Back to the future in MPN. Claire Harrison Guy s and St Thomas Hospital NHS Foundation Trust, London, UK

Transcription

1 Back to the future in MPN Claire Harrison Guy s and St Thomas Hospital NHS Foundation Trust, London, UK

2 Primary Myelofibrosis 1879: Gustav Heuck ( ) Archiv Fur Pathol 1879;78: cases of leukemia with peculiar blood and marrow findings - Massive splenomegaly - Constitutional symptoms - Fibrous material in the bones Tefferi Leukemia 2008;22:3-13

3 Louis Henri Vaquez (27 August ) was a French Physician In 1892 he was the first to describe polycythaemia vera or polycythaemia rubra vera, which is also known as "Osler-Vaquez disease Vaquez described the disease in a 40- year-old male suffering from chronic cyanosis, distended veins, vertigo, dysnea, hepatosplenomegaly, palpitations and marked erythrocytosis

4 Later known as ESSENTIAL THROMBOCYTHAEMIA or ET

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6 Myeloproliferative milestones William Dameshek Some speculations on the myeloproliferative syndromes Axelrad & Prchal EPO independence Fialkow Stem cell origin 1980s - PVSG studies reported

7 Bloodletting 18th Century Persian manuscript illustration

8 Myeloproliferative milestones William Dameshek Some speculations on the myeloproliferative syndromes Axelrad & Prchal EPO independence ASPIRIN 1976 benefits - Fialkow Stem cell origin patients with PV PT-1 largest randomised study in ET 1980s - PVSG studies reported Description of JAK2V617F mutation, ECLAP study and PT JAK inhibitors (ruxolitinib) reach the clinic Phase I/II trials of ruxolitinib reported TARGET HCT or PCT in PV is confimed at 0.45 by Phase III trials of ruxolitinib in MF reported and FDA approval Description of Calreticulin gene mutations Phase III trials of ruxolitinib in PV

9 Myeloproliferative milestones William Dameshek Some speculations on the myeloproliferative syndromes Axelrad & Prchal EPO independence Fialkow Stem cell origin 1980s - PVSG studies reported Description of JAK2V617F mutation, ECLAP study and PT JAK inhibitors reach the clinic Phase I/II trials of INCB18424 reported Phase III trials of ruxolitinib in MF reported and FDA approval 2013 `- Description of Calreticulin gene mutations Phase III trials of ruxolitinib in PV

10 Beyond JAK2 V617F Mutation: Molecular Complexity of MPNs Mutations affecting the JAK-STAT Signaling JAK2 MPL LNK c-cbl SOCS1-3 CALR Mutations affecting the epigenetic regulation TET2 EZH2 ASXL1 IDH1/2 DNMT3A JAK2V617F Mutations associated with Leukemic transformation IDH1/2 IKZF1 TP53 NF1 RUNX1 NRAS KRAS DNMT3A 10

11 IDEAL REALITY

12 Thrombosis-free survival Age at Age diagnosis at diagnosis (years) No. patients with diagnosis Order matters at 100 a younger age 90 ** JAK2- first TET2-first Age at diagnosis for ET, PV, MF, smf JAK2-first patients present JAK2-first. are more likely to present as PV ORDER and phenotype PV AND ET * TET2 FIRST TET2-first * JAK2 FIRST JAK2-first P V ET ET PV TET2-first (n=18). and have increased risk of thrombosis (art + venous) JAK2-first (n=30) Ortmann, Kent et al NEJM 2015 Days from diagnosis P=0.002

13 TET2-first Model for effect of mutation order on MPN biology 737 wildtype TET2 mut JAK2 het JAK2 hom time First demonstration in any cancer that mutation order influences stem/progenitor cell behaviour, clinical presentation and response to therapy. Ortmann, Kent et al NEJM 2015

14 Myeloproliferative milestones William Dameshek Some speculations on the myeloproliferative syndromes MPD support is born later becomes Axelrad & Prchal EPO independence Fialkow Stem cell origin 1980s - PVSG studies reported Description of JAK2V617F mutation, ECLAP study and PT MPD JAK inhibitors reach becomes the clinic MPN Phase I/II trials of INCB18424 reported Phase III trials of ruxolitinib in MF reported and FDA approval 2013 `- Description of Calreticulin gene mutations Phase III trials of ruxolitinib in PV

15 17/11/14

16 What s new and clinical trials?

17 Its not all about drugs.. Sometimes research is asking a simple question how are your symptoms? or even just for a small amount of blood this study led to our discoveries of JAK2 and CALR mutations Bloodletting 18th Century Persian manuscript illustration

18 MPN trial portfolio in the UK ET PT-1 low and intermediate risk data collection MF ERNEST registry Momelolinib vs Ruxolitinib ET and PV First line: PEGASYS vs HC MPD RC 112 Refractory/intolerant to HU: MAJIC Response, Relief, ARD closed Second line: Momelotinib vs BAT anaemic on ruxolitinib Pfixer Smo vs BAT PERSIST 2 pacritinib vs BAT plts < 100 Phase I low platelets ruxolitinib Telomerase Combinations: Ruxolitinib+Pbinostat,+BKM120,+LDE225 Ruxolitinib pre BMT study MPD RC114 MDS/AML after MPN: Phazar - data collecton only / ruxolitinib + 5 azacytidine All MPN: MEASURES for symptoms MOSAICC epidemiology Sample banks Nick Cross and Tony

19 WHY DO MPNs DEVELOP?? CIs: Mary Frances McMullin, Andrew Duncombe, Lesley Ashton

20 Primary endpoint for ET next Spring MAJ C Only on-going study in PV ( & ET) likely to answer questions about transformation and thrombosis 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 40 slots left for PV patients

21 JAK1 & 2 Inhibitors in MPNs Efficacy Summary Myelofibrosis Polycythemia Vera Essential Thrombocythemia Yes Spleen Const. Sympt. Anemia Survival Counts Const. Sympt. Vasc Events Counts Const. Sympt. Vasc Events Occasion al Ruxolitinib - Approved P III P III P III P III P III P III?P III P II P II P II SAR PH III JAKARTA (HOLD) Pacritinib- PIII Ongoing (Persist 1 complete MF) CYT387 Momelotinib SIMPLIFY studies P III P III P II P III P II P II P II P II P II P II LY P I P I Ongoing Trials Not Reported Yet No NS-018 BMS PH II PH II INCB (JAK1 Alone) P I P I PI CEP701 P II P II P II P II P II P II 2011 MFMER

22 Pacritinib A Selective JAK2/FLT3 Inhibitor Not associated with clinically significant treatment-emergent anemia or thrombocytopenia in clinical studies 1 Kinase JAK1 IC 50 (nm) no effect at 100 nm JAK2 wt 6.0 JAK2 V617F 9.4 JAK TYK FLT3-ITD 13.4 FLT3 D835Y 4.7 CSF1R 39.5 IRAK CSF1R, colony stimulating factor 1 receptor; FLT, FMS-like tyrosine kinase; IC 50, half-maximal inhibitory concentration; IRAK1, interleukin-1 receptor associated kinase; ITD, internal tandem duplication; JAK, Janus kinase; TYK, tyrosine kinase. 1. William AD, et al. J Med Chem. 2011;54: Hart S, et al. Leukemia. 2011;25:

23 Phase 3 Trials with Pacritinib PERSIST-1 Eligibility Criteria Primary or Secondary MF (Int 1 or higher) No prior treatment with JAK2 inhibitors 2:1 Randomization* n = ~320 Pacritinib Best Available Therapy (BAT) excluding ruxolitinib Primary Endpoint % of patients achieving 35% reduction in spleen size from baseline to Week 24* Stratified for platelet counts of 100,000/µL and 50,000/µL Enrollment Complete: N = 327; Topline data Q Sites: ~90 in Europe, Australia, Russia and U.S. Principal Investigators: Ruben Mesa, M.D., Mayo Clinic Cancer Center, Arizona Claire Harrison, M.D., Guy s Hospital, London *Cross-over from BAT allowed after progression or assessment of the primary endpoint.

24 Change From Baseline, % RESULTS OF PERSIST-1 TRIAL Spleen Volume Reduction 35% At Week 24 as Assessed by MRI/CT ITT population: 19.1% vs 4.7%, PAC vs BAT (p=0.0003) Evaluable a population: 25.0% vs 5.9%, PAC vs BAT (p=0.0001) 60 PAC (n=168) BAT (n=85) Patients 35% decrease a Patients had both baseline and Week 24 spleen assessment by MRI or CT. BAT, best available therapy; CT, computed tomography; ITT, intent to treat; MRI, magnetic resonance imaging; PAC, pacritinib.

25 Mean Platelets 10 9 /L (± SEM) Mean Hgb (g/dl) (± SEM) Less Myelosuppression With Pacritnib: Platelets and Hemoglobin Over Time.. Mean Platelets 10 9 /L (± SEM) Mean Hgb (g/dl) (± SEM) PAC BAT p= a PAC BAT p= a BL BL Weeks Weeks Patients With Baseline Platelets <50,000/μL a Based on linear regression using mixed model. Patients With Baseline Hgb <10 g/dl BAT, best available therapy; PAC, pacritinib; SEM, standard error of the mean.

26 Second Phase 3 Trial of Pacritinib in MF PERSIST-2 Eligibility Criteria Patients with platelet counts 100,000/µL, prior/current JAK2 therapy allowed 1:1:1 Randomization 1 n = 300 Pacritinib 400 mg QD Pacritinib 200 mg BID Best Available Therapy (BAT) 2 Co-Primary Endpoints % of patients achieving 35% reduction in spleen volume from baseline to Week 24 (MRI/CT) Patients achieving 50% reduction in total symptom score (TSS) from baseline to Week 24 Status: Reached agreement with FDA on SPA in Oct. 2013; First patient randomized August 2014 Sites: Predominantly U.S.; Europe, Australia, New Zealand and Russia Principal Investigator: Srdan Verstovsek, M.D., MD Anderson, Texas Anticipated Patient Accrual: ~10-12 months (target LPFV Q1 2015) 1 Cross-over from BAT allowed after progression or assessment of the primary endpoint 2 BAT may include ruxolitinib at the approved dose for platelet count

27 Momelotinib (CYT387) Momelotinib is an oral small-molecule, ATP-competitive, JAK1 and JAK2 inhibitor A previous phase I/II study of momelotinib in subjects with myelofibrosis (n = 166) demonstrated improvements in splenomegaly, symptoms and anaemia 1 1 Pardanani et al. ASH 2012

28 Phase 3 Studies with Momelotinib 200 mg Tablet QD for Myelofibrosis N = 420 1:1 randomization Momelotinib + placebo Ruxolitinib + placebo SIMPLIFY-1 JAK inhibitor naïve Randomized, Double Blind Primary endpoint: Spleen Response by MRI at week 24 Day 1 Week 24 Year 5 N = 150 2:1 randomization Momelotinib N = 100 Best Available Therapy (ruxolitinib or no treatment allowed) N = 50 Day 1 Week 24 SIMPLIFY-2 Previous JAK inhibitor exposure Randomized, Open Label Required ruxolitinib dose adjustment to < 20mg BID and concurrent hematologic toxicity Primary endpoint: Spleen Response by MRI at week 24 Year 5

29 Combination Therapy with Ruxolitinib Therapies being tested WITH JAK2 inhibitors Allogeneic Hematopoietic Cell Transplantation Danazol (androgenic steroids) IMiD (lenalidomide or pomalidomide) Erythropoietin-stimulating agents GS-6624 (LOXL2) Azacytidine Decitabine Panobinostat BKM120 Hh inhibitors (LDE125) Planned: RAD001 (Everolimus) MEK inhibitor PRM-151 Pfizer Smo inhibitor

30 Newer Drugs for MPN (Excluding JAKi) Class Agent* Target PI3K pathway inhibitors BKM120/Buparlisib RAD001/Everolimus PI3K/Akt/ mtor Histone deacetylase (HDAC) inhibitors Panobinostat Vorinostat Givinostat Pacrinostat HDACs (different classes) HSP90 DNA methyltransferase inhibitors Azacitidine Decitabine DNA methyltransferase Hedgehog inhibitors LDE225 Smo Telomerase inhibitors Imetelstat Telomerase Bone marrow fibrosis inhibitors Pentraxin DAMPs and monocytes / macrophages * list not exhaustive

31 Imetelstat Tefferi et al. NEJM - September 3, 2015

32 Some patients achieve remission!

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35 CRISPR: Gene Therapy Finally Coming to MPNs? Clustered Regularly Interspaced Short Palindromic Repeat Bacterial immune response system leveraged for genome editing 36 MPNforum Magazine. CRISPR/Cas9: Gene Editing with Precision.

36 The landscape is changing Guy s a hospital for the incurables and criminally insane Guy s, London Thanks to many patients, teams & colleagues for dedication & sharing data