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EP4611753A1 - Inhibiteur de pim-1 pour le traitement de néoplasmes myéloprolifératifs - Google Patents

Inhibiteur de pim-1 pour le traitement de néoplasmes myéloprolifératifs

Info

Publication number
EP4611753A1
EP4611753A1 EP23814322.6A EP23814322A EP4611753A1 EP 4611753 A1 EP4611753 A1 EP 4611753A1 EP 23814322 A EP23814322 A EP 23814322A EP 4611753 A1 EP4611753 A1 EP 4611753A1
Authority
EP
European Patent Office
Prior art keywords
subject
pharmaceutically acceptable
acceptable salt
compound
inhibitor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23814322.6A
Other languages
German (de)
English (en)
Inventor
Emily M. BROOKS
Jason M. Foulks
Sujan KABIR
Claudia A. LEBEDINSKY
Jian MEI
Mark L. WADE
Clifford J. Whatcott
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sumitomo Pharma America Inc
Original Assignee
Sumitomo Pharma America Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sumitomo Pharma America Inc filed Critical Sumitomo Pharma America Inc
Publication of EP4611753A1 publication Critical patent/EP4611753A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present technology relates to PIM kinase inhibitors, particularly selective PIM1 kinase inhibitors, for monotherapy and combination therapies for the treatment of myeloproliferative neoplasms such as myelofibrosis (MF).
  • MF myelofibrosis
  • BACKGROUND [003] Despite meaningful advancements in the treatment of many hematological malignancies, significant unmet needs persist. Drug resistance, toxicities, poor response, and poor overall survival remain substantial challenges that require the development and evaluation of novel therapeutic agents.
  • MF Myelofibrosis
  • MPN myeloproliferative neoplasms
  • JAK2 inhibitor such as ruxolitinib
  • PIM kinase family have been implicated in the regulation of cell growth, survival, and cell cycle and are overexpressed in various cancers.
  • PIM1 kinase has been 1 48285867.1 found to be significantly overexpressed in MF patients.
  • TP-3654 is a highly selective oral PIM-1 kinase inhibitor.
  • the disclosure provides a method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) having the following structure: or a pharmaceutically acceptable salt thereof, wherein the subject has poor bone marrow functioning characterized by: thrombocytopenia (e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L); anemia (e.g. a Hgb level ⁇ 10, 9, or 8 g/dL); transfusion dependence; or a combination thereof; and wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • thrombocytopenia e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L
  • anemia e.g. a Hgb level ⁇ 10, 9, or 8 g/dL
  • transfusion dependence e.g. a combination
  • the disclosure provides a method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor, wherein the subject has poor bone marrow functioning characterized by: thrombocytopenia (e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L); anemia (e.g.
  • the disclosure provides a method of treating a myeloproliferative neoplasm in a human subject in need thereof, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and optionally has relapsed disease or is refractory to the JAK inhibitor, comprising administering to the subject a therapeutically effective amount of Compound (1) having the following structure: Compound (1), or a pharmaceutically acceptable salt thereof, wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • the disclosure is also based on the discovery that Compound (1) is able to treat the symptomatic burden of myeloproliferative neoplasms, particularly as measured by the about 50% reductions in Total Symptoms Score (“TSS50”), when other treatments under development have failed.
  • TSS50 Total Symptoms Score
  • the disclosure provides a method of treating a myeloproliferative neoplasm by inducing TSS50 in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) having the following structure: Compound (1), or a pharmaceutically acceptable salt thereof, wherein the myeloproliferative neoplasm is treated by inducing TSS50 in the subject, optionally at a time point between and including about 12 and 100 weeks (e.g., between and including about 20 and 75 weeks or between and including about 24 and 48 weeks).
  • the disclosure is also based on the discovery that there are minimal or no overlapping hematological toxicities when Compound (1) or another selective PIM1 inhibitor is administered in combination with other treatments for myeloproliferative neoplasms such as a JAK inhibitor and/or ACVR inhibitor (e.g., ruxolitinib and momelotinib), such as anemia, thrombocytopenia, transfusion dependence, or a combination of two or more thereof.
  • a JAK inhibitor and/or ACVR inhibitor e.g., ruxolitinib and momelotinib
  • each of the molecules in the combination meaningfully contributes to the efficacy of the therapy, particularly in terms of TSS improvements and/or spleen volume reduction.
  • the disclosure provides a method of treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject Compound (1) having the following structure: or a pharmaceutically acceptable salt thereof, and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • Compound (1) having the following structure: or a pharmaceutically acceptable salt thereof, and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • the disclosure provides a method of treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a selective PIM1 inhibitor and a JAK inhibitor and/or ACVR inhibitor (e.g., ruxolitinib or momelotinib) or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • a selective PIM1 inhibitor and a JAK inhibitor and/or ACVR inhibitor e.g., ruxolitinib or momelotinib
  • ACVR inhibitor e.g., ruxolitinib or momelotinib
  • a pharmaceutically acceptable salt thereof e.g., anemia and/or thrombocytopenia and/or transfusion dependence
  • the disclosure is still further based on the remarkable results observed from Compound (1) relative to other treatments for myeloproliferative neoplasms, in human subjects previously treated with a JAK inhibitor, and the enhanced probability of clinically meaningful improvements in SVR35 or TSS50.
  • the disclosure provides a method of inducing a probability of SVR35 in a human subject affected by a myeloproliferative neoplasm about ⁇ 15% or 20%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and optionally has relapsed disease or is refractory to the JAK inhibitor, comprising administering to the subject a therapeutically effective amount of Compound (1) having the following structure: Compound (1), or a pharmaceutically acceptable salt thereof, wherein the treatment induces a probability of SVR35 in the subject ⁇ 15% or 20%.
  • the disclosure provides a method of inducing a probability of TSS50 in a human subject affected by a myeloproliferative neoplasm about ⁇ 30%, 35%, 40%, 45%, or 50%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and optionally has relapsed disease or is refractory to the JAK inhibitor, comprising administering to the subject a therapeutically effective amount of Compound (1) having the following structure: Compound (1), or a pharmaceutically acceptable salt thereof, wherein the treatment induces a probability of TSS50 in the subject about ⁇ 30%, 35%, 40%, 45%, or 50%.
  • FIG.1A shows the in vitro effect of momelotinib, pacritinib, ruxolitinib, and the HCl salt of Compound (1) on human erythroid (CFU-E, BFU-E), according to the examples.
  • FIG.1B shows the in vitro effect of momelotinib, pacritinib, ruxolitinib, and the HCl salt of Compound (1) on human megakaryocyte (CFU-MK), according to the examples.
  • FIG.1C shows the in vitro effect of momelotinib, pacritinib, ruxolitinib, and the HCl salt of Compound (1) on human granulocyte-monocyte (CFU-GM), according to the examples.
  • FIG.2A shows the in vitro effect of ruxolitinib, the HCl salt of Compound (1), and combinations thereof on human megakaryocyte (CFU-Mk), according to the examples.
  • FIG.2B shows the in vitro effect of pacritinib, the HCl salt of Compound (1), and combinations thereof on human megakaryocyte (CFU-MK), according to the examples.
  • FIG.4C shows the in vitro effect of momelotinib, the HCl salt of Compound (1), and combinations thereof on human granulocyte-monocyte (CFU-GM), according to the examples.
  • FIG.5A shows patient platelet counts during monotherapy treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5B shows patient hemoglobin during monotherapy treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5C shows patient neutrophil during monotherapy treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5D shows average patient blood counts (platelet, hemoglobin, and neutrophil) during monotherapy treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5E shows best percent change of patient spleen volume reduction during monotherapy treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5F shows best percent change of patient total symptom score reduction during monotherapy treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5G shows best percent change of patient spleen volume reduction and total symptom score reduction during monotherapy treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5H shows patient cytokine modulation, spleen volume reduction, and total symptom score reduction during monotherapy treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5I shows patient cytokine modulation and total symptom score reduction at 4 weeks, 8 weeks, and 12 weeks of treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5J shows patient cytokine modulation and total symptom score reduction at 12 weeks of treatment with the HCl salt of Compound (1), according to the examples.
  • FIG.5K shows mean hemoglobin and platelet counts throughout 24-weeks of treatment for 22-evaluable patients treated with the HCl salt of Compound (1), according to the examples.
  • MPN abnormal stem cells produce excess numbers of one or more types of blood cells (e.g., red blood cells, white blood cells, and/or platelets).
  • myeloproliferative neoplasms include, but are not limited to, polycythemia vera (PV), primary or essential thrombocythemia (ET), pre-MF, primary or idiopathic MF, secondary MF (e.g., MF secondary to polycythemia vera or essential thrombocythemia).
  • the MPN includes PV.
  • the MPN includes primary or essential thrombocythemia.
  • the MPN includes pre-MF.
  • the MPN includes primary or idiopathic MF. In some embodiments, the MPN includes secondary MF (e.g., MF secondary to polycythemia vera or essential thrombocythemia).
  • Compounds of the disclosure or “disclosed compounds” refer to any of the active compounds disclosed herein, including compounds targeting PIM kinase (i.e., Compound (1)), any of the compounds disclosed herein targeting JAK and/or ACVR or any compounds known in the art to have any of these activities, all of which are incorporated herein by reference.
  • “Drugs” or “disclosed drugs” refer to compounds targeting JAK and/or ACVR, for example ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, or a pharmaceutically acceptable salt thereof, as well as ropeginterferon alfa-2b (an interferon) and navtemadelin (an MDM2 inhibitor) or their pharmaceutically acceptable salts, or combinations of two or more thereof.
  • “PIM kinase inhibitor,” as used herein, refers to a compound that inhibits the activity of a Proviral Insertion in Murine Lymphomas (PIM) kinase.
  • PIM kinase refers to a family of serine/threonine kinases that regulate several signaling pathways that are fundamental to cancer development and progression.
  • the PIM family includes PIM1, PIM2, and PIM3.
  • a PIM inhibitor can have activity on all PIM family members or one or more subtypes of the PIM family.
  • a PIM inhibitor can be selected for action on a specific subtype of the PIM family, for example a PIM inhibitor can act at a lower concentration on PIM1 of the PIM family than on other members of the PIM family. More specifically, a PIM inhibitor can selectively act on PIM1 compared to its action on, for example, PIM2.
  • a PIM inhibitor inhibits one or more PIM subtypes comprising PIM1.
  • a PIM1 inhibitor is selective for PIM1 (e.g., acts at a lower concentration) compared to other PIM subtypes, particularly in comparison to PIM1 inhibition, in which case it can be referred to as a “selective PIM1 inhibitor” or “selective PIM1 kinase inhibitor.”
  • a selective PIM1 inhibitor will commonly exhibit a PIM1/PIM2 IC50 ratio of less than about 0.05, 0.045, 0.04, 0.035, 0.03, or 0.025, determined as described in Foulks, Neoplasia Vol.16, No.5, 2014.
  • the selective PIM1 inhibitor will exhibit a PIM1/PIM2 IC 50 ratio of from about 0.001 to 0.05, from about 0.005 to 0.04, or from about 0.01 to 0.03.
  • a particular example of a selective PIM1 kinase inhibitor is Compound (1) having the following structure: Compound (1), or a pharmaceutically acceptable salt thereof (a/k/a TP-3654 or cmpd 1).
  • Another particular example of a selective PIM1 kinase inhibitor is Compound (2) having the following structure: Compound (2), or a pharmaceutically acceptable salt thereof (a/k/a SGI-1776 or cmpd 2). Additional examples are given by reference to publications in the body of this disclosure, which are herein incorporated by reference.
  • JAK inhibitor refers to a compound that inhibits the activity of a Janus kinase.
  • Janus kinase refers to a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway.
  • the JAK family includes JAK1, JAK2, JAK3, and TYK2.
  • a JAK inhibitor can have activity on all JAK family members or one or more subtypes of the JAK family.
  • a JAK inhibitor can be selected for action on a specific subtype of the JAK family, for example, a JAK inhibitor can act at a lower concentration on JAK2 of the JAK family than on other members of the JAK family.
  • a JAK inhibitor can selectively act on JAK2 compared to its action on, for example, JAK1.
  • a JAK inhibitor inhibits one or more JAK subtypes comprising JAK2.
  • a JAK inhibitor inhibits one or more JAK subtypes comprising JAK1 and JAK2 (e.g., ruxolitinib).
  • the JAK inhibitor may include ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, gandotinib, lestaurtinib, momelotinib, pacritinib, PF- 04965842, updacitinib, perficitinib, fedratinib, cucurbitacin I, CHZ868, decernotinib, CEP- 33779, R348, fibotinib, ABT-494 which compounds are known in the art, or combinations of two or more thereof.
  • the JAK inhibitor may include BMS-911543, ASN002, itacitinib, NS-018, AZD1480, gandotinib, or combinations of two or more thereof.
  • the JAK inhibitor may include ruxolitinib, gandotinib, lestaurtinib, momelotinib, pacritinib, fedratinib, or combinations of two or more thereof.
  • the JAK inhibitor may include ruxolitinib, fedratinib, pacritinib, or momelotinib, or a pharmaceutically acceptable salt thereof, or combinations of two or more thereof.
  • the JAK inhibitor may include ruxolitinib or a pharmaceutically acceptable salt thereof (e.g., ruxolitinib phosphate).
  • the JAK inhibitor may include fedratinib or a pharmaceutically acceptable salt thereof.
  • the JAK inhibitor may include pacritinib or a pharmaceutically acceptable salt thereof.
  • the JAK inhibitor may include momelotinib or a pharmaceutically acceptable salt thereof.
  • a “JAK1 inhibitor” as used herein refers to a compound that functions as an inhibitor to JAK1.
  • a JAK1 inhibitor is selective for JAK1 (e.g., acts at a lower concentration) compared to other JAK subtypes.
  • a “JAK2 inhibitor” as used herein refers to a compound that functions as an inhibitor to JAK2. In some embodiments, a JAK2 inhibitor is selective for JAK2 (e.g., acts at a lower concentration) compared to other JAK subtypes.
  • ACVR inhibitor refers to a compound that inhibits the activity of activin receptor.
  • Activin receptor refers to a receptor which binds activin and belongs to the Transforming growth factor beta superfamily of ligands (TGF ⁇ ), which are involved in a host of physiological processes including, growth, cell differentiation, homeostasis, osteogenesis, apoptosis and many other functions. The two types of activin receptors are activin type 1 and activin type 2.
  • Activin type 1 receptors transduce signals for a variety of TGF ⁇ ligands and activin type 2 receptors modulate signals for TGF ⁇ ligands.
  • the three types of activin type I receptors are ACVR1, ACVR1B, and ACVR1C, which each bind to a specific type II receptor-ligand complex.
  • the two types of activin type 2 receptors are ACVR2A and ACVR2B.
  • An ACVR inhibitor can have activity on all activin receptor family members or one or more subtypes of the activin receptor family.
  • An ACVR inhibitor can be selected for action on a specific subtype of the activin receptor family, for example, an ACVR inhibitor can act at a lower concentration on ACVR1 of the activin receptor family than on other members of the activin receptor family.
  • an ACVR inhibitor inhibits one or more activin receptors comprising ACVR1.
  • the ACVR inhibitor may include momelotinib, pacritinib, luspatercept, or pharmaceutically acceptable salts thereof, or combinations of two or more thereof.
  • the ACVR inhibitor may include momelotinib or a pharmaceutically acceptable salt thereof.
  • the ACVR inhibitor may include pacritinib or a pharmaceutically acceptable salt thereof.
  • the ACVR inhibitor may include luspatercept or a pharmaceutically acceptable salt thereof.
  • An “ACVR1 inhibitor” as used herein refers to a compound that functions as an inhibitor to ACVR1.
  • an ACVR1 inhibitor is selective for type 1 kinase activin A receptor (e.g., acts at a lower concentration) compared to other activin receptors.
  • a compound may be an ACVR inhibitor and a JAK inhibitor.
  • Embodiments of the present disclosure also include administration of prodrugs of the disclosed compounds. “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the disclosure. Thus, the term “prodrug” refers to a metabolic precursor of a compound of the disclosure that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a human subject in need thereof, but is converted in vivo to an active compound of the disclosure.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the disclosure, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a subject (see, Bundgard, H., Design of Prodrugs (1985), pp.79, 2124 (Elsevier, Amsterdam)).
  • a discussion of prodrugs is provided in Higuchi, T., et al., A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound of the disclosure in vivo when such prodrug is administered to a subject.
  • Prodrugs of a compound of the disclosure may be prepared by modifying functional groups present in the compound of the disclosure in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the disclosure.
  • Prodrugs include compounds of the disclosure wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the disclosure is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of the disclosure, and the like.
  • Embodiments of the disclosure are also meant to encompass administration of all pharmaceutically acceptable compounds of the disclosed compounds being isotopically- labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I.
  • radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to a pharmacologically important site of action.
  • isotopically-labeled compounds of structure (I), (II) or (III), for example, those incorporating a radioactive isotope are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of structure (I), (II) or (III) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Preparations and Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
  • Embodiments of the disclosure are also meant to encompass the in vivo metabolic products of the disclosed compounds.
  • Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes.
  • embodiments include compounds produced by a process comprising administering a compound of this disclosure to a human subject for a period of time sufficient to yield a metabolic product thereof.
  • Such products are typically identified by administering a radio-labeled compound of the disclosure in a detectable dose to an animal, such as a rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • use of a therapeutic agent described herein optionally comprises use of a pharmaceutically acceptable salt of the therapeutic agent instead of, or in addition to, the parent compound.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanes
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, and which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2 dimethylaminoethanol, 2 diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N ethylpiperidine, polyamine resins and the like.
  • basic ion exchange resins such as am
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • the compounds of the disclosure, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-, or as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (–), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC).
  • HPLC high-pressure liquid chromatography
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • a “pharmaceutical composition” refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of a biologically active compound to humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients for the compound of the disclosure.
  • Effective amount refers to that amount of a compound of the disclosure which, when administered to a human subject, is sufficient to effect treatment, as defined below, of a cancer, such as a MPN) in the subject.
  • the amount of a compound of the disclosure which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, the manner of administration, and the age of the subject to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • an “effective amount” or “therapeutically effective amount” is referenced herein, it will be understood also to encompass a “safe and effective amount” or “therapeutically safe and effective amount.” To be effective, it will be understood that the intervention achieves a clinically meaningful response. In like manner, to be safe, it will be understood that the intervention is devoid of clinically meaningful adverse events, i.e. adverse events which would justify pausing or discontinuing therapy.
  • a “clinically significant” or “clinically meaningful” response means a response which is both statistically significant, and meaningful from a patient’s, clinician’s, or caregiver’s perspective, typically based on a static measure such as CGI-S or a retrospective evaluation of improvement such as the CGI-C, as described generally in various publications of the United States Food and Drug Administration, including FDA 2018, FDA 2019, and FDA 2020.
  • a treatment or benefit is described herein, it will be understood that the treatment or benefit preferably shows clinically significant efficacy in a population of patients to a degree of statistical significance.
  • a clinically “meaningful” response is synonymous with an “improvement.”
  • a clinically meaningful response in a myeloproliferative neoplasm, or a clinically meaningful improvement in splenomegaly means SVR25.
  • a clinically meaningful response in a myeloproliferative neoplasm, or a clinically meaningful improvement in splenomegaly means SVR35.
  • a clinically meaningful response in a myeloproliferative neoplasm means TSS50.
  • a clinically meaningful response in a myeloproliferative neoplasm, or a clinically meaningful response in bone marrow fibrosis means a fibrosis grade decrease of ⁇ 1.
  • a clinically meaningful response in a myeloproliferative neoplasm means an increase in platelet counts by ⁇ 50 x 10 9 /L.
  • a clinically meaningful response in a myeloproliferative neoplasm means an increase in platelet counts by ⁇ 1 grade.
  • a clinically meaningful response in a myeloproliferative neoplasm means resolution of thrombocytopenia (commonly defined as platelet counts less than 150 x 10 9 /L).
  • a clinically meaningful response in a myeloproliferative neoplasm means an increase in Hgb of ⁇ 2 g/dL. In another embodiment, a clinically meaningful response in a myeloproliferative neoplasm means an increase in Hgb by ⁇ 1 grade. In another embodiment, a clinically meaningful response in a myeloproliferative neoplasm means resolution of anemia (commonly defined as Hgb ⁇ 10 g/dL). In another embodiment, a clinically meaningful response in a myeloproliferative disorder means conversion of transfusion dependence to transfusion independence.
  • the clinically meaningful improvement is based on probabilities of achieving TSS50 or SVR35, recognizing that not all patients will benefit equally.
  • a clinically meaningful improvement in TSS50 when Compound (1) is administered as monotherapy, a clinically meaningful improvement in TSS50 will include probabilities of achieving TSS50 ⁇ 30, 35, or 40 percent, and a clinically meaningful improvement in SVR35 will include probabilities of achieving SVR35 ⁇ 20 or 25 percent.
  • a clinically meaningful improvement in TSS50 will include probabilities of achieving TSS50 ⁇ 40 or 45 percent
  • a clinically meaningful improvement in SVR35 will include probabilities of achieving SVR35 ⁇ 20, 25 or 30 percent.
  • a clinically meaningful improvement in TSS50 will include probabilities of achieving TSS50 ⁇ 50, 55, or 60 percent, and a clinically meaningful improvement in SVR35 will include probabilities of achieving SVR35 ⁇ 40, 45, or 50 percent.
  • symptomatic burden refers to constitutional or systemic (“whole body”) symptoms (e.g., fatigue, night sweats, weight loss, pruritus, fever, bone pain, joint pain, or a combination of two or more thereof).
  • any of the foregoing clinically meaningful responses is observed for about 12 weeks or more, about 24 weeks or more, about 48 weeks or more, about 72 weeks or more, or about 96 weeks or more.
  • “Treating” or “treatment,” as used herein covers the treatment of the disease or condition of interest in a human, having the disease or condition of interest, and includes: (i) preventing the disease or condition from occurring in the subject, in particular, when such subject is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving the total symptoms resulting from the disease or condition, i.e., relieving pain without addressing the underlying disease or condition.
  • “treating” or “treatment” includes achieving complete or partial remission, cytogenetic remission or molecular remission of the MF, and achieving clinical improvement, a hematological response (e.g., platelets, red blood cell, and/or white blood cells), a spleen response, a total symptoms score response or stable disease (collectively referred to as “improvement” of MF), (sometimes referred to as IWG-MRT response criteria) as those terms are defined in Tefferi, A., et al., Blood 2013, 122:1395-1398 (see, in particular, Table 1 of Tefferi), the relevant teachings of which are incorporated herein by reference in their entireties.
  • any of the foregoing improvements is observed for about 12 weeks or more, about 24 weeks or more, about 48 weeks or more, about 72 weeks or more, or about 96 weeks or more (i.e., the improvement is observed at the foregoing timepoints following initiation of treatment, but not necessarily at all or any timepoints before the foregoing timepoints). In some embodiments, any of the foregoing improvements is observed following treatment for about 12 weeks or more, about 24 weeks or more, about 48 weeks or more, about 72 weeks or more, or about 96 weeks or more (i.e., the improvement is not observed until the foregoing timepoints following initiation of treatment) .
  • any of the foregoing improvements is observed following treatment for about 26 weeks or more, about 40 weeks or more, about 52 weeks or more, or about 80 weeks or more.
  • the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms has been identified by clinicians.
  • the term “JAK-resistant” or “JAK-inhibitor resistant” in reference to a disease or condition refers to a human subject having the disease or condition and having been treated with a JAK inhibitor and exhibited an inadequate response or no response.
  • the MPN may be ruxolitinib-resistant.
  • the term “inadequate” or “inadequate response” in reference to a drug treatment refers to a human subject having a relapsed and/or refractory response to the drug (e.g., ruxolitinib and/or fedratinib), a human subject who could not tolerate the drug (i.e., intolerant), a human subject that had a suboptimal response including an inferior spleen volume reduction, total symptom reduction, cytokine modulation, survival time, or a combination of two or more thereof.
  • the drug e.g., ruxolitinib and/or fedratinib
  • the drug e.g., ruxolitinib and/or fedratinib
  • a human subject who could not tolerate the drug i.e., intolerant
  • a human subject that had a suboptimal response including an inferior spleen volume reduction, total symptom reduction, cytokine modulation, survival time, or a combination of two
  • inadequate response may refer to a lack of: bone marrow fibrosis reduction, and/or normalization or increased platelet count, and/or normalization or increased neutrophil count, and/or normalization or increased hemoglobin count, and/or transfusion improvement (including conversion into transfusion independence).
  • inadequate response may refer to side effects that require discontinuation of treatment with the JAK inhibitor.
  • “Poor bone marrow function” refers to various states in which the bone marrow is not functioning properly, including myelosuppressed states in which the bone marrow doesn't make enough blood cells or platelets, and is commonly manifested in conditions such as thrombocytopenia (low platelet count), anemia (low hemoglobin concentrations), or transfusion dependence.
  • thrombocytopenia i.e. platelet counts are less than or equal to 150, 100, 75, or 50 x 10 9 /L, anemia (i.e. Hgb ⁇ 10, 9, or 8), or transfusion dependence, or a combination of such symptoms of poor bone marrow function.
  • transfusion independence or “transfusion independent” refers to the patient needing no blood transfusion and an Hgb ⁇ 8 for at least twelve weeks.
  • Transfusion dependence or “transfusion dependent” refers to a patient that is not transfusion independent.
  • a transfusion dependent patient may be in need of at least one blood transfusion in the previous 12 weeks.
  • a transfusion dependent patient may be in need of two or more blood transfusions in the previous 12 weeks.
  • the patient may be in need of one, two, or more blood transfusions in the previous 8 weeks.
  • transfusion improvement refers to decreased need for blood transfusion or blood part transfusion (e.g., red blood cells, white blood cells, and/or platelet transfusion).
  • the subject may become transfusion independent (i.e., no longer in need of blood or blood parts (e.g., red blood cells, white blood cells, and/or platelet transfusion), commonly based on the 12 weeks immediately preceding treatment.
  • the subject may have relapsed following treatment with a drug (e.g., ruxolitinib and/or fedratinib).
  • a drug e.g., ruxolitinib and/or fedratinib
  • “relapsed” or “relapsed response” to a drug refers to a human subject who has previously achieved ⁇ 35% decrease in spleen volume (a/k/a “SVR35”) and/or ⁇ 50% decrease in the total symptoms score (a/k/a “TSS50”) during treatment with the drug (e.g., ruxolitinib), but then a loss of either of these responses during treatment.
  • the subject may have exhibited a refractory response to a drug (e.g., ruxolitinib and/or fedratinib).
  • a drug e.g., ruxolitinib and/or fedratinib
  • “refractory” or “refractory response” to a drug refers to a human subject who never achieved ⁇ 35% decrease in spleen volume and/or ⁇ 50% decrease in the total symptoms score during treatment with the drug.
  • a subject has been “previously treated” with a JAK inhibitor. Previous treatment can last more than 3, 6, 9, or even 12 months before a decision is made to commence administration of Compound (1).
  • the physician might choose to discontinue administration of the JAK inhibitor, and administer Compound (1) either as monotherapy or in combination with another JAK inhibitor and/or ACVR inhibitor or other MPN treatment.
  • the JAK inhibitor will be ruxolitinib.
  • Compound (1) will most commonly be co-administered with momelotinib.
  • the subject may not have tolerated the drug (i.e., drug intolerance) (e.g., ruxolitinib and/or fedratinib).
  • drug intolerance refers to a subject’s inability to tolerate adverse effects of the drug at therapeutic or subtherapeutic doses.
  • Adverse effects include, but are not limited to, anemia, thrombocytopenia, transfusion dependence, neutropenia, bruising, dizziness, headache, urinary tract infection, tiredness, shortness of breath, weight gain, gas, diarrhea, constipation, herpes zoster, or combinations of two or more thereof.
  • the subject may have had an inferior spleen volume reduction following treatment with a drug (e.g., ruxolitinib and/or fedratinib).
  • a drug e.g., ruxolitinib and/or fedratinib
  • an inferior spleen volume reduction may refer to less than 35% spleen volume reduction (including less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, or no measurable reduction, based on the subject’s baseline spleen volume (i.e., spleen volume prior to starting treatment). I.e., the subject does not achieve SVR35.
  • the spleen volume reduction may be measured 24 weeks after the first treatment dose.
  • the subject may have had an inferior total symptom reduction following treatment with a drug (e.g., ruxolitinib and/or fedratinib).
  • a drug e.g., ruxolitinib and/or fedratinib
  • an inferior response to a drug or an inferior total symptom reduction may refer to less than 50% total symptom reduction (including less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, or no measurable reduction). I.e., the subject does not achieve TSS50.
  • the total symptom reduction may be measured 24 weeks (i.e., week 24) after the first treatment dose.
  • the subject may have had an inferior cytokine modulation following treatment with a drug (e.g., ruxolitinib and/or fedratinib).
  • a drug e.g., ruxolitinib and/or fedratinib.
  • an inferior cytokine modulation may refer to a down-regulation ⁇ 20%.
  • an inferior cytokine modulation may refer to a down-regulation ⁇ 15%.
  • an inferior cytokine modulation may refer to a down-regulation ⁇ 10%.
  • an inferior cytokine modulation may refer to the cytokine not returning to normal levels (i.e., cytokine level in a gender-matched, healthy cohort).
  • the subject may have had an inferior survival time following treatment with a drug (e.g., ruxolitinib and/or fedratinib).
  • an inferior survival time may refer to a survival rate of less than 1 year following the first treatment dose.
  • “normal levels” or “normalization” refers to the level of the measured component (e.g., platelet, white blood cell (e.g., neutrophil), red blood cells (e.g., hemoglobin), spleen volume, bone marrow fibrosis reduction, total symptom score, cytokine levels) in a gender-matched, healthy cohort.
  • normalization may result in transfusion improvement (including conversion into transfusion independence).
  • the term “1-grade” or “1 grade” in reference to a subject’s platelet count, hemoglobin count, neutrophil count, or bone marrow fibrosis refers to a change in the subject’s grade from one grade to the subsequent grade.
  • the change from Grade 1 to Grade 2 is a change in 1-grade
  • the change from Grade 1 to Grade 3 is a change in 2-grades.
  • a 1-grade change may be a change from Grade 1 to Grade 2, from Grade 2 to Grade 3, or from Grade 3 to Grade 4.
  • platelet count refers to a platelet count of greater than or equal to 75 x 10 9 /L
  • Gram 2 refers a subject with a platelet count less than 75 x 10 9 /L and greater than or equal to 50 x 10 9 /L
  • Grade 3 refers to a subject with a platelet count less than 50 x 10 9 /L and greater than or equal to 25 x 10 9 /L
  • Grade 4 is a subject with a platelet count less than 25 x 10 9 /L.
  • a term “up-grade” refers to change grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4.
  • the term “up- grade” indicates worsening disease conditions from the platelet count aspect.
  • the term “down-grade” refers to change grade from grade 4 to grade 3, 2, or 1, or from grade 3 to grade 2 or 1, or from grade 2 to 1.
  • the term “down-grade” indicates improving disease conditions from the platelet count aspect.
  • neutrophil count refers to a neutrophil count of greater than or equal to 1500/L
  • Gram 2 refers a subject with a neutrophil count less than 1500/L and greater than or equal to 1000/L
  • Grade 3 refers to a subject with a neutrophil count less than 1000/L and greater than or equal to 500/L
  • Grade 4 is a subject with a neutrophil count less than 500/L.
  • up-grade refers to change grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4. The term “up- grade” indicates worsening disease conditions from the neutrophil count aspect.
  • hemoglobin count refers to a hemoglobin count of greater than or equal to 10.0 g/dL
  • Gram 2 refers a subject with a hemoglobin count less than 10.0 g/dL and greater than or equal to 8.0 g/dL
  • Gram 3 refers to a subject with a hemoglobin count less than 8.0 g/dL.
  • a term “up-grade” refers to change grade 1 to grade 2 or 3, or from grade 2 to grade 3.
  • the term “up-grade” indicates worsening disease conditions from the hemoglobin count aspect.
  • the term “down-grade” refers to change grade from grade 3 to grade 2 or 1, or from grade 2 to grade 1.
  • the term “down-grade” indicates improving disease conditions from the hemoglobin count aspect.
  • bone marrow fibrosis reduction” or “BMFR” or “reduction of bone marrow fibrosis” refers to an improvement or decrease in bone marrow fibrosis of 1 grade or more.
  • bone marrow fibrosis refers to a loose network of reticulin with many intersections, especially in perivascular areas.
  • “Grade 2” refers to diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of thick fibers mostly consistent with collagen, and/or focal osteosclerosis.
  • “Grade 3” refers to diffuse and dense increase in reticulin with extensive intersections and coarse bundles of thick fibers consistent with collagen, usually associated with osteosclerosis.
  • a term “up-grade” refers to change grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4.
  • up-grade indicates worsening disease conditions from the bone marrow fibrosis aspect.
  • down-grade refers to change grade from grade 4 to grade 3, 2, or 1, or from grade 3 to grade 2 or 1, or from grade 2 to 1.
  • the term “down-grade” indicates improving disease conditions from the bone marrow fibrosis aspect.
  • spleen volume is evaluated using either CT or MRI imaging scan of the abdomen and determining the volume of the spleen during treatment.
  • a subject with ⁇ 20% decrease in spleen volume (i.e., spleen volume reduction) at the 24th week (i.e., week 24) compared to spleen volume prior to the first treatment dose is designated as having a spleen volume reduction in response to treatment of SVR20.
  • the subject may have a ⁇ 35% decrease in spleen volume at the 24th week (i.e., week 24) compared to spleen volume prior to the first treatment dose is designated as having a spleen volume reduction in response to treatment of SVR35.
  • a subject may have a spleen volume decrease of at least about 35% (including at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%) at the 24th week (i.e., week 24) compared to spleen volume prior to the first treatment dose.
  • the patient when the subject had an inadequate response to a JAK inhibitor, the patient may have a spleen volume decrease of less than 35%, less than 25%, less than 20%, or less than 15% at the 24th week (i.e., week 24) compared to spleen volume prior to the first treatment dose with the JAK inhibitor.
  • cytokine refers to a small protein(s) important in cell signaling. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.
  • cytokine modulation refers to increased cytokine levels (i.e., up- regulation) or decreased cytokine levels (i.e., down-regulation) in the subject’s serum compared to the subject’s cytokine level prior to the first treatment dose. In some embodiments, the cytokine modulation in the subject may refer to the subject’s cytokine returning to normal levels.
  • the cytokine modulation in the subject may be an up- regulation.
  • the up-regulation may refer to an increase of a cytokine by ⁇ about 20%, ⁇ about 25%, ⁇ about 35%, ⁇ about 45%, ⁇ about 50%, ⁇ about 60%, ⁇ about 75%, ⁇ about 100%, ⁇ about 150%, ⁇ about 200%, ⁇ about 250%, ⁇ about 300%, or ⁇ about 500% compared to the cytokine level prior to the first treatment dose.
  • the up-regulation may refer to an increase of a cytokine by ⁇ about 25% compared to the cytokine level prior to the first treatment dose.
  • the up-regulation may refer to an increase of a cytokine by ⁇ about 50% compared to the cytokine level prior to the first treatment dose.
  • the cytokine up-regulation may be measured 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, or 20 hours (i.e., day 0) after the first treatment dose.
  • the cytokine up-regulation may be measured 6 hours, 8 hours, 10 hours, or 12 hours (i.e., day 0) after the first treatment dose.
  • the cytokine up-regulation may be measured 24 hours (i.e., day 1) after the first treatment dose.
  • the cytokine up-regulation may be measured 4 weeks (i.e., week 4) after the first treatment dose. In some embodiments, the cytokine up-regulation may be measured 6 weeks (i.e., week 6) after the first treatment dose. In some embodiments, the cytokine up-regulation may be measured 8 weeks (i.e., week 8) after the first treatment dose. In some embodiments, the cytokine up-regulation may be measured 10 weeks (i.e., week 10) after the first treatment dose. In some embodiments, the cytokine up-regulation may be measured 12 weeks (i.e., week 12) after the first treatment dose. [00118] In some embodiments, the cytokine modulation in the subject may be a down- regulation.
  • the down-regulation may refer to a decrease of a cytokine by ⁇ about 20%, ⁇ about 25%, ⁇ about 35%, ⁇ about 45%, ⁇ about 50%, ⁇ about 60%, ⁇ about 75%, ⁇ about 100%, ⁇ about 150%, ⁇ about 200%, ⁇ about 250%, ⁇ about 300%, or ⁇ about 500% compared to the cytokine level prior to the first treatment dose.
  • the down-regulation may refer to a decrease of a cytokine by ⁇ about 25% compared to the cytokine level prior to the first treatment dose.
  • the down-regulation may refer to a decrease of a cytokine by ⁇ about 30% compared to the cytokine level prior to the first treatment dose. In some embodiments, the down-regulation may refer to a decrease of a cytokine by ⁇ about 40% compared to the cytokine level prior to the first treatment dose. In some embodiments, the down-regulation may refer to a decrease of a cytokine by ⁇ about 50% compared to the cytokine level prior to the first treatment dose. In some embodiments, the down-regulation may refer to a decrease of a cytokine by ⁇ about 60% compared to the cytokine level prior to the first treatment dose.
  • the down-regulation may refer to a decrease of a cytokine by ⁇ about 70% compared to the cytokine level prior to the first treatment dose. In some embodiments, the down-regulation may refer to a decrease of a cytokine by ⁇ about 80% compared to the cytokine level prior to the first treatment dose. In some embodiments, the down-regulation may refer to a decrease of a cytokine such that the cytokine is at a normal level (i.e., cytokine level in a gender- matched, healthy cohort).
  • the cytokine down-regulation may be measured 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, or 20 hours (i.e., day 0) after the first treatment dose. In some embodiments, the cytokine down-regulation may be measured 6 hours, 8 hours, 10 hours, or 12 hours (i.e., day 0) after the first treatment dose. In some embodiments, the cytokine down-regulation may be measured 24 hours (i.e., day 1) after the first treatment dose. In some embodiments, the cytokine down-regulation may be measured 4 weeks (i.e., week 4) after the first treatment dose.
  • the cytokine down-regulation may be measured 6 weeks (i.e., week 6) after the first treatment dose. In some embodiments, the cytokine down-regulation may be measured 8 weeks (i.e., week 8) after the first treatment dose. In some embodiments, the cytokine down-regulation may be measured 10 weeks (i.e., week 10) after the first treatment dose. In some embodiments, the cytokine down-regulation may be measured 12 weeks (i.e., week 12) after the first treatment dose. In some embodiments, the cytokine down-regulation may be measured 6 months after the first treatment dose. In some embodiments, the cytokine down-regulation may be measured 12 months after the first treatment dose.
  • the cytokine down-regulation may be measured 18 months after the first treatment dose. In some embodiments, the cytokine down-regulation may be measured 24 months after the first treatment dose. [00119] In some embodiments, the cytokine modulation in the subject may be an up- regulation of certain cytokines and a down-regulation of other cytokines as defined above.
  • the cytokine may include adiponectin, angiopoietin 1, angiotensin II, beta-2 microglobulin, bone morphogenetic protein (BMP) and subtypes thereof (e.g., BMP1, BMP6, and BMP7), bone morphogenetic protein Rcp2, brain-derived neurotrophic factor (BDNF), C-C motif chemokine ligand (CCL) and subtypes thereof (e.g., CCL14 and CCL21), cluster of differentiation 40 ligand (CD40L), cluster of differentiation 40 (CD40), colony stimulating factor (CSF1), complement factor D, C-reactive protein (CRP), C-X3-C motif chemokine receptor 1 (CX3CR1), C-X-C motif chemokine ligand (CXL) and subtypes thereof (e.g., CXL11, CXCL12, and CXCL16), Dickkopf WNT Signaling Pathway Inhibitor 1 (D
  • the cytokine may include EGFR, PDGF-BB, EPO, IP-10, TIMP-1, IL-2R-alpha, IL-1R-a, IL-12p40, IL-12p70, IL-15, MMP-3, MMP-9, VEGF, IL-2, IL-6, MIP-1 beta, TNF-a, TGF-beta, or a combination of two or more thereof.
  • the cytokine may include IL-1Ra, IL-6, IL-10, IL-12, IL-12, TGF-beta, EGFR, ferritin, GRO-a, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, VCAM-1, or a combination of two or more thereof.
  • the cytokine modulation is a down-regulation of adiponectin, angiopoietin 1, angiotensin II, beta-2 microglobulin, bone morphogenetic protein (BMP) and subtypes thereof (e.g., BMP1, BMP6, and BMP7), bone morphogenetic protein Rcp2, brain-derived neurotrophic factor (BDNF), C-C motif chemokine ligand (CCL) and subtypes thereof (e.g., CCL14 and CCL21), cluster of differentiation 40 ligand (CD40L), cluster of differentiation 40 (CD40), colony stimulating factor (CSF1), complement factor D, C-reactive protein (CRP), C-X3-C motif chemokine receptor 1 (CX3CR1), C-X-C motif chemokine ligand (CXL) and subtypes thereof (e.g., CXL11, CXCL12, and CXCL16), Dickkopf WNT Signaling Pathway
  • BMP bone morphogen
  • the down-regulated cytokine may include B2MICG, BMP1, BMP6, BMP7, BMP-Rcp2, CD40L, CRP, ferritin, FGF, GCSF, GM-CSF, HGF, IFN, IL-1, IL-10, IL-12, IL-13, 1L-15, IL-17, IL-17A, IL-1B, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL- 6, IL-7, IL-8, IFN, IFNa, IFNg, INF-g-IP, IP10, leptin, MBP R2, MBP7, MCP1, MIP1a, MIP1b, MCP2, MIG, MMP, PAL1, PDGF-BB, PTX, RANTES, TNF, TNF-1, TNF-a, TNF- RII, VCAM1, VEGF, VEGFb, VEGR, or a combination of two or more
  • the down-regulated cytokine may IL-6, IL-10, IL-12, IL-18, TGF-b, EGFR, Ferritin, GRO-a, IL-1RA, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, VCAM-1, or a combination of two or more thereof.
  • the down-regulated cytokine may include MIG, EN-RAGE, MMP-9, CD40, FRTN, ICAM-1, TIMP-1, IL-18, SCF, MPO, IP-10, IL-2R-alpha, IL-8, MIP-1 beta, IL-12p40, EPO, or a combination of two or more thereof.
  • the down-regulated cytokine may include MCP-1, MIP-1 alpha, RANTES, IL-13, or a combination of two or more thereof.
  • the down-regulated cytokine may include IL-8, MMP-9, PAI-1, IL-2, CXL11, CSF1, UPAR, CRP, FLT-3L, EPO, INF-a, LEP, or a combination of two or more thereof.
  • the down-regulated cytokine may include IL-8, MMP-9, PAI-1, IL-2, or a combination of two or more thereof.
  • the down-regulated cytokine may include CXL11, CSF1, UPAR, or a combination of two or more thereof.
  • the down-regulated cytokine may include IL-1Ra, IL-6, IL-10, IL-12, IL-12, TGF-beta, EGFR, ferritin, GRO-a, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, VCAM-1, or a combination of two or more thereof.
  • the down-regulated cytokine may include IL-6, IL-12p40, MMP9, EN-RAGE, or a combination of two or more thereof.
  • IL-6 may be down-regulated about ⁇ 60%
  • IL-12p40 may be down- regulated about ⁇ 75%
  • MMP9 may be down-regulated about ⁇ 50%
  • EN-RAGE may be down-regulated about ⁇ 60%, or a combination of two or more thereof.
  • up-titrating or “up-titration” refers to increasing the amount of a compound or drug disclosed herein administered per day. This may include increasing the amount of the compound or drug at any given administration (e.g., increase a dose of 100 mg to 200 mg) and/or administering the compound or drug more times per day (e.g., increase the number of daily doses from once a day to twice a day).
  • Up-titrating the dose amount and/or the number of daily doses of Compound (1) will result in an increase in the total daily dose of Compound (1) or the pharmaceutically acceptable salt thereof.
  • Up-titrating the dose amount and/or the number of daily doses of ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin will result in an increase in the total daily dose of the ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or the pharmaceutically acceptable salt thereof.
  • up-titration may begin from a given starting dose. In some embodiments, up- titration may occur every 4 weeks. In some embodiments, up-titration may continue until a maximum tolerated dose level is reaches or earlier if the subject exhibits MNP (e.g., MF) improvement such as bone marrow fibrosis reduction, total symptom reduction, cytokine modulation (e.g., cytokine reduction or normalization), normalization or increased platelet count, normalization or increased neutrophil count, normalization or increased hemoglobin count, transfusion improvement (including conversion into transfusion independence), spleen volume reduction, or a combination of two or more thereof.
  • MNP e.g., MF
  • cytokine modulation e.g., cytokine reduction or normalization
  • transfusion improvement including conversion into transfusion independence
  • spleen volume reduction or a combination of two or more thereof.
  • bone marrow fibrosis, total symptom score, cytokine levels, platelet count, neutrophil count, hemoglobin count, and/or spleen volume may be measured every 2 to 4 weeks during treatment.
  • down-titrating or “down-titration” refers to decreasing the amount of a compound or drug disclosed herein administered per day. This may include decreasing the amount of the compound or drug at any given administration and/or administering the compound or drug less times per day.
  • the amount of the compound or drug may be reduced by half (e.g., decrease a dose of 200 mg to 100 mg) and/or the number of daily administrations may be reduced by half (e.g., decrease the number of daily doses from twice a day to once a day). Down-titrating the dose amount and/or the number of daily doses of Compound (1) will result is a decrease in the total daily dose of Compound (1) or the pharmaceutically acceptable salt.
  • a subject being treated with a stable dose of a JAK inhibitor and Compound (1) may have the administration of Compound (1) interrupted if new adverse event occurs.
  • administration of Compound (1) may be restarted after the adverse event has resolved.
  • the total daily dose of Compound (1) may be reduced.
  • administration of Compound (1) may be discontinued.
  • the total daily dose of Compound (1) may be reduced or remain the same depending on the severity of the adverse event.
  • the adverse event is a platelet count reduction
  • resolution of the adverse event may be achieved when the subject’s platelet count has increased to the platelet count when treated with only the JAK inhibitor (i.e., subject’s baseline JAK inhibitor platelet count).
  • the adverse event is a platelet count reduction
  • resolution of the adverse event may be achieved when the subject’s platelet count has increased 1 grade (e.g., from grade 4 to grade 3).
  • the adverse event is a platelet count reduction
  • resolution of the adverse event may be achieved when the subject’s platelet count has increased at least 25 x 10 9 /L. In some embodiments, if the adverse event is a platelet count reduction, resolution of the adverse event may be achieved when the subject’s platelet count has increased at least 35%.
  • the terms “not substantial,” “not substantially,” and “insubstantial” can be used herein to characterize the lack of adverse effects from the disclosed treatments. As used herein, “not substantial,” “not substantially,” or “unsubstantial” refers to about 45% or less. In some embodiments, not substantial refers to about 40% or less. In some embodiments, not substantial refers to about 35% or less.
  • not substantial refers to about 30% or less, about 25% or less, about 20% or less, about 15% or less, or about 10% or less.
  • a decrease of a subject’s platelet count by no more than 35% is not a substantial decrease (including ⁇ about 34%, ⁇ about 33%, ⁇ about 32%, ⁇ about 31%, ⁇ about 30%, ⁇ about 25%, ⁇ about 20%, ⁇ about 15%, ⁇ about 10%, or ⁇ about 5%).
  • an unsubstantial decrease of a subject’s platelet count is by less than 1 grade (i.e., a platelet count decrease such that the subject remains in the same grade).
  • substantially refers to about 25% or more. In some embodiments, substantial refers to about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, or about 55% or more.
  • stable refers to little or no change such as a change of no more than about ⁇ 10%. In some embodiments, stable refers to about ⁇ 8%. In some embodiments, stable refers to about ⁇ 5%, about ⁇ 2%, or about ⁇ 1%. For example, in some embodiments, a subject’s platelet count does not substantially decrease when it remains stable (i.e., ⁇ 10%).
  • a subject s platelet count, hemoglobin, neutrophil count, or bone marrow fibrosis is stable when the subject remains in the same grade (e.g., platelet count decreases, but subject remains in Grade-2).
  • the monotherapy of the Compound (1) or the combination therapy that includes Compound (1) is continued at the dosage on which stability was achieved.
  • total symptom reduction refers to a reduction of total symptom score of greater than or equal to about 50% (a/k/a TSS50) (including ⁇ about 55%, ⁇ about 60%, ⁇ about 65%, ⁇ about 70%, ⁇ about 75%, ⁇ about 80%, ⁇ about 85%, ⁇ about 90%, ⁇ about 95%, ⁇ about 99%, or about 100%) from the subject’s total symptom score immediately before treatment is begun.
  • MPN-SAF MPN Symptoms Assessment Form
  • MFSAF or MF-SAF Myelofibrosis Symptom Assessment Form
  • MPN-SAF TSS Abbreviated version of the MPN- SAF
  • the total symptom reduction may be measured about 4 weeks after the first treatment dose and TSS50 observed at this time point. In some embodiments, the total symptom reduction may be measured about 12 weeks after the first treatment dose, and TSS50 observed at this time point. In some embodiments, the total symptom reduction may be measured about 24 weeks after the first treatment dose, and TSS50 observed at this time point.
  • the total symptom reduction may be measured about 36 weeks after the first treatment dose, and TSS50 observed at this time point.
  • Compound (1) has no overlapping hematological toxicities with ruxolitinib or momelotinib in terms of thrombocytopenia, neutropenia, or anemia when the drugs are combined at the dose levels reported in Table V.
  • “increased neutrophil count” or “increased neutrophil” refers to an increase in neutrophils or an increase in white blood cells.
  • “increased hemoglobin count” or “increased hemoglobin” refers to an increase in hemoglobin or an increase in red blood cells.
  • “about” refers to ⁇ 10% of the given value. In some embodiments, about may be ⁇ 5% of the given value.
  • the disclosure provides a method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject has poor bone marrow functioning characterized by: thrombocytopenia (e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L); anemia (e.g.
  • thrombocytopenia e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L
  • anemia e.g.
  • the disclosure provides a method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor, wherein the subject has poor bone marrow functioning characterized by: thrombocytopenia (e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L); anemia (e.g.
  • the disclosure provides a method of treating a myeloproliferative neoplasm in a human subject in need thereof, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and optionally has relapsed disease or is refractory to the JAK inhibitor, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • the disclosure provides a method of treating a myeloproliferative neoplasm by inducing TSS50 in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the myeloproliferative neoplasm is treated by inducing TSS50 in the subject, optionally at a time point between and including 24 and 48 weeks.
  • the disclosure provides a method of treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject Compound (1) or a pharmaceutically acceptable salt thereof, and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject Compound (1) or a pharmaceutically acceptable salt thereof, and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces
  • the disclosure provides a method of treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a selective PIM1 inhibitor and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • a selective PIM1 inhibitor and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • the disclosure provides a method of inducing a probability of SVR35 in a human subject affected by a myeloproliferative neoplasm ⁇ 15% or 20%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and optionally has relapsed disease or is refractory to the JAK inhibitor, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the treatment induces a probability of SVR35 in the human subject ⁇ 15% or 20%.
  • the foregoing probabilities are absolute probabilities, without reference to any comparator. The foregoing probabilities further assume the subject remains on treatment.
  • the disclosure provides a method of inducing a probability of TSS50 in a human subject affected by a myeloproliferative neoplasm ⁇ 30%, 35%, 40%, 45%, or 50%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and optionally has relapsed disease or is refractory to the JAK inhibitor, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the treatment induces a probability of TSS50 in the human subject ⁇ 30%, 35%, 40%, 45%, or 50%.
  • the foregoing probabilities are absolute probabilities, without reference to any comparator.
  • the present technology provides a method for treating a myeloproliferative neoplasm in a human subject in need thereof, wherein the method includes administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • the subject has a platelet count of less than about 200 ⁇ 10 9 /L (e.g., less than about 150, 100, 75, 50, or 25 ⁇ 10 9 /L; less than 150, 100, 75, 50, or 25 ⁇ 10 9 /L; less than 50 or 25 ⁇ 10 9 /L; or less than 25 ⁇ 10 9 /L).
  • the present technology provides a method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject has had one or more previous treatments comprising Compound (1) or the pharmaceutically acceptable salt.
  • the subject exhibits (a) a platelet count reduction of less than 1 grade compared to a baseline platelet grade, (b) a platelet count reduction of less than or equal to 25 x 10 9 /L compared to a baseline platelet count, and/or (c) a platelet count reduction of less than or equal to 35% compared to a baseline platelet count.
  • the platelet count reduction is determined by a change comparing the baseline platelet count and a second platelet count.
  • the baseline platelet count is the platelet count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt.
  • the second platelet count is determined at least 2 weeks after administering Compound (1) or the pharmaceutically acceptable salt.
  • the present technology provides a method for treating a myeloproliferative neoplasm in a human subject in need thereof, wherein the method includes a combination therapy comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and a JAK inhibitor or a pharmaceutically acceptable salt thereof and/or an ACVR inhibitor or a pharmaceutically acceptable salt thereof.
  • the JAK inhibitor and ACVR inhibitor may be the same compound.
  • the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 15 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 20 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 200 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 150 ⁇ 10 9 /L.
  • the subject has a platelet count of less than about 100 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 50 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L and less than or equal to about 200 ⁇ 10 9 /L.
  • the present technology provides a method for treating a myeloproliferative neoplasm in a human subject in need thereof, wherein the method includes a combination therapy comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, navtemadelin, or a pharmaceutically acceptable salt thereof.
  • the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L.
  • the subject has a platelet count of greater than or equal to about 15 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 20 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 200 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 150 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 100 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 50 ⁇ 10 9 /L.
  • the subject has a platelet count of less than 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L and less than or equal to about 200 ⁇ 10 9 /L.
  • the present technology provides a method for treating myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, navtemadelin, or a pharmaceutically acceptable salt thereof, wherein the subject has a baseline platelet count less than or equal to 200 ⁇ 10 9 /L and/or greater than or equal to 10 ⁇ 10 9 /L.
  • the ruxolitinib or the pharmaceutically acceptable salt is in a dose of about 5 mg to about 25 mg; fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg; pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg; momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg; luspatercept or the pharmaceutically acceptable dose is in a dose of about 0.5 mg/kg to 1.75 mg/kg based on the subject’s body weight; ropeginterferon alfa-2b or the pharmaceutically acceptable salt is in a dose of about 50 to 500 ⁇ g (e.g., about 50 to 150 ⁇ g, about 100 to 300 ⁇ g, about 200 to 400 ⁇ g, or about 300 to 500 ⁇ g; and navtemadelin or the pharmaceutically acceptable salt is in a dose of about 100 to 300 mg (e.g., about 100 to 150 mg, about 150 to 300 mg, or
  • the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 15 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 20 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 200 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 150 ⁇ 10 9 /L.
  • the subject has a platelet count of less than about 100 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 50 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L and less than or equal to about 200 ⁇ 10 9 /L.
  • the present technology provides a method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject ruxolitinib fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, navtemadelin, or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 15 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 20 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 200 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 150 ⁇ 10 9 /L.
  • the subject has a platelet count of less than about 100 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 50 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L and less than or equal to about 200 ⁇ 10 9 /L.
  • the present technology provides a method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, therapy, comprising: administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and continuing to administer to the subject the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, during which the subject either (a) does not receive the therapy (e.g., JAK therapy such as ruxolitinib), or (b) receives a reduced amount of the therapy (e.g., JAK therapy such as ruxolitinib).
  • the therapy e.g., JAK therapy such as ruxolitinib
  • a reduced amount of the therapy e.g., JAK therapy such as r
  • the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 15 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 20 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 200 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 150 ⁇ 10 9 /L.
  • the subject has a platelet count of less than about 100 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 50 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L and less than or equal to about 200 ⁇ 10 9 /L.
  • the present technology provides a method for treating a myeloproliferative neoplasm in a human subject in need thereof, the method includes administering to the subject Compound (1) or a pharmaceutically acceptable salt thereof; and an ACVR inhibitor (e.g., ACVR1 inhibitor), wherein the subject has a platelet count of less than 200 ⁇ 10 9 /L and/or greater than or equal to 10 ⁇ 10 9 /L.
  • the ACVR1 inhibitor may be in a dose of about 50 mg to about 250 mg.
  • the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L.
  • the subject has a platelet count of greater than or equal to about 15 ⁇ 10 9 /L.
  • the subject has a platelet count of greater than or equal to about 20 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 200 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 150 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 100 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 50 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than 25 ⁇ 10 9 /L.
  • the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L and less than or equal to about 200 ⁇ 10 9 /L.
  • the present technology provides a method for treating myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and a JAK inhibitor, wherein the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L and/or a platelet count of less than about 200 ⁇ 10 9 /L.
  • the JAK inhibitor may be in a dose of about 5 mg to about 25 mg, about 200 mg to about 500 mg, or about 100 mg to about 200 mg.
  • the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 15 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 20 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 200 ⁇ 10 9 /L.
  • the subject has a platelet count of less than about 150 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 100 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 50 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L and less than or equal to about 200 ⁇ 10 9 /L.
  • the present technology provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient; Compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or a pharmaceutically acceptable salt thereof.
  • the present technology provides a kit comprising Compound (1) or a pharmaceutically acceptable salt thereof; ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or a pharmaceutically acceptable salt thereof; and written instructions for administering Compound (1) or a pharmaceutically acceptable salt thereof, in combination with the ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or a pharmaceutically acceptable salt thereof, to treat a myeloproliferative neoplasm (e.g., MF).
  • a myeloproliferative neoplasm e.g., MF
  • any of the methods disclosed herein may result in the subject exhibiting bone marrow fibrosis reduction and/or total symptom score reduction and/or cytokine modulation (e.g., cytokine reduction or normalization), and/or normalization or increased platelet count, and/or normalization or increased neutrophil count, and/or normalization or increased hemoglobin count, and/or transfusion improvement (including conversion into transfusion independence) and/or spleen volume reduction.
  • any of the methods disclosed herein may result in the subject exhibiting increased survival ( ⁇ 1 year) and/or decreased rate of leukemia transformation and/or transplant eligibility.
  • any of the methods disclosed herein may result in the subject exhibiting (a) a platelet count reduction of less than 1 grade compared to a baseline platelet grade, (b) a platelet count reduction of less than or equal to 25 x 10 9 /L compared to a baseline platelet count, and/or (c) a platelet count reduction of less than or equal to 35% compared to a baseline platelet count.
  • the platelet count reduction is determined by a change comparing the baseline platelet count and a second platelet count.
  • the baseline platelet count is the platelet count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt.
  • the second platelet count is determined at least 2 weeks after administering Compound (1) or the pharmaceutically acceptable salt.
  • any of the methods disclosed herein may result in the subject exhibiting (a) a neutrophil count reduction of less than 1 grade compared to a baseline neutrophil grade, (b) a neutrophil count reduction of less than or equal to 500/L compared to a baseline neutrophil count, and/or (c) a neutrophil count reduction of less than or equal to 35% compared to a baseline neutrophil count.
  • the neutrophil count reduction is determined by a change comparing the baseline neutrophil count and a second neutrophil count.
  • the baseline neutrophil count is the neutrophil count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt.
  • the second neutrophil count is determined at least 2 weeks after administering Compound (1) or the pharmaceutically acceptable salt.
  • any of the methods disclosed herein may result in the subject exhibiting (a) a hemoglobin count reduction of less than 1 grade compared to a baseline hemoglobin grade, (b) a hemoglobin count reduction of less than or equal to 5.0 g/dL compared to a baseline hemoglobin count, and/or (c) a hemoglobin count reduction of less than or equal to 35% compared to a baseline hemoglobin count.
  • the hemoglobin count reduction is determined by a change comparing the baseline hemoglobin count and a second hemoglobin count.
  • the baseline hemoglobin count is the hemoglobin count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt.
  • the second hemoglobin count is determined at least 2 weeks after administering Compound (1) or the pharmaceutically acceptable salt.
  • a method for treating myeloproliferative neoplasms in a human subject in need thereof comprising administering to the subject an effective amount of a PIM kinase inhibitor.
  • Another embodiment provides a method for decreasing proliferation of hematopoietic cells in a subject, the method comprising contacting the cells with a PIM kinase inhibitor (e.g., an effective amount of a PIM kinase inhibitor).
  • Another embodiment provides a method for treating a subject having or at risk of developing an MPN such as MF, the method comprising administering to the subject a composition comprising a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • the methods described herein involve identifying a subject being at risk of developing an MPN such as MF.
  • the methods described herein further include administering Compound 1, or a pharmaceutically acceptable salt thereof (e.g., an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof), to a subject identified as being at risk of developing an MPN such as MF.
  • the methods further include administering Compound 1, or a pharmaceutically acceptable salt thereof (e.g., an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof), to a subject suspected to have an MPN such as MF.
  • an MPN such as MF
  • provided are methods for prophylactically treating a an MPN such as MF comprising administering Compound 1, or a pharmaceutically acceptable salt thereof (e.g., an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof), to a human subject in need thereof.
  • methods for preventing and MPN such as MF comprising administering Compound 1, or a pharmaceutically acceptable salt thereof (e.g., an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof), to a human subject in need thereof.
  • provided are methods for inhibiting formation or deposition of MF tissue the method including contacting MF tissue with Compound 1, or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit formation or deposition of MF tissue.
  • provided herein is a method for treating a subject having or at risk of developing an MPN such as MF, the method comprising administering to the subject in need thereof a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.
  • a method for treating a myeloproliferative neoplasm in a human subject in need thereof the method comprising administering an effective amount of a PIM kinase inhibitor.
  • the PIM kinase inhibitor is a PIM1 kinase inhibitor.
  • a method for treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject, a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L.
  • the baseline platelet count is less than or equal to about 150 ⁇ 10 9 /L. In some embodiments, the baseline platelet count is less than or equal to about 100 ⁇ 10 9 /L. In some embodiments, the baseline platelet count is less than or equal to about 50 ⁇ 10 9 /L.
  • the baseline platelet count is less than or equal to about 25 ⁇ 10 9 /L. In some embodiments, the baseline platelet count is greater than or equal to about 5, 10, 15, 20, 25, or 35 ⁇ 10 9 /L. [00168] In some embodiments, the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 15 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 20 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 25 ⁇ 10 9 /L.
  • the subject has a platelet count of less than about 200 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 150 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 100 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than about 50 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of less than 25 ⁇ 10 9 /L. In some embodiments, the subject has a platelet count of greater than or equal to about 10 ⁇ 10 9 /L and less than or equal to about 200 ⁇ 10 9 /L.
  • the method comprises continuing administering to the subject a therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, wherein the subject has a platelet count reduction of (a) less than 1 grade, or (b) less than or equal to 25 x 10 9 /L, and/or (c) less than or equal to 35%, and the platelet count reduction is determined by a change in the baseline platelet count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt and a second platelet count determined at least 2 weeks after administering.
  • the subject has a platelet count reduction of (a) less than 1 grade.
  • the subject has a platelet count reduction of (b) less than or equal to 25 x 10 9 /L. In some embodiments, the subject has a platelet count reduction of (c) less than or equal to 35%.
  • the method comprises continuing administering to the subject a therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, wherein the subject has a neutrophil count reduction of (a) less than 1 grade compared to a baseline neutrophil grade, (b) less than or equal to 500/L compared to a baseline neutrophil count, and/or (c) less than or equal to 35% compared to a baseline neutrophil count, and the neutrophil count reduction is determined by a change in the baseline neutrophil count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt and a second neutrophil count determined at least 2 weeks after administering.
  • the subject has a neutrophil count reduction of (a) less than 1 grade. In some embodiments, the subject has a neutrophil count reduction of (b) less than or equal to 500/L. In some embodiments, the subject has a neutrophil count reduction of (c) less than or equal to 35%.
  • the method comprises continuing administering to the subject a therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, wherein the subject has a hemoglobin count reduction of (a) less than 1 grade compared to a baseline hemoglobin grade, (b) less than or equal to 5.0 g/dL compared to a baseline hemoglobin count, and/or (c) less than or equal to 35% compared to a baseline hemoglobin count, and the hemoglobin count reduction is determined by a change in the baseline hemoglobin count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt and a second hemoglobin count determined at least 2 weeks after administering.
  • the subject has a hemoglobin count reduction of (a) less than 1 grade. In some embodiments, the subject has a hemoglobin count reduction of (b) less than or equal to 5.0 g/dL. In some embodiments, the subject has a hemoglobin count reduction of (c) less than or equal to 35%. [00172] In some embodiments, the method results in the subject exhibiting bone marrow fibrosis reduction, total symptom reduction, cytokine modulation, or a combination of two or more thereof. In some embodiments, the method results in the subject exhibiting bone marrow fibrosis reduction. In some embodiments, the method results in the subject exhibiting total symptom reduction.
  • the method results in the subject exhibiting cytokine modulation.
  • the method results in the subject exhibiting normalization or increased platelet count, normalization or increased neutrophil count, normalization or increased hemoglobin count, transfusion improvement (including conversion into transfusion independence), or a combination of two or more thereof.
  • the method results in the subject exhibiting normalization or increased platelet count.
  • the method results in the subject exhibiting normalization or increased neutrophil count.
  • the method results in the subject exhibiting normalization or increased hemoglobin count.
  • the method results in the subject exhibiting transfusion improvement (including conversion into transfusion independence).
  • a method for treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein: the subject has had one or more previous treatments comprising Compound (1) or the pharmaceutically acceptable salt and has a platelet count reduction of (a) less than 1 grade, (b) less than or equal to 25 x 10 9 /L, and/or (c) less than or equal to 35%, the platelet count reduction is determined by a change in the baseline platelet count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt and a second platelet count determined at least 2 weeks after administering, and the method results in the subject exhibiting bone marrow fibrosis reduction, total symptom reduction, cytokine modulation, or a combination of two or more thereof.
  • the method results in the subject exhibiting bone marrow fibrosis reduction. In some embodiments, the method results in the subject exhibiting total symptom reduction. In some embodiments, the method results in the subject exhibiting cytokine modulation. In some embodiments, the method results in the subject exhibiting bone marrow fibrosis reduction, total symptom reduction, and cytokine modulation. [00175] In some embodiments, the subject has not been treated with a JAK inhibitor for at least 2 weeks prior to administering Compound (1) or the pharmaceutically acceptable salt.
  • the total symptom reduction is a symptom selected from the group consisting of fever, night sweats, early satiety, weight loss, fatigue, weakness, shortness of breath, enlarged spleen or liver, left upper abdominal pain, bone or joint pain, easy bruising, easy bleeding, and combinations of two or more thereof.
  • the total symptom reduction refers to minimizing, lessening, or ameliorating fever, night sweats, early satiety, weight loss, fatigue, weakness, shortness of breath, enlarged spleen or liver, left upper abdominal pain, bone or joint pain, easy bruising, easy bleeding, or a combination of two or more thereof.
  • the method results in the subject exhibiting spleen volume reduction. [00179] In some embodiments, the method results in bone marrow fibrosis reduction. [00180] In some embodiments, the method results in improving overall survival. [00181] In some embodiments, the method results in the subject exhibiting normalization or increased platelet count, normalization or increased neutrophil count, normalization or increased hemoglobin count, transfusion improvement (including conversion into transfusion independence), or a combination of two or more thereof. [00182] In some embodiments, the methods of the current disclosure result in a durable response based on one or more measures of efficacy described herein.
  • a durable response can be defined based on satisfaction of the efficacy measure at various timepoints, including 12 weeks, 24 weeks, 48 weeks, 72 weeks, or 96 weeks.
  • the therapeutic effective amounts of the drugs does not induce any overlapping hematological toxicities. I.e., Compound (1) does not exacerbate the anemia, thrombocytopenia, or transfusion dependence induced by the ruxolitinib or momelotinib.
  • Other embodiments are based on the probability of achieving certain therapeutic endpoints.
  • the method induces a probability of SVR35 in the subject ⁇ 15% or 20%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and optionally has relapsed disease or is refractory to the JAK inhibitor.
  • the method induces a probability of TSS50 in the subject ⁇ 30%, 35%, 40%, 45%, or 50%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and optionally has relapsed disease or is refractory to the JAK inhibitor.
  • the subject has had an inadequate response to JAK inhibitor therapy.
  • the subject is intolerant of a JAK inhibitor therapy, is resistant to a JAK inhibitor therapy, or is ineligible for a JAK inhibitor therapy.
  • the subject experiences relapse from a prior JAK inhibitor therapy.
  • the subject experiences relapse from a prior bone marrow transplant.
  • the method further comprises administering to the subject an effective amount of a JAK inhibitor and/or an ACVR inhibitor or a pharmaceutically acceptable salt thereof (i.e., the PIM kinase inhibitor is administered concurrently with or sequentially to the JAK inhibitor and/or an ACVR inhibitor or a pharmaceutically acceptable salt thereof).
  • the JAK inhibitor is a JAK2 inhibitor. In some embodiments, the JAK inhibitor is a JAK1 inhibitor.
  • the myeloproliferative neoplasm is polycythemia vera. In some other specific embodiments, the myeloproliferative neoplasm is essential thrombocythemia. In still other embodiments, the myeloproliferative neoplasm is MF.
  • the structure of the PIM kinase inhibitor, the JAK inhibitor, and/or an ACVR inhibitor are not particularly limited provided the inhibitor has satisfactory activity against the desired target (i.e., PIM and JAK, respectively).
  • Exemplary PIM kinase inhibitors which are included within the scope of embodiments of the present disclosure include the generic and specific compounds disclosed in PCT Pub. No. WO 2016/161248; WO 2015/019320; WO 2014/033530WO 2014/033631; WO 2014/0200216; WO 2013/175388; WO 2013/013188; WO 2013/020371; WO 2012/154274; WO 2012/129338; WO 2012/080990; WO 2012/120415; WO 2012/004217; WO 2011/057784; WO 2011/079274; WO 2010/0148351; WO 2010/135581; WO 2010/026121; WO 2010/026122; WO 2010/026124; WO 2010/022076; WO 2010/0000978; WO 2010/022081; WO 2009/064486; WO 2009/109576; WO 2008/082839; WO 2008/106692; WO 2008/058126;
  • the PIM kinase inhibitor is PIM447 or INCB053914.
  • Other PIM kinase inhibitors are known in the art, and such inhibitors are also included in certain embodiments of the disclosure.
  • the structure of the JAK inhibitor and/or an ACVR inhibitor for use in the present methods is also not particularly limited provided it has sufficient activity against JAK when used in combination with the PIM inhibitor.
  • the JAK inhibitor has sufficient activity against JAK2, when used in combination with the PIM inhibitor. In some embodiments, the JAK inhibitor has sufficient activity against JAK1, when used in combination with the PIM inhibitor.
  • Exemplary JAK inhibitors all of which are included within the scope of certain embodiments of the disclosure, are described in PCT Pub.
  • Additional therapeutic agents may be used in combination with a PIM kinase inhibitor (i.e., Compound (1) or a pharmaceutically acceptable salt thereof) for treatment of a myeloproliferative neoplasm according to embodiments of the disclosure.
  • a PIM kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • Combinations of additional therapeutic agents can be administered simultaneously (e.g., in the same or different formulation) or sequentially with the PIM kinase inhibitor.
  • a PIM kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • a PIM kinase inhibitor can be administered before a JAK inhibitor or before an ACVR inhibitor.
  • PIM kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • the JAK or ACVR inhibitor can be optionally administered in combination with the PIM kinase inhibitor and the additional therapeutic agent(s). That is, in some embodiments, the method comprises administering the PIM kinase inhibitor and an additional therapeutic agent.
  • additional therapeutic agents include hydroxyurea, interferon alpha, cladribine, thalidomide (including derivatives thereof, e.g., pomalidomide, lenolidamide), corticosteroids (e.g., prednisone), everolimus, androgens (e.g., testosterone) and combinations thereof.
  • the additional therapeutic agents may be used for supportive care, such as corticosteroids, non-steroidal anti-inflammatory drugs, and/or analgesics to control symptoms.
  • the methods described herein can be performed in conjunction with other medical procedures.
  • the method further comprises performing a transfusion, administering radiation therapy, performing a splenectomy, or performing a stem cell transplant.
  • the method further comprises administering an angiotensin mimetic (e.g., TXA127).
  • angiotensin mimetic e.g., TXA127.
  • MPN myeloproliferative neoplasms
  • the MPN is polycythemia vera.
  • the MPN is essential thrombocythemia.
  • the MPN is MF.
  • Some embodiments provide a method for decreasing proliferation of hematopoietic cells in a subject, the method comprising contacting the cells with a PIM kinase inhibitor. In some more specific embodiments, the method further comprises administering to the subject an effective amount of an ACVR inhibitor. In some more specific embodiments, the method further comprises administering to the subject an effective amount of an ACVR1 inhibitor. In some more specific embodiments, the method further comprises administering to the subject an effective amount of a JAK inhibitor. In some embodiments, the JAK inhibitor is a JAK2, or JAK1, or JAK1/2 inhibitor. [00197] In some embodiments, the disclosure is directed at a method of restoring hematological balance.
  • the disclosure is directed to a method for decreasing proliferation of cells expressing JAK2 V617F in a human cell, the method comprising contacting the cell with a PIM kinase inhibitor as disclosed herein and optionally a JAK inhibitor as disclosed herein.
  • the invention is directed to a method for decreasing proliferation of cells expressing MPL W515L in a human cell, the method comprising contacting the cell with a PIM kinase inhibitor as disclosed herein and optionally a JAK inhibitor as disclosed herein.
  • the technology is directed to a method for decreasing proliferation of cells expressing a calreticulin (CALR) mutation in a human cell, the method comprising contacting the cell with a PIM kinase inhibitor as disclosed herein and optionally a JAK inhibitor or an ACVR as disclosed herein.
  • the disclosure is directed to a method for decreasing proliferation or overproduction of red blood cells, white blood cells, or platelets in a human cell, the method comprising contacting the cell with a PIM kinase inhibitor as disclosed herein and optionally a JAK inhibitor or an ACVR as disclosed herein.
  • the human cell is a bone marrow cell.
  • the myeloproliferative neoplasm of the subject treated for a myeloproliferative neoplasm according to the embodiments described herein comprises a JAK2 mutation, a thrombopoietin receptor (MPL) mutation, or a calreticulin (CALR) mutation.
  • the MPN comprises a JAK2 and an MPL mutation.
  • the MPN comprises a JAK2 and a CALR mutation.
  • the MPN comprises a MPL and a CALR mutation.
  • the MPN comprises a JAK2, MPL, and CALR mutation.
  • a JAK2 mutation comprises a JAK2 V617 mutation.
  • JAK2 V617F refers to a mutated JAK2 possessing a V ⁇ F amino acid substitution at position 617 with respect to the human, wildtype JAK2 (UniProt.060674).
  • a MPL mutation comprises a MPL W515L mutation.
  • MPL W515L refers to a mutated thrombopoietin receptor (MPL) possessing a W ⁇ L substitution at position 515 with respect to the human, wildtype MPL (UniProt. P40238).
  • the mutation in CALR comprises a CALR exon 9 indel.
  • a method for treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L.
  • Ruxolitinib or the pharmaceutically acceptable salt is commonly administered in a dose of about 5 mg to about 25 mg.
  • the fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg; pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg; momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg; luspatercept is in a dose of about 0.5 mg/kg to 1.75 mg/kg based on the subject’s body weight, ropeginterferon alfa-2b or the pharmaceutically acceptable salt is in a dose of 50 to 500 ⁇ g, and navtemadelin or the pharmaceutically acceptable salt is in a dose of 120 to 240 mg.
  • a method for treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or the pharmaceutically acceptable salt; wherein: the subject has a baseline platelet count of greater than or equal to 25 ⁇ 10 9 /L.
  • the ruxolitinib or the pharmaceutically acceptable salt is commonly administered in a dose of about 5 mg to about 25 mg.
  • the fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg; pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg; momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg; luspatercept is in a dose of about 0.6 mg/kg or 1.75 mg/kg based on the subject’s body weight; ropeginterferon alfa-2b or the pharmaceutically acceptable salt is in a dose of 50 to 500 ⁇ g; and navtemadelin or the pharmaceutically acceptable salt is in a dose of 120 to 240 mg.
  • the baseline platelet count in the combination treatment is less than or equal to about 150 ⁇ 10 9 /L. In some embodiments, the baseline platelet count in the combination treatment is less than or equal to about 100 ⁇ 10 9 /L. In some embodiments, the baseline platelet count in the combination treatment is less than or equal to about 75 ⁇ 10 9 /L. In some embodiments, the baseline platelet count in the combination treatment is less than or equal to about 50 ⁇ 10 9 /L. In some embodiments, the baseline platelet count in the combination treatment is greater than or equal to about 10 ⁇ 10 9 /L. In some embodiments, the baseline platelet count in the combination treatment is greater than or equal to about 25 ⁇ 10 9 /L.
  • the baseline platelet count in the combination treatment is greater than or equal to about 35 ⁇ 10 9 /L.
  • a method for treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib or a pharmaceutically acceptable salt thereof.
  • the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L; and ruxolitinib or the pharmaceutically acceptable salt is in a dose of about 5 mg to 25 mg.
  • a method for treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and fedratinib or a pharmaceutically acceptable salt thereof.
  • the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L and/or a baseline platelet count of greater than or equal to 25 ⁇ 10 9 /L; and fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg.
  • a method for treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and pacritinib or a pharmaceutically acceptable salt thereof.
  • the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L and/or a baseline platelet count of greater than or equal to 25 ⁇ 10 9 /L; and pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg.
  • method for treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and momelotinib or a pharmaceutically acceptable salt thereof.
  • the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L and/or a baseline platelet count of greater than or equal to 25 ⁇ 10 9 /L; and momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg.
  • a method for treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and luspatercept.
  • the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L and/or a baseline platelet count of greater than or equal to 25 ⁇ 10 9 /L; and luspatercept is in a dose of about 0.5 mg/kg or 1.75 mg/kg based on the subject’s body weight.
  • the baseline platelet count is measured within one week prior to initiation of the administering Compound (1) or the pharmaceutically acceptable salt.
  • the subject has not been treated with any JAK inhibitor therapy for at least 2 weeks prior to administering Compound (1) or the pharmaceutically acceptable salt.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events comprising: administering to the subject a dose from about 5 mg to about 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33 % to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • the adverse event in the combination treatment of Compound (1) or the pharmaceutically acceptable salt and ruxolitinib is thrombocytopenia, anemia, bruising, dizziness, headache, diarrhea, or a combination of two or more thereof.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a ruxolitinib therapy comprising about 5 mg to about 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof
  • the method comprises: administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; continuing to administer to the subject the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, during which the subject either (a) does not receive the therapy (e.g., JAK therapy such as ruxolitinib), or (b) receives a reduced amount of the therapy (e.g., JAK therapy such as ruxolitinib).
  • the therapy e.g., JAK therapy such as ruxolitinib
  • a reduced amount of the therapy e.g., JAK therapy such as ruxolitinib
  • the reduced amount of the therapy comprises less than about 80% amount of the therapy or the pharmaceutically acceptable salt. In some embodiments, the reduced amount of the therapy comprises less than about 75% amount of the therapy or the pharmaceutically acceptable salt. In some embodiments, the reduced amount of the therapy comprises less than about 50% amount of the therapy or the pharmaceutically acceptable salt. In some embodiments, the reduced amount of the therapy comprises less than about 25% amount of the therapy or the pharmaceutically acceptable salt. In some embodiments, the reduced amount of the therapy comprises less than about 20% amount of the therapy or the pharmaceutically acceptable salt. In some embodiments, the reduced amount of the therapy comprises about 10% to about 80% amount of the therapy or the pharmaceutically acceptable salt.
  • the reduced amount of the therapy comprises about 30% to about 70% amount of the therapy or the pharmaceutically acceptable salt. In some embodiments, the reduced amount of the therapy comprises about 40% to about 60% amount of the therapy or the pharmaceutically acceptable salt.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events comprising: administering to the subject a dose from about 200 mg to about 500 mg of fedratinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • the adverse event in the combination treatment of Compound (1) or the pharmaceutically acceptable salt and fedratinib is thrombocytopenia, anemia diarrhea, nausea, vomiting, encephalopathy, or a combination of two or more thereof.
  • the reduced amount of the fedratinib therapy comprises ⁇ 50% or 75% amount of fedratinib or the pharmaceutically acceptable salt.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events comprising: administering to the subject a dose from about 100 mg to about 200 mg of pacritinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • the adverse event in the combination treatment of Compound (1) or the pharmaceutically acceptable salt and pacritinib is thrombocytopenia, anemia diarrhea, nausea, peripheral edema, or a combination of two or more thereof.
  • the reduced amount of the pacritinib therapy comprises ⁇ 50% or 75% amount of pacritinib or the pharmaceutically acceptable salt.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events comprising: administering to the subject a dose from about 50 mg to about 200 mg of momelotinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • the adverse event in the combination treatment of Compound (1) or the pharmaceutically acceptable salt and momelotinib is thrombocytopenia, anemia diarrhea, nausea, dizziness, or a combination of two or more thereof.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a momelotinib therapy comprising from about 50 mg to about 200 mg of momelotinib or a pharmaceutically acceptable salt thereof, wherein the method comprises: administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; continuing to administer to the subject the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, during which the subject either (a) does not receive the momelotinib therapy, or (b) receives a reduced amount of the momelotinib therapy.
  • the subject receives a reduced amount of the momelotinib therapy.
  • the reduced amount of the momelotinib therapy comprises ⁇ 50% or 75% amount of momelotinib or the pharmaceutically acceptable salt.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events comprising: administering to the subject a dose from about 0.6 mg/kg or 1.75 mg/kg of luspatercept for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • the adverse event in the combination treatment of Compound (1) or the pharmaceutically acceptable salt and luspatercept is fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, hypersensitivity, or a combination of two or more thereof.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a luspatercept therapy comprising from about 0.5 mg/kg or 1.75 mg/kg of luspatercept, wherein the method comprises: administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; continuing to administer to the subject the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, during which the subject either (a) does not receive the luspatercept therapy, or (b) receives a reduced amount of the luspatercept therapy.
  • the reduced amount of the luspatercept therapy comprises ⁇ 50% or 75% amount of luspatercept.
  • administration of the combination minimizes, lessens, or ameliorates adverse events in the subject.
  • administration of the combination reduces bone marrow fibrosis in the subject.
  • administration of the combination reduces spleen volume in the subject.
  • administration of the combination results in the subject exhibiting normalization or increased platelet count, normalization or increased neutrophil count, normalization or increased hemoglobin count, transfusion improvement (including conversion into transfusion independence), or a combination of two or more thereof.
  • administration of the combination results in the subject exhibiting normalization or increased platelet count. [00233] In some embodiments, administration of the combination results in the subject exhibiting normalization or increased neutrophil count. [00234] In some embodiments, administration of the combination results in the subject exhibiting normalization or increased hemoglobin count. [00235] In some embodiments, administration of the combination results in the subject exhibiting transfusion improvement (including conversion into transfusion independence). [00236] In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 120 mg to about 1500 mg. [00237] In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 240 mg to about 1440 mg daily.
  • the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 240 mg to about 1000 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 240 mg to about 900 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 240 mg to about 800 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 240 mg to about 700 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 240 mg to about 600 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 240 mg to about 500 mg.
  • the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 350 mg to about 1350 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 400 mg to about 1150 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 500 mg to about 1050 mg. [00239] In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 350 mg to about 1000 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 450 mg to about 900 mg.
  • the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 450 mg to about 800 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 450 mg to about 750 mg. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 470 mg to about 730 mg. [00240] In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 120 mg to about 580 mg, about 581 mg to about 1040 mg, or about 1041 mg to about 1500 mg. [00241] In some embodiments, administering the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is at least once daily.
  • administering the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is at least twice daily. In some embodiments, administering the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is at least three times daily. In some embodiments, administering the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is at least four times daily. [00242] In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 120 mg/day to about 3000 mg/day. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 350 mg/day to about 2100 mg/day.
  • the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 550 mg/day to about 2000 mg/day. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 700 mg/day to about 1950 mg/day. [00243] In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 120 mg/day to about 800 mg/day. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 200 mg/day to about 750 mg/day. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 250 mg/day to about 650 mg/day.
  • the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 240 mg to about 1440 mg twice daily. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 360 mg to about 1440 mg twice daily. In some embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is about 1440 mg twice daily. [00245] In some embodiments, ruxolitinib or the pharmaceutically acceptable salt is about 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg. In some embodiments, the dose amount of ruxolitinib or the pharmaceutically acceptable salt may be about 2.5 mg.
  • the dose amount of ruxolitinib or the pharmaceutically acceptable salt may be about 5 mg. In some embodiments, the dose amount of ruxolitinib or the pharmaceutically acceptable salt may be about 7.5 mg. In some embodiments, the dose amount of ruxolitinib or the pharmaceutically acceptable salt may be about 10 mg. In some embodiments, the dose amount of ruxolitinib or the pharmaceutically acceptable salt may be about 12.5 mg. In some embodiments, the dose amount of ruxolitinib or the pharmaceutically acceptable salt may be about 15 mg. In some embodiments, the dose amount of ruxolitinib or the pharmaceutically acceptable salt may be about 20 mg.
  • the dose amount of ruxolitinib or the pharmaceutically acceptable salt may be about 25 mg.
  • the dose amount of fedratinib or the pharmaceutically acceptable salt may be about 100 mg.
  • the dose amount of fedratinib or the pharmaceutically acceptable salt may be about 200 mg.
  • the dose amount of fedratinib or the pharmaceutically acceptable salt may be about 400 mg.
  • the dose amount of fedratinib or the pharmaceutically acceptable salt may be about 500 mg.
  • the dose amount of pacritinib or the pharmaceutically acceptable salt may be about 50 mg.
  • the dose amount of pacritinib or the pharmaceutically acceptable salt may be about 100 mg. In some embodiments, the dose amount of pacritinib or the pharmaceutically acceptable salt may be about 200 mg. [00248] In some embodiments, the dose amount of momelotinib or the pharmaceutically acceptable salt may be about 25 mg. In some embodiments, the dose amount of momelotinib or the pharmaceutically acceptable salt may be about 50 mg. In some embodiments, the dose amount of momelotinib or the pharmaceutically acceptable salt may be about 100 mg. In some embodiments, the dose amount of momelotinib or the pharmaceutically acceptable salt may be about 200 mg.
  • the dose amount of luspatercept may be about 0.6 mg/kg based on the subject’s body weight. In some embodiments, the dose amount of luspatercept may be about 0.8 mg/kg based on the subject’s body weight. In some embodiments, the dose amount of luspatercept may be about 1.0 mg/kg based on the subject’s body weight. In some embodiments, the dose amount of luspatercept may be about 1.25 mg/kg based on the subject’s body weight. In some embodiments, the dose amount of luspatercept may be about 1.33 mg/kg based on the subject’s body weight.
  • the dose amount of luspatercept may be about 1.50 mg/kg based on the subject’s body weight. In some embodiments, the dose amount of luspatercept may be about 1.75 mg/kg based on the subject’s body weight. In some embodiments, luspatercept is administrated once every 3 weeks by subcutaneous injection for at least 21 weeks. [00250] In some embodiments, administering ruxolitinib, fedratinib, pacritinib, or momelotinib, or the pharmaceutically acceptable salt is at least one dose a day.
  • administering ruxolitinib, fedratinib, pacritinib, or momelotinib, or the pharmaceutically acceptable salt is at least two doses a day. [00251] In some embodiments, administering Compound (1) or the pharmaceutically acceptable salt and ruxolitinib, fedratinib, pacritinib, or momelotinib, or the pharmaceutically acceptable salt thereof is concurrent.
  • administering Compound (1) or the pharmaceutically acceptable salt and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or the pharmaceutically acceptable salt is sequential.
  • the myeloproliferative neoplasm is a JAK inhibitor- resistant myeloproliferative neoplasm.
  • the subject has been previously treated with a JAK inhibitor and exhibited an inadequate response.
  • the inadequate response is resistance or intolerance to the JAK inhibitor, loss or failure to obtain significant spleen response or total symptom response, and/or developing clinically significant reduction of count of blood cells, neutropenia, or thrombocytopenia.
  • the subject has not been previously treated with a JAK inhibitor.
  • the present technology further comprises monitoring complete blood counts in the subject and titrating the dose amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • the monitoring comprises assessing platelet counts and increasing the dose amount or frequency (i.e., up-titrating) if the platelet count change is (a) less than 1 grade, (b) decreased by less than 25 x 10 9 /L, and/or (c) decreased by less than 35%, based on the subject’s baseline platelet count (i.e., platelet count prior to starting treatment).
  • the monitoring comprises assessing platelet counts and decreasing the dose amount or less frequency (i.e., down-titrating) if the platelet count change is (a) up 1 or more grades, (b) decreased by more than 25 x 10 9 /L, and/or (c) decreased by more than 35%.
  • the platelet count has moved up from grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4.
  • the monitoring comprises assessing neutrophil counts and decreasing the dose amount or less frequency (i.e., down-titrating) if the neutrophil count change is (a) up 1 or more grades, (b) decreased by more than 500/L, and/or (c) decreased by more than 35%.
  • the neutrophil count has moved up from grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4.
  • the monitoring comprises assessing hemoglobin counts and decreasing the dose amount or less frequency (i.e., down-titrating) if the hemoglobin count change is (a) up 1 or more grades, (b) decreased by more than 5.0 g/dL, and/or (c) decreased by more than 35%.
  • the hemoglobin count has moved up from grade 1 to grade 2 or 3, or from grade 2 to grade 3.
  • the monitoring is performed prior to, during, and/or after the treatment.
  • the monitoring is performed once a week or every 2 to 4 weeks. In some embodiments, the monitoring is performed once a week.
  • the monitoring is performed every other week. In some embodiments, the monitoring is performed every 3 weeks. In some embodiments, the monitoring is performed every 4 weeks. [00267] In some embodiments, the monitoring further comprises continuing the titrating the dose amount or frequency until achieving a desired stable clinical state. [00268] In some embodiments, the method further comprises monitoring complete blood counts in the subject and titrating the dose amount of ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or a pharmaceutically acceptable salt thereof.
  • the method further comprises monitoring complete blood counts in the subject and titrating the dose amount of ruxolitinib or a pharmaceutically acceptable salt thereof.
  • the method further comprises monitoring complete blood counts in the subject and titrating the dose amount of fedratinib or a pharmaceutically acceptable salt thereof.
  • the method further comprises monitoring complete blood counts in the subject and titrating the dose amount of pacritinib or a pharmaceutically acceptable salt thereof.
  • the method further comprises monitoring complete blood counts in the subject and titrating the dose amount of momelotinib or a pharmaceutically acceptable salt thereof.
  • the method further comprises monitoring complete blood counts in the subject and titrating the dose amount of luspatercept.
  • the method monitoring comprises assessing platelet counts in the subject prior to, during, and/or after the treatment.
  • titrating when administered in combination with Compound (1), comprises starting ruxolitinib or a pharmaceutically acceptable salt thereof in the subject at a dose: 20 mg twice daily if baseline platelet count is greater than 200 ⁇ 10 9 /L, 10 mg twice daily if baseline platelet count is from 100 ⁇ 10 9 /L to 200 ⁇ 10 9 /L, 5 mg twice daily if baseline platelet count is from 50 ⁇ 10 9 /L to less than 100 ⁇ 10 9 /L.
  • the method comprises increasing the dose amount of ruxolitinib if the subject’s response is insufficient and platelet and neutrophil counts are adequate.
  • the method when administered in combination with Compound (1), comprises increasing the dose of ruxolitinib or the pharmaceutically acceptable salt in the amount of 5 mg twice daily increments to a maximum of 25 mg twice daily.
  • the method comprises increasing the dose amount of ruxolitinib or a pharmaceutically acceptable salt thereof in the subject that meets all of the following conditions: (a) failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume as measured by computed tomography (CT) or magnetic resonance imaging (MRI); (b) platelet count greater than 125 ⁇ 10 9 /L at 4 weeks and platelet count never below 100 ⁇ 10 9 /L; and (c) ANC Levels greater than 0.75 ⁇ 10 9 /L.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • the method comprises increasing the dose amount of ruxolitinib or a pharmaceutically acceptable salt thereof in the subject by increments of 5 mg daily to a maximum of 10 mg twice daily if: a) the platelet count has remained at least 40 ⁇ 10 9 /L, b) the platelet count has not fallen by more than 20% in the prior 4 weeks, c) the ANC is more than 1 ⁇ 10 9 /L, and d) the dose has not been reduced or interrupted for an adverse event or hematological toxicity in the prior 4 weeks.
  • titrating the dose amount of ruxolitinib or a pharmaceutically acceptable salt thereof is in according to Table (a) for thrombocytopenia for the subject whose starting treatment with a platelet count of 100 ⁇ 10 9 /L or greater: Table (a) [00281] In some embodiments, titrating the dose amount of ruxolitinib or a pharmaceutically acceptable salt thereof is in according to Table (b) for thrombocytopenia for the subject whose starting treatment with a platelet count of 50 ⁇ 10 9 /L to less than 100 ⁇ 10 9 /L: Table (b) [00282] In some embodiments, the method comprises starting fedratinib or a pharmaceutically acceptable salt thereof in the subject at 200, 300, or 400 mg once daily for patients with a baseline platelet count of greater than or equal to 50 x 10 9 /L.
  • the method comprises reducing the dose amount of fedratinib to 100 mg or below, or temporarily stopping the doses if adverse reactions develop.
  • the adverse reaction of the fedratinib therapy is anemia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with active bleeding, grade 3 or higher nausea, vomiting, diarrhea, anemia, or elevations of alanine transaminase (ALT), aspartate aminotransferase (AST), or bilirubin.
  • the method comprises starting pacritinib or a pharmaceutically acceptable salt thereof in the subject at 100 mg or 200 mg twice daily for patients with a baseline platelet count below 50 x 10 9 /L. [00286] In some embodiments, the method comprises reducing the doses amount of pacritinib to 100 mg or below if adverse reactions develop. [00287] In some embodiments, the adverse reaction of the pacritinib therapy is diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema.
  • the method further comprises temporarily stopping the dose of pacritinib if any clinically significant worsening of thrombocytopenia that last more than 7 days, until toxicity is resolved, and restarting pacritinib or the pharmaceutically acceptable salt at 50% of last dose given.
  • the method comprises starting luspatercept in the subject at 0.5 mg/kg or 1 mg/kg by subcutaneous injection once every 3 weeks.
  • titrating the dose of luspatercept based on responses according to Table (c): Table (c) [00292] In some embodiments, titrating the dose of luspatercept is based on responses according to Table (d): Table (d) [00293] In some embodiments, the method of administering momelotinib or a pharmaceutically acceptable salt thereof in the subject at a dose of about 50 mg to about 200 mg when the subject is suffering from intermediate or high-risk primary or secondary (post- PV or post-ET) myelofibrosis with hemoglobin level ⁇ 10. [00294] In some embodiments, the method results in the subject exhibiting total symptom stability.
  • the method results in the subject exhibiting total symptom reduction. [00296] In some embodiments, the method results in the subject exhibiting partial symptom reduction. [00297] In some embodiments, the method results in the subject exhibiting spleen volume reduction. [00298] In some embodiments, the method results in the subject exhibiting normalization or increased platelet count, normalization or increased neutrophil count, normalization or increased hemoglobin count, transfusion improvement (including conversion into transfusion independence), or a combination of two or more thereof. [00299] In some embodiments, method results in the subject being cytogenetic remission or molecular partial or complete remission. [00300] In some embodiments, the method improves clinically meaningful overall survival in the subject.
  • the method ameliorates anemia in the subject.
  • the method results in ⁇ 20 g/L increasing in hemoglobin level or changing transfusion-depending to transfusion-independent in the subject.
  • the method results in improvement of Patient Global Impression of Change (PGIC) questionnaire (at least 1 score increase) at week 24.
  • PGIC Patient Global Impression of Change
  • a myeloproliferative neoplasm is myelofibrosis.
  • the myelofibrosis is intermediate-risk myelofibrosis.
  • the myelofibrosis is high-risk myelofibrosis.
  • the myelofibrosis is primary myelofibrosis.
  • the myelofibrosis is secondary myelofibrosis. (e.g., post- PV myelofibrosis and post-ET myelofibrosis).
  • the pharmaceutically acceptable salt thereof is a hydrochloric acid salt.
  • the hydrochloric acid salt of Compound (1) is in a crystalline form.
  • administering Compound (1) or the pharmaceutically acceptable salt is for a period from about one week to about two years.
  • administering Compound (1) or the pharmaceutically acceptable salt is for a period from about 15 weeks to about one year. [00313] In some embodiments, administering Compound (1) or the pharmaceutically acceptable salt is for from about 24 weeks to about one year. [00314] In some embodiments, the subject with MF is stratified into a risk group using the Dynamic International Prognostic Scoring System (DIPSS), Mutation-enhanced International Prognostic Scoring System plus karyotype (MIPSS70+), or other systems. Risk factors using DIPSS include age, symptomatic burden (e.g., weight loss, fever, or excessive sweating), white blood cell counts, hemoglobin, and peripheral blasts.
  • DIPSS Dynamic International Prognostic Scoring System
  • MIPSS70+ Mutation-enhanced International Prognostic Scoring System plus karyotype
  • Risk factors using DIPSS include age, symptomatic burden (e.g., weight loss, fever, or excessive sweating), white blood cell counts, hemoglobin
  • Patients having low-risk MF have a DIPSS score of 0.
  • the MF is low-risk MF.
  • Patients having intermediate-risk MF have a DIPSS score of 1 to 4.
  • a DIPSS score of 1-2 is also referred to as intermediate-1 risk, and is typically associated with a median survival of about 14.2 years.
  • a DIPSS score of 3 or 4 is also referred to as intermediate-2 risk, and is typically associated with a median survival of 4 years.
  • the MF is intermediate-risk MF (e.g., intermediate-1 risk MF, intermediate-2 risk MF).
  • Patients having high-risk MF have a DIPSS score of 5 or 6, associated with a median survival of 1.5 years.
  • the MF is high-risk MF.
  • the MPN is a ruxolitinib-resistant MPN (e.g., ruxolitinib- resistant MF).
  • the MPN e.g., MF
  • the MPN has been previously treated with ruxolitinib, e.g., in the absence of a PIM kinase inhibitor (i.e., Compound (1) or a pharmaceutically acceptable salt thereof).
  • treating the MPN in accordance with the methods described herein results in complete remission in the subject.
  • bone marrow shows age-adjusted normocellularity, ⁇ 5% blasts and ⁇ grade 1 MF according to the European classification; and hemoglobin ⁇ 100 g/L and ⁇ upper normal limit (UNL), and neutrophil count ⁇ 1 ⁇ 10 9 /L and ⁇ UNL in peripheral blood; and platelet count ⁇ 100 ⁇ 10 9 /L and ⁇ UNL, and ⁇ 2% immature myeloid cells, except that in splenectomized patients, ⁇ 5% immature myeloid cells is allowed; and resolution of disease symptoms (e.g., total symptoms), non-palpable spleen and liver, and no evidence of extramedullary hematopoiesis (EMH).
  • EMH extramedullary hematopoiesis
  • treating the MPN in accordance with the methods described herein results in partial remission in the subject.
  • partial remission means the subject meets the following criteria for ⁇ 12 weeks: hemoglobin ⁇ 100 g/L and ⁇ UNL, and neutrophil count ⁇ 1 ⁇ 10 9 /L and ⁇ UNL in peripheral blood; and platelet count ⁇ 100 ⁇ 10 9 /L and ⁇ UNL, and ⁇ 2% immature myeloid cells, except that in splenectomized patients, ⁇ 5% immature myeloid cells is allowed; and resolution of disease symptoms (e.g., total symptoms), non-palpable spleen and liver, and no evidence of extramedullary hematopoiesis (EMH).
  • EMH extramedullary hematopoiesis
  • partial remission means bone marrow shows age-adjusted normocellularity, ⁇ 5% blasts and ⁇ grade 1 MF according to the European classification; and hemoglobin ⁇ 85 but ⁇ 100 g/L, and neutrophil count ⁇ 1 ⁇ 10 9 /L and ⁇ UNL in peripheral blood; and platelet count ⁇ 50 but ⁇ 100 ⁇ 10 9 /L, and ⁇ 2% immature myeloid cells, except that in splenectomized patients, ⁇ 5% immature myeloid cells is allowed; and resolution of disease symptoms (e.g., total symptoms), non-palpable spleen and liver, and no evidence of extramedullary hematopoiesis (EMH).
  • EMH extramedullary hematopoiesis
  • treating the MPN in accordance with the methods described herein results in the subject being cytogenetic complete remission, cytogenetic partial remission, molecular complete remission, or molecular partial remission. In some embodiments, treating the MPN in accordance with the methods described herein results in cytogenetic or molecular remission in the subject.
  • cytogenetic complete remission or “molecular complete remission” refers to the subject having eradication of pre-existing abnormality for ⁇ 6 months.
  • cytogenetic partial remission refers to the subject having ⁇ 50% reduction in abnormal metaphases in patients with at least 10 abnormal metaphases at before treatment.
  • the subject may have progenitor cells that possess acquired mutations within the JAK2, CALR and MPL genes.
  • common mutations in JAK2 include the V617F mutation and mutations (e.g., substitutions, deletions, insertions, duplications) of exon 12.
  • Common mutations in CALR include exon 9 mutations.
  • Common mutations in MPL include exon 10 mutations (e.g., W515L and W515K).
  • Cytogenetic and molecular testing is typically conducted using allele-specific quantitative PCR (qPCR), digital PCR or next-generation sequencing.
  • qPCR allele-specific quantitative PCR
  • digital PCR digital PCR
  • next-generation sequencing The foregoing methods are reviewed in Haslam, K. and Langabeer, S.E., “Monitoring Residual Disease in the Myeloproliferative Neoplasms: Current Applications and Emerging Approaches,” Biomed. Res. Intl.2016:7241591, the relevant teachings of which are incorporated herein by reference in their entireties.
  • the methods can be defined based on other baseline characteristics. Thus, in some embodiments, the subject has moderate or severe splenomegaly at baseline.
  • the subject has a baseline spleen size of, e.g., ⁇ 450, 600, 750, 1,000, 1,500, or 2,000 cm 3 by imaging.
  • the subject has a total symptoms score (TSS) at baseline greater than 15, 20, 25, 30, 35, 40, 45, or 50.
  • TSS total symptoms score
  • the subject is in need of cytokine modulation.
  • the subject has a JAK2V16F mutation.
  • the subject has a CALR mutation.
  • the subject has a MPLW515L mutation. [00325]
  • the subject is characterized by poor bone marrow functioning at baseline.
  • the subject is characterized by thrombocytopenia at baseline (e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L).
  • the subject is characterized by anemia at baseline (e.g. a Hgb level ⁇ 10, 9, or 8 g/dL).
  • the subject is characterized by transfusion dependence at baseline.
  • the subject is characterized by serious thrombocytopenia or anemia at baseline (i.e. a platelet count ⁇ 50 x 10 9 /L or a Hgb level ⁇ 8 g/dL).
  • the subject has grade 2 or higher fibrosis at baseline.
  • the subject has an absolute neutrophil count of greater than 1 ⁇ 10 9 /L at baseline. In some embodiments, the subject has a peripheral blood blast less than 10% at baseline.
  • the myeloproliferative neoplasm is responsive to selective PIM1 inhibition. E.g., the myeloproliferative neoplasm is responsive to a selective PIM1 kinase inhibitor having a PIM1/PIM2 IC50 ratio of less than 0.05, 0.045, 0.04, 0.035, 0.03, or 0.025, wherein IC 50 is determined as described in Foulks, Neoplasia Vol.16, No.5, 2014.
  • compositions are directed to pharmaceutical compositions.
  • the PIM kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • JAK inhibitor e.g., ruxolitinib, fedratinib, pacritinib, momelotinib, or luspatercept, or a pharmaceutically acceptable salt thereof
  • ACVR inhibitor e.g., momelotinib, pacritinib, luspatercept, or a pharmaceutically acceptable salt thereof
  • ropeginterferon alfa- 2b, navtemadelin, or other therapeutic agent may be formulated together or separately according to methods known in the art.
  • Certain embodiments comprise a pharmaceutically acceptable carrier or excipient, a PIM kinase inhibitor and/or a JAK inhibitor and/or ACVR inhibitor.
  • the pharmaceutical composition comprises a PIM kinase inhibitor and/or JAK inhibitor and/or ACVR inhibitor according to any of the foregoing described embodiments.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for injection.
  • Suitable routes of administration also include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal routes of administration.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compound described herein is administered topically.
  • a PIM kinase inhibitor and/or JAK kinase inhibitor and/or ACVR inhibitor is administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes are used as appropriate.
  • a PIM kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • JAK kinase inhibitor e.g., ruxolitinib, fedratinib, pacritinib, momelotinib, or a pharmaceutically acceptable salt thereof
  • ACVR inhibitor e.g., momelotinib, pacritinib, luspatercept, or a pharmaceutically acceptable salt thereof
  • ropeginterferon alfa-2b or navtemadelin is administered orally.
  • a PIM kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • a JAK kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • dosing is about once, twice, three times, four times, five times, six times, or more than six times per day.
  • dosing is about once a month, once every two weeks, once a week, or once every other day.
  • a PIM kinase inhibitor and another agent e.g., a JAK2 inhibitor are administered together about once per day to about 6 times per day.
  • a PIM kinase inhibitor and another agent e.g., JAK inhibitor
  • the administration continues for less than about 7 days.
  • the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year.
  • the administration continues for from about seven days to about five years (e.g., from about seven days to about two years, from about seven days to about one year).
  • the administration continues for 28 days.
  • the administration continues for one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • Administration of the PIM kinase inhibitor and optionally JAK or ACVR inhibitor may continue as long as necessary.
  • a PIM kinase inhibitor and optionally JAK or ACVR inhibitor are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a PIM kinase inhibitor and optionally JAK or ACVR inhibitor are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a PIM kinase inhibitor and optionally JAK or ACVR inhibitor are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. [00335] In some embodiments, one or more cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.
  • the PIM kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • JAK kinase inhibitor e.g., ruxolitinib, or a pharmaceutically acceptable salt thereof
  • an ACVR inhibitor are administered.
  • the PIM kinase inhibitor (i.e., Compound (1) or a pharmaceutically acceptable salt thereof) and/or JAK kinase inhibitor (e.g., ruxolitinib, or a pharmaceutically acceptable salt thereof), and/or an ACVR inhibitor are administered on a cycle, for example, a 28-day cycle.
  • one or more cycles of the PIM kinase inhibitor and/or JAK kinase inhibitor are each independently administered once or twice per day for 28 days on a 28-day cycle.
  • the PIM kinase inhibitor and optionally JAK or ACVR inhibitor are administered in dosages. Due to intrasubject variability in compound pharmacokinetics, individualization of dosing regimen is provided in certain embodiments. Dosing for a compound of embodiments of the disclosure may be found by routine experimentation in light of the instant disclosure and/or can be derived by one of ordinary skill in the art.
  • the PIM kinase inhibitors and optionally JAK or ACVR inhibitor are formulated into pharmaceutical compositions.
  • pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • a pharmaceutical composition refers to a mixture of (1) a PIM kinase inhibitor, (2) a combination of a PIM kinase inhibitor and a JAK kinase inhibitor, (3) a combination of a PIM kinase inhibitor and an ACVR inhibitor, or (4) a combination of a PIM kinase inhibitor, and a JAK kinase inhibitor, with other chemical components.
  • compositions facilitates administration of the compound(s) to an organism.
  • therapeutically effective amount(s) of inhibitors of PIM kinase and optionally JAK kinase inhibitors or ACVR inhibitors are administered in a pharmaceutical composition to a human subject having a disease, disorder or medical condition to be treated as provided herein.
  • therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the inhibitor(s) are formulated in an aqueous solution.
  • the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
  • inhibitors targeting at least two super- enhancer components are formulated for transmucosal administration.
  • transmucosal formulations include penetrants that are appropriate to the barrier to be permeated.
  • appropriate formulations include aqueous or non- aqueous solutions.
  • such solutions include physiologically compatible buffers and/or excipients.
  • compounds described herein are formulated for oral administration. Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are optionally added.
  • Disintegrating agents include, by way of example only, cross linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • dosage forms such as dragee cores and tablets, are provided with one or more suitable coating.
  • concentrated sugar solutions are used for coating the dosage form.
  • the sugar solutions optionally contain additional components, such as and by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes.
  • inhibitors targeting PIM kinase, JAK kinase, and/or ACVR may be formulated into other oral dosage forms.
  • Oral dosage forms include push fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • push fit capsules contain the active ingredients in admixture with one or more fillers.
  • Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • soft capsules contain one or more active compounds that are dissolved or suspended in a suitable liquid.
  • suitable liquids include, by way of example only, one or more fatty oils, liquid paraffins, or liquid polyethylene glycols.
  • stabilizers are optionally added.
  • a particular composition comprises a PIM kinase inhibitor (i.e., Compound (1) or a pharmaceutically acceptable salt thereof), and a polyglycolized glyceride.
  • Polyglycolized glycerides refers to mixtures of monoesters, diesters and triesters of glycerols and monoesters and diesters of polyethylene glycols with a mean relative molecular mass between about 200 and 6000. Polyglycolized glycerides may be obtained by partial transesterification of triglycerides with polyethylene glycol or by esterification of glycerol and polyethylene glycol with fatty acids. In some embodiments, the fatty acid component contains between 8-22 carbon atoms, for example, between 10-18 carbon atoms. Examples of natural vegetable oils from which polyglycolized glycerides can be derived include palm kernel oil and palm oil.
  • Suitable polyol compounds generally have a molecular weight ranging from about 200 to about 6000 g/mol and preferably contain polyethylene glycol, although other polyols may be employed, such as polyglycerols or sorbitol.
  • Polyglycolized glycerides are available on the market under the trade name Gelucire®. Examples of polyglycolized glycerides useful in various embodiments include WL 2514CS, LABRASOL, LABRAFIL, Gelucire 44/14 (lauroyl polyoxy-32 glycerides), Gelucire 33/01, Gelucire 35/10, Gelucire 37/02, Gelucire 50/13, Gelucire 44/11 and mixtures thereof.
  • “Gelucire® 44/14” or “Gelucire 44/14” is a lipid-based excipient manufactured by Gattefosse Corporation, Westwood, N.J. comprising a mixture of pegylated fatty acid esters and glycerides.
  • the number 44 denotes the melting point of the compound and 14 indicates hydrophile/lipophile balance (HLB) value.
  • HLB hydrophile/lipophile balance
  • Other Gelucire excipients similarly indicate values for melting point and HLB values. For example, Gelucire 33/01, Gelucire 35/10, Gelucire 37/02, Gelucire 50/13 and Gelucire 44/11.
  • the composition of the PIM kinase inhibitor and the polyglycolized glyceride is formulated for oral administration, e.g., in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compound (1) herein may be in free-base form, or in a pharmaceutically acceptable salt form. In some embodiments, Compound (1) is present as a free base. In some embodiments, Compound (1) is present as a salt. In some embodiments, Compound (1) is present as a hydrochloride salt.
  • a composition comprising the PIM kinase inhibitor disclosed herein and a polyglycolized glyceride can optionally be used in place of the PIM kinase inhibitor in any of the methods disclosed herein.
  • the PIM kinase inhibitor and/or JAK kinase inhibitors and/or ACVR inhibitors are formulated for buccal or sublingual administration.
  • Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.
  • the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi dose containers. Preservatives are, optionally, added to the injection formulations.
  • the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles.
  • Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form.
  • suspensions of the active compounds are prepared as appropriate oily injection suspensions.
  • suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the PIM kinase inhibitor and/or JAK kinase inhibitors and/or ACVR inhibitors are administered topically.
  • the compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • the PIM kinase inhibitor and/or JAK kinase inhibitors and/or ACVR inhibitors are formulated for transdermal administration.
  • transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • transdermal delivery of inhibitors is accomplished by means of iontophoretic patches and the like.
  • transdermal patches provide controlled delivery of inhibitors.
  • the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers are used to increase absorption.
  • Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the PIM kinase inhibitors and/or JAK kinase inhibitors and/or ACVR inhibitors are formulated for administration by inhalation.
  • Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders.
  • compositions of inhibitors are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount.
  • capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the PIM kinase inhibitors and/or JAK kinase inhibitors and/or ACVR inhibitors are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable.
  • Pharmaceutical compositions comprising inhibitors are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and inhibitors, described herein as an active ingredient.
  • the active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein.
  • the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of inhibitors presented herein are also considered to be disclosed herein.
  • compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • Methods for the preparation of compositions comprising the PIM kinase inhibitors and/or JAK kinase inhibitors and/or ACVR inhibitors described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, but are not limited to, gels, suspensions and creams.
  • the form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • compositions comprising the PIM kinase inhibitors and/or JAK kinase inhibitors and/or ACVR inhibitors illustratively take the form of a liquid where the agents are present in solution, in suspension or both.
  • a liquid composition includes a gel formulation.
  • the liquid composition is aqueous.
  • useful aqueous suspensions contain one or more polymers as suspending agents.
  • Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
  • Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected, for example, from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of inhibitors.
  • solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
  • Certain acceptable nonionic surfactants for example polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
  • useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, one or more salts in an amount required to bring osmolality of the composition into an acceptable range, one or more preservatives to inhibit microbial activity, one or more surfactants to enhance physical stability or for other purposes, one or more antioxidants to enhance chemical stability where required, or a combination of two or more thereof.
  • aqueous suspension compositions are packaged in single- dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • other delivery systems for hydrophobic pharmaceutical compounds are employed.
  • Liposomes and emulsions are examples of delivery vehicles or carriers useful herein.
  • organic solvents such as N-methyl pyrrolidone are also employed.
  • the compounds described herein are delivered using a sustained release system.
  • the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents.
  • the PIM kinase inhibitor and optional JAK inhibitor and/or ACVR inhibitor can be administered concurrently or separately. When multiple therapeutic agents are administered which are not presented in the same dosage form, administration of the various therapeutic agents (e.g.
  • PIM Kinase Inhibitor, and/or JAK inhibitor, and/or ACVR inhibitor can be administered simultaneously in separate dosage forms, contemporaneously in separate dosage forms, sequentially in separate dosage forms, or per a protocol schedule.
  • one of the inhibitors may be administered via a bolus followed by a separate bolus of the second inhibitor after an appropriate period of time.
  • Slower administration, such as a longer duration infusion can be used for administration of one or both of the inhibitors.
  • the skilled clinician can determine appropriate administration methods and orders, which are all within the scope of the present disclosure.
  • Some embodiments thus provide a separate dosage form comprising a PIM kinase inhibitor (i.e., Compound (1) or a pharmaceutically acceptable salt thereof) and an additional therapeutic agent (e.g., an additional therapeutic agent described herein), wherein the PIM kinase inhibitor and the additional therapeutic agent are associated with one another.
  • a PIM kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • an additional therapeutic agent e.g., an additional therapeutic agent described herein
  • the dosage form comprises a PIM kinase inhibitor (i.e., Compound (1) or a pharmaceutically acceptable salt thereof) and a JAK kinase inhibitor (e.g., ruxolitinib, or a pharmaceutically acceptable salt thereof) and/or an ACVR inhibitor.
  • a PIM kinase inhibitor i.e., Compound (1) or a pharmaceutically acceptable salt thereof
  • a JAK kinase inhibitor e.g., ruxolitinib, or a pharmaceutically acceptable salt thereof
  • ACVR inhibitor is as described herein.
  • kits comprising a PIM kinase inhibitor (i.e., Compound (1) or a pharmaceutically acceptable salt thereof) and written instructions for administering the PIM kinase inhibitor for treatment of a myeloproliferative neoplasm is provided.
  • the kit further comprises a JAK inhibitor and written instructions for administering the JAK inhibitor in combination with the PIM kinase inhibitor.
  • the kit further comprises an ACVR inhibitor and written instructions for administering the JAK inhibitor in combination with the PIM kinase inhibitor.
  • the PIM kinase inhibitor is as described herein.
  • the JAK inhibitor is as described herein.
  • the ACVR inhibitor is as described herein.
  • the myeloproliferative neoplasm is as described herein.
  • the PIM kinase inhibitors such as Compound (1) or a pharmaceutically acceptable salt thereof and optional JAK inhibitors and/or optional ACVR can be prepared according to methods known in the art. Exemplary preparation procedures are provided in PCT Pub.
  • Embodiment 1 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject has poor bone marrow functioning characterized by: (a) thrombocytopenia (e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L); (b) anemia (e.g.
  • Embodiment 2 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor, wherein the subject has poor bone marrow functioning characterized by: (a) thrombocytopenia (e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L); (b) anemia (e.g.
  • Embodiment 3 a Hgb level ⁇ 10, 9, or 8 g/dL); (c) transfusion dependence; or (d) a combination thereof; wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject Compound (1) or a pharmaceutically acceptable salt thereof, and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • a method of treating a myeloproliferative neoplasm in a human subject in need thereof comprising administering to the subject a selective PIM1 inhibitor and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • a selective PIM1 inhibitor and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities (e.g., anemia and/or thrombocytopenia and/or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.
  • Embodiment 9 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor, wherein the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L).
  • Embodiment 10 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L).
  • Embodiment 11 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising: administering to the subject, a therapeutically effective amount of a selective PIM1 inhibitor, and continuing administering to the subject a therapeutically effective amount of the selective PIM1 inhibitor, wherein: the subject has a platelet count reduction of (a) less than 1 grade, or (b) less than or equal to 25 x 10 9 /L, and/or (c) less than or equal to 35%, and the platelet count reduction is determined by a change in the baseline platelet count determined within one week prior to administering the selective PIM1 inhibitor and a second platelet count determined at least 2 weeks after administering.
  • Embodiment 12 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject, a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and continuing administering to the subject a therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, wherein: the subject has a platelet count reduction of (a) less than 1 grade, or (b) less than or equal to 25 x 10 9 /L, and/or (c) less than or equal to 35%, and the platelet count reduction is determined by a change in the baseline platelet count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt and a second platelet count determined at least 2 weeks after administering.
  • Embodiment 13 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a selective PIM1 inhibitor, wherein: the subject has had one or more previous treatments comprising the selective PIM1 inhibitor and has a platelet count reduction of (a) less than 1 grade, (b) less than or equal to 25 x 10 9 /L, and/or (c) less than or equal to 35%, the platelet count reduction is determined by a change in the baseline platelet count determined within one week prior to administering the selective PIM1 inhibitor and a second platelet count determined at least 2 weeks after administering, and the method results in the subject exhibiting bone marrow fibrosis reduction, total symptom reduction, cytokine modulation, or a combination of two or more thereof.
  • Embodiment 14 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) Compound (1) or a pharmaceutically acceptable salt thereof, wherein: the subject has had one or more previous treatments comprising Compound (1) or the pharmaceutically acceptable salt and has a platelet count reduction of (a) less than 1 grade, (b) less than or equal to 25 x 10 9 /L, and/or (c) less than or equal to 35%, the platelet count reduction is determined by a change in the baseline platelet count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt and a second platelet count determined at least 2 weeks after administering, and the method results in the subject exhibiting bone marrow fibrosis reduction, total symptom reduction, cytokine modulation, or a combination of two or more thereof.
  • Embodiment 15 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, navtemadelin, or a pharmaceutically acceptable salt thereof, or a combination of two or more thereof, wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); ruxolitinib or the pharmaceutically acceptable salt is in a dose of about 5 mg to about 25 mg; fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg; pacritinib or the pharmaceutically acceptable salt is in a dose of
  • Embodiment 16 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, navtemadelin, or a pharmaceutically acceptable salt thereof, or a combination of two or more thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); ruxolitinib or the pharmaceutically acceptable salt is in a dose of about 5 mg to about 25 mg; fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg; pacritinib or the pharmaceutically acceptable salt is
  • Embodiment 17 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L).
  • Embodiment 18 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and ruxolitinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and ruxolitinib or the pharmaceutically acceptable salt is in a dose of about 5 mg to about 25 mg.
  • a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L)
  • ruxolitinib or the pharmaceutically acceptable salt is in a dose of about 5 mg to about 25 mg.
  • Embodiment 19 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof; and ruxolitinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and ruxolitinib or the pharmaceutically acceptable salt is in a dose of about 5 mg to about 25 mg.
  • Embodiment 20 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and fedratinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg.
  • a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L)
  • fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg.
  • Embodiment 21 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and fedratinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg.
  • the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg.
  • Embodiment 22 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and pacritinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg.
  • a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L)
  • pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg.
  • Embodiment 23 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and pacritinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg.
  • Embodiment 24 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and momelotinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg.
  • a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L)
  • momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg.
  • Embodiment 25 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and momelotinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg.
  • a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L)
  • momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg.
  • Embodiment 26 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and luspatercept; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and luspatercept is in a dose of about 0.5 mg/kg or 1.75 mg/kg based on the subject’s body weight.
  • a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L)
  • luspatercept is in a dose of about 0.5 mg/kg or 1.75 mg/kg based on the subject’s body weight.
  • Embodiment 27 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and luspatercept; wherein: the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L); and luspatercept is in a dose of about 0.5 mg/kg or 1.75 mg/kg based on the subject’s body weight.
  • the subject has a baseline platelet count of less than or equal to 200 ⁇ 10 9 /L (e.g., less than or equal to 150, 100, 75, 50, or 25 ⁇ 10 9 /L)
  • luspatercept is in a dose of about 0.5 mg/kg or 1.75 mg/kg based on the subject’s body weight.
  • Embodiment 28 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and ruxolitinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and ruxolitinib or the pharmaceutically acceptable salt is in a dose of about 5 mg to about 25 mg.
  • Embodiment 29 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and ruxolitinib or the pharmaceutically acceptable salt is in a dose of about 5 mg to about 25 mg.
  • Embodiment 30 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and fedratinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg.
  • a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L)
  • fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg.
  • Embodiment 31 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and fedratinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg.
  • a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L)
  • fedratinib or the pharmaceutically acceptable salt is in a dose of about 200 mg to about 500 mg.
  • Embodiment 32 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and pacritinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg.
  • a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L)
  • pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg.
  • Embodiment 33 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and pacritinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and pacritinib or the pharmaceutically acceptable salt is in a dose of about 100 mg to about 200 mg.
  • Embodiment 34 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and momelotinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg.
  • a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L)
  • momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg.
  • Embodiment 35 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and momelotinib or a pharmaceutically acceptable salt thereof; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg.
  • a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L)
  • momelotinib or the pharmaceutically acceptable salt is in a dose of about 50 mg to about 200 mg.
  • Embodiment 36 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor and luspatercept; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and luspatercept is in a dose of about 0.5 mg/kg or 1.75 mg/kg based on the subject’s body weight.
  • a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L)
  • luspatercept is in a dose of about 0.5 mg/kg or 1.75 mg/kg based on the subject’s body weight.
  • Embodiment 37 A method for treating a myeloproliferative neoplasm in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and luspatercept; wherein: the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L); and luspatercept is in a dose of about 0.5 mg/kg or 1.75 mg/kg based on the subject’s body weight.
  • the subject has a baseline platelet count of greater than or equal to 10 ⁇ 10 9 /L (e.g., great than or equal to 15, 25, 50, 75, or 100 ⁇ 10 9 /L)
  • luspatercept is in a dose of about 0.5 mg/kg or 1.75 mg/kg based on the subject’s body weight.
  • Embodiment 38 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 5 mg to about 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor.
  • Embodiment 39 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 5 mg to about 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33 % to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • Embodiment 40 The method of embodiment 38 or 39, wherein the adverse event is thrombocytopenia, anemia, bruising, dizziness, headache, diarrhea, or a combination of two or more thereof.
  • Embodiment 41 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a ruxolitinib therapy comprising about 5 mg to about 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof, the method comprises: administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor; and continuing to administer to the subject the therapeutically effective amount of the selective PIM1 inhibitor, during which the subject either (a) does not receive the ruxolitinib therapy, or (b) receives a reduced amount of the ruxolitinib therapy.
  • Embodiment 42 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a ruxolitinib therapy comprising about 5 mg to about 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof, the method comprises: administering to the subject a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof; and continuing to administer to the subject the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, during which the subject either (a) does not receive the ruxolitinib therapy, or (b) receives a reduced amount of the ruxolitinib therapy.
  • Embodiment 43 The method of embodiment 41 or 42, wherein the reduced amount of the ruxolitinib therapy comprises ⁇ 50% or 75% of the ruxolitinib therapy.
  • Embodiment 36 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 200 mg to about 500 mg of fedratinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor.
  • Embodiment 45 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 200 mg to about 500 mg of fedratinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • Embodiment 46 The method of embodiment 44 or 45, wherein the adverse event is thrombocytopenia, anemia diarrhea, nausea, vomiting, encephalopathy, or a combination of two or more thereof.
  • Embodiment 47 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a fedratinib therapy comprising from about 200 mg to about 500 mg of fedratinib or a pharmaceutically acceptable salt thereof, the method comprises: administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor; and continuing to administer to the subject the therapeutically effective amount of the selective PIM1 inhibitor, during which the subject either (a) does not receive the fedratinib therapy, or (b) receives a reduced amount of the fedratinib therapy.
  • Embodiment 48 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a fedratinib therapy comprising from about 200 mg to about 500 mg of fedratinib or a pharmaceutically acceptable salt thereof, the method comprises: administering to the subject a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof; and continuing to administer to the subject the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, during which the subject either (a) does not receive the fedratinib therapy, or (b) receives a reduced amount of the fedratinib therapy.
  • Embodiment 49 The method of embodiment 47 or 48, wherein the reduced amount of the fedratinib therapy comprises ⁇ 50% or 75% of the fedratinib therapy.
  • Embodiment 50 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 100 mg to about 200 mg of pacritinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor.
  • Embodiment 51 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 100 mg to about 200 mg of pacritinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • Embodiment 52 The method of embodiment 50 or 51, wherein the adverse event is thrombocytopenia, anemia diarrhea, nausea, peripheral edema, or a combination of two or more thereof.
  • Embodiment 53 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a pacritinib therapy comprising about 100 mg to about 200 mg of pacritinib or a pharmaceutically acceptable salt thereof, the method comprises: administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor; and continuing to administer to the subject the therapeutically effective amount of the selective PIM1 inhibitor, during which the subject either (a) does not receive the pacritinib therapy, or (b) receives a reduced amount of the pacritinib therapy.
  • Embodiment 54 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a pacritinib therapy comprising about 100 mg to about 200 mg of pacritinib or a pharmaceutically acceptable salt thereof, the method comprises: administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and continuing to administer to the subject the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, during which the subject either (a) does not receive the pacritinib therapy, or (b) receives a reduced amount of the pacritinib therapy.
  • Embodiment 55 The method of embodiment 53 or 54, wherein the reduced amount of the pacritinib therapy comprises ⁇ 50% or 75% of the pacritinib therapy.
  • Embodiment 56 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 50 mg to about 200 mg of momelotinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor.
  • Embodiment 57 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 50 mg to about 200 mg of momelotinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof.
  • Embodiment 58 The method of embodiment 56 or 57, wherein the adverse event is thrombocytopenia, anemia diarrhea, nausea, dizziness, or a combination of two or more thereof.
  • Embodiment 59 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a momelotinib therapy comprising from about 50 mg to about 200 mg of momelotinib or a pharmaceutically acceptable salt thereof, wherein the method comprises: administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor; and continuing to administer to the subject the therapeutically effective amount of the selective PIM1 inhibitor, during which the subject either (a) does not receive the momelotinib therapy, or (b) receives a reduced amount of the momelotinib therapy.
  • Embodiment 60 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a momelotinib therapy comprising from about 50 mg to about 200 mg of momelotinib or a pharmaceutically acceptable salt thereof, wherein the method comprises: administering to the subject a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof; and continuing to administer to the subject the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, during which the subject either (a) does not receive the momelotinib therapy, or (b) receives a reduced amount of the momelotinib therapy.
  • Embodiment 61 The method of embodiment 59 or 60, wherein the reduced amount of the momelotinib therapy comprises ⁇ 50% or 75% of the momelotinib therapy.
  • Embodiment 62 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 0.6 mg/kg or 1.75 mg/kg of luspatercept for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor.
  • Embodiment 63 A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising: administering to the subject a dose from about 0.6 mg/kg or 1.75 mg/kg of luspatercept for a period of up to about 36 months; determining or having determined if the subject had an adverse event during the treatment period; reducing the dose amount from about 33% to about 80%, or temporarily stopping the dose; and administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • Embodiment 64 The method of embodiment 62 or 63, wherein the adverse event is fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, hypersensitivity, or a combination of two or more thereof.
  • Embodiment 65 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a luspatercept therapy comprising from about 0.5 mg/kg or 1.75 mg/kg of luspatercept, wherein the method comprises: administering to the subject a therapeutically effective amount of a selective PIM1 inhibitor; and continuing to administer to the subject the therapeutically effective amount of the selective PIM1 inhibitor, during which the subject either (a) does not receive the luspatercept therapy, or (b) receives a reduced amount of the luspatercept therapy.
  • Embodiment 66 A method of treating a myeloproliferative neoplasm in a human subject in need thereof while the subject is undergoing a luspatercept therapy comprising from about 0.5 mg/kg or 1.75 mg/kg of luspatercept, wherein the method comprises: administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof; and continuing to administer to the subject the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, during which the subject either (a) does not receive the luspatercept therapy, or (b) receives a reduced amount of the luspatercept therapy.
  • Embodiment 67 The method of embodiment 65 or 66, wherein the reduced amount of the luspatercept therapy comprises ⁇ 50% or 75% of the luspatercept therapy.
  • Embodiment 67a A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising administering to the subject therapeutically effective doses of ropeginterferon alfa-2b and Compound (1) or pharmaceutically acceptable salts thereof.
  • Embodiment 67b A method of treating a myeloproliferative neoplasm in a human subject in need thereof, without causing a clinically significant risk of adverse events, comprising administering to the subject therapeutically effective doses of navtemadelin and Compound (1) or pharmaceutically acceptable salts thereof.
  • Embodiment 68 The method of any of the foregoing embodiments wherein the subject has poor bone marrow functioning characterized by thrombocytopenia (e.g. a platelet count of ⁇ 150, 100, 75, 50, or 25 ⁇ 10 9 /L).
  • Embodiment 69 Embodiment 69.
  • Embodiment 70 The method of any of the foregoing Embodiments wherein the subject has poor bone marrow functioning characterized by transfusion dependence.
  • Embodiment 71 The method of any of the foregoing Embodiments wherein the subject has poor bone marrow functioning characterized by a platelet count of ⁇ 100 x 10 9 /L.
  • Embodiment 72 The method of any of the foregoing Embodiments wherein the subject has poor bone marrow functioning characterized by a platelet count of ⁇ 100 x 10 9 /L.
  • Embodiment 75 The method of any of the foregoing Embodiments wherein the subject has poor bone marrow functioning characterized by a platelet count of ⁇ 50 x 10 9 /L.
  • Embodiment 73 The method of any of the foregoing Embodiments wherein the subject has poor bone marrow functioning characterized by a Hgb level ⁇ 10 g/dL.
  • Embodiment 74 The method of any of the foregoing Embodiments wherein the subject has poor bone marrow functioning characterized by a Hgb level ⁇ 8 g/dL.
  • Embodiment 75 Embodiment 75.
  • Embodiment 76 The method of any of the foregoing Embodiments, wherein the subject has poor bone marrow functioning characterized by: (a) a platelet count of ⁇ 50 ⁇ 10 9 /L; (b) a Hgb level ⁇ 8 g/dL; (c) transfusion dependence; or (d) a combination thereof.
  • Embodiment 77 The method of any of the foregoing Embodiments, wherein the subject has poor bone marrow functioning characterized by: (a) a platelet count of ⁇ 50 ⁇ 10 9 /L; (b) a Hgb level ⁇ 8 g/dL; (c) transfusion dependence; or (d) a combination thereof.
  • Embodiment 78 The method of any of the foregoing Embodiments for treating a myeloproliferative neoplasm by inducing TSS50 in a human subject in need thereof, wherein the myeloproliferative neoplasm is treated by inducing TSS50 in the subject at a time point between and including 24 and 48 weeks.
  • Embodiment 79 Embodiment 79.
  • Embodiment 80 The method of any of the foregoing Embodiments, comprising administering to the subject Compound (1) or a pharmaceutically acceptable salt thereof and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities selected from anemia, thrombocytopenia, and transfusion dependence.
  • Embodiment 80 The method of any of the foregoing Embodiments, comprising administering to the subject Compound (1) or a pharmaceutically acceptable salt thereof and ruxolitinib or momelotinib or a pharmaceutically acceptable salt thereof in amounts that induce no overlapping hematological toxicities in terms of anemia and thrombocytopenia and transfusion dependence.
  • Embodiment 81 The method of any of the foregoing Embodiments, for treating a myeloproliferative neoplasm by inducing a probability of SVR35 in the subject ⁇ 15% or 20%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and has relapsed disease or is refractory to the JAK inhibitor, wherein the treatment induces a probability of SVR35 in the human subject > 15% or 20%.
  • Embodiment 81a Embodiment 81a.
  • Embodiment 81b when undertaken as monotherapy, for treating a myeloproliferative neoplasm by inducing a probability of SVR35 in the subject ⁇ 20% or 25%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and has relapsed disease or is refractory to the JAK inhibitor, wherein the treatment induces a probability of SVR35 in the human subject > 20% or 25%.
  • Embodiment 81c when undertaken in combination with momelotinib, for treating a myeloproliferative neoplasm by inducing a probability of SVR35 in the subject ⁇ 20% or 30%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and has relapsed disease or is refractory to the JAK inhibitor, wherein the treatment induces a probability of SVR35 in the human subject > 20% or 30%.
  • Embodiment 81c Embodiment 81c.
  • Embodiment 82 when undertaken in combination with ruxolitinib, for treating a myeloproliferative neoplasm by inducing a probability of SVR35 in the subject ⁇ 40% or 50%, wherein the treatment induces a probability of SVR35 in the human subject > 40% or 50%.
  • Embodiment 82a for treating a myeloproliferative neoplasm by inducing a probability of TSS50 in the subject ⁇ 30%, 35%, 40%, 45%, or 50%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and has relapsed disease or is refractory to the JAK inhibitor, wherein the treatment induces a probability of TSS50 in the human subject ⁇ 30%, 35%, 40%, 45%, or 50%.
  • Embodiment 82b when undertaken as monotherapy, for treating a myeloproliferative neoplasm by inducing a probability of TSS50 in the subject ⁇ 30% or 40%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and has relapsed disease or is refractory to the JAK inhibitor, wherein the treatment induces a probability of TSS50 in the human subject ⁇ 30% or 40%.
  • Embodiment 82c when undertaken in combination with momelotinib, for treating a myeloproliferative neoplasm by inducing a probability of TSS50 in the subject ⁇ 40% or 45%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and has relapsed disease or is refractory to the JAK inhibitor, wherein the treatment induces a probability of TSS50 in the human subject ⁇ 40% or 45%.
  • Embodiment 82c Embodiment 82c.
  • Embodiment 83 when undertaken in combination with ruxolitinib, for treating a myeloproliferative neoplasm by inducing a probability of TSS50 in the subject ⁇ 50% or 60%, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and has relapsed disease or is refractory to the JAK inhibitor, wherein the treatment induces a probability of TSS50 in the human subject ⁇ 50% or 60%.
  • Embodiment 83 Embodiment 83.
  • Embodiment 85 The method of any of the foregoing Embodiments, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm and has relapsed disease or is refractory to the JAK inhibitor.
  • Embodiment 84 The method of any of the foregoing Embodiments, wherein the subject has previously been treated by a JAK inhibitor for the myeloproliferative neoplasm for ⁇ 3, 6, 9, or 12 months and has relapsed disease or is refractory to the JAK inhibitor.
  • Embodiment 85 Embodiment 85.
  • Embodiment 86 The method of any of the foregoing Embodiments, by inducing SVR35 and TSS50 in the subject, wherein the myeloproliferative neoplasm is treated by inducing SVR35 and TSS50 in the subject, optionally at a time point between and including 24 and 48 weeks.
  • a clinically meaningful response in the subject selected from: (a) a clinically meaningful decrease in splenomegaly from a baseline spleen size of, e.g., ⁇ 450, 600, 750, 1,000, 1,500, or 2,000 cm 3 by imaging; (b) a clinically meaningful reduction in an elevated TSS from a baseline TSS of, e.g., ⁇ 15, 20, 25, 30, 35, 40, 45, or 50 per the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0; (c) a clinically meaningful improvement in poor bone marrow function selected from thrombocytopenia (e.g.
  • Embodiment 87 Embodiment 87.
  • Embodiment 88 The method of any of the foregoing Embodiments, by inducing a clinically meaningful decrease in an elevated TSS (e.g.
  • Embodiment 89 The method of any of the foregoing Embodiments, by inducing a clinically meaningful reduction in fibrosis (e.g. ⁇ 1 grade) from a baseline fibrosis of, e.g., grade 2 or higher, wherein the clinically meaningful reduction is induced in response to the administration.
  • Embodiment 90 The method of any of the foregoing Embodiments, by inducing a clinically meaningful reduction in fibrosis (e.g. ⁇ 1 grade) from a baseline fibrosis of, e.g., grade 2 or higher, wherein the clinically meaningful reduction is induced in response to the administration.
  • Embodiment 91 The method of any of the foregoing Embodiments, by inducing a clinically meaningful response in the subject selected from: (a) complete remission; (b) partial remission; (c) clinical improvement; and (d) stable disease; wherein the clinically meaningful response is evaluated by IWG-MRT response criteria; and the clinically meaningful response is induced in the subject in response to the administration.
  • Embodiment 92 Embodiment 92.
  • Embodiment 95 The method of any of the foregoing Embodiments, wherein the subject at baseline has splenomegaly (e.g., ⁇ 450, 600, 750, 1,000, 1,500, or 2,000 cm 3 by imaging).
  • Embodiment 93 The method of any of the foregoing Embodiments, wherein the subject at baseline has elevated TSS (e.g., ⁇ 15, 20, 25, 30, 35, 40, 45, or 50 per the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0).
  • Embodiment 94 The method of any of the foregoing Embodiments, wherein the subject at baseline has fibrosis (e.g., grade 2 or higher).
  • Embodiment 95 The method of any of the foregoing Embodiments, wherein the subject at baseline has fibrosis (e.g., grade 2 or higher).
  • Embodiment 96 The method of any of the foregoing Embodiments, wherein the subject at baseline has ⁇ 2 or 3 measurable symptoms of myelofibrosis per MFSAF v4.
  • Embodiment 97 The method of any of the foregoing Embodiments, wherein the subject has previously been treated by a BET inhibitor (e.g. pelabresib), an ACVR1 inhibitor (e.g. pacritinib), or a telomerase inhibitor (e.g. imetelstat), optionally for ⁇ 3 or 6 months.
  • Embodiment 98 Embodiment 98.
  • Embodiment 101 The method of any of the foregoing Embodiments, wherein the myeloproliferative neoplasm is Intermediate-1, Intermediate-2, or High Risk myelofibrosis on the DIPSS scoring system.
  • Embodiment 99 The method of any of the foregoing Embodiments, wherein the myeloproliferative neoplasm is Low Risk myelofibrosis on the DIPSS scoring system.
  • Embodiment 100 The method of any of the foregoing Embodiments, wherein the subject is positive for a mutation selected from JAK2V617F, MPLW515L, or CALR, or a combination of two or three of the mutations.
  • Embodiment 101 Embodiment 101.
  • Embodiment 102 The method of any of the foregoing Embodiments, wherein the Compound (1) or a pharmaceutically acceptable salt thereof is administered as monotherapy for the myeloproliferative neoplasm and the subject has previously been treated with a JAK inhibitor.
  • Embodiment 103 Embodiment 103.
  • Embodiment 104 The method of any of Embodiments 1-101, wherein the Compound (1) or a pharmaceutically acceptable salt thereof is administered in combination with momelotinib or a pharmaceutically acceptable salt thereof, wherein the subject has previously been treated with a JAK inhibitor other than momelotinib or a pharmaceutically acceptable salt thereof and has poor bone marrow functioning.
  • Embodiment 104 The method of any of Embodiments 1-101, wherein the Compound (1) or a pharmaceutically acceptable salt thereof is administered in combination with ruxolitinib or a pharmaceutically acceptable salt thereof, wherein the subject is treatment na ⁇ ve to a JAK inhibitor prior to initiating the method.
  • Embodiment 105 Embodiment 105.
  • Embodiment 106 The method of any of the foregoing Embodiments, further comprising administering a BET inhibitor (e.g. pelabresib), an ACVR1 inhibitor (e.g.
  • Embodiment 107 The method of any of the foregoing Embodiments, optionally comprising administering the Compound (1) or a pharmaceutically acceptable salt thereof BID.
  • Embodiment 108 The method of any one of the foregoing embodiments, comprising continuing administering to the subject a therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt, wherein: the subject has a platelet count reduction of (a) less than 1 grade, or (b) less than or equal to 25 x 10 9 /L, and/or (c) less than or equal to 35%, and the platelet count reduction is determined by a change in the baseline platelet count determined within one week prior to administering Compound (1) or the pharmaceutically acceptable salt and a second platelet count determined at least 2 weeks after administering.
  • Embodiment 109 The method of any one of the foregoing embodiments, wherein the method minimizes, lessens, or ameliorates adverse events in the subject.
  • Embodiment 110 The method of any one of the foregoing embodiments, wherein the method results in an improvement in symptoms selected from the group consisting of fever, night sweats, early satiety, weight loss, fatigue, weakness, shortness of breath, enlarged spleen or liver, left upper abdominal pain, bone or joint pain, easy bruising, easy bleeding, and combinations of two or more thereof.
  • Embodiment 111 The method of any one of the foregoing embodiments, wherein the method results in minimizing, lessening, or ameliorating of fever, night sweats, early satiety, weight loss, fatigue, weakness, shortness of breath, enlarged spleen or liver, left upper abdominal pain, bone or joint pain, easy bruising, easy bleeding, or a combination of two or more thereof.
  • Embodiment 112 The method of any one of the foregoing embodiments, wherein the method results in a down-regulation of adiponectin, angiopoietin 1, angiotension II, beta- 2 microglobulin, bone morphogenetic protein (BMP) and subtypes thereof (e.g., BMP1, BMP6, and BMP7), bone morphogenetic protein Rcp2, brain-derived neurotrophic factor (BDNF), C-C motif chemokine ligand (CCL) and subtypes thereof (e.g., CCL14 and CCL21), cluster of differentiation 40 ligand (CD40L), cluster of differentiation 40 (CD40), colony stimulating factor (CSF1), complement factor D, C-reactive protein (CRP), C-X3-C motif chemokine receptor 1 (CX3CR1), C-X-C motif chemokine ligand (CXL) and subtypes thereof (e.g., CXL11, CXCL12, and
  • Embodiment 113 The method of any one of the foregoing embodiments, wherein the method results in a down-regulation of IL-1Ra, IL-6, IL-10, IL-12, IL-12, TGF-beta, EGFR, ferritin, GRO-a, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, VCAM-1, or a combination of two or more thereof.
  • Embodiment 114 The method of any one of the foregoing embodiments, wherein the method improves clinically meaningful overall survival in the subject.
  • Embodiment 115 The method of any one of the foregoing embodiments, wherein the method results in the subject exhibiting normalization or increased platelet count, normalization or increased neutrophil count, normalization or increased hemoglobin count, transfusion improvement (including conversion into transfusion independence), or a combination of two or more thereof.
  • Embodiment 116 The method of any one of the foregoing embodiments, wherein the method results in the subject exhibiting bone marrow fibrosis reduction, total symptom reduction, cytokine modulation, or a combination of two or more thereof.
  • Embodiment 117 The method of any one of the foregoing embodiments, wherein the method results in a Total Symptoms Score (TSS) reduction of greater than 50%.
  • Embodiment 119 The method of any one of the foregoing embodiments, wherein the method results in a Total Symptoms Score (TSS) reduction of greater than 70%.
  • Embodiment 120 The method of any one of the foregoing embodiments, wherein the method reduces bone marrow fibrosis in the subject.
  • Embodiment 121 The method of any one of the foregoing embodiments, wherein the method results in at least 1 grade reduction of bone marrow fibrosis in the subject.
  • Embodiment 122 The method of any one of the foregoing embodiments, wherein the method reduces spleen volume in the subject.
  • Embodiment 123 The method of any one of the foregoing embodiments, wherein the method results in clinical improvement of blood cells or neutropenia counts, and/or ameliorating thrombocytopenia.
  • Embodiment 124 The method of any one of the foregoing embodiments, wherein the method results in the subject being cytogenetic remission or molecular partial or complete remission.
  • Embodiment 125 The method of any one of the foregoing embodiments, wherein the method results in partial or complete remission in the subject.
  • Embodiment 126 The method of any one of the foregoing embodiments, wherein the method ameliorates anemia in the subject.
  • Embodiment 127 The method of any one of the foregoing embodiments, wherein the method results in ⁇ 20 g/L increasing in hemoglobin level or changing transfusion- depending to transfusion-independent in the subject.
  • Embodiment 128 The method of any one of the foregoing embodiments, wherein the method results in improvement of Patient Global Impression of Change (PGIC) questionnaire (at least 1 score increase) at week 24.
  • PGIC Patient Global Impression of Change
  • Embodiment 129 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 120 mg to about 3000 mg.
  • Embodiment 130 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 240 mg to about 1440 mg daily.
  • Embodiment 131 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 240 mg to about 1200 mg.
  • Embodiment 132 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 240 mg to about 1000 mg.
  • Embodiment 133 The method of any one of the foregoing embodiments, the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt is from about 240 mg to about 900 mg.
  • Embodiment 134 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 240 mg to about 800 mg.
  • Embodiment 135 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 240 mg to about 700 mg.
  • Embodiment 136 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 240 mg to about 600 mg.
  • Embodiment 137 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 240 mg to about 500 mg.
  • Embodiment 138 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 350 mg to about 1350 mg.
  • Embodiment 139 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 400 mg to about 1250 mg.
  • Embodiment 140 The method of any one of the foregoing embodiments, wherein the therapeutically effective amount of Compound (1) or the pharmaceutically acceptable salt from about 450 mg to about 1150 mg.
  • Embodiment 141 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 500 mg to about 1050 mg.
  • Embodiment 142 The method of any one of the foregoing embodiments, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 550 mg to about 1000 mg.
  • Embodiment 143 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 350 mg to about 1000 mg.
  • Embodiment 144 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 450 mg to about 900 mg.
  • Embodiment 145 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 450 mg to about 800 mg.
  • Embodiment 146 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 450 mg to about 750 mg.
  • Embodiment 147 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 470 mg to about 730 mg.
  • Embodiment 148 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 120 mg to about 580 mg, about 581 mg to about 1040 mg, or about 1041 mg to about 1500 mg.
  • Embodiment 149 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 120 mg/day to about 1500 mg/day.
  • Embodiment 150 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 350 mg/day to about 2100 mg/day.
  • Embodiment 151 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 550 mg/day to about 2000 mg/day.
  • Embodiment 152 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 700 mg/day to about 1950 mg/day.
  • Embodiment 153 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 120 mg/day to about 800 mg/day.
  • Embodiment 154 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 200 mg/day to about 750 mg/day.
  • Embodiment 155 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 250 mg/day to about 650 mg/day.
  • Embodiment 156 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount from about 240 mg to about 1440 mg twice daily.
  • Embodiment 157 The method of any one of embodiments 1-128, wherein Compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1440 mg twice daily.
  • Embodiment 158 The method of any one of the foregoing embodiments, comprising administering the selective PIM1 inhibitor or Compound (1) or its pharmaceutically acceptable salt at least once daily.
  • Embodiment 159 The method of any one of the foregoing embodiments, comprising administering the selective PIM1 inhibitor or Compound (1) or its pharmaceutically acceptable salt at least twice daily.
  • Embodiment 160 The method of any one of the foregoing embodiments, comprising administering the selective PIM1 inhibitor or Compound (1) or its pharmaceutically acceptable salt twice daily.
  • Embodiment 161 The method of any one of the foregoing embodiments, comprising administering the selective PIM1 inhibitor or Compound (1) or its pharmaceutically acceptable salt at least three times daily.
  • Embodiment 162 The method of any one of the foregoing embodiments, comprising administering the selective PIM1 inhibitor or Compound (1) or its pharmaceutically acceptable salt at least four times daily.
  • Embodiment 163 The method of any one of the foregoing embodiments, further comprising administering ruxolitinib or its pharmaceutically acceptable salt in an amount of about 5 mg, 10 mg, 15 mg, or 25 mg.
  • Embodiment 164 The method of any one of the foregoing embodiments, further comprising administering fedratinib or its pharmaceutically acceptable salt in an amount of about 200 mg or 400 mg.
  • Embodiment 165 The method of any one of the foregoing embodiments, further comprising administering pacritinib or its pharmaceutically acceptable salt in an amount of about 100 mg or 200 mg.
  • Embodiment 166 The method of any one of the foregoing embodiments, further comprising administering momelotinib or its pharmaceutically acceptable salt in an amount of about 100 mg or 200 mg.
  • Embodiment 167 The method of any one of the foregoing embodiments, further comprising administering luspatercept in an amount of at least about 1 mg/kg or 1.25 mg/kg based on the subject’s body weight.
  • Embodiment 168 The method of embodiment 167, wherein luspatercept is administrated once every 3 weeks by subcutaneous injection for at least 21 weeks.
  • Embodiment 169 The method of any one of embodiments 163-166, wherein administering ruxolitinib, fedratinib, pacritinib, or momelotinib, or the pharmaceutically acceptable salt is at least one dose a day.
  • Embodiment 170 The method of any one of embodiments 163-166, wherein administering ruxolitinib, fedratinib, pacritinib, or momelotinib, or the pharmaceutically acceptable salt is at least two doses a day.
  • Embodiment 171 The method of any one of embodiments 163-168, comprising administering Compound (1) or the pharmaceutically acceptable salt and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or the pharmaceutically acceptable salt thereof concurrently.
  • Embodiment 172 The method of any one of embodiments 163-168, comprising administering Compound (1) or the pharmaceutically acceptable salt and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or the pharmaceutically acceptable salt is sequentially.
  • Embodiment 173 The method of any one of the foregoing embodiments, wherein, when a baseline platelet count is referenced, the baseline platelet count is measured within one week prior to initiation of the administering Compound (1) or the pharmaceutically acceptable salt.
  • Embodiment 174 The method of any one of the foregoing embodiments, further comprising monitoring complete blood counts in the subject and titrating a dose amount of Compound (1) or a pharmaceutically acceptable salt thereof.
  • Embodiment 175 The method of any one of the foregoing embodiments, further comprising monitoring platelet counts and increasing the dose amount or frequency (i.e., up- titrating) if the platelet count change is (a) less than 1 grade, (b) decreased by less than 25 x 10 9 /L, and/or (c) decreased by less than 35%, based on the subject’s baseline platelet count (i.e., platelet count prior to starting treatment).
  • Embodiment 176 The method of any one of the foregoing embodiments, further comprising monitoring platelet counts and decreasing the dose amount or lessening the dose frequency (collectively, down-titrating) if the platelet count change is (a) up 1 or more grades, (b) decreased by more than 25 x 10 9 /L, and/or (c) decreased by more than 35%.
  • Embodiment 177 The method of claim 175, wherein the platelet count has moved up from grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4.
  • Embodiment 178 The method of any one of embodiments 164-177, wherein the monitoring is performed prior to, during, and/or after the treatment.
  • Embodiment 179 The method of any one of embodiments 174-178, wherein the monitoring is performed once a week or every 2 to 4 weeks.
  • Embodiment 180 The method of any one of embodiments 174-179, further comprising continuing the titrating the dose amount or frequency until achieving a desired stable clinical state.
  • Embodiment 181 The method of any one of the foregoing embodiments, further comprising when ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or a pharmaceutically acceptable salt thereof is administered, monitoring complete blood counts in the subject and titrating the dose amount of ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, ropeginterferon alfa-2b, or navtemadelin, or pharmaceutically acceptable salt thereof.
  • Embodiment 182 The method of any one of the foregoing embodiments, further comprising monitoring comprising assessing platelet counts in the subject prior to, during, and/or after the treatment.
  • Embodiment 183 The method of any one of the foregoing embodiments, further comprising, when ruxolitinib or its pharmaceutically acceptable salt is administered, starting ruxolitinib or its pharmaceutically acceptable salt at a dose: 20 mg twice daily if baseline platelet count is greater than 200 ⁇ 10 9 /L, 10 mg twice daily if baseline platelet count is from 100 ⁇ 10 9 /L to 200 ⁇ 10 9 /L, 5 mg twice daily if baseline platelet count is from 50 ⁇ 10 9 /L to less than 100 ⁇ 10 9 /L.
  • Embodiment 184 The method of embodiment 183, further comprising increasing the dose amount if the subject’s response is insufficient and platelet and neutrophil counts are adequate.
  • Embodiment 185 The method of embodiment 184, comprising increasing the dose in the amount of 5 mg twice daily increments to a maximum of 25 mg twice daily.
  • Embodiment 186 The method of embodiment 184 or 185, comprising increasing the dose amount of ruxolitinib or a pharmaceutically acceptable salt thereof in the subject that meets all of the following conditions: failure to achieve a reduction from pretreatment baseline in either palpable spleen length of 50% or a 35% reduction in spleen volume as measured by computed tomography (CT) or magnetic resonance imaging (MRI); platelet count greater than 125 ⁇ 10 9 /L at 4 weeks and platelet count never below 100 ⁇ 10 9 /L; and ANC Levels greater than 0.75 ⁇ 10 9 /L.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • Embodiment 187 The method of embodiment 184 or 185, comprising increasing the dose amount of ruxolitinib or a pharmaceutically acceptable salt thereof in the subject by increments of 5 mg daily to a maximum of 10 mg twice daily if: the platelet count has remained at least 40 ⁇ 10 9 /L, the platelet count has not fallen by more than 20% in the prior 4 weeks, the ANC is more than 1 ⁇ 10 9 /L, and the dose has not been reduced or interrupted for an adverse event or hematological toxicity in the prior 4 weeks.
  • Embodiment 188 The method of embodiment 184 or 185, comprising titrating the dose amount of ruxolitinib or a pharmaceutically acceptable salt thereof according to Table (a) for thrombocytopenia for the subject whose treatment started with a platelet count of 100 ⁇ 10 9 /L or greater: Table (a)
  • Embodiment 189 The method of embodiment 184 or 185, comprising titrating the dose amount of ruxolitinib or a pharmaceutically acceptable salt thereof according to Table (b) for thrombocytopenia for the subject whose treatment started with a platelet count of 50 ⁇ 10 9 /L to less than 100 ⁇ 10 9 /L: Table (b)
  • Embodiment 190 The method of any one of embodiments 1-182, further comprising, when fedratinib is administered, starting fedratinib or a pharmaceutically acceptable salt thereof in the subject at 200, 300, or 400 mg once daily for
  • Embodiment 191 The method of embodiment 190, comprising reducing the dose amount of fedratinib to 100 mg or below, or temporarily stopping the doses if adverse reactions develop.
  • Embodiment 192 The method of embodiment 191, wherein the adverse reaction is anemia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with active bleeding, grade 3 or higher nausea, vomiting, diarrhea, anemia, or elevations of alanine transaminase (ALT), aspartate aminotransferase (AST), or bilirubin.
  • the adverse reaction is anemia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with active bleeding, grade 3 or higher nausea, vomiting, diarrhea, anemia, or elevations of alanine transaminase (ALT), aspartate aminotransferase (AST), or bilirubin.
  • Embodiment 193 The method of any of embodiments 1-182, further comprising, when pacritinib is administered, starting pacritinib or a pharmaceutically acceptable salt thereof in the subject at 100 mg or 200 mg twice daily for patients with a baseline platelet count below 50 x 10 9 /L.
  • Embodiment 184 The method of embodiment 183, comprising reducing the dose amount of pacritinib to 100 mg or below if adverse reactions develop.
  • Embodiment 195 The method of embodiment 194, wherein the adverse reaction is diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema.
  • Embodiment 196 The method of embodiment 194 or 195, further comprising temporarily stopping the dose if any clinically significant worsening of thrombocytopenia that lasts more than 7 days, until toxicity is resolved, and restarting pacritinib or the pharmaceutically acceptable salt at 50% of last dose given.
  • Embodiment 197 The method of any of embodiments 1-182, further comprising, when luspatercept is administered, starting luspatercept in the subject at 0.5 mg/kg or 1 mg/kg by subcutaneous injection once every 3 weeks.
  • Embodiment 198 The method of embodiment 197, comprising titrating the dose amount of luspatercept if the subject’s response is insufficient or adverse actions develop.
  • Embodiment 199 The method of embodiment 198, further comprising titrating the dose based on responses according to Table (c): Table (c)
  • Embodiment 200 The method of embodiment 198, comprising titrating the dose based on responses according to Table (d): Table (d)
  • Embodiment 201 The method of any of embodiment 1-182, further comprising, when momelotinib is administered, administering momelotinib or a pharmaceutically acceptable salt thereof in the subject at a dose of about 50 mg to about 200 mg when the subject is suffering from intermediate or high-risk primary or secondary (post-PV or post-ET) myelofibrosis with hemoglobin level ⁇ 10.
  • Embodiment 202 The method of any one of the foregoing embodiments, wherein the myeloproliferative neoplasm is responsive to selective PIM1 inhibition.
  • Embodiment 203 The method of any one of the foregoing embodiments, wherein the myeloproliferative neoplasm is a JAK inhibitor-resistant myeloproliferative neoplasm.
  • Embodiment 204 The method of any one of the foregoing embodiments, wherein the myeloproliferative neoplasm is myelofibrosis.
  • Embodiment 205 The method of any one of embodiments 1-203, wherein the myeloproliferative neoplasm is intermediate-risk myelofibrosis or high-risk myelofibrosis.
  • Embodiment 206 The method of any one of the embodiments 1-203, wherein the myeloproliferative neoplasm is primary or idiopathic myelofibrosis.
  • Embodiment 207 The method of any one of embodiments 1-203, wherein the myeloproliferative neoplasm is secondary myelofibrosis. (e.g., post-PV myelofibrosis and post-ET myelofibrosis).
  • Embodiment 208 The method of any one of embodiments 1-203, wherein the myeloproliferative neoplasm is selected from polycythemia vera (PV), primary or essential thrombocythemia (ET), or pre-myelofibrosis.
  • Embodiment 209 The method of any one of the foregoing embodiments, wherein the subject has not been previously treated with a JAK inhibitor.
  • Embodiment 210 The method of any one of the foregoing embodiments, wherein the subject has not been treated with a JAK inhibitor for at least 2 weeks prior to administering Compound (1) or the pharmaceutically acceptable salt.
  • Embodiment 211 The method of any one of the foregoing embodiments wherein the subject has been previously treated with a JAK inhibitor and exhibited an inadequate response.
  • Embodiment 212 The method of any one of the foregoing embodiments, wherein the subject has been previously treated with a JAK inhibitor and exhibited an inadequate response defined as resistance or intolerance to the JAK inhibitor, loss or failure to obtain significant spleen response or total symptom response, and/or developing clinically significant reduction of count of blood cells, neutropenia, or thrombocytopenia.
  • Embodiment 213 The method of any one of the foregoing embodiments, wherein the subject is intolerant of a JAK inhibitor therapy, is resistant to a JAK inhibitor therapy, or is ineligible for a JAK inhibitor therapy.
  • Embodiment 214 The method of any one of the foregoing embodiments, wherein the subject has experienced relapse from a prior JAK inhibitor therapy.
  • Embodiment 215 The method of any one of the foregoing embodiments, wherein the subject has experienced relapse from a prior bone marrow transplant.
  • Embodiment 216 The method of any one of the foregoing embodiments, wherein the subject has moderate or severe splenomegaly at baseline.
  • Embodiment 217 The method of any one of the foregoing embodiments, wherein the subject has a total symptoms score (TSS) at baseline greater than 15, 20, 25, 30, 35, 40, 45, or 50.
  • TSS total symptoms score
  • Embodiment 218 The method of any one of the foregoing embodiments, wherein the subject is in need of cytokine modulation.
  • Embodiment 219 The method of any one of the foregoing embodiments, wherein the subject has a JAK2V16F mutation.
  • Embodiment 220 The method of any one of the foregoing embodiments, wherein the subject has a CALR mutation.
  • Embodiment 221 The method of any one of the foregoing embodiments, wherein the subject has grade 2 or higher fibrosis.
  • Embodiment 222 The method of any one of the foregoing embodiments, wherein the subject has an absolute neutrophil count of greater than 1 ⁇ 10 9 /L.
  • Embodiment 223 The method of any one of the foregoing embodiments, wherein the subject has a peripheral blood blast less than 10%.
  • Embodiment 224 The method of any one of the foregoing embodiments, wherein the subject has a baseline platelet count of less than 200 ⁇ 10 9 /L.
  • Embodiment 225 The method of any one of the foregoing embodiments, wherein the subject has a baseline platelet count of less than 150 ⁇ 10 9 /L.
  • Embodiment 226 The method of any one of the foregoing embodiments, wherein the subject has a baseline platelet count of less than 100 ⁇ 10 9 /L.
  • Embodiment 227 The method of any one of the foregoing embodiments, wherein the subject has a baseline platelet count of less than 50 ⁇ 10 9 /L.
  • Embodiment 228 The method of any one of the foregoing embodiments, wherein the subject has a baseline platelet count of greater than 10 ⁇ 10 9 /L.
  • Embodiment 229 The method of any one of the foregoing embodiments, wherein the subject has a baseline platelet count of greater than 25 ⁇ 10 9 /L.
  • Embodiment 230 The method of any one of the foregoing embodiments, wherein the subject has a baseline platelet count of greater than 35 ⁇ 10 9 /L.
  • Embodiment 231 The method of any one of the foregoing embodiments, wherein Compound (1) or its pharmaceutically acceptable salt is administered for a period from about one week to about two years.
  • Embodiment 232 The method of any one of the foregoing embodiments, wherein Compound (1) or its pharmaceutically acceptable salt is administered for a period from about 15 weeks to about one year.
  • Embodiment 233 The method of any one of the foregoing embodiments, wherein Compound (1) or its pharmaceutically acceptable salt is administered for a period from about 24 weeks to about one year.
  • Embodiment 234 The method of any one of the foregoing embodiments, wherein Compound (1) or the pharmaceutically acceptable salt is administered orally.
  • Embodiment 235 The method of any one of the foregoing embodiments, wherein a hydrochloric acid salt of Compound (1) is administered orally.
  • Embodiment 236 The method of any one of the foregoing embodiments, wherein a crystalline hydrochloric acid salt of Compound (1) is administered orally.
  • Embodiment 237 The method of any one of the foregoing embodiments, when a selective PIM1 inhibitor is administered, the selective PIM1 inhibitor has a PIM1/PIM-2 IC50 ratio of less than 0.05, 0.045, 0.04, 0.035, 0.03, or 0.025.
  • Example 1 In vitro hematological tolerability of Compound (1), ruxolitinib, pacritinib, and momelotinib individually [00613] The potential effects of Compound (1), ruxolitinib, pacritinib and momelotinib (collectively referred to as test compounds) on human myeloid, erythroid and megakaryocyte progenitor proliferation were evaluated using colony forming cell assays to generate IC50 values.
  • Clonogenic progenitors of human erythroid (CFU-E, BFU-E), granulocyte- monocyte (CFU-GM), and multipotential (CFU-GEMM) lineages were assessed in a semi- solid methylcellulose-based media formulation containing rhIL-3 (10 ng/mL), rhGM-SCF (10 ng/mL), rhSCF (50 ng/mL), and Epo (3 U/mL).
  • rhIL-3 10 ng/mL
  • rhGM-SCF 10 ng/mL
  • rhSCF 50 ng/mL
  • Epo (3 U/mL Epo
  • the cells were thawed rapidly, diluted in 10 mL of Iscove’s modified Dulbecco’s medium containing 10% fetal bovine serum (IMDM + 10% FBS) and washed by centrifugation (approximately 1500 r.p.m. for 10 minutes at room temperature). The supernatant was discarded and the cell pellets were resuspended in a known volume of IMDM + 10% FBS. A cell count (3% glacial acetic acid) and viability assessment (trypan blue exclusion test) was performed for the bone marrow sample.
  • Iscove’s modified Dulbecco’s medium containing 10% fetal bovine serum IMDM + 10% FBS
  • FBS fetal bovine serum
  • Clonogenic progenitors of human megakaryocyte were assessed in a collagen-based media formulation containing rhIL-3 (10 ng/mL), rhIL-6 (10 ng/mL), and Tpo (50 ng/mL).
  • Clonogenic progenitors of the human erythroid (CFU-E and BFU-E), myeloid (CFU-GM), and megakaryocyte (CFU-Mk) lineages were set up in the media formulations described above.
  • test compounds were added to the medium to give the final desired concentrations (10, 3.33, 1, 0.333, 0.1, 0.0333, 0.01 and 0.00333 ⁇ M).5- Fluorouracil (Sigma Aldrich) was used as a positive control for progenitor proliferation (inhibition of colony growth) and was introduced to the human bone marrow cultures at 1.0, 0.1, and 0.01 ⁇ g/mL. Solvent control cultures (containing no compound but 0.1% DMSO) as well as standard controls (containing no compound and no DMSO) were also initiated. Once introduced into the matrices, the tubes were vortexed to ensure an equal distribution throughout.
  • the human megakaryocyte cultures were transferred from the 35 mm dishes to labeled glass slides, fixed with methanol/acetone fixative, and then stained with anti-human CD41 antibody and an alkaline phosphate detection system according to manufacturers’ instructions.
  • the colonies were assessed microscopically and scored by trained personnel and divided into the following categories based on size: CFU-Mk (3-20), CFU-Mk (21-49), and CFU-Mk ( ⁇ 50).
  • CFU-Mk 3-20
  • CFU-Mk (21-49) CFU-Mk ( ⁇ 50).
  • Statistical analysis The mean ⁇ standard deviation of three replicate cultures was calculated for both erythroid and myeloid progenitors. Two-tailed standard t-tests were performed to assess if there was a difference in the number of colonies generated between solvent control and treated cultures.
  • Pacritinib significantly inhibited erythroid progenitor proliferation from 10 – 0.333 ⁇ M and additionally myeloid progenitor proliferation at 0.1 ⁇ M, which provided IC 50 values of 0.28 and 0.17 ⁇ M for erythroid and myeloid progenitor proliferation (FIG.1A and 1C, respectively).
  • Ruxolitinib significantly inhibited both erythroid and myeloid progenitor proliferation from 10 – 0.033 ⁇ M, which provided IC 50 values of 0.11 and 0.10 ⁇ M for erythroid and myeloid progenitor proliferation (FIG.1A and 1C, respectively) — making ruxolitinib the most potent compound of the test compounds.
  • Compound (1) inhibited erythroid progenitor proliferation at 10 and 3.33 ⁇ M and myeloid progenitor proliferation at 1.0 ⁇ M, which provided IC 50 values of 4.25 and 1.31 ⁇ M for erythroid and myeloid progenitor proliferation (FIG.1A and 1C, respectively) — making Compound (1) the least inhibitory on erythroid and myeloid progenitor cells.
  • FIG.1B A similar trend was seen in the megakaryocyte progenitor assay with momelotinib and pacritinib significantly inhibiting the total CFU-Mk from 10 – 0.333 ⁇ M, which provided IC50 values of 0.30 and 0.34 ⁇ M, respectively (FIG.1B).
  • ruxolitinib was the most potent with significant inhibition of the total CFU-Mk at concentrations of 0.033 ⁇ M and higher, which provided IC 50 value of 0.2 ⁇ M (FIG.1B).
  • Compound (1) inhibited the total CFU-Mk at 10, 3.33 and 1.0 ⁇ M, which provided IC50 value of 1.56 ⁇ M — making Compound (1) the least inhibitory on megakaryocyte progenitor cells.
  • Compound (1) had the least inhibition on progenitors of human erythroid (CFU-E, BFU-E), granulocyte-monocyte (CFU-GM), and multipotential (CFU-GEMM) lineages.
  • Compound (1) as a monotherapy is expected to be well tolerated with lower myelosuppressive adverse events compared to JAK inhibitors (e.g., ruxolitinib, pacritinib, and momelotinib). Accordingly, Compound (1) should be safe (A) to use in patients with normal or below normal platelets, red blood cells, and/or neutrophils and (B) at doses up to 3000 mg/day and in some embodiments more than 3000 mg/day.
  • JAK inhibitors e.g., ruxolitinib, pacritinib, and momelotinib.
  • Example 2 In vitro hematological tolerability of Compound (1), ruxolitinib, pacritinib, and momelotinib in combination [00624] Following the method of Example 1, combinations of Compound (1) with ruxolitinib, pacritinib, or momelotinib were evaluated. The combinations were made by adding the HCl salt of Compound (1) to the standard dose responses of momelotinib, pacritinib and ruxolitinib to provide a concentration of the HCl salt of Compound (1) at 4.4 and 1.6 ⁇ M (human erythroid and myeloid progenitor proliferation) or 1.6 and 0.5 ⁇ M (human megakaryocyte progenitor proliferation).
  • 1.6 ⁇ M human erythroid and myeloid progenitor proliferation
  • 1.6 and 0.5 ⁇ M human megakaryocyte progenitor proliferation
  • FIGS.2A-4C are human megakaryocytes (CFU-MK)
  • FIGS.3A-3C are human erythroid (CFU-E, BFU-E)
  • FIGS. 4A-4C are human granulocyte-monocyte (CFU-GM).
  • the combination caused a greater change in the IC 50 value compared to the single agents of the myeloid progenitor (CFU-GM) (FIGS.4A-4C) as compared to the erythroid progenitor (CFU-E, BFU-E) (FIGS.3A-3C).
  • the combination also caused more megakaryocyte inhibition (IC 50 values ranging from 0.002 – 0.055 ⁇ M) when compared to the single agents alone (FIGS.2A-2C).
  • combination with Compound (1) should be safe (A) to use in patients with normal platelets, red blood cells, and/or neutrophils at doses at or below 3000 mg/day or (B) to use in patients with below normal platelets, red blood cells, and/or neutrophils at doses below 3000 mg/day (such as at or below 2000 mg/day).
  • Example 3 Clinical trial study treating MF patients with HCl salt of Compound (1) [00627] Patients with MF (primary MF, post-PV MF, post-ET MF) and DIPSS intermediate-1, intermediate-2, or high risk were enrolled in a Phase 1/2 clinical study. All patients were previously treated with a JAK inhibitor and exhibited an inadequate response.
  • Platelet count ⁇ 25 ⁇ 10 9 /L (without the assistance of growth factors or platelet transfusions) b. Absolute neutrophil count (ANC) ⁇ 1 ⁇ 10 9 /L without the assistance of granulocyte growth factors. 6. Peripheral blood blast count ⁇ 10%. 7. Eastern Cooperative Oncology Group (ECOG) performance status ⁇ 2. 8. Life expectancy ⁇ 3 months. 9. Adequate renal function, as determined by clinical laboratory tests (serum creatinine ⁇ 1.5 ⁇ upper limit of normal (ULN), and calculated creatinine clearance ⁇ 30 mL/min) (using Cockcroft-Gault formula). 10.
  • Adequate hepatic function (ALT/AST ⁇ 3 ⁇ ULN, total bilirubin ⁇ 1.5 ⁇ ULN; or ALT/AST ⁇ 5 ⁇ ULN, direct bilirubin ⁇ 2 ⁇ ULN if due to MF); and coagulation ([PT and PTT] ⁇ 1.5 ⁇ ULN).
  • Capable of providing signed informed consent as described in which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol 13.
  • Female breastfeeding patients may be enrolled if they interrupt breastfeeding. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug. 14. Splenomegaly during the screening period as demonstrated by splenic length ⁇ 5 cm below the costal margin by palpation or spleen volume of ⁇ 450 cm 3 by magnetic resonance Imaging (MRI) or computerized tomography (CT) scan 15.
  • MRI magnetic resonance Imaging
  • CT computerized tomography
  • NCI CTCAE Grade ⁇ 2 e.g., serum potassium, magnesium and calcium
  • Severe chronic obstructive pulmonary disease with hypoxemia (defined as resting O 2 saturation of ⁇ 90% breathing room air). Unwilling or unable to comply with procedures required in this protocol Known infection with human immunodeficiency virus, hepatitis B, or hepatitis C. Patients with history of chronic hepatitis that is currently not active are eligible. Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor. Currently receiving any other investigational agent. 22. Exhibited allergic reactions to a similar structural compound, biological agent, or formulation. 23.
  • the best spleen volume reduction ranged from 3 to 42% (median best change -13%) (FIG.5E) over their treatment duration.
  • Nine out of 10 patients with baseline measurements i.e., total symptom score was measured before treatment began
  • the best total symptom reduction ranged from 31 to 100% (median best change -70%) (FIG.5F).
  • 4 patients exhibited reduced spleen size and reduced symptoms while 1 patient exhibited spleen volume reduction and increased symptoms and 1 patient exhibited spleen volume increase and reduced symptoms. Cytokine modulation was observed as early as within the first 24 hours.
  • Cytokine changes over treatment duration was available for 7 patients. More reductions in cytokines were observed in patients who had more total symptoms reduction (FIGS.5H, 5I, and 5J). Bone marrow fibrosis reduction from grade 3 to 2 was seen in one patient who also achieved spleen and symptoms responses and showed reductions in MF associated cytokines: IL6 (68%), IL12p40 (83%), MMP9 (56%), and EN-RAGE (68%), and was on active treatment for >18 months. Myelosuppressive adverse events (i.e., anemia, neutropenia, thrombocytopenia) were observed in 1 patient. [00634] Compound (1) monotherapy showed spleen volume reduction and total symptoms reduction in patients previously treated with JAK inhibitors.
  • Table IV compares the results reported at this interim analysis, in relapsed / refractory patients, to two approved JAK therapies, and three other treatments under development or previously under development for the treatment of myelofibrosis: Table IV [00640] Toxicities were also evaluated from this interim dataset and tabulated in Table V, relative to toxicities reported for other MF treatments.
  • Example 4 Clinical trial study treating MF patients with a combination of Compound (1) and ruxolitinib [00642]
  • patient enrollment will be substantially the same as described in Example 3.
  • patients will be on a stable dose of ruxolitinib from 5mg QD to 25mg BID (no dose change within the previous 12 weeks) for treating MF with a platelet count of ⁇ 50 x 10 9 /L and exhibiting an inadequate response (e.g., an inferior response and/or relapse and/or refractory MF disease).
  • the combination therapy of the HCl salt of Compound (1) with ruxolitinib should lead to an increase in survival and/or decreased rate of leukemia transformation and/or transplant eligibility for patients having an acceptable safety profile.
  • spleen volume reduction In carrying out this protocol, one or more of the following will be observed in some or all of the patient population: spleen volume reduction; improvement in total symptom scores. Based upon the foregoing and without wanting to be bound by theory, it is not expected that any of the following will be observed in the patient population: (i) adverse effects to platelet count; (ii) adverse effects to neutrophil count; or (iii) adverse effects to hemoglobin count.
  • patients receiving the combination therapy will exhibit a normalization or improvement in platelet count, neutrophil count, hemoglobin, and/or transfusion improvement, which may include conversion into transfusion independence. It will also be observed that patients will exhibit a reduction or normalization of cytokines and/or improvement in bone marrow fibrosis by at least 1 grade.
  • the combination therapy of the HCl salt of Compound (1) with ruxolitinib will be seen to provide an increase in survival and/or decreased rate of leukemia transformation and/or a decrease in patients becoming transplant eligible with an acceptable safety profile.
  • Example 5 Clinical trial study treating MF patients with a combination of Compound (1) and momelotinib
  • patient enrollment will be substantially the same as described in Example 3, however, patients will be (A) newly diagnosed with MF or (B) have an inadequate response to a previous treatment with a JAK inhibitor (e.g. ruxolitinib or fedratinib), and, at least at the beginning of the study, will have a platelet count ⁇ 50x10 9 /L. Patients will receive momelotinib from 100 to 200 mg QD and Compound (1) in dose from 240 mg QD to 1440 mg BID. Safety and clinical response will be evaluated.
  • a JAK inhibitor e.g. ruxolitinib or fedratinib
  • Example 6 Clinical trial study treating MF patients with a combination of Compound (1) and pacritinib [00647] For combination treatment with the HCl salt of Compound (1), patient enrollment will be substantially the same as described in Example 3.
  • patients will be (A) newly diagnosed with MF, (B) have relapsed and/or refractory to a previous treatment with a JAK inhibitor (e.g. ruxolitinib or fedratinib), or (C) discontinued from JAK inhibitor therapy due to adverse event.
  • a JAK inhibitor e.g. ruxolitinib or fedratinib
  • Patients will receive pacritinib from 100 to 200 mg QD and Compound (1) in dose from 240 mg QD to 1440 mg BID. Safety and clinical response will be evaluated.
  • It is expected in this treatment population one or more of the following will be observed in some or all of the patient population: spleen volume reduction; improvement in total symptom scores.
  • Example 7 Hematological evaluation of selective PIM1 kinase inhibitors and their impact on platelet counts. [00649] In order to determine the impact of PIM1 selectivity on hematological function, a comparative analysis was undertaken comparing human clinical data reported for 5 different PIM kinase inhibitors.
  • TP-3654 as compared to pan-PIM inhibitors spares megakaryocytopoiesis (cell numbers and ploidy) and affects cytokine elaboration by megakaryocytes (MK) generated in vitro from mononuclear cells (MNC) form the peripheral blood or bone marrow aspirates from PV, ET, pre-MF and MF patients and normal controls.
  • MK megakaryocytes
  • MNC mononuclear cells
  • Improvements versus pan-PIM inhibitors can further be expected on (1) viability, (2) cell number and (3) apoptosis of MNCs isolated from peripheral blood or bone marrow aspirates of PV, ET, pre-MF and MF patients with JAK2V617F and normal controls before (0 hrs, baseline) and after treatment with TP-3654 for 24 hrs, 48 hrs and 72 hrs, and on MPN driver mutated hematopoietic colony formation after 48 hrs of treatment. * * * * * * * * * * * * * * * * * * [00652] All of the U.S. patents, U.S. patent application publications, U.S.

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Abstract

L'invention concerne des méthodes de traitement de néoplasmes myéloprolifératifs, en particulier chez des patients présentant un mauvais fonctionnement de la moelle osseuse, et chez des patients humains difficiles à traiter, notamment ceux qui présentent une maladie récidivante ou réfractaire. Les méthodes de l'invention comprennent l'administration d'un composé (1) présentant la structure suivante ou d'un sel pharmaceutiquement acceptable de celui-ci, et éventuellement d'un inhibiteur des Janus kinases (JAK) et/ou d'un inhibiteur d'ACVR, à un sujet humain en ayant besoin.
EP23814322.6A 2022-10-31 2023-10-30 Inhibiteur de pim-1 pour le traitement de néoplasmes myéloprolifératifs Pending EP4611753A1 (fr)

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US202363506526P 2023-06-06 2023-06-06
PCT/US2023/078187 WO2024097653A1 (fr) 2022-10-31 2023-10-30 Inhibiteur de pim-1 pour le traitement de néoplasmes myéloprolifératifs

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