WO2013013195A1 - Compositions and methods for treating polycythemia vera and essential thrombocythemia - Google Patents

Compositions and methods for treating polycythemia vera and essential thrombocythemia Download PDF

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Publication number
WO2013013195A1
WO2013013195A1 PCT/US2012/047704 US2012047704W WO2013013195A1 WO 2013013195 A1 WO2013013195 A1 WO 2013013195A1 US 2012047704 W US2012047704 W US 2012047704W WO 2013013195 A1 WO2013013195 A1 WO 2013013195A1
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compound
subject
amino
ylethoxy
pyrrolidin
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PCT/US2012/047704
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French (fr)
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Pamela Cohen
Frank Neumann
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Sanofi
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • compositions and methods for treating polycythemia vera and/or essential thrombocythemia relate to treatment of polycythemia vera and/or essential thrombocythemia with compounds that inhibit JAK2 or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • Polycythemia vera is a clonal stem cell disease belonging, along with myelofibrosis (“MF”) and essential thrombocythemia (“ET”), to the 3 classic BCR-ABL- negative myelopoliferative neoplasms (“MPNs”).
  • Polycythemia vera affects proliferation of erythroid, myeloid, and megakaryocyte cell lineages leading primarily to increased hematocrit, leukocytosis and thrombocytosis.
  • patients with PV suffer from splenomegaly and disease-associated symptoms such as pruritus, night sweats, fatigue, and bone pain.
  • PV if progressive despite standard therapies, is associated with an increased risk of thrombosis, bleeding, and progression to MF or even acute myeloid leukemia.
  • a mutation in the JAK2 kinase (JAK2V617F) was found in BCR-ABL-negative classic MPNs. Levine RL et al., Cancer Cell. 2005, 7(4):387-97. This mutation is present in more than 90% of patients with PV.
  • Standard therapies for PV include phlebotomys and low dose aspirin. Hydroxyurea therapy may also be considered for high-risk PV.
  • PV patients treated with hydroxyurea may become intolerant or who develop PV that is resistant to hydroxyurea. There is a therapeutic need for those patients with high- risk PV who do not tolerate or who have PV that is resistant to hydroxyurea.
  • Essential thrombocythemia is a clonal stem cell disease belonging, along with myelofibrosis (“MF”) and polycythemia vera (“PV”), to the 3 classic BCR-ABL- negative myelopoliferative neoplasms (“MPNs”).
  • Essential thrombocythemia is characterized by megakaryocyte hyperplasia and consecutive thrombocytosis.
  • patients with ET suffer from splenomegaly and disease-associated symptoms such as pruritus, night sweats, fatigue, and bone pain. ET, if progressive despite standard therapies, is associated with an increased risk of thrombosis, bleeding, and progression to MF or even acute myeloid leukemia.
  • JAK2 kinase JAK2 kinase
  • JAK2V617F JAK2 kinase
  • Standard therapies for ET include hydroxyurea in high-risk ET. Low-dose aspirin therapy may also be considered for ET. Barbui T et al., J Clin Oncol 2011, 29(6):761-70. ET patients treated with hydroxyurea may become intolerant or resistant to hydroxyurea. There is a therapeutic need for those ET patients who do not tolerate or who have hydroxyurea- resistant ET.
  • PV polycythemia vera
  • the subject has PV
  • the effective amount of N-tert-butyl-3-[(5-methyl-2- ⁇ [4- (2-pyrrolidin-l-ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
  • the dose is administered orally.
  • the subject has PV that is resistant to hydroxyurea or the patient is intolerant to hydroxyurea treatment.
  • the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML).
  • MF myelofibrosis
  • AML acute myeloid leukemia
  • the subject has an increased risk of developing MF.
  • the subject may have one or more of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation.
  • the subject has been previously treated with another JAK 2 inhibitor such as Ruxolitinib.
  • the subject is selected for treatment based on one or more of the following criteria: (i) the subject has PV that is resistant to hydroxyurea or the patient is intolerant to hydroxyurea treatment; (ii) the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib; and (iv) the subject has an increased risk of developing MF, for example, the subject may have one or more of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation.
  • a method described herein may further comprise a step of determining whether the subject meets one or more of the above-mentioned criteria before treatment.
  • the methods described herein further comprise monitoring JAK2V617F mutant allele in blood cells from the subject.
  • the blood cell is granulocyte.
  • the JAK2V617F mutation is monitored in granulocytes from the subject.
  • the methods further comprise monitoring STAT3 phosphorylation level in blood cells.
  • the dose or amount administered (such as the dose or amount orally administered) is about any of 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day.
  • the compound is administered over a period of at least 32 weeks.
  • the compound is provided in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
  • the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
  • the methods further comprise instructing the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the methods further comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the methods further comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19.
  • benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
  • the compound is administered orally.
  • the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment.
  • the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML).
  • MF myelofibrosis
  • AML acute myeloid leukemia
  • the subject has an increased risk of developing MF.
  • the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • the subject is selected for treatment based on one or more of the following criteria: (i) the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment; (ii) the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the subject has an increased risk of developing MF; and (iv) the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • a method described herein may further comprise a step of determining whether the subject meets one or more of the above-mentioned criteria before treatment.
  • the methods described herein further comprise monitoring JAK2V617F mutant allele in blood cells from the subject.
  • the blood cells are granulocytes.
  • the methods further comprise monitoring STAT3 phosphorylation level in blood cells.
  • the dose or amount administered (such as the dose or amount orally administered) is about any of 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day.
  • the compound is administered over a period of at least 32 weeks.
  • the compound is provided in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
  • the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
  • the methods further comprise instructing the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the methods further comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the methods comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19.
  • kits or articles of manufacture comprising (a) a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin- 4-yl)amino] benzenesulfonamide, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) a package insert or a label indicating that i) the compound is useful for treating a subject having polycythemia vera and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound.
  • the package insert or the label indicates that the dose is 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day. In some embodiments, the package insert or the label indicates that the compound is administered over a period of at least 32 weeks.
  • the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
  • the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
  • the package insert or label indicates that the compound is useful for treating a subject having PV that is resistant to hydroxyurea treatment or that the compound is useful for treating a subject having PV where the subject is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having PV in the absence of MF or AML. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing MF.
  • the subject has at least one of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation.
  • the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • the package insert or the label instructs the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the package insert or the label instructs the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the methods further comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19.
  • kits or articles of manufacture comprising (a) a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin- 4-yl)amino] benzenesulfonamide, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) a package insert or a label indicating that i) the compound is useful for treating a subject having essential thrombocythemia and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound.
  • the package insert or the label indicates that the dose is 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day. In some embodiments, the package insert or the label indicates that the compound is administered over a period of at least 32 weeks.
  • the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
  • the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
  • the package insert or label indicates that the compound is useful for treating a subject having ET that is resistant to hydroxyurea treatment or for treating a subject who is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having ET in the absence of MF or AML. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing MF. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • the package insert or the label instructs the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the package insert or the label instructs the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the package insert or the label instructs the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19.
  • PV polycythemia vera
  • the use is according to any of the methods of treating PV provided herein.
  • the compound is for oral administration.
  • the subject has PV that is resistant to hydroxyurea treatment.
  • the subject is intolerant to hydroxyurea treatment.
  • the subject has an increased risk of developing myelofibrosis.
  • the subject has at least one of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygosity for the JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation.
  • the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • the treatment further comprises monitoring JAK2V617F mutant allele in granulocytes from the subject.
  • the treatment further comprises monitoring STAT3 phosphorylation level in blood cells.
  • the blood cells are granulocytes.
  • the compound is for oral
  • the compound is for oral administration over a period of at least 32 weeks.
  • the compound (such as when used in administration) is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4- (2-pyrrolidin- 1 -ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
  • the capsule contains about 50 mg or about 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
  • the treatment further comprises instructing the subject to ingest the effective amount of the compound on an empty stomach.
  • the treatment further comprises instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4.
  • the treatment further comprises instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of
  • the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia.
  • the compound is in a pharmaceutical composition, for example, a pharmaceutical composition comprising N-tert-butyl-3-[(5- methyl-2- ⁇ [4- (2-pyrrolidin- 1 -ylethoxy)phenyl] amino ⁇ pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier.
  • the compound is N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate.
  • the use is according to any of the methods of treating ET provided herein.
  • the compound is for oral administration.
  • the subject has ET that is resistant to hydroxyurea treatment.
  • the subject is intolerant to hydroxyurea treatment.
  • the subject has an increased risk of developing myelofibrosis.
  • the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • the treatment further comprises monitoring JAK2V617F mutant allele in granulocytes from the subject.
  • the treatment further comprises monitoring STAT3 phosphorylation level in blood cells from the subject.
  • the blood cells are granulocytes.
  • the compound is for oral administration at a dose or amount of about any of 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, the compound is for oral administration over a period of at least 32 weeks.
  • the compound (such as when used in administration) is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin- 4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
  • the capsule contains about 50 mg or about 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
  • the treatment further comprises instructing the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the treatment further comprises instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the treatment further comprises instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19. In some embodiments, the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia.
  • MF myelofibrosis
  • the compound is in a pharmaceutical composition, for example, a pharmaceutical composition comprising N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier.
  • the compound is N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.
  • a compound for use in treating polycythemia vera (PV) in a subject wherein the compound is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has PV, wherein the compound is for administration to the subject at an amount of about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
  • the use is according to any of the methods of treating PV provided herein.
  • the compound is for oral administration. In some embodiments,
  • the compound is N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.
  • a compound for use in treating essential thrombocythemia (ET) in a subject wherein the compound is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has ET, wherein the compound is for administration to the subject at an amount of about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
  • the use is according to any of the methods of treating ET provided herein.
  • the compound is for oral administration. In some embodiments,
  • the compound is N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.
  • delay development of a disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or symptoms of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • an "effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to effect beneficial or desired results.
  • beneficial or desired results can include, for example, one or more results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results can include, for example one or more clinical results such as decreasing one or more symptoms and pathological conditions resulting from or associated with the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
  • An effective dosage can be administered in one or more administrations.
  • An effective dosage of drug, compound, or pharmaceutical composition can be, for example, an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an "effective dosage" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • an effective dose results in a reduction in hematocrit.
  • an effective dose results in a hematocrit level below 45% lasting for a minimum of 3 months in the absence of phlebotomy after completion of 8 cycles of therapy.
  • an effective dose results in hematocrit ⁇ 45% without phlebotomy or response in 3 or more of the other criteria.
  • an effective dose results in one or more of the following: i) hematocrit ⁇ 45% without phlebotomy; ii) platelet count ⁇ 400 x 10 9 /L; iii) white blood cell count ⁇ 10 x 10 9 /L; iv) normal spleen size on imaging; v) absence or reduction in disease-related symptoms (such as microvascular disturbances, pruritus, headache).
  • an effective dose results in a platelet count ⁇ 400 x 10 9 /L for a minimum of 3 months after completion of 8 cycles of therapy.
  • an effective dose results in one or more of the following responses: i) platelet count ⁇ 400xl0 9 /L; ii) absence of or reduction in disease-related symptoms (such as microvascular disturbances, pruritus, headache); iii) normal spleen size on imaging; iv) white blood cell count ⁇ 10xl0 9 /L.
  • in conjunction with refers to administration of one treatment modality in addition to another treatment modality.
  • in conjunction with can refer to administration of one treatment modality before, during or after administration of the other treatment modality to the individual.
  • a "patient” or a “subject” refers to a mammal including a human, a dog, a horse, a cow or a cat, etc.
  • pharmaceutically acceptable refers to the fact that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and can be administered to a subject.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • references to "about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X” includes description of "X.” [0042] It is understood that aspects and variations of the compositions and methods provided herein can include “consisting” and/or “consisting essentially of aspects and variations.
  • pharmaceutical compositions comprising N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable excipient or carrier.
  • the compound and the pharmaceutical compositions described herein can be used for treating or delaying development of polycythemia vera (PV) and/or essential
  • N-ieri-Butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide has the following chemical structure:
  • the compound provided herein may be formulated into therapeutic compositions as natural or salt forms.
  • Pharmaceutically acceptable non-toxic salts include the base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases such as, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like.
  • Such salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as, for example, hydrochloric acid, sulfuric acid, or phosphoric acid, or organic acids such as acetic acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, mandelic acid, and the like.
  • Salts of the compounds provided herein can include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like.
  • Salts of the compounds provided herein can also include amine salts formed by the protonation of an amino group with suitable organic acids, such as p-toluenesulfonic acid, acetic acid, methanesulfonic acid and the like.
  • suitable organic acids such as p-toluenesulfonic acid, acetic acid, methanesulfonic acid and the like.
  • Additional excipients which are contemplated for use in the practice of the compositions and methods provided herein are those available to those of ordinary skills in the art, for example, those found in the United States Pharmacopeia Vol. XXII and National Formulary Vol. XVII, U.S. Pharmacopeia Convention, Inc., Rockville, Md. (1989), the relevant contents of which are incorporated herein by reference.
  • the compounds provided herein can include polymorphs.
  • the compound described herein may be in alternative forms.
  • the compound described herein may include a hydrate form.
  • "hydrate” refers to a compound provided herein which is associated with water in the molecular form, i.e., in which the H-OH bond is not split, and may be represented, for example, by the formula R.H 2 0, where R is a compound provided herein.
  • a given compound may form more than one hydrate including, for example, monohydrates (R.H 2 0) or polyhydrates (R.nH 2 0 wherein n is an integer greater than 1) including, for example, dihydrates (R.2H 2 0), trihydrates (R.3H 2 0), and the like, or fractional hydrates, such as, for example, R.n/2H 2 0, R.n/3H 2 0, R.n/4H 2 0 and the like wherein n is an integer.
  • the compounds described herein may also include acid salt hydrate forms.
  • acid salt hydrate refers to a complex that may be formed through association of a compound having one or more base moieties with at least one compound having one or more acid moieties or through association of a compound having one or more acid moieties with at least one compound having one or more base moieties, said complex being further associated with water molecules so as to form a hydrate, wherein said hydrate is as previously defined and R represents the complex herein described above.
  • the compound is N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2- pyrrolidin- 1 -ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide
  • compositions for the administration of the compound described herein, either alone or in combination with other therapeutic agents may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy and methods described in Example 4 of PCT/US2010/056280 filed
  • Such methods can include bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as hard or soft capsules.
  • capsules suitable for oral administration comprising an admixture of (i) a compound which is N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) an excipient (e.g., a microcrystalline cellulose), and (iii) a lubricant (e.g., sodium stearyl fumarate), wherein the admixture is contained in the capsule.
  • an excipient e.g., a microcrystalline cellulose
  • a lubricant e.g., sodium stearyl fumarate
  • Microcrystalline cellulose may be used as a filler and/or diluent in the capsules provided herein.
  • Sodium stearyl fumarate may be used as a lubricant in the capsules provided herein.
  • the microcrystalline cellulose is a silicified microcrystalline cellulose.
  • a silicified microcrystalline cellulose may be composed of microcrystalline cellulose and colloidal silicon dioxide particles.
  • the silicified microcrystalline cellulose is a combination of 98% microcrystalline cellulose and 2% colloidal silicon dioxide.
  • the capsule may contains about 10 mg to 680 mg of the compound, wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the capsule contains about 10 mg to about 650 mg. In some
  • the capsule contains about 100 mg to about 600 mg. In some embodiments, the capsule contains about 200 mg to about 550 mg. In some embodiments, the capsule contains about 300 mg to about 500 mg. In some embodiments, the capsule contains about 10 mg, about 20 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 650 mg of the compound. In some embodiments, the capsule is a hard gelatin capsule.
  • the compound is N-ie/t-butyl-3-[(5- methyl-2- ⁇ [4- (2-pyrrolidin- 1 -ylethoxy)phenyl] amino ⁇ pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate.
  • the weight ratio of the compound to microcrystalline cellulose (such as silicified microcrystalline cellulose) in the capsule is between about 1 : 1.5 to about 1 : 15 (e.g. , between about 1 :5 to about 1 : 10, between about 1 :5 to about 1 : 12, or between about 1 : 10 to about 1 : 15), wherein the weight of the compound is the free base moiety weight of the compound.
  • the weight ratio of the compound to sodium stearyl fumarate in the capsule is between about 5: 1 to about 50: 1 (e.g.
  • the capsule contains about 5% to about 50% (e.g. , about 5% to about 10% or about 5% to about 35%) compound of the total fill weight of the capsule, wherein the weight of the compound is the free base moiety weight of the compound.
  • the capsule contains about 40% to about 95% (e.g. , about 50% to about 90% or about 60% to about 90%) microcrystalline cellulose (such as silicified
  • the capsule contains about 0.2% to about 5% (e.g. , about 0.2% to about 2% or about 0.5% to about 1.5%, or about 0.5%, about 1%, or about 1.5%) sodium stearyl fumarate of the total fill weight of the capsule.
  • unit dosage forms comprising an admixture of (i) 50 mg or 100 mg of a compound which is N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight is the free base moiety weight of the compound, (ii) an excipient (e.g., a microcrystalline cellulose), and (iii) a lubricant (e.g., sodium stearyl fumarate).
  • an excipient e.g., a microcrystalline cellulose
  • a lubricant e.g., sodium stearyl fumarate
  • the unit dosage form is in the form of a capsule, and the admixture is contained in the capsule.
  • the compound is N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin- l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.
  • the weight ratio of the compound to microcrystalline cellulose (such as silicified microcrystalline cellulose) in the unit dosage form is between about 1 : 1.5 to about 1 : 15 (e.g. , between about 1 :5 to about 1 : 10, between about 1 :5 to about 1 : 12, or between about 1 : 10 to about 1 : 15), wherein the weight of the compound is the free base moiety weight of the compound.
  • the weight ratio of the compound to sodium stearyl fumarate in the unit dosage form is between about 5: 1 to about 50: 1 (e.g.
  • the capsule contains about 5% to about 50% (e.g. , about 5% to about 10% or about 5% to about 35%) compound of the total weight of the admixture, wherein the weight of the compound is the free base moiety weight of the compound.
  • the capsule contains about 40% to about 95% (e.g. , about 50% to about 90% or about 60% to about 90%) microcrystalline cellulose (such as silicified
  • the capsule contains about 0.2% to about 5% (e.g. , about 0.2% to about 2% or about 0.5% to about 1.5%, or about 0.5%, about 1%, or about 1.5%) sodium stearyl fumarate of the total weight of the admixture.
  • Methods of Treatment and Prevention of Polycythemia Vera comprising administering to the subject an effective amount of a compound which is N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin- 4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • the subject has PV in the absence of progression to MF or AML.
  • the subject has increased risk of developing MF.
  • the subject has PV that is resistant or intolerant to hydroxyurea.
  • the subject is a human subject.
  • the effective amount of N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin-4- yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
  • Diagnosis of PV may be made according to the revised World Health Organization (WHO) criteria. See Vardiman et al., Blood 114:937-51, 2009. Diagnosis of PV may require the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria.
  • WHO World Health Organization
  • Major criteria include: 1) hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume ((a) hemoglobin or hematocrit greater than the 99 th percentile of method- specific reference range for age, sex, altitude of residence, (b) hemoglobin greater than 17 g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from a person's baseline value that cannot be attributed to correction of iron deficiency, or (c) elevated red cell mass greater than 25% above mean normal predicted value); 2) presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation.
  • Minor criteria include: 1) bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocyte proliferation; 2) serum erythropoietin level below the reference range for normal; 3) endogenous erythroid colony formation in vitro.
  • a subject having polycythemia vera in the absence of myelofibrosis may be a subject that does not have post-polycythemia vera myelofibrosis.
  • Required criteria for having post-PV MF include: 1) documentation of previous diagnosis of polycythemia vera as defined by the World Health Organization (WHO) criteria. See Tefferi et al., Blood
  • bone marrow fibrosis grade 2-3 (on 0-3 scale) according to the European classification as diffuse, often course fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, course fiber network with areas of collagenization (positive trichrome stain) (Thiele et al., Haematologica 90: 1128-1132, 2005) or grade 3-4 (on 0-4 scale) according to the standard classification as diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis (Manoharan et al, Br J Haematol 43: 185-190, 1979).
  • Additional criteria for post-PV MF where two criteria are required include: 1) anemia, below the reference range for appropriate age, sex, gender and altitude considerations, or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment with erythrocytosis; 2) a leukoerythroblastic peripheral blood picture; 3) increasing splenomegaly defined as either an increase in palpable splenomegaly of greater or equal to 5 cm (distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly; and 4) development of one or more of the following three constitutional symptoms: greater than 10% weight loss in 6 months, night sweats, or unexplained fever (greater than 37.5°C).
  • a subject having PV has increased risk of progression to MF.
  • a subject having PV with increased risk of progression to myelofibrosis may have one or more of the following risk factors: 1) disease duration with PV for at least 10 years; 2) presence of the JAK2 V617F mutation (e.g., homozygous JAK2 V617F mutation); 3) an elevated serum lactate dehydrogenase level; 4) presence of endogenous megakaryocytic colony formation. See Alvarez-Larran et al., Br J Haematol 146:504-509, 2009.
  • a subject having PV may be resistant or intolerant to hydroxyurea if the subject on hydroxyurea treatment has a hematocrit greater than 45%, or phlebotomy twice in the last six months and at least once in the last three months. See Barosi et al., Br. J. Haematol.
  • the subject has a point mutation from valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) (JAK2V617F) if the subject is a human, or a point mutation corresponding to the valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) if the subject is a non-human mammal.
  • the subject is negative for the valine 617 to phenylalanine mutation of JAK2 if the subject is a human, or negative for a mutation corresponding to the valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) if the subject is a non-human mammal.
  • Whether a subject is positive or negative for JAK2V617F can be determined by a polymerase chain reaction ("PCR") analysis using genomic DNA from bone marrow cells or blood cells (e.g. , leukocytes or granulocytes).
  • the PCR analysis can be an allele- specific PCR (e.g. , allele- specific quantitative PCR) or PCR sequencing.
  • the subject has PV that is resistant to hydroxyurea or the patient is intolerant to hydroxyurea treatment.
  • the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML).
  • the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • the subject has an increased risk of developing MF.
  • the subject may have one or more of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocyte colony formation.
  • the subject is selected for treatment based on one or more of the following criteria: (i) the subject has PV that is resistant to hydroxyurea or the patient is intolerant to hydroxyurea treatment; (ii) the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib; and (iv) the subject has an increased risk of developing MF, for example, the subject may have one or more of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having
  • a method described herein may further comprise a step of determining whether the subject meets one or more of the above-mentioned criteria before treatment.
  • the subject treated with the methods described herein has previously received another JAK2 inhibitor treatment.
  • the previous therapy may be a JAK2 inhibitor (e.g. INCBO 18424 or Ruxolitinib (available from Incyte), CEP-701 (lestaurtinib, available from Cephalon), or XL019 (available from Exelixis)), CYT387 (available from YB Biosciences, SB 1518 (available from SBio), and AZD1480 (available from AstraZeneca) (See Verstovsek S., Hematology Am Soc Hematol Educ Program. 2009:636-42).
  • the subject has received another JAK2 inhibitor treatment (e.g.
  • the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is intolerant to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)).
  • the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is intolerant to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)).
  • the subject has received another JAK2 inhibitor treatment (e.g.
  • INCBO 18424 or Ruxolitinib available from Incyte) and is not responsive or partially responsive to such JAK2 inhibitor treatment (e.g. INCB018424 or Ruxolitinib (available from Incyte)).
  • the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and has undesirable drug toxocitity to such JAK2 inhibitor treatment (e.g. INCBO 18424 or
  • the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and has failed such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)).
  • the subject having PV with resistance or intolerance to another JAK2 inhibitor treatment e.g. INCBO 18424 or Ruxolitinib (available from Incyte)
  • the another JAK2 inhibitor is
  • the subject does not have splenectomy.
  • the subject does not receive concomitant treatment with or use of drugs to herbal agents known to be at least moderate inhibitors or inducers of CYP3A4.
  • CYP3A4 Based on in vitro evaluations, N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide is metabolized by human CYP3A4.
  • Agents that may increase N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide plasma concentrations i.e., CYP3A4 inhibitors
  • decrease N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide plasma concentrations i.e., CYP3A4 inducers
  • herbal agents and foods e.g.
  • Agents that are sensitive substrates for metabolism by CYP3A4 should be used with caution as coadministration with N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2- pyrrolidin- 1 -ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide may result in higher plasma concentrations of the coadministered agent.
  • a list of clinically relevant substrates of CYP3A4 include alfentanil, Cyclosporine, Diergotamine, ethinyl estradiol, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, clarithromycin erythromycin, telithromycin, alprazolam, diazepam, midazolam, triazolam, indinavir, ritonavir, saquinavir, prokinetic, cisapride, astemizole, chlorpheniramine, amlodipine, diltiazem, felodipine, nifedipine, verapamil, atorvastatin, cerivastatin, lovastatin, simvastatin, aripiprazole, gleevec, halopericol, sildenafil, tamoxifen, taxanes, trazodone, and Vincri
  • a list of clinically relevant inducers of CYP3A4 include carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, and troglitazone.
  • a list of clinically relevant inhibitors of CYP3A4 include indinavir, nelfinavir, ritonavir,
  • the subject does not receive concomitant treatment with or use of drugs to herbal agents known to be at least moderate inhibitors or inducers of
  • the subject may be treated by orally administering at a dose of about 50 mg per day to 500 mg per day of a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight is the free base moiety weight of the compound.
  • the compound is administered at a dose of 50 mg/day, 100 mg/day, 200 mg/day, 300 mg/day, or 400 my/day.
  • the compound may be in a capsule and/or a unit dosage form described herein.
  • the compound administered is in an admixture with a microcrystalline cellulose and sodium stearyl fumarate, and the admixture is in a capsule.
  • the compound is administered orally.
  • the compound is administered to the subject daily for at least 1 cycle, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles of a 28-day cycle. In some embodiments, the compound is administered to the subject daily for at least 6 cycles of a 28-day cycle, at least 8 cycles of a 28-day cycle, at least 10 cycles of a 28-day cycle, at least 12 cycles of a 28-day cycle, at least 15 cycles of a 28-day cycle, at least 18 cycles of a 28-day cycle, or at least 24 cycles of a 28- day cycle.
  • the compound is administered to the subject daily for at least 4 weeks, at least 8 weeks, at least 10 weeks, at least 20 weeks, at least 30 weeks, at least 32 weeks, at least 40 weeks, or at least 50 weeks. In some embodiments, the compound is administered to the subject daily for at least one month, at least two month, at least three month, at least four month, at least five month, at least six month, at least eight month, or at least one year. In some embodiments, the compound is administered once a day.
  • the treatment provided herein ameliorates one or more symptoms associated with PV in the subject.
  • the treatment described herein may produce one or more of the following: reduction in hematocrit (e.g., hematocrit level below about 45% for a minimum of 3 months in the absence of phlebotomy), reduction in platelet count (e.g., ⁇ 400 x 10 9 /L), reduction of white blood cell count (e.g., ⁇ 10 x 10 9 /L), reduction in spleen size (e.g., normal or close to normal spleen size measured by imaging, or reduction of spleen size or spleen volume by at least about any of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%), and amelioration of other disease-related symptoms (such as microvascular disturbances, pruritus, and headache).
  • reduction in hematocrit e.g., hemato
  • the treatment described herein may be effective in reducing thrombocytosis, decrease JAK2V617F allele burden, reducing bone marrow fibrosis, and/or reducing bone marrow cellularity.
  • the reduction, decrease, amelioration, or improvement can be at least by 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 % compared to the level prior to commencing treatment with the compound provided herein.
  • the treatment provided herein leads to a complete response. In some embodiments, the treatment provided herein leads to a partial response.
  • the criteria for complete response and partial response may be according to any of the criteria known in the field, for example according to the European LeukemiaNet consensus criteria.
  • Also provided herein are methods of monitoring treatment of PV to a subject comprising (a) administering to the subject an effective amount of a compound which is N- ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof; (b) monitoring a JAK2V617F mutant allele in granulocytes from the subject and/or STAT3 phosphorylation level in blood cells from the subject.
  • the methods may further comprise determining if the subject should continue or discontinue with the treatment.
  • Methods of Treatment and Prevention of Essential thrombocythemia comprising administering to the subject an effective amount of a compound which is N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin- 4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • the subject ET in the absence of progression to MF or AML.
  • the subject has increased risk of developing MF.
  • the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment.
  • the subject is a human subject.
  • the effective amount of N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin- l-ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day for oral administration, and wherein the specified weight is the free base moiety weight of the compound.
  • Diagnosis of ET may be made according to the revised World Health Organization (WHO) criteria. See Vardiman et al., Blood 114:937-51, 2009. Diagnosis of ET requires the meeting of four criteria.
  • WHO World Health Organization
  • the criteria include: 1) sustained platelet count equal to or greater than 450 x 10 9 /L during the work-up process; 2) bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes and no significant increase of left-shift of neutrophil granulopoiesis or erythropoisis; 3) not meeting WHO criteria for polycythemia vera, primary myelofibrosis, BCR-ABLl-positive CML, or myelodysplasia syndrome, or other myeloid neoplasm.
  • a subject having ET without progression to MF may be a subject that does not have post-essential thrombocythemia myelofibrosis.
  • Required criteria for having post-essential thrombocythemia myelofibrosis include: 1) documentation of a previous diagnosis of essential thrombocythemia as defined by the World Health Organization (WHO) criteria (See Tefferi et al., Blood 110: 1092-1097, 2007); 2) bone marrow fibrosis grade 2-3 (on 0-3 scale) according to the European classification as diffuse, often course fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, course fiber network with areas of collagenization (positive trichrome stain) (Thiele et al., Haematologica 90: 1128- 1132, 2005) or grade 3-4 (on 0-4 scale) according to the standard classification as diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and dense increase
  • a subject having ET has increased risk of progression to MF.
  • a subject having ET may be resistant or intolerant to hydroxyurea if the subject on hydroxyurea treatment has platelet count higher than 600 x 10 9 /L. See Barosi et al.,
  • the subject has a point mutation from valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) (JAK2V617F) if the subject is a human, or a point mutation corresponding to the valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) if the subject is a non-human mammal.
  • the subject is negative for the valine 617 to phenylalanine mutation of JAK2 if the subject is a human, or negative for a mutation corresponding to the valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) if the subject is a non-human mammal.
  • Whether a subject is positive or negative for JAK2V617F can be determined by a polymerase chain reaction ("PCR") analysis using genomic DNA from bone marrow cells or blood cells (e.g. , whole blood leukocytes).
  • the PCR analysis can be an allele- specific PCR (e.g. , allele- specific quantitative PCR) or PCR sequencing.
  • the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment.
  • the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML).
  • MF myelofibrosis
  • AML acute myeloid leukemia
  • the subject has an increased risk of developing MF.
  • the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • the subject is selected for treatment based on one or more of the following criteria: (i) the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment; (ii) the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the subject has an increased risk of developing MF; and (iv) the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • a method described herein may further comprise a step of determining whether the subject meets one or more of the above-mentioned criteria before treatment.
  • the subject treated with the methods described herein has previously received another JAK2 inhibitor treatment.
  • the previous therapy may be a JAK2 inhibitor (e.g. INCBO 18424 or Ruxolitinib (available from Incyte), CEP-701 (lestaurtinib, available from Cephalon), or XL019 (available from Exelixis)) (See Verstovsek S.,
  • the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is resistant to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)).
  • the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is intolerant to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)).
  • the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is not responsive or partially responsive to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)).
  • the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and has undesirable drug toxocitity to such JAK2 inhibitor treatment (e.g. INCBO 18424 or
  • the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and has failed such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)).
  • the subject having ET with resistance or intolerance to another JAK2 inhibitor treatment e.g. INCBO 18424 or Ruxolitinib (available from Incyte)
  • the another JAK2 inhibitor is Ruxolitinib.
  • the subject does not have splenectomy.
  • the subject does not receive concomitant treatment with or use of drugs to herbal agents known to be at least moderate inhibitors or inducers of
  • Agents that may increase N-ie/t-butyl-3- [(5-methyl-2- ⁇ [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino ⁇ pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate plasma concentrations i.e., CYP3A4 inhibitors
  • N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate plasma concentrations i.e., CYP3A4 inducers
  • herbal agents and foods e.g.
  • a list of clinically relevant substrates of CYP3A4 include alfentanil, Cyclosporine, Diergotamine, ethinyl estradiol, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, clarithromycin erythromycin, telithromycin, alprazolam, diazepam, midazolam, triazolam, indinavir, ritonavir, saquinavir, prokinetic, cisapride, astemizole, chlorpheniramine, amlodipine, diltiazem, felodipine, nifedipine, verapamil, atorvastatin, cerivastatin, lovastatin, simvastatin, aripiprazole, gleevec, halopericol, sildenafil, tamoxifen, taxens, trazodone, and Vincri
  • a list of clinically relevant inducers of CYP3A4 include carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, and troglitazone.
  • a list of clinically relevant inhibitors of CYP3A4 include indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, erythromycin, grapefruit juice, verapamil, diltiazem, cimetidine, amiodarone, fluvoxamine, mibefradil, and Troleandomycin. See reference Flockhart et al.,
  • the subject may be treated by orally administering at a dose of about 50 mg per day to 500 mg per day of a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight is the free base moiety weight of the compound.
  • the compound is administered at a dose of 50 mg/day, 100 mg/day, 200 mg/day, 300 mg/day, or 400 my/day.
  • the compound may be in a capsule and/or a unit dosage form described herein.
  • the compound administered is in an admixture with a microcrystalline cellulose and sodium stearyl fumarate, and the admixture is in a capsule.
  • the compound is administered orally.
  • the compound is administered to the subject daily for at least 1 cycle, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles of a 28-day cycle. In some embodiments, the compound is administered to the subject daily for at least 6 cycles of a 28-day cycle, at least 8 cycles of a 28-day cycle, at least 10 cycles of a 28-day cycle, at least 12 cycles of a 28-day cycle, at least 15 cycles of a 28-day cycle, at least 18 cycles of a 28-day cycle, or at least 24 cycles of a 28- day cycle.
  • the compound is administered to the subject daily for at least 4 weeks, at least 8 weeks, at least 10 weeks, at least 20 weeks, at least 30 weeks, at least 32 weeks, at least 40 weeks, or at least 50 weeks. In some embodiments, the compound is administered to the subject daily for at least one month, at least two month, at least three month, at least four month, at least five month, at least six month, at least eight month, or at least one year. In some embodiments, the compound is administered once a day.
  • the treatment provided herein ameliorates one or more symptoms associated with ET in the subject.
  • the treatment described herein may produce one or more of the following: reduction of platelet count (e.g., a platelet count ⁇ 400 x 10 9 /L or ⁇ 600 x 10 9 /L or a decrease >50% from baseline), white blood cell count (e.g., ⁇ 10 x 10 9 /L), reduction in spleen size (e.g., normal or close to normal spleen size measured by imaging or reduction of spleen size or spleen volume by at least about any of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%), and amelioration of other disease-related symptoms (such as microvascular disturbances, pruritus, and headache).
  • platelet count e.g., a platelet count ⁇ 400 x 10 9 /L or ⁇ 600 x 10 9 /L or
  • the treatment described herein may be effective in reducing thrombocytosis, decrease JAK2V617F allele burden, reducing bone marrow fibrosis, and/or reducing bone marrow cellularity.
  • the reduction, decrease, amelioration, or improvement can be at least by 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 % compared to the level prior to commencing treatment with the compound provided herein.
  • the treatment provided herein leads to a complete response. In some embodiments, the treatment provided herein leads to a partial response.
  • the criteria for complete response and partial response may be according to any of the criteria known in the field, for example according to the European LeukemiaNet consensus criteria.
  • Also provided herein are methods of monitoring treatment of ET in a subject comprising (a) administering to the subject an effective amount of a compound which is N- ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof; (b) monitoring a JAK2V617F mutant allele in granulocytes from the subject and/or STAT3 phosphorylation level in blood cells from the subject.
  • the methods may further comprise determining if the subject should continue or discontinue with the treatment.
  • articles of manufacture or kits containing a compound which is N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin- 4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • the article of manufacture or the kit further includes instructions for using the compounds described herein in the methods provided herein.
  • the article of manufacture or the kit further comprises a label or a package insert providing the instructions.
  • the compound is in a capsule and/or a unit dosage form described herein.
  • the article of manufacture or kit may further comprise a container.
  • Suitable containers include, for example, bottles, vials (e.g. , dual chamber vials), syringes (such as single or dual chamber syringes) and test tubes.
  • the container may be formed from a variety of materials such as glass or plastic, and the container may hold the compound, for example in the formulation to be administered.
  • the article of manufacture or the kit may further comprise a label or a package insert, which is on or associated with the container, may indicate directions for reconstitution and/or use of the compound.
  • the package insert or the label is in a position which is visible to prospective purchasers.
  • the label or package insert may further indicate that the compound is useful or intended for treating or preventing PV in a subject.
  • the package insert or the label indicates that the compound is useful for treating that i) the compound is useful for treating a subject having PV and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound.
  • the package insert or the label indicates that the dose is 50 mg, 100 mg, 200 mg, or 400 mg per day.
  • the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
  • the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
  • the package insert or label indicates that the compound is useful for treating a subject having PV that is resistant to hydroxyurea treatment or for treating a subject having PV where the subject is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing MF. In some embodiments, the subject has at least one of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocyte colony formation. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • another JAK2 inhibitor such as Ruxolitinib.
  • the label or package insert may further indicate that the compound is useful or intended for treating or preventing ET in a subject.
  • the package insert or the label indicates that the compound is useful for treating that i) the compound is useful for treating a subject ET and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound.
  • the package insert or the label indicates that the dose is 50 mg, 100 mg, 200 mg, or 400 mg per day.
  • the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3- [(5-methyl-2- ⁇ [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino ⁇ pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
  • the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
  • the package insert or label indicates that the compound is useful for treating a subject having ET that is resistant to hydroxyurea treatment or for treating a subject that is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing MF. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
  • a randomized open-label study is conducted of the orally administered N-tert-butyl- 3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate (the drug substance) in patients with polycythemia vera (PV) that is resistant to hydroxyurea treatment and patients with PV who are intolerant to hydroxyurea.
  • PV polycythemia vera
  • the subjects in this study were administered with capsule form of the drug substance as described in Example 3.
  • the study is designed to investigate (1) the efficacy of daily oral doses of 100, 200 and 400 mg of the drug substance in patients with PV that is resistant to hydroxyurea treatment and patients with PV who are intolerant to hydroxyurea to induce the absence of requirement for phlebotomy and a hematocrit below 45% for a minimum of 3 months; (2) the safety of the drug substance; (3) the efficacy of daily oral doses of 100, 200 and 400 mg the drug substance in inducing complete or partial clinicohematologic responses; (4) the pharmacokinetics of the drug substance after single and repeat doses; (5) the
  • PV World Health Organization
  • Diagnosis requires the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria:
  • Hemoglobin or hematocrit > 99th percentile of method-specific reference range for age, sex, altitude of residence; or hemoglobin > 17 g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from a person's baseline value that cannot be attributed to correction of iron deficiency; or elevated red cell mass > 25% above mean normal predicted value.
  • Patients are randomized in a 1: 1: 1 ratio to 1 of 3 drug substance dose groups: 100, 200 and 400 mg (free base) daily (approximately 10 patients per dose level). Patients remain on study treatment for a minimum of 8 cycles in the absence of disease progression or unacceptable toxicity. Patients who have completed 8 cycles of therapy who are tolerating study treatment and benefit clinically are allowed to continue treatment. For patients randomized to 100 or 200 mg/day, cross-over to a higher dose level may be permitted after the patient completes 8 cycles of therapy.
  • the drug substance is supplied as hard capsules containing 100 mg or 50 mg of the free base form of the drug substance.
  • the capsule contains a blend of the drug substance and microcrystalline cellulose, with a small quantity of sodium stearyl fumarate added as a lubricant to facilitate manufacturing.
  • the capsules are orally self-administered as a single agent, once daily on an empty stomach (1 hour before or 2 hours after meals), beginning on day 1 of the study and thereafter at approximately the same time each day in consecutive, 28- day cycles.
  • Assessment of clinicohematologic response to treatment with the drug substance is performed at the end of cycles 4 and 8 or at the end of treatment (EOT) based on European LeukemiaNet consensus criteria and at the 30-day follow-up visit
  • spleen size by palpation at the end of each cycle, EOT, and at the 30-day follow-up visit
  • spleen volume in patients with palpable spleens at baseline, by magnetic resonance imaging (MRI) at the end of Cycles 4 and 8 or EOT
  • MPN-SAF responses at the end of cycles 1, 4, and 8 or EOT, and at the 30-day follow-up visit
  • EQ-5D responses at the end of Cycle 8 or EOT.
  • Bone marrow analysis including cytogenetics, cellularity and cell composition (e.g., blast count), and reticulin fibrosis, is performed at baseline and thereafter (a) in patients achieving complete (clinicohematologic) response, at the time of complete response and again 6 months later if they still have complete response, and (b) every 6 months in patients with cytogenetic abnormalities or reticulin fibrosis at baseline.
  • Hematocrit is measured at the end of each cycle and phlebotomy requirements during the study is recorded.
  • JAK2V617F mutant allele in granulocytes is measured at baseline and at the end of cycles 4 and 8 or EOT. Allele burden is also measured in patients who develop disease progression.
  • STAT3 phosphorylation is analyzed predose and at 2 and 6 hours postdose on day 1 of cycle 1 and prior to dosing on days 2 and 15 of cycle 1 and on day 1 of cycle 2. STAT3 phosphorylation is also measured in patients who develop disease progression.
  • Example 2 A randomized open-label study is conducted of orally administered N-tert-butyl-3- [(5-methyl-2- ⁇ [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino ⁇ pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate (the drug substance) in patients with essential thrombocythemia (ET) that is resistant to hydroxyurea treatment or patients having ET that are intolerant to hydroxyurea treatment.
  • the subjects in this study are administered with capsule form of the drug substance as described in Example 3.
  • This study is designed to investigate (1) efficacy of daily oral doses of 50, 100, 200, and 400 mg of the drug substance (weight given of free base form) in patients with ET that is resistant to hydroxyurea treatment and patients who are intolerant to hydroxyurea treatment for reduction of platelet count to ⁇ 400 x 10 9 /L for a minimum of 3 months; (2) the safety of daily oral doses of 50, 100, 200 and 400 mg drug substance in patients with ET that is resistant to hydroxyurea treatment or patients who are intolerant to hydroxyurea treatment; (3) the efficacy of daily oral doses of 50, 100, 200 and 400 mg drug substance in inducing complete or partial clinicohematologic responses; (4) the pharmacokinetics of the drug substance after single and repeat doses; (5) the pharmacodynamics of the drug substance as measured by changes in JAK2V617F allele burden in those patients with JAK2V617F mutation, and/or STAT3 phosphorylation inhibition; (6) the effects of the drug substance on histological,
  • ET is resistant to hydroxyurea treatment or where the patient is intolerant to hydroxyurea treatment (per LeukemiaNet consensus criteria).
  • ET that is resistant to hydroxyurea treatment is defined as patient on hydroxyurea with a platelet count >600 x 10 9 /L (Barosi et al., Leukemia, 21(2):277-80, 2007). TABLE 2. Criteria for Essential Thrombocythemia (ET)
  • Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes. No significant increase of left-shift of neutrophil granulopoiesis or erythropoisis.
  • lymphoproliferative disorders lymphoproliferative disorders.
  • the presence of a condition associated with reactive thrombocytosis does not exclude the possibility of ET if other criteria are met.
  • Patients are randomized in a 1: 1: 1 ratio to 1 of 3 the dose groups: 100, 200 and 400 mg daily (approximately 10 patients per dose level). Patients remain on study treatment for a minimum of 8 cycles in the absence of disease progression or unacceptable toxicity. Patients who have completed 8 cycles of therapy who are tolerating study treatment and benefit clinically are allowed to continue treatment. For patients randomized to 100 or 200 mg/day, cross-over to a higher dose level may be permitted after the patient completes 8 cycles of therapy.
  • the drug substance is supplied as hard capsules containing 100 mg or 50 mg of the free base form.
  • the capsule contains a blend the drug substance and microcrystalline cellulose, with a small quantity of sodium stearyl fumarate added as a lubricant to facilitate manufacturing.
  • the capsules are orally self-administered, once daily on an empty stomach (1 hour before or 2 hours after meals), beginning on day 1 of the study and thereafter at approximately the same time each day in consecutive, 28-day cycles.
  • Platelet counts are measured at the end of each cycle. A platelet count ⁇ 400 x 10 9 /L for a minimum of 3 months after completion of 8 cycles of therapy is considered a response.
  • Bone marrow analysis including cytogenetics, cellularity and cell composition (e.g., blast count), and reticulin fibrosis, is performed at baseline and thereafter (a) in patients achieving complete (clinicohematologic) response, at the time of complete response and again 6 months later if they still have complete response, and (b) every 6 months in patients with cytogenetic abnormalities or reticulin fibrosis at baseline.
  • JAK2V617F mutant allele in granulocytes is measured by a central laboratory at baseline and at the end of cycles 4 and 8 or EOT. Allele burden also is measured in patients who develop disease progression.
  • STAT3 phosphorylation is analyzed predose and at 2 and 6 hours postdose on day 1 of cycle 1 and prior to dosing on days 2 and 15 of cycle 1 and on day 1 of cycle 2.
  • STAT3 phosphorylation also is measured in patients who develop disease progression.
  • Pharmacogenomic analysis related to drug metabolizing enzymes and genes possibly involved in the JAK-STAT pathway or related to MPNs is performed prior to dosing on cycle 1 day 1.
  • Safety is evaluated based on the incidence of treatment-emergent adverse events (TEAEs), and changes in clinical laboratory parameters, red blood cell transfusion requirements, Eastern Cooperative Oncology Group (ECOG) performance status (PS), vital signs, and body weight relative to baseline.
  • Adverse events is assessed and reported using terminology of the National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Platelet counts is measured at the end of each cycle.
  • NCI National Cancer Institute
  • CCAE Common Terminology Criteria for Adverse Events
  • N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino ⁇ pyrimidin- 4-yl)amino]benzenesulfonamide dihydrochloride monohydrate drug products were provided as 50 mg and 100 mg capsule strengths, where the weights (the unit formula weights) are specified for the amount of active (i.e., free base) moiety (N-iert-butyl-3-[(5-methyl-2- ⁇ [4-(2- pyrrolidin- 1 -ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide) .
  • the quantitative composition of each strength of drug product capsule is shown in Table 3.
  • Silicified microcrystalline cellulose is a combination of microcrystalline cellulose and colloidal silicon dioxide.
  • A. Dry granulation of components (implemented for all three drug product strengths): 1. N-ieri-butyl-3-[(5-methyl-2- ⁇ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino ⁇ pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate., sodium stearyl fumarate, and about 50% of silicified microcrystalline cellulose were blended within a conical blender for 5 minutes. 2. The blend was passed through a conical mill equipped with a round 18-mesh screen and round impeller. The blend was recharged into the conical blender. 3.
  • silicified microcrystalline cellulose was sifted through the conical mill and added to the blender. The mixture was blended for 15 minutes. 4. The final blend was passed through a roller compactor. 5. The roller compacted ribbons were passed through a conical mill equipped with a round 16- mesh screen and round impeller. 6. The milled material was blended within the conical blender for 5 minutes to ensure homogeneity. 7. In-process check (IPC) samples were withdrawn from the conical blender using a sample thief. Samples were subjected to potency analysis.
  • IPC In-process check
  • Capsule-filling (implemented for all three drug product strengths): 1. If potency was outside 98-102% (w/w) nominal, the capsule fill weight was adjusted accordingly. 2. The prepared material was encapsulated using automatic capsule filling machine. The prepared capsules were bottled and stored at 20-28 °F (68-82 °C) and ambient humidity.
  • Capsules may also be made according to the method described in Example 5 of PCT Application No. PCT/US2011/059643, filed November 7, 2011 (with publication No. WO 2012/061833).

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Abstract

Provided herein are compositions and methods for treating polycythemia vera (PV) and/or essential thrombocythemia (ET) in a subject. The methods comprise administering to the subject an effective amount of compound which is which is N-ieri-butyl-3-[(5-methyl-2- { [4-(2-pyrrolidin-l-ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt or a hydrate thereof.

Description

COMPOSITIONS AND METHODS FOR TREATING POLYCYTHEMIA VERA AND ESSENTIAL THROMBOCYTHEMIA
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the priority benefit of U.S. provisional application Serial No. 61/510,406, filed July 21, 2011, U.S. provisional application Serial No. 61/510,409, filed July 21, 2011, French application No. 1251748, filed February 27, 2012, and French application No. 1251749, filed February 27, 2012, the contents of each of which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
[0002] Provided herein are compositions and methods for treating polycythemia vera and/or essential thrombocythemia. The compositions and methods provided herein relate to treatment of polycythemia vera and/or essential thrombocythemia with compounds that inhibit JAK2 or a pharmaceutically acceptable salt thereof or a hydrate thereof.
BACKGROUND
[0003] Polycythemia vera ("PV"), is a clonal stem cell disease belonging, along with myelofibrosis ("MF") and essential thrombocythemia ("ET"), to the 3 classic BCR-ABL- negative myelopoliferative neoplasms ("MPNs"). Polycythemia vera affects proliferation of erythroid, myeloid, and megakaryocyte cell lineages leading primarily to increased hematocrit, leukocytosis and thrombocytosis. In addition, patients with PV suffer from splenomegaly and disease-associated symptoms such as pruritus, night sweats, fatigue, and bone pain. PV, if progressive despite standard therapies, is associated with an increased risk of thrombosis, bleeding, and progression to MF or even acute myeloid leukemia. A mutation in the JAK2 kinase (JAK2V617F) was found in BCR-ABL-negative classic MPNs. Levine RL et al., Cancer Cell. 2005, 7(4):387-97. This mutation is present in more than 90% of patients with PV. This genetic aberration and other MPN-associated mutations directly (e.g., MPL mutations) or indirectly (e.g., LNK or CBL) lead to the above mentioned disease- related symptoms. Pardanani AD et al., Blood. 2006, 108:3472-3476; Scott LM et al., N Engl J Med. 2007, 356:459-468. [0004] Standard therapies for PV include phlebotomys and low dose aspirin. Hydroxyurea therapy may also be considered for high-risk PV. Barbui T et al., J Clin Oncol 2011,
29(6):761-70. PV patients treated with hydroxyurea may become intolerant or who develop PV that is resistant to hydroxyurea. There is a therapeutic need for those patients with high- risk PV who do not tolerate or who have PV that is resistant to hydroxyurea.
[0005] Essential thrombocythemia ("ET") is a clonal stem cell disease belonging, along with myelofibrosis ("MF") and polycythemia vera ("PV"), to the 3 classic BCR-ABL- negative myelopoliferative neoplasms ("MPNs"). Essential thrombocythemia is characterized by megakaryocyte hyperplasia and consecutive thrombocytosis. In addition, patients with ET suffer from splenomegaly and disease-associated symptoms such as pruritus, night sweats, fatigue, and bone pain. ET, if progressive despite standard therapies, is associated with an increased risk of thrombosis, bleeding, and progression to MF or even acute myeloid leukemia. A mutation in the JAK2 kinase (JAK2V617F) was found in BCR-ABL-negative classic MPNs. Levine RL et al., Cancer Cell. 2005, 7(4):387-97. This mutation is present in nearly half of those with ET. This genetic aberration and other MPN-associated mutations directly (e.g., MPL mutations) or indirectly (e.g., LNK or CBL) lead to the above mentioned disease-related symptoms. Pardanani AD et al., Blood. 2006, 108:3472-3476; Scott LM et al., N Engl J Med. 2007, 356:459-468.
[0006] Standard therapies for ET include hydroxyurea in high-risk ET. Low-dose aspirin therapy may also be considered for ET. Barbui T et al., J Clin Oncol 2011, 29(6):761-70. ET patients treated with hydroxyurea may become intolerant or resistant to hydroxyurea. There is a therapeutic need for those ET patients who do not tolerate or who have hydroxyurea- resistant ET.
[0007] All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
[0008] Provided herein are methods of treating polycythemia vera (PV) in a subject, comprising administering to the subject an effective amount of a compound which is N-tert- butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has PV, wherein the effective amount of N-tert-butyl-3-[(5-methyl-2-{ [4- (2-pyrrolidin-l-ylethoxy)phenyl] amino }pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the dose is administered orally.
[0009] In some embodiments, the subject has PV that is resistant to hydroxyurea or the patient is intolerant to hydroxyurea treatment. In some embodiments, the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML). In some
embodiments, the subject has an increased risk of developing MF. For example, the subject may have one or more of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation. In some embodiments, the subject has been previously treated with another JAK 2 inhibitor such as Ruxolitinib. In some embodiments, the subject is selected for treatment based on one or more of the following criteria: (i) the subject has PV that is resistant to hydroxyurea or the patient is intolerant to hydroxyurea treatment; (ii) the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib; and (iv) the subject has an increased risk of developing MF, for example, the subject may have one or more of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation. In some embodiments, a method described herein may further comprise a step of determining whether the subject meets one or more of the above-mentioned criteria before treatment.
[0010] In some embodiments, the methods described herein further comprise monitoring JAK2V617F mutant allele in blood cells from the subject. In some embodiments, the blood cell is granulocyte. In some embodiments the JAK2V617F mutation is monitored in granulocytes from the subject. In some embodiments, the methods further comprise monitoring STAT3 phosphorylation level in blood cells.
[0011] In some embodiments, the dose or amount administered (such as the dose or amount orally administered) is about any of 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day. In some embodiments, the compound is administered over a period of at least 32 weeks. In some embodiments, the compound is provided in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
[0012] In some embodiments, the methods further comprise instructing the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the methods further comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the methods further comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19.
[0013] Also provided herein are methods of treating essential thrombocythemia (ET) in a subject, comprising administering to the subject an effective amount of a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4- yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has ET, wherein the effective amount of N-tert-butyl-3-[(5- methyl-2- { [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]
benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the compound is administered orally.
[0014] In some embodiments, the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment. In some embodiments, the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML). In some embodiments, the subject has an increased risk of developing MF. In some embodiments, the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib. In some embodiments, the subject is selected for treatment based on one or more of the following criteria: (i) the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment; (ii) the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the subject has an increased risk of developing MF; and (iv) the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib. In some embodiments, a method described herein may further comprise a step of determining whether the subject meets one or more of the above-mentioned criteria before treatment. [0015] In some embodiments, the methods described herein further comprise monitoring JAK2V617F mutant allele in blood cells from the subject. In some embodiments, the blood cells are granulocytes. In some embodiments, the methods further comprise monitoring STAT3 phosphorylation level in blood cells.
[0016] In some embodiments, the dose or amount administered (such as the dose or amount orally administered) is about any of 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day. In some embodiments, the compound is administered over a period of at least 32 weeks. In some embodiments, the compound is provided in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
[0017] In some embodiments, the methods further comprise instructing the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the methods further comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the methods comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19.
[0018] Also provided herein are kits or articles of manufacture comprising (a) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin- 4-yl)amino] benzenesulfonamide, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) a package insert or a label indicating that i) the compound is useful for treating a subject having polycythemia vera and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound.
[0019] In some embodiments, the package insert or the label indicates that the dose is 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day. In some embodiments, the package insert or the label indicates that the compound is administered over a period of at least 32 weeks. In some embodiments, the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
[0020] In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having PV that is resistant to hydroxyurea treatment or that the compound is useful for treating a subject having PV where the subject is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having PV in the absence of MF or AML. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing MF. In some embodiments, the subject has at least one of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
[0021] In some embodiments, the package insert or the label instructs the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the package insert or the label instructs the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the methods further comprise instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19.
[0022] Also provided herein are kits or articles of manufacture comprising (a) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin- 4-yl)amino] benzenesulfonamide, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) a package insert or a label indicating that i) the compound is useful for treating a subject having essential thrombocythemia and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound.
[0023] In some embodiments, the package insert or the label indicates that the dose is 50 mg per day, 100 mg per day, 200 mg per day, or 400 mg per day. In some embodiments, the package insert or the label indicates that the compound is administered over a period of at least 32 weeks. In some embodiments, the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
[0024] In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having ET that is resistant to hydroxyurea treatment or for treating a subject who is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having ET in the absence of MF or AML. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing MF. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
[0025] In some embodiments, the package insert or the label instructs the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the package insert or the label instructs the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the package insert or the label instructs the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19.
[0026] Also provided herein are uses of a compound in the manufacture of a medicament for treating polycythemia vera (PV) in a subject, wherein the compound is N-tert-butyl-3-[(5- methyl-2- { [4- (2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has PV, wherein the compound is for administration to the subject at an amount of about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the use is according to any of the methods of treating PV provided herein. For example, in some embodiments, the compound is for oral administration. In some embodiments, the subject has PV that is resistant to hydroxyurea treatment. In some embodiments, the subject is intolerant to hydroxyurea treatment. In some embodiments, the subject has an increased risk of developing myelofibrosis. In some embodiments, the subject has at least one of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygosity for the JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation. In some embodiments, the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib. In some embodiments, the treatment further comprises monitoring JAK2V617F mutant allele in granulocytes from the subject. In some embodiments, the treatment further comprises monitoring STAT3 phosphorylation level in blood cells. In some embodiments, the blood cells are granulocytes. In some embodiments, the compound is for oral
administration at a dose or amount of about any of 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, the compound is for oral administration over a period of at least 32 weeks. In some embodiments, the compound (such as when used in administration) is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4- (2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule. In some embodiments, the capsule contains about 50 mg or about 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the treatment further comprises instructing the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the treatment further comprises instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the treatment further comprises instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of
CYP2C19. In some embodiments, the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia. In some embodiments, the compound is in a pharmaceutical composition, for example, a pharmaceutical composition comprising N-tert-butyl-3-[(5- methyl-2- { [4- (2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier. In some embodiments, the compound is N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate.
[0027] Also provided herein are uses of a compound in the manufacture of a medicament for treating essential thrombocythemia (ET) in a subject, wherein the compound is N-tert- butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has ET, wherein the compound is for administration to the subject at an amount of about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the use is according to any of the methods of treating ET provided herein. For example, in some embodiments, the compound is for oral administration. In some embodiments, the subject has ET that is resistant to hydroxyurea treatment. In some embodiments, the subject is intolerant to hydroxyurea treatment. In some embodiments, the subject has an increased risk of developing myelofibrosis. In some embodiments, the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib. In some embodiments, the treatment further comprises monitoring JAK2V617F mutant allele in granulocytes from the subject. In some
embodiments, the treatment further comprises monitoring STAT3 phosphorylation level in blood cells from the subject. In some embodiments, the blood cells are granulocytes. In some embodiments, the compound is for oral administration at a dose or amount of about any of 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, the compound is for oral administration over a period of at least 32 weeks. In some embodiments, the compound (such as when used in administration) is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin- 4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule. In some embodiments, the capsule contains about 50 mg or about 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the treatment further comprises instructing the subject to ingest the effective amount of the compound on an empty stomach. In some embodiments, the treatment further comprises instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4. In some embodiments, the treatment further comprises instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP2C19. In some embodiments, the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia. In some embodiments, the compound is in a pharmaceutical composition, for example, a pharmaceutical composition comprising N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof and a pharmaceutically acceptable carrier. In some embodiments, the compound is N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.
[0028] Also provided herein is a compound for use in treating polycythemia vera (PV) in a subject, wherein the compound is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has PV, wherein the compound is for administration to the subject at an amount of about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the use is according to any of the methods of treating PV provided herein. In some embodiments, the compound is for oral administration. In some
embodiments, the compound is N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.
[0029] Also provided herein is a compound for use in treating essential thrombocythemia (ET) in a subject, wherein the compound is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has ET, wherein the compound is for administration to the subject at an amount of about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the use is according to any of the methods of treating ET provided herein. In some embodiments, the compound is for oral administration. In some
embodiments, the compound is N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.
[0030] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the compositions and methods provided herein. These and other aspects of the compositions and methods provided herein will become apparent to one of skill in the art.
DETAILED DESCRIPTION
I. Definitions [0031] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results can include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.
[0032] As used herein, "delaying development of a disease" means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or symptoms of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
[0033] As used herein, an "effective dosage" or "effective amount" of drug, compound, or pharmaceutical composition is an amount sufficient to effect beneficial or desired results. For prophylactic use, beneficial or desired results can include, for example, one or more results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results can include, for example one or more clinical results such as decreasing one or more symptoms and pathological conditions resulting from or associated with the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. An effective dosage can be administered in one or more administrations. An effective dosage of drug, compound, or pharmaceutical composition can be, for example, an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective dosage" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved. [0034] In some embodiments for treating PV, an effective dose results in a reduction in hematocrit. In some embodiments, an effective dose results in a hematocrit level below 45% lasting for a minimum of 3 months in the absence of phlebotomy after completion of 8 cycles of therapy. In some embodiments, an effective dose results in hematocrit <45% without phlebotomy or response in 3 or more of the other criteria. In some embodiments, an effective dose results in one or more of the following: i) hematocrit <45% without phlebotomy; ii) platelet count <400 x 109/L; iii) white blood cell count <10 x 109/L; iv) normal spleen size on imaging; v) absence or reduction in disease-related symptoms (such as microvascular disturbances, pruritus, headache).
[0035] In some embodiments for treating ET, an effective dose results in a platelet count <400 x 109/L for a minimum of 3 months after completion of 8 cycles of therapy. In some embodiments, an effective dose results in one or more of the following responses: i) platelet count <400xl09/L; ii) absence of or reduction in disease-related symptoms (such as microvascular disturbances, pruritus, headache); iii) normal spleen size on imaging; iv) white blood cell count <10xl09/L.
[0036] As used herein, "in conjunction with" refers to administration of one treatment modality in addition to another treatment modality. As such, "in conjunction with" can refer to administration of one treatment modality before, during or after administration of the other treatment modality to the individual.
[0037] As used herein, a "patient" or a "subject" refers to a mammal including a human, a dog, a horse, a cow or a cat, etc.
[0038] The term "pharmaceutically acceptable" refers to the fact that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and can be administered to a subject.
[0039] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
[0040] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly indicates otherwise.
[0041] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X." [0042] It is understood that aspects and variations of the compositions and methods provided herein can include "consisting" and/or "consisting essentially of aspects and variations.
II. Compounds and Pharmaceutical Compositions
[0043] Provided herein is a compound which is N-ieri-butyl-3-[(5-methyl-2-{ [4-(2- pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof. Also provided herein are pharmaceutical compositions comprising N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable excipient or carrier. The compound and the pharmaceutical compositions described herein can be used for treating or delaying development of polycythemia vera (PV) and/or essential
thrombocythemia (ET) in a subject. N-ieri-Butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide has the following chemical structure:
Figure imgf000014_0001
[0044] The compound provided herein may be formulated into therapeutic compositions as natural or salt forms. Pharmaceutically acceptable non-toxic salts include the base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases such as, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like. Such salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as, for example, hydrochloric acid, sulfuric acid, or phosphoric acid, or organic acids such as acetic acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, mandelic acid, and the like. [0045] Salts of the compounds provided herein can include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the compounds provided herein can also include amine salts formed by the protonation of an amino group with suitable organic acids, such as p-toluenesulfonic acid, acetic acid, methanesulfonic acid and the like. Additional excipients which are contemplated for use in the practice of the compositions and methods provided herein are those available to those of ordinary skills in the art, for example, those found in the United States Pharmacopeia Vol. XXII and National Formulary Vol. XVII, U.S. Pharmacopeia Convention, Inc., Rockville, Md. (1989), the relevant contents of which are incorporated herein by reference.
[0046] In addition, the compounds provided herein can include polymorphs. The compound described herein may be in alternative forms. For example, the compound described herein may include a hydrate form. As used herein, "hydrate" refers to a compound provided herein which is associated with water in the molecular form, i.e., in which the H-OH bond is not split, and may be represented, for example, by the formula R.H20, where R is a compound provided herein. A given compound may form more than one hydrate including, for example, monohydrates (R.H20) or polyhydrates (R.nH20 wherein n is an integer greater than 1) including, for example, dihydrates (R.2H20), trihydrates (R.3H20), and the like, or fractional hydrates, such as, for example, R.n/2H20, R.n/3H20, R.n/4H20 and the like wherein n is an integer.
[0047] The compounds described herein may also include acid salt hydrate forms. As used herein, "acid salt hydrate" refers to a complex that may be formed through association of a compound having one or more base moieties with at least one compound having one or more acid moieties or through association of a compound having one or more acid moieties with at least one compound having one or more base moieties, said complex being further associated with water molecules so as to form a hydrate, wherein said hydrate is as previously defined and R represents the complex herein described above.
[0048] In some embodiments, the compound is N-iert-butyl-3-[(5-methyl-2-{ [4-(2- pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide
dihydrochloride monohydrate and has the following chemical structure:
Figure imgf000016_0001
[0049] The pharmaceutical compositions for the administration of the compound described herein, either alone or in combination with other therapeutic agents, may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy and methods described in Example 4 of PCT/US2010/056280 filed
November 10, 2010 (with publication No. WO 2012/060847) and U.S. Ser. No. 61/410,924 filed November 7, 2010. Such methods can include bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as hard or soft capsules.
[0050] Provided herein are capsules suitable for oral administration comprising an admixture of (i) a compound which is N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) an excipient (e.g., a microcrystalline cellulose), and (iii) a lubricant (e.g., sodium stearyl fumarate), wherein the admixture is contained in the capsule. Methods known in the art and described herein may be used for making the capsules. See, e.g. , Example 3 herein, and Example 5 in PCT/US2010/056280 filed November 10, 2010 (with publication No. WO 2012/060847) and U.S. Ser. No.
61/410,924 filed November 7, 2010. Capsules may also be made according to the method described in Example 5 of PCT Application No. PCT/US2011/059643, filed November 7, 2011 (with publication No. WO 2012/061833). Microcrystalline cellulose may be used as a filler and/or diluent in the capsules provided herein. Sodium stearyl fumarate may be used as a lubricant in the capsules provided herein. In some embodiments, the microcrystalline cellulose is a silicified microcrystalline cellulose. For example, a silicified microcrystalline cellulose may be composed of microcrystalline cellulose and colloidal silicon dioxide particles. In some embodiments, the silicified microcrystalline cellulose is a combination of 98% microcrystalline cellulose and 2% colloidal silicon dioxide.
[0051] In some embodiments, the capsule may contains about 10 mg to 680 mg of the compound, wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the capsule contains about 10 mg to about 650 mg. In some
embodiments, the capsule contains about 100 mg to about 600 mg. In some embodiments, the capsule contains about 200 mg to about 550 mg. In some embodiments, the capsule contains about 300 mg to about 500 mg. In some embodiments, the capsule contains about 10 mg, about 20 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, or about 650 mg of the compound. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the compound is N-ie/t-butyl-3-[(5- methyl-2- { [4- (2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate.
[0052] In some embodiments, the weight ratio of the compound to microcrystalline cellulose (such as silicified microcrystalline cellulose) in the capsule is between about 1 : 1.5 to about 1 : 15 (e.g. , between about 1 :5 to about 1 : 10, between about 1 :5 to about 1 : 12, or between about 1 : 10 to about 1 : 15), wherein the weight of the compound is the free base moiety weight of the compound. In some embodiments, the weight ratio of the compound to sodium stearyl fumarate in the capsule is between about 5: 1 to about 50: 1 (e.g. , between about 5: 1 to about 10: 1, between about 5: 1 to about 25: 1, between about 5: 1 to about 40: 1, between about 7: 1 to about 34: 1, or between about 8: 1 to about 34: 1), wherein the weight of the compound is the free base moiety weight of the compound.
[0053] In some embodiments, the capsule contains about 5% to about 50% (e.g. , about 5% to about 10% or about 5% to about 35%) compound of the total fill weight of the capsule, wherein the weight of the compound is the free base moiety weight of the compound. In some embodiments, the capsule contains about 40% to about 95% (e.g. , about 50% to about 90% or about 60% to about 90%) microcrystalline cellulose (such as silicified
microcrystalline cellulose) of the total fill weight of the capsule. In some embodiments, the capsule contains about 0.2% to about 5% (e.g. , about 0.2% to about 2% or about 0.5% to about 1.5%, or about 0.5%, about 1%, or about 1.5%) sodium stearyl fumarate of the total fill weight of the capsule.
[0054] Also provided herein are unit dosage forms comprising an admixture of (i) 50 mg or 100 mg of a compound which is N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight is the free base moiety weight of the compound, (ii) an excipient (e.g., a microcrystalline cellulose), and (iii) a lubricant (e.g., sodium stearyl fumarate). In some embodiments, the unit dosage form is in the form of a capsule, and the admixture is contained in the capsule. In some embodiments, the compound is N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin- l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate.
[0055] In some embodiments, the weight ratio of the compound to microcrystalline cellulose (such as silicified microcrystalline cellulose) in the unit dosage form is between about 1 : 1.5 to about 1 : 15 (e.g. , between about 1 :5 to about 1 : 10, between about 1 :5 to about 1 : 12, or between about 1 : 10 to about 1 : 15), wherein the weight of the compound is the free base moiety weight of the compound. In some embodiments, the weight ratio of the compound to sodium stearyl fumarate in the unit dosage form is between about 5: 1 to about 50: 1 (e.g. , between about 5: 1 to about 10: 1, between about 5: 1 to about 25: 1, between about 5: 1 to about 40: 1, between about 7: 1 to about 34: 1, or between about 8: 1 to about 34: 1), wherein the weight of the compound is the free base moiety weight of the compound.
[0056] In some embodiments, the capsule contains about 5% to about 50% (e.g. , about 5% to about 10% or about 5% to about 35%) compound of the total weight of the admixture, wherein the weight of the compound is the free base moiety weight of the compound. In some embodiments, the capsule contains about 40% to about 95% (e.g. , about 50% to about 90% or about 60% to about 90%) microcrystalline cellulose (such as silicified
microcrystalline cellulose) of the total weight of the admixture. In some embodiments, the capsule contains about 0.2% to about 5% (e.g. , about 0.2% to about 2% or about 0.5% to about 1.5%, or about 0.5%, about 1%, or about 1.5%) sodium stearyl fumarate of the total weight of the admixture.
III. Methods of Treatment and Prevention of Polycythemia Vera [0057] Provided herein are methods for treating, delaying development, and/or preventing PV in a subject comprising administering to the subject an effective amount of a compound which is N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin- 4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof. In some embodiments, the subject has PV in the absence of progression to MF or AML. In some embodiments, the subject has increased risk of developing MF. In some embodiments, the subject has PV that is resistant or intolerant to hydroxyurea. In some embodiments, the subject is a human subject. In some embodiments, the effective amount of N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4- yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
[0058] Methods for diagnosing various types of PV are known in the art. Diagnosis of PV may be made according to the revised World Health Organization (WHO) criteria. See Vardiman et al., Blood 114:937-51, 2009. Diagnosis of PV may require the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria. Major criteria include: 1) hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume ((a) hemoglobin or hematocrit greater than the 99th percentile of method- specific reference range for age, sex, altitude of residence, (b) hemoglobin greater than 17 g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from a person's baseline value that cannot be attributed to correction of iron deficiency, or (c) elevated red cell mass greater than 25% above mean normal predicted value); 2) presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation. Minor criteria include: 1) bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocyte proliferation; 2) serum erythropoietin level below the reference range for normal; 3) endogenous erythroid colony formation in vitro.
[0059] A subject having polycythemia vera in the absence of myelofibrosis may be a subject that does not have post-polycythemia vera myelofibrosis. Required criteria for having post-PV MF include: 1) documentation of previous diagnosis of polycythemia vera as defined by the World Health Organization (WHO) criteria. See Tefferi et al., Blood
110: 1092-1097, 2007; 2) bone marrow fibrosis grade 2-3 (on 0-3 scale) according to the European classification as diffuse, often course fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, course fiber network with areas of collagenization (positive trichrome stain) (Thiele et al., Haematologica 90: 1128-1132, 2005) or grade 3-4 (on 0-4 scale) according to the standard classification as diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis (Manoharan et al, Br J Haematol 43: 185-190, 1979). Additional criteria for post-PV MF where two criteria are required include: 1) anemia, below the reference range for appropriate age, sex, gender and altitude considerations, or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment with erythrocytosis; 2) a leukoerythroblastic peripheral blood picture; 3) increasing splenomegaly defined as either an increase in palpable splenomegaly of greater or equal to 5 cm (distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly; and 4) development of one or more of the following three constitutional symptoms: greater than 10% weight loss in 6 months, night sweats, or unexplained fever (greater than 37.5°C).
[0060] In some embodiments, a subject having PV has increased risk of progression to MF. A subject having PV with increased risk of progression to myelofibrosis may have one or more of the following risk factors: 1) disease duration with PV for at least 10 years; 2) presence of the JAK2 V617F mutation (e.g., homozygous JAK2 V617F mutation); 3) an elevated serum lactate dehydrogenase level; 4) presence of endogenous megakaryocytic colony formation. See Alvarez-Larran et al., Br J Haematol 146:504-509, 2009.
[0061] A subject having PV may be resistant or intolerant to hydroxyurea if the subject on hydroxyurea treatment has a hematocrit greater than 45%, or phlebotomy twice in the last six months and at least once in the last three months. See Barosi et al., Br. J. Haematol.
148:961-3, 2010.
[0062] In some embodiments, the subject has a point mutation from valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) (JAK2V617F) if the subject is a human, or a point mutation corresponding to the valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) if the subject is a non-human mammal. In some embodiments, the subject is negative for the valine 617 to phenylalanine mutation of JAK2 if the subject is a human, or negative for a mutation corresponding to the valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) if the subject is a non-human mammal. Whether a subject is positive or negative for JAK2V617F can be determined by a polymerase chain reaction ("PCR") analysis using genomic DNA from bone marrow cells or blood cells (e.g. , leukocytes or granulocytes). The PCR analysis can be an allele- specific PCR (e.g. , allele- specific quantitative PCR) or PCR sequencing. See Kittur J et ah , Cancer 2007, 109(11):2279-84 and McLornan D et ah , Ulster Med J. 2006, 75(2): 112-9, each of which is expressly incorporated herein by reference.
[0063] In some embodiments, the subject has PV that is resistant to hydroxyurea or the patient is intolerant to hydroxyurea treatment. In some embodiments, the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML). In some embodiments, the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib. In some embodiments, the subject has an increased risk of developing MF. For example, the subject may have one or more of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocyte colony formation. In some embodiments, the subject is selected for treatment based on one or more of the following criteria: (i) the subject has PV that is resistant to hydroxyurea or the patient is intolerant to hydroxyurea treatment; (ii) the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib; and (iv) the subject has an increased risk of developing MF, for example, the subject may have one or more of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having
homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation. In some embodiments, a method described herein may further comprise a step of determining whether the subject meets one or more of the above-mentioned criteria before treatment.
[0064] In some embodiments, the subject treated with the methods described herein has previously received another JAK2 inhibitor treatment. The previous therapy may be a JAK2 inhibitor (e.g. INCBO 18424 or Ruxolitinib (available from Incyte), CEP-701 (lestaurtinib, available from Cephalon), or XL019 (available from Exelixis)), CYT387 (available from YB Biosciences, SB 1518 (available from SBio), and AZD1480 (available from AstraZeneca) (See Verstovsek S., Hematology Am Soc Hematol Educ Program. 2009:636-42). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is resistant to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is intolerant to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is not responsive or partially responsive to such JAK2 inhibitor treatment (e.g. INCB018424 or Ruxolitinib (available from Incyte)). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and has undesirable drug toxocitity to such JAK2 inhibitor treatment (e.g. INCBO 18424 or
Ruxolitinib (available from Incyte)). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and has failed such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)). In some embodiments, the subject having PV with resistance or intolerance to another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) has a hematocrit greater than 45%, or phlebotomy twice in the last six months and at least once in the last three months. In some embodiments, the another JAK2 inhibitor is
Ruxolitinib. In some embodiments, the subject does not have splenectomy.
[0065] In some embodiments, the subject does not receive concomitant treatment with or use of drugs to herbal agents known to be at least moderate inhibitors or inducers of CYP3A4. Based on in vitro evaluations, N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide is metabolized by human CYP3A4. Agents that may increase N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide plasma concentrations (i.e., CYP3A4 inhibitors) or decrease N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide plasma concentrations (i.e., CYP3A4 inducers), including herbal agents and foods (e.g. grapefruit/grapefruit juice), should be avoided in subjects being treated as described herein. In addition, in vitro data have indicated that N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide inhibits CYP3A4 in a time-dependent fashion. Agents that are sensitive substrates for metabolism by CYP3A4 should be used with caution as coadministration with N-iert-butyl-3-[(5-methyl-2-{ [4-(2- pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide may result in higher plasma concentrations of the coadministered agent. A list of clinically relevant substrates of CYP3A4 include alfentanil, Cyclosporine, Diergotamine, ethinyl estradiol, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, clarithromycin erythromycin, telithromycin, alprazolam, diazepam, midazolam, triazolam, indinavir, ritonavir, saquinavir, prokinetic, cisapride, astemizole, chlorpheniramine, amlodipine, diltiazem, felodipine, nifedipine, verapamil, atorvastatin, cerivastatin, lovastatin, simvastatin, aripiprazole, gleevec, halopericol, sildenafil, tamoxifen, taxanes, trazodone, and Vincristine. A list of clinically relevant inducers of CYP3A4 include carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, and troglitazone. A list of clinically relevant inhibitors of CYP3A4 include indinavir, nelfinavir, ritonavir,
clarithromycin, itraconazole, ketoconazole, nefazodone, erythromycin, grapefruit juice, verapamil, diltiazem, cimetidine, amiodarone, fluvoxamine, mibefradil, and Troleandomycin. See reference Flockhart et al., http://medicine.iupui.edu/clinpharm/ddis/clinicaltable.aspx., 2009.
[0066] In some embodiments, the subject does not receive concomitant treatment with or use of drugs to herbal agents known to be at least moderate inhibitors or inducers of
CYP2C19.
[0067] The subject (such as a human) may be treated by orally administering at a dose of about 50 mg per day to 500 mg per day of a compound which is N-tert-butyl-3-[(5-methyl-2- { [4-(2-pyrrolidin-l-ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight is the free base moiety weight of the compound. In some embodiment, the compound is administered at a dose of 50 mg/day, 100 mg/day, 200 mg/day, 300 mg/day, or 400 my/day. The compound may be in a capsule and/or a unit dosage form described herein. In some embodiments, the compound administered is in an admixture with a microcrystalline cellulose and sodium stearyl fumarate, and the admixture is in a capsule. In some
embodiments, the compound is administered orally.
[0068] In some embodiments, the compound is administered to the subject daily for at least 1 cycle, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles of a 28-day cycle. In some embodiments, the compound is administered to the subject daily for at least 6 cycles of a 28-day cycle, at least 8 cycles of a 28-day cycle, at least 10 cycles of a 28-day cycle, at least 12 cycles of a 28-day cycle, at least 15 cycles of a 28-day cycle, at least 18 cycles of a 28-day cycle, or at least 24 cycles of a 28- day cycle. In some embodiments, the compound is administered to the subject daily for at least 4 weeks, at least 8 weeks, at least 10 weeks, at least 20 weeks, at least 30 weeks, at least 32 weeks, at least 40 weeks, or at least 50 weeks. In some embodiments, the compound is administered to the subject daily for at least one month, at least two month, at least three month, at least four month, at least five month, at least six month, at least eight month, or at least one year. In some embodiments, the compound is administered once a day.
[0069] In some embodiments, the treatment provided herein ameliorates one or more symptoms associated with PV in the subject. For example, the treatment described herein may produce one or more of the following: reduction in hematocrit (e.g., hematocrit level below about 45% for a minimum of 3 months in the absence of phlebotomy), reduction in platelet count (e.g., <400 x 109/L), reduction of white blood cell count (e.g., <10 x 109/L), reduction in spleen size (e.g., normal or close to normal spleen size measured by imaging, or reduction of spleen size or spleen volume by at least about any of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%), and amelioration of other disease-related symptoms (such as microvascular disturbances, pruritus, and headache). In some embodiments, the treatment described herein may be effective in reducing thrombocytosis, decrease JAK2V617F allele burden, reducing bone marrow fibrosis, and/or reducing bone marrow cellularity. The reduction, decrease, amelioration, or improvement can be at least by 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 % compared to the level prior to commencing treatment with the compound provided herein.
[0070] In some embodiments, the treatment provided herein leads to a complete response. In some embodiments, the treatment provided herein leads to a partial response. The criteria for complete response and partial response may be according to any of the criteria known in the field, for example according to the European LeukemiaNet consensus criteria.
[0071] Also provided herein are methods of monitoring treatment of PV to a subject, comprising (a) administering to the subject an effective amount of a compound which is N- ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof; (b) monitoring a JAK2V617F mutant allele in granulocytes from the subject and/or STAT3 phosphorylation level in blood cells from the subject. In some embodiments, the methods may further comprise determining if the subject should continue or discontinue with the treatment.
Methods of Treatment and Prevention of Essential thrombocythemia [0072] Provided herein are methods for treating, delaying development, and/or preventing ET in a subject comprising administering to the subject an effective amount of a compound which is N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin- 4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof. In some embodiments, the subject ET in the absence of progression to MF or AML. In some embodiments, the subject has increased risk of developing MF. In some
embodiments, the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment. In some embodiments, the subject is a human subject. In some embodiments, the effective amount of N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin- l-ylethoxy)phenyl] amino }pyrimidin-4-yl)amino] benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day for oral administration, and wherein the specified weight is the free base moiety weight of the compound.
[0073] Methods for diagnosing various types of ET are known in the art. Diagnosis of ET may be made according to the revised World Health Organization (WHO) criteria. See Vardiman et al., Blood 114:937-51, 2009. Diagnosis of ET requires the meeting of four criteria. The criteria include: 1) sustained platelet count equal to or greater than 450 x 109/L during the work-up process; 2) bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes and no significant increase of left-shift of neutrophil granulopoiesis or erythropoisis; 3) not meeting WHO criteria for polycythemia vera, primary myelofibrosis, BCR-ABLl-positive CML, or myelodysplasia syndrome, or other myeloid neoplasm. Under criterion 3) not meeting the WHO criteria for polycythemia vera requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range in the presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels, and red cell mass measurement is not required. Under criterion 3) not meeting the WHO criteria for primary myelofibrosis requires the absence of relevant reticulin fibrosis, collagen fibrosis, peripheral blood leukoerythroblastosis, or markedly hypercellular marrow accompanied by megakaryocyte morphology that is typical for primary myelofibrosis such as small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei and dense clustering. Under criterion 3) not meeting the WHO criteria for BCR-ABLl-positive CML requires the absence of BCR- ABL1. Under criterion 3) not meeting the WHO criteria for myelodysplasia syndrome requires the absence of dyserythropoiesis and dysgranulopoiesis; 4) demonstration of JAK2 V617F or other clonal marker, or in the absence of JAK2 V617F, no evidence of reactive thrombosis. Under criterion 4) causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery, infection, inflammation, connective tissue disease, metastatic cancer, and lymphoproliferative disorders. However, the presence of a condition associated with reactive thrombocytosis does not exclude the possibility of ET if other criteria are met.
[0074] A subject having ET without progression to MF may be a subject that does not have post-essential thrombocythemia myelofibrosis. Required criteria for having post-essential thrombocythemia myelofibrosis include: 1) documentation of a previous diagnosis of essential thrombocythemia as defined by the World Health Organization (WHO) criteria (See Tefferi et al., Blood 110: 1092-1097, 2007); 2) bone marrow fibrosis grade 2-3 (on 0-3 scale) according to the European classification as diffuse, often course fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, course fiber network with areas of collagenization (positive trichrome stain) (Thiele et al., Haematologica 90: 1128- 1132, 2005) or grade 3-4 (on 0-4 scale) according to the standard classification as diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis (Manoharan et al., Br J Haematol 43: 185-190, 1979). Additional criteria for post-essential thrombocythemia myelofibrosis where two criteria are required include: 1) anemia, below the reference range for appropriate age, sex, gender and altitude
considerations, and a greater than or equal to 2 mg/ml decrease from baseline hemoglobin level; 2) a leukoerythroblastic peripheral blood picture; 3) increasing splenomegaly defined as either an increase in palpable splenomegaly of greater than or equal to 5 cm (distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly; 4) increased lactate dehydrogenase (LDH) above reference level; 5) development of one or more of the following three constitutional symptoms: greater than 10% weight loss in 6 months, night sweats, or unexplained fever (greater than 37.5°C).
[0075] In some embodiments, a subject having ET has increased risk of progression to MF.
[0076] A subject having ET may be resistant or intolerant to hydroxyurea if the subject on hydroxyurea treatment has platelet count higher than 600 x 109/L. See Barosi et al.,
Leukemia 21:277-80, 2007. [0077] In some embodiments, the subject has a point mutation from valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) (JAK2V617F) if the subject is a human, or a point mutation corresponding to the valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) if the subject is a non-human mammal. In some embodiments, the subject is negative for the valine 617 to phenylalanine mutation of JAK2 if the subject is a human, or negative for a mutation corresponding to the valine 617 to phenylalanie in the Janus kinase 2 (JAK2 kinase) if the subject is a non-human mammal. Whether a subject is positive or negative for JAK2V617F can be determined by a polymerase chain reaction ("PCR") analysis using genomic DNA from bone marrow cells or blood cells (e.g. , whole blood leukocytes). The PCR analysis can be an allele- specific PCR (e.g. , allele- specific quantitative PCR) or PCR sequencing. See Kittur J et ah , Cancer 2007, 109(11):2279-84 and McLornan D et ah , Ulster Med J. 2006, 75(2): 112-9, each of which is expressly incorporated herein by reference.
[0078] In some embodiments, the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment. In some embodiments, the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML). In some embodiments, the subject has an increased risk of developing MF. In some embodiments, the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib. In some embodiments, the subject is selected for treatment based on one or more of the following criteria: (i) the subject has ET that is resistant to hydroxyurea treatment or the subject is intolerant to hydroxyurea treatment; (ii) the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia (AML); (iii) the subject has an increased risk of developing MF; and (iv) the subject has been previously treated with another JAK2 inhibitor such as Ruxolitinib. In some embodiments, a method described herein may further comprise a step of determining whether the subject meets one or more of the above-mentioned criteria before treatment.
[0079] In some embodiments, the subject treated with the methods described herein has previously received another JAK2 inhibitor treatment. The previous therapy may be a JAK2 inhibitor (e.g. INCBO 18424 or Ruxolitinib (available from Incyte), CEP-701 (lestaurtinib, available from Cephalon), or XL019 (available from Exelixis)) (See Verstovsek S.,
Hematology Am Soc Hematol Educ Program. 2009:636-42). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is resistant to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is intolerant to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and is not responsive or partially responsive to such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and has undesirable drug toxocitity to such JAK2 inhibitor treatment (e.g. INCBO 18424 or
Ruxolitinib (available from Incyte)). In some embodiments, the subject has received another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) and has failed such JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)). In some embodiments, the subject having ET with resistance or intolerance to another JAK2 inhibitor treatment (e.g. INCBO 18424 or Ruxolitinib (available from Incyte)) has platelet count higher than 600 x 109/L. In some embodiments, the another JAK2 inhibitor is Ruxolitinib. In some embodiments, the subject does not have splenectomy.
[0080] In some embodiments, the subject does not receive concomitant treatment with or use of drugs to herbal agents known to be at least moderate inhibitors or inducers of
CYP3A4. Based on in vitro evaluations, N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate is metabolized by human CYP3A4. Agents that may increase N-ie/t-butyl-3- [(5-methyl-2- { [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate plasma concentrations (i.e., CYP3A4 inhibitors) or decrease N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate plasma concentrations (i.e., CYP3A4 inducers), including herbal agents and foods (e.g. grapefruit/grapefruit juice), should be avoided in patients receiving the compound. In addition, in vitro data have indicated that N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate inhibits CYP3A4 in a time-dependent fashion. Agents that are sensitive substrates for metabolism by CYP3A4 should be used with caution as coadministration with N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate may result in higher plasma concentrations of the coadministered agent. A list of clinically relevant substrates of CYP3A4 include alfentanil, Cyclosporine, Diergotamine, ethinyl estradiol, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, clarithromycin erythromycin, telithromycin, alprazolam, diazepam, midazolam, triazolam, indinavir, ritonavir, saquinavir, prokinetic, cisapride, astemizole, chlorpheniramine, amlodipine, diltiazem, felodipine, nifedipine, verapamil, atorvastatin, cerivastatin, lovastatin, simvastatin, aripiprazole, gleevec, halopericol, sildenafil, tamoxifen, taxens, trazodone, and Vincristine. A list of clinically relevant inducers of CYP3A4 include carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, and troglitazone. A list of clinically relevant inhibitors of CYP3A4 include indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, erythromycin, grapefruit juice, verapamil, diltiazem, cimetidine, amiodarone, fluvoxamine, mibefradil, and Troleandomycin. See reference Flockhart et al.,
http://medicine.iupui.edu/clinpharm/ddis/clinicaltable.aspx., 2009.
[0081] The subject (such as a human) may be treated by orally administering at a dose of about 50 mg per day to 500 mg per day of a compound which is N-tert-butyl-3-[(5-methyl-2- { [4-(2-pyrrolidin-l-ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the specified weight is the free base moiety weight of the compound. In some embodiment, the compound is administered at a dose of 50 mg/day, 100 mg/day, 200 mg/day, 300 mg/day, or 400 my/day. The compound may be in a capsule and/or a unit dosage form described herein. In some embodiments, the compound administered is in an admixture with a microcrystalline cellulose and sodium stearyl fumarate, and the admixture is in a capsule. In some
embodiments, the compound is administered orally.
[0082] In some embodiments, the compound is administered to the subject daily for at least 1 cycle, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, at least 7 cycles, at least 8 cycles of a 28-day cycle. In some embodiments, the compound is administered to the subject daily for at least 6 cycles of a 28-day cycle, at least 8 cycles of a 28-day cycle, at least 10 cycles of a 28-day cycle, at least 12 cycles of a 28-day cycle, at least 15 cycles of a 28-day cycle, at least 18 cycles of a 28-day cycle, or at least 24 cycles of a 28- day cycle. In some embodiments, the compound is administered to the subject daily for at least 4 weeks, at least 8 weeks, at least 10 weeks, at least 20 weeks, at least 30 weeks, at least 32 weeks, at least 40 weeks, or at least 50 weeks. In some embodiments, the compound is administered to the subject daily for at least one month, at least two month, at least three month, at least four month, at least five month, at least six month, at least eight month, or at least one year. In some embodiments, the compound is administered once a day.
[0083] In some embodiments, the treatment provided herein ameliorates one or more symptoms associated with ET in the subject. For example, the treatment described herein may produce one or more of the following: reduction of platelet count (e.g., a platelet count <400 x 109/L or <600 x 109/L or a decrease >50% from baseline), white blood cell count (e.g., <10 x 109/L), reduction in spleen size (e.g., normal or close to normal spleen size measured by imaging or reduction of spleen size or spleen volume by at least about any of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%), and amelioration of other disease-related symptoms (such as microvascular disturbances, pruritus, and headache). In some embodiments, the treatment described herein may be effective in reducing thrombocytosis, decrease JAK2V617F allele burden, reducing bone marrow fibrosis, and/or reducing bone marrow cellularity. The reduction, decrease, amelioration, or improvement can be at least by 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 % compared to the level prior to commencing treatment with the compound provided herein.
[0084] In some embodiments, the treatment provided herein leads to a complete response. In some embodiments, the treatment provided herein leads to a partial response. The criteria for complete response and partial response may be according to any of the criteria known in the field, for example according to the European LeukemiaNet consensus criteria.
[0085] Also provided herein are methods of monitoring treatment of ET in a subject, comprising (a) administering to the subject an effective amount of a compound which is N- ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof; (b) monitoring a JAK2V617F mutant allele in granulocytes from the subject and/or STAT3 phosphorylation level in blood cells from the subject. In some embodiments, the methods may further comprise determining if the subject should continue or discontinue with the treatment.
V. Articles of Manufactures and Kits
[0086] Also provided herein are articles of manufacture or kits containing a compound which is N-iert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin- 4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof. In some embodiments, the article of manufacture or the kit further includes instructions for using the compounds described herein in the methods provided herein. In some embodiments, the article of manufacture or the kit further comprises a label or a package insert providing the instructions. In some embodiments, the compound is in a capsule and/or a unit dosage form described herein.
[0087] In some embodiments, the article of manufacture or kit may further comprise a container. Suitable containers include, for example, bottles, vials (e.g. , dual chamber vials), syringes (such as single or dual chamber syringes) and test tubes. The container may be formed from a variety of materials such as glass or plastic, and the container may hold the compound, for example in the formulation to be administered. The article of manufacture or the kit may further comprise a label or a package insert, which is on or associated with the container, may indicate directions for reconstitution and/or use of the compound. In some embodiments, the package insert or the label is in a position which is visible to prospective purchasers.
[0088] In some embodiments, the label or package insert may further indicate that the compound is useful or intended for treating or preventing PV in a subject. In some embodiments, the package insert or the label indicates that the compound is useful for treating that i) the compound is useful for treating a subject having PV and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the package insert or the label indicates that the dose is 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having PV that is resistant to hydroxyurea treatment or for treating a subject having PV where the subject is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing MF. In some embodiments, the subject has at least one of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygous JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocyte colony formation. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
[0089] The label or package insert may further indicate that the compound is useful or intended for treating or preventing ET in a subject. In some embodiments, the package insert or the label indicates that the compound is useful for treating that i) the compound is useful for treating a subject ET and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the package insert or the label indicates that the dose is 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3- [(5-methyl-2- { [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule. In some embodiments, the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having ET that is resistant to hydroxyurea treatment or for treating a subject that is intolerant to hydroxyurea treatment. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing MF. In some embodiments, the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with another JAK2 inhibitor such as Ruxolitinib.
[0090] The following are examples of the methods and compositions provided herein. It is understood that various other embodiments may be practiced, given the general description provided above.
EXAMPLES
Example 1
[0091] A randomized open-label study is conducted of the orally administered N-tert-butyl- 3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate (the drug substance) in patients with polycythemia vera (PV) that is resistant to hydroxyurea treatment and patients with PV who are intolerant to hydroxyurea. The subjects in this study were administered with capsule form of the drug substance as described in Example 3.
Study Summary
[0092] The study is designed to investigate (1) the efficacy of daily oral doses of 100, 200 and 400 mg of the drug substance in patients with PV that is resistant to hydroxyurea treatment and patients with PV who are intolerant to hydroxyurea to induce the absence of requirement for phlebotomy and a hematocrit below 45% for a minimum of 3 months; (2) the safety of the drug substance; (3) the efficacy of daily oral doses of 100, 200 and 400 mg the drug substance in inducing complete or partial clinicohematologic responses; (4) the pharmacokinetics of the drug substance after single and repeat doses; (5) the
pharmacodynamics of the drug substance as measured by changes in JAK2V617F allele burden in those patients with JAK2V617F mutation, and/or STAT3 phosphorylation inhibition; (6) the effects of the drug substance on histological, cytogenetic and molecular responses in bone marrow; (7) baseline myeloproliferative neoplasm (MPN)-associated symptoms, as well as overall impact in quality of life, through serial administration of the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (See Scherber et al., Blood 116:4095, 2010); (8) generic health-related quality of life and utility values using the EuroQol EQ-5D™ questionnaire (See the EuroQol Group, EuroQol-a new facility of the measurement of health-related quality of life, Health Policy 16: 199-208, 1990); (9) the effects of the drug substance on histological, cytogenetic and molecular responses in bone marrow; (10) the effects of the drug substance on leukocytosis and thrombocytosis; (11) changes in endogenous erythroid colony formation; (12) replenishment of iron in iron-deficient patients (Fe/ Ferritin/ Transferrin/%Transferrin saturation); (13) pharmacogenomic analysis related to drug metabolizing enzymes and genes possibly involved in the JAK-STAT pathway or related to myeloproliferative neoplasms (MPNs).
Patients
[0093] Patients included in the study have a diagnosis of PV, according to the revised World Health Organization (WHO) criteria (see Table 1) that is resistant to hydroxyurea treatment or the patient with PV is intolerant to hydroxyurea treatment (per LeukemiaNet consensus criteria). PV that is resistant to hydroxy urea is defined as patient on hydroxyurea with a hematocrit >45% or phlebotomy two times in the last 6 months, with at least one time in the last 3 months (Barosi et al., Br J Haematol, 148(6):961-3, 2010). Table 1. Criteria for Polycythemia Vera (PV)
Criteria for Polycythemia Vera (PV)
Diagnosis requires the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria:
Major criteria
1. Hemoglobin > 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume*
2. Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation
Minor criteria
1. Bone marrow biopsy showing hypercellularity for age with trilineage growth
(panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation
2. Serum erythropoietin level below the reference range for normal
3. Endogenous erythroid colony formation in vitro
*Hemoglobin or hematocrit > 99th percentile of method-specific reference range for age, sex, altitude of residence; or hemoglobin > 17 g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from a person's baseline value that cannot be attributed to correction of iron deficiency; or elevated red cell mass > 25% above mean normal predicted value.
[0094] Patients are randomized in a 1: 1: 1 ratio to 1 of 3 drug substance dose groups: 100, 200 and 400 mg (free base) daily (approximately 10 patients per dose level). Patients remain on study treatment for a minimum of 8 cycles in the absence of disease progression or unacceptable toxicity. Patients who have completed 8 cycles of therapy who are tolerating study treatment and benefit clinically are allowed to continue treatment. For patients randomized to 100 or 200 mg/day, cross-over to a higher dose level may be permitted after the patient completes 8 cycles of therapy.
Method
[0095] The drug substance is supplied as hard capsules containing 100 mg or 50 mg of the free base form of the drug substance. The capsule contains a blend of the drug substance and microcrystalline cellulose, with a small quantity of sodium stearyl fumarate added as a lubricant to facilitate manufacturing. The capsules are orally self-administered as a single agent, once daily on an empty stomach (1 hour before or 2 hours after meals), beginning on day 1 of the study and thereafter at approximately the same time each day in consecutive, 28- day cycles. [0096] Assessment of clinicohematologic response to treatment with the drug substance is performed at the end of cycles 4 and 8 or at the end of treatment (EOT) based on European LeukemiaNet consensus criteria and at the 30-day follow-up visit
[0097] Changes from baseline in the following parameters are determined: spleen size by palpation at the end of each cycle, EOT, and at the 30-day follow-up visit; spleen volume, in patients with palpable spleens at baseline, by magnetic resonance imaging (MRI) at the end of Cycles 4 and 8 or EOT; MPN-SAF responses at the end of cycles 1, 4, and 8 or EOT, and at the 30-day follow-up visit; and EQ-5D responses at the end of Cycle 8 or EOT. Bone marrow analysis, including cytogenetics, cellularity and cell composition (e.g., blast count), and reticulin fibrosis, is performed at baseline and thereafter (a) in patients achieving complete (clinicohematologic) response, at the time of complete response and again 6 months later if they still have complete response, and (b) every 6 months in patients with cytogenetic abnormalities or reticulin fibrosis at baseline.
[0098] Hematocrit is measured at the end of each cycle and phlebotomy requirements during the study is recorded. JAK2V617F mutant allele in granulocytes is measured at baseline and at the end of cycles 4 and 8 or EOT. Allele burden is also measured in patients who develop disease progression. STAT3 phosphorylation is analyzed predose and at 2 and 6 hours postdose on day 1 of cycle 1 and prior to dosing on days 2 and 15 of cycle 1 and on day 1 of cycle 2. STAT3 phosphorylation is also measured in patients who develop disease progression. Changes in endogenous erythroid colony formation and replenishment of iron in iron-deficient patients (Fe/ Ferritin/ Transferrin/ % Transferrin saturation) is measured at a single center at baseline and at the end of cycles 1, 4, and 8 or EOT. Pharmacogenomic analysis related to drug metabolizing enzymes and genes possibly involved in the JAK-STAT pathway or related to MPNs is performed prior to dosing on cycle 1 day 1. Safety will be evaluated based on the incidence of treatment-emergent adverse events (TEAEs), and changes in clinical laboratory parameters, red blood cell transfusion requirements, Eastern Cooperative Oncology Group (ECOG) performance status (PS), vital signs, and body weight relative to baseline. Adverse events will be assessed and reported using terminology of the National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Example 2. [0099] A randomized open-label study is conducted of orally administered N-tert-butyl-3- [(5-methyl-2- { [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate (the drug substance) in patients with essential thrombocythemia (ET) that is resistant to hydroxyurea treatment or patients having ET that are intolerant to hydroxyurea treatment. The subjects in this study are administered with capsule form of the drug substance as described in Example 3.
Study Summary
[0100] This study is designed to investigate (1) efficacy of daily oral doses of 50, 100, 200, and 400 mg of the drug substance (weight given of free base form) in patients with ET that is resistant to hydroxyurea treatment and patients who are intolerant to hydroxyurea treatment for reduction of platelet count to <400 x 109/L for a minimum of 3 months; (2) the safety of daily oral doses of 50, 100, 200 and 400 mg drug substance in patients with ET that is resistant to hydroxyurea treatment or patients who are intolerant to hydroxyurea treatment; (3) the efficacy of daily oral doses of 50, 100, 200 and 400 mg drug substance in inducing complete or partial clinicohematologic responses; (4) the pharmacokinetics of the drug substance after single and repeat doses; (5) the pharmacodynamics of the drug substance as measured by changes in JAK2V617F allele burden in those patients with JAK2V617F mutation, and/or STAT3 phosphorylation inhibition; (6) the effects of the drug substance on histological, cytogenetic and molecular responses in bone marrow; (7) changes in baseline myeloproliferative neoplasm (MPN)-associated symptoms, as well as overall impact in quality of life, through serial administration of the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et al., Blood 116:4095, 2010); (8) generic health- related quality of life and utility values using the EuroQol EQ-5D™ questionnaire (The EuroQol Group, Health Policy, 16(3): 199-208, 1990); (9) the effects of the drug substance on leukocytosis and thrombocytosis; and (10) pharmacogenomic analysis related to drug metabolizing enzymes and genes possibly involved in the JAK-STAT pathway or related to MPNs.
Patients
[0101] Patients included in the study have a diagnosis of ET, according to the revised WHO criteria (see Table 2), where the ET is resistant to hydroxyurea treatment or where the patient is intolerant to hydroxyurea treatment (per LeukemiaNet consensus criteria). ET that is resistant to hydroxyurea treatment is defined as patient on hydroxyurea with a platelet count >600 x 109/L (Barosi et al., Leukemia, 21(2):277-80, 2007). TABLE 2. Criteria for Essential Thrombocythemia (ET)
Criteria for Essential Thrombocythemia (ET)
Diagnosis requires meeting all 4 criteria
1. Sustained platelet count > 450 x 109/L *
2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes. No significant increase of left-shift of neutrophil granulopoiesis or erythropoisis.
3. Not meeting WHO criteria for polycythemia vera,† primary myelofibrosis,* BCR- ABL1 -positive CML,§ or myelodysplasia syndrome," or other myeloid neoplasm.
4. Demonstration of JAK2 V617F or other clonal marker, or in the absence of JAK2
V617F, no evidence of reactive thrombosis.'"
* Sustained during the work-up process.
Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range in the presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels, and red cell mass measurement is not required.
* Requires the absence of relevant reticulin fibrosis, collagen fibrosis, peripheral blood leukoerythroblastosis, or markedly hypercellular marrow accompanied by megakaryocyte morphology that is typical for primary myelofibrosis— small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei and dense clustering.
§ Requires the absence of BCR-ABL1.
" Requires the absence of dyserythropoiesis and dysgranulopoiesis.
¾ Causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery,
infection, inflammation, connective tissue disease, metastatic cancer, and
lymphoproliferative disorders. However, the presence of a condition associated with reactive thrombocytosis does not exclude the possibility of ET if other criteria are met.
[0102] Patients are randomized in a 1: 1: 1 ratio to 1 of 3 the dose groups: 100, 200 and 400 mg daily (approximately 10 patients per dose level). Patients remain on study treatment for a minimum of 8 cycles in the absence of disease progression or unacceptable toxicity. Patients who have completed 8 cycles of therapy who are tolerating study treatment and benefit clinically are allowed to continue treatment. For patients randomized to 100 or 200 mg/day, cross-over to a higher dose level may be permitted after the patient completes 8 cycles of therapy.
Method
[0103] The drug substance is supplied as hard capsules containing 100 mg or 50 mg of the free base form. The capsule contains a blend the drug substance and microcrystalline cellulose, with a small quantity of sodium stearyl fumarate added as a lubricant to facilitate manufacturing. The capsules are orally self-administered, once daily on an empty stomach (1 hour before or 2 hours after meals), beginning on day 1 of the study and thereafter at approximately the same time each day in consecutive, 28-day cycles.
[0104] Primary endpoint is reduction of platelet count. Platelet counts are measured at the end of each cycle. A platelet count <400 x 109/L for a minimum of 3 months after completion of 8 cycles of therapy is considered a response.
[0105] Assessment of clinicohematologic response to treatment with the drug substance is performed at the end of cycles 4 and 8 or at the end of treatment (EOT) based on European LeukemiaNet consensus criteria and at the 30-day follow-up visit. In addition, changes from baseline in the following parameters are determined: spleen size by palpation at the end of each cycle, EOT, and at the 30-day follow-up visit; spleen volume, in patients with palpable spleens at baseline, by magnetic resonance imaging (MRI) at the end of Cycles 4 and 8 or EOT; MPN-SAF (Myeloproliferative Neoplasm Symptom Assessment Form) responses at the end of cycles 1, 4, and 8 or EOT, and at the 30-day follow-up visit; and EQ-5D responses at the end of Cycle 8 or EOT. Bone marrow analysis, including cytogenetics, cellularity and cell composition (e.g., blast count), and reticulin fibrosis, is performed at baseline and thereafter (a) in patients achieving complete (clinicohematologic) response, at the time of complete response and again 6 months later if they still have complete response, and (b) every 6 months in patients with cytogenetic abnormalities or reticulin fibrosis at baseline. In the subset of patients who are positive for the mutation, JAK2V617F mutant allele in granulocytes is measured by a central laboratory at baseline and at the end of cycles 4 and 8 or EOT. Allele burden also is measured in patients who develop disease progression. STAT3 phosphorylation is analyzed predose and at 2 and 6 hours postdose on day 1 of cycle 1 and prior to dosing on days 2 and 15 of cycle 1 and on day 1 of cycle 2. STAT3 phosphorylation also is measured in patients who develop disease progression. Pharmacogenomic analysis related to drug metabolizing enzymes and genes possibly involved in the JAK-STAT pathway or related to MPNs is performed prior to dosing on cycle 1 day 1. Safety is evaluated based on the incidence of treatment-emergent adverse events (TEAEs), and changes in clinical laboratory parameters, red blood cell transfusion requirements, Eastern Cooperative Oncology Group (ECOG) performance status (PS), vital signs, and body weight relative to baseline. Adverse events is assessed and reported using terminology of the National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Platelet counts is measured at the end of each cycle.
Example 3. Capsule Form of N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-l- ylethoxy )phenyl]amino}pyrimidin-4-yl)amino Jbenzenesulfonamide dihydrochloride monohydrate and Process of Making
[0106] N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin- 4-yl)amino]benzenesulfonamide dihydrochloride monohydrate drug products were provided as 50 mg and 100 mg capsule strengths, where the weights (the unit formula weights) are specified for the amount of active (i.e., free base) moiety (N-iert-butyl-3-[(5-methyl-2-{ [4-(2- pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide) . The quantitative composition of each strength of drug product capsule is shown in Table 3.
Table 3. List of all components and unit formula for 50 mg, 100 mg, and 200
strengths of drug product capsules.
Figure imgf000039_0001
* Silicified microcrystalline cellulose is a combination of microcrystalline cellulose and colloidal silicon dioxide.
[0107] The process for making N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate capsules is described below:
[0108] A. Dry granulation of components (implemented for all three drug product strengths): 1. N-ieri-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate., sodium stearyl fumarate, and about 50% of silicified microcrystalline cellulose were blended within a conical blender for 5 minutes. 2. The blend was passed through a conical mill equipped with a round 18-mesh screen and round impeller. The blend was recharged into the conical blender. 3. The remaining 50% of silicified microcrystalline cellulose was sifted through the conical mill and added to the blender. The mixture was blended for 15 minutes. 4. The final blend was passed through a roller compactor. 5. The roller compacted ribbons were passed through a conical mill equipped with a round 16- mesh screen and round impeller. 6. The milled material was blended within the conical blender for 5 minutes to ensure homogeneity. 7. In-process check (IPC) samples were withdrawn from the conical blender using a sample thief. Samples were subjected to potency analysis.
[0109] B. Capsule-filling (implemented for all three drug product strengths): 1. If potency was outside 98-102% (w/w) nominal, the capsule fill weight was adjusted accordingly. 2. The prepared material was encapsulated using automatic capsule filling machine. The prepared capsules were bottled and stored at 20-28 °F (68-82 °C) and ambient humidity.
[0110] Content uniformity and dissolution were examined. HPLC method validation was performed using a one-analyst, one-run-per-analyst design, and satisfied all required criteria for specificity, precision, accuracy, linearity, and sample stability.
[0111] Capsules may also be made according to the method described in Example 5 of PCT Application No. PCT/US2011/059643, filed November 7, 2011 (with publication No. WO 2012/061833).
[0112] Although the foregoing examples have been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention.

Claims

CLAIMS What is claimed is:
1. A method of treating polycythemia vera (PV) in a subject, comprising orally administering to the subject an effective amount of a compound which is N-tert-butyl-3-[(5- methyl-2- { [4- (2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has PV, wherein the effective amount of N-tert-butyl-3-[(5- methyl-2- { [4- (2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
2. The method of claim 1, wherein the subject has PV that is resistant to hydroxyurea treatment.
3. The method of claim 1, wherein the subject is intolerant to hydroxyurea treatment.
4. The method of any one of claims 1-3, wherein the subject has an increased risk of developing myelofibrosis.
5. The method of claim 4, wherein the subject has at least one of the risk factors selected from the group consisting of 1) having PV for at least 15 years, 2) having homozygosity for the JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation.
6. The method of any one of claims 1-5, wherein the subject has been previously treated with Ruxolitinib.
7. The method of any one of claims 1-6, further comprising monitoring
JAK2V617F mutant allele in granulocytes from the subject.
8. The method of any one of claims 1-7, further comprising monitoring STAT3 phosphorylation level in blood cells.
9. The method of any one of claims 1-8, wherein the compound is administered orally at a dose of 50 mg per day.
10. The method of any one of claims 1-8, wherein the compound is administered orally at a dose of 100 mg per day.
11. The method of any one of claims 1-8, wherein the compound is administered orally at a dose of 200 mg per day.
12. The method of any one of claims 1-8, wherein the compound is administered orally at a dose of 400 mg per day.
13. The method of any one of claims 1-12, wherein the compound is administered over a period of at least 32 weeks.
14. The method of any one of claims 1-13, wherein the compound is provided in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4- (2-pyrrolidin-l-ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
15. The method of claim 14, wherein the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
16. The method of any one of claims 1-15, further comprising instructing the subject to ingest the effective amount of the compound on an empty stomach.
17. The method of any one of claims 1-16, further comprising instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4.
18. The method of any one of claims 1-17, further comprising instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of
CYP2C19.
19. The method of any one of claims 1-18, wherein the subject has PV in the absence of myelofibrosis (MF) or acute myeloid leukemia.
20. The method of any one of claims 1-19, wherein the compound is
Figure imgf000043_0001
3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate.
21. A kit comprising (a) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2- pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) a package insert or a label indicating that i) the compound is useful for treating a subject having polycythemia vera and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound.
22. The kit of claim 21, wherein the package insert or the label indicates that the dose is 50 mg, 100 mg, 200 mg, or 400 mg per day.
23. The kit of claim 21 or 22, wherein the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
24. The kit of claim 23, wherein the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
25. The kit of any one of claims 21-24, wherein the package insert or label indicates that the compound is useful for treating a subject having PV that is resistant to hydroxyurea treatment.
26. The kit of any one of claims 21-24, wherein the package insert or label indicates that the compound is useful for treating a subject having PV where the subject is intolerant to hydroxyurea treatment.
27. The kit of any one of claims 21-26, wherein the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing myelofibrosis.
28. The kit of claim 27, wherein the subject has at least one of the risk factors selected from the group consisting of 1) having polycythemia vera for at least 15 years, 2) having homozygosity for the JAK2 V617F mutant allele, 3) having an elevated serum lactate dehydrogenase level, and 4) having endogenous megakaryocytic colony formation.
29. The kit of any one of claims 21-28, wherein the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with Ruxolitinib.
30. The kit of any one of claims 21-29, wherein the compound is N-ie/t-butyl-3- [(5-methyl-2- { [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate.
31. A method of treating essential thrombocythemia (ET) in a subject, comprising orally administering to the subject an effective amount of a compound which is N-tert-butyl- 3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the subject has ET, wherein the effective amount of N-tert-butyl-3-[(5- methyl-2- { [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]
benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof is about 50 mg to about 400 mg per day, and wherein the specified weight is the free base moiety weight of the compound.
32. The method of claim 31, wherein the subject has ET that is resistant to hydroxyurea treatment.
33. The method of claim 31, wherein the subject is intolerant to hydroxyurea treatment.
34. The method of any one of claims 31-33, wherein the subject has an increased risk of developing myelofibrosis.
35. The method of any one of claims 31-34, wherein the subject has been previously treated with Ruxolitinib.
36. The method of any one of claims 31-35 further comprising monitoring JAK2V617F mutant allele in granulocytes from the subject.
37. The method of any one of claims 31-36 further comprising monitoring STAT3 phosphorylation level in blood cells from the subject.
38. The method of any one of claims 31-37, wherein the compound is
administered orally at a dose of 50 mg per day.
39. The method of any one of claims 31-37, wherein the compound is
administered orally at a dose of 100 mg per day.
40. The method of any one of claims 31-37, wherein the compound is
administered orally at a dose of 200 mg per day.
41. The method of any one of claims 31-37, wherein the compound is
administered orally at a dose of 400 mg per day.
42. The method of any one of claims 31-41, wherein the compound is administered over a period of at least 32 weeks.
43. The method of any one of claims 31-42, wherein the compound is provided in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-
{ [4-(2-pyrrolidin-l-ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
44. The method of claim 43, wherein the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
45. The method of any one of claims 31-44, further comprising instructing the subject to ingest the effective amount of the compound on an empty stomach.
46. The method of any one of claims 31-45, further comprising instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of CYP3A4.
47. The method of any one of claims 31-46, further comprising instructing the subject to avoid ingesting agents that are at least moderate inducers or inhibitors of
CYP2C19.
48. The method of any one of claims 31-47, wherein the subject has ET in the absence of myelofibrosis (MF) or acute myeloid leukemia.
49. The method of any one of claims 31-48, wherein the compound is N-tert- butyl- 3 - [ (5 -methyl-2- { [4- (2-pyrrolidin- 1 - ylethoxy)phenyl] amino } pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate.
50. A kit comprising (a) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2- pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and (b) a package insert or a label indicating that i) the compound is useful for treating a subject having essential thrombocythemia and ii) the compound is administered to the subject orally at a dose of about 50 mg to about 400 mg per day, wherein the specified weight is the free base moiety weight of the compound.
51. The kit of claim 50, wherein the package insert or the label indicates that the dose is 50 mg, 100 mg, 200 mg, or 400 mg per day.
52. The kit of claim 50 or 51, wherein the compound is in a capsule comprising an admixture of (i) a compound which is N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl] amino }pyrimidin-4-yl)amino]benzenesulfonamide or a pharmaceutically acceptable salt thereof or a hydrate thereof, (ii) a microcrystalline cellulose, and (iii) sodium stearyl fumarate, wherein the admixture is contained in the capsule.
53. The kit of claim 52, wherein the capsule contains 50 mg or 100 mg of the compound, wherein the specified weight is the free base moiety weight of the compound.
54. The kit of any one of claims 50-53, wherein the package insert or label indicates that the compound is useful for treating a subject having ET that is resistant or intolerant to hydroxyurea treatment.
55. The kit of any one of claims 50-54, wherein the package insert or label indicates that the compound is useful for treating a subject having an increased risk of developing myelofibrosis.
56. The kit of any one of claims 50-55, wherein the package insert or label indicates that the compound is useful for treating a subject that has been previously treated with Ruxolitinib.
57. The kit of any one of claims 50-56, wherein the compound is N-ie/t-butyl-3- [(5-methyl-2- { [4-(2-pyrrolidin- 1 -ylethoxy)phenyl] amino }pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate.
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