JAK2 Inhibitors for Myeloproliferative Diseases

Transcription

1 JAK2 Inhibitors for Myeloproliferative Diseases Srdan (Serge) Verstovsek M.D., Ph.D. Associate Professor Department of Leukemia University of Texas MD Anderson Cancer Center Houston, Texas, USA

2 Myeloproliferative Diseases Chronic Myelogenous Leukemia (CML) Essential Thrombocythemia (ET) Polycythemia Vera (PV) Primary Myelofibrosis (PMF) Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL) Systemic Mastocytosis (SM)

3 Incidence of Myeloproliferative Diseases Annual incidence / 100,000 population CML 1.6 ET 2.3 PV PMF 2.2 (survival ~20 years) 1.0 (survival ~5 years)

4 Primary Myelofibrosis Transformed SSC -> CD34 PE ->

5 Prognostic Scoring System for Myelofibrosis Prognostic variable Hazard ratio 95% CI P Age >65 yrs <0.001 Constitutional symptoms <0.001 Hb <10 g/dl <0.001 WBC >25 x 10 9 /L <0.001 Blood blasts >1% <0.001 Patients with all variables available: n=1,001 Cervantes. Blood. 2009;113(13):

6 Survival by Risk Group 1 Survival by PMF-PS Probability Months Cervantes. Blood. 2009;113(13): % CI 95% C I 95% CI 95% C I PMF-PS = 0 PMF-PS = 1 PMF-PS = 2 PMF-PS = 3

7 JAK-STAT Signaling A well characterized signaling pathway involved in normal hematopoiesis, inflammation, and immune function Four members of JAK family JAK1, JAK2, JAK3 and Tyk2 JAK2 mediates growth factor signaling (EPO for red blood cells and TPO for platelets) Shuai, K. & Liu,B. (2003) Nature Reviews Immunology 3:900

8 JAK2V617F Mutation Acquired Arises in multipotent progenitors Results in constitutively active JAK2 tyrosine kinase Causes disease (PV MF) in mice Present in ~50% of ET and MF patients, ~97% PV JAK2V617F

9 JAK2V617F Mutation in MPD Other mutations identified (MPL, JAK2 exon 12, TET2, ASXL1, EZH2, LNK, IDH ) Not a cause for the disease presence in humans; contributor to the disease existence JAK2 pathway dysregulation, regardless of mutational status, is a key pathologic feature of MPDs Quintás-Cardama A, Nat Rev Drug Discov Feb;10(2):

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11 JAK2 Inhibitors Not selective for mutated JAK2V617F (ATP-binding site inhibitors) May preferentially inhibit cells with mutation because they depend on always active JAK2V617F Myelosuppression is expected side effect due to JAK2 inhibition Elimination of the disease unlikely

12 JAK2 Inhibitors in Clinical Trials in MPD Agent (Company) NS-018 (NS Pharma) BMS (BMS) AZD1480 (AstraZeneca) LY (Lilly) CYT387 (YM/Cytopia) Diseases and studies MF: phase I MF: phase I MF: phase I ET/PV/MF: phase I MF: phase I/II SB1518 (S*Bio) MF: phase I/II; III planned SAR302503/TG (Sanofi Aventis/Targegen) INCB (ruxolitinib) (Incyte) MF: phase I/II; III planned MF: phase I/II; III completed ET/PV: phase II; III (PV) ongoing

13 Evaluation of JAK2 Inhibitors in MF Efficacy: Cytopenias (Anemia) Splenomegaly Quality of life/performance status Toxicity: Myelosuppression, other?

14 Phase I/II Study Of Ruxolitinib In Myelofibrosis 157 MF patients, intermediate-2 or high risk Phase 1: Established 25 mg twice a day (BID) orally as maximum tolerated dose (MTD) Thrombocytopenia was dose limiting toxicity (DLT) Phase 2: Expansion of 10, 15, and 25 mg BID cohorts Development of individualized dose optimization approach based on safety and efficacy Median time on study: 19.4 months 115/157 patients remain on study (73%) Update of Verstovsek S, N Engl J Med Sep 16;363(12):

15 Safety Update Based on 19 Month Follow up: Non-hematologic Toxicity Related Adverse Events* (%) N=157 Frequency All Grades (%) Frequency Grade 3 (%) Diarrhea Weight Increased Fatigue Headache Peripheral edema Pain in extremities Epistaxis Muscle Spasms * Assessed as at least possibly related in at least 2% of the study population with CTCAE (common terminology criteria for adverse events) used. No grade 4 toxicity recorded.

16 Safety Update Based on 19 month Follow up: Hematologic Toxicity Related and 10 mg BID 15 mg BID 25 mg BID 50 mg BID Unrelated Events N (%) Grade 3 6 (20%) 1 (3%) 12 (26%) 3 (60%) Thrombocytopenia Grade (11%) 1 (20%) Thrombocytopenia Transfusion Independent at Baseline New Onset Anemia* 6 (31%) 4 (17%) 8 (28%) NA Transfusion independent. New-onset anemia was defined as hemoglobin decline of > 20 g/l, to the grade 3 or grade 4 level, in previously transfusion-independent subjects. Optimized dosing with 15 mg BID starting dose markedly decreases hematologic AEs

17 Rapid and Durable Impact on Spleen Size Response analysis based on % spleen reduction (last on-therapy value) Proportion Of Subjects in Response Group BID, ITT 15 BID, ITT 0-24% 0-24% 25-49% 25-49% 50-99% 50-99% 100% 100% Palpable Spleen Length, cm (Mean ± SEM) LIVER LIVER 25 mg BID, N=39 15 mg BID, N=34 1 year SPLEEN 1.5 years 2 years SPLEEN Days on Therapy

18 Ruxolitinib Improves Splenomegaly in Patients With and Without JAK2 Mutation Spleen length, cm JAK mutation POSITIVE; N = 33 JAK mutation NEGATIVE; N = Time on Therapy (days) Note: 25mg BID cohort; data are censored after a dose change.

19 Splenomegaly in MF Patient Pre-Therapy

20 Splenomegaly after 2 Months of Therapy

21 Spleen Volume Decrease by MRI Parallels Spleen Size Reduction by Palpation % size reduction by palpation (response by IWG Criteria) Responder corresponds Analysis of spleen to size 35% volume reduction by MRI Proportion Achieving Response % 50% LIVER LIVER SPLEEN BEFORE THERAPY AFTER 6 MONTHS 0 SPLEEN 53% decrease In spleen volume, 32% decrease in liver volume

22 Spleen Size Reduction During 18 Month Follow-up: Reduction in Spleen Volume by MRI (ITT analysis) 70 Proportion of Subjects Showing 35% Reduction in Spleen Volume by MRI N = 25 N = 25 N = 25 N = 20 N = Months on Study Subjects initiated dosing at 15 mg BID with individual optimization Subjects with a missing observation, but subsequent data were censored for the missing data timepoint

23 Rapid and Durable Improvement in Symptoms: Optimized Dosing Regimen (15 mg BID dose) Proportion of Subjects with 50% Improvement in Score Abdominal Pain/Discomfort Itching Night Sweats Bone/Muscle Pain Months on therapy Data collected using Myelofibrosis Symptom Assessment Form (Mesa et al)

24 Improved Exercise Capacity and Body Weight 6-minute walk test (6MWT) is well established measure of exercise capacity MF patients walk meters less than age-matched healthy volunteers 80 Change in 6MWT Performance (meters) N=27 34 Meters N=26 57 meters N=21 71 meters Change in Body Weight, kg Mean Lowest Quartile Days on Study 0 1 Month 3 Months 6 Months Time on Study -9.5

25 Impact on Blood and Bone Marrow High white blood cells and high platelets decrease to normal levels % of patients achieved long lasting transfusion independence Percent blast in blood stays stable Bone marrow fibrosis does not change, stays stable JAK2V617F allele burden may decrease

26 Phase III Registration Trials COMFORT I Patients with MF (N = 309) Randomized 1:1 USA, Canada, Australia INC424 (oral) 15 mg BID or 20 mg BID Placebo (oral) BID COMFORT I Primary Endpoint Number of subjects achieving 35% reduction in spleen volume from baseline to week 24* COMFORT II Patients with MF (N = 219) Randomized 2:1 INC424 (oral) 15 mg BID or 20 mg BID Best available therapy COMFORT II Primary Endpoint Number of subjects achieving 35% reduction in spleen volume from baseline to week 48* EUROPE: Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, UK Both trials completed enrollment * As measured by MRI (or CT scan in applicable subjects).

27 Phase II study of ruxolitinib in PV (n=34) European LeukemiaNet Criteria: CR: Hct < 45% without phlebotomy platelet count < 400,000 WBC < 10,000 normal spleen no disease-related symptoms PR: Hct < 45% OR response in > 3 of the other criteria 97% overall response 50% CR 47% PR 27

28 Phase 3 Trial in PV: The RESPONSE Study I. HU resistance or intolerance (LEN criteria) II. q3month phlebotomy requirement III. Palpable spleen ( 5cm) HCT 40-45% inclusive R INCB18424 N=150 Best Available Therapy 1 o Endpoint Failure Disease Progression crossover IV. WBC >15K and/or platelet >600K N=150 Week 32 Week 80 Special protocol assessment agreement reached with FDA 1 o composite endpoint: Hct control in the absence of phlebotomy and 35% reduction in spleen volume at Week 32 2 o endpoints: Complete hematologic remission at Week 32; % of subjects who maintain 1 o endpoint response for 48 weeks NCT ; 28

29 Issues with Current JAK2 Inhibitors Not selective for JAK2V617F (patients with and without JAK2 mutation benefit) Role of other targets: JAK1 and FLT3 Toxicity profiles differ Efficacy: MF: primarily spleen size reduction and significant improvement in quality of life = better control of MF PV and ET: control of high blood cell counts and symptoms

30 THANK YOU