Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

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1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366:

2 A randomized study of the JAK inhibitor INC424 tablets compared to best available therapy in subjects with primary myelofibrosis (PMF), post-polycythemia veramyelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF) Title: COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Treatment-II: (The COMFORT-II Trial) Descriptive Title: A Randomized Study of the JAK Inhibitor INC424 Tablets Compared to Best Available Therapy in Subjects with Primary Myelofibrosis (PMF), Post- Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) Protocol Number: CINC424A2352 Phase of Study: Phase 3 EUDRACT Number: Sponsor: Novartis Version of Protocol: 06 Clean Date of Protocol: Original: 23-Mar-2009 Amendment 1: 18-Jun-2009 (UK only) Amendment 2: 23-Jul-2009 Amendment 3: 25-Feb-2010 Amendment 4: 15-Oct-2010 Amendment 5: 02-Feb-2011 Amendment 6: 01-Jun-2011 (Sweden only) Document type: Amended Protocol Version Document status: Final Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis

3 Novartis Confidential Page 2 Note to the reader: Please note the following modification related to the sponsorship change: Incyte drug code INCBO18424 is replaced with the Novartis drug code INC424 and similarly the Incyte study number INCBO18424 is replaced with the Novartis study number CINC424A2352. Starting with this Amendment 3 to the protocol the Novartis drug code and study number will be used. However all references to the IB will maintain the Incyte nomenclature.

4 Novartis Confidential Page 3 Table of contents Table of contents... 3 List of figures... 8 List of tables... 8 Amendment 6 for Sweden only... 9 Amendment Amendment Synopsis List of abbreviations and definitions of terms Introduction Background Myelofibrosis and myeloproliferative neoplasms Inhibition of Janus Kinases (JAKs) in myelofibrosis Preclinical studies relevant to the study INCB pharmacokinetics INCB preclinical safety Clinical pharmacology of INCB INCB clinical safety in healthy volunteers INCB clinical safety and efficacy in phase Trial rationale Potential risks and benefits INC424 potential risks INC424 benefits Best-available therapy risks and benefits Justification of route, dose regimen and treatment period History of Amendments Amendment # 1(UK only) Amendment # Amendment # Study objectives Primary objectives Secondary objectives Investigational plan Trial endpoints Primary efficacy endpoint Secondary efficacy endpoints... 35

5 Novartis Confidential Page Safety assessment Exploratory assessments Trial design Dose group assignment Assignment of starting dose level Study visits Criteria for disease progression Extension phase--continuation for subjects randomized to INC Extension phase--cross over for subjects randomized to control group Dose adjustments Dose increases for inadequate efficacy in the randomized treatment phase Dose increases for inadequate efficacy in the extension phase Dose adjustments for safety in all subjects receiving INC Dose reductions for concomitant CYP inhibitor usage Optional dose tapering strategy in the event of drug discontinuation Measures taken to avoid bias Subject eligibility Study population Inclusion criteria Exclusion criteria Subjects who fail to meet screening criteria Description of study visits Schedule of observations Screening and baseline evaluations Screening evaluations (day -28 to day -8) Baseline evaluations (day -7 to day -1) On-treatment evaluations On-treatment evaluations-before the primary endpoint analysis End of treatment evaluations End of study or early termination visit Follow-up evaluations Duration of participation Study assessments Demographic and other pre-treatment assessments Safety assessments... 75

6 Novartis Confidential Page Adverse events Physical examinations Vital signs lead ECG Clinical safety laboratory assessments Symptom and functional response assessments Response assessments Pharmacokinetic methods Blood collection Bioanalytical methodology Pharmacokinetic parameter assessment Pharmacodynamics method Blood collection for plasma PD assay Plasma PD assay methodology Plasma PD assay assessment Treatment of subjects Investigational product(s) description Dosage and dose regimen Storage and stability of clinical trial materials Drug accountability Preparation of study drug(s) Administration of study drug(s) Interruption and discontinuation of study drug Dose modifications Duration of treatment Prior and concomitant medications / measures Restricted and/or prohibited medications Restricted/allowed therapies Prohibited therapies Compliance Selection and withdrawal of subjects Enrollment Admittance of subjects into screening Method of assigning subjects to treatment groups Withdrawal criteria and procedures Withdrawal of subjects from study Replacement of subjects... 87

7 Novartis Confidential Page Protocol deviations Adverse events Definitions Adverse event Serious adverse event Recording, classification and reporting of adverse events Adverse event recording Adverse event classification Serious adverse events reporting Statistics Study populations Efficacy analysis Primary efficacy analyses Secondary efficacy analyses Sensitivity and subgroup analysis Handling of missing values Safety analysis Adverse events Clinical laboratory tests Vital signs Electrocardiograms Selection of sample size Level of significance and control of type one errors Interim analysis Data safety monitoring board Data management Data collection Data management Unblinding after the demonstration of superiority for the primary or key secondary endpoint Study administration Access to source documents Statement of good clinical practices Protocol adherence Study termination Financial disclosure Quality control and assurance

8 Novartis Confidential Page Sponsor audits Inspection by regulatory authorities Ethics Institutional Review Board or Independent Ethics Committee Informed consent Data privacy Record keeping / retention of records Confidentiality Use of study results References (available upon request) Appendices Appendix I - Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms Appendix II - Information regarding effectiveness of contraceptive methods Appendix III - Clinical laboratory tests Appendix IV - Eastern Cooperative Oncology Group Performance Status Appendix V - Bone marrow biopsy and aspirate evaluation Appendix VI - Restricted/prohibited medications

9 Novartis Confidential Page 8 List of figures Figure 3-1 Figure 5-1 Mean spleen size in subjects receiving BID regimens in study INCB (Mean +/- SEM) Strategies for dose increase because of inadequate efficacy (by palpation) at week 4 in subjects randomized to INC List of tables Table 3-1 Reduction of palpated spleen size and incidence of thrombocytopenia in study INCB Table 5-1 Starting dose of INC424 after cross over Table 5-2 Dose increases for inadequate efficacy for subjects who have crossed over to receive INC Table 5-3 Dose reductions in INC424 for safety in subjects with platelet count declines Table 5-4 Restarting or increasing INC424 dose after safety interruptions or dose reductions Table 7-1 Schedule of observations-prior to demonstration of superiority for the primary or key secondary endpoint Table 7-2 Schedule of observations: Extension Phase - after demonstration of superiority for the primary or key secondary endpoint... 53

10 Novartis Confidential Page 9 Amendment 6 for Sweden only Amendment rationale The MPA requested a change in the rationale of bullet #6 of Amendment 5 to clarify why the Bone marrow Biopsy is no longer mandated as this is a secondary endpoint of the study. Bullet point #6 of Amendment 5 read as follows: 6. Change the requirement of Bone Marrow Biopsy to be performed at the discretion of the investigator and not as a timed procedure. Bone marrow examinations are performed as a tool for diagnostic purposes in myelofibrosis but are not a standard requirement for the management of the disease. Transformation to acute leukemia (a secondary endpoint of the study) is an event that can be monitored with peripheral blood counts and verified, when necessary, with an additional bone marrow examination For Sweden only bullet point #6 will read as follows: [6. Change the requirement of Bone Marrow Biopsy to be performed at the discretion of the investigator and not as a mandated procedure. Bone marrow examinations are performed as a tool for diagnostic purposes in myelofibrosis but are not a standard requirement for the management of the disease. Change in bone marrow histomorphology is one of many secondary endpoints in the core phase of the study, and since the primary endpoint has been met it is no longer imperative to follow bone marrow examination during the extension phase. Transformation to acute leukemia (a secondary endpoint of the study) is an event that can be equally monitored with peripheral blood counts and verified, when necessary, with an additional bone marrow examination. Bone marrow biopsies can be performed at any time, if deemed necessary by the treating physician therefore this change does not impose any risks to patients but rather alleviates the burden in assessments- for Sweden only] Changes to the protocol There are no changes to the protocol amendment itself only the rationale. Changes to specific sections of the protocol are shown in the track changes version of the protocol using strike through red font for deletions and red underlined for insertions. IRB/IEC A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described in this amended protocol are non-substantial and do not require IRB/IEC approval prior to implementation.

11 Novartis Confidential Page 10 Amendment 5 Amendment rationale The primary rationale for this amendment is to: 1. Permit all Best Available Therapy (BAT) patients to receive INC424 and move to the Extension phase of the study after demonstration of superiority for the primary or key secondary endpoints and providing INC424 continues to show an acceptable safety profile. COMFORT II is an open-label trial, where both the treating physician and the patient know the treatment that they are receiving (either INC424 or BAT). Conventional drugs used to treat myelofibrosis provide only palliative benefit consequently both physicians and patients are requesting opportunities to access INC424 when the control of MF symptoms is clearly inadequate on BAT. 2. Include additional patient discontinuation rules, as follows, to limit exposure to patients who are not receiving benefit from treatment on INC424: a. For patients originally randomized to INC424, discontinue from extension phase when spleen volume is 25% increased over baseline at time of randomization. b. For patients originally randomized to BAT, discontinue from extension phase when spleen volume is 25% increased over imaging volume at time of crossover. 3. Modify the requirement for central imaging and review of spleen volumes, using MRI/CT scans, as follows: a. For patients who achieve a 35% reduction in spleen volume at week 48, imaging will continue every 12 weeks until 25% progression from baseline at randomization b. For patients randomized to INC424 who do not achieve a 35% reduction in spleen volume at week 48, imaging will be performed every 24 weeks until 25% progression from baseline. c. For patient randomized to BAT who crossover to INC424, one scan will be obtained 12 weeks after crossover and subsequent frequency of scans will be determined by the response at 12 weeks. If the patient meets criteria for response ( 35% reduction in spleen volume compared with the scan obtained at crossover), then scans will continue every 12 weeks until there is an increase of 25% or more compared with the crossover scan. If the patient does not meet criteria for response ( 35% reduction in spleen volume compared with the scan obtained at crossover), then scans will continue every 24 weeks until there is an increase of 25% or more compared with the crossover scan. 4. Eliminate the requirement for a maximum dose of INC424 to be 5mg BID less than the dose which caused a platelet count reduction < 100,000. Restricting the dose to no higher than 5 mg BID less than any dose that caused a platelet count < 100,000 has limited the capacity of physician-investigators to dose patients higher when their platelet counts have improved above 100,000, sometimes even to within normal range. One goal of the study,

12 Novartis Confidential Page 11 to reduce the frequency of grade 3-4 thrombocytopenia, is largely accomplished by using the dose optimization strategy of starting subjects at either 15 mg BID or 20 mg BID according to their baseline platelet count. Additionally, Table 5-3 and Table 5-4 guide physician-investigators to the correct dose to use according to the patient s current platelet count. The additional restriction of limiting dosing according to prior episodes of platelet counts < 100,000 has been noted by various physician-investigators as resulting in dosing patients at levels that are less effective and unnecessarily low based upon their current hematologic profile. 5. Continue with ECG monitoring using local read only, thus eliminating the current central read process. The need for central read is not supported based on the results of the Healthy Volunteer Study (Incyte study 138) and also to date no concerns have been noted on ongoing trials. Given the importance of monitoring electrocardiographic function with new compounds, however, it will be required to continue obtaining periodic ECG s but the readings may be performed locally. 6. Change the requirement of Bone Marrow Biopsy to be performed at the discretion of the investigator and not as a timed procedure. Bone marrow examinations are performed as a tool for diagnostic purposes in myelofibrosis but are not a standard requirement for the management of the disease. Transformation to acute leukemia (a secondary endpoint of the study) is an event that can be monitored with peripheral blood counts and verified, when necessary, with an additional bone marrow examination 7. Eliminate the blood specimen for the determination of INC424 in plasma after the week 60 visit as further sampling is not considered likely to provide additional pharmacokinetic information to the existing data base. Each patient randomized to INC424 will have (as per protocol) submitted 12 blood specimens for the determination of INC424 in plasma by the week 60 visit. These concentrations of INC424 will be used in the population pharmacokinetic analysis that will be submitted to health authorities around the world to support registration. It is estimated that approximately 156 of the 219 patients randomized to INC424 are currently ongoing. Additional data points collected (approximately just before drug administration) from the ongoing patients are not likely to provide new information or significantly alter the results generated with data up to week Eliminate sample collection for the pharmacodynamic (PD) markers and CD34+, as collection after week 48 is not likely to provide additional information regarding the pharmodynamic effect of INC424. Previous results from Incyte study 251 showed that the effect of treatment on plasma PD markers was seen within 1-3 months, so informative changes in these markers after more than a year of treatment are unlikely. 9. Change the blood sample collection for JAK mutation to eliminate the collection at week 72. In the Incyte study 251, changes in JAK2V617F allele burden only occurred in a minority of patients, and occurred very slowly. Continuing to monitor JAK mutation (allele burden) at 48 week intervals and at the End of Study visit will detect any changes in individual patients, but more frequent sampling is unlikely to add any information. 10. Continue with all central laboratory for safety with exception of pancreatic lipase and amylase as there were no safety signals detected to warrant ongoing routine monitoring. Use of central laboratory monitoring throughout the Extension phase will permit continuity in the collection of all safety data.

13 Novartis Confidential Page Eliminate IVRS use for drug supply as ongoing drug needs can easily be managed by monitoring manually at the site level. Study status The last patient was randomized to the study on 21st January 2010 and the primary endpoint of the study, is when all patients have completed their 48 week visit, which fell on the 23 rd December 2010 (± the 21 day window). Changes to the protocol Changes to specific sections of the protocol are shown in the track changes version of the protocol using strike through red font for deletions and red underlined for insertions. The following sections/changes have been made: Section 3.2 changed to permit cross-over of BAT patients after demonstration of superiority for the primary or key secondary endpoints Section 5.2 changed to permit cross-over of BAT patients post after demonstration of superiority for the primary or key secondary endpoints Section changed to permit cross-over of BAT patients post after demonstration of superiority for the primary or key secondary endpoints Section updated to define the population that will continue to require imaging the timing for MRI/CT scans Section update to eliminate the requirement of a maximum dose of 5mg BID given when platelet count has recovered Section update to eliminate the requirement of a maximum dose of 5mg BID given when platelet count has recovered Addition of Table 7-2 :schedule of observations for the extension phase post after demonstration of superiority for the primary or key secondary endpoints Section update to include crossover of BAT patients at the time after demonstration of superiority for the primary or key secondary endpoints and to eliminate PK sampling and IVRS Section additional sub-section added, referring the reader to the new schedule of observation after demonstration of superiority for the primary or key secondary endpoints (Table 7-2) Section update end of study requirements to align with changes to blood sample and IVRS Section 7.6 clarifyduration of participation as it relates to the extension and discontinuation criteria Section changes to the ECG, to require local read only Section changes to ECG analysis & reporting, to be performed locally Section update to define the population that will continue to require imaging

14 Novartis Confidential Page 13 Section update to share JAK2 results with Investigators so ongoing collection confirmed for patients with JAK2 mutation only Section update PK sampling to be deleted after the demonstration of superiority for the primary or key secondary endpoints Section change to delete IVRS after demonstration of superiority for the primary or key secondary endpoints Section update to allow for all parties to be unblinded IRB/IEC The changes described in this amended protocol require IRB/IEC approval prior to implementation. In addition, if the changes herein affect the Informed Consent, sites are required to update and submit for approval a revised Informed Consent that takes into account the changes described in this amended protocol.

15 Novartis Confidential Page 14 Amendment 4 Amendment rationale The primary rationale for this amendment is to: 1. Modify the current definition of duration of response and add an additional definition to be more consistent with the usual definition that measures duration from the time of first response until clear criteria for loss of response. The current language is modified to include all responders in the calculation of duration of response. In addition, a more conventional analysis was added. 2. Classify secondary efficacy endpoints as key and other. Response rate at week 24 should be classified as a Key Secondary Endpoint. With the designation of Key, a testing procedure can be applied that controls the overall Type I error for both the primary and key secondary endpoints. The proposal can be implemented without any effect on the primary endpoint power. 3. Extend the current +7 day window at week 48 visit to + 21 days as +7 days is not long enough in the event that there are data quality issues with the scan. In addition, a response observed up to 21 days after the visit should be allowed since the LPLV is projected to be approximately 23 December. Patients who miss their scheduled scan during the Week of 20 December 2010 may not have an opportunity to obtain this scan until the week of either 3 January 2011 or 10 January It is not expected that their spleen size would be measurably changed in weeks (new proposal) compared with weeks (current language). 4. Use stratified methods for estimation and hypothesis testing of endpoints as the study design is stratified by prognostic risk group, high risk versus intermediate-2 risk, and so the statistical methods should be stratified to match the design. 5. Align population nomenclature with ICH E9 guidelines 6. Other minor modifications to the statistical section have been incorporated. (e.g. we eliminated many formal comparisons for exploratory endpoints, introduced a time to definitive deterioration in patient reported outcomes and made some minor editorial changes). Study status The last patient was randomized to the study on 21st January 2010 and the primary endpoint of the study, when all patients should complete their 48 week visit, is projected to fall on 23 December Changes to the protocol Changes to specific sections of the protocol are shown in the track changes version of the protocol using strike through red font for deletions and red underlined for insertions. The following sections/changes have been made: Section secondary efficacy endpoints defined as key & other

16 Novartis Confidential Page 15 End notes for Table 7-1 & Section MRI window at week 48 extended from +7 to +21 days Section 10.4 a protocol deviation added Section clarification on death as an outcome in adverse event page Section updating inconsistency on SAE collection time point Section 12.1 updating population nomenclature Section duration of response redefined Section changes to the secondary endpoint analysis Section changes to the exploratory endpoint analysis Section addition & changes to the sensitivity and subgroup analysis IRB/IEC The changes described in this amended protocol require IRB/IEC approval prior to implementation. In addition, if the changes herein affect the Informed Consent, sites are required to update and submit for approval a revised Informed Consent that takes into account the changes described in this amended protocol. Summary of previous amendments Please refer to Section 3.5 History of Amendments.

17 Novartis Confidential Page 16 1 Synopsis Title Descriptive Title Study Number Study Phase Phase 3 Study Population Study Design COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Treatment-II: (The COMFORT-II Trial) A Randomized Study of the JAK Inhibitor INC424 Tablets Compared to Best Available Therapy in Subjects with Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) CINC424A2352 Male or female subjects who have been diagnosed with PMF, PPV-MF, or PET-MF, who are 18 years of age or older, meet Intermediate or High risk prognostic criteria, and have palpable splenomegaly of at least 5 cm below the costal margin. Subjects may or may not have received prior therapy for myelofibrosis. This is an open label, randomized study comparing the efficacy and safety of INC424 tablets versus Best-available therapy, as selected by the investigator. Subjects will be stratified at Baseline by prognostic category of Intermediate or High risk (Cervantes, et al 2009) and randomized to receive either INC424 tablets or to the best-available therapy. INC424 Dosage: The starting dose of INC424 tablets will be determined based on Baseline platelet count as follows: Subjects with Baseline platelet count > 200,000/µL will begin dosing at 20 mg BID (four 5 mg tablets BID) Subjects with Baseline platelet count of 100,000/µL to 200,000/µL (inclusive) will begin dosing at 15 mg BID (three 5 mg tablets BID) A standardized dosing paradigm will be used to determine dose adjustments for safety and efficacy so that each subject is titrated to their most appropriate dose. Doses will not exceed 25 mg BID. Best-available Therapy Dosage Subjects in the Control group may receive Best-available therapy at doses and schedules selected by the investigator. Best-available therapy may include a combination of available agents to treat the disease and/or its symptoms, or no therapy, and will be selected by the investigator on a subject-by-subject basis. Therapy may be changed at any time during the Randomized Treatment Phase. No experimental agents (those not approved for any indication) may be used at any time. Study Visits Subjects will have regularly scheduled Study Visits at Screening, Baseline, Day 1, and after 4, 8, 12, 16, and 24 weeks of treatment, and every 12 weeks thereafter. At these visits, blood sampling, spleen measurements, and safety assessments may be performed. Subjects will also have Interim Visits at the study clinic laboratory to collect blood samples for hematology assessments. Interim Visits will occur at weeks

18 Novartis Confidential Page 17 2, 6, 20, 30 and every 12 weeks thereafter, Additionally, at Week 4, subjects will be instructed to visit the clinic 1-3 days prior to their regularly scheduled Study Visit to provide blood samples for hematology and serum chemistry. Randomized treatment Phase Subjects will receive INC424 or Best-available therapy according to treatment assignment until one of the following criteria for disease progression has been met: 1. Increase in spleen volume of 25% from the on-study nadir (including Baseline). 2. Splenic irradiation or splenectomy. 3. Leukemic transformation defined by an increase in peripheral blood blast percentage to 20% that is sustained for at least 8 weeks 4. Leukemic transformation defined by bone marrow blast count of 20%. 5. Death. At this time, subjects who meet criteria for leukemic transformation or have had splenic irradiation will be withdrawn from the study. Subjects who have had one of these extension-qualifying progression events may be eligible to continue in the Extension Phase: Splenectomy Increase in spleen volume of 25% over on-study nadir (including Baseline) Extension Phase Subjects that were randomized to receive INC424 may continue to receive study drug in the Extension Phase after a Qualifying progression event IF in the best judgment of the investigator, the subject is still receiving clinical benefit. After a Qualifying progression event, subjects that were randomized to the Control group may be eligible for cross over to receive open-label INC424 if they meet safety criteria. After the demonstration of superiority for the primary or key secondary endpoint, in February 2011, providing INC424 continues to show an acceptable safety profile, subjects randomized to receive BAT will be able to crossover to receive INC424 and move to the extension phase of the study, no qualifying event will be required. Once crossed over, these subjects will continue to follow the protocol schedule for all visits. In addition, these subjects must return to the clinic for a post-first dose Crossover Visit at 4 weeks and Interim Visits for hematology assessments at 2 and 6 weeks after initiating therapy with INC424, even if these intervals do not correspond to regularly scheduled visits. Randomization Regardless of initial randomization, all subjects receiving INC424 in the Extension Phase will continue attending Study Visits according to the protocol schedule. Randomization will occur centrally by an Interactive Voice Response System (IVRS). Randomization will be stratified by prognostic category of Intermediate risk (2 risk factors) or High risk (3 or more risk factors).

19 Novartis Confidential Page 18 Planned Number of Study Sites and Planned Number of Subjects Coordinating Investigator Study Objectives and Endpoints Approximately 100 sites Approximately 150 subjects will be enrolled, randomized 2:1 for INC424:Best-available therapy. Dr. Claire Harrison St. Thomas s Hospital, London, UK Primary Objective: To compare the efficacy, safety and tolerability of INC424 given twice daily to the best-available therapy, in subjects with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV- MF) or post essential thrombocythemia myelofibrosis (PET-MF). Secondary Objective: To evaluate the population pharmacokinetics of INC424 Trial Endpoints: Primary Efficacy Endpoint: Proportion of subjects achieving at least 35% reduction in spleen volume from Baseline to Week 48 as measured by MRI (or by CT for applicable subjects). Key Secondary Efficacy Endpoint: Proportion of subjects achieving a 35% reduction of spleen size as measured by MRI (or CT scan where applicable) from Baseline to Week 24. Other Secondary Efficacy Endpoints: Duration of maintenance of a 35% reduction from Baseline in spleen volume. Time to achieve a first 35% reduction in spleen volume from baseline. Progression free survival. Leukemia free survival. Overall survival. Change in bone marrow histomorphology. Safety Assessment Safety and tolerability will be assessed by monitoring the frequency, duration and severity of adverse events, performing physical exams, and evaluating changes in vital signs, electrocardiograms (ECGs), and serum chemistry, hematology and urinalysis results. Exploratory Assessments: Change in spleen volume measured by MRI, and change in spleen size measured by palpation from Baseline to each visit where the variables are measured. Change in body weight from Baseline to each visit where the variable is measured. Change in Eastern Cooperative Oncology Group (ECOG) performance status from Baseline to each visit where the variable is measured.

20 Novartis Confidential Page 19 Number of Treatment Arms Dose and Mode of Administration and Duration of Treatment Dose and Mode of Administration and Duration of Treatment 2 (two) Change in EORTC QLQ-C30 score from Baseline to each visit where the variable is measured. Change in FACT-Lym scores from Baseline to each visit where the variable is measured. Change in JAK2V617F allele burden from Baseline to each visit where the variable is measured. Changes in cytokine and other plasma protein marker levels from Baseline to each visit where the variable is measured. Change in transfusion dependency during the study period as measured by the proportion of subjects who change from transfusion dependent to transfusion independent and vice versa. The population PK of INC424 INC424 tablets (5 mg) tablets will be administered as oral doses without regard to food. Starting doses will be either 15 mg BID or 20 mg BID. Protocol defines allowed dose increase of 5 mg BID. Maximum dose will not exceed 25 mg BID. Duration of Subject Participation Best-available therapy (oral or parenteral therapies) will be administered according to manufacturer s instructions and investigator discretion. Enrollment Period: Approximately 6 months. Treatment & Follow-up: The study will continue until all subjects remaining on study have completed the Week 144 evaluations. Followup will occur approximately 1 month after discontinuing study drug. Individual subject participation depends upon the ability to tolerate the treatment regimen and upon the time to a progression event mandating study withdrawal. The maximum duration of treatment is not expected to exceed approximately 168 to 180 weeks for any subject. The study is comprised of 5 phases: Screening and Baseline: a combined period of up to 28 days, with the Baseline period being up to 7 days. Randomized treatment phase: Indefinite period from Study Day 1 to the occurrence of an event comprising progressive disease or until the study is concluded, whichever comes first. Extension Phase (including crossover of Control Group subjects): Period beginning with a Qualifying progression event or permitted cross-over after demonstration of superiority for the primary or key secondary endpoint and providing INC424 continues to show an acceptable safety profile and continuing until the subject is no longer receiving benefit from INC424 or until the study is concluded i.e 96 weeks after the last patient last visit ( LPLV) for the primary endpoint analysis Follow-up: 28 days (+9) following the last dose of study drug or open label INC424.

21 Novartis Confidential Page 20 Summary of Entrance Criteria Key INCLUSION criteria: Male or female subjects, aged 18 years or older, with diagnosis of PMF, PPV-MF or PET-MF. Subjects with a palpable spleen length of 5 cm or greater below the costal margin Subjects must have either 2 (Intermediate risk) or 3 or more (High risk) prognostic factors (Cervantes, et al 2009). These prognostic factors are: a) Age > 65 yrs b) Presence of constitutional symptoms (weight loss, fever, night sweats) c) Marked anemia (Hgb < 10g/dL) d) Leukocytosis (history of WBC > 25 x 10 9 /L) e) Circulating blasts 1% Subjects with peripheral blood blasts of < 10% Subjects must have been on a stable therapeutic regimen for at least 2 weeks before Screening and at least 4 weeks prior to Baseline. Key EXCLUSION criteria: Subjects with a life expectancy of < 6 months. Subjects with inadequate bone marrow reserve as follows: a) Absolute neutrophil count (ANC) that is 1000/µL. b) Platelet count that is < 100,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions. Subjects with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason. Subjects having clinically significant infections or current malignancies.

22 Novartis Confidential Page 21 Statistical Methods Data Safety Monitoring Board (DSMB) After approximately 150 randomized subjects have either completed Week 48 or withdrawn from the study, the following endpoints will be evaluated, with all INC424 treated subjects combined as one group regardless of dose. Primary Endpoint Analysis: Percent of subjects who have 35% or greater reduction in spleen volume at Week 48 will be estimated with 95% confidence intervals. Treatment effect will be tested using a CMH test stratified by baseline prognostic category. Other Endpoint Analysis Percent of subjects who have 35% reduction in spleen volume at Week 24 will be estimated with 95% confidence intervals. Treatment effect will be tested using CMH test stratified by baseline prognostic category. The median duration of 35% spleen volume reduction will be estimated using Kaplan-Meier method. Time to achieve a first 35% reduction in spleen volume from baseline, will be estimated with the Kaplan Meier method, based on initial randomization. Survival curves for leukemia free survival, overall survival and PFS, will be estimated with the Kaplan Meier method; the treatment difference will be tested using a log rank test. For PFS, the earliest time when any event is observed as follows: For spleen size increase, the progression date will be the date of the first MRI showing a 25% or greater increase in spleen volume from on-study nadir (including Baseline). For leukemic transformation, the progression date will be the date of the bone marrow blast count of 20% or greater, OR the date of the first peripheral blast count of 20% or greater, that is subsequently confirmed to have been sustained for at least 8 weeks. For splenic irradiation, splenectomy, or death, the date of progression will be the actual date of the event. All clinical safety data (vital signs, ECGs, routine laboratory tests and adverse events) will be tabulated and listed. An independent Data Safety Monitoring Board (DSMB) will be established and will routinely review ongoing data as governed by the DSMB charter.

23 Novartis Confidential Page 22 2 List of abbreviations and definitions of terms Term Definition AE ALT ANC AUC AUC 0-12h BAT BID BMI BUN CBC CDER Cl/F cm CMH CML C max C min CFR CNS ecrf CRO CT CTCAE CYPs dl DLT DSMB ECG ECOG EEC EMEA EORTC-QLQ-C30 ET FDA FACT-lym g GCP adverse event/experience alanine aminotransferase absolute neutrophil count area under the plasma concentration vs. time curve area under the plasma concentration vs. time curve over one steady-state dosing interval best-available therapy two times per day body mass index blood urea nitrogen complete blood count Center for Drug Evaluation and Research apparent oral-dose clearance centimeter Cochran-Mantel-Haenszel, stratified chi square test chronic myelogenous leukemia maximum observed plasma concentration minimum (trough) steady-state plasma concentration Code of Federal Regulations central nervous system electronic case report form contract research organization computed tomography Common Terminology Criteria for Adverse Events cytochrome P450 system of metabolizing enzymes, includes isozymes designated CYP3A4, CYP2C11, CYP2C13 deciliter dose limiting toxicity Data Safety Monitoring Board electrocardiogram Eastern Cooperative Oncology Group equivalent effective concentration European Medicines Agency European Organisation for Research and Treatment of Cancer: Quality-of-life Questionnaire for Cancer essential thrombocythemia Food and Drug Administration Functional Assessment of Chronic illness Therapy for patients with Lymphoma gram Good Clinical Practice

24 Novartis Confidential Page 23 GLP Good Laboratory Practices herg human-ether-a-go-go related gene Hgb hemoglobin hscrp high sensitivity assay for c-reactive protein HIV human immunodeficiency virus HU hydroxyurea IB Investigator s Brochure ICF informed consent form ICH International Conference on Harmonization IEC Independent Ethics Committee IgM immunoglobulin M LPLV last patient last visit IVRS Interactive Voice Recognition System JAK Janus kinase kg kilograms MF myelofibrosis MPD myeloproliferative disorder mg milligram ml milliliter mm millimeter µl microliter µm micromolar MedDRA Medical Dictionary for Regulatory Activities MRI magnetic resonance imaging MTD maximum tolerated dose nm nanomolar NOAEL no-observed-adverse-effect-level PD pharmacodynamic PFS Progression free survival PK pharmacokinetic(s) PMF primary myelofibrosis PPV-MF post polycythemia vera-myelofibrosis PET-MF post essential thrombocythemia-myelofibrosis PRO patient reported outcome pstat3 phosphorylated Signal-Transducer and Activator of Transcription-3 PV polycythemia vera QD once daily RAP Report and Analysis Plan RH relative humidity SAE serious adverse event/experience STAT signal transducers and activators of transcription time of maximum plasma concentration T max

25 Novartis Confidential Page 24 ULN WBC upper limit of normal white blood cell count

26 Novartis Confidential Page 25 3 Introduction 3.1 Background INC424 phosphate is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) that is currently under development for treatment of primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV-MF) and post essential thrombocythemia myelofibrosis (PET-MF) Myelofibrosis and myeloproliferative neoplasms The four classic myeloproliferative diseases include chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Myelofibrosis (MF) can present as a de novo disorder (PMF) or evolve from previous PV or ET (PPV-MF or PET-MF). Regardless of whether MF developed from PV, ET or as a primary disorder, it is characterized by a clonal stem cell proliferation associated with production of elevated serum levels of multiple inflammatory and proangiogenic cytokines, a characteristic bone marrow stromal pattern that includes varying degrees of collagen fibrosis, osteosclerosis and angiogenesis and a peripheral blood smear showing a leukoerythroblastic pattern with varying degrees of circulating progenitor cells. The abnormal bone marrow milieu is associated with the release of hematopoietic stem cells into the blood, extramedullary hematopoiesis, and organomegaly. Clinically MF is characterized by progressive anemia, leukopenia or leukocytosis, thrombocytopenia or thrombocythemia and multi-organ extramedullary hematopoiesis most prominently involving the liver and spleen. Patients experience severe constitutional symptoms, sequelae of massive splenomegaly (pain, limitations of movement, early satiety, shortness of breath, hepatic obstruction, and splenic infarction), a hypermetabolic state with cachexia, occasional hematopoietic failure, occasional progression to leukemia, and premature death. The median age at diagnosis is approximately 60 to 65 years. The incidence of PMF has been estimated at 1.5 cases per 100,000 people. Survival in MF varies with the presence or absence of specific risk factors. Cervantes, et al (2009) have recently published a multi-center analysis of risk factors and their impact on prognosis in patients with myelofibrosis. They identified age of greater than 65 years, presence of constitutional symptoms of weight loss, fever, or night sweats, anemia (Hgb less than 10 g/dl) leukocytosis (WBC greater than 25,000 x 10 9 /L), and a circulating blast percentage of greater than 1% as most predictive of outcome. They demonstrated that patients with no risk factors fell into a low-risk group with a median survival of 135 months, patients with one risk factor fell into an intermediate-1 group with a median survival of 95 months, patients with two risk factors fell within an intermediate-2 group with a median survival of 48 months, and patients with 3 or more risk factors formed a high-risk group with a median survival of 27 months (Cervantes, et al 2009). For a small subset of patients who are young, otherwise healthy and have a histocompatible donor, allogeneic stem cell transplantation may provide a curative option, although a risk of significant mortality is associated with the procedure. Currently available drug therapies, which include hydroxyurea, busulfan, 6-mercaptopurine, anagrelide, thalidomide, lenalidomide, interferon, corticosteroids, and erythropoiesis stimulating agents or growth

27 Novartis Confidential Page 26 factors, have not been shown to improve survival. Some have been suspected of increasing the risk of leukemic transformation, are frequently poorly tolerated, and have limited effectiveness in improving splenomegaly and constitutional symptoms. Splenectomy, performed in approximately 10% of the patient cohort reported by Cervantes, et al (2009) is associated with significant morbidity and mortality. Splenic irradiation is also employed to reduce symptoms secondary to splenomegaly, but symptomatic improvement is variable and short-lived; and transient and life-threatening pancytopenia and increased risk of leukemic transformation have been observed Inhibition of Janus Kinases (JAKs) in myelofibrosis A considerable number of cytokine and growth factor receptors utilize non-receptor tyrosine kinases, the Janus kinases (JAKs), to transmit extracellular ligand binding into an intracellular response. For example, erythropoietin, thrombopoietin and granulocyte monocyte colony stimulating factor are all known to signal through receptors that utilize JAK2. JAKs activate a number of downstream pathways implicated in proliferation and survival, including the STATs (signal transducers and activators of transcription), a family of important latent transcription factors. Myelofibrosis is a clonal stem cell disease characterized by molecular (JAK2V617F, MPLW515L/K) and cytogenetic (13q-,20q-) markers (Pikman 2006, Scott 2007). The JAK2V617F mutation has been identified in over 95% of patients with PV and approximately 50% of patients with ET and PMF. Furthermore, in a preclinical setting, animal studies have demonstrated that this mutation can lead to an MF-like syndrome. The JAK2V617F mutation alters the JAK2 tyrosine kinase making it constitutively active. As a result, polycythemia, thrombocythemia and leukocytosis can develop independently from growth factor regulation. Even in patients lacking a confirmed JAK2 mutation, the detection of STAT activation suggests dysregulated JAK activity. In fact, regardless of the mutational status of JAK2, the malignant cells appear to retain their responsiveness to JAK activating cytokines and/or growth factors; and therefore, may benefit from JAK inhibition Preclinical studies relevant to the study INCB represents a novel, potent, and selective inhibitor of JAK1 and JAK2. INCB potently inhibits JAK1 and JAK2 [half maximal inhibitory concentration (IC 50 ) 0.4 to 1.7 nm], yet it does not significantly inhibit (< 30% inhibition) a broad panel of 26 kinases when tested at 200 nm (approximately 100x the average IC 50 value for JAK enzyme inhibition) and does not inhibit JAK3 at clinically relevant concentrations. Pharmacological data obtained in in vivo model systems support the potential utility of orally administered INCB in the treatment of malignancies, including MPDs such as PMF, PPV-MF, and PET-MF. INCB retains activity against the JAK2V617F mutant and is effective in reducing splenomegaly in mice inoculated with cells carrying this mutation. Additional details as to the in vivo pharmacology of INCB may be found in the Investigator s Brochure (IB) INCB pharmacokinetics Single and multiple dose pharmacokinetic studies have been conducted in multiple species and are reported in the IB.

28 Novartis Confidential Page INCB preclinical safety The toxicologic and toxicokinetic profiles of INCB were characterized in single and repeat oral dose studies of up to 6 months in duration in rats and dogs. Genetic toxicology, safety pharmacology, and embryo-fetal toxicology studies have also been conducted. In a 6 month study in rats, doses up to 60 mg/kg/day were evaluated. An adverse decrease in body weight gain was noted in male, but not in female rats. A dose related decrease in lymphocytes was noted. Minimal-to-mild lymphoid depletion in spleens and in mandibular lymph nodes was noted at the 60 mg/kg/day dose level; at lower doses, lymphoid tissues were within normal histologic limits. The no-observed-adverse-effect level (NOAEL) for oral administration of INCB for 26 weeks was 30 mg/kg/day for the males (unbound AUC µm*h), due to adverse effects on body weight at 60 mg/kg/day, and 60 mg/kg/day for female rats (unbound AUC 4.64 µm*h). (Lower parent drug levels in male rats are due to male rat specific isozymes 2C11, 2C13 and CYP3A2 which metabolize INCB to active metabolites). Additional details on rat toxicology studies are available in the IB. In the 6 month dog study, doses studied included 0.5, 2.5, 5, and 10 mg/kg/day. Demodectic mange, lymphopenia, eosinopenia, decreases in erythron parameters, moderate to severe cellular depletion of lymphoid tissues, bacterial pneumonia, viral-induced papillomas, microscopic invasive demodectic mange, and prostate hypoplasia/atrophy were seen in high dose dogs. Deaths attributed to bacterial pneumonia occurred in 3 of 14 dogs given 10 mg/kg/day. Demodectic mange was observed in several animals given 5 mg/kg/day and, microscopically, in one animal given 2.5 mg/kg/day. These events most likely reflect a response to the immunosuppressive effects of INCB All tissues were normal in the 0.5 mg/kg/day group. The NOAEL dose was defined at 2.5 mg/kg/day (unbound AUC 0.76 µm*h) due to minimal findings which were not present in recovery animals. The low dose, 0.5 mg/kg/day, was defined as the no-observed effect-level (NOEL). Additional details regarding dog toxicology studies are available in the IB. INCB was not genotoxic in the bacterial mutagenicity assay, the in vitro chromosome aberration assay, or the in vivo micronucleus assay in rats. In embryo-fetal assessments in rat and rabbit, maternal toxicity and minimal embryo-fetal toxicity were noted at the highest doses evaluated. INCB was not teratogenic in either rat or rabbit. The NOAEL dose for the rat and rabbit study was 30 mg/kg/day. Additional toxicology and safety pharmacology information is available in the IB Clinical pharmacology of INCB Following oral, single-dose administration of INCB capsules, INCB is absorbed rapidly, typically attaining peak plasma concentrations within 1 to 3 hours after administration for all doses. After attaining C max at approximately 2 hours after administration, the INCB plasma concentrations declined with a mean terminal-phase disposition t 1/2 of approximately 3-5 hours. The mean INCB C max and AUC increased with approximately linear proportionality to dose for the entire dose range evaluated of 5 to 200 mg. There was no significant food effect on absorption or exposure. Therefore, INCB can be dosed without regard to meals.

29 Novartis Confidential Page 28 No accumulation was seen following administration of repeated oral doses of 15 to 50 mg INCB twice daily, and 50 to 100 mg INCB once daily for 10 days. PK parameters were similar to those seen following the administration of single doses. INCB is metabolized in the liver by the cytochrome (CYP) P450 metabolizing enzyme system, predominantly by the 3A4 isozyme. The effects of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of INCB administered as single oral doses shows that with concomitant dosing of ketoconazole, the observed AUC increase is approximately 2-fold, and the calculated equivalent constant concentration for the pstat3 (phosphorylated Signal-Transducer and Activator of Transcription protein-3) pharmacodynamic effect was also increased approximately 2-fold. Thus, a dose reduction of 50% for INCB (See Section 5.3.4) is appropriate for subjects who take oral ketoconazole or other potent CYP3A4 inhibitors as concomitant medication. A more modest effect on the PK parameters of INCB was demonstrated with concomitant dosing of the moderate CYP3A4 inhibitor erythromycin. No dose adjustments are necessary when INCB is co-administered with erythromycin, or by extension, with other moderate or weak inhibitors of CYP3A4. Additional details as to the clinical pharmacology of INCB may be found in the IB. An open-label study to assess the effect of CYP3A4 inducers on INCB pharmacokinetics and pharmacodynamics revealed that, as expected, rifampin significantly decreased the exposure to INCB However, essentially no difference in ex vivo cytokine-induced STAT3 phosphorylation was observed with or without rifampin induction. This suggests that CYP3A4 induction with rifampin results in metabolism of INCB to active metabolites which also inhibit JAKs. Increased levels of active metabolites were seen with rifampin dosing. These data indicate that the dose of INCB may not need to be modified when dosed with CYP3A4 inducers. However, potent CYP 3A4 inducers will be prohibited in the study to reduce any potential risk of dosing improperly with these agents (Section 9.8.2) INCB clinical safety in healthy volunteers INCB has been administered in single or multiple doses to over 90 healthy subjects. INCB was examined in a 10-day multiple dose study in a total of 71 healthy volunteers in 6 cohorts who received doses of 50 mg QD, 100 mg QD, 15 mg BID, 25 mg BID or 50 mg BID of INCB or placebo (Study INCB ). INCB was well tolerated in the study, with most adverse events reported by both INCB treated and placebo-treated subjects. Adverse events were, in general, mild, assessed as unrelated to study drug and resolved without intervention. Neutropenia as an adverse event was noted in 3 subjects receiving the highest dose of INCB018424, 50 mg BID. Neutropenia at the Grade 4 level, assessed as severe, led to study drug discontinuation on Day 5 in one subject, and was reported as a Serious Adverse Event (SAE). There was a decline in mean absolute neutrophil count (ANC) and to a lesser extent, mean white blood cell count (WBC) values with INCB doses of 15 mg BID or higher. In general, these declines in ANC or WBC were observed early during the 10-day dosing period with BID regimens; did not worsen with continued dosing, and returned to Baseline levels within 1 to 2 days following the last dose of study drug; suggestive of a neutrophil margination effect. Doses of 25 mg BID and 100 mg

30 Novartis Confidential Page 29 QD were determined to be maximum tolerated doses (MTDs) in this study. For additional details, consult the IB INCB clinical safety and efficacy in phase 2 Study INCB is an on-going Phase 1/ 2 open label study of INCB in patients with PMF, PPV-MF or PET-MF. Over 150 subjects have been enrolled at twice daily dose regimens of 10 mg BID to 50 mg BID, or once daily regimens of 25 mg QD to 200 mg QD. Subjects enrolled since August 2008 have had individually titrated dose regimens that begin at doses of 10 mg BID or 15 mg BID, and can increase up to 20 mg BID or 25 mg BID. Data from the ongoing Study INCB demonstrate marked and durable reductions in spleen size. In this study spleen size has been measured as palpable length below the left costal margin. Figure 3-1 illustrates the mean reduction in absolute spleen size (measured by palpation) for subjects receiving BID regimens. Figure 3-1 Mean spleen size in subjects receiving BID regimens in study INCB (Mean +/- SEM) Spleen Size, cm mg BID N=23 to Start 15 mg BID N=32 to Start 25 mg BID N=39 to Start N= N=19 N=15 N=9 N= Days on Therapy As noted in Figure 3-1, BID regimens are associated with a prompt decrease in spleen size. Noting that the 15 mg BID dose group has a mean spleen size at baseline that is ~ 2.5 cm smaller than the 10 mg BID or 25 mg BID dose groups, the reduction in spleen length appears dose-dependent. For the 25 mg BID dose, the effect on decreasing spleen size is still evident after many months of continued dosing. Spleen reduction occurred regardless of presence/absence of the JAK2V617F mutation (data not shown).

31 Novartis Confidential Page 30 Progressive myeloproliferative disorders are associated with weight loss and cachexia. Dysregulation and abnormal elevation of a variety of pro-inflammatory cytokines may produce a hypercatabolic state which contributes to the weight loss and wasting seen in patients with myelofibrosis. After an initial weight loss (presumably due to the rapid decrease in splenomegaly and hepatomegaly and loss of ascites and/or pleural effusions) there is a gain in total body weight that appears to be dose-dependent (data not shown). Weight gains are present in most subjects, including those with BMI at baseline in the lowest quartile (BMI below ~ 22). For the subjects with available data, there was a prompt shift in the Eastern Cooperative Oncology Group (ECOG) performance scores in individuals with scores of 1 or 2 towards a score of 0, and this improvement was maintained over 6 months (data not shown). The Modified Myelofibrosis Symptom Assessment Form developed by Mesa et al, and based on an international internet-based survey of over 1000 patients with myeloproliferative diseases (Mesa, et al 2007), is being used to probe a range of constitutional symptoms that are related to splenomegaly (including impaired ability to move around and early satiety) and elevated cytokines (including fatigue, night sweats and pruritis). Based on preliminary data, between 35% and 95% of subjects report a given symptom at baseline. After 2 or more weeks of INCB therapy, 44% to 79% of subjects showed a reduction in individual symptom scores of at least 50% when all doses were combined and assessed together (data not shown). In summary, INCB is associated with prompt and marked reduction in spleen size, gains in total body weight, improvement in ECOG status performance scores and improvement in constitutional symptoms that can be debilitating in this patient population. Refer to the IB for more complete information. INCB has been well tolerated by this aged population with advanced disease. Most adverse events were mild to moderate in severity, considered unrelated to study drug administration and not dose dependent. Related adverse events occurring in at least 5 of the 152 subjects (3%) included in the safety database through February 11, 2009 were restricted to anemia (20 subjects), thrombocytopenia (32 subjects), diarrhea (8 subjects), fatigue (9 subjects), headache (5 subjects) and clinically insignificant QT abnormality that was not present after correction for heart rate (5 subjects). Both anemia and thrombocytopenia represent JAK-inhibitor myelosuppression, and are therefore not unexpected. In study subjects, thrombocytopenia of Grade 3 severity occurred in 3.4% of subjects receiving 10 mg BID of INCB018424, 0% of subjects receiving 15 mg BID of INCB018424, 23% of subjects receiving 25 mg BID of INCB018424, 60% of subjects receiving 50 mg BID of INCB018424, 0% of subjects receiving 25 mg QD of INCB018424, 23% of subjects receiving 50 mg QD of INCB and 17% of subjects receiving 100 mg QD of INCB Thrombocytopenia of Grade 4 severity occurred in 0% of subjects receiving 10 mg BID of INCB018424, 0% of subjects receiving 15 mg BID of INCB018424, 6.4% of subjects receiving 25 mg BID of INCB018424, 20% of subjects receiving 50 mg BID of INCB018424, 0% of subjects receiving 25 mg QD of INCB018424, 4.5% of subjects receiving 50 mg QD of INCB and 0% of subjects receiving 100 mg QD of INCB For the 25 mg BID dose group, subjects exhibiting these Grade 3 or 4 declines in platelets had, in general, entered the study with platelet counts below 200,000 /µl. For nearly all subjects, thrombocytopenia was rapidly reversible and manageable with dose interruption and/or reduction. Anemia, though dose dependent, largely reflects the low hemoglobin status at baseline in this disease population.

32 Novartis Confidential Page 31 Because of the advanced disease present in many of the participants in Study INCB , there are a number of SAEs that have been reported that were assessed as unrelated to study drug. Of related SAEs reported in the study to date, the most frequent are those reflecting inhibition of bone marrow function(s) (ie, thrombocytopenia) and activation of inflammatory cytokines when the inhibitory influence of INCB is removed due to drug interruption or discontinuation. See the IB for complete details on INCB clinical study findings. 3.2 Trial rationale INC424 is an inhibitor of the Janus kinases (JAKs) that is under development for the treatment of primary or secondary MF, PV, ET, Post PV-MF, Post ET-MF and other malignancies. As described in Section above, data from the ongoing Phase 1/2 Study INCB has demonstrated marked reductions in spleen size and inflammatory cytokine levels. Symptoms frequently reported by MF patients, such as night sweats and pruritis (which are thought to be caused by elevated cytokine levels) are decreased from baseline levels in INC424 -treated subjects, as reported by patient-reported symptom assessments. Subjects receiving INC424 show increased total body weight and improved appetite. Patients with a variety of symptoms and limitations that affect conduct of daily activities, such as fatigue, lack of energy, and difficulty walking or bending, have improved on INC424 therapy. Current therapies for MF have limited efficacy, and most countries have no drugs approved for this indication. Most patients are managed initially with a wait-and-see approach, since the goal of treatment is symptomatic and not disease-modifying. However, certain drugs approved for other indications have been tried with limited success. The most commonly used drug is hydroxyurea, used primarily to control splenomegaly and elevated WBC and/or platelet counts. Other chemotherapy agents such as busulfan, 6-mercaptopurine, pipobroman, or thioguanine have been used. Immunomodulatory agents such as thalidomide and lenalidomide and alpha interferon are sometimes employed. Agents aimed primarily at constitutional symptoms (such as prednisone), thrombocythemia (such as anagrelide), or even non-specific marrow-toxic agents (such as radiophosphorus or cladribine) have been tried. Splenectomy and splenic irradiation have been used to control spleen-related symptoms. No approach is considered to be the standard of care, and no intervention has been associated with an improvement of overall survival. Study CINC424A2352 is a randomized, open label trial which compares INC424 therapy to best currently available therapy as determined by the investigator for each individual subject randomized to the Control Group. The Control Group therapy may also consist of no therapy, i.e., watchful waiting or a combination of agents. Study CINC424A2352 will assess the impact of therapy on spleen size, evaluate durability of response, and give additional data on the long-term safety of INC424 use. In Study CINC424A2352, the Randomized Treatment Phase will start on Study Day 1 and will continue until the subject meets defined criteria for disease progression. During this phase, all subjects in both arms will undergo an objective evaluation of spleen size using MRI or CT. The percentage of subjects achieving a 35% reduction in spleen volume at 48 weeks has been identified as the primary endpoint for efficacy. Magnetic resonance imaging (MRI) has been chosen as the primary modality of spleen size (volume) measurement. Subjects who are not candidates for MRI (including at

33 Novartis Confidential Page 32 sites where MRI is unavailable) will be evaluated with sequential computed tomography (CT). Spleen volume will be assessed by a central reader. While investigators will be able to follow spleen size by palpation, results of MRI (or CT) spleen volume assessments will only be made know to the investigator if a subject has reached a protocol-defined criterion for disease progression based upon increase in spleen volume. Subjects having reached this endpoint may be eligible to continue study participation in the Extension Phase, and if originally randomized to the Control group, may cross over to receive INC424. After demonstration of superiority for the primary or key secondary endpoint, and providing INC424 continues to show an acceptable safety profile, all patients on the control arm will be permitted to crossover and receive INC424 in the extension phase. The study will continue until all enrolled subjects have either completed 144 weeks of therapy, or withdrawn from the study. At this point, treatment will be concluded for all subjects in the Randomized Treatment Phase and for subjects in the Extension Phase, regardless of initial randomization. The rates of leukemic-free survival, progression-free survival, overall survival, and durability of response will be determined and compared between the randomized treatment groups, using data from both the Randomized Treatment Phase and Extension phase. Additional assessments will include analysis of JAK mutation status, cytokine levels, and change in symptoms as assessed by the FACT-lym and EORTC QLQ-C30 questionnaires. 3.3 Potential risks and benefits INC424 potential risks The primary clinical risks with INC424 treatment are the potential sequelae of decreased thrombopoiesis and to a much lesser extent hemopoiesis and myelopoiesis, most probably the result of JAK2 dependent signaling which is inhibited by INC424. Dose-dependent, reversible thrombocytopenia is observed with INC424 and is its primary adverse effect, but only two cases of mild epistaxis in a thrombocytopenic patient considered possibly related to INC424 treatment have occurred in approximately 150 treated subjects. A theoretical risk of neutropenia exists with INC424 treatment, although only a few examples of Grade 3 or 4 neutropenia have been observed in MF patients in the previous open-label study, generally in subjects who entered the study with baseline ANC levels near the lower limit of laboratory normal. Worsening of anemia has been seen in some patients. No cases of opportunistic infections have been observed. A few subjects have had an apparent worsening of their prestudy constitutional symptoms following rapid cessation of INC424 therapy and a gradual tapering of INC424 and use of steroids in fragile subjects may be prudent when stopping INC424 therapy. Additional information is available in the IB. These risks will be managed in the current study by using platelet and neutrophil counts for baseline stratification of starting dose and in-study dose adjustments INC424 benefits The initial efficacy results of Study INCB are notable. Decreases in spleen size have been marked. Subjects have reported marked improvements in their quality of life and their performance status has improved. Evaluation of pharmacodynamic markers has shown inhibition of JAK signaling in circulating leukocytes and reduction in plasma levels of inflammatory, prothrombotic, and angiogenic cytokines. In those subjects with prolonged

34 Novartis Confidential Page 33 exposure to INC424 (> 12 months therapy), these positive effects have been maintained. In the present study, it is anticipated that INC424 therapy will be associated with reductions in splenomegaly and MF associated symptoms and reductions in inflammatory cytokine levels. It is hypothesized that treatment will result in improvements in progression free survival Best-available therapy risks and benefits The summary of product characteristics for individual therapies that may be used in the Control arm of this study should be consulted for a description of the potential risks and benefits of each medication. 3.4 Justification of route, dose regimen and treatment period INC424 is administered orally. In the ongoing study in MF patients, Study INCB , BID dose regimens from 10 mg BID to 50 mg BID have been examined; Based on ongoing efficacy and safety data, it appeared that there is some individual variability in terms of sensitivity to thrombocytopenia and also clinical response, such that an optimal dose for a given individual is likely to be between 10 mg BID and 25 mg BID, and that some opportunity for individual titration of dose within this range might offer the best balance of safety and efficacy for any individual patient. Therefore, subjects enrolled in Study INCB since August 2008 have initiated therapy at 15 mg BID, unless platelet count at baseline was < 200,000/µL, in which case initial dosing was at 10 mg BID. For these patients, the study protocol dictates a mandatory dose increase of 5 mg BID at Week 4 (to doses of 20 mg BID or 15 mg BID, respectively) for inadequate efficacy and adequate platelet count and ANC levels. A second, optional dose increase may occur at Week 8. Preliminary data for the first 2 months of dosing at 15 mg BID is illustrated in Table 3-1, and is compared to available data for subjects dosed at 10 mg BID and 25 mg BID. Importantly, based on available information, at least 1/3 of subjects starting therapy at 15 mg BID have increased their dose to 20 mg BID, and approximately 10% have increased the dose to 25 mg BID. Table 3-1 Reduction of palpated spleen size and incidence of thrombocytopenia in study INCB Parameter 25 mg BID 15 mg BID 10 mg BID N as of February 1, Proportion achieving at least 50% reduction in spleen size a 56% (22 of 39) 54% (15 of 28) 33% (8 of 24) Proportion with Grade 3 thrombocytopenia 23.4% 0% 3.4% Proportion with Grade 4 thrombocytopenia 6.4% 0% 0% a Only subjects with a palpable spleen at Baseline and at least 2 month of spleen size data are included in the spleen reduction analysis. Notably, the incidence of thrombocytopenia to date at 15 mg BID, including those subjects with subsequent dose escalations to 20 mg BID and 25 mg BID is similar to that of the 10 mg BID dose group. Based on these data, in Study INCB , 20 mg BID will be the starting dose for all subjects entering the study with a platelet count > 200,000/µL, and 15 mg BID will be the starting dose for all subjects entering the study with platelet count between 100,000/µL and 200,000/µL (inclusive). With this dosing scheme, subjects with higher

35 Novartis Confidential Page 34 platelet counts will start at a dose more likely to result in robust spleen reduction, while subjects with a smaller platelet level will begin with a dose that appears to have a very low incidence of thrombocytopenia. An optional dose increase of 5 mg BID for inadequate efficacy will occur at Week 4 up to a maximum dose of 20 mg BID to 25 mg BID, provided platelet counts and ANC levels are in a satisfactory range. Mandatory dose decreases for safety reasons will be dictated by platelet count and ANC levels. These dose increases and decreases are summarized in Section 5.3, Dose Adjustments, and Section 9.4, Interruption and Discontinuation of Study Drug. 3.5 History of Amendments Amendment # 1(UK only) The duration of study treatment for the Core and Extension was clarified as 144 weeks after last patient first treatment in the Core study. A final analysis will be conducted at this time. In addition, if commercial drug is not available at the conclusion of the study an open-label extension study would be available to those continuing patients who may continue to benefit from study treatment Amendment # 2 Similar to Amendment 1 the duration of study treatment for the Core and Extension was clarified as 144 weeks after last patient first treatment in the Core study. A final analysis will be conducted at this time. In addition, if commercial drug is not available at the conclusion of the study an open-label extension study would be available to those continuing patients who may continue to benefit from study treatment. Monitoring frequency and discontinuation criteria for toxicity have been clarified with more frequent pregnancy testing and extending contraception discussions/requirements to males. At week 4 and week 12, an ECG 2 hours post INC424 dose was added. The window for baseline MRI has been extended to accommodate operational considerations to include central confirmation on acceptable MRI quality with repeat testing if needed. In addition more detail has been included for the efficacy endpoints and for Inclusion Criterion # 4, anemia is further clarified and for criterion # 6 total bilirubin has been replaced with direct bilirubin. Consideration for the use of CYP3A4 inducers has been revised to allow the use of certain inducers where no good alternative may be available Amendment # 3 Following the acquisition of the development rights for compound INC424 by Novartis the sponsorship of the trail changes from Incyte Corporation to Novartis and the data management, adverse event and administrative sections have been aligned to the Novartis processes and procedures. In addition removal of an interim analysis at the time of the NDA filing to the FDA of protocol INCB has been deleted to assure that the primary analysis of the study is not compromised.

36 Novartis Confidential Page 35 4 Study objectives 4.1 Primary objectives To compare the efficacy, safety and tolerability of INC424 given twice daily compared to the best-available therapy, in subjects with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV-MF) or post essential thrombocythemia myelofibrosis (PET-MF). 4.2 Secondary objectives To evaluate the population pharmacokinetics of INC Investigational plan 5.1 Trial endpoints Primary efficacy endpoint Proportion of subjects achieving at least 35% reduction in spleen volume from Baseline to Week 48 as measured by MRI (or by CT for subjects unable to undergo MRI) Secondary efficacy endpoints Key secondary efficacy endpoint Proportion of subjects achieving a 35% reduction of spleen size as measured by MRI (or CT scan where applicable) from Baseline to Week 24. Other secondary efficacy endpoints Duration of maintenance of a 35% reduction from Baseline in spleen volume. Time to achieve a first 35% reduction in spleen volume from baseline. Progression free survival. Leukemia free survival. Overall survival. Change in bone marrow histomorphology Safety assessment Safety and tolerability will be assessed by: monitoring the frequency, duration and severity of adverse events, performing physical exams, and evaluating changes in vital signs, electrocardiograms (ECGs), and serum chemistry, hematology and urinalysis results Exploratory assessments Change in spleen volume measured by MRI and change in spleen size measured by palpation from Baseline to each visit where the variables are measured. Change in body weight from Baseline to each visit where the variable is measured

37 Novartis Confidential Page 36 Change in Eastern Cooperative Oncology Group (ECOG) performance status from Baseline to each visit where the variable is measured. Change in EORTC QLQ-C30 score from Baseline to each visit where the variable is measured. Change in FACT-Lym score from Baseline to each visit where the variable is measured. Changes in cytokine and other plasma protein marker levels from Baseline to each visit where the variable is measured. Change in JAK2V617F allele burden from Baseline to each visit where the variable is measured. Change in transfusion dependency during the study period as measured by the proportion of subjects who change from transfusion-dependent to transfusion-independent and vice versa. Population PK of INC Trial design This is an open label, randomized study comparing the efficacy and safety of INC424 tablets versus best-available therapy, as selected by the investigator, in MF subjects with splenomegaly of at least 5 cm below the costal margin by manual palpation, and either 2 (Intermediate risk) or 3 or more (High risk) prognostic factors (Cervantes, et al 2009). Subjects will be stratified at Baseline by prognostic category of Intermediate or High risk. The prognostic factors are: Age > 65 yrs Presence of constitutional symptoms (weight loss, fever, night sweats) Marked anemia (Hgb < 10g/dL)* Leukocytosis (history of WBC > 25 x 10 9 /L) Circulating blasts 1% * A hemoglobin value < 10 g/dl must be demonstrated during the Screening Visit for subjects who are not transfusion dependent. Subjects receiving regular transfusions of packed red blood cells will be considered to have hemoglobin < 10 g/dl for the purpose of evaluation of risk factors. The study is comprised of 5 phases: Screening and Baseline: a combined period of up to 28 days with the Baseline period being no more than 7 days. (This period may be extended in limited circumstances See Section 7.2.1) Randomized Treatment Phase: The period from Study Day 1 (day of randomization) to the occurrence of an event comprising progressive disease or until the study is concluded, whichever comes first. Progressive disease is defined as meeting one of the following criteria: 1. Increase in spleen volume of 25% from on-study nadir. 2. Splenic irradiation or splenectomy. 3. Leukemic transformation as defined by an increase in peripheral blood blast percentage to 20% that is sustained for at least 8 weeks.

38 Novartis Confidential Page Leukemic transformation as defined by a bone marrow blast count of 20%. 5. Death. At this time, subjects meeting criteria for leukemic transformation, or having had splenic irradiation will be withdrawn from the study. Subjects having a 25% increase in spleen volume from the on-study nadir OR splenectomy may be eligible to continue to the Crossover/ Extension Phase. Extension Phase (including crossover of Control Group subjects): A period beginning with progressive disease characterized by a Qualifying endpoint ( 25% increase in spleen volume from on-study nadir, or splenectomy) or permitted cross-over after demonstration of superiority for the primary or key secondary endpoint and providing INC424 continues to have an acceptable safety profile and continuing until the earlier of the following events: a) the subject is no longer receiving clinical benefit, b) the subject chooses to withdraw from the study, or c) the study ends (all enrolled subjects have completed 144 weeks of therapy or have withdrawn from the study). Follow-up: 28 to 37 days following the last dose of study drug or open label INC Dose group assignment During the study, subjects will be randomized to receive either INC424 tablets or bestavailable therapy selected at the discretion of the investigator on a subject by subject basis. Best-available therapy may include no therapy or a combination of agents for the treatment of the disease and its symptoms Assignment of starting dose level INC424 dosage: The starting dose of INC424 tablets will be determined based on Baseline platelet count as follows: Subjects with Baseline platelet count > 200,000/µL will begin dosing at 20 mg BID (four 5 mg tablets BID) Subjects with Baseline platelet count of 100,000/µL to 200,000/µL (inclusive) will begin dosing at 15 mg BID (three 5 mg tablets BID) A standardized dosing paradigm will be used to determine dose adjustments for safety and efficacy so that each subject is titrated to their most appropriate dose (see Section 5.3 Dose Adjustments). Doses will not exceed 25 mg BID. Best-available therapy dosage: Subjects in the Control group may receive Best-available therapy at doses and schedules selected by the investigator. Therapy may be changed at any time during the study EXCEPT during the screening period. No experimental agent (not approved for any indication) may be used for any purpose at any time. It is recommended that Control group subjects who cannot maintain platelet counts 50,000/µL, neutrophils 500/µL, or experience another Grade 4

39 Novartis Confidential Page 38 toxicity should either decrease the dose of best-available myelofibrosis therapy or switch to an alternative approach, which might include the option of no active therapy Study visits Screening and baseline visits Screening tests will be performed at one or more clinic visits, over a period not to exceed 28 days prior to Study Day 1. Once the results of screening tests have confirmed subject eligibility, the Baseline period (of up to 7 days duration) may begin. The Baseline tests will be performed at one or more clinic visits that occur within this period prior to the scheduled Study Day 1. The utilization of the full 7-day window should be anticipated, to provide time to receive validation of the Baseline MRI, and to obtain hematology and serum chemistry results from the Central clinical laboratory prior to the day of randomization (Study Day 1). Randomized treatment phase visits On Study Day 1, the subject will be randomized to a treatment group, and the Randomized Treatment Phase will begin. During this phase, subjects will have regularly scheduled Study Visits at Day 1, and after 4, 8, 12, 16, and 24 weeks of treatment, and every 12 weeks thereafter. At these visits, blood sampling, spleen measurements, and safety assessments may be performed. A window of ± 7 days will be permitted for evaluations to be performed at each Study Visit. This window may be used to complete study visit procedures over a 7 day period. For example, an investigative center may elect to have a subject arrive at the site up to 7 days in advance of the scheduled visit date to provide laboratory samples or undergo MRI. (For the 48 week MRI/CT visit a -7 and +21 day window will be permitted.) The subject would then return on the date of the scheduled visit and complete any remaining procedures. This option allows for the laboratory test results to be available to the investigator on the day of the examination, when study medication is dispensed. It is recommended that for study Visits in which MRIs will be conducted (Baseline and Weeks 12, 24, 36 etc), both the clinic visit and the MRI scan be scheduled several visits in advance, in order to insure that the scan can be conducted within the Visit window. Subjects will also have Interim Visits at the study clinic laboratory to collect blood samples for hematology assessments at the Central Laboratory. (Collection of blood samples at Interim Visits may be performed at sites other than the primary study clinic ONLY under conditions specified in the laboratory manual.) The samples must be analyzed at the Central Laboratory to insure consistency. Interim Visits, in which hematologic evaluations are performed, will occur at Weeks 2, 6, 20, 30 and every 12 weeks thereafter; with a window of ± 3 days. Additional Interim Visits will be scheduled by the investigator to closely monitor hematologic parameters when a subject has had the dose of INC424 interrupted, decreased or increased. Additionally, at Week 4, subjects will be instructed to visit the clinic 1-3 days prior to their regularly scheduled Study Visit to provide blood samples for hematology and serum chemistry, in order to have the results available at the Week 4 visit.

40 Novartis Confidential Page 39 Extension phase visits (including crossover of control group) Subjects who participate in the Extension phase (See Section 5.2.5) will continue following the study schedule according to their duration of participation in the study. Additional Crossover Visits and Interim Visits will be necessary to evaluate eligibility for Extension, dispense study drug if crossing over from the Control group, and evaluate safety, tolerability, and efficacy for subjects continuing in this Phase. Scheduling of these visits will use guidelines described in Section and Section Criteria for disease progression Subjects having experienced protocol-defined disease progression are considered to have reached a study endpoint, and the end of the Randomized Treatment Phase. At this point, subjects will either be withdrawn from the study, or may continue in the Extension phase if eligible. Disease progression events may be either Qualifying or non-qualifying (for Extension Phase) and are defined as follows: Progression events that qualify for continuation in the extension phase Subjects who have had splenectomy will be considered to have had disease progression; the subject may be considered for the Extension Phase of the study. The date of the progression event will be the date of the procedure. For subjects who have progressive splenomegaly as defined by a 25% increase in spleen volume compared to the on-study nadir (including Baseline), the investigator will be notified via the central reader that the subject has reached an endpoint of disease progression; the subject may then be considered for the Extension Phase of the study. The date of the progression event will be the date of the MRI (or CT) scan noting the increase. Progression events that do not qualify for continuation in the extension phase Subjects who have had splenic irradiation will be considered to have had disease progression. The date of the progression event will be the date of the first radiation fraction. Subjects having had irradiation will be withdrawn from the study. Subjects who undergo leukemic transformation as defined by a bone marrow blast count of 20% at any time during the study will be considered to have disease progression, and should be withdrawn from the study. For subjects having a peripheral blood blast count of 20%, the subject should continue with the study regimen according to randomized group until the increase has been sustained at all sampling times for a period of 8 weeks or more, indicating leukemic transformation. At the discretion of the investigator, an unscheduled bone marrow biopsy may be conducted to confirm leukemic transformation as an alternative to awaiting confirmation from peripheral blood samples. Once confirmed by either means, the subject should be withdrawn from the study. Subjects who have expired during the course of study will be considered to have reached the study endpoint, regardless of whether the death is considered disease-related.

41 Novartis Confidential Page Extension phase--continuation for subjects randomized to INC424 Subjects that were randomized to receive INC424 may continue to receive INC424 in the Extension Phase after a Qualifying event has occurred (Section 5.2.4) IF, in the best judgement of the investigator, the subject is still receiving clinical benefit. The dose may be increased to improve efficacy (safety permitting) and dose adjustments for safety should continue to be applied (See Section 5.3). If the dose of INC424 will be increased, the subject should have a supplemental study visit (same as Crossover visit described in Section and in Section 7) at 4 weeks after the dose increase, and Interim Visits at 2 and 6 weeks following the dose increase, even if these intervals do not correspond to a scheduled Study Visit Extension phase--cross over for subjects randomized to control group Identifying subjects eligible for cross over Once the Qualifying progression event has occurred or if after demonstration of superiority for the primary or key secondary endpoint and providing INC424 continues to have an acceptable safety profile, subjects originally randomized to the Control group may cross over to receive INC424 in the Extension Phase if they meet safety criteria described in Section The decision to cross over will be based upon a discussion between the subject and the investigator. Evaluation of the subject s eligibility for crossover and initiation of dosing with INC424 should occur at one of the scheduled Study Visits in order to perform a physical examination, evaluate eligibility, choose the starting dose, and dispense INC424. If a Qualifying endpoint is recognized and the subject and investigator wish to initiate crossover prior to the next scheduled visit, a Crossover Visit should be scheduled for this purpose Treatment of crossover subjects Study schedule After the Crossover or Study Visit in which INC424 therapy is initiated, an additional study visit (Crossover Visit) will be required at 4 weeks ± 7 days after beginning INC424 therapy, in order to provide safety and efficacy data to support dose optimization of INC424. Additionally, Interim Visits will occur at 2 and 6 weeks after initiating therapy, to provide hematology data for safety. It may be possible to schedule this 4-week post-initial dose Crossover Visit within the ± 7 day window for a regularly scheduled Study Visit. In these cases, the regularly scheduled Study Visit evaluations supersede those scheduled for the Crossover Visit. If the 4 week post-initial dose Crossover Visit does not coincide with a regular visit, it should be added as a separate visit to conduct the observations described in Section 7. In addition to the Crossover Visits, an MRI scan should be scheduled 12 weeks (±7 days) from the first dose of study drug in the Extension Phase. MRI/CT scans -after demonstration of superiority for the primary or key secondary endpoint The frequency of MRI/CT scans will be either every 12 or 24 weeks. The criteria is outlined in Section

42 Novartis Confidential Page 41 Subsequent to any scheduling accommodations for the post-cross over visits, the subject will return to following his/her regular visit schedule for observations Initiation of INC424 The initial dose of INC424 for a subject crossing over from the Control group will be selected following the same rules as for subjects who were randomized to INC424 tablets at the start of the study EXCEPT that 1) subjects with platelet counts 75,000/µL but less than 100,000/µL will be permitted to begin dosing at 10 mg BID, and 2) subjects with platelet counts of at least 50,000/µL may (with Sponsor s permission) be permitted to begin dosing at 5 mg BID. Starting dose rules are illustrated in Table 5-1. Table 5-1 Most Recent Hematology Parameters Platelets > 200,000/µL Starting dose of INC424 after cross over Platelets 100,000/µL but 200,000/µL Platelets 75,000/µL but < 100,000/µL Starting dose 20 mg BID 15 mg BID 10 mg BID Platelets 50,000/µL but < 75,000/ µl 5 mg BID ** Platelets < 50,000/µL ANC < 500/µL Cannot Start Cannot Start Subjects not meeting these criteria may need time to stop or taper their best-available therapy regimen, and be re-tested to qualify to receive INC424. For subjects crossing over because of progressive splenomegaly, if platelet counts and/or ANC remain below these thresholds at the time of the later of: (a) 8 weeks, or (b) the next regularly scheduled Study Visit, following the date of the Qualifying event, the subject should be withdrawn from the study, and that visit will constitute the Follow-up Visit. Subjects having had splenectomy who wish to cross over to receive INC424 should not begin dosing until they are clinically stable and have stable hematology parameters. A subject who has not reached starting criteria within 12 weeks after splenectomy should be withdrawn. Subjects who cross over MAY increase beyond the starting dose for lack of adequate efficacy (Section 5.3.2) and MUST decrease dosage for safety as described in Section Dose adjustments Dose increases for inadequate efficacy in the randomized treatment phase Dose increases at week 4 As indicated in Section 3.4 Justification of Route, Dose Regimen and Treatment Period, the initial dose of INC424, will be determined by the Baseline platelet count. In order to optimize each subject s dosage, after the first 4 weeks of therapy, doses may be increased by 5 mg BID for subjects randomized to INC424 who meet all of the following conditions: Inadequate efficacy is demonstrated by palpable spleen length below the costal margin that has been reduced by LESS THAN 40% at the Week 4 visit relative to Baseline.

43 Novartis Confidential Page 42 Platelet count at the Week 4 blood draw is > 150,000/µL and platelet count has never been below 150,000/µL at a prior laboratory evaluation while receiving INC424. (See Figure 5-1) Absolute neutrophil count levels have remained at or above 1000/µL since enrollment in the study. Figure 5-1 Strategies for dose increase because of inadequate efficacy (by palpation) at week 4 in subjects randomized to INC424 Patients with Inadequate Response at Week 4 Starting Dose 20 mg BID Starting Dose 15 mg BID PC always > 150 K /µl And ANC always > 1000/µL PC <150 K/µL Or PC was <150 K/µL Or ANC is/was <1000/µL PC always > 150 K /µl And ANC always > 1000/µL PC <150 K/µL Or PC was <150 K/µL Or ANC is/was <1000/µL New Dose 25 mg BID No Increase In Dose New Dose 20 mg BID No Increase In Dose PC = Platelet count given in thousands/µl, ANC = Absolute Neutrophil Count are cells per µl Dose increases beyond week 4 After Week 4, dose increases in INC424 are allowed during the Randomized treatment phase ONLY for those subjects who exhibit an INCREASE in palpable spleen size. The rules for these optional dose increases are as follows: The dose increases may only occur in the two-week period following a study visit at which a regularly scheduled MRI occurs (e.g., the 2 weeks following Week 12, 24, 36, etc). The MRI for that study visit must have been performed. The platelet count and ANC data for that visit must be available. The palpable spleen length for that Study Visit must show a 2 cm or greater INCREASE in length compared to the on-study nadir (lowest palpable spleen measurement during the study, including Baseline). The subject must not have had a prior safety-related dose reduction. The subject must have had a platelet count 150,000/µL at every assessment since Baseline. The subject must have had ANC 1000/µL at every assessment since Baseline.

44 Novartis Confidential Page 43 The dose increase may only be an increase of 5 mg BID. The total dose may never exceed 25 mg BID. Following a dose increase, platelet count and ANC levels should be assessed approximately 2 weeks after the dose adjustment. If a regularly scheduled Study Visit or Laboratory-only Visit does not coincide with this required blood draw (within the Visit window), an unscheduled Interim Visit should be held to collect samples for hematology. Dose adjustments for safety, and reinstitution of doses as described in Section will apply whether the subject is on the original dose, or a dose that was increased for lack of efficacy Dose increases for inadequate efficacy in the extension phase As indicated in Section , subjects who cross over to receive INC424 after meeting a disease progression endpoint, or after demonstration of superiority for the primary or key secondary endpoint, will have initiated INC424 therapy at doses determined by the platelet count at the time of cross over; these doses will range from 5 mg BID to 20 mg BID. For these subjects OR for subjects originally randomized to INC424 who continue in the Extension phase, the dose of INC424 can be increased for inadequate efficacy using the following guidelines: Subjects must have been receiving INC424 for at least 4 weeks prior to considering a dose increase for inadequate efficacy. Inadequate efficacy is defined as a spleen size reduction, as measured by palpation, of LESS THAN 40% relative to the measurement prior to initiating INC424 therapy. For subjects who cross over subsequent to splenectomy, inadequate efficacy will be based on the investigator s judgment, considering all available data for the subject. Dose increases must be in increments of 5 mg BID. Dose increases may not be instituted more often than every 4 weeks. Doses may never exceed 25 mg BID. Dose increases may only occur with improved platelet counts relative to the time that the crossover (or the last dose increase) occurred as illustrated in Table 5-2. Table 5-2 will serve as the dose adjustment guide for the first, and any subsequent, dose increase for inadequate efficacy. Table 5-2 Dose increases for inadequate efficacy for subjects who have crossed over to receive INC424 Current Dose IF Platelet Count per µl is: And ANC per µl is: New Dose may be used: 5 mg BID 50,000 to < 75,000 < 750 Must remain at 5 mg BID 5 mg BID 75, mg BID 10 mg BID 100, mg BID 15 mg BID 150, mg BID 20 mg BID 150, mg BID

45 Novartis Confidential Page Dose adjustments for safety in all subjects receiving INC Interruption or dose reduction For all subjects who are receiving INC424, including subjects who were randomized to INC424 and subjects, regardless of initial randomization who are currently in the Extension Phase, there are mandatory dose decreases or interruptions for declining platelet counts or ANC levels that might be observed while on INC424 therapy. In addition to mandatory dose interruption or decrease for hematologic toxicities, there are mandatory criteria for permanent discontinuation of INC424 (See Section 9.4 and Section 10.2) Dosing must be held if platelet counts decline below 50,000/µL (Grade 3 laboratory abnormality by Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0), or if ANC falls below 500/µL while receiving INC424. Doses must be decreased for platelet count values < 125,000/µL as shown in Table 5-3 with optional restarting or resuming prior dose after recovery (Section ). In order to provide sufficient data to make the dose adjustment decisions, it is recommended that hematology parameters be obtained at least weekly for platelet count <100,000 /µl or ANC < 1000/µL and at least two times weekly for platelet count < 50,000/µL or ANC < 500/µL. The dose reduction strategy in Table 5-3 covers the starting doses (15 mg BID and 20 mg BID), possible doses after an increase for inadequate efficacy (20 mg BID and 25 mg BID), and doses that might be present after a prior dose reduction or in the Extension Phase (down to 5 mg BID). Table 5-3 Platelet Count at Time of Decline (in thousands) 125 K/µL Dose reductions in INC424 for safety in subjects with platelet count declines Dose at the Time of Platelet Decline 25 mg BID 20 mg BID 15 mg BID 10 mg BID 5 mg BID Dose that MUST be Instituted No dose reduction required 100 to < 125 K/µL 20 mg BID 20 mg BID 15 mg BID 10 mg BID 5 mg BID 75 to < 100 K/µL 10 mg BID 10 mg BID 10 mg BID 10 mg BID 5 mg BID 50 to < 75 K/µL 5 mg BID 5 mg BID 5 mg BID 5 mg BID 5 mg BID < 50 K/µL MUST STOP DOSING Restarting or re-instituting previous dose Dosing may be restarted or increased following recovery of platelet counts and/or ANC to acceptable levels as illustrated in Table 5-4 below, provided ANC levels are 500/µL. The objective for restarting or escalating after a reduction for safety is to find the highest safe dose of INC424 for each subject, with increases in dose generally not more than in increments of 5 mg BID and not more often than every 2 weeks. Subjects who are restarting after a reduction for thrombocytopenia may not receive doses above 20 mg BID maximum. Similarly, ANC levels that decline to < 500/µL necessitate immediate dose interruption. ANC level recovery to above 500 /µl but less than 750/µL will allow dosing to be restarted at 5 mg BID, and ANC levels between 750/µL but < 1000/µL may restart at 10 mg BID. Absolute

46 Novartis Confidential Page 45 neutrophil count level increases to above 1000/µL will allow a further dose increase to a maximum of 20mg BID. The Investigator should exercise caution in resuming any dose of INC424 which resulted in a platelet count < 50K/uL or ANC falling below 500/uL. After restarting, using the guidelines in Table 5-4, if it is found that a subject cannot tolerate the lowest allowed dose (5mg BID, or 5mg QD with concomitant CYP3A4 inhibitor, see Section 5.3.4) without platelets falling below 50,000/µL, neutrophils falling below 500/µL, or Hgb falling below 6.5g/dL despite the use of transfusion therapy, drug must be permanently discontinued (Section 9.4 and Section 10.2). Table 5-4 Current Platelet Count (in thousands) Restarting or increasing INC424 dose after safety interruptions or dose reductions < 50 K/µL Continue hold Dose Restart or Dose Increase Guidelines 50 to < 75 K/µL 5 mg BID for at least 2 weeks; if stable, may increase to 10 mg BID 75 to < 100 K/µL 10 mg BID for at least 2 weeks; if stable, may increase to 15 mg BID 100 to < 125 K/µL 15 mg BID 125 K/µL Current ANC Level 20 mg BID < 500/µL Continue hold Dose Restart or Dose Increase Guidelines 500 to < 750/µL 5 mg BID for at least 2 weeks; if stable, may increase to 10 mg BID 750 to < 1000/µL 10 mg BID for at least 2 weeks; if stable, may increase to 15 mg BID 1000 to < 1500/ µl 15 mg BID for at least 2 weeks; if stable may increase to 20 mg BID 1500/µL 20 mg BID NOTE: Whether the dose interruption occurred because of neutropenia, thrombocytopenia or both, when restarting, both the platelet count and ANC must be considered to determine the restart dose, with the lower calculated dose being used Dose reductions for concomitant CYP inhibitor usage INC424 is metabolized in the liver by the cytochrome (CYP) P450 metabolizing enzyme system, predominantly by the 3A4 isozyme. With concomitant dosing of potent CYP inhibitors such as oral ketoconazole, plasma exposure of INC424 increases approximately 2- fold. Thus, a dose reduction of ~ 50% for INC424 is appropriate for subjects who take ketoconazole or other potent CYP3A4 inhibitors as concomitant medication. BID doses will be decreased to the corresponding once daily dose as follows: If dose is 25 mg BID, change dose to 25 mg QD If dose is 20 mg BID, change dose to 20 mg QD If dose is 15 mg BID, change dose to 15 mg QD If dose is 10 mg BID, change dose to 10 mg QD If dose is 5 mg BID, change dose to 5 mg QD

47 Novartis Confidential Page 46 Potent inhibitors of CYP3A4 include oral ketoconazole, clarithromycin, itraconazole, nefazodone, telithromycin. (Flockhart 2007) Based on the very low overall bioavailability of topical ketoconazole, no dosage adjustment is needed for use with topical ketoconazole. NOTE: once the course of therapy using a CYP 3A4 inhibitor has been completed, the subject should resume their prior BID dose regimen of INC424 beginning the next day Optional dose tapering strategy in the event of drug discontinuation When a decision is made to permanently discontinue INC424 therapy for reasons other than low platelet counts or ANC levels, a dose tapering strategy may be considered, based on evaluation of the condition of the subject, current dosing regimen and the clinical judgment of the investigator. If considered to be medically necessary, the investigator may use any treatment to manage withdrawal from INC424 including a gradual tapering of the study drug dosage or use of other medications to manage side-effects of discontinuation. Short-term courses of corticosteroids have been used to moderate the withdrawal of INC424 and may be considered as part of a tapering strategy. Corticosteroids may be started prior to, or concurrent with, INC424 tapering in anticipation of the possibility of occurrence of withdrawal symptoms. When a decision has been made to discontinue the subject with utilization of a tapering strategy, regardless of the use of concomitant medications, safety data will continue to be assessed in accordance with the protocol for a period of time as least through the continued administration on INC Measures taken to avoid bias The study is a randomized, open label study. The open label design is necessary to accommodate the wide variety of treatments for MF that may be considered best-available, and the necessity of using frequent modifications and dose adjustment in these therapies depending upon the subject s condition and safety margins. However, the primary endpoint, change in splenic volume is objective. MRI (or CT) results of spleen volume measurements will not be provided to Investigators unless the subject has reached an endpoint of 25% increase in spleen volume relative to the on-study nadir (including Baseline). Images will be read and measured by an external expert, who will be blinded to treatment assignment A Data Safety and Monitoring Board (DSMB) will assess risk: benefit and study conduct as described in the DSMB charter. 6 Subject eligibility 6.1 Study population Male or female individuals who have been diagnosed with PMF, PPV-MF or PET-MF, who are 18 years of age or older, have palpable splenomegaly, are currently not candidates for stem cell transplantation and have 2 or more risk factors as defined by Cervantes, et al (2009), placing them in an intermediate-2 or high-risk prognostic group. Subjects may or may not have received any prior therapy for myelofibrosis. All subjects receiving at least one dose of study drug will be included in the safety population and in the assessment of other endpoints. The Screening and Baseline Period is defined as the period beginning on the day that written informed consent is given. This Period cannot exceed 28 consecutive days prior to

48 Novartis Confidential Page 47 randomization on Day 1. Subjects who are receiving therapy for MF must maintain a stable dosing regimen starting 2 weeks prior to the beginning of the Screening/Baseline Period, and if not on any therapy, the subject should remain so. Therapies should not be added or discontinued, and doses of therapies may not be adjusted at any time during the 28 days prior to the start of Baseline evaluations. Subjects who are randomized to the Control group may have necessary adjustments made to their treatment regimen after study Day Inclusion criteria All subjects must meet the following inclusion criteria: 1. Subjects 18 years of age or older. 2. Subjects must be diagnosed with PMF, PPV-MF or PET-MF, according to the 2008 World Health Organization criteria (Table 2 in Tefferi and Vardiman (2008), Appendix I), irrespective of JAK2 mutation status. 3. Subjects with myelofibrosis requiring therapy must be classified as high risk (3 or more prognostic factors) OR intermediate risk level 2 (2 or more prognostic factors). The prognostic factors, defined by the International Working Group (Cervantes, et al 2009) are: Age > 65 yrs Presence of constitutional symptoms (weight loss, fever, night sweats) Marked anemia (Hgb < 10g/dL)* Leukocytosis (history of WBC > 25 x10 9 /L) Circulating blasts 1% * A hemoglobin value < 10 g/dl must be demonstrated during the Screening Visit for subjects who are not transfusion dependent. Subjects receiving regular transfusions of packed red blood cells will be considered to have hemoglobin < 10 g/dl for the purpose of evaluation of risk factors. 4. Subjects with peripheral blood blast count of < 10%. 5. Subjects with an ECOG performance status of 0, 1, 2 or 3 (Appendix IV). 6. Subjects must have a palpable spleen measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion. 7. Subjects must have been on a stable therapeutic regimen for at least 2 weeks before Screening and no less than 4 weeks prior to Baseline. 8. Subjects who have not previously received treatment with a JAK inhibitor 6.3 Exclusion criteria Any of the following are cause for exclusion from the study: 1. Subjects with a life expectancy of less than 6 months. 2. Females who are pregnant or are currently breastfeeding. 3. Subjects of childbearing potential who are unwilling to take appropriate precautions (from Screening through Follow-up) to avoid fathering a child or becoming pregnant.

49 Novartis Confidential Page 48 Females of non-childbearing potential are those 55 years of age or older who have a history of amenorrhea for at least 1 year, OR those who have been surgically sterile for at least 3 months For subjects of childbearing potential, appropriate precautions are those that are at least 99% effective in preventing the occurrence of pregnancy. These methods should be communicated to the subjects and their understanding confirmed. (Appendix II). 4. Subjects with inadequate bone marrow reserve as demonstrated by: a Absolute neutrophil count (ANC) that is 1000/µL. b Platelet count that is < 100,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions. 5. Subjects with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason. 6. Subjects with inadequate liver or renal function as demonstrated by: a Direct bilirubin > 2.0x ULN. b Alanine aminotransferase (ALT) > 2.5x institutional upper limit of normal (ULN). c Creatinine > 2.0 mg/dl. 7. Subjects with clinically significant bacterial, fungal, parasitic or viral infection which require therapy: a Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed b Patients with known active hepatitis A, B, C or who are HIV-positive. 8. Subjects must not currently have the option of stem cell transplantation, either because they are not a candidate, or because a suitable donor is not available. 9. Subjects with history of malignancy in past 5 years except for treated, early-stage squamous or basal cell carcinoma of the skin. 10. Subjects with cardiac disease which in the Investigator s opinion may jeopardize the safety of the subject or the compliance with the protocol. 11. Subjects with currently uncontrolled or unstable angina. 12. Subjects under ongoing treatment with another investigational medication or having been treated with an investigational medication within 14 days or 6 half-lives (whichever is longer) prior to enrollment. 13. Subjects for whom the dose or dose-regimen of any therapies used to treat MF has been modified at any time from 2 weeks prior to the start of Screening through the beginning of Baseline evaluations. 14. Subjects who have had splenic irradiation within 12 months prior to Screening. 15. Subjects with currently rapid or paroxysmal atrial fibrillation. 16. Subjects undergoing treatment with hematopoietic growth factor receptor agonists (ie, erythropoietin (Epo), granulocyte colony stimulating factor (GCSF), romiplostim, eltrombopag) at any time within 2 weeks prior to Screening or 4 weeks prior to Baseline.

50 Novartis Confidential Page Subjects with recent (approximately 6 months) myocardial infarction or acute coronary syndrome. 18. Resting heart rate > 110 beats per minute. 19. Resting systolic blood pressure > 160 mm Hg. 20. Resting diastolic blood pressure > 100 mm Hg. 21. Subjects who are unable to comprehend or are unwilling to sign an informed consent form (ICF). 22. Subjects with active alcohol or drug addiction that would interfere with their ability to comply with the study requirements. 23. Subjects with any concurrent condition that, in the Investigator s opinion, would jeopardize the safety of the subject or compliance with the protocol. 6.4 Subjects who fail to meet screening criteria A subject who has a laboratory test result(s) or an ECG finding that does not satisfy the entrance criteria may have the test(s) repeated once. These tests may be repeated as soon as the investigator believes that the retest result is likely to be within the acceptable range to satisfy the entrance criteria, but must be completed within the 4 week period prior to the start of treatment. If the retest meets eligibility criteria, the subject may proceed to the Baseline evaluations, will not be required to sign another ICF, and the original subject identification number assigned by Interactive Voice Response System (IVRS) will be used. In the event that the laboratory test(s) or ECG cannot be performed within the 4 week period prior to the start of treatment, or the subject s medical condition has changed significantly during the screening period so that inclusion/exclusion criteria are no longer met, the subject is considered a Screen failure, and must be withdrawn from the study. If the subject and investigator choose to re-screen the subject, the subject must sign a new ICF, a new subject identification number will be assigned by IVRS, and all required Screening activities must be performed when the subject is re-screened for participation in the study. Only one re-screen period per subject will be permitted. Patients who complete the informed consent process and do not meet all entry criteria and therefore who do not receive first dose of study medication will be considered screen failures. The screening failure data to be collected in the clinical database will be the demography module and reason for failure.

51 Novartis Confidential Page 50 7 Description of study visits 7.1 Schedule of observations Table 7-1 Evaluation Informed consent / Eligibility criteria Schedule of observations-prior to demonstration of superiority for the primary or key secondary endpoint Screen Baseline On-treatment Evaluations (Window is ± 7 days for Study Visits and ± 3 days for Interim Visits) Day -28 to Day -8 Day -7 to Day -1 X X Medical history, prior medications X X Serology / HIV laboratory tests X Concomitant medications/control group therapy Day 1 Interim Visits (a) Week 4 Week 8 or 16 Crossover (k) Week 12 Week 24 Wk 36 & q24 Week 48 wks (j) Wk 72 & q24 wks (j) End of Study Follow up (+9) 28d after last dose X X X X X X X X X Transfusion history/status X X X X X X X X X X X Physical exam and measurement of weight (b) Measurement of spleen by palpation X(b) X X X X X(b) X X X X(b) X X X X X X X X X X Vital signs X X X X X X X X X X ECOG performance status X X X X(k) X X X EORTC QLQ-C30 & FACT-lym questionnaires X X(k) X 12-lead ECG X X(c) X(c) X(c) X X X X Serum chemistry tests X X X(d) X X X X X X X Lipid panel X X X X X Hematology X X X X(d) X X X X X X X Survival Q 3 monthly (l)

52 Novartis Confidential Page 51 Evaluation Screen Baseline On-treatment Evaluations (Window is ± 7 days for Study Visits and ± 3 days for Interim Visits) Day -28 to Day -8 Day -7 to Day -1 Day 1 Interim Visits (a) Week 4 Week 8 or 16 Crossover (k) Week 12 Week 24 Wk 36 & q24 Week 48 wks (j) Wk 72 & q24 wks (j) PT and PTT X X X X Pregnancy test (e) X X X X X X X X X X X Urinalysis X X X X X Blood sample for CD34+count / JAK mutation X X X X X Blood sample for PD markers X X X X X Blood sample for INC424plasma PK (f) X(f) X X(f) X X X MRI of abdomen (h) X X X X X BM aspiration, biopsy and cytogenetics (g) X X(g) X(g) Contact IVRS (i) X X X X X X X X X Randomize subject X Drug accountability assessment X X X X X X X Administer morning dose of INC424 Dispense study drug and Reminder Card X X X X X X X X X X Record Adverse Events X X X X X X X X X X X Survival/incidence leukemia/ new ANP therapy End of Study Follow up (+9) 28d after last dose Survival Q 3 monthly (l) (a) Interim Visits (laboratory only) will be conducted for hematology assessments (and serum pregnancy tests for women of childbearing potential); the window for Interim Visits will be ± 3 days. Interim visits will be conducted at Weeks 2, 6, 20, 30, 42, 54, and every 12 weeks thereafter. Additionally, subjects who cross over from the Control Group OR increase dose of INC424 should have Interim Visits at 2 and 6 weeks after the initialization or increase. (b) A comprehensive physical examination will be performed at Screening, Week 24, Week 48 and at the Follow-up visit. All other physical examinations will be targeted (symptom directed). All physical exams will include a measurement of body weight. Height will be measured at screening only. (c) 12-lead ECG will be performed at the Baseline visit only if not conducted during Screening Visit, or if conducted and found to include an abnormality deemed clinically X

53 Novartis Confidential Page 52 Evaluation Screen Baseline On-treatment Evaluations (Window is ± 7 days for Study Visits and ± 3 days for Interim Visits) Day -28 to Day -8 Day -7 to Day -1 Day 1 Interim Visits (a) Week 4 Week 8 or 16 Crossover (k) Week 12 Week 24 Wk 36 & q24 Week 48 wks (j) Wk 72 & q24 wks (j) End of Study Follow up (+9) 28d after last dose Survival Q 3 monthly (l) significant. At Week 4 and Week 12, ECG for patients randomized to INC424 should be conducted approximately 2 hours after the dose of study drug is administered, but NOT within 5 minutes prior to or 15 minutes after any blood sample collection. (d) Subjects must provide blood samples for hematology and serum chemistries 1-3 days prior to the scheduled Week 4 visit in order to support possible dose increases for inadequate efficacy at the Week 4 visit. (e) For women of childbearing potential, a Serum pregnancy test will be obtained at Screening and Follow-up visits and at all Interim visits. Conduct urine pregnancy test at all other on-treatment Study Visits. If a positive urine pregnancy test occurs, a serum test should be performed to confirm the result. More frequent pregnancy testing may be required in some localities-see the laboratory manual. (f) Blood sampling for plasma pharmacokinetics of INC424 for subjects randomized to receive it. Weeks 4 and 12: Subject will withhold the morning dose of INC424 on the day of the Week 4 or 12 Study Visit. At the study clinic, an initial PK sample will be drawn, just prior to administration of the morning dose of study drug, followed by two l timed PK samples; drawn as directed in Section 7.3. At all other timepoints: The subject will self-administer the morning dose of INC424 and record the time of the dose on the reminder card. Collection of the PK sample at any time during the study visit is permitted, and non-uniformity of sampling time is encouraged. (g) Biopsy and aspiration should be performed every 48 weeks (Baseline, Week 48, 96, 144 etc). Bone marrow aspiration and biopsy evaluation will include staining for fibrosis and cytogenetics. Cytogenetic testing will not be repeated after the Baseline visit if a subject has no cytogenetic abnormalities at Baseline; staining for fibrosis will continue at the indicated treatment visits for all subjects. (h) MRI will be conducted as the preferred modality to measure spleen size. For subjects in whom MRI is contraindicated, CT may be utilized. The same method should be used for all visits for a given subject unless a new contraindication to the use of MRI occurs. (A -7 / + 21 day window will be permitted for the week 48 MRI/CT.) (i) IVRS must be contacted at the Screening visit to obtain subject identification number, at Day 1 visit to randomize subject, at each Study Visit AND anytime subject s dose has been adjusted. See IVRS manual for more information. (j) Week 36 and every 24 weeks thereafter includes Weeks 36, 60, 84, 108, 132, 156, 180, etc Week 72 and every 24 weeks thereafter includes Weeks 72, 96, 120, 144, 168, 192, etc. (k) ECOG performance status, EORTC and FACT-lym questionnaires are not performed at Crossover Visits. (l) All patients will be followed every 3 months for survival, incidence of leukemia and start of new antineoplastic therapy. A Crossover Visit will be scheduled if a subject originally randomized to Control meets a Qualifying progression event and wishes to begin receiving INC424 at a time other than a regular Study Visit. ADDTIONALLY, a Crossover Visit will be scheduled at the end of 4 weeks after initiation or increase of INC424 dose, to assess safety and efficacy. If a Crossover Visit occurs during the window of a regularly scheduled Visit, the evaluations listed for the regular Study Visit should be conducted in lieu of the Crossover Visit evaluations. At the first Crossover Visit, an MRI should be scheduled for 12 weeks (± 7 days) after the first Extension Phase dose of study drug; the scan need not correspond with a Study Visit. Protocol-scheduled MRIs will be omitted after this point for subjects in the Extension Phase.

54 Novartis Confidential Page 53 Table 7-2 Evaluation Schedule of observations: Extension Phase - after demonstration of superiority for the primary or key secondary endpoint On-treatment Evaluations (Window is ± 7 days for Study Visits and ± 3 days for Interim Visits) Interim Visits (1) Crossover (2) Informed consent / Eligibility criteria(4) X Concomitant medications/control group therapy Week 60 (3) Wk 72 & q24 wks Follow up (+9) X X X X X Transfusion history/status X X X X X Physical exam and measurement of weight Survival End of Study 28d after last dose Q 3 monthly (9) X X X X X(5) Measurement of spleen by palpation X X X X X Vital signs X X X X X ECOG performance status X X 12-Lead ECG ( local read) X X X Serum chemistry (6) X X X X X Hematology X X X X X X PT and PTT X Pregnancy test (7) X X X X X X Urinalysis X X Blood sample for INC424plasma PK (8) X X Blood sample for JAK mutation (10) X X MRI of abdomen (11) X X Dispense study drug and Reminder Card X X X Record Adverse Events X X X X X Survival/incidence leukemia/ new ANP therapy X

55 Novartis Confidential Page 54 Evaluation On-treatment Evaluations (Window is ± 7 days for Study Visits and ± 3 days for Interim Visits) Interim Visits (1) Crossover (2) Week 60 (3) Wk 72 & q24 wks Follow up (+9) Drug accountability assessment X X X X X Survival End of Study 28d after last dose Q 3 monthly (9) (1) Interim Visits (laboratory only) will be conducted for hematology assessments (and serum pregnancy tests for women of childbearing potential); the window for Interim Visits will be ± 3 days. Interim visits will be conducted at Weeks 54, and every 12 weeks thereafter. Additionally, subjects who cross over from the Control Group OR increase dose of INC424 should have Interim Visits at 2 and 6 weeks after the initialization or increase (2) Control arm patients will be permitted to cross-over to INC424 (3) Week 60 and every 24 weeks thereafter includes weeks 84,108,132 etc (4) Subjects will be re-consented to the extension study, and to a new pharmacogenomic consent which will now include long term storage of pharmacogenomic samples leftover from the previous analysis. (5) A comprehensive physical examination will be performed at Week 48 and at the Follow-up visit. All other physical examinations will be targeted (symptom directed). All physical exams will include a measurement of body weight. (6) Blood samples for hematology and serum chemistries will not include lipase or amylase. (7) For women of childbearing potential, a Serum pregnancy test will be obtained at Screening and Follow-up visits and at all Interim visits. Conduct urine pregnancy test at all other on-treatment Study Visits. If a positive urine pregnancy test occurs, a serum test should be performed to confirm the result. More frequent pregnancy testing may be required in some localities-see the laboratory manual. (8) Blood sampling for plasma pharmacokinetics of INC424 for subjects will be obtained only at crossover visit & week 60. (9) All patients will be followed every 3 months for survival, incidence of leukemia and start of new antineoplastic therapy. (10) JAK 2 mutation will be monitored at 48 week intervals after week 60 i.e week 108 and the end of study. (11) MRI or CT, to focus on patients whose scans will contribute to an updated estimation of the duration of response. The frequency of MRI/CT scans will be either every 12 or 24 weeks. The criteria for this is outlined in Section

56 Novartis Confidential Page Screening and baseline evaluations Screening evaluations (day -28 to day -8) Prospective participants will be scheduled for a screening visit by site staff. Site staff should inform subjects to come to the clinic after an overnight fast of at least 8 hours or since midnight. The required procedures will be scheduled over a 1- to 3-week period. The following procedures will be performed: Obtain informed consent before any study specific procedures are conducted. Contact IVRS to obtain a subject identification number. Discussion of methods known to be at least 99% effective in preventing pregnancy (Appendix II). Subjects must agree to take appropriate precautions to avoid fathering a child or becoming pregnant while on the study. Additionally, because the effects on male fertility have not been determined, males should not father children for at least 6 months after completing therapy with INC424. Male subjects should be informed that if they plan to father children in the future, they may wish to seek counseling on the option of sperm cryopreservation prior to starting study medication. Review of medical history and prior medication history (see Section 9.7, Prior and Concomitant Medications/Measures). Record the identity and dose of all medications used to treat underlying myelofibrosis disease, and confirm that subject has been on a stable regimen (which may include no therapy) for at least 2 weeks prior to the start of Screening. These therapies should not be added, discontinued, or dose-adjusted during the Screening period; subjects should continue this stable regimen through the day prior to randomization (Day -1). Review of transfusion history. Comprehensive (complete) physical examination including height, body weight and spleen length. See Section The edge of the spleen shall be determined by palpation, measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion. The spleen should be measured in the same manner at all subsequent visits. Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Eastern Cooperative Oncology Group (ECOG) status must be 0, 1, 2 or 3 (Appendix IV). 12-lead electrocardiogram (ECG) performed in the recumbent position after 5 minutes of rest. Urine sampling for urinalysis (Appendix III). Blood sampling for the following: Serum chemistry tests, hematology and PT, PTT (Appendix III). Serum pregnancy test (females of childbearing potential only). (Appendix III) Serology tests for HIV and hepatitis. (Appendix III) Record adverse events.

57 Novartis Confidential Page 56 Determine if subject meets the inclusion/exclusion criteria Baseline evaluations (day -7 to day -1) The results from the Screening visit evaluations will be reviewed to determine if the subject continues to meet the eligibility requirements as specified in the protocol. Subjects who have signed the informed consent form and meet all the entry criteria (see Inclusion/Exclusion Criteria) will be enrolled in the study. Procedures for the Baseline visit may be conducted over 1 to 7 days as needed. Blood samples for hematology and serum chemistry should be performed at least 3 days prior to the intended Study Day 1, in order to allow ample time for results to be returned from the Central Laboratory. Subjects must be reminded to arrive for the Baseline blood sample collection after an overnight fast of at least 8 hours. The MRI scan should be acquired on Day -7 prior to the intended Study Day 1, to allow time for the Central reader to verify image quality prior to randomization. Image verification must be received before the subject can be randomized. If, in exceptional circumstances, positive confirmation of the adequacy of the Baseline scan is received from the Central reader, but receipt is delayed beyond the 7 day period, the Baseline window for MRI may be extended for a period of an additional 3 days. This extension applies to the MRI and is only for receipt of image verification. (All other evaluations must occur no more than 7 days prior to Study Day 1.) In the event that the image is determined by the Central reader to have been performed incorrectly, the Baseline MRI should be rescheduled for the earliest date possible (ie, a new study Day 1 should be projected and all Baseline evaluations should be repeated within 7 days prior to this date). In this circumstance only, the maximum combined length of the Screening/Baseline period may be extended from 28 to 56 days (from the first day of screening to Study Day 1) if required to accommodate rescheduling of the MRI. All evaluations should be recorded in the source documents and promptly entered in the ecrf. The following procedures will be performed at the Baseline visit and prior to enrollment for all subjects: Subjects should arrive at the clinic fasted. Confirm that the subject continues to meet all relevant inclusion and exclusion criteria, considering evaluations occurring at screening and baseline. Update medication history; confirm that all drugs used to treat underlying myelofibrosis disease (Best-available therapy) have been continued on a stable regimen for at least the prior 28 days. Update transfusion history status. MRI of the abdomen will be performed, to assess spleen and liver volumes. CT scan may be performed if subject is not a candidate for MRI. The Baseline scan will be transmitted to a Central reader for confirmation of evaluability. The scan will be considered complete ONLY upon receipt of acceptance verification by the Central reader. If the Central reader indicates that the Baseline scan is not acceptable, the test must be repeated before the subject can be randomized.

58 Novartis Confidential Page 57 Blood sampling for serum chemistry tests, lipid panel and hematology (see Appendix III). Be sure to ship laboratory samples to the Central Laboratory immediately so that Baseline data are available for subjects to begin dosing Eastern Cooperative Oncology Group (ECOG) status must be 0, 1, 2 or 3 (Appendix IV). Complete EORTC QLQ-C30 quality-of-life questionnaire. Complete FACT-Lym questionnaire. Targeted physical examination including body weight and measurement of spleen by palpation (Section ). Record adverse events. Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. 12-lead ECG performed in the recumbent position after 5 min of rest, ONLY if not conducted during the Screening Visit, or if conducted and found to include an abnormality deemed clinically significant. Bone marrow aspiration and biopsy, cytogenetic profile. NOTE: a bone marrow aspiration and biopsy is required UNLESS an aspirate and biopsy from the same institution was obtained within the previous 3 months, all data from the samples are available for review by the Study Investigator of Study INC424A2352, and the subject has not been on any therapy for MF during the intervening period. The prior data will need to be entered into the ecrf for this study, with explanation as to the origin of the data. Blood sample for PD will be collected. Blood sampling for JAK2 mutation assay. Blood sample for CD34+ cell count (Appendix III). Urine pregnancy test for all women of childbearing potential. Subjects will be instructed to hold all drugs to treat MF on the morning of the Day 1 Visit, in case the subject is randomized to receive INC On-treatment evaluations On-treatment evaluations are scheduled for Study Visits at Day 1, and at the end of Weeks 4, 8, 12, 16, 24 and every 12 weeks thereafter. In addition, subjects will visit the clinic site (or alternative site as described in the lab manual) for Interim (laboratory) Visits to provide blood samples for hematology after Weeks 2, 6, 20, 30 and every 12 weeks thereafter. Subjects should be told to arrive for all Study Visits after an overnight fast of at least 8 hours. Lab draws for hematology drawn at Interim Visits need not be fasted. If it is determined that the subject has had a Qualifying disease progression event and wishes to continue in the Extension Phase, a Crossover Visit should occur (either as one of the regular Study Visits, or as a separately scheduled visit). If INC424 was initiated or dose-increased at this visit, a second Crossover Visit will occur 4 weeks later, as well as Interim Visits at 2 and 6 weeks afterward. When a regularly scheduled visit serves as a Crossover Visit, the regularly scheduled evaluations will always supersede Crossover Visit evaluations, where they differ. If it is determined at any Study Visit that the subject will discontinue study drug that day, then

59 Novartis Confidential Page 58 that study visit will be the End of Study Visit, and the End of Study Visit procedures will be followed. After 4 weeks of treatment (Week 4 Visit), subjects receiving INC424 may have the dose of INC424 increased because of inadequate efficacy. At this visit or anytime during the study, the dose may be adjusted for safety, following the guidelines described in Section 5.3, Dose Adjustments. The individual study visit descriptions describe activities that must occur to support and document these dose changes. If a subject originally randomized to the Control group reaches a study endpoint and crosses over to receive open-label INC424, treatment with INC424 should now follow the dose increase and decrease guidelines as described in Section 5.3, Dose Adjustments. As is the case for subjects who are randomized to INC424 at the outset, the individual study visit descriptions describe activities that must occur to support and document dose changes of INC424. This study schedule is designed to closely monitor the dose limiting toxicities of INC424. If, at any time during the study, a subject experiences unexpected signs or symptoms, additional safety evaluations should be conducted at a regular Study Visit or unscheduled visit. For example, weekly monitoring is advised for subjects with platelet counts < 100,000/µL or neutrophils < 1000/µL, and bi-weekly for platelets < 50,000/µL or neutrophils < 500/µL. Additionally, x-ray examination of the thorax, echocardiography, and pulmonary function testing and/or arterial blood gas analysis should be considered in subjects developing new or worsening cardiopulmonary symptoms including cough, shortness of breath, exercise intolerance or peripheral edema. Women of childbearing potential will be monitored regularly for pregnancy status, either by serum or urine pregnancy tests as described in the study schedule. If local requirements mandate more frequent testing, applicable sites will conduct monthly testing. See Section 5.3 and Section 9.4 for criteria for mandatory reduction, interruption, or discontinuation of study drug based upon results of safety monitoring On-treatment evaluations-before the primary endpoint analysis Day 1 The Day 1 visit may occur as soon all Baseline evaluations have been completed, and the laboratory data (including platelet count) from the Baseline Visit are available. The following procedures will be performed and all observations will be recorded in the ecrf: Record any concomitant medications. Determine the date and time of last administration of prior therapy (if any) for treatment of MF. Update transfusion history status. Contact the IVRS for assignment of study drug (randomization). The following information will be required during the IVRS call in order to complete the randomization group assignment.

60 Novartis Confidential Page 59 The subject s risk level as defined by the International Working Group (Cervantes, et al 2009) High risk (3 or more prognostic factors) OR Intermediate risk level 2 (2 or more prognostic factors) The subject s platelet count Additional details will be provided in the IVRS manual. Administer the morning dose of INC424 Study drug for the first 28 days (plus overage) will be dispensed along with dosing instructions. If randomized to the Control group, review Best-available therapy regimen (any medications used to treat underlying myelofibrosis disease). From this point forward, the Best-available therapy regimen may be altered at any time during the Randomized treatment Phase according to judgment of the investigator. Record adverse events Subjects will be instructed to call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. These adverse events will be recorded on the ecrf. Subjects will be given a reminder card with the following instructions for upcoming visits. To visit the site clinic for the Interim Visit at the end of Week 2 To visit the site clinic 1-3 days prior to the Week 4 Visit for blood sampling after an overnight fast of at least 8 hours. NOT to take the morning dose of study drug on the day of the Week 4 visit. To arrive for the Study Visit having fasted for at least 8 hours To bring the study drug and the reminder card to the clinic with them. To record the time of the evening dose of study drug on the prior day Week 1 through week 2 Subjects will self-administer INC424 twice daily as instructed, morning and evening (at approximately 12-hour intervals), in an outpatient setting. For the Control group, bestavailable therapy will be administered according to the manufacturer s instructions, and investigator directions. Subjects will call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Site staff will call subjects to remind them to visit the site clinic for the Interim Visit at the end of Week Week 2 (± 3 days) Subjects will attend the study clinic for an Interim Visit to provide blood samples for analysis at the Central Laboratory. Blood samples will be drawn for hematology only; fasting will not be required. Serum pregnancy test will be performed for women of childbearing potential.

61 Novartis Confidential Page Week 3 through week 4 Subjects will continue to self-administer INC424 or best-available therapy, and report unfavorable symptoms as described above. Site staff will call subjects to remind them to visit the site for the Week 4 Visit AND additionally, to visit the clinic 1 to 3 days prior to the visit day after an overnight fast of at least 8 hours. Subject will attend the study clinic to provide blood samples for serum chemistry tests and hematology (Appendix III). The laboratory results should be available prior to the Week 4 Study Visit. Site staff will remind subjects of the Week 4 visit, to follow instructions contained in the reminder card and bring the card with them to the Study Visit Week 4 (± 7 days) The following procedures will be performed and all observations will be recorded in the ecrf: Subjects should arrive at the clinic fasted. Subjects should arrive at the clinic without having taken the morning dose of study drug, if randomized to INC424. Review of concomitant medications Review of best-available therapy regimen (if randomized to Control group). Update transfusion history status. A targeted physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). The dose of INC424 may be increased by 5 mg BID for inadequate efficacy defined as a palpable spleen length reduced by less than 40% relative to Baseline, provided all requirements for dose increase are met (see Section 5.3 Dose Adjustments). The dose of INC424 may need to be decreased because of low platelet counts or ANC levels (see Section 5.3). IVRS will be contacted with new (changed) OR ongoing dose information for INC424. Dose changes that are necessary between study visits will be communicated immediately and directly to the subject by telephone; the communication will be documented in the source documents. Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Determination of ECOG performance status. Blood sample for PT, PTT. Blood sample for plasma PD markers. Blood sample for lipid panel. For Subjects randomized to receive INC424, a blood sample will be collected for trough plasma level determination. This sample should be collected early in the day.

62 Novartis Confidential Page 61 Record time of evening dose of INC424. Administration of the subject s morning dose of INC424 (following the PK sample draw). Record the exact time of the dose administration. Blood samples for determination of plasma levels should be drawn between 0 and 2 hours, and again 2-4 hours after administering the morning dose of INC424. Record the exact time of these 2 blood draws. 12-lead ECG performed in the recumbent position after 5 minutes of rest. For patients randomized to INC424, the ECG should be conducted approximately 2 hours following the administration of study drug, but NOT less than 5 minutes before or 15 minutes after the collection of any blood sample. Urine pregnancy test for women of childbearing potential. Urine sample for urinalysis Drug accountability assessment (see Section 9.1.3). Record adverse events. Study drug for the next 28 days (plus overage) will be dispensed along with dosing instructions. Subjects will be instructed to call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Subjects will be given a reminder card with the following instructions for upcoming visits: To visit the site clinic for the Interim Visit at the end of Week 6. To arrive for the Week 8 Study Visit having fasted for at least 8 hours. To bring the study drug and reminder card to the clinic with them. To record the time of the morning dose of study drug on the Visit day Week 5 through week 6 Subjects will self-administer INC424 twice daily as instructed, morning and evening (at approximately 12-hour intervals), in an outpatient setting. Best-available therapy will be administered according to the manufacturer s instructions, and investigator directions. Subjects will call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Site staff will call subjects to remind them to visit the site clinic for the Interim Visit at the end of Week 6 ± 3 days Week 6 (± 3 days) Subjects will attend the study clinic for an Interim Visit to provide blood samples for analysis at the Central Laboratory. Blood samples will be drawn for hematology only; fasting will not be required. Serum pregnancy test will be performed for women of childbearing potential.

63 Novartis Confidential Page Week 7 through week 8 Subjects will continue to self-administer INC424 or best-available therapy, and report unfavorable symptoms as described above. Site staff will call to remind subjects of the Week 8 visit, to follow instructions contained in the reminder card and bring the card with them to the Study Visit Week 8 (± 7 days) The following procedures will be performed and all observations will be recorded in the ecrf: Subjects should arrive at the clinic fasted. Review of concomitant medications. Review of best-available therapy regimen (if randomized to Control group). Update transfusion history status. A targeted physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Determination of ECOG performance status. Complete EORTC QLQ-C30 quality-of-life questionnaire. Complete FACT-lym questionnaire. Blood sampling for serum chemistry tests and hematology (see Appendix III). Blood sample for INC424 plasma level determination. Record time of morning dose in ecrf from subject reminder card. Urine pregnancy test for women of childbearing potential. IVRS will be contacted with new (changed) OR ongoing dose information for INC424. Dose changes that are necessary between study visits will be communicated immediately and directly to the subject by telephone; the communication will be documented in the source documents. Drug accountability assessment (see Section 9.1.3). Record adverse events. Study drug for the next 28 days (plus overage) will be dispensed along with dosing instructions. Subjects will be instructed to call the Investigator or designated research staff if they experience any signs and/or symptoms that are of moderate or greater severity. These adverse events will be recorded on the ecrf. Subjects will be given a reminder card with the following instructions for upcoming visits: NOT to take the morning dose of study drug on the day of the Week 12 visit. To arrive for the Study Visit having fasted for at least 8 hours. To bring the study drug and reminder card to the clinic with them.

64 Novartis Confidential Page 63 To record the time of the evening dose of study drug on the prior day Week 9 through week 12 Subjects will self-administer INC424 twice daily as instructed, morning and evening (at approximately 12-hour intervals), in an outpatient setting. Best-available therapy will be administered according to the manufacturer s instructions, and investigator directions. Subjects will call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Site staff will call to remind subjects of the Week 12 visit, to follow instructions contained in the reminder card and bring the card with them to the Study Visit Week 12 (± 7 days) The following procedures will be performed and all observations will be recorded in the ecrf: Subjects should arrive at the clinic fasted. Review of concomitant medications. Review of best-available therapy regimen (if randomized to Control group). Update transfusion history status. A targeted physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Blood sampling for serum chemistry tests, lipid panel, and hematology (see Appendix III). Blood sampling for JAK2 mutation assay. Blood sample for CD34+ cell count (Appendix III). For Subjects randomized to receive INC424, a blood sample will be collected for trough plasma level determination. This sample should be collected early in the day. Record time of evening dose of INC424. Administration of the subject s morning dose of INC424 (Following the PK sample draw). Record the exact time of the dose administration. Blood samples for determination of plasma levels should be drawn between 0 and 2 hours, and again 2-4 hours after administering the morning dose of INC424. Record the exact time of these 2 blood draws. 12-lead ECG performed in the recumbent position after 5 minutes of rest. For patients randomized to INC424, the ECG should be conducted approximately 2 hours following the administration of study drug, but NOT less than 5 minutes before or 15 minutes after the collection of any blood sample. Urine pregnancy test for women of childbearing potential. IVRS will be contacted with new (changed) OR ongoing dose information for INC424. Dose changes that are necessary between study visits will be communicated immediately

65 Novartis Confidential Page 64 and directly to the subject by telephone; the communication will be documented in the source documents. MRI of the abdomen will be performed to assess spleen and liver volumes. CT scan may be performed if subject is not a candidate for MRI. The same modality should be used for all visits unless a new contraindication to MRI prohibits its use. Drug accountability assessment (see Section 9.1.3). Record adverse events. Study drug for the next 28 days (plus overage) will be dispensed along with dosing instructions. Subjects will be instructed to call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. These adverse events will be recorded on the ecrf. Subjects will be given a reminder card with the following instructions for upcoming visits: To visit the site clinic for the Interim Visit at the end of Week 16. To arrive for the Week 16 Study Visit having fasted for at least 8 hours. To bring the study drug and reminder card to the clinic with them. To record the time of the morning dose of study drug Week 13 through week 15 Subjects will self-administer INC424 twice daily as instructed, morning and evening (at approximately 12-hour intervals), in an outpatient setting. Best-available therapy will be administered according to the manufacturer s instructions, and investigator directions. Subjects will call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Site staff will call to remind subjects of the Week 16 visit, to follow instructions contained in the reminder card and bring the card with them to the Study Visit Week 16 (± 7 days) The following procedures will be performed and all observations will be recorded in the ecrf: Subjects should arrive at the clinic fasted. Review of concomitant medications. Review of best-available therapy regimen (if randomized to Control group). Update transfusion history status. A targeted physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Determination of ECOG performance status. Complete EORTC QLQ-C30 quality-of-life questionnaire.

66 Novartis Confidential Page 65 Complete FACT-lym questionnaire. Blood sampling for serum chemistry tests and hematology (see Appendix III). Blood sample for INC424 plasma level determination. Record time of morning dose of INC424. Urine pregnancy test for women of childbearing potential. IVRS will be contacted with new (changed) OR ongoing dose information for INC424. Dose changes that are necessary between study visits will be communicated immediately and directly to the subject by telephone; the communication will be documented in the source documents. Drug accountability assessment (see Section 9.1.3). Record adverse events. Study drug for the next 56 days (plus overage) will be dispensed along with dosing instructions. Subjects will be instructed to call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Subjects will be given a reminder card with the following instructions for upcoming visits: To visit the site clinic for the Interim Visit at the end of Week 20. To arrive for the Week 24 Study Visit having fasted for at least 8 hours. To bring the study drug and reminder card to the clinic with them. To record the time of the morning dose of study drug Week 17 through week 20 Subjects will self-administer INC424 twice daily as instructed, morning and evening (at approximately 12-hour intervals), in an outpatient setting. Best-available therapy will be administered according to the manufacturer s instructions, and investigator directions. Subjects will call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Site staff will call subjects to remind them to visit the site clinic for the Interim Visit at the end of Week 20 ± 3 days Week 20 (± 3 days) Subjects will attend the study clinic for an Interim Visit to provide blood samples for analysis at the Central Laboratory. Blood samples will be drawn for hematology only; fasting will not be required. Serum pregnancy test will be performed for women of childbearing potential Week 21 through week 24 Subjects will continue to self-administer INC424 or best-available therapy, and report unfavorable symptoms as described above. Site staff will call to remind subjects of the Week 24 visit, to follow instructions contained in the reminder card and bring the card with them to the Study Visit.

67 Novartis Confidential Page Week 24 (± 7 days) The following procedures will be performed and all observations will be recorded in the ecrf: Subjects should arrive at the clinic fasted. Review of concomitant medications. Review of best-available therapy regimen (if randomized to Control group). The identity and dose of any medications to treat MF must be recorded in the ecrf. Update transfusion history status. A complete physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Determination of ECOG performance status. Complete EORTC QLQ-C30 quality of life questionnaire. Complete FACT-lym questionnaire. 12-lead ECG performed in the recumbent position after 5 minutes of rest. Blood sampling for serum chemistry tests, lipid panel, PT, PTT and hematology (see Appendix III). Blood sampling for INC424 plasma level determination. Record time of morning dose of INC424 tablets in the ecrf from subject reminder card. Urine pregnancy test for women of childbearing potential. Urine sample for urinalysis. MRI of the abdomen will be performed to assess spleen and liver volumes. CT scan may be performed if subject is not a candidate for MRI. The same modality should be used for all visits unless a new contraindication to MRI prohibits its use. Drug accountability assessment (see Section 9.1.3). Blood sampling for CD34+ cell count. Blood sample for plasma PD markers. Blood sampling for JAK2 mutation assay. Record adverse events. IVRS will be contacted with new (changed) OR ongoing dose information for INC424. Dose changes that are necessary between study visits will be communicated immediately and directly to the subject by telephone; the communication will be documented in the source documents. INC424 for the next 84 days (plus overage) will be dispensed along with dosing instructions. Subjects will be instructed to call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity.

68 Novartis Confidential Page 67 Subjects will be given a reminder card with the following instructions for upcoming visits: To visit the site clinic for the Interim Visit at the end of Week 30. To arrive for the Week 36 Study Visit having fasted for at least 8 hours. To bring the study drug and reminder card to the clinic with them. To record the time of the morning dose of study drug Week 25 through week 36 Subjects will self-administer INC424 twice daily as instructed, morning and evening (at approximately 12-hour intervals), in an outpatient setting. Best-available therapy will be administered according to the manufacturer s instructions, and investigator directions. Subjects will call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Interim Visit for hematology assessment will be performed at Week 30 (± 3 days). Site staff will call subjects to remind them to visit the site clinic for the Interim Visit. Fasting will not be required. Site staff will call to remind subjects of the Week 36 visit, to follow instructions contained in the reminder card and bring the card with them to the Study Visit Week 36 (± 7 days) and each 24 weeks thereafter (weeks 60, 84, 108, 132, etc) The following procedures will be performed and all observations will be recorded in the ecrf: Subjects should arrive at the clinic fasted. Review of concomitant medications. Review of best-available therapy regimen (if randomized to Control group). Update transfusion history status. A targeted physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Blood sampling for serum chemistry tests and hematology (see Appendix III). Blood sampling for INC424 plasma level determination. Record time of morning dose of INC424. Urine pregnancy test for women of childbearing potential. IVRS will be contacted with new (changed) OR ongoing dose information for INC424. Dose changes that are necessary between study visits will be communicated immediately and directly to the subject by telephone; the communication will be documented in the source documents

69 Novartis Confidential Page 68 MRI of the abdomen will be performed to assess spleen and liver volumes. CT scan may be performed if subject is not a candidate for MRI. The same modality should be used for all visits unless a new contraindication to MRI prohibits its use. Drug accountability assessment (see Section 9.1.3). Record adverse events. Study drug for the next 84 days (plus overage) will be dispensed along with dosing instructions. Subjects will be instructed to call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Subjects will be given a reminder card with the following instructions for upcoming visits: To visit the site clinic for the Interim Visit 6 weeks from the current date. To arrive for the Study Visit at the end of the next 12 week cycle having fasted for at least 8 hours To bring the study drug and reminder card to the clinic with them. To record the time of the morning dose of study drug Week 37 through week 48 Subjects will self-administer INC424 twice daily as instructed, morning and evening (at approximately 12-hour intervals), in an outpatient setting. Best-available therapy will be administered according to the manufacturer s instructions, and investigator directions. Subjects will call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Interim Visits for hematology assessment (and serum pregnancy test for women of childbearing potential) will be performed at Week 42 (± 3 days). Site staff will call subjects to remind them to visit the site clinic for the Interim Visit. Fasting will not be required. Site staff will call to remind subjects of the Week 48 visit, to follow instructions contained in the reminder card and bring the card with them to the Study Visit Week 48 (± 7 days and for MRI + 21 days) The following procedures will be performed and all observations will be recorded in the ecrf: Subjects should arrive at the clinic fasted. Review of concomitant medications. Review of best-available therapy regimen (if randomized to Control group). Update transfusion history status. A complete physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest.

70 Novartis Confidential Page 69 Determination of ECOG performance status. Complete EORTC QLQ-C30 quality of life questionnaire. Complete FACT-lym questionnaire. 12-lead ECG performed in the recumbent position after 5 minutes of rest. Blood sampling for serum chemistry tests, lipid panel, PT, PTT and hematology (see Appendix III). Blood sampling for INC424 plasma level determination. Record time of morning dose of INC424. Urine sample for urinalysis. Urine pregnancy test for women of childbearing potential. MRI of the abdomen will be performed to assess spleen and liver volumes. CT scan may be performed if subject is not a candidate for MRI. The same modality should be used for all visits unless a new contraindication to MRI prohibits its use. Drug accountability assessment (see Section 9.1.3). Blood sampling for CD34+ cell count. Blood sample for plasma PD markers. Blood sampling for JAK2 mutation assay. Bone marrow aspiration and biopsy, cytogenetic profile. Cytogenetic profile will only be performed for subjects who had abnormalities at Baseline. Record adverse events. IVRS will be contacted with new (changed) OR ongoing dose information for INC424. Dose changes that are necessary between study visits will be communicated immediately and directly to the subject by telephone; the communication will be documented in the source documents. INC424 for the next 84 days (plus overage) will be dispensed along with dosing instructions. Subjects will be instructed to call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Subjects will be given a reminder card with the following instructions for upcoming visits: To visit the site clinic for the Interim Visit 6 weeks from the current date. To arrive for the Study Visit at the end of the next 12 week cycle having fasted for at least 8 hours. To bring the study drug and reminder card to the clinic with them. To record the time of the morning dose of study drug Weeks 49 and afterward Subjects will self-administer INC424 twice daily as instructed, morning and evening (at approximately 12-hour intervals), in an outpatient setting. Best-available therapy will be

71 Novartis Confidential Page 70 administered according to the manufacturer s instructions, and investigator directions. Subjects will call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Interim Visits for hematology assessment will be performed at every 6week interval not covered by a regular Study Visit (Corresponding to Weeks 54, 66, 78, 90, 102, 114, etc.). Site staff will call subjects to remind them to visit the site clinic for the Interim Visits. Fasting will not be required. Site staff will call to remind subjects of the next regular Study Visit, to follow instructions contained in the reminder card and bring the card with them to the Study Visit Week 72 (± 7 days) and each 24 weeks thereafter (week 96, 120, 144, 168, 192, etc) The following procedures will be performed and all observations will be recorded in the ecrf: Subjects should arrive at the clinic fasted. Review of concomitant medications. Review of best-available therapy regimen (if randomized to Control group). Update transfusion history status. A targeted physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Determination of ECOG performance status. 12-lead ECG performed in the recumbent position after 5 minutes of rest. Blood sampling for serum chemistry tests, lipid panel, and hematology (see Appendix III). Blood sampling for INC424 plasma level determination. Record time of morning dose of INC424 tablets in the ecrf from subject reminder card. Urine pregnancy test for women of childbearing potential. MRI of the abdomen will be performed to assess spleen and liver volumes. CT scan may be performed if subject is not a candidate for MRI. The same modality should be used for all visits unless a new contraindication to MRI prohibits its use. Drug accountability assessment (see Section 9.1.3). Blood sampling for CD34+ cell count. Blood sample for plasma PD markers. Blood sampling for JAK2 mutation assay. Bone marrow aspiration and biopsy, cytogenetic profile should be performed every 48 weeks starting with Week 96 [Week 96, 144, 192, 240, etc] Cytogenetic profile will only be performed for subjects who had abnormalities at Baseline. Record adverse events.

72 Novartis Confidential Page 71 IVRS will be contacted with new (changed) OR ongoing dose information for INC424. Dose changes that are necessary between study visits will be communicated immediately and directly to the subject by telephone; the communication will be documented in the source documents. INC424 for the next 84 days (plus overage) will be dispensed along with dosing instructions. Subjects will be instructed to call the Investigator or designated research staff if they experience any unexpected and unfavorable signs and/or symptoms that are of more than moderate severity. Subjects will be given a reminder card with the following instructions for upcoming visits: To visit the site clinic for the Interim Visit at the 6 week interval separating the current Study Visit from the next. To arrive for the Study Visit at the end of the next 12 week cycle having fasted for at least 8 hours. To bring the study drug and reminder card to the clinic with them. To record the time of the morning dose of study drug Crossover visits If a subject originally randomized to the Control Group is determined to have met a Qualifying disease progression event, or after demonstration of superiority for the primary or key secondary endpoint providing INC424 continues to have an acceptable safety profile and wishes to enter the Extension Phase of the study to receive INC424, the decision to crossover and initiate treatment with INC424 may occur at any regular Study Visit. If the subject is found to have met a Qualifying progression event between Study Visits and the subject and investigator prefer not to wait for the next scheduled Study Visit to initiate treatment, a Crossover Visit may be scheduled. This will be an extra visit and does not substitute for following the study schedule. Additionally, 4 weeks after initiation of dosing with INC424, a post-dose Crossover Visit should be scheduled to evaluate the subject s response to therapy, including possible dose adjustment. Thus, up to 2 Crossover Visits are possible. (The same schedule will be followed for subjects originally randomized to INB and receive drug in the Extension Phase if the dose of INC424 will be increased). At any Crossover Visit, the subject should undergo the following evaluations and all observations will be recorded in the ecrf: Subjects should arrive at the clinic fasted. Review of concomitant medications. Update transfusion history status. A targeted physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Blood sampling for serum chemistry tests and hematology (see Appendix III).

73 Novartis Confidential Page 72 Blood sample for INC424 plasma level determination (at the 4-week post-dose Crossover Visit). For subjects that cross-over after demonstration of superiority for the primary or key secondary endpoint, PK sampling will no longer be required after week 60. Urine pregnancy test for women of childbearing potential. IVRS will be contacted with new (changed) OR ongoing dose information for INC424. Dose changes that are necessary between study visits will be communicated immediately and directly to the subject by telephone; the communication will be documented in the source documents. IVRS will not be used after demonstration of superiority for the primary or key secondary endpoint. Drug accountability assessment for subjects already taking INC424 (see Section 9.1.3). Record adverse events. Study drug for the period until the next Study Visit (plus overage) will be dispensed along with dosing instructions. Subjects will be instructed to call the Investigator or designated research staff if they experience any signs and/or symptoms that are of moderate or greater severity. These adverse events will be recorded on the ecrf. Schedule an MRI for evaluation of spleen size 3 months (±7 days) after the date of first dose (or dose increase) for any subject in the Extension Phase. It is not necessary for this to correspond with a regular Study Visit. For subjects originally randomized to the Control group, this will comprise the final evaluation of spleen size; further MRI evaluations at scheduled visits will be omitted. Subjects will be given a reminder card for upcoming Study Visits, Interim Visits, or Crossover Visits. The reminder card will include the dates of the visit, whether the subject should arrive at the clinic fasted, a space to record the morning dose on the day of a Study Visit, and instruction to bring study drug with them. Scheduling of Visits following Crossover should follow guidelines described above and in Section When a Crossover Visit overlaps the permitted window (± 7 days) of a regular Study Visit, the scheduled Study Visit can substitute for the Crossover Visit, and the evaluations scheduled at that Study Visit will supersede those of the Crossover Visit Extension Phase following the demonstration of superiority for the primary or key secondary endpoint Please refer to Table 7-2 for schedule of assessments 7.4 End of treatment evaluations End of study or early termination visit The End of Study or Early Termination Visit constitutes the final study visit where study drug has been taken. An End of Study Visit may occur with a planned discontinuation for any reason (eg, at Week 20, it is determined that subject will participate in the study only 1 more month; therefore, the Week 24 Visit will become the End of Study Visit).

74 Novartis Confidential Page 73 The following procedures will be performed and all observations will be recorded in the ecrf: Review of concomitant medications. Update transfusion history status. A targeted physical examination will be performed, including body weight and measurement of spleen by palpation (Section ). Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest. Determination of ECOG performance status. 12-lead ECG performed in the recumbent position after 5 minutes of rest. Blood sampling for serum chemistry tests, hematology and PT, PTT (see Appendix III). Blood sampling for CD34+ cell count. If the end of study/termination visit falls after the demonstration of superiority for the primary or key secondary endpoint no CD34+ sample will be taken. Blood sampling for JAK2 mutation assay. Blood sample for plasma PD markers. If the end of study/termination visit falls after the demonstration of superiority for the primary or key secondary endpoint no PD sample will be taken. Urine sample for urinalysis. Urine pregnancy test for women of childbearing potential only. Drug accountability assessment (see Section 9.1.3). IVRS will be notified of the subject withdrawal, if the subject withdraws after the demonstration of superiority for the primary or key secondary endpoint, IVRS will no longer be in use Record adverse events. Subjects will be asked to return to the clinic between 28 and 37 days later for a final Follow-up Visit. 7.5 Follow-up evaluations The following evaluations will be performed 28 (+ 9) days after the completion of the End of Study or Early Termination Visit or approximately 1 month post-dosing for a subject who is discontinuing from the study: The following procedures will be performed and all observations will be recorded in the ecrf: Review of concomitant medications. Review of transfusion history. A complete physical examination will be performed, including body weight and measurement of spleen by palpation. Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be performed in a sitting position after 5 minutes of rest.

75 Novartis Confidential Page lead ECG performed in the recumbent position after 5 min of rest. Blood sampling for serum chemistry tests and hematology (see Appendix III). Urine sample for urinalysis. Serum pregnancy test for women of childbearing potential only. Record adverse events. 7.6 Duration of participation The individual subject participation is intended to continue as long as the subject does not have disease worsening, is able to tolerate the study drug, and is receiving some clinical benefit up to the end of the study, which will occur when all enrolled subjects have completed 144 weeks of therapy or withdrawn from the study. Study Investigators will be notified of the projected study end date when the study is fully enrolled. The maximum duration of treatment is not expected to exceed approximately 168 to 180 weeks for any subject. In order not to withhold therapy from subjects who may be benefiting from it, subjects receiving INC424 when the study is concluded may be eligible to receive INC424 in a separate open-label extension study until the commercial product becomes available, if, in the opinion of the investigator, treatment with INC424 is that subject s best therapeutic option. Additionally, subjects randomized to the Control group that remain in the Randomized treatment Phase when the study is concluded, will be similarly eligible to receive INC424 in the separate open label extension, irrespective of disease progression. Extension Phase following the demonstration of superiority for the primary or key secondary endpoint Discontinuation criteria: To limit exposure for patients who are not receiving benefit from treatment on INC424 additional patient discontinuation criteria will be applied as follows: a. For patients originally randomized to INC424, discontinue from extension phase when spleen volume is 25% increased over baseline at time of randomization. b. For patients originally randomized to BAT, discontinue from extension phase when spleen volume is 25% increased over imaging volume at time of crossover. If the patient does not discontinue for the above criteria, the duration of the extension phase will be 96 weeks after the LPLV for the primary endpoint i.e 4 Jan Study assessments 8.1 Demographic and other pre-treatment assessments After written informed consent is obtained, demographic data and a complete medical and medication history will be collected at Screening. Height and body weight measurements will be done, body mass index (BMI) will be calculated automatically in the ecrf database.

76 Novartis Confidential Page 75 Order of assessments Multiple assessments are scheduled simultaneously during the Study Visits; it is possible that the assessments may need to be scheduled over more than one day. In order to standardize the study visits, a suggested order of assessments is implied by the ordering of events in the Description of Study Visits. Where feasible, vital signs and ECG measurements should occur prior to blood sampling. The timing of PK sampling and ECGs for Weeks 4 and 12 (for subjects randomized to INC424) are specified in the study-specific evaluations for that day. For all other visits, no effort should be made to standardize the time of PK sampling; collection of the sample at any time during the day is permitted, and non-uniformity of sampling time is encouraged. This meal or snack may be provided at the site, or the subject may consume the meal or snack at the site cafeteria or other nearby food location. 8.2 Safety assessments Adverse events Adverse events will be monitored continuously during the study. Subjects will be instructed to report all AEs during the study and subjects will be assessed for the occurrence of AEs throughout the study. In order to avoid bias in eliciting AEs, subjects will be asked general, nonleading questions such as "How are you feeling?". All AEs (serious and nonserious) must be recorded on the source documents and case report forms regardless of the assumption of a causal relationship with the study drug. The definition, reporting, and recording requirements for AEs are described in Section Physical examinations A comprehensive physical examination will be performed as noted in the Description of Study Visits (Section 7). The comprehensive physical examination will include the following organ/body system assessments: skin; HEENT (head, eyes, ears, nose, neck and throat); thyroid; lungs; cardiovascular; abdomen (liver, spleen); lymph nodes; neurological examination, assessment of edema and extremities. A targeted physical examination will be performed as indicated in Section 7.3 (On-Treatment Evaluations) and will always include liver and spleen, and assessment of edema. In addition, the targeted physical will include body systems as indicated by subject symptoms, AEs, prior physical examinations, or other findings as determined by the investigator. Both complete and targeted physicals will include a measurement of spleen size, assessed by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion Vital signs Vital sign measurements (blood pressure, heart rate, respiratory rate and body temperature) will be collected on the days and times noted in the Description of Study Visits (Section 7). Vital signs will be taken with the subject in the sitting position after 5 minutes of rest. Body temperature may be measured orally or via the ear.

77 Novartis Confidential Page lead ECG Twelve-lead ECGs will be obtained for each subject during the study as per the Description of Study Visits (Section 7). Baseline ECGs will be obtained at Screening. All 12-lead ECGs obtained at subsequent time points during the study will be compared with this prerandomization 12-lead ECG as follows: For ECG morphology, all postdose ECG recordings will be compared to the prerandomization ECG tracing. For the calculation of changes in cardiac intervals (QT interval), the intervals from the Screening will be used as the Baseline for comparison of all postdose intervals. Twelve-lead ECGs will be acquired using an ECG analysis system with analysis and printing capabilities, as well as digital transmission capabilities to a central capture module at the central ECG laboratory. The Investigator and research staff will receive adequate training by a qualified person on the use and operation of the analysis system. The successful digital submission of a 12-lead ECG, meeting quality standards, to the central ECG laboratory by the site must be ensured prior to enrollment of the first subject. The ECG study manual for procedures that must be followed for the recording and transmission of ECGs and the operator s manual with instructions for operating the digital capture module will be shipped to the site along with the device. At the time of the implementation of amendment 5 the sites will no longer require ECG s to be centrally read but will require locally read ECG s only ECG analysis and reporting The investigator or another appropriately trained individual will perform the initial ECG analysis of the data collected for each subject. ECG data will be sent to the central ECG laboratory for their review. ECGs transmitted to the Central Laboratory will be analyzed by a cardiologist and reported back to the sites via fax or . All ECGs will be analyzed according to ECG abnormality criteria taking into account the protocol requirements. The overall ECG interpretation will be indicated by a flagging system which will help distinguish between a normal ECG, ECG abnormalities where no further investigation is required, and ECG abnormalities where trial exclusion, further cardiovascular investigation, and/or prompt action may be necessary depending on the clinical context. A suitable flag will be included in the Overall ECG Interpretation section of the report when an ECG is considered to be technically unacceptable or un-interpretable. If several different abnormalities exist corresponding to different levels of flagging, the label will reflect the most severe level. Flagging by the central expert cardiologist of these significant abnormalities should only be regarded as a suggestion. This service is intended to assist the Investigator in his/her interpretation of the ECG and decision-making. It is not intended to replace the Investigator s expert judgment and knowledge of the subject s medical condition. At the time of implementation of amendment 5, all ECG s will be performed and read locally at the respective study sites.

78 Novartis Confidential Page Clinical safety laboratory assessments A Central Laboratory will perform the clinical laboratory tests. Samples for hematology, serum chemistry, and urinalysis will be prepared using standard procedures. All subjects will have samples of blood and urine collected on the days and times noted in the Description of Study Visits (Section 7) for analysis of serum chemistry, hematology, and urinalysis. Appendix III provides a complete list of blood chemistry and hematology tests that will be performed. Please refer to the laboratory manual provided by the Central Lab for further details and specifications for sample handling, processing and shipping Pregnancy test Subjects who are older than age 55 and have a history of amenorrhea for 1 year, or subjects who have been surgically sterile for at least 3 months, will not be considered to be of childbearing potential. All other female subjects will have regular pregnancy testing at Screening and throughout the study as indicated in the Description of Study Visits (Section 7). A positive urine pregnancy test will be confirmed with a serum pregnancy test. Pregnancy status will be documented at each visit when the test is performed, including the Follow-Up Visit Serology Appendix III provides a complete list of serology tests to be performed at the Screening Visit Urine sampling Appendix III provides a complete list of urinalysis to be performed. 8.3 Symptom and functional response assessments Response assessments Primary response assessments Imaging. The primary measure of spleen size will be by MRI. MRI of the abdomen will be performed at Baseline, and at visits corresponding to Weeks 12, 24, 36, 48 and every 12 weeks thereafter. MRI will be performed with a body coil because the objective is to measure organ volume, not to find very small lesions. MRIs will be performed by local radiologists who will be instructed to not provide a quantitative measure of spleen volume, but may provide a qualitative assessment such as enlarged, smaller, larger, etc. However, should a quantitative result be provided to the investigator, this will not be considered a protocol violation, and the subject will still be evaluable. The scans from an individual subject will be read by a central reader upon transfer from the site radiologist. The central MRI radiologists will be blinded to initial treatment assignment (Please refer to Imaging Guidelines and Imaging Charter). Spleen and liver volume will be obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares. The MRI will not determine spleen length below the costal margin, as there are no validated approaches for determining this measurement. Procedure specific training acquisition parameters for scanning and image capture will be provided by the vendor.

79 Novartis Confidential Page 78 When a post-treatment assessment indicates that a subject has experienced a 25% increase in spleen volume compared to the on-study nadir (including Baseline), the investigator will be notified. Subjects originally randomized to Control who have meet Qualifying disease progression events and continue to the Extension Phase will have one post-treatment MRI performed at the protocol scheduled time, but will not continue to have routine MRIs performed at the subsequent 3 month intervals. Post demonstration of superiority for the primary or key secondary endpoints The frequency of scans for the different patient groups will be as follow: a. For patients who achieve a >= 35% reduction in spleen volume at week 48, imaging will continue every 12 weeks until 25% progression from baseline at randomization b. For patients randomized to INC424 who do not achieve a >= 35% reduction in spleen volume at week 48, imaging will be performed every 24 weeks until 25% progression from baseline. c. For patient randomized to BAT who crossover to INC424, one scan will be obtained 12 weeks after crossover and subsequent frequency of scans will be determined by the response at 12 weeks. If the patient meets criteria for response (>= 35% reduction in spleen volume compared with the scan obtained at crossover), then scans will continue every 12 weeks until there is an increase of 25% or more compared with the crossover scan. If the patient does not meet criteria for response (>= 35% reduction in spleen volume compared with the scan obtained at crossover), then scans will continue every 24 weeks until there is an increase of 25% or more compared with the crossover scan. The Sponsor or the sponsor designee will notify the investigative site/investigator of each imaging result, if imaging should continue and when imaging is no longer be required. MRI is the preferred method for obtaining spleen volume data. However, CT scans may be performed at the visits where MRI would be conducted if the subject is not a candidate for MRI (because of the presence of metal clips in the body, or because of claustrophobia, for example), or if MRI is unavailable to the study site. CT scans will be similarly processed by a Central Laboratory. Procedure specific training for scanning and image capture will be provided by the Vendor. NOTE: Generally, the same method (MRI or CT) should be used for all visits for a given subject unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurs. Please contact the sponsor if a modality change is required. Spleen length. Spleen length will be assessed by manual palpation at every study visit, and will be used to determine if dose increases for lack of efficacy should be considered. Investigators will be provided with a soft centimeter ruler so that palpable spleen length is measured in centimeters and not in finger breadths. The edge of the spleen shall be determined by palpation, and measured in centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion.

80 Novartis Confidential Page Additional response assessments JAK2V617F allele burden. JAK2V617F allele burden in a subset of subjects enrolling in the study with evidence of a JAK2 mutation will be monitored at the site level. Analysis will be conducted at pre-dose (Baseline) for all subjects, and at study visits indicated in the Description of Study Visits (Section 7) only in subjects with the mutant allele present in the pre-dose sample. Instructions for sample preparation and shipping will be provided in a laboratory manual. At the time of the demonstration of superiority for the primary or key secondary endpoint, the JAK2 mutation status for patients ongoing will be shared with the Investigators. Subjects that have the JAK2 mutation will continue at this time to follow sampling for the JAK2 as outlined in Table 7-2. Bone marrow fibrosis. Bone marrow fibrosis will be measured in grades (see Appendix V), on aspirate and/or biopsy samples obtained at Screening, and at study visits indicated in the Description of Study Visits (Section 7). Collection, processing and staining of bone marrow aspirations and biopsy samples will be done in accordance with standard procedures at the investigative sites. The bone marrow biopsy and aspirate should be assessed by an experienced hematopathologist using his/her standard examination. Bone marrow fibrosis should be graded using the European consensus grading system (Tefferi, et al 2006, Appendix V). During or following the study conduct, at the Sponsor s discretion, a central review of any or all of the bone marrow studies may be conducted by external expert(s) in hematopathology Cytogenetic profile. Cytogenetic profile will be determined at Baseline using the aspirates/biopsy samples used for fibrosis determination. Subjects exhibiting abnormal cytogenetic profiles will be monitored at study visits indicated in the Description of Study Visits (Section 7). Cytogenetic testing will not be repeated after Baseline for subjects who do not exhibit Baseline abnormalities. Quality of life assessment. Quality of life (QoL) and symptoms of MF will be assessed in subjects as described in the Description of Study Visits (Section 7) using the EORTC QLQ-C30 questionnaire and FACT-lym questionnaire. The EORTC QLQ-C30 and instructions, and the FACT-lym and instructions will be provided as separate documents. No Quality of life questionnaires will be completed after week Pharmacokinetic methods Blood collection Pharmacokinetic samples will be obtained at the visits indicated in Section 7. The exact date and time of the PK blood draws will be recorded along with the date and time of the last dose of INC424 preceding the blood draw. Instructions for sample preparation and shipping will be provided in a laboratory manual. On predose PK sampling days - patients who forget to postpone their dose and take their medication at home will be excluded from pharmacokinetic analysis for that day, i.e. they

81 Novartis Confidential Page 80 should not have blood samples collected on that day. PK sampling should be deferred to the next visit. No PK sampling will be required after week Bioanalytical methodology The plasma samples will be analyzed for INC424 by a validated LC/MS/MS assay, carried out by the Sponsor s designee Pharmacokinetic parameter assessment For each subject, the observed plasma concentration of INC424 will be determined in samples drawn at visits described in the schedule of observations. The time of the prior dose will be recorded on a subject reminder card, and this information will be entered onto the ecrf. 8.5 Pharmacodynamics method Blood collection for plasma PD assay Plasma samples will be collected at Screening, and at study visits indicated in the Description of Study Visits (Section 7) for the analysis of plasma cytokines and other plasma protein markers. Plasma samples will be stored frozen at a central facility. The samples will be analyzed by a Central Laboratory in a batch analysis at times determined by the sponsor. Instructions for sample preparation and shipping will be provided in a laboratory manual Plasma PD assay methodology Upon the completion of sample collection, samples will be submitted to a designated CRO for Analysis by Multi-Analyte Profile (Human MAP ) Technology, a bead based immunoassay platform for the determination of the plasma levels of approximately 89 protein analytes Plasma PD assay assessment For each subject, the plasma concentration of analytes at multiple times will be determined. The primary data analysis will consist of an evaluation of 20 selected analytes that were identified from a preliminary analysis using samples obtained in Study INCB , including: IL-1 beta, IL-6, IL-8, IL-1RA, TNF alpha, TNFRII, MCP-1, MIP-1 beta, ICAM-1, VCAM-1, CD40, beta-2-microglobulin, CRP, EGF, VEGF, FGF-basic, PAI-1, myeloperoxidase, erythropoietin, and leptin. Data on additional markers included in HumanMAP may be analyzed based on hypothesis driven testing of markers that have new or emerging biology. In addition, remaining plasma samples may also be assayed and the data evaluated for levels of additional plasma markers not included in HumanMAP based on hypothesis driven testing of markers that have new or emerging biology. No PD sampling will be required after implementation of Amendment 5. However patients will be asked to consent to long-term storage (up to 15 years) of leftover plasma and blood samples for future use in research to understand INC424 and/or myeloproliferative disorders or to develop lab tests for monitoring disease or therapy.

82 Novartis Confidential Page 81 9 Treatment of subjects 9.1 Investigational product(s) description Dosage and dose regimen INC424 tablets will be administered orally without regards to food in an outpatient setting in accordance with specified dosing schedules (See Section 5). The dosage strength is 5 mg/tablet INC424 phosphate (free base equivalent). Administration instructions will be provided at Study Visits. The administration instructions will state that medication is For Clinical Trial Use Only Storage and stability of clinical trial materials INC424 5 mg tablets are packaged as 60-count in high-density polyethylene (HDPE) bottles. The bottles will include labeling For Clinical Trial Use Only. Stability studies will be conducted on all clinical batches to support the clinical trial Drug accountability Responsibility for drug accountability at the study site rests with the Investigator; however, the Investigator may assign some of the drug accountability duties to an appropriate pharmacist or designee. Inventory and accountability records must be maintained and readily available for inspection by the study monitor and are open to inspection at any time by any applicable regulatory authorities. The Investigator or designee will be expected to collect and retain all used, unused, and partially used containers of INC424 tablets until the end of the study. The Investigator or designee must maintain records that document investigational product delivery to the study site, the inventory at the site, the use by each subject from each supply dispensed based on tablet count, and the return to the Investigator or designee. These records should include dates, quantities, batch/serial numbers (if available), retest dates (as required), and any unique code numbers assigned to subjects participating in the study. The Investigator must ensure that the investigational product is used only in accordance with the protocol. The Investigator will also maintain records adequately documenting that the subjects were provided the study drug specified and reconciling all investigational products that were received. In order to determine INC424 use by subjects, tablets (or capsules) will be counted at every scheduled visit during the treatment phase of the trial (not at visits to the clinic laboratory to give blood samples). All returned study drug should be kept in zip lock bags with the subject s initials, date of visit and date the bottles were returned written on the bag and documented in the Source Documents. Completed accountability records will be archived by the site. At the completion of the study, the Investigator or designee will oversee shipment of any remaining INC424 back to the Sponsor or Sponsor s designee for destruction according to institutional standard operating procedures. If local procedures mandate site destruction of investigational supply, prior written approval must be obtained from Novartis.

83 Novartis Confidential Page Preparation of study drug(s) No preparation of INC424 is necessary. 9.3 Administration of study drug(s) Subjects will self-administer the study drug. INC424 tablets will be taken twice daily (BID), approximately 12 hours apart (morning and night). Subjects will not take the morning dose of INC424 tablets on the day of the Week 4 and Week 12 study visits; INC424 will be administered in the clinic in order to obtain peak and trough plasma levels of INC424. On all other days corresponding to Study Visits, subjects will take the morning dose of study drug prior to the Study Visit, and will note on the subject reminder card the time that medications were taken. 9.4 Interruption and discontinuation of study drug In some circumstances, it may be necessary to temporarily interrupt treatment as a result of adverse experiences that may have an unclear relationship to study drug. Except in cases of emergency or for protocol mandated holds for ANC or platelet count, it is recommended that the Investigator consult with the Sponsor (or a representative of the Sponsor) before temporarily interrupting therapy. Treating investigators may employ any means necessary to ensure patient safety, particularly in medical circumstances not anticipated by this protocol. Additionally, the Investigator must obtain approval from the Sponsor before restarting study drugs that were temporarily discontinued for an adverse experience. Dosing must be halted immediately if either of the following occur: Platelet counts fall below 50,000/µL ANC levels fall below 500/µL Dosing may be reinstated following dose holding using the re-start schema detailed in Section 5.3 Dose Adjustments. In order to provide sufficient data to make the dose adjustment decisions, it is recommended that hematology parameters be obtained at least weekly for platelet count < 100,000/µL or ANC < 1000/µL and at least two times weekly for platelet count < 50,000/µL or ANC < 500/µL. (Note: subjects with platelet counts of < 20,000/µL should be hospitalized, unless local or national practice does not permit it). If a subject on a dose-hold requires frequent testing for safety parameters, these tests may be performed at a local laboratory, and confirmed by the Central laboratory as soon as it is possible to do so. Decisions to re-start or increase dose must always be made based upon the analysis of the Central laboratory, and never upon a local laboratory result. If the study drug is interrupted for any reason for more than 8 weeks, dosing may not be restarted, except in the case of splenectomy, for which a maximum 12 week period of study drug interruption is permitted. Although study guidelines provide for dose reduction/interruption for the management of hematologic or non-hematologic toxicities that occur during the course of the study, the following guidelines should be used to determine whether permanent discontinuation of study drug is necessary.

84 Novartis Confidential Page 83 Discontinuation of study drug for hematologic toxicity Study drug MUST be permanently discontinued if the lowest allowed dose (5 mg BID, or 5 mg QD with concomitant CYP3A4 inhibitor) is not tolerated due to the following: Platelets cannot be maintained 50,000/µL Absolute neutrophil count cannot be maintained 500/µL. Hemoglobin cannot be maintained 6.5g/dL despite the use of transfusion therapy (or if the subject will not accept blood transfusions). Discontinuation of study drug for non-hematologic toxicity Study drug MUST be permanently discontinued if the lowest allowed dose (5 mg BID, or 5 mg QD with concomitant CYP3A4 inhibitor) is not tolerated due to the following: The occurrence of a Grade 4 laboratory abnormality that is considered at least possibly related to the study drug, and is clinically significant in the view of the investigator. Exceptions NOT requiring study withdrawal are serum iron, total bilirubin not accompanied by direct bilurubin of 2X ULN, triglycerides, total cholesterol, HDL cholesterol, or abnormalities in urinalysis not accompanied by at least a Grade 3 elevation of serum creatinine. Recurrence of a Grade 4 clinical event (non-laboratory based) after re-challenge with the study drug. Exceptions NOT requiring study withdrawal are fatigue, insomnia, obesity, constitutional symptoms (disabling but not life threatening), salivary gland changes, arthritis, and joint effusion. Study drug MAY be permanently discontinued for a Grade 4 clinical event that has NOT been confirmed upon rechallenge with the study drug, at the option of the Investigator. In the event that any subject permanently discontinues the study drug, regardless of reason, reasonable efforts should be made to have the subject return for an early termination visit and have the End of Treatment evaluations completed as described in Section 7.4. All patients will be followed for overall survival and incidence of leukemia up to last patient last visit. Threemonthly survival, incidence of leukemia, and documentation of new antineoplastic therapy will be collected. For those patients who withdraw consent from treatment they should be asked if the site can follow and provide information as above to the sponsor. The date the subject discontinued the study drug and the specific reason for discontinuation will be recorded in the ecrf. This will include reasons such as discontinued due to disease worsening or withdrawn due to adverse event. This information will be used to summarize the reasons for study withdrawal. 9.5 Dose modifications Dose modification information is provided in Section 5.3 Dose Adjustments. 9.6 Duration of treatment INC424 or best-available therapy will be administered in the Randomized Treatment Phase until the subject has reached an endpoint of protocol-defined disease progression or until the

85 Novartis Confidential Page 84 study is concluded, whichever comes first. In the Extension Phase, INC424 treatment can continue until the study is concluded unless one or more withdrawal criteria are met or at the Investigator s or subject s discretion to discontinue from the study. 9.7 Prior and concomitant medications / measures All concomitant medications and treatments must be recorded in the ecrf. Any prior medication received up to 30 days prior to the first dose of study drug will be recorded in the CRF. All prior medications used to treat MF disease will be recorded. All Concomitant treatments during the trial will also be recorded in the CRF. 9.8 Restricted and/or prohibited medications Restricted/allowed therapies The following medications have restrictions on use or doses or require changes to the way in which INC424 is administered during the study: Systemic corticosteroid doses greater than the equivalent of 10 mg prednisolone per day are prohibited, unless use is part of an INC424 dose tapering strategy (see Section Optional Dose Tapering Strategy). In subjects for whom warfarin or heparin use will be initiated, the degree of thrombocytopenia should be considered, coagulation parameters monitored and dose of anti-coagulant adjusted accordingly. Hematopoietic growth factor receptor agonists (ie, erythropoietin (Epo), granulocyte colony stimulating factor (GCSF), romiplostim, eltrombopag) are not recommended. INC424 may interfere with efficacy, and they may cause an increase in spleen size. Low dose aspirin ( 150 mg/day) and non steroidal anti-inflammatory agents (acetaminophen, ibuprofen) may be used. Aspirin in doses exceeding 150 mg per day is prohibited. Inducers or inhibitors of the metabolizing enzyme CYP3A4 (Appendix VI Flockhart 2007): When concomitant administration of a potent inhibitor of CYP3A4 is required for subject management, the dose of INC424 tablets must be adjusted (See Section 5.3.4). Potent inhibitors of CYP3A4 include oral ketoconazole, clarithromycin, itraconazole, nefazodone, telithromycin. The use of potent CYP3A inducers is prohibited (Section 9.8.2). The use of mild-to-moderate inhibitors OR inducers of CYP3A4 (Appendix VI) is discouraged; alternative therapies should be considered wherever possible. Should one of these medications be medically necessary, its use should be documented; however dose adjustment of INC424 is not required Prohibited therapies The following medications are prohibited during the study: Any investigational medication other than INC424. Use of such medications within 14 days or 6 half-lives, whichever is longer, prior to the first dose of study drug and during

86 Novartis Confidential Page 85 the study (including Extension Phase) through the Follow-up Visit is prohibited by subjects in both the INC424 and the Control groups of the study. Use of HU, interferon, thalidomide, busulfan, lenalidomide, or anagrelide is not permitted at any time during participation in the study unless the subject is randomized to the Control group (best-available therapy group) in the study. Potent inducers of CYP3A4 (rifampin and St. John s Wort) are not permitted. 9.9 Compliance Compliance with the INC424 regimen will be assessed by the investigator and/or study personnel at each visit using pill counts and information on the Study Medication ecrf page. For the purpose of this study a subject will be considered sufficiently compliant with INC424 treatment if they have shown to have taken, at least 80% of their prescribed dose over the total duration of study drug dosing, using dispensing and return of pills information as described above as a surrogate for taken. Compliance with best-available treatment regimens used in Control group subjects will not be assessed. 10 Selection and withdrawal of subjects 10.1 Enrollment Admittance of subjects into screening To reach a target enrollment of 150 subjects, study enrollment will end when the number of patients enrolled in the study, plus 50% of the number in screening, equals 150, provided that the number of patients enrolled is at least Method of assigning subjects to treatment groups Randomization will occur centrally by an Interactive Voice Response System (IVRS). Randomization will be stratified by Baseline prognostic risk level, as defined by Cervantes, et al (2009) into two strata: Strata 1 Intermediate Risk Level 2 (2 risk factors) Strata 2 High Risk Level (3 or more risk factors) Sites will contact an Interactive Voice Response System (IVRS) to obtain the subject study drug assignment. The investigator or designee will select the assigned bottles from their stock that corresponds to the number provided by IVRS and dispense the medication. The investigator will enter the bottle numbers in the ecrf. At subsequent medication dispensing visits, the investigator or designee will follow the same procedures as described above. Full details will be provided in the IVRS manual. IVRS will not be in use after the implementation of the amendment 5.

87 Novartis Confidential Page Withdrawal criteria and procedures Withdrawal of subjects from study Subjects may choose to withdraw from this study at any time without penalty of jeopardizing their health care or loss of benefits to which the subject is otherwise entitled. Every reasonable effort should be made to determine the reason a subject withdraws prematurely and this information should be recorded in the ecrf. A subject MAY be withdrawn from the study if, in the Investigator s medical judgment, the subject is non-compliant with the study requirements. A subject MUST be withdrawn from the study if she becomes pregnant, or if he intends to father a child during the anticipated duration of study participation. Patients must/may be withdrawn from the study prematurely for one of the following reasons: Death Adverse event(s) (Please also refer to additional information later in this Section.) Consent is withdrawn Protocol deviation Disease progression i.e. the subject experiences an event of disease progression that does not qualify for continuation in the study s Extension Phase (Section 5.2.4). Lost to follow-up Non compliance with taking study medication Non compliance with study procedures Termination of the clinical trial by the sponsor New cancer therapy Other e.g. if the study drug has been interrupted for 8 weeks or more for any reason, except in the case of splenectomy where a maximum of 12 weeks of drug interruption is permitted, further participation would be injurious to the subject s health or well being in the Investigator s medical judgment, administrative reasons Adverse events Adverse events that may lead to study drug discontinuation include the following: The study drug has been permanently discontinued for safety according to the criteria specified in Section 9.4. Specifically: Hematologic toxicity. The lowest allowed dose (5 mg BID, or 5 mg QD with concomitant CYP3A4 inhibitor) is not tolerated due to the following: Platelets cannot be maintained 50,000/µL Absolute neutrophil count cannot be maintained 500/µL. Hemoglobin cannot be maintained 6.5g/dL despite the use of transfusion therapy (or if the subject will not accept blood transfusions).

88 Novartis Confidential Page 87 Non-hematologic toxicity. The lowest allowed dose (5 mg BID, or 5 mg QD with concomitant CYP3A4 inhibitor) is not tolerated due to the following: The occurrence of a Grade 4 laboratory abnormality that is considered at least possibly related to the study drug, and is clinically significant in the view of the investigator. Exceptions NOT requiring study withdrawal are serum iron, total bilirubin not accompanied by direct bilurubin of 2X ULN, triglycerides, total cholesterol, HDL cholesterol, or abnormalities in urinalysis not accompanied by at least a Grade 3 elevation of serum creatinine. Recurrence of a Grade 4 clinical event (non-laboratory based) after re-challenge with the study drug. Exceptions NOT requiring study withdrawal are fatigue, insomnia, obesity, constitutional symptoms such as fever, salivary gland changes, arthritis, and joint effusion. However, should these events meet the criteria for SAE (such as disability or requiring hospitalization), they would be reported as such and with the appropriate action regarding to study drug, which may include study drug discontinuation. Study drug MAY be permanently discontinued for a Grade 4 clinical event that has NOT been confirmed upon rechallenge with the study drug, at the option of the Investigator If a subject is withdrawn from the study: The study site monitor must be notified. The reasons for discontinuation must be documented in the subject s medical record and ecrf. Patients who discontinue study drug before completing the study should be scheduled for a visit as soon as possible: The End of Treatment Visit procedures should be completed at the last study visit, if possible while subject is still receiving study drug or open labelinc424. At a minimum, all patients who discontinue study treatment, including those who refuse to return for a final visit, will be contacted for safety evaluations during the 28 days following the last dose of study drug. The Follow-up Visit should be performed 28 to 37 days after the last dose of study drug was taken (i.e., days after the End of Study Visit). Patients lost to follow up should be recorded as such on the ecrf. Patients who discontinue study drug should be considered withdrawn from the study after the final visit assessments are performed or when it is clear that the patient will not return for these assessments Replacement of subjects Subjects will not be replaced Protocol deviations Any relevant deviations from the protocol or Reporting Analysis Plan (RAP) will be documented (including rationale) and summarized in the final clinical study report. These include, but are not limited to the following:

89 Novartis Confidential Page 88 Subjects who did not meet all inclusion and exclusion criteria. Subjects who took concomitant medications specifically prohibited by the protocol. Subjects who received the wrong study drug. Subjects in the BAT arm that crossover to INC424 without meeting the protocol defined endpoint of disease progression 11 Adverse events 11.1 Definitions Adverse event An adverse event (AE) is any unfavorable and unintended sign, symptom, syndrome, or illness that develops or worsens during the period of observation in the clinical study. An adverse event may be: A new illness/condition. Worsening of a concomitant illness/condition. An effect of the study drug, including comparator. A combination of two or more of these factors. No causal relationship with the study drug or with the clinical study itself is implied by the use of the term adverse event. Adverse events (but not Serious Adverse Events, please refer to Section ) are collected from the time the subject ingests the first dose of study drug up to approximately 30 days after the last dose of study drug is administered (i.e., until the Follow-up Visit). All subjects who have adverse events, whether considered associated with the use of the investigational product or not, must be monitored to determine the outcome. The clinical course of the adverse event will be followed up according to accepted standards of medical practice, even after the end of the period of observation, until a satisfactory explanation is found or the Investigator considers it medically justifiable to terminate follow-up Events related to disease under study Worsening of a pre-existing illness other than disease under study will be assessed as an AE. Worsening of a sign or symptom of the disease under treatment will normally be measured by efficacy parameters and not considered an adverse event unless Novartis or the reporting physician considers that the study drug contributed to the worsening. NOTE: disease progression based on a 25% increase in spleen volume is not considered an adverse event. Worsening of a sign or symptom of the disease under treatment assessed as a clinically significant worsening of the disease from Baseline must be documented as an AE. In addition, if such an AE meets the definition of an SAE (as defined in Section ), it must be reported as such (see Section 11.2 Recording, Classification and Reporting of Adverse Events).

90 Novartis Confidential Page Clinically significant laboratory abnormalities Any laboratory abnormalities deemed clinically significant by the Investigator should be reported as an adverse event. A clinically significant abnormality is a confirmed abnormality (by repeat test) that is changed sufficiently from Baseline so that in the judgment of the Investigator a change in management is warranted. This alteration may include: monitoring the laboratory test further, initiating other diagnostic tests or procedures, changing ongoing treatment, or administering new treatment. Whenever possible, the etiology of the abnormal findings will be documented on the CRF. Repeated additional tests and/or other evaluations required to establish the significance and etiology of an abnormal result should be obtained when clinically indicated. Any clinically significant laboratory abnormalities that are either unexplained or considered treatment-related should be promptly reported to the Sponsor. Any additional relevant laboratory results obtained by the Investigator during the course of this study will be supplied to the Sponsor and recorded on the CRF Surgical procedures Surgical procedures themselves are not adverse events; they are therapeutic measures for conditions that require surgery. The condition for which the surgery is required may be an adverse event, if it occurs or is detected during the study period. Planned surgical measures permitted by the clinical study protocol and the condition(s) leading to these measures are not adverse events, if the condition(s) was (were) known before the start of the study drug. In the latter case, the condition should be reported as medical history Overdose There is no known antidote for INC424 overdosage and what constitutes an overdose has not been defined. However, for the purposes of this study, an overdose will be defined as the use of INC424 in doses in excess of that specified in the protocol. Subjects overdosed should be treated with appropriate supportive care until recovery. Use of INC424 in doses in excess of that specified in the protocol should not be recorded in the CRFs as an AE of Overdose. An overdose with associated SAEs should be recorded as the SAE diagnosis/symptoms on the relevant AE and SAE forms in the CRFs. An overdose with associated non-serious AEs should be recorded as the AE diagnosis/symptoms on the relevant AE forms in the CRFs. In addition, the overdose should be reported on the separate Clinical Study Overdose Report. An overdose without associated symptoms should not be recorded as an AE in the CRFs Pregnancy Pregnancy, in and of itself, is not regarded as an adverse event, unless there is suspicion that study drug may have interfered with the effectiveness of a contraceptive medication or method. The procedures that will be followed based on whether a pregnancy is confirmed by a positive serum or urine test result are listed below: Investigator and subject must notify each other immediately. Investigator must notify the sponsor immediately. Discontinue study drug immediately.

91 Novartis Confidential Page 90 Perform the required End-of-treatment visit study evaluations. Investigator must complete and submit the Pregnancy Initial and Follow-up report forms to the Sponsor. A serum pregnancy test must be performed to confirm the urine test result. (The serum test should be performed at the investigative site to ensure the test will be performed promptly and the result available immediately for review.) Withdraw the subject from the study. If a negative serum test does not confirm the urine test result, then: The Investigator will use his/her expert judgment, based on an assessment of the potential benefit/risk to the subject, to determine if it is in the subject s best interest to resume study drug and continue participation in the study. Any pregnancy diagnosed during the study, or that occurs within 28 days after stopping study drug, must be reported immediately to the Investigator. The outcome of all such pregnancies (ie, spontaneous miscarriage, elective termination, normal birth, or congenital abnormality) must be documented and followed-up on a form that will be provided by the Sponsor. The pregnancy will be followed to term and the outcome, including any premature termination, must be reported to the Sponsor. All live births must be followed for a minimum of 30 days or to the first well-baby visit. All reports of congenital abnormalities/birth defects and spontaneous abortions/miscarriages should be reported as an SAE for this study. Elective abortion procedures, without complications, should not be considered as adverse events Serious adverse event Serious adverse events (SAEs) occurring after signing the Informed Consent are recorded on the Adverse Event ecrf. An SAE is any medical occurrence that: Results in death. Is life threatening at the time of the event as it occurred (the subject was at an immediate risk of death at the time of the SAE). Requires inpatient hospitalization or prolongation of an existing hospitalization. Results in persistent or significant disability/incapacity defined as a substantial disruption of a person s ability to conduct normal life functions Is a congenital anomaly/birth defect. Is an important medical event that, when based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above in the definition for a serious adverse event. (Examples of such events include allergic bronchospasm requiring intensive treatment at an emergency room or at home, blood dyscrasias, convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.) NOTE: disease progression based on a 25% increase in spleen volume is not considered a serious adverse event.

92 Novartis Confidential Page Recording, classification and reporting of adverse events Adverse event recording Adverse events fall into the categories of nonserious and serious. All adverse events must be recorded in the AE module in the CRF, regardless of apparent causality from use of the study drug. The adverse event should be reported in standard medical terminology and will be coded according to MedDRA. If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its individual symptoms. If a definitive diagnosis is not possible, the individual symptoms and signs should be recorded. The following information should be captured for all adverse events: start date, and end date or outcome (e.g., ongoing), severity of the event, seriousness of the event, Investigator s opinion of the relationship to investigational product, action taken with regard to study drug and treatment required for the adverse event, and information regarding the resolution/outcome. Clinical or laboratory abnormalities classified as Grade 4 or Grade 5 according to the NCI- CTCAE v 3.0 scale will be considered to meet the definition of a life-threatening serious adverse event and should be reported as an SAE. Adverse events for which there is no CTCAE scale (see Section ) reported as Grade 4 (life threatening) severity must also be reported as an SAE. Adverse events classified as serious must be reported to Novartis using expeditious handling to comply with regulatory requirements. See also Section for Serious Adverse Event definitions and Section for more information on Serious Adverse Events Reporting Adverse event classification The intensity of an adverse event will be graded according to the protocol-defined toxicity criteria based on the NCI-CTCAE v3.0 ([National Cancer Institute (2006)] NCI Common Terminology Criteria for Adverse Events, Published August 9, 2006). If the AE term is not included in the CTCAE, the intensity will be graded on a 4-point scale: Mild (Grade 1): Transient or mild discomfort; no limitation in activity; no medical intervention/therapy required. Moderate (Grade 2): Mild to moderate limitation in activity; some assistance may be needed; no or minimal medical intervention/therapy required. Severe (Grade 3): Marked limitation in activity, some assistance usually required; medical intervention/therapy required; hospitalizations possible. Life-threatening (Grade 4): Extreme limitation in activity; significant assistance required; significant medical intervention/therapy required; hospitalization or hospice care probable. Death (Grade 5) should not be used in this study; rather, this information will be collected in the Adverse event page or Survival Information ecrf page for all patients. Adverse event monitoring should be continued until 4 weeks after the last dose of study drug. When the intensity of an adverse event changes over time for a reporting period (eg, between visits, etc.), each change in intensity will be reported as an adverse event until the event

93 Novartis Confidential Page 92 resolves. For example, two separate adverse events will be reported if a subject experiences Grade 1 diarrhea for 3 days, meeting the definition of an adverse event, and then after 3 days the event increases to a Grade 3 intensity that lasts for 2 days and then resolves. The Grade 1 event will be reported as an adverse event with a start date equal to the day the event met the adverse event definition and a stop date equal to the day that the event increased in intensity from Grade 1 to Grade 3. The Grade 3 event will also be reported as an adverse event with the start date equal to the day the event changed in intensity from Grade 1 to Grade 3 and a stop date on the day that the event changed intensity again or resolved. For analysis purposes, this will be considered one adverse event for this subject and the maximum intensity will be recorded. The relationship or association of the adverse event to a study drug will be characterized as unrelated, unlikely, possible, probable or definite: Unrelated: There is not a temporal relationship to the study drug administration or the adverse event is clearly and incontrovertibly due only to progress of the underlying disease, or to extraneous causes. Unlikely: There is little or no chance that the study drug caused the reported adverse event; the event is most likely due to another competing cause, including concomitant illnesses, progression or expression of the disease state, or a reaction to a concomitant medication appearing to explain the reported adverse event. Possible: The association of the adverse event with the study drug is unknown; however, the adverse event is not reasonably attributed to any other condition. Probable: A reasonable temporal association exists between the adverse event and study drug, and based upon the Investigator s clinical experience, there is no other obvious competing cause. Dechallenge is positive and rechallenge is ambiguous or not done. Definite: There is a reasonable causal relationship between the study drug and the AE, when the event responds to withdrawal of the study drug (dechallenge) and recurs with the rechallenge by administration of the study drug Serious adverse events reporting To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient signs informed consent and until 4 weeks after the patient has stopped study treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after this 4-week period should only be reported to Novartis if the investigator suspects a causal relationship to the study drug. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously reported one should be reported separately as a new event. Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form. The investigator must assess and record the relationship of each SAE to each specific study drug (if there is more than one study drug), complete the SAE Report Form in English,

94 Novartis Confidential Page 93 and send the completed, signed form by fax within 24 hours to the local Novartis Drug Safety and Epidemiology Department. The telephone and telefax number of the contact persons in the local department of Drug Safety and Epidemiology, specific to the site, are listed in the investigator folder provided to each site. The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report form documentation at the study site. Follow-up information is sent to the same person to whom the original SAE Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original report. Each re-occurrence, complication, or progression of the original event should be reported as a follow-up to that event regardless of when it occurs. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the blind was broken or not if applicable, and whether the patient continued or withdrew from study participation. If the SAE is not previously documented in the Investigator s Brochure or Package Insert (new occurrence) and is thought to be related to the Novartis study drug, a Drug Safety and Epidemiology Department associate may urgently require further information from the investigator for Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), to inform all investigators involved in any study with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as per national regulatory requirements in participating countries. 12 Statistics The analyses will take place when all subjects have completed the Week 48 visit or discontinued. All available data at this time point will be included in the analyses. When the last remaining subject has completed Week 144 evaluations, a final analysis will be conducted on all data; the updated efficacy endpoint analyses will focus on duration of response and overall survival Study populations The populations to be analyzed include the following: Full analysis set (FAS): consists of all subjects who were randomized and put into strata. Treatment groups for this population will be defined according to the treatment assignment at the time of randomization regardless of the actual study medication the subject might take during his/her continued participation in the study. Following the intent-to-treat principle, subjects will be analyzed according to the treatment and strata they are assigned to at randomization. Per-protocol set: consists of all subjects in the FAS who did not meet the criteria for major protocol deviations. A list of major protocol deviations will be detailed in the analysis plan.

95 Novartis Confidential Page 94 Safety set: consists of all subjects in the FAS and if randomized to the active group who have taken at least 1 dose of study medication. Subjects will be analyzed according to the treatment actually received. Pharmacokinetic (PK) analysis set: all subjects who received at least 1 dose of INC424 and provided at least 1 plasma sample (one PK measurement) will be considered as potential pharmacokinetic (pharmacodynamic) evaluable subjects. The study pharmacokineticist will review data listings of subject dosing and sample records to identify subjects to be excluded from analyses of PK data Efficacy analysis The primary efficacy variable will be analyzed using subjects from the FAS who have a Baseline spleen volume measurement. The FAS including patients without baseline spleen volume measurement and per protocol population will be used for supportive sensitivity analyses of the primary end point. Secondary efficacy analyses will be based on FAS only. Subjects will be analyzed according to their randomized treatment. All subjects randomized to INC424 will be pooled into one group regardless of the initial and the titrated final dose Primary efficacy analyses Primary endpoint Proportion of subjects achieving 35% reduction in spleen volume from baseline to Week 48 as measured by MRI (or CT for subjects unable to undergo MRI) Analysis of primary efficacy endpoint The null-hypothesis is that there is no difference in the proportions of subjects achieving 35% reduction in spleen volume reduction from baseline to Week 48 and the alternative hypothesis is that the proportions are different. The proportion of subjects who have 35% reduction in spleen volume at Week 48 will be estimated with 95% confidence intervals. Treatment effect will be tested using CMH test Secondary efficacy analyses Secondary efficacy endpoints The key secondary efficacy endpoint is defined as: Proportion of subjects achieving a 35% reduction of spleen size as measured by MRI (or CT scan where applicable) from Baseline to Week 24. Other secondary efficacy endpoints are: Duration of maintenance of a 35% reduction from Baseline in spleen volume. Time to achieve a first 35% reduction in spleen volume from baseline. Progression free survival. Leukemia free survival. Overall survival.

96 Novartis Confidential Page 95 Change in bone marrow histomorphology. The duration of 35% reduction from baseline in spleen volume is defined as the longest duration of consecutive measurements of 35% reduction observed prior to the time of database freeze for subjects who have at least one measured 35% reduction. Specifically: 1. If the first MRI showing 35% reduction from baseline in spleen volume is the last MRI performed on a patient prior to database freeze for the primary analysis then the duration of maintenance will be considered censored with duration of at least one day. 2. If the last observed spleen volume value still represents 35% reduction from Baseline at the time of database freeze and this measure belongs to the longest duration, the duration will be considered as censored with a duration of at least the observed duration plus one day Analyses of secondary efficacy endpoints The percent of subjects who have 35% or greater reduction in spleen volume at Week 24 will be estimated with 95% confidence intervals. Treatment effect will be tested using a CMH test stratified by the stratification factors at randomization. The median duration of 35% spleen volume reduction with 95% confidence intervals will be estimated on patients achieving such reduction using Kaplan-Meier method. Analysis of time to achieve a first 35% reduction in spleen volume from baseline and duration of first 35% reduction in spleen volume will be done only on patients who achieve this reduction, presenting Kaplan-Meier estimates with 95% confidence intervals, minimum and maximum. PFS, leukemia free survival, and overall survival will be estimated with the Kaplan Meier method, based on initial randomization. Hazard ratios and the corresponding 95% confidence intervals will be estimated using the Cox proportional hazards model stratified by baseline prognostic category. For treatment comparison, a stratified 2-sided log-rank test will be used. For PFS, the earliest time when any event is observed as follows: For spleen volume increase, the progression date will be the date of the first MRI showing a 25% or greater increase in spleen volume as compared to the on-study nadir (the onstudy period includes the Baseline evaluation). For leukemic transformation determined by bone marrow blast count of 20% or greater, the progression date will be the date of the biopsy. For leukemic transformation determined by peripheral blast count, the date of progression will be the date of the first peripheral blast count of 20% or greater that is subsequently confirmed by EITHER 8 weeks of sustained high blast counts [ie, no intervening counts of < 20%] OR by bone marrow biopsy. For splenic irradiation, splenectomy, or death, the date of progression will be the actual date of the event.

97 Novartis Confidential Page Exploratory analyses Change in spleen volume measured by MRI and change in spleen size measured in palpation from Baseline to each visit where the variables are measured. Change in body weight from Baseline to each visit where the variable is measured. Change in Eastern Cooperative Oncology Group (ECOG) performance status from Baseline to each visit where the variable is measured. Change in EORTC QLQ-C30 response from Baseline to each visit where the variable is measured. Change in FACT-lym response from Baseline to each visit where the variable is measured. Change in JAK2V617F allele burden from Baseline to each visit where the variable is measured. Changes in cytokine and other plasma protein marker levels from Baseline to each follow up visit where the variable is measured. Change in transfusion dependency during the study period as measured by the proportion of subjects who change from transfusion dependent to transfusion independent and vice versa. Population PK of INC424 in subjects receiving INC Analyses of exploratory endpoints Change in spleen volume measured by MRI, change in spleen size measured by palpation, and change in body weight at each visit will be tabulated with summary statistics. The ECOG performance score will be summarized descriptively by treatment and visit. The summary will include the number and percent of subjects at each reported value. A shift summary including the number and percent of subjects will also be produced by treatment and visit for baseline vs. post-baseline scores. Data from the EORTC QLQ-C30 questionnaire will be analyzed using the standardized scores. Change from baseline will be calculated with the data collected at the baseline visit (Days -3 to -1) as the baseline. The 5 functional scales, 3 symptom scales, 1 global health status/qol scales, and 6 single-item scales will be summarized descriptively by treatment. The treatment effect over time will be estimated in repeated measurement analysis for patients with at least 1 post-baseline scale score. Data from FACT-Lymphoma Scores will be analyzed in the sum scores. Change and percent change from baseline to each scheduled visit when the FACT-Lymphoma scores were collected will be calculated with the data collect from the last visit prior to and at Day 1 as the baseline. The scores will be summarized descriptively by treatment. The treatment effect over time will be estimated in repeated measurement analysis for patients with at least one postbaseline scale score. Time to definitive deterioration will be estimated for ECOG performance score and for selected scales for QLQ C30 and FACT-Lym according to minimally important difference specified for each instrument.

98 Novartis Confidential Page 97 Percent change for each plasma protein marker from Baseline to each visit will be tabulated with summary statistics. The proportion of subjects who are transfusion dependent as well as the proportion of subjects whose transfusion status (dependent or independent) changed (from dependent to independent or vice versa) at each visit will be tabulated with summary statistics. For the purposes of this assessment, transfusion dependence at Baseline will be defined as subjects who received at least 2 units of red blood cell product(s) over an 8 week period prior to the Screening Visit date. New onset of transfusion dependence will be defined as the use of 2 or more units of red blood cell product(s) during the final 8 weeks of a subject s participation prior to database freeze in a subject who was not transfusion dependent at Baseline. New onset transfusion independency will be defined as the use of 0 or 1 unit of red blood cell product(s) during the final 8 weeks of a subject s participation prior to database freeze in a subject who met the definition of transfusion dependence at Baseline. Subjects who were not transfusion dependent at Baseline and who required transfusions during the study, but not during the last 8 weeks of observation, will be considered as temporarily transfusion-requiring, but this will not be part of the exploratory analyses. Such subjects will be considered transfusion independent in the exploratory analysis. PK data will be analyzed by nonlinear mixed effect methods using appropriate software (eg, NONMEM). If there is sufficient demographic diversity in the population, an attempt will be made to evaluate the effect of demographic characteristics and Baseline characteristics (eg, age, weight, sex, race, renal function, smoking history) on the population PK profile Sensitivity and subgroup analysis Primary efficacy analyses will be carried out using the per protocol population. The main sensitivity analysis will be done for the proportion of subjects achieving 35% reduction in spleen volume from baseline to Week 48 using a logistic regression model with baseline spleen volume and treatment as the model effects adjusted to baseline prognostic category. The odds ratio with a 95% confidence interval of achieving 35% reduction in spleen volume will be presented. Another logistic regression model will be fit with baseline spleen volume, sex (male or female), MF type (PMF, PPV-MF or PET-MF), baseline prognostic category (Intermediate or High), previous HU use, platelet count and treatment (active or control) as the model effects. This analysis will produce the odds ratio with 95% confidence interval of active versus control after adjusting for the covariates. The main analysis will be repeated for all patients in FAS considering those who did not have a baseline MRI measurement of spleen volume as not achieving 35% reduction at week 48. Proportion of subjects achieving 35% reduction in spleen volume at week 24 and week 48 will be compared by non-stratified chi-square test. For within-group comparisons, the 1-sample t-test will be used to test for any mean change from baseline.

99 Novartis Confidential Page 98 The percent change from baseline to week 48 will be analyzed in an analysis of covariance (ANCOVA) model with baseline and treatment as the model effects for a between-group comparison. Baseline treatment and strata treatment interactions will be explored to see if there is a significant qualitative interaction. If the interaction effect is significant at an alpha level of 0.10, further exploratory analyses of quantitative interactions will be conducted to assess treatment effect by baseline spleen volume and strata. Additional analysis of duration of maintenance of spleen volume reduction will be performed considering duration as the interval with the start date of the first spleen volume measurement that is >=35% reduction from baseline and the end date of the first scan that is no longer = 35% reduction AND that is a >25% increase over nadir. If the end date is not observed prior to data base cut-off, duration will be censored at the last assessment. Censoring date is defined as the date of the last adequate assessment of the spleen volume. Patients who have more than 1 consecutive missing spleen volume assessment will be censored for duration of maintenance of spleen volume reduction at the last adequate assessment prior to the consecutive missing assessments, regardless of the occurrence of a subsequent spleen PD. PFS, LFS, and OS will be analyzed according to the original randomization group (active or control). However, for OS and LFS, sensitivity analyses will also be conducted with the data being censored at the end of the Randomized Treatment Phase for those subjects who enter the Extension Phase prior to experiencing leukemia or death. Unstratified analyses of PFS, LFS and OS will also be performed, reporting hazard ratios with 95% confidence intervals. For the PFS analysis in case the progression is documented between scheduled visits the sensitivity analysis will be performed assigning dates of events only at scheduled visit. For subjects who have dropped out of the study but the assessment of disease progression was carried out, the subject will be treated as disease progressed (if disease progression is observed). Subgroup analyses The primary endpoint will be summarized between 2 treatment groups within each of the following subgroups: Sex: male or female. Age Group: 65 years or > 65 years. Race: Caucasian or non-caucasian. MF type: PMF, PPV-MF, PET-MF. Baseline prognostic category: Intermediate or High. Baseline spleen volume group: median or > median. Baseline platelet count category: <200K or 200K. Previous HU use: use or non-use.

100 Novartis Confidential Page 99 ECOG performance score category: 0-1 or 2-3. For each subgroup defined by the factors above a univariate logistic regression model will be fit to estimate treatment differences providing odds ratios (active versus control) with 95% confidence interval Handling of missing values All subjects with missing Baseline values where a change from Baseline is calculated or when the Baseline is used as a covariate will be excluded from the analysis of that variable. For subjects who dropped out due to lack of efficacy or treatment related adverse events, Reduction of spleen volume will be considered as less than 35%. No last observation carried forward will be used for primary and secondary efficacy analyses. Handling of QoL values will be according to the QLQ-C30 and FACT-lym manuals, and is detailed in the Report and Analysis Plan (RAP). For subjects who missed one scheduled visit that included a spleen volume assessment (MRI or CT), data from subsequent visits will be included in assessment of progression free survival (PFS). For subjects missing more than one consecutive visit in which assessment of spleen volume was scheduled, data handling will be described in Section Safety analysis Adverse events Adverse events will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA ) preferred term and by organ class. Severity of adverse events will be based on the scale as indicated in Section The subset of adverse events that are considered by the Investigator to have a possible, probable or definite relationship to study drug will be considered to be treatment-related adverse events. If the Investigator does not specify the relationship of the adverse event to study drug, the adverse event will be considered to be treatment-related. The incidence of adverse events and treatment-related adverse events will be tabulated Clinical laboratory tests The clinical laboratory data will be analyzed using summary statistics (eg, means and frequencies), and no formal statistical comparisons among the treatments are planned Vital signs Descriptive statistics and mean change from Baseline will be determined for vital signs (oral temperature, blood pressure and pulse) at each assessment time. Vital sign results will be reviewed for clinically notable abnormalities according to the criteria shown below; subjects exhibiting clinically notable vital sign abnormalities will be listed.

101 Novartis Confidential Page 100 Parameter High Threshold Low Threshold Systolic blood pressure > 160 mm Hg < 85 mm Hg Diastolic blood pressure > 95 mm Hg < 50 mm Hg Respiratory Rate > 24 per minute < 8 per minute Heart rate > 100 bpm < 45 bpm Note: mm Hg = millimeters of mercury; bpm = beats per minute Electrocardiograms Descriptive statistics and mean change from Baseline will be determined for each ECG parameter at each assessment time. Electrocardiogram results will be reviewed for clinically notable abnormalities according to predefined criteria. Subjects exhibiting clinically notable ECG abnormalities will be listed. Adverse events will be reported for clinically notable abnormalities that are considered clinically significant in the judgment of the Investigator Selection of sample size For the spleen volume reduction, we assumed that at least 35% of subjects in the active treatment group and no more than 10% in the Control (best-available therapy) group would achieve a 35% reduction from Baseline to Week 48. Under this assumption, a sample size of 150 subjects (100 in active and 50 in Control) would provide at least 90% power at a twosided level of 0.05 using the Chi-square test. This sample size of 150 subjects will provide 81.6% power at a two-sided level of 0.05 using CMH test under following assumption: ratio of patients with baseline prognostic category of intermediate/high risk is 1:1, response rate for intermediate risk for active treatment group is 40%, control group - 15%, for high risk the response rate for active treatment group is 30% and control group is 5%. For currently enrolled 219 patients the power of CMH test would be 93.7% Level of significance and control of type one errors All tests will be two sided at the 0.05 level. The familywise alpha level will be controlled at 0.05 overall for two pre-specified comparisons. Specifically, this study will be claimed to have achieved the efficacy objective when the primary endpoint shows a significant treatment effect at two-sided alpha=0.05. Conditional on significance of the primary endpoint, the treatment effect on the key secondary endpoint will be tested at two-sided alpha=0.05. No alpha adjustment will be carried out for the remaining secondary endpoints Interim analysis No formal interim analysis with efficacy stopping boundaries is planned. A Data Safety Monitoring Board (DSMB) will be established to monitor the risk:benefit ratio and the conduct of the trial. Since the interim analysis will not be used to stop or alter this trial, the study will be completed according to plan and no type-one error adjustment will be made.

102 Novartis Confidential Page Data safety monitoring board An independent Data Safety Monitoring Board will be formed. It will consist of qualified individuals who are not involved with the conduct of the study. The establishment, composition, role, duty and responsibilities of the DSMB will be addressed in the approved DSMB charter. The Sponsor will not have a representative on the DSMB, but the rationale for any proposed change to the study or study conduct will be reviewed with the Sponsor. Responsibility for the study continues to reside with the Sponsor. The DSMB will have oversight for the current trial INC424A2352 and a companion trial in myelofibrosis INCB sponsored by Incyte Corporation and running concurrently in the United States, Canada and Australia. Enrollment to the double-blind randomized INCB trial will trigger DSMB meetings and the DSMB will review predefined data from both trials and can recommend changes to either study based on their review of both data. The DSMB will consist of an interdisciplinary group of clinicians and biostatisticians who have experience in myelofibrosis and the conduct of randomized clinical trials. The committee will be comprised of five members (including the DSMB chair). A quorum will be considered to be at least three members. At the conclusion of each meeting the DSMB chair will report their findings to the sponsors, Incyte and Novartis, in writing. 14 Data management 14.1 Data collection Designated investigator staff will enter the data required by the protocol into the Electronic Case Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. Designated investigator or site staff will not be given access to the EDC system until they have been trained. Automatic validation programs check for data discrepancies in the ecrfs and, by generating appropriate error messages, allow the data to be confirmed or corrected on a timely manner before it is reviewed by the data management (DM) group. The investigator must certify that the data entered into the Electronic Case Report Forms are complete and accurate. Data reported in the ecrf that are derived from source documents should be consistent with the source documents or the discrepancies should be explained. External data e.g. central laboratory, IVRS, central ECG etc. will have an interface with the clinical data base, visible to data management but not to the site research staff Data management With the exception of the data manager, IVRS coordinator, pharmacokinetist, and drug supply manager, all other members of the clinical team will be blinded to patient randomization to treatment. However, for data cleaning purposes, additional Novartis employees, who have no direct involvement with the execution of the study, will be employed

103 Novartis Confidential Page Unblinding after the demonstration of superiority for the primary or key secondary endpoint With the demonstration of superiority for the primary or key secondary endpoint, all clinical team personal will be unblinded to the patient treatment. Data management will be performed from electronic case report forms (ecrfs). Novartis data management will review the data entered into the ecrfs by investigational staff for completeness and accuracy and instruct the site personnel to make any required corrections or additions. Obvious errors will be documented and corrected by Novartis. Queries are sent to the investigational site using an electronic data query. Designated investigator site staff are required to respond to the query and make any necessary changes to the data. Randomization codes and data about study drug dispensed to the patient will be tracked using an Interactive Voice Randomization System. The system will be supplied by a vendor(s), who will also manage the database and will be loaded electronically and integrated into the Clinical Data Base (CDB). All ecrf data will be entered into a validated database. External data will be imported to the database electronically. All data entry, verification and validation will be performed in accordance with the current standard Novartis operating procedures and Data Management Plan (DMP). The DMP will fully document the DM work and data flow within this clinical study. Versions for the computer systems and the coding will be defined in the DMP as will timelines. Data management will be performed under the responsibility of Novartis BDM department. During and at the conclusion of the study any protocol violations will be determined. After these actions have been completed and the database has been declared to be complete and accurate, it will be locked. Any changes to the database after that time can only be made by joint written agreement between the Global Head of Biometrics and Data Management and the Global Head of Oncology Clinical Development. 15 Study administration 15.1 Access to source documents Qualified representatives of the Sponsor or Sponsor designees ( study monitors ) will monitor the study according to a predetermined monitoring plan. Monitoring visits provide the Sponsor with the opportunity to: Evaluate the progress of the study Verify the accuracy and completeness of ecrfs. Assure that all protocol requirements, applicable laws and/or regulations, and Investigator s obligations are being fulfilled. Resolve any inconsistencies in the study records. The investigator must allow the study monitors to periodically review, at mutually convenient times, during the study and after the study has been completed, all ecrfs and office, hospital, and laboratory records supporting the participation of each subject in the study. The ecrfs and other documentation supporting the study must be kept up-to-date by the investigator and the research staff at the investigative site. These study materials must be available for review

104 Novartis Confidential Page 103 by the study monitor, and/or other qualified representatives of the Sponsor, at each monitoring visit. The study monitor will review the various records of the study (ecrfs, subject medical and laboratory records, and other pertinent data). The study monitor will verify the ecrf data against original source documentation for accuracy and completeness. The study monitor will identify data discrepancies and collaborate with the investigator and research staff to resolve the discrepancies in a timely manner. Protocol deviations will also be identified and recorded on a Protocol Deviation Log. The study monitor will follow an Issue Escalation plan in order to ensure that each issue identified during a monitoring visit is appropriately documented, reported, and resolved in a timely manner in accordance with the plan s requirements Statement of good clinical practices The study will be conducted in adherence to the study protocol to ICH GCP consolidated guidelines (E6) and applicable regulatory requirements Protocol adherence Each investigator must adhere to the protocol as described in this document and agree that deviations to the protocol, with the exception of medical emergencies, must be discussed and approved by the Sponsor prior to seeking approval from the IRB/IEC. Each Investigator is responsible for enrolling subjects who have met the protocol inclusion and exclusion criteria. The IRB/IEC that granted original approval, or the IRB/IEC currently responsible for overseeing the conduct of the study, must be notified of all changes in and deviations from the protocol that may increase risk to the subject, and/or that may adversely affect the rights of the subject or validity of the investigation. The investigator must send a copy of the approval letter from the IRB/IEC to the Sponsor or CRO and retain the original in the site study regulatory file Study termination Both the Sponsor and the investigator reserve the right to terminate the study, according to the terms specified in the study contract. The investigator is to notify the IRB/IEC in writing of the study s completion or early termination, and send a copy of the notification to the Sponsor or CRO and retain one copy for the site study regulatory file Financial disclosure All clinical Investigators participating in clinical studies subject to FDA Regulation Title 21 Code of Federal Regulations (CFR) Part 54 - Financial Disclosure by Clinical Investigators are required prior to study initiation to submit a completed Clinical Investigator Financial Certification/Disclosure Request Form that sufficiently details any financial interests and arrangements that apply. For the purpose of this regulation, clinical Investigator is defined as any investigator or sub-investigator who is directly involved in the treatment or evaluation of research subjects, including the spouse and any dependent child of the investigator, but not that of any sub-investigators. These requirements apply to both US and foreign clinical Investigators conducting covered clinical studies.

105 Novartis Confidential Page 104 Any new investigators or sub-investigators added to the covered clinical study during its conduct must also submit a completed Clinical Investigator Financial Disclosure Request Form. At the conclusion of the covered clinical study, the investigators will be reminded of their obligation to report to the Sponsor/designee any changes to the financial disclosure information previously reported. The clinical investigators will also be reminded that they must report any changes in their financial information regarding significant equity interests and significant payments for a period of 1 year after completion of their participation in the covered clinical study Quality control and assurance Sponsor audits At some point during the study, individuals from the Sponsor s Quality Assurance department and/or their authorized representative may visit the investigator s site to conduct an audit of the study. The purpose of this visit will be to determine the investigator s adherence to the protocol, applicable regulations, and the Sponsor s procedures, in addition to assessing the accuracy of the study data. Prior to initiating this audit, the investigator will be contacted by the Sponsor to arrange a convenient time for this visit. The investigator and staff are expected to cooperate with the auditors and allow access to all subject records supporting the ecrfs and other study-related documents Inspection by regulatory authorities At some point during the investigational product s development program, a regulatory authority may visit the investigator to conduct an inspection of the study and the site. The investigator and staff are expected to cooperate with the inspectors and allow access to all source documents supporting the ecrfs and other study-related documents. The investigator must immediately notify the Sponsor when contacted by any regulatory authority for purposes of conducting an inspection. 16 Ethics 16.1 Institutional Review Board or Independent Ethics Committee It is the responsibility of the investigator to assure that all aspects of the ethics review are conducted in accordance with the Declaration of Helsinki as described in the International Conference on Harmonisation (ICH) E6: Guideline for Good Clinical Practice (GCP), and/or local laws, whichever provides the greatest level of protection for the study participants. The protocol and any information supplied to the subject to obtain informed consent, including written informed consent form(s), subject recruitment procedures (eg, advertisements), and written information to be provided to subjects (information leaflets), must be reviewed and approved by a qualified IRB/IEC prior to enrollment of participants in the study. Prior to initiation of the study, the Sponsor must receive documentation of the IRB/IEC approval, which specifically identifies the study/protocol, and a list of the committee members. Amendments to the protocol and revisions to the informed consent must also be submitted to and, if required, approved by the IRB/IEC.

106 Novartis Confidential Page 105 Investigators must submit progress reports to the IRB/IEC in accordance with the IRB/IEC requirements. Annual re-approval of the study must be obtained. Copies of progress reports and Annual re-approvals must be sent to the Sponsor. When the Sponsor provides the investigator with a safety report, the investigator must promptly forward a copy to the IRB/IEC. After completion or termination of the study, the investigator must submit a final report to the IRB/IEC and to the Sponsor. The investigator, as part of the records retention requirements for the study, must maintain documentation of all submissions, correspondence, and approvals to and from the IRB/IEC. Each clinical Investigator is responsible to conduct the study in accordance with the protocol, all applicable laws, regulations, and GCP according to ICH guidelines Informed consent Preparation of the consent form is the responsibility of the investigator and the sponsor, and must include all elements required by the ICH, GCP, and applicable regulatory requirements, and must adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. A template will be provided by the Sponsor. The Sponsor or designee must review and approve all changes to site-specific informed consent forms. The consent form must include a statement that the Sponsor or designee and regulatory authorities have direct access to subject records. Prior to the beginning of the study, the investigator must have the IEC s written approval/favorable opinion of the written informed consent form and any other information to be provided to the subjects. Before being enrolled in the clinical study, subjects must consent to participate after the nature, scope, and possible consequences of the study have been explained in a form understandable to them. An informed consent document that includes both information about the study and the consent form will be prepared and given to the subject. This document will contain all the elements required by the ICH E6 Guideline for Good Clinical Practice and any additional elements required by local regulations. The document must be in a language understandable to the subject and must specify who informed the subject. Where required by local law, the person who informs the subject must be a physician. A copy of the signed consent document must be given to the subject. The original signed consent document will be retained by the investigator. The investigator will not undertake any measures specifically required only for the clinical study until valid consent has been obtained. The investigator must inform the subject s primary physician about the subject s participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.

107 Novartis Confidential Page Data privacy Applicable data privacy laws and regulations must be adhered to. The investigator and the Sponsor are responsible for ensuring that sensitive information is handled in accordance with local requirements (eg, HIPAA). Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of protected information must be obtained. 17 Record keeping / retention of records The investigator must ensure that all records pertaining to the conduct of the clinical study, informed consent forms, drug accountability records, source documents, and other study documentation are adequately maintained for a period of 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. The investigator must not destroy any records associated with the study without receiving approval from the Sponsor. The investigator must notify the Sponsor in the event of accidental loss or destruction of any study records. If the investigator leaves the institution where the study was conducted, the Sponsor must be contacted to arrange alternative record storage options. Whenever possible, an original recording of an observation must be retained as the source document. However, a photocopy of a record is acceptable provided it is legible and is a verified copy of the original document. All ecrf data entered by the site (including audit trail), as well as computer hardware and software (for accessing the data), will be maintained or made available at the site in compliance with applicable record retention regulations. The Sponsor will retain the original ecrf data and audit trail Confidentiality Subject names will not be supplied to the Sponsor. Only the subject number and subject initials (where permitted by local regulations) will be recorded in the ecrf, and if the subject name appears on any other document (i.e., laboratory report), it must be obliterated on the copy of the document to be supplied to the Sponsor. Study findings stored on a computer will be stored in accordance with local data protection laws. The subjects will be informed that representatives of the Sponsor, IRB/IEC, or regulatory authorities may inspect their medical records to verify the information collected, and that all personal information made available for inspection will be handled in strictest confidence and in accordance with local data protection laws. 18 Use of study results By signing the study protocol, the investigator and his or her institution agree that the results of the study may be used by the Sponsor, Novartis, for the purposes of national and international registration, publication, and information for medical and pharmaceutical

108 Novartis Confidential Page 107 professionals. If necessary, the authorities will be notified of the investigator s name, address, qualifications, and extent of involvement. In recognition of the importance of disseminating information relating to any novel or important observations or results from the work to be performed under the protocol, but recognizing the Sponsor s (Novartis) right to protect its confidential information, the investigators shall have the right to publish or publicly present the results of the study in accordance with the following terms: Investigators and their institutions agree that they will submit to Novartis all proposed publications, papers, abstracts, slides, and/or other written materials related to the study at least 60 days before the submission of the contemplated publication. During this period, Novartis shall have the opportunity to review and comment upon the contents of the publication with regard to Novartis s confidential and proprietary information. Investigators agree to discuss in good faith any Novartis request for modification of a proposed publication and agree to remove any confidential information Novartis requests. The standard length of the Novartis review period will be 30 days. In the event Novartis determines that an enabling description of patentable subject matter is contained in such written material or outline, it shall notify the investigator and institution within the review period and the publication or disclosure will be withheld for a reasonable period of 30 days, not to exceed 60 days total from the date the investigator first submits to Novartis the materials proposed for submission for publication, to permit appropriate patent application(s) to be prepared and filed by Novartis, if it so elects. Investigators and their institutions agree not to publish or publicly present any interim results of studies without the prior written consent of Novartis. To the extent that participation in the protocol is part of a multi-center study, all parties agree to initially publish or publicly present their results only together with the other study sites, unless specific written permission is obtained in advance from Novartis to disclose separately such results; provided, however, if there has been no multi-center publication within 12 months of the completion of the multi-center studies by all sites, then Investigators and their institution shall be entitled to publish separately its study results after complying with the other terms of this section. Novartis shall serve as the coordinator of multi-center study disclosures and, in the event of a disagreement among the investigators in a multi-center study, the lead Investigator and a representative of Novartis shall serve as co-arbiters of such dispute. Any publication(s) resulting from the study shall give appropriate credit to the scientific contributions made by Novartis personnel. For such manuscript(s), masthead roles for clinical Investigators will be determined based primarily on scientific contribution to the protocol and data interpretation and secondarily on subject enrollment.

109 Novartis Confidential Page References (available upon request) Cervantes F, Dupriez B, Pereira A, et al (2009) A new prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood; 113: Flockhart DA (2007) Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine. Incyte Corporation Investigator s Brochure (2008) INCB Phosphate Capsules/Tablets, Version 7, November Mesa RA, Niblack J, Wadleigh M, et al (2007) The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international internet-based survey of 1179 MPD patients. Cancer; National Cancer Institute (2006) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (CTCAE) online at NCI website:august 9, Oken MM, Creech RH, Tormey DC, et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol;5: Pikman Y, Lee BH, Mercher T, et al (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med;3(7): Scott LM, Tong W, Levine RL, et al (2007) JAK2 Exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med;356: Tefferi A, Barosi G, Mesa RA, et al (2006) International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood;108: Tefferi A, Vardiman JW (2008) Classification and diagnosis of myeloprofliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia;22: Trussell J (2004) Contraceptive failure in the United States. Contraception;70: World Medical Association Declaration Of Helsinki Ethical Principles for Medical Research Involving Human Subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975, 35th WMA General Assembly, Venice, Italy, October 1983, 41st WMA General Assembly, Hong Kong, September 1989, 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996, and the 52nd WMA General Assembly, Edinburgh, Scotland, October Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo Available at

110 Novartis Confidential Page Appendices List of Appendices Appendix I Appendix II Appendix III Appendix IV Appendix V Appendix VI Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms (Tefferi and Vardiman 2008) Information Regarding Effectiveness of Contraceptive Methods Clinical Laboratory Tests Eastern Cooperative Oncology Group Performance Status Bone Marrow Biopsy and Aspirate Evaluations Restricted and Prohibited Medications

111 Novartis Confidential Page 110 Appendix I - Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-ofcare diagnostic algorithms (Tefferi and Vardiman 2008)

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