WO2025111214A1

WO2025111214A1 - [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3- carbonyl)amino]acetic acid (roxadustat) for the treatment of anemia in subjects with myelodysplastic syndrome (mds)

Info

Publication number: WO2025111214A1
Application number: PCT/US2024/056333
Authority: WO
Inventors: Lixia ZHU
Original assignee: Fibrogen Inc
Current assignee: Fibrogen Inc
Priority date: 2023-11-22
Filing date: 2024-11-18
Publication date: 2025-05-30
Anticipated expiration: 2026-05-22

Abstract

The present invention relates to the use of roxadustat in the manufacture of a medicament for treating anemia in a subject having anemia associated with myelodysplastic syndrome (MDS). Methods for treating anemia in a subject having anemia associated with myelodysplastic syndrome comprising administering to the subject a therapeutically effective amount of roxadustat, thereby treating the anemia are also described.

Description

[(4-HYDROXY-1-METHYL-7-PHENOXYISOQUINOLINE-3-

CARBONYL)AMINO]ACETIC ACID (ROXADUSTAT) FOR THE TREATMENT OF ANEMIA IN SUBJECTS WITH MYELODYSPLASTIC SYNDROME (MDS)

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No.

63/601,857 filed November 22, 2023, the disclosure of which is hereby incorporated by reference in its entirety.

BACKGROUND

[0002] The myelodysplastic syndromes (MDS) are clonal disorders of bone marrow characterized by ineffective hematopoiesis leading to peripheral blood cytopenia (anemia, neutropenia, and thrombocytopenia) and an increased predisposition to developing acute myeloid leukemia (AML), especially in a high-risk MDS category. The reported 3 -year survival rate is 42% and the 5-year survival rate is 29% in MDS patients, but those with higher risks for development of AML tend to have lower survival. The main features of MDS are peripheral blood cytopenia related to clonal stem cell disorder characterized by progressive ineffective hematopoiesis. (Tefferi and Vardiman (2009) N Engl J Med 361(19): 1872-85). Clonal evolution of abnormal hematopoietic stem cells is a multistep process involving genetic changes which can be identified by standard cytogenetic techniques and advanced molecular testing.

[0003] Anemia is the most common clinical presentation in lower-risk MDS, which results in prolonged red blood cell (RBC) transfusion requirements and risks related to RBC transfusion itself, iron overload, and significant impairment of the quality of life in affected patients. The pathophysiology of anemia in MDS is complex, involving ineffective erythropoiesis, dysregulated cytokine signaling, dysplastic features of hematopoietic progenitors, and increased apoptosis of erythroid precursors, among other factors. The erythroid dysfunction in MDS often presents with fatigue and low hemoglobin level. Anemia in MDS becomes more symptomatic when Hb levels fall below 9.0 g/dL, and as erythroid dysfunction continues to decline RBC transfusion may become necessary supportive treatment. Dependency on RBC transfusion has been associated with shorter life expectancy in patients with MDS.

[0004] The disease burden of anemia in MDS is high and anemia impacts patients in all MDS categories of the International Prognostic Scoring System (IPSS-R). Severe anemia interferes with patients’ quality of life and ability to work, as well as negatively impacting the function of other organ systems due to insufficient oxygen delivery to tissues. When RBC transfusions become necessary to sustain bodily functions, frequent trips to the hospital become burdensome and the risk of transfusion-related infections can further threaten MDS patients, some of whom may also have a primary neutropenia due to bone marrow dysfunction or secondary neutropenia associated with medications for the treatment of MDS. Infection is the number one cause of death in MDS patients. Additional risks with transfusion include transfusion reactions (risk accumulates with exposure to more antigens through transfusions), and the iron overload from cumulative transfusions may lead to additional organ complications, particularly in heart, liver, and endocrine organs.

[0005] The off-label use of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in MDS patients is typically at doses comparable to the ESA hyporesponsive ESRD-dialysis patients (such as those at or above the highest dose quartile), which leads to levels of blood ESA two orders of magnitude above the normal physiologic range of circulating erythropoietin (Epo). Exposure to high ESA levels may be a contributing factor in the increased cardiovascular and thrombotic risk observed in ESA treated chronic kidney disease (CKD) patients and the very high doses of ESA required to treat anemia in oncology patients (up to 5 times the dose required in anemia associated with CKD) potentially contribute to ESA’s cancer progression risks.

[0006] Roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, promotes coordinated erythropoiesis through increasing endogenous erythropoietin, improving iron availability, and reducing hepcidin. Administration of roxadustat has been shown to increase red blood cell production while maintaining plasma erythropoietin levels within or near normal physiologic range in multiple subpopulations of CKD patients, including in the presence of inflammation, and without a need for supplemental intravenous iron. Anemia in CKD patients is substantially due to a reduction in endogenous erythropoietin production by the diseased kidney, that is, CKD produces an erythropoietindeficiency anemia. Although erythropoietin is almost exclusively made in the kidney, roxadustat surprisingly demonstrated an ability to increase endogenous erythropoietin production even in end-stage renal disease patients.

[0007] Roxadustat has the potential to address anemia with more physiologic Epo exposure than seen with ESAs. Intermittent dosing of roxadustat results in transient activation of hypoxia inducible factor (HIF), intermittent induction of endogenous, physiologic-range Epo, increased sensitivity to erythropoietin in the erythroid progenitor cells in the bone marrow, and dose-dependent erythropoiesis. This suggests a coordinated mechanism of roxadustat erythropoiesis that is different from ESA therapy, including beneficial effects on iron handling, while overcoming barriers to erythropoiesis such as inflammation and iron availability, which are present in many chronic disease conditions including MDS.

[0008] Roxadustat is approved in China, Europe, Japan, and numerous other countries for the treatment of anemia in CKD patients on dialysis and patients not on dialysis. In an open label, dose-selection, lead-in stage of a phase 3 study of roxadustat for the treatment of anemia in patients with lower-risk myelodysplastic syndrome, a reduction in RBC transfusion of greater than or equal to 50% was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. (Henry et al. (2022) Am J Hematol 97: 174-184). In the subsequent placebo-controlled portion of the study, however, roxadustat did not show superiority over placebo, where the proportion of patients who achieved red blood cell transfusion independence in the first 28 weeks was 47.5% for the roxadustat arm compared to 33.3% for placebo (p=0.217). (News release. FibroGen, Inc. May 5, 2023; https://bit.ly/42glbPP).

[0009] Therefore, improved treatment options for the management of anemia in patients with MDS are needed.

SUMMARY

[0010] The present invention provides use of roxadustat in the manufacture of a medicament for treating anemia in a subject having anemia associated with myelodysplastic syndrome (MDS), as well as methods for treating anemia in a subject having anemia associated with MDS comprising administering to the subject a therapeutically effective amount of roxadustat, thereby treating the anemia.

[0011] The present invention also provides use of roxadustat in the manufacture of a medicament for reducing the number of blood transfusions received by a subject having anemia associated with myelodysplastic syndrome (MDS). In one embodiment, the subject receives at least two packed red blood cell (pRBC) transfusions every four weeks prior to said use. As disclosed herein, medicaments comprising roxadustat decreased transfusion burden and increased transfusion independence in subjects having anemia associated with MDS. In one embodiment, the medicament provided a statistically significant reduction in the number of transfusions the subject received and extended transfusion independence in subjects that received at least two pRBC transfusions every four weeks prior to use. Thus, in particular embodiments, the present invention provides use of roxadustat in the manufacture of a medicament for treating a subject with anemia associated with MDS, wherein the subject receives at least two pRBC transfusions every four weeks prior to said use.

[0012] The present invention also provides methods for reducing the number of blood transfusions received by a subject having anemia associated with MDS, the method comprising administering to the subject a therapeutically effective amount of roxadustat, thereby reducing the number of transfusions received by the subject. In one embodiment, the subject receives at least two pRBC transfusions every four weeks prior to said administering. As disclosed herein, administration of roxadustat decreased transfusion burden and increased transfusion independence in subjects having anemia associated with MDS. In one embodiment, the administration of roxadustat provided a statistically significant reduction in the number of transfusions the subject received and extended transfusion independence in subjects that receive at least two pRBC transfusions every four weeks prior to said administration. Thus, in particular embodiments, the present invention provides a method for treating a subject with anemia associated with MDS, wherein the subject receives at least two packed red blood cell transfusions every four weeks, the method comprising administering to the subject a therapeutically effective amount of roxadustat, thereby treating the anemia.

[0013] In various embodiments, the subject has a hemoglobin level of less than or equal to 100 g/L prior to said use or administration of roxadustat. In one aspect, the subject has been diagnosed with primary MDS as confirmed by bone marrow aspirate and biopsy. In some embodiments, the MDS is classified by the IPSS-R as very low, low, or intermediate risk with less than 5% bone marrow blasts. In other embodiments, the MDS is classified by diagnosis of IPSS-R as high risk or very high risk. In some embodiments, the subject is transfusion dependent prior to treatment. In some embodiments, the subject receives at least 2 pRBCs transfusions during any 8-week period prior to said use or administration of roxadustat. In some embodiments, the subject receives 2 to 4 pRBC transfusions during any 8-week period prior to said use or administration of roxadustat. In some embodiments, the subject receives 1 pRBC transfusion every 8-weeks in at least two consecutive 8-week periods prior to said use or administration of roxadustat.

[0014] In one embodiment, the medicament or method results in a reduction in the number of transfusions receive by the subject compared to their baseline. In some embodiments, the medicament or method results in at least 40%, at least 50%, at least 60%, or at least 70% reduction in the number of transfusions receive by the subject compared to their baseline. In another embodiment, the medicament or method results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 56 weeks of treatment. In another embodiment, the medicament or method results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 28 weeks of treatment. In another embodiment, the medicament or method results in transfusion independence in the subject for at least 20 weeks (140 consecutive days) during treatment. [0015] In some embodiments, the medicament or method increases the mean hemoglobin (Hb) in the subject at least 10 g/L, at least 15 g/L, or at least 20 g/L over four weeks of use or administration. In some embodiments, the medicament or method increases the mean Hb in the subject at least 10 g/L, at least 15 g/L, or at least 20 g/L over eight weeks of use or administration. In some embodiments, the medicament or method maintains the mean Hb in the subject between about 100 g/L to about 120 g/L.

[0016] In some embodiments, the subject is at least 18 years old. In some embodiments, the subject weighs at least 45 kg. In some embodiments, the subject has Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2. In some embodiments, the subject is at least 18 years old, weighs at least 45 kg, has a diagnosis of MDS, has an ECOG PS of 0, 1, or 2, and has a hemoglobin level of less than or equal to 100 g/L prior to treatment with roxadustat.

[0017] In some embodiments, the subject has a transferrin saturation (TSAT) >20% and ferritin >100 ng/mL prior to said use or administration of roxadustat. In some embodiments, the subject has a TSAT >20% and ferritin >400 ng/mL prior to said use or administration of roxadustat. In some embodiments, the subject has C-reactive protein (CRP) level < ULN (upper limit of normal) prior to said use or administration of roxadustat. In some embodiments, the subject has CRP level >ULN prior to said use or administration of roxadustat. In some embodiments, the subject has a serum erythropoietin (Epo) level <200 U/L prior to said use or administration of roxadustat. In some embodiments, the subject has an Epo level >200 U/L and <400 U/L prior to said use or administration of roxadustat.

[0018] In some embodiments, the medicament is labeled for administration to the subject based on a dose of roxadustat relative to body weight of the subject. In some embodiments, the subject has a body weight of 45 to less than 70 kg and the dose of roxadustat is 100-200 mg, particularly about 150 mg. In some embodiments, the subject has a body weight of 70 to 100 kg and the dose of roxadustat is 150-250 mg, particularly about 200 mg. In some embodiments, the subject has a body weight of greater than 100 kg and the dose of roxadustat is 200-300 mg, particularly about 250 mg. In some embodiments, the dose is about 1.5 to 3.5 milligrams of roxadustat per kilogram of the subject’s body weight. In some embodiments, the dose is about 2.0 to 3.5 milligrams of roxadustat per kilogram of the subject’s body weight. In some embodiments, the dose is about 2.0 to 2.5 milligrams of roxadustat per kilogram of the subject’s body weight. In various embodiments, doses are administered at least 2 days apart and no more than 4 days apart.

[0019] In some embodiments, the medicament is labeled to administer a dose of roxadustat three times a week. In some embodiments, the subject has a body weight of 45 to less than 70 kg and the roxadustat is administered at 100 to 200 mg, particularly about 150 mg, three times per week. In some embodiments, the subject has a body weight of 70 to 100 kg and the roxadustat is administered at 150-250 mg, particularly about 200 mg, three times per week. In some embodiments, the subject has a body weight of greater than 100 kg and the roxadustat is administered at 200-300 mg, particularly about 250 mg, three times per week.

[0020] In some embodiments, the roxadustat is crystalline Form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9, and 27.4° 20±0.2° 20. In some embodiments, the roxadustat is a solid having a unimodal particle distribution of D90 less than 43 pm. In some embodiments, the roxadustat is a solid having a unimodal particle distribution of D90 of about 21 pm to about 29 pm; a D50 of about 12 pm to about 17 pm; and a D10 of about 6 pm to about 10 pm. In some embodiments the roxadustat is a solid having a unimodal particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.

[0021] In some embodiments, the medicament is formulated for oral administration.

In some embodiments, the medicament further comprises a pharmaceutically acceptable excipient. In some embodiments, the medicament according to any embodiment described herein is a tablet or a capsule. In some embodiments, the medicament according to any embodiment described herein is a tablet or capsule comprising 20 mg, 50 mg, 100 mg, or 150 mg roxadustat and at least one appropriate excipient for oral delivery.

[0022] In some embodiments the medicament according to any embodiment described herein is a tablet. In some embodiments, the medicament according to any embodiment described herein is a tablet comprising a tablet core and a coating, wherein the tablet core comprises [(4-hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]- acetic acid according to any embodiment described herein and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate, and the coating comprises a photostabilizing agent comprising 0.1 to about 0.4 mg/cm² titanium dioxide and from about 0.1 to about 0.4 mg/cm² Allura Red AC in aluminum lake wherein the amount of titanium dioxide and Allura Red AC in aluminum lake is based on surface area of the tablet core. In some embodiments, the amount of roxadustat in the tablet is selected from about 20 mg, about 50 mg, about 100 mg, or about 150 mg. In some embodiments, the coating is present in an amount from about 3% to about 8% w/w based on the weight of the tablet core.

[0023] In some embodiments the medicament according to any embodiment described herein is a capsule. In some embodiments, the medicament according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell wherein: the capsule fill comprises 20 mg of roxadustat according to any embodiment described herein and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, iron oxide yellow, and gelatin. In some embodiments, the capsule comprises 20 mg of roxadustat. In some embodiments, the capsule comprises 50 mg of roxadustat. In some embodiments, the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg of roxadustat and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, iron oxide yellow, and gelatin. In some embodiments, the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 50 mg of roxadustat and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising Allura red AC, titanium dioxide, iron oxide yellow, and gelatin.

[0024] In some embodiments, the medicament is formulated in a capsule wherein said capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg of roxadustat, 101.84 mg of lactose monohydrate 310, 9.36 mg of microcrystalline cellulose PH101, 6.48 mg of povidone K30, 5.76 mg of croscarmellose sodium, and 0.56 mg of magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, iron oxide yellow, and gelatin, wherein the titanium dioxide is 1%, by weight of the capsule shell and the iron oxide yellow is 2% by weight of the capsule shell. In some embodiments, the medicament is formulated in a capsule wherein said capsule comprises a capsule fill and a capsule shell; wherein the capsule fill comprises 50 mg of roxadustat, 254.6 mg of lactose monohydrate (310), 23.4 mg of microcrystalline cellulose PH101, 16.20 mg of povidone K30, 14.40 mg of croscarmellose sodium, and 1.4 mg of magnesium stearate; and the capsule shell is a gelatin shell comprising Allura red AC, titanium dioxide, iron oxide yellow, and gelatin, wherein the Allura red AC is 1 % by weight of the capsule shell, the titanium dioxide is 1%, by weight of the capsule shell and the iron oxide yellow is 1% by weight of the capsule shell. In some embodiments, the roxadustat is crystalline Form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9, and 27.4° 29±0.2° 29. In some embodiments, the roxadustat has a unimodal particle size distribution of D99 of 21 pm to 29 pm, a D59 of 12 pm to 17 pm, and a D19 of 6 pm to 19 pm.

[0025] In particular embodiments, the medicament is labeled for treating anemia in a subject having MDS, wherein the subject has a blood hemoglobin level <100 g/L prior to treatment, and comprises orally administering to the subject 50 mg to 400 mg of roxadustat three times a week, wherein the blood hemoglobin level in the subject is increased following administration of the roxadustat, compared with the subject’s hemoglobin level prior to administration of the roxadustat provided the blood hemoglobin level does not exceed 139 g/L; provided the roxadustat is administered at least 2 days apart and no more than 4 days apart. In various embodiments, the medicament is labeled to provide an amount of roxadustat to be administered to the subject based on the weight of the subject as disclosed herein.

[0026] In some embodiments the medicament is further labeled to optionally increase or decrease the dose of roxadustat until the subject achieves and maintains a blood hemoglobin level of 100 to 120 g/L, providing the dose does not exceed 400 mg. In some embodiments the increasing or decreasing the dose of roxadustat results in a dose of 50 mg, 70 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg.

BRIEF DESCRIPTION OF DRAWINGS

[0027] FIG. 1 is a graphical representation of the study design described in

Example 1.

[0028] FIG. 2 is a graph showing the percentage of patients with a high transfusion burden, that achieved transfusion independence within 28 weeks of treatment and achieved transfusion independence by the end of treatment, in patients receiving roxadustat vs. placebo.

[0029] FIG. 3 is a graph showing the mean change of PROMIS-fatigue score from baseline vs. weeks for patients receiving roxadustat vs. placebo. DETAILED DESCRIPTION

DEFINITIONS

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications cited herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing the methodologies, reagents, and tools reported in the publications that might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0031] The articles “a” and “an” as used herein mean “one or more” or “at least one,” unless otherwise indicated. That is, reference to any element of the present invention by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present.

[0032] The term “about” when used before a numerical designation, e.g., temperature, time, amount, and concentration, including a range, indicates approximations which may vary by ±10%, ±5%, or ±1%.

[0033] “Administration” refers to introducing an agent or medicament into a patient.

An oral route of administration is preferred for medicaments of the present invention. The related terms and phrases “administering” and “administration of’, when used in connection with an agent or medicament (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by selfadministration by the patient, and/or to indirect administration, which may be the act of prescribing a medicament. For example, a physician who instructs a patient to self-administer a medicament and/or provides a patient with a prescription for a medicament is administering the medicament to the patient. In any event, administration entails delivery of the medicament to the patient.

[0034] The term “anemia” as used herein refers to a reduction in the number of red blood cells and/or level of hemoglobin in blood relative to normal blood levels. For example, a subject is considered anemic when their hematocrit falls below 36% and/or their blood hemoglobin falls below 100 g/L. Anemia can develop in MDS patients and can also be associated with disorders in iron transport, processing, and utilization. [0035] Patients who have lower-risk MDS and present with moderate-to-severe anemia (Hb <10 g/dL), have a serum EPO level <500 U/L, and/or require <2 RBC transfusions per month should be considered for anemia therapy. The target Hb for lower-risk MDS patients is generally in the range of 10 to 12 g/dL or a decrease in red-cell transfusion received by four pRBC transfusions over a period of 8 weeks. (Carraway and Saygin (2020) Hematology Am Soc Hematol Educ Program 2020(l):426-433).

[0036] The term “pharmaceutically acceptable” indicates that the material does not have properties that would cause one of skill in the art to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. Further, the material is considered to be safe for administration in humans or animals.

[0037] “P -value” or “probability value” is the probability under the assumption of no effect or no difference (null hypothesis) of obtaining a result equal to or more extreme than what was actually observed. A statistically significant test result (P < 0.05) means that the test hypothesis is false or should be rejected.

[0038] The terms “subject,” “individual,” or “patient” are used interchangeably and as used herein are intended to include human and non-human animals. Non-human animals include all mammals such as non-human primates, sheep, dogs, cats, cows, and horses. The medicaments are particularly suitable for treating human patients having a disease or disorder described herein.

[0039] “Strength of roxadustat”, “strength of API” or “strength” refer to the amount of roxadustat (compound of Formula (I)) in a particular medicament. It will also be understood that when referring to an “x mg tablet” or “x mg capsule”, x is the amount of roxadustat in the tablet or capsule. For example, a 20 mg capsule means that there is 20 mg of roxadustat in the capsule formulation.

[0040] “Therapeutically effective amount” as used herein refers to the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. In the present case, the effect can include increasing a subject’s blood hemoglobin level or reducing the requirement for blood transfusions necessary to maintain an acceptable hemoglobin level.

[0041] “Transfusion” as used herein refers to RBC transfusion and includes all types of RBC transfusions including whole blood and packed red blood cell (pRBC) transfusions.

[0042] The term “transfusion burden” refers to the number of RBC transfusions received by the subject. A decrease in transfusion burden or a reduction in transfusion burden refers to a reduction or decrease in the number of transfusions received by the subject over a set period of time compared with the number of transfusions received over the same period of time at baseline (i.e. , prior to treatment, e.g., with roxadustat).

[0043] “Transfusion Independence” (TI) is defined as the absence of any RBC transfusion during any consecutive 8 weeks (56 days) or more.

[0044] “Treatment”, “treating”, and “treat” are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition.

[0045] Roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, is a compound of Formula (I):

also known as [(4-hydroxy-l-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid. Roxadustat is disclosed in International Publication W02004/108681, U.S. Patent 7323475, and China Patent Publication 102977016.

[0046] Roxadustat promotes coordinated erythropoiesis through increasing endogenous erythropoietin, improving iron availability, and reducing hepcidin.

Administration of roxadustat has been shown to increase red blood cell production while maintaining plasma erythropoietin levels within or near normal physiologic range in multiple subpopulations of chronic kidney disease (CKD) patients, including in the presence of inflammation, and without a need for supplemental intravenous iron. Anemia in CKD patients is substantially due to a reduction in endogenous erythropoietin production by the diseased kidney, that is, CKD produces an erythropoietin-deficiency anemia. Although erythropoietin is almost exclusively made in the kidney, roxadustat surprisingly demonstrated an ability to increase endogenous erythropoietin production even in end-stage renal disease patients. Roxadustat is approved in China, Europe, Japan, and numerous other countries for the treatment of anemia in CKD patients on dialysis and patients not on dialysis.

[0047] The pathophysiology of anemia in MDS is complex, involving ineffective erythropoiesis, dysregulated cytokine signaling, dysplastic features of hematopoietic progenitors, and increased apoptosis of erythroid precursors, among other factors. The erythroid dysfunction in MDS often presents with fatigue and low hemoglobin level, becoming more symptomatic when Hb levels fall below 9.0 g/dL. As erythroid dysfunction continues to decline, RBC transfusion can become necessary supportive treatment.

[0048] The present invention provides use of roxadustat in the manufacture of a medicament for treating anemia in a subject having anemia associated with myelodysplastic syndrome (MDS), as well as methods for treating anemia in a subject having anemia associated with MDS comprising administering to the subject a therapeutically effective amount of roxadustat, thereby treating the anemia. In some embodiments, the medicament or method increases the mean hemoglobin (Hb) in the subject at least 10 g/L, at least 15 g/L, or at least 20 g/L over four weeks of use or administration. In some embodiments, the medicament or method increases the mean Hb in the subject at least 10 g/L, at least 15 g/L, or at least 20 g/L over eight weeks of use or administration. In some embodiments, the medicament or method maintains the mean Hb in the subject between about 80 g/L to about 120 g/L. In some embodiments, the medicament or method maintains the mean Hb in the subject between about 100 g/L to about 120 g/L.

[0049] The present invention also provides use of roxadustat in the manufacture of a medicament for reducing the number of blood transfusion received by a subject having anemia associated with myelodysplastic syndrome (MDS). As disclosed herein, medicaments comprising roxadustat decreased transfusion burden and increased transfusion independence in subjects having anemia associated with MDS. In one embodiment, the medicament provided a statistically significant reduction in the number of transfusion received and extended transfusion independence in subjects that required at least two pRBC transfusions every four weeks prior to treatment. Thus, in particular embodiments, the present invention provides use of roxadustat in the manufacture of a medicament for treating a subject with anemia associated with MDS, wherein the subject receives at least two pRBC transfusions every four weeks prior to said use.

[0050] The present invention also provides methods for reducing the number of blood transfusion received by a subject having anemia associated with MDS, the method comprising administering to the subject a therapeutically effective amount of roxadustat, thereby reducing the number of transfusions received by the subject. As disclosed herein, administration of roxadustat decreased transfusion burden and increased transfusion independence in subjects having anemia associated with MDS. In one embodiment, the administration of roxadustat provided a statistically significant reduction in the number of transfusions received and extended transfusion independence in subjects that required at least two pRBC transfusions every four weeks. Thus, in particular embodiments, the present invention provides a method for treating a subject with anemia associated with MDS, wherein the subject receives at least two packed red blood cell transfusions every four weeks, the method comprising administering to the subject a therapeutically effective amount of roxadustat, thereby treating the anemia.

[0051] In various embodiments, the subject has a hemoglobin level of less than or equal to 100 g/L prior to said use or administration of roxadustat. In various embodiments, the subject has a hemoglobin level of less than or equal to 80 g/L prior to said use or administration of roxadustat. In one aspect, the subject has been diagnosed with primary MDS as confirmed by bone marrow aspirate and biopsy. In some embodiments, the MDS is classified by the IPSS-R as very low, low, or intermediate risk with less than 5% bone marrow blasts. In other embodiments, the MDS is classified by diagnosis of IPSS-R as high risk or very high risk. In some embodiments, the subject is transfusion dependent prior to treatment. In some instances, the subject receives at least 2 pRBC transfusions during any 8- week period prior to said use or administration of roxadustat. In some instances, the subject receives at least 2 pRBC transfusions during any 4-week period prior to said use or administration of roxadustat. In some embodiments, the subject receives 2 to 4 pRBC transfusions during any 8-week period prior to said use or administration of roxadustat. In some embodiments, the subject receives 2 to 4 pRBC transfusions of during any 4-week period prior to said use or administration of roxadustat. In some embodiments, the subject receives 1 pRBC transfusion every 8-weeks in at least two consecutive 8-week periods prior to said use or administration of roxadustat.

[0052] In one embodiment, the medicament or method results in a reduction in the number of transfusions received by the subject compared to their baseline. In some embodiments, the medicament or method results in at least 40%, at least 50%, at least 60%, or at least 70% reduction in the number of transfusions received by the subject compared to their baseline. In some embodiments, the medicament or method results in at least 75%, at least 80%, at least 85%, or at least 90% reduction in the number of transfusions received by the subject compared to their baseline. In some embodiments, the medicament or method results in about 95% to about 100% reduction in the number of transfusions received by the subject compared to their baseline. For example, if the subject at baseline required 2 pRBC transfusions per 4-week period, the use or administration of roxadustat reduces transfusion burden to at most 1 pRBC transfusion per 40-week period (95% reduction). In another embodiment, the medicament or method results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 56 weeks of treatment. In another embodiment, the medicament or method results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 28 weeks of treatment. In another embodiment, the medicament or method results in transfusion independence in the subject for at least 20 weeks (140 consecutive days) during treatment.

[0053] Roxadustat

[0054] In some embodiments, the roxadustat according to any embodiment described herein is amorphous, an anhydrous polymorph, a solvate, a hydrate, or a hemihydrate. In some embodiments the roxadustat according to any embodiment described herein, is as described in International Patent Publication WO2014/014835, U.S. Patent 8883823, and China Patent Publication 107382859; each of which is herein incorporated by reference in its entirety. In some embodiments, the roxadustat according to any embodiment described herein is amorphous, crystalline form A, crystalline form B, crystalline form C, or crystalline form D, as described in WO2014/014835. In some embodiments, the roxadustat according to any embodiment described herein is an amorphous solid. In some embodiments, the roxadustat according to any embodiment described herein is crystalline form A or crystalline form B. In some embodiments, the roxadustat according to any embodiment described herein is crystalline form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 16.2, and 27.4° 29±0.2° 29. In some embodiments, the roxadustat according to any embodiment described herein is crystalline form A characterized by an X- ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9, and 27.4° 29±9.2° 29. In some embodiments, the roxadustat according to any embodiment described herein is crystalline form A, characterized by an X-ray powder diffraction pattern as shown in Table 1.

[0055] Table 1: X-Ray Powder Diffraction Pattern of Crystal Form A of

Roxadustat

[0056] In some embodiments, the roxadustat according to any embodiment described herein has a particle size distribution as described in China Patent Publication 116199628. In some embodiments, the roxadustat is a solid having a unimodal particle distribution of D90 less than 43 pm. In some embodiments, the roxadustat is a solid having a unimodal particle distribution of D90 of about 21 pm to about 29 pm; a D50 of about 12 pm to about 17 pm; and a DIO of about 6 pm to about 10 pm. In some embodiments, the roxadustat is crystalline form A having a unimodal particle distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a DIO of 6 pm to 10 pm. [0057] Medicaments of roxadustat

[0058] In one aspect, the medicament comprises roxadustat alone. In another aspect, the medicament comprises roxadustat and at least one pharmaceutically acceptable excipient. In various embodiments, the medicament comprises solid roxadustat Form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9, and 27.4° 29±0.2° 29. In various embodiments, the medicament comprises solid roxadustat having a unimodal particle distribution of D90 of about 21 pm to 29 pm; a D59 of about 12 pm to 17 pm; and a DI 9 of about 6 pm to 19 pm. In various embodiments, the medicament comprises solid roxadustat Form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9, and 27.4° 29±9.2° 29 and having a unimodal particle distribution of D99 of about 21 pm to 29 pm; a D59 of about 12 pm to 17 pm; and a D19 of about 6 pm to 19 pm.

[0059] In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of a diluent, a binder, a disintegrant, and a lubricant, or combinations thereof. In some embodiments, the medicament comprises roxadustat and at least one pharmaceutically acceptable excipient formulated for oral administration. In some embodiments, the pharmaceutically acceptable excipients for the roxadustat oral pharmaceutical formulation comprise lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate. In some embodiments, the roxadustat oral pharmaceutical formulation according to any embodiment described herein is a tablet or a capsule. In some embodiments, the roxadustat oral pharmaceutical formulation according to any embodiment described herein is a tablet or capsule comprising 29 mg, 59 mg, 199 mg, or 159 mg roxadustat and at least one appropriate excipient for oral delivery. [0060] In some embodiments, the roxadustat oral pharmaceutical formulation according to any embodiment described herein further comprises a photostabilizer. In some embodiments, the photostabilizer is selected from one or more of Allura Red AC, titanium dioxide, and iron oxide yellow. In some embodiments, the photostabilizer comprises titanium dioxide and iron oxide yellow. In some embodiments, the photostabilizer comprises Allura Red AC and titanium dioxide. In some embodiments, the photostabilizer comprises Allura Red AC, titanium dioxide, and iron oxide yellow. In some embodiments, the medicament formulated for oral administration is as described in International Patent Application Publication WO2914/197669, U.S. Patent 19765672, China Patent Application Publication 111728951, and/or China Patent Publication 116199628. [0061] In some embodiments, the medicament according to any embodiment described herein is a tablet. In some embodiments, the medicament according to any embodiment described herein is a tablet comprising a tablet core and a coating wherein: the tablet core comprises [(4-hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]- acetic acid according to any embodiment described herein and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the coating comprises a photostabilizing agent comprising 0.1 to about 0.4 mg/cm² titanium dioxide and from about 0.1 to about 0.4 mg/cm² Allura Red AC in aluminum lake wherein the amount of titanium dioxide and Allura Red AC in aluminum lake is based on surface area of the tablet core. In some embodiments, the amount of roxadustat in the tablet is selected from about 20 mg, about 50 mg, about 100 mg, or about 150 mg. In some embodiments, the coating is present in an amount from about 3% to about 8% w/w based on the weight of the tablet core.

[0062] In some embodiments, the medicament according to any embodiment described herein is a capsule. In some embodiments, the medicament according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell wherein: the capsule fill comprises roxadustat according to any embodiment described herein and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, iron oxide yellow and/or Allura Red AC, and gelatin. In some embodiments, the capsule comprises 20 mg of roxadustat. In some embodiments, the capsule comprises 50 mg of roxadustat. In some embodiments, the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg of roxadustat, 101.84 mg of lactose monohydrate 310, 9.36 mg of microcrystalline cellulose PH101, 6.48 mg of povidone K30, 5.76 mg of croscarmellose sodium, and 0.56 mg of magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, iron oxide yellow, and gelatin, wherein the titanium dioxide is 1%, by weight of the capsule shell and the iron oxide yellow is 2% by weight of the capsule shell. In some embodiments, the medicament is formulated in a capsule wherein said capsule comprises a capsule fill and a capsule shell; wherein the capsule fill comprises 50 mg of roxadustat, 254.6 mg of lactose monohydrate (310), 23.4 mg of microcrystalline cellulose PH101, 16.20 mg of povidone K30, 14.40 mg of croscarmellose sodium, and 1.4 mg of magnesium stearate; and the capsule shell is a gelatin shell comprising Allura red AC, titanium dioxide, iron oxide yellow, and gelatin, wherein the Allura red AC is 1% by weight of the capsule shell, the titanium dioxide is 1%, by weight of the capsule shell, and the iron oxide yellow is 1% by weight of the capsule shell.

[0063] In particular embodiments, the medicament is labeled for treating anemia in a subject having MDS, wherein the subject has a blood hemoglobin level <100 g/L prior to treatment, and comprises orally administering to the subject 50 mg to 400 mg of roxadustat three times a week, wherein the blood hemoglobin level in the subject is increased following administration of the roxadustat, compared with the subject’s hemoglobin level prior to administration of the roxadustat provided the blood hemoglobin level does not exceed 130 g/L; provided the roxadustat is administered at least 2 days apart and no more than 4 days apart. In various embodiments, the medicament is labeled to provide an amount of roxadustat to be administered to the subject based on the weight of the subject as disclosed herein.

[0064] In some embodiments, the medicament is labeled for administration to the subject based on a dose of roxadustat relative to body weight of the subject. In some embodiments, the subject has a body weight of 45 to less than 70 kg and the dose of roxadustat is 100-200 mg, particularly about 150 mg. In some embodiments, the subject has a body weight of 70 to 100 kg and the dose of roxadustat is 150-250 mg, particularly about 200 mg. In some embodiments, the subject has a body weight of greater than 100 kg and the dose of roxadustat is 200-300 mg, particularly about 250 mg. In some embodiments, the dose is about 1.5 to 3.5 milligrams of roxadustat per kilogram of the subject’s body weight. In some embodiments, the dose is about 2.0 to 3.5 milligrams of roxadustat per kilogram of the subject’s body weight. In some embodiments, the dose is about 2.0 to 2.5 milligrams of roxadustat per kilogram of the subject’s body weight. In various embodiments, doses are administered at least 2 days apart and no more than 4 days apart.

[0065] In some embodiments, the medicament is labeled to administer a dose of roxadustat three times a week. In some embodiments, the subject has a body weight of 45 to less than 70 kg and the roxadustat is administered at 100 to 200 mg, particularly about 150 mg, three times per week. In some embodiments, the subject has a body weight of 70 to 100 kg and the roxadustat is administered at 150-250 mg, particularly about 200 mg, three times per week. In some embodiments, the subject has a body weight of greater than 100 kg and the roxadustat is administered at 200-300 mg, particularly about 250 mg, three times per week.

[0066] In some embodiments the medicament is further labeled to optionally increase or decrease the dose of roxadustat until the subject achieves and maintains a blood hemoglobin level of 100 to 120 g/L, providing the dose does not exceed 400 mg. In some embodiments the increasing or decreasing the dose of roxadustat results in a dose of 50 mg, 70 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg.

[0067] It will be understood by one of skill in the art that more than one roxadustat medicament may be administered to a subject to achieve a desired dose. For example, if the subject requires a dose of 100 mg of roxadustat, this dose can be achieved by administration of two 50 mg capsules or tablets taken concurrently or a dose of 100 mg can be achieved by administration of five 20 mg tablets or capsules. A 120 mg dose of roxadustat can be achieved, for example, by administration of a 70 mg tablet or capsule and a 50 mg tablet or capsule; by administration of six 20 mg tablets or capsules; or by administration or two 50 mg tablets or capsules and one 20 mg tablet or capsule. A 150 mg dose can be achieved, for example, by administration of one 150 mg tablet or capsule; by administration of three 50 mg tablets or capsules; by administration of a 100 mg tablet or capsule and a 50 mg tablet or capsule; or by administration of a 50 mg tablet or capsule and five 20 mg tablets or capsules.

[0068] Subjects

[0069] The present invention provides use of roxadustat to treat a subject having anemia associated with MDS. In one aspect, the subject has been diagnosed with primary MDS as confirmed by bone marrow aspirate and biopsy. In some embodiments, the MDS is classified by the IPSS-R as very low, low, or intermediate risk with less than 5% bone marrow blasts. In other embodiments, the MDS is classified by the IPSS-R as high risk or very high risk. In some embodiments the subject according to any embodiment described herein has a hemoglobin level <100 g/L prior to roxadustat treatment. In some embodiments the subject according to any embodiment described herein has a hemoglobin level < 80 g/L prior to roxadustat treatment. In some embodiments, the subject is transfusion dependent prior to treatment. In some embodiments, the subject receives at least 2 pRBC transfusions during any 8-week period prior to said use or administration of roxadustat. In some embodiments, the subject receives at least 2 pRBC transfusions during any 4-week period prior to said use or administration of roxadustat. In some embodiments, the subject receives 2 to 4 pRBC transfusions during any 8-week period prior to said use or administration of roxadustat. In some embodiments, the subject receives 2 to 4 pRBC transfusions during any 4-week period prior to said use or administration of roxadustat. In some embodiments, the subject receives 1 transfusion of pRBC every 8-weeks in at least two consecutive 8-week periods prior to said use or administration of roxadustat. [0070] In some embodiments, the subject is at least 18 years old. In some embodiments, the subject weighs at least 45 kg. In some embodiments, the subject has ECOG PS of 0, 1, or 2. In some embodiments, the subject is at least 18 years old, weighs at least 45 kg, has a diagnosis of MDS, has an ECOG PS of 0, 1, or 2, and has a hemoglobin level of less than or equal to 100 g/L prior to treatment with roxadustat.

[0071] The ECOG PS describes the level of functioning of a subject in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.). It was developed by the Eastern Cooperative Oncology Group (ECOG), now the ECOG-ACRIN Cancer Research Group, and was published in 1982. An ECOG PS score of 0 indicates a subject that is fully active and able to carry on all pre-disease performance without restriction. An ECOG PS score of 1 indicates a subject restricted in physically strenuous activity but still ambulatory and able to carry out work of a light or sedentary nature, e.g., light house and/or office work, whereas an ECOG PS score of 2 indicates a subject that is ambulatory, capable of all selfcare, and up and about more than 50% of waking hours but unable to carry out any work activities.

[0072] In some embodiments, the subject has a transferrin saturation (TSAT) >20% and ferritin >100 ng/mL prior to said use or administration of roxadustat. In some embodiments, the subject has a TSAT >20% and ferritin >400 ng/mL prior to said use or administration of roxadustat. In some embodiments, the subject has C-reactive protein (CRP) level < ULN (upper limit of normal) prior to said use or administration of roxadustat. In some embodiments, the subject has CRP level >ULN prior to said use or administration of roxadustat. In some embodiments, the subject has a serum erythropoietin (Epo) level <200 U/L prior to said use or administration of roxadustat. In some embodiments, the subject has an Epo level >200 U/L and <400 U/L prior to said use or administration of roxadustat.

[0073] Transferrin is a blood plasma glycoprotein that is for transport of ferric ions through the blood to various tissues, such as the liver, spleen, and bone marrow. Each transferrin molecule contains binding sites for two ferric ions, and the extent to which the full complement of these binding sites on transferrin in the blood are occupied by ferric ions is referred to as transferrin saturation (TSAT). Ferritin, on the other hand, is the primary intracellular iron-storage protein keeping iron in a soluble and non-toxic form. Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum where this plasma ferritin serves as an indirect marker of the total amount of iron stored in the body. This iron regulatory system is often disrupted during inflammation, leading to increased sequestration of iron in storage and reduced circulating iron. High serum ferritin with low TSAT levels may imply a condition of iron sequestration. C-reactive protein (CRP) is an acute-phase reactant protein found in blood plasma, whose circulating concentrations rise during the acute phase of an inflammatory/infectious process. Thus, elevated CRP levels are also an indication of potential inflammation and resulting iron sequestration. In subjects having TSAT >20%, ferritin >100 ng/mL, and a CRP < ULN, iron sequestration and a resulting anemia due to inflammation are unlikely.

[0074] Erythropoietin (Epo) is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia that stimulates red blood cell production in the bone marrow. Low levels of Epo (around 10 mU/mL) are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover, but elevated levels of Epo (up to 10,000 mU/mL) occur due to kidney hypoxia generally resulting from anemia or lung dysfunction. In patients with chronic kidney disease (CKD), normochromic normocytic anemia may develop due to Epo deficiency. As the glomerular filtration rate (GFR) falls below 60 mL/min/1.73 m2 (Stage 3a CKD), Epo production by the kidneys falls and anemia due to CKD results. Both erythropoiesis-stimulating agents (ESAs) and roxadustat have been approved for use in treating anemia due to CKD. In subjects having Epo level >200 U/L and eGFR >60 mL/min/1.73m², CKD and an anemia resulting therefrom are unlikely. Thus, anemia in these subjects is likely due to another cause.

[0075] In some embodiments of the invention, the blood hemoglobin level in the subject is increased following use or administration of roxadustat compared with the subject’s hemoglobin level prior to use or administration of roxadustat. In some embodiments of the invention, the subject reaches and maintains a hemoglobin level of >100 g/L for the remaining duration of treatment with roxadustat. In some embodiments, the subject reaches a hemoglobin level of >100 g/L 5-9 weeks following initiation of use or administration of roxadustat and maintains a hemoglobin level of >100 g/L for the remaining duration of treatment. In some embodiments, the subject reaches and maintains a hemoglobin level of >100 g/L up to 130 g/L during treatment.

[0076] Dose

[0077] A therapeutically effective dose of roxadustat, according to any embodiment described herein, refers to that amount that results in the subject achieving an increase in hemoglobin level or reduction in transfusion burden.

[0078] In some embodiments, a therapeutically effective dose of roxadustat, according to any embodiment described herein, refers to that amount that results in an increase in the subject’s hemoglobin level, compared with the hemoglobin level prior to use or administration of roxadustat. In some embodiments, a therapeutically effective dose refers to that amount that results in a >10 g/L increase in the subject’s hemoglobin level, compared with the hemoglobin level prior to treatment. In some embodiments, a therapeutically effective dose refers to that amount that results in a >10 g/L increase in the subject’s hemoglobin level, compared with the hemoglobin level prior to treatment, provided the blood hemoglobin level does not exceed 130 g/L. In some embodiments, a therapeutically effective dose refers to that amount that results in a >15 g/L increase in the subject’s hemoglobin level, compared with the hemoglobin level prior to treatment, provided the blood hemoglobin level does not exceed 130 g/L. In some embodiments, a therapeutically effective dose refers to that amount that results in a >15 g/L increase in the subject’s hemoglobin level, compared with the hemoglobin level prior to treatment, provided the blood hemoglobin level does not exceed 130 g/L. In some embodiments, a therapeutically effective dose refers to that amount that results in a >20 g/L increase in the subject’s hemoglobin level, compared with the hemoglobin level prior to treatment. In some embodiments, a therapeutically effective dose refers to that amount that results in a >20 g/L increase in the subject’s hemoglobin level, compared with the hemoglobin level prior to treatment, provided the blood hemoglobin level does not exceed 130 g/L.

[0079] In one embodiment, a therapeutically effective dose of roxadustat, according to any embodiment described herein, refers to that amount that results in a reduction in the number of transfusions received by the subject compared to their baseline. In some embodiments, a therapeutically effective dose refers to that amount that results in at least 40%, at least 50%, at least 60%, or at least 70% reduction in the number of transfusions received by the subject compared to their baseline. In some embodiments, a therapeutically effective dose refers to that amount that results in at least 75%, at least 80%, at least 85%, or at least 90% reduction in the number of transfusions received by the subject compared to their baseline. In some embodiments, a therapeutically effective dose refers to that amount that results in about 95% to about 100% reduction in the number of transfusions received by the subject compared to their baseline. For example, if the subject at baseline received 2 pRBC transfusions per 4-week period, the use or administration of roxadustat reduces transfusion burden to at most 1 pRBC transfusion per 8-week period (75% reduction) or at most 1 pRBC transfusion per 10-week period (80% reduction). In another embodiment, a therapeutically effective dose refers to that amount that results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 56 weeks of treatment. In another embodiment, a therapeutically effective dose refers to that amount that results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 28 weeks of treatment. In another embodiment, a therapeutically effective dose refers to that amount that results in transfusion independence in the subject for at least 20 weeks (140 consecutive days) during treatment.

[0080] In some embodiments, a therapeutically effective dose of roxadustat medicament, according to any embodiment described herein, is based on the weight of the subject. In some embodiments, the subject has a body weight of 45 to less than 70 kg and the dose of roxadustat is 100-200 mg, particularly about 150 mg. In some embodiments, the subject has a body weight of 70 to 100 kg and the dose of roxadustat is 150-250 mg, particularly about 200 mg. In some embodiments, the subject has a body weight of greater than 100 kg and the dose of roxadustat is 200-300 mg, particularly about 250 mg. In some embodiments, the dose is about 1.5 to 3.5 milligrams of roxadustat per kilogram of the subject’s body weight. In some embodiments, the dose is about 2.0 to 3.5 milligrams of roxadustat per kilogram of the subject’s body weight. In some embodiments, the dose is about 2.0 to 2.5 milligrams of roxadustat per kilogram of the subject’s body weight. In various embodiments, doses are administered at least 2 days apart and no more than 4 days apart.

[0081] In some embodiments, the roxadustat medicament is labeled for administering a therapeutically effective dose to the subject two to three times a week. In some embodiments, the roxadustat medicament is labeled for administering a therapeutically effective dose to the subject three times a week. In some embodiments, the roxadustat medicament is labeled for administering about 50 to 400 mg of roxadustat to the subject two to three times a week. In some embodiments, the roxadustat medicament is labeled for administration of a roxadustat dose selected from the group consisting of 150 mg, 200 mg, and 250 mg two to three times per week. In some embodiments, the roxadustat medicament is labeled for administering about 50 mg, about 70 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, or about 400 mg of roxadustat to the subject two to three times a week. In some embodiments, the roxadustat medicament is labeled for administering about 50 mg, about 70 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, or about 350 mg of roxadustat to the subject three times a week. In some embodiments, roxadustat is administered at least 2 days apart and no more than 4 days apart.

[0082] It will be understood by one of skill in the art that the symptoms and outcomes may vary with age, gender, and burden of disease. Based on Hb level, roxadustat doses may be titrated to achieve and maintain a Hb level of 100 to 130 g/L and to minimize the need for blood transfusion. Dose adjustments can be made periodically, for example, once every 4 weeks, by taking into account both the current Hb level and change in Hb level over the period, for example, over the previous 4 weeks.

ADDITIONAL EMBODIMENTS

[0083] Embodiments include the following:

[0084] Embodiment 1. Use of roxadustat in the manufacture of a medicament for treating anemia in a subject having anemia associated with myelodysplastic syndrome (MDS).

[0085] Embodiment 2. Use of roxadustat in the manufacture of a medicament for reducing the number of blood transfusion received by a subject having anemia associated with MDS.

[0086] Embodiment 3. The use according to embodiment 1 or 2, wherein the subject is transfusion dependent prior to use of roxadustat.

[0087] Embodiment 4. The use according to any one of embodiments 1 to 3, wherein the subject receives at least 2 pRBC transfusions during an 8-week period prior to use of roxadustat.

[0088] Embodiment 5. The use according to any one of embodiments 1 to 3, wherein the subject receives at least 2 pRBC transfusions every 4 weeks prior to said use. [0089] Embodiment 6. The use according to any one of embodiments 1 to 3, wherein the subject receives 2 to 4 pRBC transfusions during an 8-week period prior to use of roxadustat.

[0090] Embodiment 7. The use according to any one of embodiments 1 to 3, wherein the subject receives 2 to 4 pRBCs transfusions during a 4-week period prior to use of roxadustat. [0091] Embodiment 8. The use according to any one of embodiments 1 to 3, wherein the subject receives 1 pRBC transfusion every 8-weeks in at least two consecutive 8-week periods prior to use of roxadustat.

[0092]

[0093] Embodiment 9. The use of any one of embodiments 1 to 8, wherein the subject has a hemoglobin level of less than or equal to 100 g/L prior to said use of roxadustat. [0094] Embodiment 10: Use of roxadustat in the manufacture of a medicament for treating anemia in a subject having anemia associated with myelodysplastic syndrome, wherein the subject has a hemoglobin level of less than or equal to 8 g/dL prior to said use of roxadustat.

[0095] Embodiment 11. The use according to embodiment 8, wherein the subject is transfusion dependent prior to use of roxadustat.

[0096] Embodiment 12. The use according to embodiments 10 or 11, wherein the subject receives at least 2 pRBC transfusions during an 8-week period prior to use of roxadustat.

[0097] Embodiment 13. The use according to embodiments 10 or 11, wherein the subject receives at least 2 pRBC transfusions every 4 weeks prior to said use.

[0098] Embodiment 14. The use according to embodiments 10 or 11, wherein the subject receives 2 to 4 pRBC transfusions during an 8-week period prior to use of roxadustat. [0099] Embodiment 15. The use according to embodiment 10 or 11, wherein the subject receives 2 to 4 pRBCs transfusions during a 4-week period prior to use of roxadustat.

[0100] Embodiment 16. The use according to embodiments 10 or 11, wherein the subject receives 1 pRBC transfusion every 8-weeks in at least two consecutive 8-week periods prior to use of roxadustat.

[0101] Embodiment 17. The use of any one of embodiments 1 to 16, wherein the subject has been diagnosed with primary MDS as confirmed by bone marrow aspirate and biopsy.

[0102] Embodiment 18. The use of any one of embodiments 1 to 17, wherein the

MDS is classified by the IPSS-R as very low, low, or intermediate risk with less than 5% bone marrow blasts.

[0103] Embodiment 19. The use of any one of embodiments 1 to 17, wherein the

MDS is classified by the IPSS-R as high risk or very high risk. [0104] Embodiment 20. The use of any one of embodiments 1 to 19, wherein the use of roxadustat results in a reduction in the number of transfusions received by the subject compared to their baseline.

[0105] Embodiment 21. The use of any one of embodiments 1 to 20, wherein the use of roxadustat results in at least 40%, at least 50%, at least 60%, or at least 70% reduction in the number of transfusions received by the subject compared to their baseline.

[0106] Embodiment 22. The use of any one of embodiments 1 to 20, wherein the use of roxadustat results in at least 75%, at least 80%, at least 85%, or at least 90% reduction in the number of transfusions received by the subject compared to their baseline.

[0107] Embodiment 23. The use of any one of embodiments 1 to 20, wherein the use of roxadustat results in at least about 95% or at least about 100% reduction in the number of transfusions received by the subject compared to their baseline.

[0108] Embodiment 24. The use of any one of embodiments 1 to 20, wherein the use of roxadustat results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 56 weeks of treatment.

[0109] Embodiment 25. The use of any one of embodiments 1 to 20, wherein the medicament results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 28 weeks of treatment.

[0110] Embodiment 26. The use of any one of embodiments 1 to 20, wherein the medicament results in transfusion independence in the subject for at least 20 weeks (140 consecutive days) during treatment.

[0111] Embodiment 27. Use of roxadustat in the manufacture of a medicament for maintaining a hemoglobin level of >8 without RBC transfusions, in a subject having anemia associated with myelodysplastic syndrome that is transfusion dependent prior to use of roxadustat.

[0112] Embodiment 28. The use according to embodiment 27, wherein the subject receives at least 2 pRBC transfusions during an 8-week period prior to use of roxadustat.

[0113] Embodiment 29. The use according to embodiment 27, wherein the subject receives at least 2 pRBC transfusions every 4 weeks prior to said use.

[0114] Embodiment 30. The use according to embodiment 27, wherein the subject receives 2 to 4 pRBC transfusions during an 8-week period prior to use of roxadustat.

[0115] Embodiment 31. The use according to a embodiment 27, wherein the subject receives 2 to 4 pRBCs transfusions during a 4-week period prior to use of roxadustat. [0116] Embodiment 32. The use according to embodiment 27, wherein the subject receives 1 pRBC transfusion every 8-weeks in at least two consecutive 8-week periods prior to use of roxadustat.

[0117] Embodiment 33. The use of any one of embodiments 27 to 32, wherein the subject has been diagnosed with primary MDS as confirmed by bone marrow aspirate and biopsy.

[0118] Embodiment 34. The use of any one of embodiments 27 to 33, wherein the

[0119] Embodiment 35. The use of any one of embodiments 27 to 33, wherein the

MDS is classified by the IPSS-R as high risk or very high risk.

[0120] Embodiment 36. The use of any one of embodiments 27 to 35, wherein the use of roxadustat results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 56 weeks of treatment.

[0121] Embodiment 37. The use of any one of embodiments 27 to 35, wherein the medicament results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 28 weeks of treatment.

[0122] Embodiment 38. The use of any one of embodiments 27 to 35, wherein the medicament results in transfusion independence in the subject for at least 20 weeks (140 consecutive days) during treatment.

[0123] Embodiment 39. A method for treating anemia in a subject having anemia associated with MDS, the method comprising administering to the subject a therapeutically effective amount of roxadustat, thereby treating the anemia.

[0124] Embodiment 40. A method for reducing the number of blood transfusion received by a subject having anemia associated with MDS, the method comprising administering to the subject a therapeutically effective amount of roxadustat, thereby reducing the number of blood transfusions received by the subject.

[0125] Embodiment 41. The method according to embodiment 39 or 40, wherein the subject is transfusion dependent prior to said administering of roxadustat.

[0126] Embodiment 42. The method according to any one of embodiments 39 to

41, wherein the subject receives at least 2 pRBC transfusions during an 8-week period prior to use of roxadustat.

[0127] Embodiment 43. The method according to any one of embodiments 39 to

41, wherein the subject receives at least 2 pRBC transfusions every 4 weeks prior to said use. [0128] Embodiment 44. The method according to any one of embodiments 39 to

41, wherein the subject receives 2 to 4 pRBC transfusions during an 8-week period prior to said administering.

[0129] Embodiment 45. The method according to any one of embodiments 39 to

41, wherein the subject receives 1 pRBC transfusions every 8-weeks in at least two consecutive 8-week periods prior to said administering.

[0130] Embodiment 46. The method of any one of embodiments 39 to 45, wherein the subject has a hemoglobin level of less than or equal to 100 g/L prior to said administering.

[0131] Embodiment 47. The method of any one of embodiments 39 to 46, wherein the subject has been diagnosed with primary MDS as confirmed by bone marrow aspirate and biopsy.

[0132] Embodiment 48. The method of any one of embodiments 39 to 47, wherein the MDS is classified by the IPSS-R as very low, low, or intermediate risk with less than 5% bone marrow blasts.

[0133] Embodiment 49. The method of any one of embodiments 39 to 47, wherein the MDS is classified by the IPSS-R as high risk or very high risk.

[0134] Embodiment 50. The method of any one of embodiments 39 to 49, wherein the method results in a reduction in the number of transfusions received by the subject compared to their baseline.

[0135] Embodiment 51. The method of any one of embodiments 39 to 50, wherein the method results in at least 40%, at least 50%, at least 60%, or at least 70% reduction in the number of transfusions received by the subject compared to their baseline.

[0136] Embodiment 52. The method of any one of embodiments 39 to 50, wherein the method results in at least 75%, at least 80%, at least 85%, or at least 90% reduction in the number of transfusions received by the subject compared to their baseline.

[0137] Embodiment 53. The method of any one of embodiments 39 to 50, wherein the method results in at least about 95% or at least about 100% reduction in the number of transfusions received by the subject compared to their baseline.

[0138] Embodiment 54. The method of any one of embodiments 39 to 50, wherein the method results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 56 weeks of treatment.

[0139] Embodiment 55. The method of any one of embodiments 39 to 50, wherein the method results in transfusion independence in the subject for at least 8 weeks (56 consecutive days) within the first 28 weeks of treatment. [0140] Embodiment 56. The method of any one of embodiments 39 to 50, wherein the method results in transfusion independence in the subject for at least 20 weeks (140 consecutive days) during treatment.

[0141] Embodiment 57. The use or method of any one of embodiments 1 to 56, wherein the medicament or method increases the mean hemoglobin (Hb) in the subject at least 10 g/L, at least 15 g/L, or at least 20 g/L over four weeks of treatment.

[0142] Embodiment 58. The use or method of any one of embodiments 1 to 57, wherein the medicament or method increases the mean Hb in the subject at least 10 g/L, at least 15 g/L, or at least 20 g/L over eight weeks of use or administration.

[0143] Embodiment 59. The use or method of any one of embodiments 1 to 58, wherein the medicament or method maintains the mean Hb in the subject between about 80 g/L to about 120 g/L.

[0144] Embodiment 60. The use or method of embodiment 59, wherein the subject maintains a hemoglobin level of 80 to 90 g/L.

[0145] Embodiment 61. The use or method of embodiment 59, wherein the subject maintains a hemoglobin level of 90 to 100 g/L.

[0146] Embodiment 62. The use or method of embodiment 59, wherein the subject maintains a hemoglobin level of 100 to 110 g/L.

[0147] Embodiment 63. The use or method of embodiment 59, wherein the subject maintains a hemoglobin level of 110 to 120 g/L.

[0148] Embodiment 64. The use or method of any one of embodiments 1 to 63, wherein the subject is at least 18 years old.

[0149] Embodiment 65. The use or method of any one of embodiments 1 to 64, wherein the subject weighs at least 45 kg.

[0150] Embodiment 66. The use or method of any one of embodiments 1 to 65, wherein the subject has Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2.

[0151] Embodiment 67. The use or method of any one of embodiments 1 to 63, wherein the subject is at least 18 years old, weighs at least 45 kg, has a diagnosis of MDS, has an ECOG PS of 0, 1, or 2.

[0152] Embodiment 68. The use or method of any one of embodiments 1 to 67, wherein the subject has a transferrin saturation (TSAT) >20% and ferritin >100 ng/mL prior to said use or administration of roxadustat. [0153] Embodiment 69. The use or method of any one of embodiments 1 to 67, wherein the subject has a TSAT >20% and ferritin >400 ng/mL prior to said use or administration of roxadustat.

[0154] Embodiment 70. The use or method of any one of embodiments 1 to 69, wherein the subject has C -reactive protein (CRP) level < ULN (upper limit of normal) prior to said use or administration of roxadustat.

[0155] Embodiment 71. The use or method of any one of embodiments 1 to 69, wherein the subject has CRP level >ULN prior to said use or administration of roxadustat.

[0156] Embodiment 72. The use or method of any one of embodiments 1 to 71, wherein the subject has a serum erythropoietin (Epo) level < 200 U/L prior to said use or administration of roxadustat.

[0157] Embodiment 73. The use or method of any one of embodiments 1 to 71, wherein the subject has an Epo level >200 U/L and < 400 U/L prior to said use or administration of roxadustat.

[0158] Embodiment 74. The use or method of any one of embodiments 1 to 73, wherein the medicament is labeled for administration to the subject based on a dose of roxadustat relative to body weight of the subject.

[0159] Embodiment 75. The use or method of embodiment 74, wherein the subject has a body weight of 45 to less than 70 kg and the dose of roxadustat is 100-200 mg, particularly about 150 mg.

[0160] Embodiment 76. The use or method of embodiment 74, wherein the subject has a body weight of 70 to 100 kg and the dose of roxadustat is 150-250 mg, particularly about 200 mg.

[0161] Embodiment 77. The use or method of embodiment 74, wherein the subject has a body weight of greater than 100 kg and the dose of roxadustat is 200-300 mg, particularly about 250 mg.

[0162] Embodiment 78. The use or method of any one of embodiments 74 to 70, wherein the dose is about 1.5 to 3.5 milligrams of roxadustat per kilogram of the subject’s body weight.

[0163] Embodiment 79. The use or method of any one of embodiments 74 to 70, wherein the dose is about 2.0 to 3.5 milligrams of roxadustat per kilogram of the subject’s body weight. [0164] Embodiment 80. The use or method of any one of embodiments 74 to 70, wherein the dose is about 2.0 to 2.5 milligrams of roxadustat per kilogram of the subject’s body weight.

[0165] Embodiment 81. The use or method of any one of embodiments 74 to 73, wherein doses are administered at least 2 days apart and no more than 4 days apart.

[0166] Embodiment 82. The use or method of any one of embodiments 74 to 74, wherein the medicament is labeled to administer a dose of roxadustat three times a week.

[0167] Embodiment 83. The use or method of embodiments 74, wherein the subject has a body weight of 45 to less than 70 kg and the roxadustat is administered at 100 to 200 mg, particularly about 150 mg, three times per week.

[0168] Embodiment 84. The use or method of embodiments 74, wherein the subject has a body weight of 70 to 100 kg and the roxadustat is administered at 150-250 mg, particularly about 200 mg, three times per week.

[0169] Embodiment 85. The use or method of embodiments 74, wherein the subject has a body weight of greater than 100 kg and the roxadustat is administered at 200-300 mg, particularly about 250 mg, three times per week.

[0170] Embodiment 86. The use or method of any one of embodiments 1 to 85, wherein the roxadustat is crystalline Form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9, and 27.4° 20±0.2° 20.

[0171] Embodiment 87. The use or method of any one of embodiments 1 to 86, wherein the roxadustat is a solid having a unimodal particle size distribution with a D90 less than 43 pm.

[0172] Embodiment 88. The use or method of any one of embodiments 1 to 87, wherein the roxadustat is a solid having a unimodal particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.

[0173] Embodiment 89. The use or method of any one of embodiments 1 to 88, wherein the roxadustat is formulated in a medicament for oral administration.

[0174] Embodiment 90. The use or method of embodiment 89, wherein the medicament further comprises a pharmaceutically acceptable excipient.

[0175] Embodiment 91. The use or method of embodiment 89 or 90, wherein the medicament is a tablet or a capsule.

[0176] Embodiment 92. The use or method of embodiment 91, wherein the tablet or capsule comprises 20 mg, 50 mg, 100 mg, or 150 mg roxadustat and at least one appropriate excipient for oral delivery. [0177] Embodiment 93. The use or method of embodiment 91, wherein the medicament is a tablet.

[0178] Embodiment 94. The use or method of embodiment 93, wherein the tablet comprises a tablet core and a coating, wherein the tablet core comprises [(4-hydroxy- 1 - methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate, and the coating comprises a photostabilizing agent comprising 0.1 to about 0.4 mg/cm2 titanium dioxide and from about 0.1 to about 0.4 mg/cm2 Allura Red AC in aluminum lake wherein the amount of titanium dioxide and Allura Red AC in aluminum lake is based on surface area of the tablet core.

[0179] Embodiment 95. The use or method of embodiment 93 or 94, wherein the amount of roxadustat in the tablet is selected from about 20 mg, about 50 mg, about 100 mg, or about 150 mg.

[0180] Embodiment 96. The use or method of embodiment 94, wherein the coating is present in an amount from about 3% to about 8% w/w based on the weight of the tablet core.

[0181]

[0182] Embodiment 97. The use or method of embodiment 91, wherein the medicament is a capsule.

[0183] Embodiment 98. The use or method of embodiment 97, wherein the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg or 50 mg of roxadustat and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, iron oxide yellow and/or Allura Red AC, and gelatin.

[0184] Embodiment 99. The use or method of embodiment 97 or 98, wherein the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg of roxadustat and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, iron oxide yellow, and gelatin.

[0185] Embodiment 100. The use or method of embodiment 97 or 98, wherein the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 50 mg of roxadustat and pharmaceutically acceptable excipients comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising Allura red AC, titanium dioxide, iron oxide yellow, and gelatin.

[0186] Embodiment 101. The use or method of any one of embodiments 97 to 99, wherein capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg of roxadustat, 101.84 mg of lactose monohydrate 310, 9.36 mg of microcrystalline cellulose PH101, 6.48 mg of povidone K30, 5.76 mg of croscarmellose sodium, and 0.56 mg of magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, iron oxide yellow, and gelatin, wherein the titanium dioxide is 1%, by weight of the capsule shell and the iron oxide yellow is 2% by weight of the capsule shell.

[0187] Embodiment 102. The use or method of any one of embodiments 97, 98, or

99, wherein the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 50 mg of roxadustat, 254.6 mg of lactose monohydrate (310), 23.4 mg of microcrystalline cellulose PH101, 16.20 mg of povidone K30, 14.40 mg of croscarmellose sodium, and 1.4 mg of magnesium stearate; and the capsule shell is a gelatin shell comprising Allura red AC, titanium dioxide, iron oxide yellow, and gelatin, wherein the Allura red AC is 1% by weight of the capsule shell, the titanium dioxide is 1%, by weight of the capsule shell and the iron oxide yellow is 1 % by weight of the capsule shell.

[0188] Embodiment 103. The use of any one of embodiments 89 to 102, wherein the medicament is further labeled to optionally increase or decrease the dose of roxadustat until the subject achieves and maintains a blood hemoglobin level of 100 to 120 g/L, providing the dose does not exceed 400 mg.

[0189] Embodiment 104. The use of embodiment 103, wherein the increasing or decreasing the dose of roxadustat results in a dose of 50 mg, 70 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg.

[0190] Embodiment 105. The use of any of embodiments 1 to 38 or 57 to 105, wherein the medicament is the sole medicament for treating the anemia.

[0191] Embodiment 106. The method of any of embodiments 33 to 102, wherein the roxadustat is the sole therapeutic compound administered. EXAMPLES

[0192] Example 1: A Randomized, Double-Blind, Placebo-controlled,

Multicenter Phase 3 Study to Investigate the Efficacy and Safety of Roxadustat for Treatment of Anemia in Subjects with Myelodysplastic Syndrome (MDS)

[0193] Study Design

[0194] The study consisted of a screening period of up to 6 weeks, followed by a 52- week treatment period and a subsequent 4-week follow-up period (FIG 1.).

[0195] All screening procedures were to be completed within 28 days prior to Day 1 of treatment; however, the screening window could be extended up to 42 days (6 weeks) if necessary to complete certain eligibility assessments, e.g., bone marrow exam, endogenous erythropoietin evaluation. Lower risk MDS (IPSS-R very low risk, lower risk, or intermediate risk) had to be documented prior to Day 1 of treatment. Results from bone marrow examination and cytogenetic analysis performed within 16 weeks prior to Day 1 of treatment could be used. There was no minimum time from diagnosis to registration/randomization except to allow for proper IPSS-R classification to be made and to show transfusion dependence for patients. Patients were deemed to have low RBC transfusion burden (LTB) if they had received 1 to 4 pRBC documented transfusions within 8 weeks prior to registration/randomization. Patients with 1 pRBC/8-weeks had to have a documented history of requiring 1 pRBC/8 weeks in 2 consecutive periods of 8 weeks in the 16 weeks preceding registration/randomization.

[0196] Patients with elevated serum erythropoietin levels (>400 mIU/mL) at a first screening were allowed to repeat tests after at least 7 days to confirm eligibility. If the erythropoietin level dropped to 400 mIU/mL or less, the patient would then qualify for the double blind (DB) study. However, if the serum erythropoietin level remained elevated (>400 upon repeat), the patient might then have qualified for the open label (OL) high- erythropoietin cohort provided all other eligibility criteria were met.

[0197] Treatment Period (52 weeks): Approximately 160 eligible lower-risk MDS patients with LTB were randomized 3:2 to roxadustat or matching placebo. Patients in the DB component of the study were randomized with the following stratifications: Serum EPO level either less than 200 mIU/mL OR greater than 200 mIU/mL and less than 400 mIU/mL; IPSS-R low risk/very low risk vs intermediate risk group classification; and RBC transfusion burden 1 pack of red blood cells (pRBC) per 8 weeks over 16 consecutive weeks versus 2-4 pRBC per 8 weeks. The percentage of patients having 1 pRBC transfusion at baseline was capped at 30% for the DB portion of the study. The subjects underwent 52 weeks of study treatment. Study visits were scheduled every 2 weeks (±3 days) up to the Week 31 visit and then every 4 weeks (±4 days) up to the Week 47 visit. The interval between Week 47 and Week 52 visits was 6 weeks. Patients who discontinued treatment early (for any reason) were to remain in the study through the 52 week study period, but at a reduced visit schedule of every 8 weeks.

[0198] Follow-up period (4 weeks after the early termination [ET]/end of treatment

[EOT] visit): all subjects who completed 52 weeks of treatment underwent a 4-week followup period. Subjects who discontinued treatment early were encouraged to complete the EOT visit.

[0199] Target Subjects Population and Sample Size

[0200] Eligible subjects were at least 18 years of age and 45 kg body weight with a diagnosis of primary MDS (confirmed by bone marrow aspirate and biopsy prior to treatment Day 1), classified by the IPSS-R as very low, low, or intermediate risk with <5% bone marrow blasts. Subjects also required a hemoglobin less than or equal to 10 g/dL, ECOG performance score of 0, 1, or 2, and an RBC transfusion requirement of either 2 to 4 pRBC during the 8-weeks prior to registration/ randomization or 1 pRBC during the 8-weeks prior to registration/ randomization and a documented history of requiring 1 pRBC/8-weeks in 2 consecutive periods of 8 weeks in the 16 weeks preceding registration/ randomization.

[0201] There was no restriction on prior use of recombinant erythropoietins or analogues (erythropoiesis-stimulating agents [ESAs]), except that the patient must not have received any ESA within the 8 weeks prior to Day 1 registration/ randomization. Subjects were excluded if they had clinically significant anemia due to non-MDS etiologies such as iron deficiency, vitamin B12 or folate deficiency, autoimmune or hereditary hemolysis, hemorrhage, or hereditary anemia such as sickle cell anemia or thalassemia.

[0202] The study enrolled, randomized, and treated 140 subjects (82 subjects to roxadustat and 58 subjects to placebo). Of the randomized subjects, 59 (42.1%) subjects completed study treatment in accordance with the protocol (30 subjects in the roxadustat group and 29 subjects in the placebo group). All 140 treated subjects were included in the Safety Analysis Set, 137 (97.9%) subjects in the Full Analysis Set (FAS), and 127 (90.7%) subjects in the Per Protocol Set (PPS). [0203] The FAS was defined as all patients enrolled into this study who received at least 1 dose of study medication and at least 1 corresponding on-treatment Hb assessment. Patients were included in the treatment group to which they were randomized for the FAS analysis. The PPS included all patients who received at least 8 weeks of treatment with corresponding on-treatment Hb assessments and were without major protocol deviations that affected the assessment of study endpoints. The PPS population was used for supportive and/or sensitivity analyses of the efficacy endpoints. The Safety Analysis Set (SAF) was defined as all subjects who took at least one dose of study drug. Patients were included in the treatment group based on the treatment they actually received for the SAF analysis.

[0204] Key demographics and baseline characteristics of the Safety Analysis Set

(SAF) are shown in Table 2.

[0205] Table 2: Demographics and Baseline Characteristics (Full Analysis Set)

Abbreviations: CRP = C-reactive protein; ECOG = Eastern Cooperative Oncology Group; eGFR = estimated glomerular filtration rate; EPO = erythropoietin; Hb = hemoglobin; 1PSS-R = International Prognostic Scoring System - Revised; MDS = myelodysplastic syndrome; MDS-RS = MDS with ring sideroblasts; OL = open label; pRBC = pack of red blood cells; SD = standard deviation; TSAT = transferrin saturation; ULN = upper limit of normal; WHO = World Health Organization [1] Baseline Hb value of central laboratory is defined as the mean of screening Hb value and Week 1 Day 1 Hb value prior to treatment. If Hb value of central laboratory is not available for baseline, the Hb value of local laboratory is used for substitution

The p-values of comparability of baseline characteristics among treatment groups is derived using analysis of variance (ANOVA) model for continuous variables and Chi-Square test (or Fisher's exact test if cell count < 5) for categorical variables. [0206] Treatment of Subjects

[0207] A dose-ranging study was conducted wherein the first 8 patients received a starting dose of 1.5 mg/kg roxadustat (Dose Level 1), the next 8 patients received a starting dose of 2.0 mg/kg roxadustat (Dose-Level 2), and the last 8 patients received a starting dose of 2.5 mg/kg roxadustat (Dose-Level 3). Upon reviewing efficacy and safety of the doseranging study, the 2.5 mg/kg (Dose Level 3) was identified as the starting dose group for the DB component. Patients in the exploratory OL high-erythropoietin component also received the same starting dose. The starting dose for each patient was determined per body weight ranges as shown in Table 3 based on actual patient weight on registration/ randomization day/ Day 1.

[0208] Table 3: Roxadustat Starting Dose

Abbreviation: TIW: 3 times per week

[0209] All patients received roxadustat/placebo doses three times per week (TIW) for the entire duration of the study. Roxadustat/placebo was dispensed to patients with instructions for self-administration of the tablets orally on each dosing day, according to the dosing schedule. The first dose of roxadustat /placebo was administered on Day 1 after completion of all procedures, including laboratory draws. Study drug doses were to be administered at least 2 days apart and no more than 4 days apart at approximately the same time every day. Roxadustat/placebo could be taken with water and with or without food.

[0210] Dose Adjustments

[0211] There were 2 periods for the study drug dosing: the correction phase and the maintenance phase. In the correction phase, dose adjustments occurred every 8 weeks until transfusion independence (TI) for at least 8 continuous weeks was achieved. The maintenance phase began once TI for at least 8 continuous weeks (>56 consecutive days) had been achieved. During this phase, dose adjustment was reviewed every 4 weeks. A modified dose adjustment algorithm as shown in Table 4 was applied to patients who attained TI > 56 days. Dose step levels were 50mg, 70 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, and 350 mg. Down-titration of the dose was allowed at any time.

[0212] Table 4: Modified Dose Adjustment Algorithm

* A change in Hb from 4 weeks earlier of < -1.0 g/dL meant a Hb value that was lower by more than 1.0 g/dL compared to 4 weeks earlier, e.g., a Hb of 9.4 g/dL compared to 10.6 g/dL 4 weeks earlier.

[0213] Following commencement of study treatment, patients were evaluated for response after 8 weeks (beginning at Week 9) and, if the patient had required 1 or more pRBC transfusion(s) in that period the dose was increased by 1 dose level based on the body weight category. After each dose adjustment, the patient remained on that dose level for a minimum of 8 weeks before further adjustment was permitted based on the next scheduled visit.

[0214] The down titration of the study treatment was allowed at any time but was required if any of the following criteria were met: transfusion independent for at least 56 days consecutively and Hb at least 12 g/dL or transfusion independent for at least 56 days consecutively and the rate of rise of Hb at least 2.5 g/dL over 4 weeks. Hb levels were to be retested for confirmation every 2 weeks after a dose reduction. If a patient achieved TI in the initial 8-weeks of the study or had undergone treatment with the maximum allowable dose, i.e., 400 mg TIW or 3.5mg/kg for at least 8-weeks, a dose reduction by 1-dose level was allowed. [0215] The maximum allowable roxadustat dose (per dose) in this study was 3.5 mg/kg or 400 mg per dose, whichever was lower. At any time during the study, the prescribed dose could not exceed the maximum allowable dose.

[0216] Study Objectives and Endpoints

Open-label High-Erythropoietin Component

[0217] The objective of the OL high-erythropoietin component was to explore the efficacy and safety of roxadustat in these patients in order to evaluate whether they should be allowed to participate in the DB placebo-controlled component.

Double Blind Component

[0218] The primary objective of the DB component was to evaluate the efficacy of roxadustat in the treatment of anemia in patients with lower risk MDS with a low burden of RBC transfusion. Secondary objectives included evaluation of the safety of roxadustat in this patient population, evaluation of the impact of roxadustat on RBC transfusion requirements, evaluation of pharmacokinetics (PK) and pharmacodynamics (PD) of roxadustat in MDS patients, and evaluation of the effect of roxadustat on quality-of-life parameters.

[0219] Results

[0220] Although subjects having a transfusion burden of 1 pRBC transfusion per 4 weeks receiving roxadustat did not show significant transfusion independence relative to placebo-treated subjects (Table 5), roxadustat did significantly reduce TI in subjects having a transfusion burden of 2 or more pRBC transfusions per 4 weeks compared to placebo (Table 6).

[0221] Table 5: Transfusion Independence in Subjects Requiring 1 pRBC transfusion/week

Number of Tl periods per Tl Responder [4] n 25 16

Mean (SD) 89.9 (54.79) 90.3 (53.06)

Median 115.0 107.0

Min, Max 2, 145 1, 143

By the End of'52-week Study Treatment Period Roxadustat/Placebo

Roxadustat Placebo Odds Ratio

(N=44) (N=31) |95% CI | |3 | p- value (31

RBC Transfusion Independence [1], 28 (63.6) [47.8, 77.6] 18 (58.1) [39.1, 75.5] 1.057 (0.385, 2.903] 0.916 n (%) [95% Cl] [2]

Number of Tl periods per Tl Responder [4] n 28 18

Mean (SD) 148.5 (115.21) 148.9 (111.48)

Median 151.0 109.0

Min, Max 1, 321 1, 309

T1 is estimated in the duration begins with the first dose date (Day 1) and ends with the date of end of treatment or last visit date at week 28/52, which comes earlier. RBC transfusions after end of treatment are recorded on CRF until the last visit at week 52 from first dose but are not used to define Tl.

[1] RBC Transfusion Independence is defined as the absence of any intravenous RBC transfusion (packed cell or whole blood) during any consecutive 56 days during the treatment period. Subjects who have discontinued treatment early for any reasons prior to week 8 are classified as non-responders.

[2] The RBC Tl response rate and its two-sided 95% confidence intervals are calculated based on the exact method of Clopper-Pearson.

[3] The odds ratio along with its 95% Cl are calculated based on the Cochran-Mantel-Haenszel (CMH) chi-square test adjusting for the stratification factors (EPO level and 1PSS-R risk category).

[4] Tl is measured by moving windows of any 8 weeks (56 consecutive days) by day (e.g. Days 1 to 56, Days 2 to 57, Days 3 to 58). The number means the amount of any 8 weeks (56 consecutive days) that meets the criterion of Tl.

[0222] Table 6: Transfusion Independence in Subjects Requiring >2 pRBC transfusion/week

Number of Tl periods per Tl Responder [4] n 13 3

Mean (SD) 58.8 (47.77) 107.3 (50.54)

Median 44.0 135.0

Min, Max 8, 142 49, 138

By the End of52-week Study Treatment Period

RBC Transfusion Independence [1], 16 (44.4) [27.9, 61.9] 5 (19.2) [6.6, 39.4] 3.369 (1.014, 11.189] 0.048 n (%) [95% Cl] [2]

Number of Tl periods per Tl Responder [4] n 16 5

Mean (SD) 113.4 (108.71) 132.6 (113.16)

Median 59.5 111.0

Min, Max 8, 311 7, 274

Tl is estimated in the duration begins with the first dose date (Day 1) and ends with the date of end of treatment or last visit date at week 28/52, which comes earlier. RBC transfusions after end of treatment are recorded on CRF until the last visit at week 52 from first dose but are not used to define Tl.

[3] The odds ratio along with its 95% Cl are calculated based on the Cochran-Mantel-Haenszel (CMH) chi-square test adjusting for the stratification factors (EPO level and 1PSS-R risk category). [4] T1 is measured by moving windows of any 8 weeks (56 consecutive days) by day (e.g. Days 1 to 56, Days 2 to 57, Days 3 to 58). The number means the amount of any 8 weeks (56 consecutive days) that meets the criterion of Tl.

[0223] These results show that roxadustat can reduce the transfusion burden in MDS patients experiencing anemia. Although statistical significance was not seen in low transfusion burden patients, this was likely due to the low level of transfusion requirements seen in both roxadustat and placebo patient populations during the treatment period.

[0224] Roxadustat also showed a statistically significant improvement in time to transfusion independence relative to placebo in the FAS population (Table 7).

[0225] Table 7: Time to Transfusion Independence (Full Analysis Set)

Number of Subjects with 52 (65.0) 29 (50.9) 0.061 1.649 [1.032, 2.633] 0.036

Transfusion Independence, n (%) [ 1 ]

Number of Subjects Censored, n (%) 28 (35.0) 28 (49.1)

Median Time to Transfusion 16.29 [6.43, 27.71] 38.29 [10.29, NE]

Independence (Weeks), [95% Cl] [2]

NE = Not Evaluable.

[1] Tl Response is defined as the absence of any intravenous RBC transfusion (packed cell or whole blood) during any consecutive 56 days anytime during the study. Tl is estimated in the duration begins with the first dose date (Day 1) and ends with the end of study or treatment discontinuation or death, which comes earlier. RBC transfusions after end of treatment are recorded on CRF until the last visit at week 52 from first dose and are used to define Tl. If subject had more than one 56-day period with transfusion free, only the first period is used for analysis.

[2] The time to transfusion independence (in weeks) is measured from the day of first study drug to the first day of Tl response. For subjects who have a Tl response period, time to transfusion independence is calculated as (first day of Tl response - day of first study drug +1) / 7. For subjects who do not have a Tl response period, time to transfusion independence is calculated as duration = (date of the end of study or treatment discontinuation or death, which comes earlier - day of first study drug + l)/7. Median time to Transfusion Independence is estimated using Kaplan-Meier (K-M) method and its associated 2-sided 95% Cis for each treatment group is calculated using the method of Brookmeyer and Crowley.

[3] p-value is from a stratified log-rank test stratified by centrally confirmed 1PSS-R category (Intermediate vs. Low- risk/very low risk), transfusion burden ( 1 pRBC/8-weeks over 16 consecutive weeks vs. 2-4 pRBC/8-weeks) and baseline EPO level (<=200 mlU/mL vs. >200 mlU/mL and <=400 mlU/mL).

[4] Hazard Ratio and its 95% Cl and p-value are from Cox regression adjusting for baseline hemoglobin, centrally confirmed 1PSS-R category (Intermediate vs. Low-risk/very low risk), transfusion burden ( 1 pRBC/8-weeks over 16 consecutive weeks vs. 2-4 pRBC/8-weeks) and baseline EPO level (<=200 mlU/mL vs. >200 mlU/mL and <=400 mlU/mL).

[5] The estimated event free rate and its 95% Cl at each visit is estimated as event free probability by Kaplan-Meier Product Limit method.

[0226] Additional subgroup analysis of the FAS population (Table 8) showed trends toward greater response in the roxadustat population compared to the placebo population with respect to the subjects that had previously received ESA treatment. The anemia in these subjects had been generally refractory to ESA treatment but showed response with roxadustat treatment. [0227] Table 8: 28 Week Response Rates by Subgroup Analysis (Full Analysis

Set)

T1 is estimated in the duration begins with the first dose date (Day 1) and ends with the date of end of treatment or last visit date at week 28, which comes earlier.

[2] The RBC TI response rate and its two-sided 95% confidence intervals are calculated based on the exact method of Clopper-Pearson.

[3] The odds ratio along with its 95% CI are calculated based on the Cochran-Mantel-Haenszel (CMH) chi-square test adjusting for the stratification factors (EPO level and IPSS-R risk category).

[0228] Additional subgroup analysis of the FAS showed that in patients with a higher transfusions burden of at least 2 pRBC transfusions every four weeks, roxadustat, showed a statistically significant improvement in achieving transfusion independence for >8 weeks within the first 28 weeks of treatment and by the end of treatment (EOT) relative to placebo (Table 9, Fig. 2)

[0229] Table 9: More Patients With a Higher Transfusion Burden® Receiving

Roxadustat Achieved TI vs Placebo

“Higher transfusion burden defined as >2 pRBC transfusions every four weeks. OR: Odds ratio.

[0230] The results of the study also indicated that patients in the FAS that received roxadustat had an improved PROMIS-fatigue score from baseline vs. patients that received placebo over the same time period (FIG. 3).

[0231] Furthermore, as shown in Table 10, in transfusion independent responders, more patients in the roxadustat vs placebo arm had Hb concentration increases of >1.5 g/dL: 45.5% vs 17.4% (p=0.044)

[0232] Table 10: Additional Exposure and Efficacy Results

^bFull analysis set (all randomized patients who received >1 dose of study drug and had >1 corresponding on- treatment Hb assessment). EOT, end of treatment; Hb, hemoglobin; pRBC, packed red blood cells; Q8W, every 8 weeks; SD, standard deviation; TI, transfusion independence.

[0233] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

1. Use of roxadustat in the manufacture of a medicament for treating anemia in a subject having anemia associated with myelodysplastic syndrome (MDS), wherein the subject receives at least 2 pRBC transfusions during an 8-week period prior to said use of roxadustat.

2. Use of roxadustat in the manufacture of a medicament for reducing the number of blood transfusion received by a subject having anemia associated with MDS, wherein the subject receives at least 2 pRBC transfusions during an 8-week period prior to said use of roxadustat.

3. Use of roxadustat in the manufacture of a medicament for treating anemia in a subject having anemia associated with myelodysplastic syndrome, wherein the subject has a hemoglobin level of less than or equal to 8 g/dL prior to said use of roxadustat.

4. A method for treating anemia in a subject having anemia associated with MDS, wherein the subject receives at least 2 pRBC transfusions during an 8-week period prior to treatment, the method comprising administering to the subject a therapeutically effective amount of roxadustat, thereby treating the anemia.

5. A method of reducing the number of blood transfusions received by a subject having anemia associated with MDS, the method comprising administering to the subject a therapeutically effective amount of roxadustat, thereby reducing the number of blood transfusions received by the subject, receives at least 2 pRBC transfusions during an 8-week period prior to said administration.

6. The use of any of claims 1 to 3, wherein the subject receives at least two pRBC transfusions every four-weeks prior to said use of roxadustat.

7. The method of either of claims 4 or 5, wherein the subject receives at least two pRBC transfusions every four-weeks prior to said use of roxadustat.