (HU) � INCB 18424 treatment in MF, Post PV-MF, and Post ET-MF has been well tolerated and associated with reductions in spleen size and symptom relief 2
Phase II Study of INCB 18424 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 % p y , one phlebotomy in last 3 months • ET: Platelets > 650 x 10 9 /L unless on therapy Polycythemia vera (N=34) P l th i (N 34) 10 mg BID 10 mg BID 25 mg BID 25 mg BID 50 mg QD 50 mg QD 10 mg BID 10 mg BID ( ( (n=7) (n=7) ) ) ( ( (n=8) (n=8) ) ) (n=7) (n=7) ( ( ) ) (n=12) (n=12) ( ( ) ) Part 1 Part 2 Essential Thrombocythemia (N=39) Essential Thrombocythemia (N=39) 10 mg BID 10 mg BID 25 mg BID 25 mg BID 50 mg QD 50 mg QD 25 mg BID 25 mg BID (n=8) (n=8) (n=8) (n=8) (n=8) (n=8) (n=15) (n=15) Part 1 Part 2 3
ET Patient Characteristics Characteristic (median) ET (n = 39) Age, years 51 Female 64% Months from Diagnosis 88 Refractory to HU Refractory to HU 87% 87% No. Prior Therapies 1 (1-3) Hct % 41.0 Platelets x10 9 /L 849 (mean 1009) WBC x10 9 /L 8.2 Splenomegaly Splenomegaly 4 (10%) 4 (10%) Size, cm (range) 5 (3-7) JAK2 V617F positive 65% JAK2 V617F allele burden 16% 4
ET Patient Disposition � 28 of 39 (72%) continue on study with a median follow- up of 21 months (range 4-27) up of 21 months (range 4 27) � 11 patients (28%) have discontinued treatment – 5 due to lack of response – 6 due to different medical reasons: fatigue, weight gain, GI disorder, renal insufficiency, foot pain (2) Current Dose Distribution < 5 mg BID < 5 mg BID 5-10 mg BID 5-10 mg BID 15 mg BID 15 mg BID 20-25 mg BID 20-25 mg BID > 25 mg BID > 25 mg BID 3% 40% 17% 33% 7% 5
Overall Safety in ET Treatment-related AEs* All Grades; n (%) Grade 3; n (%) Anemia 29 (74) 0 Weight increase 9 (23) 0 Herpes zoster Herpes zoster 2 (5) 2 (5) 0 0 Hyperuricemia 2 (5) 0 Leukopenia 2 (5) 2 (5) Pain in extremity 2 (5) 0 Palpitations 2 (5) 0 *Occurring in at least 2 subjects; at least ‘possibly’ related g j p y � No treatment-related Grade 4 AEs have occurred on study � Hematologic AEs are generally reversible and managed with dose reduction or temporary interruption reduction or temporary interruption 6
Serious Adverse Events in ET � Five patients have reported 5 treatment-emergent SAEs: Five patients have reported 5 treatment emergent SAEs: – Gastric bleeding g (unrelated): continued therapy ( ) py – Bronchitis (unrelated): continued therapy – Cholecystitis (unlikely related): continued therapy – Headache (unlikely related): continued therapy – Renal failure (possibly related): discontinued therapy 7
Platelet Count Reduction in ET 1750 All Patients (n=39) 9 /L) 1500 Baseline >1000 x 10 9 /L Baseline >1000 x 10 /L ount (x10 n + SEM) (n=14) 1250 1000 Platelet Co (mean 750 750 500 250 P 0 0 3 6 9 12 15 18 21 Months of Treatment � 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 8 achieved a greater than 50% reduction
ET Results: WBC, Splenomegaly, Symptoms � WBC counts for all 11 patients with baseline >10 x 10 9 /L normalized within first month and were maintained for a median of 14 months � Of 4 patients with splenomegaly at baseline all have achieved and maintained non-palpable spleen (3) or a > 50% reduction (1) through last follow-up visit % of ET Patients with a > 50% Reduction in Symptom Scores 90 80 80 70 ts n 60 tie 50 a f P P 40 o 30 % 20 83% 68% 65% 64% 10 0 9 Night Sweats Bone Pain Pruritus Peripheral Numbness n=12 n=22 n=18 n=28
ET Response � Response Criteria - European LeukemiaNet 1 – CR: Platelet count < 400 x10 9 /L, WBC < 10 x10 9 /L, normal spleen, no disease-related symptoms (pruritus headache microvascular disturbances) (pruritus, headache, microvascular disturbances) – PR: Platelet count < 600 x10 9 /L OR decrease > 50% from baseline � 90% overall response – 26% CR 26% CR – 64% PR 10 1 Barosi et al., Blood 113:4829-4833, 2009
PV Patient Characteristics Characteristic (median) PV (n = 34) Age, years 58 Female 50% Months from Diagnosis 115 Refractory to HU Refractory to HU 74% 74% No. Prior Therapies 1 (1-3) Hct % 46.7 Phlebotomy in last 6 months 76% Platelets x10 9 /L 527 WBC x10 9 /L 13.2 Splenomegaly 25 (74%) Size, cm (range) 9 (1-21) JAK2 V617F positive JAK2 positive 100% 100% JAK2 V617F allele burden 72% 11
PV Patient Disposition � 28 of 34 (82%) continue on study with a median follow-up of 21 months (range 8-28) � 6 patients (18%) have discontinued treatment: – 1 due to lack of response – 4 due to different medical reasons: shortness of breath desire to 4 due to different medical reasons: shortness of breath, desire to conceive, abdominal pain/leucopenia, renal tumor – 1 for disease progression Current Dose Distribution < 5 mg BID g 5-10 mg BID g 15 mg BID g 20-25 mg BID g > 25 mg BID g 0% 66% 14% 14% 7% 12
Overall Safety in PV Treatment-related AEs* All Grades; n (%) Grade 3; n (%) Anemia 25 (74) 0 Thrombocytopenia 10 (29) 2 (6) Leukopenia p 5 (15) ( ) 0 Weight increase 5 (15) 0 Diarrhea 3 (9) 0 Hyperuricemia Hyperuricemia 3 (9) 3 (9) 0 0 Insomnia 3 (9) 0 Palpitations 3 (9) 0 *Occurring in at least 3 subjects; at least ‘possibly’ related *O i i t l t 3 bj t t l t ‘ ibl ’ l t d � No treatment-related Grade 4 AEs have occurred on study � Hematologic AEs are generally reversible and managed with dose reduction or t temporary interruption i t ti 13
Serious Adverse Events in PV � Five subjects have reported 8 treatment-emergent Five subjects have reported 8 treatment emergent serious adverse events (SAEs): – Pneumonia and, one year later, congestive heart failure (both unrelated): continued therapy – Pneumonia (unrelated): continued therapy Pneumonia (unrelated): continued therapy – Gastric bleeding (unlikely related): continued therapy – Renal tumor (possibly related): discontinued therapy ( y ) y – Thrombocytopenia and anemia (unrelated) and atrial flutter (possibly related): discontinued therapy 14
PV Results: Hematocrit Control (Hct ≤ 45%) without Phlebotomy 97% of patients have achieved hematocrit ≤ 45% without the use of phlebotomy without the use of phlebotomy 100 100 it Hematocr ebotomy 80 Without Phl Achieving 60 40 Patients A Control W 20 n=34 n=34 n=34 n=33 n=31 n=29 n=28 n=19 C % 0 1 3 6 9 12 15 18 21 15 Months of Treatment
PV Results: Splenomegaly Rapid and Durable Reductions in Palpable Spleen Length 12 12 Baseline Spleen > 0 cm Baseline Spleen > 0 cm h en Length (n=25) Baseline Spleen > 5 cm 9 (n=17) SEM) able Splee (mean + S (cm) ) 6 Palpa 3 3 0 0 3 6 9 12 15 18 21 Months of Treatment • 80% of patients with palpable splenomegaly (n=25) achieved ≥ 50% reduction as of the last follow-up (68% achieved complete resolution of palpable splenomegaly) 16
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