5Calreticulin (CALR) Within ER - chaperone ensuring quality control of glycoprotein folding- calcium homeostasisOutside ER- found in cytoplasmic, cell surface and extracellular compartments- roles in: proliferationapoptosisphagocytosisimmunogenic cell death
12New Response Criteria for MPNs ET2PV2MF1Complete responsePartial responseClinical improvementStable diseaseNo responseRelapseOther responsesMolecularCytogenetic andmolecular1. Tefferi A et al. Blood. 2013;122: Barosi G et al. Blood. 2013;121:
13New Response Criteria for MF: Complete Response1 Required criteria: for all response categories, benefit must last for ≥12 wks to qualify as a responseBone marrow:Age-adjusted normocellularity;<5% blasts;≤Grade 1 MF; andPeripheral blood:Hemoglobin ≥ 100 g/L and <UNL;Neutrophils ≥ 1 x 109/L and <UNL;Platelets ≥ 100 x 109/L and <UNL;<2% immature myeloid cells; andClinical:Resolution of disease symptomsSpleen and liver not palpableNo evidence of EMHEMH: extramedullary hematopoiesis1. Tefferi A et al. Blood. 2013;122:
14New Response Criteria for MF: Other Categories1 Clinical improvementAchievement of anemia, spleen, or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropeniaAnemia responseTransfusion-independent pts: a ≥20 g/L increase in Hb levelTransfusion-dependent pts: becoming transfusion independentSpleen responseBaseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable, ORBaseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by ≥50%Baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for spleen responseSymptoms responseA ≥50% reduction in the MPN-SAF TSSCI: clinical improvement; LCM: left costal margin.1. Tefferi A et al. Blood. 2013;122:
15Myeloproliferative Neoplasms Hematology Highlights 2014 Burden and Biology of MPNsJAK2 Inhibition in 2014JAK2 Inhibition and beyond
17Patient Disposition – 3 Year FU Comfort I Ruxolitinib (n = 155)Placebo(n = 151)Placebo Ruxolitinib (n=111)Median exposure, weeks14537105Still on treatment, n (%)77 (49.7)57 (51.4)Crossed over, n (%)111 (73.5)Discontinued, n (%)78 (50.3)40 (26.5)54 (48.6)Primary reasons for discontinuation, n (%)*Death15 (19.2)7 (17.5)11 (20.4)Adverse event9 (22.5)8 (14.8)Consent withdrawn12 (15.4)Disease progression18 (23.1)13 (32.5)15 (27.8)All patients originally randomized to placebo crossed over or discontinued within 3 months of the primary analysisMedian time to crossover: 41.1 weeksASH 2013* Percentages are calculated based on the number of patients who discontinued within the respective treatment group.
18Mean Daily Dose of Ruxolitinib Over Time ASH 2013252015105Mean Daily Dose (mg, BID) ± SEM81624327210413614448881206456961284080112Weeks20 mg BID starting dose15 mg BID starting dose986220 mg BID4915 mg BIDNumber of patients100557769332673309335Approximately 70% of patients had dose adjustments during the first 12 weeks of therapyBy week 24, patients originally randomized to RUX 15 mg BID and 20 mg BID were titrated to a mean dose of ~10 mg BID and mg BID, respectively
19Percentage Change in Spleen Size ASH 2013Mean reductions in spleen volume and palpable spleen length with ruxolitinib were stable over timeRuxolitinibPlaceboWeeksMean Percentage Change from Baseline148139120107100841323573n =122448729614448153152150141130110102147136109479079Spleen VolumeSpleen Length
20Improvements in EORTC QLQ-C30 Over Time ASH 2013Global Health Status/QoLFatigue10-10-15-25-355-5-20-302010-5-15155-10Mean Change From BaselineMean Change From Baseline12243648607284961081201321441224364860728496108120132144WeeksRUXPBOWeeksArrows indicate improvementRole FunctioningPhysical Functioning2510-5-15-25155-10-2020Mean Change From BaselineWeeks155-5-1010Mean Change From Baseline12243648607284961081201321441224364860728496108120132144Weeks
21Overall Survival ASH 2013 HR=0.69 (95% CI: 0.46, 1.03); P=0.067 Overall survival favored patients originally randomized to ruxolitinib compared with patients originally randomized to placebo153144129114105Placebo15414913411910710092858958879388268281551481431311241151111081RuxolitinibNumber of patients at risk145137125122112101451068419Randomized to Placebo RuxolitinibRandomized to Ruxolitinib1.00.80.60.40.224405672104120136168176ProbabilityWeeks163248648096128152160422549913357397HR=0.69 (95% CI: 0.46, 1.03); P=0.067No. of deaths: Ruxolitinib=42; Placebo=54Median follow-up: 149 weeksPercent of at-risk placebo who crossed over or discontinued**By week 80, all patients originally randomized to placebo discontinued or crossed over to ruxolitinib therapy21
22Overall Survival: Rank-Preserving Structural Failure Time (RPSFT) Analysis ASH 20131.00.80.60.40.282440567288104120136168176ProbabilityWeeks163248648096112128152144160HR=0.36 (95% CI: 0.204, 1.035)Placebo RuxolitinibRuxolitinibPlacebo-RPSFTRPSFT is a recognized method to estimate HR after adjusting for crossover1-5Hazard ratio of 0.36 is consistent with the hypothesis that ITT analysis underestimates the survival benefit of ruxolitinib relative to “true placebo”(1) Robins J, Tsiatis A. Commun Stat Theory Methods. 1991;20: ; (2) Demetri GD, et al. Clin Cancer Res. 2012;18: ; (3) National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance Issued September 23, 2009; (4) Sternberg CN, et al. Eur J Cancer. 2013;49: ; (5) National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance Issued February 2011.22
23Mean Platelet Count and Hemoglobin Level Over Time ASH 2013Platelet CountHemoglobin370115RuxolitinibPlaceboRuxolitinibPlacebo110320105270Mean Platelets (x109/L)Mean Hemoglobin (g/L)10022095170901208512243648607284961081201321441224364860728496108120132144WeeksWeeksNumber of patientsNumber of patientsRUX155144143136124112110107104100948879155145143136124113110107104100948879PBO15112811282371511321138337
24Incidence of New Onset All Grade Non-hematologic Adverse Events Regardless of Causality ASH 2013Incidence (%)Ruxolitinib0–<12 months (n=155)12–<24 months (n=130)24–<36 months (n=103)≥36 months (n=82)Fatigue29.015.215.37.7Diarrhea27.86.710.83.9Ecchymosis220.127.116.11Peripheral edema21.38.412.6Dyspnea18.104.22.168.3Dizziness18.13.03.5Pain in extremity18.06.24.2Headache22.214.171.124Nausea6.85.9Constipation14.58.610.19.0Abdominal pain13.83.6Insomnia3.7Vomiting126.96.36.199.5Pyrexia188.8.131.52Cough13.113.34.06.0Arthralgia184.108.40.206.3Upper respiratory tract infection11.13.2There was no change in the rate, distribution, or severity of nonhematologic adverse events in the ruxolitinib group with longer-term treatment; most nonhematologic adverse events were grade 1 or 2Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the beginning of the interval minus half of the censored patients during the time interval).Adverse event is included if the incidence was >10% at any yearly interval.
25Incidence of New Onset Grade 3 or 4 Non-hematologic Adverse Events Regardless of Causality ASH 2013Incidence (%)Ruxolitinib0–<12 months (n=155)12–<24 months (n=130)24–<36 months (n=103)≥36 months (n=82)Fatigue220.127.116.11Pneumonia18.104.22.168Abdominal pain4.23.2Arthralgia2.1DiarrheaDyspnea2.22.5Pain in extremity1.1Hyperuricemia1.4FallGI hemorrhageSeptic shockMuscular weaknessHypoxiaSepsis0.71.7EpistaxisRenal failure acute2.4Abdominal pain upperMyocardial infarction4.8Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the beginning of the interval minus half of the censored patients during the time interval).Adverse event is included if the incidence was ≥2 patients at any yearly interval.
26BM Morphology in a Ruxolitinib-Treated Patient: A Case Demonstrating Improvement on Ruxolitinib ASH 201324 MoPost RuxolitinibGrade 248 MoPost RuxolitinibGrade 0Baseline BiopsyGrade 3Kvasnicka HM, et al. ASCO (abstr 7030).Permission to use images from Kvasnicka, HM
27Dynamics of BM Changes Following Ruxolitinib Treatment at 48 Mo ASH 2013Kvasnicka, et al. ASH Abstract 4055.
35MPNs – Cumulative Benefits Ruxolitinib + drug X for Deeper Marrow Changes Impact Clinical StatusSTUDY COMBINATION(JAK2 PLUS HDAC Inhibitors)Ruxolitinib Plus PanobinostatMt. Sinai Trial: NCTUK Trial: NCTImproved Marrow DysfunctionSTUDY COMBINATION (JAK2 PLUS LOXL2 Inhibitors)Ruxolitinib Plus GS-6624NCTImproved SurvivalSTUDY COMBINATION (JAK2 PLUS rhPTX-2 (Anti-fibrosing))Ruxolitinib Plus PRM -151Opening SoonImproved Spleen BurdenSTUDY COMBINATION (JAK2 PLUS PI3 Kinase Inhibitor)Ruxolitinib Plus BKM120NCTImproved Symptom BurdenSTUDY COMBINATION(JAK2 PLUS Hedgehog Inhibitor)Ruxolitinib Plus LDE225NCT
37Imetelstat: A Telomerase Inhibitor Telomerase enzyme:Reverse transcriptase comprised of an RNA component (hTR) and a reverse transcriptase catalytic protein subunit (hTERT)Binds to the 3’ strand of DNA and adds TTAGGG nucleotide repeats to offset the loss of telomeric DNA occurring with each replication cycleNot active in somatic cells; transiently upregulated in normal hematopoietic progenitor cells to support controlled proliferationHighly upregulated in malignant progenitor cells, enabling continued and uncontrolled proliferationimetelstat binds to RNA template preventing maintenance of telomeresImetelstat:(hTERT)Proprietary: 13-mer thio-phosphoramidate oligonucleotide complementary to hTR, with covalently-bound lipid tail to increase cell permeability/tissue distributionLong half-life in bone marrow, spleen, liver (estimated human t½ = 41 hr with doses 7.5 – 11.7 mg/kg);Potent competitive inhibitor of telomerase: IC50 = nM (cell-free)Target: malignant progenitor cell proliferation(hTR)Tefferi et. al. ASH 2013
38Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosisGeron’s independent efficacy analysis of the first 22 MF patients enrolled in the studyTefferi et. al. ASH 2013– 10 –
39Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosisGeron’s independent efficacy analysis of the first 22 MF patients enrolled in the studyTefferi et. al. ASH 2013– 10 –
40Change in Spleen Volume at Week 12 by Dose Cohort Median % Change in Spleen Volume*Percentage Change FromBaseline at Week 12n=7n=38n=9*Only patients with baseline and week 12 data were included.INCB ASH Mascarenhas et. al
41Improvement in TSS at Week 12 by Dose Cohort ≥50% Reduction in TSS*Median % Change in TSS†n=6n=34n=8Percentage Change FromBaseline at Week 12Percentage of Patientsn=9n=43n=10*Patients who discontinued prior to the week 12 visit were considered nonresponders; 20%-33% of patients in each group discontinued prior to week 12.†Only patients with baseline and week 12 data were included.INCB ASH Mascarenhas et. al
42Mean Hemoglobin Levels Over Time by Dose Cohort 100 mg BID200 mg BID600 mg QDMean (±SEM) Hemoglobin (g/dL)Mean (±SEM) Hemoglobin (g/dL)WeeksWeeksAll PatientsPatients entering the study without transfusion requirements*n, patientsn, patients100 mg BID200 mg BID600 mg QD10986100 mg BID4541433937200 mg BID2921600 mg QD7642422232119155*Receipt of 2 or more units of red blood cell product transfusions in the 12 weeks prior to day 1.INCB ASH Mascarenhas et. al
43MPNs – Cumulative Benefits Difficult PV-ET Clinical StatusSTUDY (ET and PV)MPD-RC 112 Peg Inf a2a vs. Hydroxyurea (PH III)NCTSTUDY (ET and PV)MPD-RC 111 Peg Inf a2a AFTER Hydroxyurea(PH III)NCTImproved Marrow DysfunctionImproved SurvivalSTUDY (PV)AOP Peg Inf a2a vs Hydroxyurea (PH III)NCTImproved Spleen BurdenSTUDY COMBINATION (PV)Ruxolitinib Vs. Hydroxyurea (RELIEF)NCTImproved Symptom BurdenFUTURE STUDY COMBINATIONJAK2 Inhibitor Plus PEG INFa 2a/bImproved Vascular Event Risk (?PV)