Biomarkers and patient selection in the treatment of myelofibrosis

Abstract

Transfusion independence and overall survival in myelofibrosis patients can be improved by selecting patient-specific treatment methods. The patient's baseline ferritin level can be used as a biomarker to select first-line treatment. The patient's ferritin level during treatment can inform decisions about terminating treatment or changing treatment to maintain transfusion dependency and / or to convert the patient from transfusion need or transfusion dependency to transfusion independence.

Description

[Technical field]

[0001] The present invention relates to a method of using a subject's ferritin levels before and during treatment for myelofibrosis to select first-line and / or second-line treatments for myelofibrosis. In particular, a patient's ferritin levels provide a biomarker that can be used to determine when a patient should be treated with momelotinib, a compound known to treat anemia and help patients achieve or maintain transfusion independence. [Background technology]

[0002] Myelofibrosis (MF) is a disease that affects approximately 40,000-50,000 patients worldwide, of which 70-80% are classified as intermediate-risk to high-risk MF patients. The median survival for all patients with MF is approximately 6 years, but for patients classified as intermediate-2 risk or high-risk MF, it is significantly worse at 4 years and 2.25 years, respectively.

[0003] Myelofibrosis can arise de novo as primary MF (PMF) or from pre-existing myeloproliferative neoplasms (MPN), primarily polycythemia vera (PV) or essential thrombocythemia (ET). Once these conditions reach an overt fibrotic stage, they are virtually indistinguishable clinically.

[0004] The three major disease manifestations of MF include (1) anemia, often associated with thrombocytopenia or other cytopenias; (2) systemic symptoms such as fatigue, night sweats, fever, cachexia, bone pain, pruritus, and weight loss; and (3) organomegaly due to extramedullary hematopoiesis, primarily in the spleen and, less frequently, in the liver, which can cause commonly associated symptoms such as abdominal distension and pain, early satiety, dyspnea, and diarrhea.

[0005] Ruxolitinib (RUX) is a Janus kinase (JAK) inhibitor used for the treatment of intermediate-risk and high-risk myelofibrosis (e.g., primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis). Ruxolitinib is used to treat approximately 70% of symptomatic patients, but is not approved for patients with severe thrombocytopenia.

[0006] Anemia and transfusion dependency are associated with reduced overall survival in patients with myelofibrosis. Approximately 60% of patients with myelofibrosis (MF) are anemic, and 45% become transfusion dependent within one year of diagnosis, most often progressing to transfusion dependency over time (Pardanani et al., 2013, Am. J. Hematol., vol. 88, no. 4, pp. 312-316). High hepcidin levels, moderate to severe anemia, and transfusion dependency are negative prognostic factors in MF, affecting overall survival (OS) and quality of life (Nicolosi et al., 2018, Leukemia, vol. 32, no. 5, pp. 1254-1258).

[0007] Approved JAK inhibitors (JAKi) provide splenic and symptomatic improvement but are generally myelosuppressive and do not address transfusion dependency (TD). Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 / ALK2 inhibitor with clinical activity against anemia, symptoms and splenomegaly in MF as previously demonstrated in the Phase 3 SIMPLIFY-1 and -2 trials. The SIMPLIFY 1 (S1) trial compared MMB to ruxolitinib (RUX) in JAKi-naive patients (NCT01969838) (Mesa et al., 2017, J. of Clin. Onc., vol. 35, no. 34, pp. 3844-3850). The SIMPLIFY 2 (S2) trial compared MMB with best available therapy (BAT; RUX in 88% of patients) in patients with prior RUX therapy (NCT02101268) (Harrison et al., 2018, Lancet., Vol. 5, No. 2, pp. e73-e81).

[0008] MMB was shown to be effective in correcting anemia in head-to-head comparisons with RUX in JAKi-naive and previously RUX-treated patients. Preclinical and clinical translational studies demonstrated that the ability of MMB to address anemia and transfusion dependency is mechanistically linked to differential suppression of ACVR1 / ALK2-mediated hepcidin production (Asshoff et al., 2017, Blood., vol. 129, no. 13, pp. 1923-1830 and Oh et al., 2020, Blood Adv., vol. 4, no. 18, pp. 4282-4291).

[0009] Transfusion independence, particularly at 24 weeks of treatment, is associated with improved overall survival in myelofibrosis patients. There is a need for methods of determining or predicting a 24 week transfusion independent response in myelofibrosis patients and methods of treating patients with myelofibrosis that provide a 24 week transfusion independent response. Summary of the Invention

[0010] According to the present specification, the following embodiments are provided.

[0011] Embodiment 1 is a method of treating myelofibrosis in a subject, comprising administering to a subject identified as having (i) myelofibrosis, and (ii) a ferritin level greater than 90 ng / mL, a therapeutically effective amount of momelotinib, or a pharma- ceutical acceptable salt thereof.

[0012] Embodiment 2 is the method of embodiment 1, wherein the subject is identified as having a ferritin level greater than 90 ng / mL and less than 650 ng / mL.

[0013] Embodiment 3 is the method of embodiment 1, wherein the subject is identified as having a ferritin level greater than 650 ng / mL.

[0014] Embodiment 4 is the method of embodiment 3, further comprising administering to the subject a therapeutically effective amount of a second therapeutic agent.

[0015] Embodiment 5 is the method of any one of embodiments 1 to 4, further comprising determining ferritin levels in a sample from a subject with myelofibrosis.

[0016] Embodiment 6 is the method of any one of Embodiments 1-5, wherein momelotinib, or a pharma- ceutically acceptable salt thereof, is administered for a multi-week treatment period.

[0017] Embodiment 7 is the method of embodiment 6, wherein the multi-week treatment period is 12 weeks or longer.

[0018] Embodiment 8 is the method of embodiment 6, wherein the multi-week treatment period is 24 weeks or longer.

[0019] Embodiment 9 is the method of embodiment 6, wherein the multi-week treatment period is 36 weeks or longer.

[0020] Embodiment 10 is the method of any one of embodiments 1-9, further comprising determining ferritin levels in the subject's sample once a month, or twice a month, or once a week during the treatment period.

[0021] Embodiment 11 is the method of embodiment 10, wherein the ferritin level in the subject's sample is measured once a week.

[0022] Embodiment 12 is the method of embodiment 10 or 11, wherein the subject is determined to maintain ferritin levels within a predetermined range during the treatment period.

[0023] Embodiment 13 is the method of embodiment 10 or 11, wherein the subject is determined to have a ferritin level that is not within a predetermined range during the treatment period.

[0024] Embodiment 14 is the method of embodiment 10 or 11, wherein the subject is determined to have a ferritin level that is not within the predetermined range during the treatment period, and the method further comprises terminating administration of momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent.

[0025] Embodiment 15 is a method for determining whether a subject has a ferritin level that is not within a predetermined range during a treatment period, and the method further comprises: terminating administration of momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent; and Follow these steps: administering to a subject determined to have a ferritin level of less than 90 ng / mL a therapeutically effective amount of a JAK inhibitor; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject determined to have a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or administering to a subject determined to have a ferritin level greater than 650 ng / mL a therapeutically effective amount of momelotinib or a pharma- ceutically acceptable salt thereof, and optionally a second therapeutic agent. administering a second treatment comprising 12. The method of embodiment 10 or 11, further comprising:

[0026] Embodiment 16 is any one of the methods of embodiments 12 to 15, wherein the predetermined range of ferritin levels during the treatment period is 90 ng / mL or more, or the predetermined range of ferritin levels during the treatment period is 90 ng / mL or more and 650 ng / mL or less.

[0027] Embodiment 17 is the method of any one of embodiments 12-15, wherein the predetermined range of ferritin levels during the treatment period is greater than 650 ng / mL.

[0028] Embodiment 18 is a method of maintaining transfusion independence in a subject being treated for myelofibrosis, comprising: (i) administering to a subject identified as having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level of less than 90 ng / mL a therapeutically effective amount of a JAK inhibitor; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level of greater than 650 ng / mL. The method includes:

[0029] Embodiment 19 is a method for converting a subject being treated for myelofibrosis from transfusion requirement or transfusion dependency to transfusion independence, comprising: (i) administering a therapeutically effective amount of a JAK inhibitor to a subject identified as having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level of less than 90 ng / mL; or (i) administering to a subject identified as having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level greater than 90 ng / mL a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level of greater than 650 ng / mL. The method includes:

[0030] Embodiment 20 is the method of embodiment 18 or 19, wherein the JAK inhibitor is selected from momelotinib or a pharma- ceutically acceptable salt thereof, ruxolitinib, or fedratinib.

[0031] Embodiment 21 is the method of embodiment 20, wherein the JAK inhibitor is momelotinib or a pharma- ceutically acceptable salt thereof, or ruxolitinib.

[0032] Embodiment 22 is the method of embodiment 20, wherein the JAK inhibitor is ruxolitinib.

[0033] Embodiment 23 is the method of embodiment 20, wherein the JAK inhibitor is momelotinib or a pharma- ceutically acceptable salt thereof.

[0034] Embodiment 24 is the method of any one of embodiments 4, or 18-23, wherein the second therapeutic agent is a BET protein inhibitor or a BRD4 inhibitor.

[0035] Embodiment 25 is the method of embodiment 24, wherein the second therapeutic agent is selected from GSK2820151, GSK525762, GS-5829, RO6870810(IV), BAY1238097, CC-90010, BMS-986158, 1NCB054329, 1NCB057643, ODM-207, AZD5153, FT-1101, ABBV-744, ABBV-075, PLX51107, BI894999, OTX015 / MK8628, ZEN003694, RVX-000222, CPI-0610, apabetalone, and fedratinib.

[0036] Embodiment 26 is a method of treating or preventing anemia in a subject being treated for myelofibrosis, comprising administering a therapeutically effective amount of momelotinib, or a pharma- ceutical acceptable salt thereof, to a subject identified as (i) having myelofibrosis, and (ii) having or at risk for anemia, and (iii) having a ferritin level of 90 ng / mL or greater.

[0037] Embodiment 27 is the method of any one of embodiments 18 to 26, further comprising an earlier step of determining ferritin levels in a sample from a subject with myelofibrosis.

[0038] Embodiment 28 is the method of any one of Embodiments 18-27, wherein momelotinib or a pharma- ceutically acceptable salt thereof is administered for a multi-week treatment period.

[0039] Embodiment 29 is the method of embodiment 28, wherein the multi-week treatment period is 12 weeks or longer.

[0040] Embodiment 30 is the method of embodiment 28, wherein the multi-week treatment period is 24 weeks or longer.

[0041] Embodiment 31 is the method of embodiment 28, wherein the multi-week treatment period is 36 weeks or longer.

[0042] Embodiment 32 is the method of any one of embodiments 18-31, further comprising determining ferritin levels in the subject's sample once a month, or twice a month, or once a week during the treatment period.

[0043] Embodiment 33 is the method of embodiment 32, wherein the ferritin level in the subject's sample is measured weekly.

[0044] Embodiment 34 is the method of embodiment 32 or 33, wherein the subject is determined to maintain ferritin levels within a predetermined range during the treatment period.

[0045] Embodiment 35 is the method of embodiment 32 or 33, wherein the subject is determined to have a ferritin level that is not within a predetermined range during the treatment period.

[0046] Embodiment 36 is the method of embodiment 32 or 33, wherein the subject is determined to have a ferritin level that is not within the predetermined range during the treatment period, and the method further comprises a step of terminating administration of the JAK inhibitor, or momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent.

[0047] Embodiment 37 is a method for determining whether a subject has a ferritin level that is not within a predetermined range during a treatment period, and the method further comprises: terminating administration of the JAK inhibitor, or momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent; and Follow these steps: administering to a subject determined to have a ferritin level of less than 90 ng / mL a therapeutically effective amount of a JAK inhibitor; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject determined to have a ferritin level greater than 90 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject determined to have a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or administering to a subject determined to have a ferritin level greater than 650 ng / mL a therapeutically effective amount of momelotinib or a pharma- ceutically acceptable salt thereof, and optionally a second therapeutic agent. administering a second treatment comprising 34. The method of embodiment 32 or 33, further comprising:

[0048] Embodiment 38 is any one of the methods of embodiments 34-37, wherein the predetermined range of ferritin levels during the treatment period is 90 ng / mL or more, or the predetermined range of ferritin levels during the treatment period is 90 ng / mL or more and 650 ng / mL or less.

[0049] Embodiment 39 is the method of any one of embodiments 34-37, wherein the predetermined range of ferritin levels during treatment is greater than 650 ng / mL.

[0050] Embodiment 40 is the method of any one of embodiments 1 to 39, wherein the subject is a human.

[0051] Embodiment 41 is the method of any one of embodiments 1 to 40, wherein the subject is an adult human.

[0052] Embodiment 42 is the method of any one of embodiments 1 to 41, wherein the subject has previously been treated with a JAK inhibitor therapy other than momelotinib.

[0053] Embodiment 43 is the method of embodiment 42, wherein the subject has previously been treated with ruxolitinib.

[0054] Embodiment 44 is the method of embodiment 42 or 43, wherein the subject has had an inadequate response to or is intolerant to ruxolitinib.

[0055] Embodiment 45 is the method of any one of embodiments 42-44, wherein the subject has not responded or has become unresponsive to previous ruxolitinib therapy.

[0056] Embodiment 46 is the method of any one of embodiments 1 to 41, wherein the subject is not receiving JAK inhibitor therapy.

[0057] Embodiment 47 is the method of any one of embodiments 1 to 46, wherein the momelotinib or a pharma- ceutically acceptable salt thereof is momelotinib dihydrochloride.

[0058] Embodiment 48 is the method of any one of embodiments 1 to 46, wherein the momelotinib or a pharma- ceutically acceptable salt thereof is momelotinib dihydrochloride monohydrate.

[0059] Embodiment 49 is the method of any one of embodiments 1 to 46, wherein the momelotinib or a pharma- ceutically acceptable salt thereof is momelotinib dihydrochloride monohydrate Form II.

[0060] Embodiment 50 is the method of any one of embodiments 1-49, wherein momelotinib, or a pharma- ceutically acceptable salt thereof, is provided in a pharma- ceutically acceptable composition.

[0061] Embodiment 51 is the method of any one of embodiments 1 to 50, wherein the therapeutically effective amount is 50 mg / day to 200 mg / day.

[0062] Embodiment 52 is the method of embodiment 51, wherein the therapeutically effective amount is 200 mg / day, or 150 mg / day, or 100 mg / day, or 50 mg / day.

[0063] Embodiment 53 is the method of any one of embodiments 1 to 52, wherein momelotinib or a pharma- ceutically acceptable salt thereof is administered orally.

[0064] Embodiment 54 is the method of any one of embodiments 1 to 53, wherein momelotinib, or a pharma- ceutically acceptable salt thereof, is administered daily.

[0065] Embodiment 55 is the method of embodiment 54, wherein momelotinib or a pharma- ceutically acceptable salt thereof is administered once a day.

[0066] A further aspect of the present disclosure is momelotinib for use in the methods of treatment disclosed herein. Another aspect of the present disclosure is the use of momelotinib in the manufacture of a medicament for use in the methods of treatment disclosed herein. Additional objects and advantages will be set forth in part in the description that follows, and in part will be understood from the description, or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only, and are not intended to limit the scope of the claims.

[0067] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one or more embodiments and, together with the specification, serve to explain the principles described herein. [Brief description of the drawings]

[0068] [Figure 1] Figure 1 shows results from the SIMPLIFY-1 study, showing transfusion independence at week 24 in subjects treated with momelotinib (MMB) compared to subjects treated with ruxolitinib (RUX) for subjects grouped into platelet count (PLT) <150x109 / L, <300x109 / L, and >300x109 / L. [Diagram 2] Figure 2 illustrates results from the SIMPLIFY-1 study, showing the transfusion independence rate at week 24 in momelotinib-treated subjects compared to ruxolitinib-treated subjects for subjects grouped by hemoglobin levels (Hgb) <8 g / dL, <10 g / dL, <12 g / dL, <14 g / dL, and >14 g / dL. [Diagram 3] Figure 3 shows the results of the SIMPLIFY-1 study, showing the transfusion independence rate at week 24 in momelotinib-treated subjects compared to ruxolitinib-treated subjects, for subjects grouped by transfusion independence (TI), transfusion requirement (TR), and transfusion dependence (TD). [Figure 4] FIG. 4 compares percentage survival of myelofibrosis subjects in the SIMPLIFY-1 trial following treatment with MMB alone or following first-line treatment with RUX followed by transition to treatment with MMB. [Diagram 5] FIG. 5 compares percentage survival of myelofibrosis subjects in the SIMPLIFY-2 trial after treatment with MMB alone or after transition to treatment with MMB following first-line best available therapy (BAT) / RUX. [Figure 6] 6 shows overall survival in all patients in the SIMPLIFY-1 trial randomized to MMB by TI response at week 24. The graph compares survival of transfusion-independent non-responder myelofibrosis subjects with survival of transfusion-independent responder myelofibrosis subjects over time after randomization to MMB. [Figure 7] 7 shows overall survival in anemic patients in the SIMPLIFY-1 trial randomized to MMB by TI response at week 24. The graph compares survival of myelofibrosis subjects who are transfusion-independent nonresponders to survival of myelofibrosis subjects who are transfusion-independent responders over time after randomization to MMB. [Figure 8] 8 shows overall survival in all patients in the SIMPLIFY-2 trial randomized to MMB by TI response at week 24. The graph compares survival of transfusion-independent non-responder myelofibrosis subjects with survival of transfusion-independent responder myelofibrosis subjects over time after randomization to MMB. [Figure 9] 9 illustrates overall survival in spleen responder patients in the SIMPLIFY-1 trial randomized to MMB with spleen response at week 24. The graph compares survival of spleen non-responder myelofibrosis subjects with survival of all spleen responder myelofibrosis subjects over time. [Figure 10]10 illustrates overall survival in symptomatic responder (TSS) patients in the SIMPLIFY-1 study randomized to MMB by symptomatic response at week 24. The graph compares survival of symptomatic non-responder myelofibrosis subjects with survival of all symptomatic responder myelofibrosis subjects over time. [Figure 11] FIG. 11 compares mean ferritin levels in transfusion-independent non-responder subjects and transfusion-independent responder subjects in the 1672 study over 24 weeks of treatment. [Figure 12] FIG. 12 shows baseline ferritin and change from baseline to week 12 by transfusion independence response at week 24 in MMB subjects in SIMPLIFY-1. [Figure 13] FIG. 13 shows baseline ferritin and change from baseline to week 12 by transfusion independence response at week 24 in RUX subjects in SIMPLIFY-1. [Figure 14] FIG. 14 illustrates transfusion independence response at week 24 by baseline ferritin levels in subjects in the SIMPLIFY-1 trial. [Figure 15] FIG. 15 illustrates transfusion independence response at week 24 by baseline ferritin levels in subjects in the SIMPLIFY-2 study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0069] I. Definition It is to be understood that the invention is not limited to the particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0070] When a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range (each value to the tenth of the unit of the lower limit unless the context clearly dictates otherwise), and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of smaller ranges may be independently included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. When a stated range includes one or both of the lower and upper limits, ranges excluding one or both of those included lower and upper limits are also encompassed within the invention.

[0071] Certain ranges are represented herein by the numerical values ​​preceded by the term "about".The term "about" is used herein to provide literal support for the exact number preceded by the term, as well as for a number that is close or approximate to the number preceded by the term.When determining whether a number is close or approximate to a specifically recited number, the unrecited number that is close or approximate may be a number that provides a substantial equivalent to the specifically recited number in the context in which it is presented.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative exemplary methods and materials are described herein.

[0073] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended to serve as a predicate for the use of exclusive terminology such as "solely," "only," or the use of a "negative" limitation in connection with the recitation of claim elements.

[0074] All publications and patents cited herein are incorporated by reference as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated by reference herein to disclose and describe the methods and / or materials cited in the publications. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0075] As used herein, the term "anemic response" refers to an increase in the hemoglobin level of a patient, or a patient who was transfusion-dependent becomes transfusion-independent.Desirably, a minimum increase in hemoglobin of 0.5 g / dL, such as a minimum increase in hemoglobin of 1.0 g / dL, 1.5 g / dL or 2.0 g / dL, lasting for at least 8 weeks, is achieved, which is the level of improvement specified in the International Working Group (IWG) consensus criteria.However, smaller but still medically significant increases in hemoglobin are also considered to be within the term "anemic response".

[0076] As used herein, the term "transfusion dependent" (TD) refers to subjects who require 4 or 5 or more units of red blood cells (RBCs) or have a hemoglobin (Hgb) level of 8 g / dL or less 8 weeks prior to the initiation of treatment.

[0077] As used herein, the term "transfusion independent" or "Transfusion Independence" (TI) refers to a subject who did not require red blood cell (RBC) transfusions over a 12-week period and did not have a hemoglobin level less than 8 g / dL to 8.5 g / dL over a 12-week period. In some embodiments, the 12-week period of transfusion independence is the final 12 weeks of a 24-week study period. The RBC transfusion independence rate at week 24 of the study indicates the proportion of subjects who were transfusion independent at week 24, excluding cases associated with clinically evident bleeding.

[0078] As used herein, the term "transfusion requiring" (TR) refers to a subject whose transfusion status does not meet the requirements for either TD or TI.

[0079] As used herein, the term "week 24" or "WK24" refers to the 24th week of treatment.

[0080] As used herein, the term "week 24 transfusion independent response" (WK24TI-R) refers to the response of subjects whose transfusion status is TI at the 24th week after the start of treatment.

[0081] As used herein, the term "W24 TI non-responsive" or "W24 TI non-responder" (TI-NR) refers to a subject who does not achieve a W24 transfusion independent response (TI-R), defined as having an Hgb of 8 g / dL or greater and no RBC transfusions within the 12 weeks prior to week 24.

[0082] As used herein, the term "W24 spleen response" refers to a subject's spleen that exhibits a 35% or greater reduction in spleen volume compared to the volume at baseline (BL) or the start of treatment.

[0083] As used herein, the term "W24 symptom response" refers to a 50% or greater reduction in a subject's MFSAF total symptom score compared to the start of BL or treatment.

[0084] As used herein, the term "splenic response" refers to a reduction in the size of a patient's spleen, as determined by either palpation of a previously palpable spleen on physical examination or by diagnostic imaging. The IWG consensus criteria specifies that there is a minimum 50% reduction in palpable splenomegaly (splenic enlargement) of the spleen that is at least 10 cm at baseline (before treatment) or the spleen that is palpable more than 5 cm below the left costal margin at baseline is no longer palpable. However, smaller reductions are also considered to be within the term "splenic response". Splenic enlargement may be determined by palpation. Splenic size and volume may also be measured by diagnostic imaging, such as ultrasound, CT or MRI. In some cases, normal splenic size is considered to be approximately 11.0 cm craniocaudal length.

[0085] As used herein, the term "symptomatic response" or "symptomatic response" refers to at least a 50% reduction in a patient's average daily TSS compared to a baseline TSS determined at or before the start of treatment (e.g., as described herein).

[0086] As used herein, the terms "treatment" or "treating" refer to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms or signs caused by a disease or condition and / or reducing the extent of a disease or condition); b) slowing or arresting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of a disease or condition); c) relieving the disease, i.e., causing regression of clinical symptoms; and / or d) improving or stabilizing or preventing a decline in one or more clinical endpoints (e.g., as described herein), including, but not limited to, transfusion independence, conversion from transfusion dependence to independence, total symptom score (TSS), splenic response ratio (SRR), and improvement in anemia.

[0087] The term "effective amount" refers to an amount that may be effective to elicit a desired biological or medical response when administered to a subject to treat a disease, and includes the amount of a compound that is sufficient to effect such treatment for the disease. The effective amount varies depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. The effective amount may include a range of amounts.

[0088] The terms "subject" and "patient" are used interchangeably and refer to an animal, such as a mammal (including humans), that has been or will be the object of treatment, observation, or experiment. The methods described herein may be useful in human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. A variety of other mammals may be treated using the methods of the present disclosure. For example, but not limited to, mammals may be treated, such as cows, sheep, goats, horses, dogs, cats, guinea pigs, rats, or other bovine, ovine, equine, canine, feline, rodent, or murine species.

[0089] "Human in need thereof" refers to a human who may have or is suspected of having a disease or condition that would benefit from a particular treatment, e.g., being treated with a compound according to the present application. The term "subject in need thereof" or "patient in need thereof" refers to a subject or patient who may have, has been diagnosed with, or is suspected of having a disease, disorder, or condition that would benefit from the treatment described herein.

[0090] The term "therapeutically effective amount" of a compound or a pharma- ceutically acceptable salt, isomer, prodrug or solvate thereof means an amount sufficient to effect effective treatment when administered to a subject, e.g., to provide a therapeutic benefit, such as amelioration of one or more symptoms or slowing of disease progression. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, and may be readily determined.

[0091] II. SIMPLIFY-1 and SIMPLIFY-2 Clinical Trials Momelotinib (MMB) is a potent, selective, orally bioavailable, small molecule inhibitor of JAK1, JAK2 and ACVR1 developed for the treatment of myelofibrosis (MF).

[0092] However, in two phase 3 clinical trials (SIMPLIFY-1 and -2), MMB failed to meet the predefined secondary endpoint of TSS response in SIMPLIFY-1 and the primary endpoint of SRR in SIMPLIFY-2.

[0093] In the SIMPLIFY-1 trial (NCT01969838; GS-US-352-0101), the efficacy and safety of MMB versus ruxolitinib (RUX) was examined in patients with myelofibrosis who were treatment-naïve with JAK inhibitors. Patients (N=432) with high-risk, intermediate-2-risk, or symptomatic intermediate-1-risk myelofibrosis were treated with 200 mg MMB once daily or 20 mg RUX twice daily (or per label) for 24 weeks, after which all patients could receive open-label momelotinib treatment. Efficacy was assessed by splenic response, total symptom score (TSS), red blood cell transfusion rate, and transfusion independence or transfusion dependence, with the goal of demonstrating non-inferiority of MMB to RUX. The primary endpoint was at least a 35% reduction in spleen volume at 24 weeks compared to baseline.

[0094] An early analysis of the results of the SIMPLIFY 1 trial was reported by Mesa et al. (SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naive Patients with Myelofibrosis, J. Clinical Oncology, 2017, Vol. 35, No. 34, pp. 3844-3850). Analysis of the SIMPLIFY-1 trial data showed that momelotinib was non-inferior to RUX with respect to reduction in spleen size in JAKi-naive patients, thus meeting the primary endpoint of the trial. However, despite evidence of a symptomatic benefit of momelotinib in symptomatic patients in that trial, non-inferiority was not demonstrated with respect to the secondary endpoint of total symptom score (TSS) response. MMB treatment was associated with higher rates of transfusion independence, lower rates of transfusion dependence, and reduced transfusion rates compared with RUX, all of which were formally statistically significant.

[0095] In the SIMPLIFY-2 trial (NCT02101268; GS-US-352-1214), the efficacy and safety of MMB versus best available therapy (BAT) was tested in anemic or thrombocytopenic subjects with myelofibrosis previously treated with ruxolitinib (RUX). There was no lower limit for the required baseline platelet count. Efficacy was assessed by splenic response, total symptom score (TSS), red blood cell transfusion rate, and transfusion independence or transfusion dependence, with the goal of demonstrating superiority of MMB over BAT. The primary endpoint was at least a 35% reduction in spleen volume at 24 weeks compared to baseline.

[0096] An early analysis of the results of the SIMPLIFY-2 trial was reported by Harrison et al. (Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomized, open-label, phase 3 trial., Lancet Haematol, Vol. 5, 2nd Edition, February 2018, pp. e73-e81). Their analysis of the SIMPLIFY-2 trial data showed that momelotinib was not superior to BAT in reducing spleen size, and thus the trial failed to meet its primary endpoint.

[0097] Although key secondary endpoints were formally significant in the analysis by Harrison et al., they were not considered statistically significant in the hierarchy of analytical endpoints. In general, patients in the momelotinib group had greater total symptom score (TSS) responses, fewer transfusions, greater transfusion independence, and less transfusion dependency compared with patients in the BAT group. Initial analyses were complicated by the failure to mandate interruption of ruxolitinib prior to the start of randomized study treatment. By not including a mandatory break from prior ruxolitinib therapy, assessment of splenic response was unclear in subjects in either group in this study. In addition, patients enrolled in this study were not selected based on splenic progression on RUX.

[0098] A reanalysis of data from the SIMPLIFY-1 and SIMPLIFY-2 trials demonstrated that momelotinib did not cause thrombocytopenia and was associated with reduced spleen size (SSR), improved total symptom score (TSS), and platelet counts of 150 × 10 per liter without the need for dose reduction or interruption due to thrombocytopenia. 9 Momelotinib has been found to be effective in improving transfusion independence rates in patients with:

[0099] Further analysis of the data collected in these studies indicates that a patient's baseline and on-treatment serum ferritin levels provide information about the likelihood that the patient will remain or become transfusion independent if treated with momelotinib. Overall survival is improved in patients who remain transfusion independent.

[0100] III. Transfusion independence as a predictive tool Patients with myelofibrosis experience a number of disease-related symptoms, such as decreased hemoglobin levels and increased hepcidin levels, splenomegaly, cytopenias, and anemia. In almost all cases, patients receive blood transfusions, and some patients require repeated transfusions. Anemia and transfusion dependency are factors associated with reduced overall survival in patients with myelofibrosis.

[0101] Patients who remain transfusion independent demonstrate improved overall survival. Patients who remain transfusion independent at 24 weeks of treatment demonstrated the greatest improvement in overall survival with treatment.

[0102] Determining transfusion independence at week 24 (WK24 TI) is complex, and simple markers to predict or determine WK24 TI were sought. Hepcidin and hemoglobin levels in myelofibrosis patients were analyzed. The hepcidin and / or hemoglobin levels of patients were not predictive of transfusion dependence or independence of patients. However, ferritin levels in patients with myelofibrosis were found to be predictive of transfusion independence of patients, including WK24 TI.

[0103] Figures 1, 2 and 3 show week 24 TI response rates in SIMPLIFY-1 (S1) for RUX and MMB by baseline characteristics. W24 TI-R rates in S1 were higher in patients randomized to MMB versus RUX, regardless of the degree of baseline anemia or baseline platelet (PLT) count or transfusion status (EHA 2021 Poster, EP1081).

[0104] Figures 4 and 5 show survival rates in both JAKi-naïve and JAKi-exposed patients. S1 showed that in JAKi-naïve patients, a robust survival benefit was observed with extended treatment with MMB, regardless of treatment initiation. S2 showed that overall survival outcomes were best for patients previously treated with RUX (Verstovsek et al., ASH. Presentation 2020).

[0105] IV. Ferritin as a biomarker for patient selection Anemia in myelofibrosis patients is often treated with blood transfusions, and repeated transfusions can cause iron overload in the liver and blood. Ferritin is a blood protein that stores excess iron and can be elevated in patients who receive repeated transfusions. In some situations, a patient's iron and ferritin levels are correlated. However, the correlation between these two factors can be lost in patients who experience inflammation, blood transfusions, or in patients who receive certain drugs. RUX is known to generally increase ferritin in patients who receive RUX.

[0106] Ferritin is measured by routine blood tests. The normal ferritin range for a healthy human is 10 ng / mL to 300 ng / mL. For purposes of this disclosure, a blood ferritin level below 90 ng / mL is considered to be in the low to normal range. A blood ferritin level above 90 ng / mL but below 650 ng / mL is considered to be in the medium to high range. A blood ferritin level above 650 ng / mL is very high outside the normal range.

[0107] Disclosed herein is a method for selecting a treatment for a patient with myelofibrosis based on easily measurable biomarkers, particularly biomarkers that correlate with, or estimate or predict, the likelihood that the patient will be transfusion independent after 24 weeks of treatment.In some embodiments, the subject's baseline ferritin level can be used to select a first-line treatment.In some embodiments, the subject's on-treatment ferritin level can be used to determine the continuity of the first-line treatment.In some embodiments, the subject's on-treatment ferritin level can be used to select a second-line treatment.

[0108] In some embodiments, the method described herein comprises determining the ferritin level in a sample of a subject with myelofibrosis. In some embodiments, the ferritin level is a reference level before treatment, i.e., a baseline level. In some embodiments, the method described herein further comprises determining the ferritin level in a sample of the subject once a month, twice a month, or once a week during the treatment period, i.e., the ferritin level during treatment. In some embodiments, the ferritin level in a sample of the subject is measured every week.

[0109] In some embodiments, the subject is determined to maintain ferritin levels within a predetermined range during the treatment period. In some embodiments, the subject is determined to maintain ferritin levels within a predetermined range during the treatment period and treatment is continued.

[0110] In some embodiments, the subject is determined to have a ferritin level that is not within a predetermined range during the treatment period. In some embodiments, if the ferritin level is outside the range used to determine the primary treatment, the primary treatment may be terminated. In some embodiments, a secondary treatment may then be selected. In some embodiments, the secondary treatment is different from the primary treatment.

[0111] In some embodiments, the subject's ferritin levels are below 90 ng / mL. In this range, in some embodiments, the method of treatment includes administration of a JAK inhibitor.

[0112] In some embodiments, the subject's ferritin level before or during the treatment period is 90 ng / mL or higher. In some embodiments, the subject's ferritin level before or during the treatment period is 90 ng / mL or higher and 650 ng / mL or lower. If the subject's ferritin level is 90 ng / mL or higher, in some embodiments, the treatment method comprises administering momelotinib.

[0113] In some embodiments, the subject's ferritin level before or during the treatment period is 650 ng / mL or greater. In some embodiments within this range, the treatment method includes administration of momelotinib. In some embodiments within this range, the treatment method includes administration of momelotinib in combination with a second therapeutic agent.

[0114] V. Methods of Treating Myelofibrosis Provided herein is a method of treating myelofibrosis in a subject, the method comprising administering to a subject identified as having (i) myelofibrosis, and (ii) a ferritin level greater than 90 ng / mL, a therapeutically effective amount of momelotinib, or a pharma- ceutically acceptable salt thereof.

[0115] In some embodiments, the subject is identified as having a ferritin level greater than 90 ng / mL and less than 650 ng / mL. In some embodiments, the subject is identified as having a ferritin level greater than 650 ng / mL. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of a second therapeutic agent.

[0116] Provided herein is a method of maintaining transfusion independence in a subject being treated for myelofibrosis, comprising: (i) administering to a subject identified as having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level of less than 90 ng / mL a therapeutically effective amount of a JAK inhibitor; or (i) administering to a subject identified as having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level of greater than 90 ng / mL, a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level of greater than 650 ng / mL. A method is provided that includes:

[0117] Provided herein is a method for converting a subject being treated for myelofibrosis from transfusion requirement or transfusion dependency to transfusion independence, comprising: (i) administering a therapeutically effective amount of a JAK inhibitor to a subject identified as having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level of less than 90 ng / mL; or (i) administering to a subject identified as having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level greater than 90 ng / mL a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level of greater than 650 ng / mL. A method is provided that includes:

[0118] Provided herein is a method of treating or preventing anemia in a subject being treated for myelofibrosis, comprising administering a therapeutically effective amount of momelotinib, or a pharma- ceutical acceptable salt thereof, to a subject identified as (i) having myelofibrosis, (ii) having or at risk for developing anemia, and (iii) having a ferritin level of 90 ng / mL or greater.

[0119] Provided herein is a method of treating or preventing anemia in a subject being treated for myelofibrosis, comprising administering a therapeutically effective amount of momelotinib, or a pharma- ceutical acceptable salt thereof, to a subject identified as (i) having myelofibrosis, (ii) having or at risk for anemia, and (iii) having a ferritin level of greater than or equal to 90 ng / mL and less than or equal to 650 ng / mL.

[0120] In some embodiments, the methods described herein further comprise the above step of determining ferritin levels in a sample from a subject with myelofibrosis.

[0121] In some embodiments, the methods described herein further comprise determining the ferritin level in the subject's sample once a month, twice a month, or once a week during the treatment period.In some embodiments, the ferritin level in the subject's sample is measured every week.

[0122] In some embodiments, the subject is determined to maintain ferritin levels within a predetermined range during the treatment period.

[0123] In some embodiments, the subject is determined to have a ferritin level that is not within a predetermined range during the treatment period.

[0124] In some embodiments, the subject is determined to have a ferritin level that is not within the predetermined range during the treatment period, and the method further comprises terminating administration of the JAK inhibitor, or momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent.

[0125] In some embodiments, the subject is determined to have a ferritin level that is not within a predetermined range during the treatment period, and the method includes: terminating administration of the JAK inhibitor, or momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent; and Follow these steps: administering to a subject determined to have a ferritin level of less than 90 ng / mL a therapeutically effective amount of a JAK inhibitor; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject determined to have a ferritin level greater than 90 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject determined to have a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or administering to a subject determined to have a ferritin level greater than 650 ng / mL a therapeutically effective amount of momelotinib or a pharma- ceutically acceptable salt thereof, and optionally a second therapeutic agent. administering a second treatment comprising Further includes:

[0126] In some embodiments, the predetermined range of ferritin levels during treatment is less than 90 ng / mL.

[0127] In some embodiments, the predetermined range of ferritin levels during treatment is greater than or equal to 90 ng / mL.

[0128] In some embodiments, the predetermined range of ferritin levels during treatment is greater than or equal to 90 ng / mL and less than or equal to 650 ng / mL.

[0129] In some embodiments, the predetermined range of ferritin levels during treatment is greater than or equal to 650 ng / mL.

[0130] In some embodiments, the JAK inhibitor is selected from momelotinib or a pharmaceutically acceptable salt thereof, ruxolitinib, pacritinib or fedratinib. In some embodiments, the JAK inhibitor is momelotinib or a pharmaceutically acceptable salt thereof or ruxolitinib. In some embodiments, the JAK inhibitor is ruxolitinib. In some embodiments, the JAK inhibitor is pacritinib. In some embodiments, the JAK inhibitor is fedratinib. In some embodiments, the JAK inhibitor is momelotinib or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the second therapeutic agent is a BET protein inhibitor, such as a BRD4 inhibitor. In some embodiments, the BET protein inhibitor is selected from GSK2820151, GSK525762, GS-5829, RO6870810(IV), BAY1238097, CC-90010, BMS-986158, 1NCB054329, 1NCB057643, ODM-207, AZD5153, FT-1101, ABBV-744, ABBV-075, PLX51107, BI894999, OTX015 / MK8628, ZEN003694, RVX-000222, CPI-0610, apabetalone and fedratinib.

[0132] The treatment period during which a therapeutically effective stable dose is administered may be a long-term period. In some embodiments, the multiple weeks without dose reduction are 8 weeks or more, for example, 10 weeks or more. In some embodiments, the multiple weeks without dose reduction are 12 weeks or more. In some embodiments, the multiple weeks without dose reduction are 24 weeks or more (e.g., more than 24 weeks), for example, 28 weeks or more, 32 weeks or more, 36 weeks or more, 40 weeks or more, 44 weeks or more, 48 weeks or more, 52 weeks or more or more. In some embodiments, the treatment period without dose reduction is 1 year or more, for example, 2 years or more, 3 years or more, 4 years or more, 5 years or more, 6 years or more, 7 years or more, or 8 years or more.

[0133] In some embodiments, momelotinib or a pharma- ceutically acceptable salt thereof is administered for a multi-week treatment period. In some embodiments, the multi-week treatment period is 12 weeks or more. In some embodiments, the multi-week treatment period is 24 weeks or more. In some embodiments, the multi-week treatment period is 36 weeks or more.

[0134] The subject method may be utilized as a first-line treatment for myelofibrosis. The patient to be treated according to the method of the present disclosure may not have received Janus kinase inhibitor (JAKi) therapy. Second-line treatment methods are also provided. In certain embodiments, the patient to be treated according to the method of the present disclosure has been previously treated with a JAK inhibitor. In certain embodiments, the JAK inhibitor is ruxolitinib (RUX). In certain embodiments, the JAK inhibitor is fedratinib. In certain cases, the previously treated patient had an inadequate response to, or did not derive sufficient benefit from, or was intolerant to, a Janus kinase inhibitor, such as RUX or fedratinib. In some embodiments, patients who did not respond or became unresponsive to previous therapy (e.g., therapy with RUX or fedratinib) are treated according to the method of the present disclosure. In some cases, the subject did not obtain beneficial or desired clinical results from the previous therapy, for example, as determined via a primary or secondary endpoint.

[0135] In certain embodiments, the subject or patient is a subject or patient who (i) has not received any treatment for the disease (i.e., untreated), (ii) has received a previous treatment (e.g., JAKi treatment such as RUX or fedratinib) and is intolerant to the previous treatment, or (iii) has not derived sufficient benefit from, has not responded to, is resistant to, or has relapsed from a previous treatment (e.g., JAKi treatment such as RUX). In certain embodiments, the patient has not derived sufficient benefit from a previous treatment (e.g., JAKi treatment such as RUX or fedratinib) because the required dose reduction (e.g., due to adverse events) does not provide significant therapeutic benefit.

[0136] Of particular interest is the treatment of ongoing disease, which stabilizes or alleviates the patient's undesirable clinical symptoms. Expected progression-free survival time can be measured in months to years, depending on prognostic factors, including the number of recurrences, stage of the disease, and other factors. Survival extension includes, but is not limited to, at least 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 1 year, at least about 2 years, at least about 3 years or more. Overall survival time can also be measured in months to years. The patient's symptoms can remain static or can be alleviated.

[0137] The compounds of the present application or compositions thereof may be administered once, twice, three or four times a day using any suitable method described herein. Moreover, administration or treatment with MMB may continue for many days, for example, treatment usually continues for at least 7 days, 14 days or 28 days during one treatment cycle. Treatment cycles are generally known and often alternate with rest periods of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. Treatment cycles may be continuous in other embodiments.

[0138] In treating the identified subject, a suitable unit dose of the MMB compound is generally about 0.01 mg to 500 mg per kg of patient body weight per day, which may be administered in single or multiple doses. Dosage levels are about 0.1 mg / kg to about 250 mg / kg per day, for example, about 0.5 mg / kg to about 100 mg / kg per day. Suitable dosage levels may be about 0.01 mg / kg to 250 mg / kg per day, about 0.05 mg / kg to 100 mg / kg per day, or about 0.1 mg / kg to 50 mg / kg per day. Within this range, dosages may be 0.05 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 5 mg / kg, or 5 mg / kg to 50 mg / kg per day. Suitable unit doses are typically 10 mg to 500 mg, for example 50 to 400 mg, for example 100 mg, 150 mg, 200 mg, 250 mg or 300 mg. For oral administration, the composition is preferably provided in the form of a tablet containing 1.0 to 1000 milligrams of active ingredient, in particular 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of active ingredient. The dosage may be selected to be, for example, any dose within these ranges for therapeutic effectiveness and / or symptomatic adjustment of the dosage to the patient to be treated. The compound is preferably administered in a regimen of 1 to 4 times per day, preferably once or twice per day.

[0139] It will be understood that the specific dose level and frequency of dosing for any particular patient may vary and will depend on a variety of factors including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, method and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host being treated.

[0140] In some embodiments of the subject method, the therapeutically effective amount of the MMB compound described herein is a dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. In certain cases, the therapeutically effective amount is 100 mg / day to 300 mg / day, e.g., 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, or 300 mg / day. In certain cases, the therapeutically effective amount is 50 mg / day to 200 mg / day, e.g., 50 mg / day, 100 mg / day, 150 mg / day, or 200 mg / day. In some embodiments of the subject method, the therapeutically effective amount is 200 mg / day. Administration may be oral. In some cases, administration is once daily. In some cases, administration is BID, e.g., in equally divided doses. In certain cases, the MMB is administered with food. In certain cases, MMB is administered without food.

[0141] For patients who are unable to take tablets orally, a therapeutically effective amount of the MMB compound may be administered via an alternative route, for example, via a nasogastric tube.

[0142] In some embodiments, the improved prognosis from MMB treatment resulting from practicing the subject method may be manifested as the maintenance of transfusion independence. In some embodiments, the improved prognosis from MMB treatment resulting from practicing the subject method may be manifested as the achievement of transfusion independence. In some embodiments, the improved prognosis from MMB treatment resulting from practicing the subject method may be manifested as the maintenance or achievement of WK24 TI-R. In some embodiments, the improved prognosis from MMB treatment resulting from practicing the subject method may be manifested as an improvement in one or more clinical endpoints, e.g., anemia response, splenic response, and / or symptom response. In some embodiments, the improved prognosis from MMB treatment resulting from practicing the subject method may be manifested, for example, as an increase in overall survival, e.g., by at least 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 1 year, at least about 2 years, at least about 3 years, or more.

[0143] VI. Momelotinib In the methods described herein, momelotinib, or a pharma- ceutically acceptable salt thereof, is administered in a therapeutically effective amount.

[0144] Momelotinib (MMB), also known as N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide or CYT-0387, is an inhibitor of JAK (JAK1 and JAK2) and ACVR1 and has the structure of Structure I:

[0145] [ka]

[0146] "Pharmaceutically acceptable salt" refers to a salt of a compound that retains the biological effectiveness and properties of the underlying compound and is not biologically or otherwise undesirable. MMB can exist as an acid addition salt. Pharmaceutically acceptable acid addition salts of basic drugs may be prepared using inorganic and organic acids. Acids useful for reacting with MMB to form pharma-ceutically acceptable salts (acid addition salts), and methods for achieving the same, are known to those skilled in the art. When MMB exists as an acid addition salt, MMB free base can be obtained by basifying a solution of the acid salt. Solvates are formed by the interaction of a solvent with the MMB compound. Solvates of the salts of the MMB compounds described herein are also used in certain embodiments of the methods described herein. In some cases, the MMB compound solvates are hydrates.

[0147] The embodiments of the methods disclosed herein use a pharma- ceutically acceptable acid addition salt of momelotinib, or a solvate or hydrate thereof. In some embodiments, the momelotinib compound is a hydrochloride salt. In certain embodiments, the hydrochloride salt of the compound used in the subject methods is momelotinib monohydrochloride salt of structure II:

[0148] [ka]

[0149] In certain embodiments, momelotinib monohydrochloride is an anhydrate. In certain embodiments, momelotinib monohydrochloride is a hydrate, e.g., a monohydrate.

[0150] In certain embodiments, the momelotinib hydrochloride used is momelotinib dihydrochloride of structure III:

[0151] [ka]

[0152] In certain embodiments, momelotinib dihydrochloride is an anhydrate. In certain embodiments, momelotinib dihydrochloride is a hydrate, e.g., momelotinib dihydrochloride monohydrate.

[0153] The method embodiments described herein use any crystalline salt form of momelotinib, including but not limited to those forms as described in WO2015191846, the disclosure of which is incorporated herein by reference. In some embodiments, the crystalline salt forms of momelotinib are referred to as polymorphic forms of the compound.

[0154] In some embodiments, the MMB compound used is momelotinib dihydrochloride monohydrate, which is crystalline form II. Crystalline form II is characterized by one or more parameters as follows: Crystalline form II may be characterized by crystals with unit cell parameters at T=100°K: a=10.2837(6)A, b=10.4981(6)A, c=11.5143(7)A, a=83.297(2)°, β=87.649(2)°, γ=67.445(2)°, and a triclinic P-1 space group. Crystalline form II may be characterized by an X-ray powder diffraction (XRPD) pattern with peaks at 7.7°, 19.3°, 24.0°, 25.7°, and 29.6°2θ+0.2°2θ.

[0155] In some embodiments, the MMB compound used is momelotinib monohydrochloride anhydrate, which is crystalline form I. Crystalline form I may be characterized by one or more parameters as follows: Crystalline form I may be characterized by an X-ray powder diffraction ("XRPD") pattern with peaks at 13.5°, 20.9°, 26.1°, 26.6°, and 28.3°2θ+0.2°2θ.

[0156] In some embodiments, the MMB compound used is momelotinib monohydrochloride anhydrate, which is crystalline form III. Crystalline form III may be characterized by one or more parameters as follows: Crystalline form III may be characterized by an X-ray powder diffraction pattern with peaks at 12.7°, 14.6°, 17.8°, 19.7°, and 23.3°2θ+0.2°2θ.

[0157] In some embodiments, the MMB compound used is crystalline form IV of momelotinib dihydrochloride anhydrate. Crystalline form IV can be characterized by one or more parameters as follows: Crystalline form IV can have an XRPD pattern with peaks at 5.5°, 10.1°, 14.9°, 25.1°, and 26.6°2θ+0.2°2θ.

[0158] [Table 1]

[0159] The following patent applications are incorporated by reference for all purposes, including but not limited to the use of MMBs described therein: International Application No. PCT / AU2008 / 000339, filed March 12, 2008, and International Application No. PCT / AU2011 / 001551, filed November 29, 2011, and International Application No. PCT / US2015 / 035316, filed June 11, 2015, and International Application No. PCT / US2017 / 045957, filed August 8, 2017.

[0160] VII. Pharmaceutical Compositions MMB compounds are usually administered in the form of a pharmaceutical composition. The method embodiments disclosed herein include administering a pharmaceutical composition containing the MMB compounds disclosed herein or a pharma- ceutically acceptable salt or solvate or hydrate thereof, and one or more pharma- ceutically acceptable vehicles selected from carriers, adjuvants, and excipients.

[0161] The pharmaceutical composition may be administered in a single or multiple doses.The pharmaceutical composition may be administered by various methods.In certain embodiments, the pharmaceutical composition is administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0162] Oral administration is currently the preferred route for administration of the MMB compounds described herein. In currently preferred embodiments, the MMB forms or compositions described herein are formulated for oral administration using a pharma- ceutically acceptable carrier. Pharmaceutical compositions formulated for oral administration may be in the form of tablets, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, or powders.

[0163] Administration can be, for example, via capsules or enteric-coated tablets. When preparing pharmaceutical compositions containing the MMB compounds described herein or their pharma-ceutically acceptable salts or solvates or hydrates, the active ingredient is usually diluted by an excipient and / or enclosed within a carrier, which can be in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material, and acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% of the active compound by weight, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0164] To prepare solid compositions such as tablets, the primary active ingredient may be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of any of the compounds of the above formulas or a pharma-ceutically acceptable salt, prodrug, or solvate thereof. When these preformulation compositions are referred to as homogenous, the active ingredient may be evenly dispersed throughout the composition, so that the composition may be easily subdivided into equally effective unit dosage forms, such as tablets and capsules. Tablets of the MMB compounds described herein may be coated or otherwise compounded to provide a dosage form that confers the advantage of extended action or to protect against the acidic conditions of the stomach. For example, a tablet or pill may contain an inner dosage and an outer dosage component, the latter being in the form of an envelope outside the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and to allow the inner component to reach the duodenum intact or to be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0165] The specific dose level of the MMB compounds described herein for any particular subject will depend on a variety of factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject being treated. For example, the dosage may be expressed in milligrams of MMB compound per kilogram of subject body weight (mg / kg). Dosages of about 0.01 mg / kg to 200 mg / kg may be appropriate. In some embodiments, dosages of about 0.01 mg / kg to 150 mg / kg may be appropriate. In other embodiments, dosages of about 0.05 mg / kg to 100 mg / kg may be appropriate. Normalization according to subject body weight is particularly useful when adjusting dosages between subjects of widely differing sizes, such as when using drugs in both pediatric and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects.

[0166] VIII. Pharmaceutically Acceptable Vehicles Pharmaceutically acceptable vehicles include carriers, adjuvants and excipients, such as inert solid diluents and fillers, diluents (eg, sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizing agents and adjuvants.

[0167] The term "carrier" refers to diluents or fillers, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, antioxidants and other excipients and vehicles with which the MMB compound is administered. Examples of carriers that are useful in dosage forms administered in the methods described herein include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethylcellulose, hydroxymethylcellulose, hydroxyoctacosanyl hydroxystearate, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102 and silicone emulsion. However, it should be understood that the carriers selected for the pharmaceutical compositions provided in the present disclosure, and the amounts of such carriers in the compositions, may vary depending on the method of formulation (e.g., dry granulation formulation, solid dispersion formulation).

[0168] The term "diluent" or "bulking agent" generally refers to a substance used to dilute the MMB compound prior to delivery. Diluents can also act to stabilize the compound. Examples of diluents include starch, sugars, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose monohydrate, dicalcium phosphate, cellulose, compressed sugar, calcium hydrogen phosphate dehydrate, mannitol, and tricalcium phosphate.

[0169] The term "disintegrant" generally refers to a substance added to a solid preparation to facilitate its breakup or disintegration after administration, while allowing the release of the active ingredient as effectively as possible, thereby allowing rapid dissolution. Examples of disintegrants include corn starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid.

[0170] The term "precipitation inhibitor" generally refers to a substance that prevents or inhibits the precipitation of an active agent. One example of a precipitation inhibitor is hydroxypropyl methylcellulose.

[0171] The term "surfactant" generally refers to a compound that reduces the surface tension between two liquids or between a liquid and a solid. Examples of surfactants include poloxamer and sodium lauryl sulfate.

[0172] The term "glidant" generally refers to a substance used in tablet and capsule formulations to improve flow characteristics during tablet compression and to produce an anti-caking effect. Examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.

[0173] The term "binder" generally refers to any pharma- ceutically acceptable film that can be used to bind the active and inactive components of the carrier together and to keep them cohesive and separate. Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, ethylcellulose, gelatin, and polyethylene glycol.

[0174] The term "lubricant" generally refers to a substance added to a powder mixture to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. Lubricants can aid in the release of the tablet from the die during tableting and can improve powder flow. Examples of lubricants include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, or talc, and solubilizers (e.g., fatty acids, including lauric acid, oleic acid, and Cg / Cio fatty acids).

[0175] The term "antioxidant" generally refers to a substance that inhibits the oxidation of other substances. In certain embodiments of the present invention, an antioxidant is added to the pharmaceutical composition. Examples of antioxidants include ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid disodium salt, sodium sulfite, sodium metabisulfite, sodium hydrogen sulfite, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, thioglycerol, thioglycolic acid, tocopherol (vitamin E), Da tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and propyl gallate. In certain embodiments, the antioxidant is propyl gallate.

[0176] In some embodiments, the pharmaceutical composition comprises MMB, e.g., MMB dihydrochloride monohydrate crystalline form II, and an antioxidant selected from butyl hydroxyanisole (BHA), ascorbic acid, and propyl gallate. The antioxidant can be present in an amount sufficient to prevent, inhibit, and / or reduce the degradation of the active ingredient of MMB (e.g., MMB crystalline form II). By way of example, the antioxidant can be present in the pharmaceutical composition in an amount of about 0.001%, about 0.002%, about 0.005%, about 0.01%, about 0.02%, about 0.05%, about 0.1%, about 0.2%, about 0.5%, or about 1% by weight. In one embodiment, the pharmaceutical composition comprises propyl gallate in an amount of about 0.001%, about 0.01%, about 0.1%, about 0.2%, about 0.5%, or about 1% by weight. In certain embodiments, the pharmaceutical composition comprises MMB, such as MMB dihydrochloride monohydrate Form II, and about 0.2% by weight propyl gallate.

[0177] In some embodiments, the pharmaceutical composition comprises at least one or at least two diluents. In certain embodiments, the pharmaceutical composition comprises one or two diluents. In certain embodiments, the diluent is selected from mannitol, microcrystalline cellulose, lactose, dextrose, sucrose, Ludiflash, F-MELT, Advantose, galenIQ and any mixture thereof. In one embodiment, the diluent is mannitol, microcrystalline cellulose or a mixture thereof.

[0178] In some embodiments, the pharmaceutical composition comprises at least one disintegrant. In certain embodiments, the pharmaceutical composition comprises one disintegrant. In certain embodiments, the disintegrant is sodium starch glycolate. In one embodiment, the disintegrant is croscarmellose sodium. In another embodiment, the disintegrant is crospovidone.

[0179] In some embodiments, the pharmaceutical composition comprises at least one glidant. In certain embodiments, the pharmaceutical composition comprises one glidant. In one embodiment, the glidant is colloidal silicon dioxide.

[0180] In some embodiments, the pharmaceutical composition comprises at least one lubricant. In certain embodiments, the pharmaceutical composition comprises one lubricant. In one embodiment, the lubricant is magnesium stearate.

[0181] The pharmaceutical compositions comprise the pharma- ceutically acceptable carriers detailed herein, and it should be understood that each and every combination of pharma- ceutically acceptable carriers is the same as if specifically and individually recited.

[0182] IX. Unit Dosage Forms In some embodiments, the pharmaceutical compositions as described herein are formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for a subject (e.g., human subjects and other mammals), each unit containing a predetermined quantity of active material of the MMB compound calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical carrier. In certain embodiments of the invention, the unit dosage form contains at least one pharma- ceutically acceptable carrier.

[0183] In further embodiments, the unit dosage form comprises any one of the forms of MMB, such as MMB dihydrochloride monohydrate crystalline form II. In some embodiments, the unit dosage form comprises any one of the crystalline forms of MMB, such as MMB dihydrochloride monohydrate crystalline form II, in an amount of about 10 mg to about 1000 mg, about 10 mg to about 800 mg, about 10 mg to about 700 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 150 mg, about 10 mg to about 100 mg, about 10 mg to about 50 mg, about 50 mg to about 1000 mg, about 50 mg to about 800 mg, about 50 mg to about 700 mg, about 50 mg to about 500 mg, about 50 mg to about 400 mg, About 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg, about 150 mg to about 200 mg, about 200 mg to about 300 mg, about 200 mg to about 250 mg, or about 200 mg to about 300 mg.

[0184] The pharmaceutical compositions described herein can be manufactured using any conventional method, such as, but not limited to, mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, encapsulating, melt spinning, spray drying or freeze drying process. Those skilled in the art will recognize suitable methods and techniques for preparing tablets by conventional formulation. Exemplary methods and techniques for preparing powder for compression into tablets include dry granulation or wet granulation. Dry granulation generally refers to the process of forming granules without using a solution, while wet granulation generally refers to the process of granulating by adding a solution to a powder.

[0185] X. Ruxolitinib therapy Aspects of the present disclosure include a method of treating a subject with myelofibrosis using MMB as a second-line treatment.In some embodiments, the subject has been previously treated with a JAK inhibitor therapy, such as ruxolitinib, as a first-line treatment.Further details of conventional ruxolitinib therapy in SIMPLIFY 1 and 2 clinical trials can be found in the publicly accessible study protocol.

[0186] Ruxolitinib is typically administered BID in equally divided doses. The recommended dose range for patients with myelofibrosis varies tenfold from as high as 25 mg twice daily to as low as 5 mg once daily. The recommended starting dose of ruxolitinib is based on platelet count, with a pretreatment platelet count of 100–200 × 10 9 A reduced starting dose of 15 mg twice daily is recommended for patients with ≥ 100 mg / L. Complete blood count (CBC) and platelet count will be performed prior to initiating treatment and every 2-4 weeks until dose stabilization, then as clinically indicated. Doses may be titrated based on safety and efficacy. Ruxolitinib dose modification guidelines in response to symptoms or disease progression are also available in publicly accessible study protocols and reports.

[0187] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has individual components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the invention. Any recited method may be carried out in the order of events recited or in any other order which is logically possible. EXAMPLES

[0188] Below are examples of specific embodiments for carrying out the present invention. The examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should, of course, be accounted for.

[0189] Example 1. 24-Week Response and Overall Survival The relationship between W24 response and overall survival (OS) was investigated in patients randomized to MMB in the SIMPLFY-1 (S1) and SIMPLIFY-2 (S2) trials.

[0190] Responders were defined as follows: W24 TI response (TI-R): Hgb ≥ 8g / dL and no RBC transfusion within 12 weeks prior to W24 W24 spleen response: ≥35% reduction in spleen volume compared to baseline (BL) W24 Symptom Response: ≥50% reduction in MFSAF total symptom score for BL

[0191] Survival from baseline was estimated and compared by descriptive log-rank test using KM analysis (all p-values ​​are descriptive). Hazard ratios were computed using proportional hazards regression. To adjust for bias in response time, overall survival from W24 was also compared. Because patients were randomized to the control arm in both studies and crossed over to open-label MMB 24 weeks after randomized treatment, a valid comparison of overall survival between patients randomized to RUX or BAT / RUX and those randomized to MMB was not possible, therefore only the MMB arm was analyzed.

[0192] Overall survival for all patients randomized to MMB with TI response at week 24 in S1 is shown in Figure 6. Patients randomized to MMB who were TI responders at W24 had an overall survival advantage. The 3-year survival rate was 80% in MMB TI responders and 50% in MMB TI non-responders, HR=0.30; p<0.0001.

[0193] Overall survival of anemic patients randomized to MMB in S1 with TI response at week 24 is shown in Figure 7. The week 24 TI response rate in patients with anemia at baseline who received MMB treatment was 45% and in patients who received RUX the response rate was 26%. Consistent with the results in the total MMB population, S1 patients with anemia at baseline (RBC transfusion within 12 weeks prior to baseline or Hgb < 10 g / dL at baseline) also showed a significant overall survival advantage and achieved TI-R at week 24. HR = 0.32; p = 0.0006.

[0194] Overall survival of all patients randomized to MMB with TI response at week 24 in S2 is shown in Figure 8. Patients who were TI responders at W24 and randomized to MMB showed a trend towards better overall survival compared to patients who were TI non-responders. HR=0.57; p=0.0652.

[0195] The relationship between W24 spleen response and symptom response and overall survival was also investigated in MMB patients. Figures 9 and 10 show overall survival in S1 spleen and TSS responders, respectively. In S1, MMB spleen responders had an advantage in overall survival compared to MMB non-responders. HR=0.59; p=0.0904. Similarly, MMB symptom (TSS) responders had an advantage in overall survival compared to MMB non-responders. HR=0.66; p=0.1657. In S2, overall survival in MMB symptom (TSS) responders compared to MMB TSS non-responders showed HR=0.67 and p=0.2513 (data not shown).

[0196] Momelotinib (MMB) provided anemia correction effects through inhibition of JAK1, JAK2 and ACVR1 / ALK2, resulting in higher transfusion independence (TI) compared with ruxolitinib (RUX), regardless of baseline degree of anemia, baseline platelet count or transfusion status. In addition, myelofibrosis patients treated with MMB converted to or maintained TI and had significantly improved overall survival (OS).

[0197] Week 24 (W24) TI response was a strong predictor of improved survival in both the SIMPLIFY-1 and SIMPLIFY-2 trials. This analysis showed that W24 TI response was a predictor of improved survival in MMB patients who were anemic at baseline. This analysis also showed that the correlation between W24 TI response and overall survival observed with MMB supports the clinical relevance of TI in MMB-treated MF patients.

[0198] These results indicate that the likelihood of achieving a W24 TI response should be considered with regard to the choice of treatment.

[0199] Example 2: Ferritin as a biomarker for transfusion response at 24 weeks Figure 3 shows the extent to which baseline transfusion requirement influences W24 TI-R. Although MMB was better than RUX for each baseline TI / TR / TD cohort, the more transfusions a patient required at baseline, the less likely they were to become a W24 TI responder.

[0200] A previous study (the "1672 study") showed that patients with high inflammation could not achieve transfusion independence with MMB alone. Elevations in serum ferritin, C-reactive protein (CRP), hepcidin and WBC are usually associated with significant inflammation and, importantly, are easily measured in the hospital (Oh et al., 2020, Blood Adv., vol. 4, no. 18, pp. 4282-4291). This study showed that momelotinib reversed or reduced transfusion dependency in transfusion-dependent myelofibrosis patients and inhibited hepcidin. The 1672 study showed that ferritin stabilized in TI-R patients over 24 weeks of treatment. Like hepcidin, baseline ferritin is a strong negative prognostic factor in patients with MF. Figure 11 shows the mean ferritin levels of TI-R and TI-NR patients over 24 weeks in the 1672 study.

[0201] As shown below, thresholds of baseline and on-treatment ferritin levels can be used to predict MMB TI-R.

[0202] Lower levels of baseline ferritin (approximately 150ng / mL) were observed in baseline TI compared to baseline non-TI subjects (>800ng / mL) in S1, consistent with the role of ferritin in anemia in MF patients. MMB was more effective at stabilizing ferritin over time when compared to RUX. Figures 12 and 13 show that ferritin levels in MMB-treated patients remain stable with minimal changes in most TI-R patients until week 12 when compared to RUX-treated patients in S1. RUX-treated patients showing an increase in ferritin of >100ng / mL by week 12 were associated with TI-NR at week 24.

[0203] Figure 14 shows baseline ferritin levels in JAKi-naïve patients at S1. Baseline ferritin levels below 650ng / mL correlate with W24 TI-R of MMB. MMB outperformed RUX in each ferritin cohort, with W24 TI-R dramatically higher in the 90ng / mL-650ng / mL cohort. RUX was less effective in patients with ferritin levels above 90ng / mL. The overall efficacy of MMB decreased when patients had ferritin levels above 650ng / mL, but MMB was still better than RUX in patients with ferritin levels above 650ng / mL. Less than 12% of the JAKi-naïve population had ferritin levels above 650ng / mL.

[0204] Figure 15 shows baseline ferritin levels of RUX patients in S2. When these thresholds were applied to the more advanced SIMPLIFY-2 population, the same trend was seen in this study, indicating that ferritin may be a predictive biomarker for MMB W24 TI-R. MMB-treated patients with ferritin levels below 650ng / mL were more likely to have TI-R at week 24. For this study, the slightly higher TI-R rate in the cohort above 650ng / mL may be the result of switching from RUX. The rise in ferritin levels caused by RUX treatment may be reversed when treatment is switched from RUX to MMB.

[0205] Example 3: Ferritin as a biomarker for transfusion response at 24 weeks Myelofibrosis (MF) typically presents with constitutional symptoms, splenomegaly, and anemia, and the degree of anemia and transfusion dependency is one of the most important predictors of poor overall survival (OS). Momelotinib (MMB) is a differentiated JAK1, JAK2 inhibitor with potent efficacy against ACVR1 / ALK2, a key regulator of hepcidin production and iron metabolism.

[0206] MMB has demonstrated robust clinical efficacy against all three of these hallmark features of MF in the SIMPLIFY Phase 3 trials (including SIMPLIFY-1 (S1), compared directly to ruxolitinib (RUX) in JAK inhibitor (JAKi)-naïve patients, and SIMPLIFY-2 (S2), compared to best available therapy (BAT) in previously JAKi-treated patients). MMB further demonstrated robust OS extension in the JAKi-naïve (S1) and JAKi-treated (S2) populations (Verstovsek et al., 2020). Importantly, patients randomized to MMB who achieved or maintained transfusion independence (TI) through week 24 (W24) had better OS, further suggesting that the anemia-improving effect of MMB positively impacts long-term prognosis in patients with MF (Mesa et al., EHA Conference, 2021).

[0207] Increased hepcidin and ferritin are associated with dysregulated iron metabolism and inflammation, both of which have previously been shown to be strong negative prognostic factors for OS in patients with MF at the time of initial referral (Pardanani et al., 2013). A phase 2 translational biology trial previously demonstrated that MMB acutely and chronically suppresses elevated levels of hepcidin and restores iron homeostasis in transfusion-dependent patients achieving a W24 TI response (Oh et al., 2020, Blood Adv. 4(18) 4282-4291).

[0208] method Based on findings from a phase 2 translational biology trial, we retrospectively analyzed the relationship between serum ferritin, hepcidin, and C-reactive protein (CRP) and W24 TI response rates for patients randomized to MMB and RUX in the S1 trial using univariate analysis and multiple logistic regression models. These findings were then independently confirmed in previously RUX-treated patients in S2.

[0209] result These analyses identified pretreatment serum ferritin levels as having the greatest predictive interaction between MMB and RUX treatment effects on W24 TI-R rates in JAKi-naive patients in S1. The TI-R treatment effect of MMB versus RUX was significantly greater in the ≥90ng / mL cohort (62% vs. 35%, respectively) than in the <90ng / mL cohort (79% vs. 73%) (p=0.0051 for interaction). These findings were confirmed in the smaller sample size S2 study, where the TI-R treatment effect of MMB compared to BAT / RUX was greater in the ≥90ng / mL cohort (41% vs. 11%, respectively) than in the <90ng / mL cohort (57% vs. 50%).

[0210] The data further showed a significant increase in serum ferritin in patients randomized to RUX compared with MMB from baseline to W24, regardless of baseline ferritin (RUX mean ferritin change +226.1ng / mL vs. MMB +13.8ng / mL, p=0.0003).

[0211] [Table 2]

[0212] conclusion Ferritin is a well-established and easily measured clinical biomarker associated with both iron metabolism and unregulated inflammation, but it is not routinely measured in patients with myelofibrosis. Previous analyses have shown that patients treated with MMB achieving W24 TI-R had extended OS compared to non-TI responders. These new analyses extend these findings and strongly demonstrate that the treatment effect of MMB on RUX is greater in patients with baseline serum ferritin ≥90ng / mL compared to <90ng / mL, as confirmed independently in JAKi-naïve and previously RUX-experienced patients. Furthermore, the data presented here showed that S1 JAKi-naïve patients randomized to RUX had significantly elevated ferritin levels by W24 when compared to MMB. Overall, these data suggest that serum ferritin may be an important biomarker to inform first-line treatment selection and potentially guide transition to MMB in the post-RUX setting. This association should be prospectively investigated in future MMB studies.

[0213] Equivalent Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of the invention that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

[0214] Thus, the above description merely illustrates the principles of the present invention. It is understood that those skilled in the art can devise various configurations that embody the principles of the present invention and fall within its spirit and scope, even if not expressly described or shown herein. Furthermore, all examples and conditional terms recited herein are intended primarily to aid the reader in understanding the principles of the present invention and the concepts contributed by the inventors to advance the art, and should not be construed as being limited to such specifically recited examples and conditions. Furthermore, all statements herein reciting the principles, aspects, and embodiments of the present invention, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. In addition, such equivalents are intended to include both currently known equivalents and equivalents developed in the future, i.e., any developed elements that perform the same function, regardless of structure. Furthermore, nothing disclosed herein is intended to be made public, regardless of whether such disclosure is expressly recited in the claims.

[0215] Therefore, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention is embodied by the appended claims. In the claims, 35 U.S.C. §112(f) or 35 U.S.C. §112(6) is expressly defined to apply for a limitation in a claim only if the precise phrase "means for" or the precise phrase "step for" is recited at the beginning of such limitation in the claim, and if such precise phrase is not used in the limitation in the claim, 35 U.S.C. §112(f) or 35 U.S.C. §112(6) does not apply.

[0216] EMBODIMENTS OF THE PRESENT DISCLOSURE 1. A method of treating myelofibrosis in a subject, comprising administering to a subject identified as having (i) myelofibrosis, and (ii) a ferritin level greater than 90 ng / mL a therapeutically effective amount of momelotinib, or a pharma- ceutical acceptable salt thereof. 2. The method of embodiment 1, wherein the subject is identified as having a ferritin level greater than 90 ng / mL and less than 650 ng / mL. 3. The method of embodiment 1, wherein the subject is identified as having a ferritin level greater than 650 ng / mL. 4. The method of embodiment 3, further comprising administering to the subject a therapeutically effective amount of a second therapeutic agent. 5. The method of any one of embodiments 1 to 4, further comprising determining ferritin levels in a sample from a subject with myelofibrosis. 6. The method of any one of embodiments 1-5, wherein momelotinib or a pharma- ceutically acceptable salt thereof is administered for a multi-week treatment period. 7. The method of embodiment 6, wherein the multi-week treatment period is 12 weeks or longer. 8. The method of embodiment 6, wherein the multi-week treatment period is 24 weeks or longer. 9. The method of embodiment 6, wherein the multi-week treatment period is 36 weeks or longer. 10. The method of any one of embodiments 1-9, further comprising determining ferritin levels in the subject's sample once a month, or twice a month, or once a week during the treatment period. 11. The method of embodiment 10, wherein ferritin levels in the subject's sample are measured once a week. 12. The method of embodiment 10 or 11, wherein the subject is determined to maintain ferritin levels within a predetermined range during the treatment period. 13. The method of embodiment 10 or 11, wherein the subject is determined to have a ferritin level that is not within a predetermined range during the treatment period. 14. The method of embodiment 10 or 11, wherein the subject is determined to have a ferritin level that is not within a predetermined range during the treatment period, and the method further comprises terminating administration of momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent. 15. The subject is determined to have a ferritin level that is not within a predetermined range during treatment, and the method comprises: terminating administration of momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent; and Follow these steps: administering a therapeutically effective amount of a JAK inhibitor to a subject determined to have a ferritin level of less than 90 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject determined to have a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or administering to a subject determined to have a ferritin level greater than 650 ng / mL a therapeutically effective amount of momelotinib or a pharma- ceutically acceptable salt thereof, and optionally a second therapeutic agent. administering a second treatment comprising 12. The method of embodiment 10 or 11, further comprising: 16. The method of any one of embodiments 12-15, wherein the predetermined range of ferritin levels during the treatment period is 90 ng / mL or more, or the predetermined range of ferritin levels during the treatment period is 90 ng / mL or more and 650 ng / mL or less. 17. The method of any one of embodiments 12-15, wherein the predetermined range of ferritin levels during treatment is greater than 650 ng / mL. 18. A method for maintaining transfusion independence in a subject being treated for myelofibrosis, comprising: a. administering a therapeutically effective amount of a JAK inhibitor to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level of less than 90 ng / mL; or b. administering to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL a therapeutically effective amount of momelotinib or a pharma- ceutically acceptable salt thereof; or c. Administering a therapeutically effective amount of momelotinib or a pharma- ceutically acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level greater than 650 ng / mL. The method includes: 19. A method for converting a subject being treated for myelofibrosis from transfusion requirement or transfusion dependency to transfusion independence, comprising: a. administering a therapeutically effective amount of a JAK inhibitor to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level of less than 90 ng / mL; or b. administering to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level greater than 90 ng / mL a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof; or c. administering to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL, a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof; or d. Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level greater than 650 ng / mL. The method includes: 20. The method of embodiment 18 or 19, wherein the JAK inhibitor is selected from momelotinib or a pharma- ceutically acceptable salt thereof, ruxolitinib, or fedratinib. 21. The method of embodiment 20, wherein the JAK inhibitor is momelotinib or a pharma- ceutically acceptable salt thereof, or ruxolitinib. 22. The method of embodiment 20, wherein the JAK inhibitor is ruxolitinib. 23. The method of embodiment 20, wherein the JAK inhibitor is momelotinib or a pharma- ceutically acceptable salt thereof. 24. The method of any one of embodiments 4, or 18-23, wherein the second therapeutic agent is a BET protein inhibitor or a BRD4 inhibitor. 25. The method of embodiment 24, wherein the second therapeutic agent is selected from GSK2820151, GSK525762, GS-5829, RO6870810(IV), BAY1238097, CC-90010, BMS-986158, 1NCB054329, 1NCB057643, ODM-207, AZD5153, FT-1101, ABBV-744, ABBV-075, PLX51107, BI894999, OTX015 / MK8628, ZEN003694, RVX-000222, CPI-0610, apabetalone, and fedratinib. 26. A method for treating or preventing anemia in a subject being treated for myelofibrosis, comprising administering a therapeutically effective amount of momelotinib, or a pharma- ceutical acceptable salt thereof, to a subject identified as (i) having myelofibrosis, and (ii) having or at risk for anemia, and (iii) having a ferritin level of 90 ng / mL or greater. 27. The method of any one of embodiments 18 to 26, further comprising an earlier step of determining ferritin levels in a sample from a subject with myelofibrosis. 28. The method of any one of embodiments 18-27, wherein momelotinib or a pharma- ceutically acceptable salt thereof is administered for a multi-week treatment period. 29. The method of embodiment 28, wherein the multi-week treatment period is 12 weeks or more. 30. The method of embodiment 28, wherein the multi-week treatment period is 24 weeks or longer. 31. The method of embodiment 28, wherein the multi-week treatment period is 36 weeks or longer. 32. The method of any one of embodiments 18-31, further comprising determining ferritin levels in the subject's sample once a month, or twice a month, or once a week during the treatment period. 33. The method of embodiment 32, wherein ferritin levels in the subject's sample are measured weekly. 34. The method of embodiment 32 or 33, wherein the subject is determined to maintain ferritin levels within a predetermined range during the treatment period. 35. The method of embodiment 32 or 33, wherein the subject is determined to have a ferritin level that is not within a predetermined range during the treatment period. 36. The method of embodiment 32 or 33, wherein the subject is determined to have a ferritin level that is not within a predetermined range during the treatment period, and the method further comprises terminating administration of the JAK inhibitor, or momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent. 37. The subject is determined to have a ferritin level that is not within a predetermined range during the treatment period, and the method comprises: terminating administration of the JAK inhibitor, or momelotinib or a pharma- ceutically acceptable salt thereof, and / or the optional second therapeutic agent; and Follow these steps: administering a therapeutically effective amount of a JAK inhibitor to a subject determined to have a ferritin level of less than 90 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject determined to have a ferritin level of greater than 90 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharma- ceutical acceptable salt thereof to a subject determined to have a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or administering to a subject determined to have a ferritin level greater than 650 ng / mL a therapeutically effective amount of momelotinib or a pharma- ceutically acceptable salt thereof, and optionally a second therapeutic agent. administering a second treatment comprising 34. The method of embodiment 32 or 33, further comprising: 38. The method of any one of embodiments 34-37, wherein the predetermined range of ferritin levels during the treatment period is 90 ng / mL or more, or the predetermined range of ferritin levels during the treatment period is 90 ng / mL or more and 650 ng / mL or less. 39. The method of any one of embodiments 34-37, wherein the predetermined range of ferritin levels during treatment is greater than 650 ng / mL. 40. The method of any one of embodiments 1-39, wherein the subject is a human. 41. The method of any one of embodiments 1-40, wherein the subject is an adult human. 42. The method of any one of embodiments 1-41, wherein the subject has previously been treated with a JAK inhibitor therapy other than momelotinib. 43. The method of embodiment 42, wherein the subject has been previously treated with ruxolitinib. 44. The method of embodiment 42 or 43, wherein the subject has had an inadequate response to or is intolerant to ruxolitinib. 45. The method of any one of embodiments 42-44, wherein the subject has not responded or has become unresponsive to previous ruxolitinib therapy. 46. ​​The method of any one of embodiments 1-41, wherein the subject is not receiving JAK inhibitor therapy. 47. The method of any one of embodiments 1-46, wherein the momelotinib or a pharma- ceutically acceptable salt thereof is momelotinib dihydrochloride. 48. The method of any one of embodiments 1-46, wherein the momelotinib or a pharma- ceutically acceptable salt thereof is momelotinib dihydrochloride monohydrate. 49. The method of any one of embodiments 1-46, wherein the momelotinib or a pharma- ceutically acceptable salt thereof is momelotinib dihydrochloride monohydrate form II. 50. The method of any one of embodiments 1-49, wherein momelotinib or a pharma- ceutically acceptable salt thereof is provided in a pharma- ceutically acceptable composition. 51. The method of any one of embodiments 1-50, wherein the therapeutically effective amount is 50 mg / day to 200 mg / day. 52. The method of embodiment 51, wherein the therapeutically effective amount is 200 mg / day, or 150 mg / day, or 100 mg / day, or 50 mg / day. 53. The method of any one of embodiments 1-52, wherein momelotinib or a pharma- ceutically acceptable salt thereof is administered orally. 54. The method of any one of embodiments 1-53, wherein momelotinib or a pharma- ceutically acceptable salt thereof is administered daily. 55. The method of embodiment 54, wherein momelotinib or a pharma- ceutically acceptable salt thereof is administered once a day.

Claims

1. 1. A medicament for use in a method of treating myelofibrosis in a subject, comprising: the medicament comprises momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent; The pharmaceutical composition, wherein the method comprises administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as having (i) myelofibrosis and (ii) a ferritin level greater than 90 ng / mL.

2. The method of claim 1, wherein the subject is identified as having a ferritin level greater than 90 ng / mL and less than 650 ng / mL.

3. The method of claim 1, wherein the subject is identified as having a ferritin level greater than 650 ng / mL.

4. The pharmaceutical described in claim 3, wherein the method further comprises the step of administering to the subject a therapeutically effective amount of a second therapeutic agent.

5. The pharmaceutical described in claim 1, wherein the method further comprises a step of determining ferritin levels in a sample from a subject having myelofibrosis.

6. 2. The method of claim 1, wherein momelotinib or a pharmaceutically acceptable salt thereof is administered for a multi-week treatment period.

7. The pharmaceutical described in claim 1, wherein the method further comprises a step of determining ferritin levels in a sample from the subject once a month, or twice a month, or once a week during the treatment period.

8. The subject is determined to maintain a ferritin level within a predetermined range during the treatment period; or The subject is determined to have a ferritin level that is not within a predetermined range during the treatment period; or The subject is determined to have a ferritin level that is not within a predetermined range during the treatment period, and the method further comprises terminating the administration of momelotinib or a pharmaceutically acceptable salt thereof, and / or the optional second therapeutic agent; or The subject is determined to have a ferritin level that is not within a predetermined range during treatment, and the method further comprises: terminating the administration of momelotinib or a pharmaceutically acceptable salt thereof, and / or the optional second therapeutic agent; and Steps below: administering a therapeutically effective amount of a JAK inhibitor to a subject determined to have a ferritin level less than 90 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject determined to have a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent, to a subject determined to have a ferritin level greater than 650 ng / mL. administering a second treatment comprising The pharmaceutical composition of claim 7, further comprising:

9. A predetermined range of ferritin levels during the treatment period is 90 ng / mL or greater, or a predetermined range of ferritin levels during the treatment period is 90 ng / mL or greater and 650 ng / mL or less, or The pharmaceutical composition of claim 8, wherein the predetermined range of ferritin levels during treatment is greater than 650 ng / mL.

10. 1. A medicament for use in a method for maintaining transfusion independence in a subject being treated for myelofibrosis, comprising: the medicament comprises a JAK inhibitor, or the medicament comprises momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent; The method comprises: a. administering a therapeutically effective amount of a JAK inhibitor to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level less than 90 ng / mL; or b. Administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level greater than 90 ng / mL and less than or equal to 650 ng / mL; or c. Administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion independent, and (iii) having a ferritin level greater than 650 ng / mL. The pharmaceutical composition comprising:

11. 1. A medicament for use in a method for converting a subject being treated for myelofibrosis from transfusion requirement or transfusion dependence to transfusion independence, comprising: the medicament comprises a JAK inhibitor, or the medicament comprises momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent; The method comprises: a. administering a therapeutically effective amount of a JAK inhibitor to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level less than 90 ng / mL; or b. Administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level greater than 90 ng / mL; or c. Administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level greater than 90 ng / mL and less than or equal to 650 ng / mL; or d. Administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent, to a subject identified as (i) having myelofibrosis, (ii) being transfusion-requiring or transfusion-dependent, and (iii) having a ferritin level greater than 650 ng / mL. The pharmaceutical composition comprising:

12. The pharmaceutical composition of claim 10 or 11, wherein the JAK inhibitor is selected from momelotinib or a pharmaceutically acceptable salt thereof, ruxolitinib, or fedratinib.

13. The pharmaceutical composition of claim 4, 10, or 11, wherein the second therapeutic agent is a BET protein inhibitor or a BRD4 inhibitor.

14. 1. A medicament for use in a method for treating or preventing anemia in a subject being treated for myelofibrosis, comprising: the medicament comprises momelotinib or a pharmaceutically acceptable salt thereof, The method comprises: The pharmaceutical composition comprises a step of administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as (i) having myelofibrosis, (ii) having or at risk of developing anemia, and (iii) having a ferritin level of 90 ng / mL or greater.

15. The method further comprises the preceding step of determining ferritin levels in a sample from a subject with myelofibrosis; and / or 15. The method of claim 10, 11 or 14, wherein momelotinib or a pharmaceutically acceptable salt thereof is administered for a multi-week treatment period.

16. The pharmaceutical described in claim 10, 11 or 14, wherein the method further comprises a step of determining ferritin levels in a sample from the subject once a month, or twice a month, or once a week during the treatment period.

17. The subject is determined to maintain a ferritin level within a predetermined range during the treatment period; or The subject is determined to have a ferritin level that is not within a predetermined range during the treatment period; or The subject is determined to have a ferritin level that is not within a predetermined range during the treatment period, and the method further comprises terminating administration of the JAK inhibitor, or momelotinib or a pharmaceutically acceptable salt thereof, and / or the optional second therapeutic agent; or The subject is determined to have a ferritin level that is not within a predetermined range during treatment, and the method further comprises: terminating the administration of the JAK inhibitor, or momelotinib or a pharmaceutically acceptable salt thereof, and / or the optional second therapeutic agent; and Steps below: administering a therapeutically effective amount of a JAK inhibitor to a subject determined to have a ferritin level less than 90 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject determined to have a ferritin level greater than 90 ng / mL; or Administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject determined to have a ferritin level of greater than 90 ng / mL and less than or equal to 650 ng / mL; or administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof, and optionally a second therapeutic agent, to a subject determined to have a ferritin level greater than 650 ng / mL. administering a second treatment comprising The pharmaceutical composition of claim 16, further comprising:

18. A predetermined range of ferritin levels during the treatment period is 90 ng / mL or greater, or a predetermined range of ferritin levels during the treatment period is 90 ng / mL or greater and 650 ng / mL or less, or The pharmaceutical composition of claim 17, wherein the predetermined range of ferritin levels during treatment is greater than 650 ng / mL.

19. the subject has been previously treated with a JAK inhibitor therapy other than momelotinib, or The method of claim 1, 10, 11 or 14, wherein the subject has previously been treated with ruxolitinib.

20. the subject has had an inadequate response to or is intolerant to ruxolitinib, and / or the subject has not responded or has become non-responsive to prior ruxolitinib therapy, and / or The method of claim 19, wherein the subject is not receiving JAK inhibitor therapy.

21. The pharmaceutical composition according to claim 1, 10, 11 or 14, wherein the therapeutically effective amount is 50 mg / day to 200 mg / day.

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