Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • 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
  • A61P7/06—Antianaemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• Myeloproliferative disorders are diseases of the bone marrow and blood.
• Myelofibrosis is a clonal myeloproliferative disease that is characterized by exaggerated abnormalities in megakaryocytes.
• the abnormal megakaryocytes are attributed primarily to dysregulation of the JAK/STAT pathway, although there is dysregulation in a number of other pathways as well. Due to the multiple pathways affected and the array of downstream effects, myelofibrosis is a complex, heterogeneous disease with many inter related features.
• the abnormal megakaryocytes release excess platelets and cytokines, both pro-inflammatory and pro-fibrotic (transforming growth factor beta [TGF-B]), into the bone marrow.
• TGF-B transforming growth factor beta
• Bone marrow fibrosis is the hallmark of myelofibrosis, although diagnosis is not necessarily dependent on it.
• the bone marrow fibrosis is the key feature that causes the morbidity and mortality associated with the disease.
• myelofibrosis often lead to cytopenias, extramedullary hematopoiesis (EMH), organomegaly such as splenomegaly and hepatomegaly and a myriad of constitutional symptoms.
• EMH extramedullary hematopoiesis
• Myelofibrosis is a serious disease in that it is both life-threatening and greatly diminishes the quality of life of the patient before it affects survival.
• the two most common causes of death are conversion to acute myeloid leukemia (AML) and progression of the disease.
• AML acute myeloid leukemia
• the treatment paradigm is dictated by the number of risk factors present, which then correlate with different survival rates. While allogeneic hematopoietic stem cell
• HCT transplantation
• the remaining treatments are more palliative in nature, either due to their mechanism of action (e.g., treatments specifically focused on the anemia that is frequently associated with myelofibrosis) or due to the restricted effects that the treatment can elicit (e.g., the standard of care ruxolitinib).
• Ruxolitinib a JAK1/2 inhibitor
• JAK is a key regulator in hematopoiesis, immune regulation, growth and embryogenesis (Stahl M, Zeidan AM (2017). Management of Myelofibrosis: JAK Inhibition and Beyond. Expert Rev Hematol; 17(5): 459-477).
• Dysregulated JAK signaling can lead to increased thrombopoietin signaling, which is believed to be one of the causes of increased megakaryocyte production and platelets in myelofibrosis.
• JAK signaling is implicated in the release of pro -inflammatory cytokines and growth factors that cause constitutional symptoms and splenomegaly: JAK-1 plays a role in the signaling of pro- inflammatory cytokines (e.g., IL-1, IL-6, TNF-a), the cause of systemic symptoms in myelofibrosis and JAK-2 impacts growth factors and other cytokines (e.g., IL-3, IL-5) that are believed to promote splenomegaly in myelofibrosis.
• pro-inflammatory cytokines e.g., IL-1, IL-6, TNF-a
• JAK-2 impacts growth factors and other cytokines (e.g., IL-3, IL-5) that are believed to promote splenomegaly in myelofibrosis.
• IL-3 cytokines
• Ruxolitinib is considered a palliative treatment due to its lack of disease modifying effects. It does not affect the mutant allele burden or bone marrow fibrosis (Novel Therapies for Myelofibrosis, 2017, Curr Hematol Malig Rep; 12(6): 611-624). In addition, constitutional symptoms will revert back after a week off of ruxolitinib treatment (see Tefferi A (2017); Management of Primary Myelofibrosis; UpToDate; 1-23). Next, anemia negatively impacts patient quality of life, has the highest power of predicting shortened survival, and limits access to optimal standard of care.
• Ruxolitinib is not a viable treatment option for some anemic patients because ruxolitinib is known to decrease red blood cell production and hemoglobin levels.
• Anemic patients for example, are either not treated at all with ruxolitinib, given a lower dose of ruxolitinib leading to inadequate response, or give a full dose ruxolitinib, which typically leads to need for red blood cell (RBC) transfusions.
• RBC red blood cell
• FIG. 5 is a diagrammatic representation of FIG. 5.
• 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide significantly decreased spleen size, even in subjects who were resistant to ruxolitinib.
• Patient 245 as described below became resistant to ruxolitinib with her spleen increasing 25% in size (spleen volume was 12 cm by palpation).
• her spleen size was reduced to 5 cm.
• FIG. 1 shows the effects of Compound 1 on IL6 and IL10 mRNA transcript levels.
• FIG. 2 depicts histograms of Compound 1 effect on megakaryocyte differentiation.
• FIG. 3 represents the histograms and quantitation of effects on mature
• megakaryocyte marker CD42b after Treatment with Compound 1 and ruxolitinib for 10 days in stem-cell derived megakaryocyte cultures from healthy donor 2 where the grey histrogram is DMSO treated sample, blue histogram is Compound 1 treated sample, and CD42b high calculations refer to the Compound 1-treated samples.
• FIG. 4 shows the repression of BET-target genes IL8 and CCR1 in circulating blood 2 hours post-dose as a function of the plasma concentration of Compound 1.
• FIG. 5 shows the changes in hemoglobin levels and transfusion requirements in a combination arm of Compound 1 and ruxolitinib.
• FIG. 6 shows the change in platelet and hemoglobin levels in patient 247 of the monotherapy arm.
• Compound 1 is a potent and selective small molecule designed to promote anti tumor activity by selectively inhibiting the function of BET protein. See e.g., J. Med. Chem., 2016; Feb. 25; 59(4): 1330-9. Compound 1 is being investigated for its profound effects in treating hematological malignancies including progressive lymphoma. See e.g., U.S. Clinical Trials NCT02157636 and NCT01949883. It has now been found, however, that Compound 1 is also effective in treating myelofibrosis. To this end, for example, Compound 1 increased hemoglobin levels, normalized platelet counts, and reduced spleen size. Subjects who were previously transfusion dependent became transfusion independent after treatment.
• a method of treating myelofibrosis in a subject comprising administering to the subject a therapeutically effective amount of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yljacetamide, or a pharmaceutically acceptable salt thereof.
• subject and“patient” may be used interchangeably, and mean a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
• companion animals e.g., dogs, cats, and the like
• farm animals e.g., cows, pigs, horses, sheep, goats and the like
• laboratory animals e.g., rats, mice, guinea pigs and the like.
• the subject is a human in need of treatment.
• treatment refers to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progress of myelofibrosis, or one or more symptoms thereof, as described herein.
• treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
• treatment may be administered in the absence of symptoms.
• treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Symptoms specific to
• myelofibrosis include, but are not limited to, abdominal discomfort, dyspnea on exertion, early satiety, fatigue, headaches, night sweats, dizziness, fever, chills, insomnia, pruritus, or bone pain.
• Compound 1 was effective in subjects who have undergone treatment for myelofibrosis with JAK inhibitors such as ruxolitinib. Therefore, in a second embodiment, provided herein is a method of treating myelofibrosis in a subject comprising administering to the subject a therapeutically effective amount of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide, or a pharmaceutically acceptable salt thereof, wherein the subject has previously undergone treatment with a janus kinase (JAK) inhibitor (e.g., ruxolitinib).
• JAK janus kinase
• JAK janus kinase
• 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide or a
• a pharmaceutically acceptable salt thereof for treating myelofibrosis in a subject who has previously undergone treatment with a janus kinase (JAK) inhibitor (e.g., ruxolitinib).
• JK janus kinase
• the subjects described in the first and second embodiments are characterized as progressed/relapsed to a JAK inhibitor.
• the subjects described in the first and second embodiments are characterized is
• a subject who is characterized as progressed/relapsed is one who at one time responded to treatment with a JAK inhibitor (e.g., ruxolitinib), but who no longer responds.
• a JAK inhibitor e.g., ruxolitinib
• a subject who is characterized as refractory/resistant is one who is unresponsive or
• JAK inhibitor e.g., ruxolitinib
• Compound 1 was also shown to be effective as a combination treatment with the JAK inhibitor ruxolitinib. Therefore, in a fifth embodiment, provided herein is a method of treating myelofibrosis in a subject comprising administering to the subject a therapeutically effective amount of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5- e]azepin-4-yl)acetamide and a therapeutically effective amount of a janus kinase (JAK) inhibitor (e.g., ruxolitinib), or a pharmaceutically acceptable salt of any of the foregoing.
• a janus kinase (JAK) inhibitor e.g., ruxolitinib
• ruxolitinib refers to the JAK inhibitor (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile phosphate having the following formula.
• an effective amount or“therapeutically effective amount” are used interchangeably and include an amount of a compound described herein that will elicit a desired medical response in a subject having myelofibrosis, e.g., reducing the symptoms of and/or slowing the progression of the disease.
• the subject treated by the methods described herein is cytopenic.
• Cytopenic refers to subjects in which the production of one or more blood cell types ceases or is greatly reduced.
• Types of cytopenia include e.g., anemia (a deficiency of red blood cells), leukopenia or neutropenia (a deficiency of white blood cells), thrombocytopenia (a deficiency in the platelets), and pancytopenia (a deficiency in all three of red blood cells, white blood cells, and platelet counts).
• the subject treated by the methods described herein is anemic.
• a subject of the present disclosure e.g., as in any one of the first through sixth embodiments
• a subject e.g., as in any one of the first through sixth embodiments
• Subjects treatable by the present methods therefore include those having hemoglobin values less than 13.0 g/dL, less than 12.5 g/dL, less than 12.0 g/dL, less than 11.5 g/dL, less than 11.0 g/dL, less than 10.5 g/dL, less than 10.0 g/dL, less than 9.5 g/dL, less than 9.0 g/dL, or less than 8.5 g/dL for male subjects and less than 11.5 g/dL, less than 11.0 g/dL, less than 10.5 g/dL, less than 10.0 g/dL, less than 9.5 g/dL, less than 9.0 g/dL, or less than 8.5 g/dL for female subjects.
• a subject e.g., as in any one of the first through sixth
• a subject e.g., as in any one of the first through sixth embodiments
• a subject is defined herein as being anemic if their hemoglobin value ranges from 7.5 g/dL of blood to 10.5 g/dL of blood for a male subject or from 7.5 g/dL of blood to 10.5 g/dL of blood for a female subject.
• a subject (e.g., as in any one of the first through sixth embodiments) is defined herein as being anemic if their hemoglobin value ranges from 7.5 g/dL of blood to 10.0 g/dL of blood for a male subject or from 7.5 g/dL of blood to 10.0 g/dL of blood for a female subject.
• a subject (e.g., as in any one of the first through sixth embodiments) is defined herein as being anemic if their hemoglobin value ranges from 7.7 g/dL of blood to 10.7 g/dL of blood for a male subject or from 7.7 g/dL of blood to 10.5 g/dL of blood for a female subject.
• a subject e.g., as in any one of the first through sixth embodiments
• a subject is defined herein as being anemic if their hemoglobin value ranges from 7.7 g/dL of blood to 10.0 g/dL of blood for a male subject or from 7.7 g/dL of blood to 10.0 g/dL of blood for a female subject.
• subjects treated by the methods described herein are thrombocytopenic.
• a subject of the present disclosure e.g., as in any one of the first through seventh embodiments is said to be thrombocytopenic if their platelet count is less than 150,000 platelets ⁇ L of blood.
• Subjects treatable by the present methods therefore include those having platelet levels less than 140,000 platelets ⁇ L, less than 130,000 platclcts/pL, less than 120,000 platelets ⁇ L, less than 110,000 platelets ⁇ L, less than 100,000 platelets ⁇ L, less than 90,000 platelets ⁇ L, less than 80,000 platelets ⁇ L, less than 70,000 platelets ⁇ L, less than 60,000 platelets ⁇ L or less than 50,000 platelets ⁇ L, alone or in combination with one or more of the hemoglobin values described above.
• subjects treated by the methods described herein are thrombocytemic.
• a subject of the present disclosure subjects treated by the methods described herein is said to be thrombocytemic if their platelet count is more than 450,000 platelets ⁇ L of blood.
• Subjects treatable by the present methods therefore include those having platelet levels more than 450,000 platelets ⁇ L, more than 500,000 platelets ⁇ L, more than 550,000 platelets ⁇ L, or more than 600,000 platelets ⁇ L, alone or in combination with one or more of the hemoglobin values described above.
• the subject treated by the methods described herein is leukopenic.
• a subject e.g., as in any one of the first through ninth embodiments
• WBC white blood cell
• subjects treatable by the present methods include those having WBC counts of less than 3,500 WBCs ⁇ tL, 3,200 WBCs/mE, 3,000 WBCs ⁇ tL, or 2,500 WBCs/mE, alone or in combination with one or more of the hemoglobin and/or platelet values described above.
• the subject treated by the methods described herein is (e.g., as in any one of the first through tenth embodiments) neutropenic.
• a subject of the present disclosure e.g., as in any one of the first through tenth embodiments
• subjects treatable by the present methods include those having neutrophil counts of less than 1250 neutrophils ⁇ L, 1000 neutrophils ⁇ L, 750 neutrophils ⁇ L, or 500 neutrophils ⁇ L, alone or in combination with one or more of the hemoglobin, platelet, and/or WBC values described above.
• Myelofibrosis is often associated with an enlarging of the spleen. Enlarging of the spleen can result in a feeling of fullness, indigestion, and a loss of appetite.
• subjects treatable by the present methods include those having an enlarged spleen or liver.
• subjects treatable by the present methods may also be experiencing one or more additional symptoms.
• these symptoms include, but are not limited to, abdominal discomfort, dyspnea on exertion, early satiety, fatigue, headaches, night sweats, dizziness, insomnia, pruritus, or bone pain.
• subjects treated by the present methods are transfusion dependent prior to treatment with Compound 1.
• “transfusion dependent” means that a subject requires red blood cell (RBC) transfusions in order to maintain an acceptable level of hemoglobin.
• RBC red blood cell
• An acceptable level of hemoglobin is determined by those skill in the art and can range from e.g., from 13.5 to 17.5 g/dL of blood for men and from 12.0 to 15.5 g/dL of blood in women. It will be understood that subjects undergoing treatment with rux may have lower hemoglobin levels than those described above and still be deemed an“acceptable” level in order for treatment to continue.
• the compounds of the methods described herein can be formulated as
• compositions and administered to a subject such as a human, in a variety of forms adapted to the chosen route of administration.
• routes of administering such pharmaceutical compositions include, without limitation, oral, topical, buccal, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal.
• parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrathecal, intrasternal injection or infusion techniques. Methods of formulating pharmaceutical compositions are well known in the art, for example, as disclosed in“Remington: The Science and Practice of Pharmacy,” University of the Sciences in Philadelphia, ed., 21st edition, 2005, Lippincott, Williams & Wilkins, Philadelphia, PA.
• compositions of the invention can be prepared by combining a compound of the methods described herein with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi- solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
• an appropriate pharmaceutically acceptable carrier such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
• a pharmaceutically acceptable excipient such as an inert diluent or an assimilable edible carrier.
• the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
• the amount of a compound described herein in the composition will also depend upon the particular compound in the composition.
• Compound 1, or a pharmaceutically acceptable salt thereof when used as a monotherapy (i.e., without a JAK inhibitor such as ruxolitinib)
• Compound 1 when used as a monotherapy (i.e., without a JAK inhibitor such as ruxolitinib)
• Compound 1 when used as a monotherapy (i.e., without a JAK inhibitor such as ruxolitinib)
• Compound 1 may be formulated at a dose of from 50 mg to 500 mg for e.g., administration once, twice, or three times daily.
• Compound 1 may be administered at a dosage of from 100 mg to 300 mg/day, from 150 mg to 250 mg/day, or at 150 mg/day, 175 mg/day, 200 mg/day, 225 mg/day, or 250 mg/day.
• a JAK inhibitor such as ruxolitinib
• Compound 1, or a pharmaceutically acceptable salt thereof may be formulated at a dose of from 50 mg to 500 mg for e.g., administration once, twice, or three times daily.
• Compound 1 may be administered at a dosage of from 100 mg to 300 mg/day, from 100 mg to 200 mg/day, or at 100 mg/day, 125 mg/day, 150 mg/day, 175 mg/day, or 200 mg/day.
• Compound 1 can be obtained following the procedures describe in U.S. Patent No. 8,796,261 and WO 2015/195862, both of which are incorporated herein by reference.
• Compound 1 was assessed for its ability to suppress the expression of NF-KB target genes in two experiments.
• THP-1 acute leukemia cell lines were exposed to lipopolysaccharide treatment and then Compound 1 for 16 hours.
• IL6 release from the THP-1 acute leukemia cells was inhibited, with an IC50 of 0.069 mM.
• the ability of Compound 1 to suppress both IL6 and IL10 expression in TMD8 ABC-DLBCL cells was investigated (data on file).
• TMD8 cells were incubated with DMSO or 1.6 pM Compound 1 for 6 or 24 hours.
• RNA was then extracted from the cells and quantified using qRT-PCR. As shown in FIG. 1, Compound 1 substantially suppressed mRNA transcription of both IL6 and IL10 after 6 and 24 hours of treatment.
• CD34+ cells isolated from healthy donor bone marrow (data on file).
• the CD34+ cells were grown in megakaryocyte differentiation serum-free stem cell differentiation base medium with a megakaryocyte-driving cytokine cocktail for 14 days with DMSO or Compound 1 at concentrations ranging from 3 nM to 500 nM.
• the cells were then stained for CD34 (progenitor marker), CD45 (leukocyte marker) and CD41a (mature megakaryocyte marker) and assessed by FACS for viability and marker expression.
• CD41a expression and cell size were used as markers of megakaryocyte differentiation.
• Compound 1 reduced the number of cells with high CD41a expression in a concentration-dependent manner.
• CD34+ cells that were isolated from the bone marrow of two healthy donors were incubated for 10 days in megakaryocyte differentiation media with DMSO; Compound 1 alone, at a concentration of 30 to 500 nM; mxolitinib alone at concentration of 8 to 1000 nM; or Compound 1 in combination with mxolitinib at the same concentrations they were tested alone (data on file).
• the cells were then harvested for FACS analysis with live/dead stain and gating with CD34 (progenitor marker) and CD41a and CD42b (mature megakaryocyte markers).
• a panel of selected BET target genes ( CCR1 , CCR2, 1L8, FN1, CSF1R and
• Compound 1 Phase 1 clinical studies, in order to determine the relationship between systemic exposure of Compound 1 and suppression of these BET inhibitor-sensitive genes. Gene expression analysis, along with the Compound 1 plasma concentration versus time data, shows that there is a time- and concentration-dependent relationship. Consistent with non- clinical data, Compound 1-induced changes in expression were most consistently observed for IL8 and CCR1 at 2 hours post treatment, indicating the rapid effects of BET inhibition on transcription. Examples of the exposure-response relationships for CCR1 and IL8 are presented in FIG. 4. The data shown includes samples taken from patients with lymphoma who were treated with Compound 1 in Study 0610-01. Gene expression values were normalized to those measured at a single time point pre-treatment (100%). This data demonstrated the rapid on-target effects of BET inhibition on key pro-inflammatory genes and supports the use of this clinical biomarker assay.
• the first four myelofibrosis patients who enrolled in Study 0610-02 have demonstrated clinical benefit that as of July 2018 had extended at least 6 months.
• the first two myelofibrosis patients to enroll (Patients 245 and 246) received Compound 1 in combination with ruxolitinib and have received 18 treatment cycles (11 months of treatment) as of this writing.
• the next two patients to enroll (Patients 247 and 248) have received 10 cycles of Compound 1 as monotherapy (6 months of treatment) so far. All four patients remain on treatment and have experienced a reduction in their constitutional symptoms, a decrease in spleen volume and an increase in hemoglobin.
• the spleen volume of Patient 245 by MRI was 1404 cc and was 12 cm by palpation.
• the patient presented with early satiety, night sweats, and dyspnea at the start of the study.
• the lowest spleen volume by MRI was 1144 cc, a 19% reduction, at the 6-month MRI.
• the dose of ruxolitinib was reduced on Cycle 10 to 7.5 mg BID to address decreasing platelet count.
• Her platelets counts have gradually improved following the dose reduction of ruxolitinib; however still remain below the protocol- specified criteria of 100 x 10 9 /L for two treatment cycles to permit a dose increase in Compound 1. The patient has otherwise been doing well, with no substantive changes in her symptoms.
• Patient 246 is a 53 year-old female who was diagnosed with myelofibrosis in 2009. During 2002 and 2006, the patient cycled between epoetin alfa, lenalidomide and thalidomide then received lenalidomide for 7 years until 2013. She required RBC
• Patient 247 is a 46 year-old female who was diagnosed with myelofibrosis in April 2014. In 2009, it was suspected that the patient had essential thrombocytosis (ET) for which she received hydroxyurea treatment from April 2009 to December 2017. The patient also received one month of epoetin alpha in 2015, three months of imetelstat in 2016 and four months of pembrolizumab in 2017. Ruxolitinib was administered from October 2015 to May 2016. Ruxolitinib was discontinued due to worsening symptomatic splenomegaly, anemia, leukocytosis, and thrombocytosis.
• ET essential thrombocytosis

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