Update in Myeloproliferative Neoplasms January 20, 2012

November 16, 2011

FDA Indications for Ruxolitinib (Jakafi) Intermediate or high-risk Myelofibrosis =80-90% of MF patients JAK2V617F NOT required

Diagnostic Criteria for myelofibrosis Post PV or ET MF PMF Must meet all 3 major and ≥2 minor criteria Must meet both major and ≥2 minor criteria

JAK2V617F mutation: Not just for MPN anymore 95-97% PV >50% ET 50-60% MF 3-13% CMML 3-5% MDS (RARS & thrombocytosis) <5% AML

Dynamic International Prognostic Scoring System in MF DIPSS Obtained at any time during follow-up 0 = Low 1-2 = Intermediate-1 3-4 = Intermediate-2 5-6 = High Passamonti et al, Blood 2010

DIPSS-plus 3 additional factors The Dynamic International Prognostic Scoring System (DIPSS) plus prognostic model for primary myelofibrosis (PMF). The DIPSS and prognostic model for PMF uses 8 risk factors for inferior survival: age > 65 years, hemoglobin level < 10 g/dL, leukocyte count > 25 × 109/L, circulating blasts ≥ 1%, presence of constitutional symptoms, presence of unfavorable karyotype, platelet count < 100 × 109/L, and the presence of red cell transfusion need.40 *Please note that a transfusion-dependent patient automatically has 2 risk factors because of transfusion need (1 risk point) and hemoglobin level < 10 g/dL (1 risk point). **Constitutional symptoms constitute weight loss > 10% of baseline value in the year preceding diagnosis, unexplained fever, or excessive sweats persisting for > 1 month.38 ***Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q− 12p−, or 11q23 rearrangement.41 **Constitutional symptoms constitute weight loss > 10% of baseline value in the year preceding diagnosis, unexplained fever, or excessive sweats persisting for > 1 month ***Unfavorable karyotype constitutes complex karyotype or sole or 2 abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q− 12p−, or 11q23 rearrangement Tefferi, Blood 2011

COMFORT-I Primary endpoint Secondary endpoints * Patients randomized to placebo will be eligible to cross over to ruxolitinib Primary endpoint Proportion of subjects achieving >35% reduction in spleen volume from baseline to Week 24 as measured by MRI (or CT scan in applicable subjects) Secondary endpoints Duration of maintenance of a >35% reduction from baseline in spleen volume among subjects initially randomized to receive INCB018424 Proportion of subjects with >50% reduction in total symptom score from baseline to Week 24 as measured by the modified MFSAF v2.0 diary

Percent Change From Baseline in Spleen Volume in Individual Patients at Week 24 Verstovsek, S. Presented at ASCO 2011

Primary Endpoint: % of Patients with ≥35% Decrease in Spleen Volume at Week 24 (ITT) Verstovsek, S. Presented at ASCO 2011

Symptomatic Burden in MF Constitutional Symptoms Splenomegaly Myeloproliferation Functioning Percentage of patients reporting symptoms Scherber et al, Blood 2011

Percent of Patients with ≥50% Decrease in Total Symptom Score at Week 24 (ITT) Verstovsek, S. Presented at ASCO 2011

Proportion of Patients with ≥50% Reduction in Total Symptom Score Over Time Verstovsek, S. Presented at ASCO 2011

Percent Change From Baseline in Total Symptom Score in Individual Patients at Week 24 Verstovsek, S. Presented at ASCO 2011

Mean Percent Change in Individual Symptoms Verstovsek, S. Presented at ASCO 2011

Symptoms Return without drug

Increased serum cytokines in MPN MPN patients Mouse Model CD40 IFN-α IL-2R IL-11 VCAM-1 IL-2 IL-9 MIP-1α MMP-2 ICAM-1 MIP-1β IL-8 IL-7 MMP-10 IL-12 TNF IL-18 IL-13 IL-15 VEGF KC IL-10 IL-16 IL-1α,ß IL-6 TIMP-1 G-CSF IFN-γ Lower in MPN (Tyner et al, 2010) (Verstovsek et al, 2010 Slezak et al, 2009, Boissinot et al, 2010, Tefferi et al 2011)

TNF is elevated in MPN and correlates with JAK2V617F allele burden Fleischman et al, Blood 2011

Elevated IL-8 and IL-2R associated with decreased survival in PMF Intermediate-1 All patients Intermediate-2 Tefferi et al, JCO 2011

Consequences of Increased Inflammation HSC exhaustion Stress hematopoiesis Constitutional Symptoms -weight loss -fatigue -fever

Impact of Ruxolitinib on inflammatory cytokines Verstovsek et al, NEJM 2010

Ruxolitinib decreases inflammatory cytokines Verstovsek et al, NEJM 2010

JAK inhibitors: not just for MPN

Hematology Laboratory Values *Patients are included at their worst on study grade regardless of whether this represents a change from their baseline Grade 3 and 4 anemia and thrombocytopenia were more common in those with higher baseline grade Discontinuation of treatment because of anemia and thrombocytopenia was rare (1 patient in each treatment group for each event Verstovsek, S. Presented at ASCO 2011

Non-hematologic Adverse Events Observed in at Least 10% of Ruxolitinib-Treated Patients Verstovsek, S. Presented at ASCO 2011

Mean hemoglobin and Red Blood Cell Products Over Time Verstovsek, S. Presented at ASCO 2011

Red Blood Cell Transfusions Verstovsek, S. Presented at ASCO 2011

JAK2V617F allele burden Percentage of JAK2V617F mutant allele can be quantitatively measured (available at OHSU), but clinical relevance is unknown

Low JAK2V617F allele burden in PMF has negative impact

Low V617Fallele burden associated with shorter survival in PMF Guglielmelli et al, Blood 2009

Causes of Death in PMF Cervantes et al, Blood 2009.

COMFORT-I Overall Survival* * COMFORT-I was not designed nor powered to demonstrate a statistically significant difference in overall survival within the timeframe of the study endpoint. Patients who remain in COMFORT-I continue to be followed. Incyte, JP Morgan Healthcare conference Jan 9,2012

Ruxolitinib Dosing For plts 50-100 X 109/L: OHSU currently enrolling for clinical trial of ruxolitinib in thrombocytopenic patients with MF Jakafi prescribing information packet

Dose adjustment for thrombocytopenia Hold Drug for platelets <50 X 109/L Jakafi prescribing information packet

Drug Interactions: Strong CYP3A4 inhibitors will increase levels of ruxolitinib, with strong CYP3A4 inhibitors dose reduction is recommended. Patients should be closely monitored and dose titrated based on safety and efficacy. No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy Jakafi prescribing insert

How to prescribe Ruxolitinib http://www.jakafi.com/Files/RUX1066.pdf

Comparing various JAK inhibitors Drug Target Phase Disease Efficacy Toxicity INCB18424 JAK2, JAK1 Approved III MF PV/ET Splenomegaly, symptoms Anemia, thrombocytopenia TG101348, (SAR302503) JAK2, FLT3 II Anemia, thrombocytopenia, gastrointestinal SB1518 Gastrointestinal CEP701 MF, PV/ET Gastrointestinal, anemia, thrombocytopenia CYT387 JAK1, JAK2 I Splenomegaly, symptoms, anemia First dose effect, cytopenias LY2784544 JAK2 MF, ET/PV NPR AZD1480 JAK2, JAK3 I/II NS018

Clinical trials of non-JAK2 targeted therapies for MPN Drug Target Phase Disease Efficacy Toxicity RAD001 mTOR II MF Splenomegaly, symptoms Minimal Pomalidomide IMiD III Anemia PEG-IFNa-2a Biological PV/ET Erythrocytosis, thrombocytosis, symptoms Myelosuppression, depression LBH589 HDAC Splenomegaly, anemia Anemia, thrombocytopenia, gastrointestinal

Lenalidomide for MF Mayo Clinic - Blood. 2006 Aug 15;108(4):1158-64. 68 patients; lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. MD Anderson - J Clin Oncol. 2009 Oct 1;27(28):4760-6. 40 patients; lenalidomide 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) on days 1 through 21 of a 28-day cycle for six cycles with prednisone taper. ORR 30% for anemia and 42% splenomegaly by IWG-MRT criteria. ECOG Phase 2 (E4903) - Blood. 2010 Nov 25;116(22):4436-8. 48 patients; lenalidomide 10mg daily + prednisone taper; anemia improved in 19% and splenomegaly in 10% by IWG-MRT criteria.

Pomalidomide +/- prednisone in treatment of anemia in MF Tefferi et al, JCO 2009

Phase II trial of pomalidomide alone in MF Low dose pomalidomide alone (0.5mg/d) in 58 MF patients with anemia Response limited to JAK2V617F mutated patients 24% of V617F+ patients responded in terms of anemia and 9/10 became transfusion independent Response predicted by basophilia in first month of treatment 58% of patients with plts ≤ 100K experienced >50 % increase in plt count Begna et al, Leukemia 2011

rIFN-α may reverse fibrosis in early PMF Silver et al, Blood 2011

Peg-IFN-alpha2a for PV/ET Kiladjian et al Blood 2008;112:3065: 37 patients; 95% had hematologic CR; only 3 stopped tx at 12 months. Decreased JAK2V617F allele burden in 90%. Molecular CR in 7 patients. 90-180 mcg weekly. Quintas-Cardama et al JCO 2009;27:5418: 40 PV/39 ET; one prior cytoreductive treatment; 70%/76% hematologic CR; 14%/6% molecular CR. Only 10% of patients discontinued due to toxicity; no grade 4 toxicities; grade 3 were not frequent but included pain, fatigue, dyspnea, and pruritis. Tolerability of PEG-IFN-alpha-2a at 90 mcg weekly was excellent. Phase III trials comparing Hydroxyurea vs. Pegasys are underway (upfront high risk PV or ET; HU-resistant or refractory).

PEG-IFNα induces hematologic response in PV/ET Start at 90µg/week, with goal of 135µg/week Tolerable dosing Kiladjian et al, Blood 2008

90µg/wk PEG-IFNα-2a induces molecular response in PV/ET Quintas-Cardama et al, JCO 2009

Toxicities Associated with PEG-IFNα-2a -PEG-IFNα-2a 90µg/week -10% of patients discontinued due to IFN related toxicity Quintas-Cardama et al, JCO 2009

The curative approach: allogenic SCT Conditioning N Study Median Age Donor TRM (%) OS Myeloablative 551 Retr 42 RD=36 URD=20 27 47% (5-y) 562 43 RD=40 URD=9 58% (3-y) Reduced-Intensity 1033 Prosp FluBu+ATG 55 RD=33 URD=70 16 67% (5-y) 66 Prosp FluMel+/-ATG RD=32 URD=34 RD=16 URD=33 RD=78% (2-y) URD=44% (1y) Obstacles: -Donor availability -High TRM -Advanced patient age -Still ill defined morbidity -Comorbidities -Impact of cGVHD 1Guardiola et al, Blood 1999. 2Deeg et al, Blood 2003. 3Alchalby et at, Blood 2010. 4Rondelli, ASH 2011 Abst 1750.

Treatment Algorithm for myelofibrosis DIPSS/DIPSS-plus Low, Int-1 Int-2/high asymptomatic symptomatic Consider SCT Yes No observation *conventional drug therapy *ruxolitinib MyA 45-50y RI 45-65 refractory Investigational drug therapy

Treatment of Anemia: Conventional Approach -Prednisone -Danazol/Androgens -Erythropoietin stimulating agents (ESA) 15-20% response, Short lived -Thalidomide + Prednisone ≈ 20% response, neurotoxicity -Lenalidomide ≈ 20% response, myelosuppression Best in pts with del(5q31) -Splenectomy up to 50-75% response duration ≈ 1yr -RBC transfusions

Treatment goals Prevent thrombosis Prevent hemorrhage Alleviate constitutional symptoms Minimize primary and iatrogenic disease progression Improve QOL and survival