COMPOUNDS AND COMPOSITION FOR THE TREATMENT OF ANEMIA

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application No. 63/135,202, filed January 8, 2021, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors may be administered to subjects to treat or prevent diseases ameliorated by modulation of HIF- PH (e.g., Peripheral Vascular Disease (PVD), Coronary Artery Disease (CAD), heart failure, ischemia, hypoxia, and anemia). Such patients may have other co-morbid conditions, which may be related to the condition requiring treatment with HIF-PH treatment or which may occur independently. Accordingly, there remains a need for the invention of new, effective therapeutic regimens comprising administration of different therapeutics in combination.

SUMMARY

[0003] Described herein are therapeutic methods comprising administering a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, in combination with a compound (e.g., a second compound) that is an iron- containing composition. In particular, methods described herein can result in improved (e.g., synergistic) therapeutic effects and can be useful for treating, preventing, regulating, and/or controlling a disease or condition (e.g., a disease or condition as described herein) in subjects in need thereof. For example, an iron-containing composition may be administered to subjects (e.g., to treat or prevent a disease or condition such as iron deficiency, hyperphosphatemia, anemia, chronic kidney disease, and hypocalcemia) who are also receiving therapy comprising a HIF-PH inhibitor.

[0004] That is, the present invention is in part based on the finding that a combination of a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor and another agent that is an iron-containing composition can result in unexpectedly improved (e.g., synergistic) therapeutic effects. Such methods can have beneficial outcomes for a subject, including those described herein. Exemplary methods, including exemplary HIF-PH inhibitors and iron-containing compositions are described herein.

[0005] In one aspect, the present invention provides herein a method of treating anemia comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition, wherein said treating is commenced with administration of both the first and second compounds; said patient has iron deficiency anemia and/or is in need of iron supplementation at commencement of treatment; said patient has limited iron absorption and/or uptake; and/or said method results in increased improvement in said patient's iron mobilization, systemic iron, serum iron, and/or transferrin saturation (TSAT) as compared to monotherapy.

[0006] In another aspect, the present invention provides herein a method of regulating anemia comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition, wherein said treating is commenced with administration of both the first and second compounds; said patient has iron deficiency anemia and/or is in need of iron supplementation at commencement of treatment; said patient has limited iron absorption and/or uptake; and/or said method results in increased improvement in said patient's iron mobilization, systemic iron, serum iron, and/or transferrin saturation (TSAT) as compared to monotherapy.

[0007] In another aspect, the present invention provides herein a method of preventing anemia comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition, wherein said treating is commenced with administration of both the first and second compounds; said patient has iron deficiency anemia and/or is in need of iron supplementation at commencement of treatment; said patient has limited iron absorption and/or uptake; and/or said method results in increased improvement in said patient's iron mobilization, systemic iron, serum iron, and/or transferrin saturation (TSAT) as compared to monotherapy.

[0008] In another aspect, the present invention provides herein a method of controlling anemia comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition, wherein said treating is commenced with administration of both the first and second compounds; said patient has iron deficiency anemia and/or is in need of iron supplementation at commencement of treatment; said patient has limited iron absorption and/or uptake; and/or said method results in increased improvement in said patient's iron mobilization, systemic iron, serum iron, and/or transferrin saturation (TSAT) as compared to monotherapy.

[0009] In embodiments, the anemia is anemia of chronic disease.

[0010] In embodiments, the anemia is anemia secondary to or associated with chronic kidney disease (renal anemia).

[0011] In embodiments, the anemia is anemia associated with or resulting from chemotherapy (chemo-induced anemia).

[0012] In embodiments, the anemia is anemia associated with AIDS.

[0013] In embodiments, the anemia is anemia secondary to congestive heart failure.

[0014] In embodiments, the anemia is idiopathic anemia of aging.

[0015] In embodiments, the anemia is sickle cell anemia.

[0016] In embodiments, the anemia is iron deficiency anemia

[0017] In embodiments, the anemia is anemia associated with or resulting from elevated hepcidin.

[0018] In embodiments, the anemia is associated with abnormal hemoglobin or erythrocytes.

[0019] In embodiments, the anemia is associated with a condition selected from the group consisting of diabetes, cancer, ulcers, kidney disease, immunosuppressive disease, infection, and inflammation.

[0020] In embodiments, the anemia is associated with a procedure or treatment selected from the group consisting of radiation therapy, chemotherapy, dialysis, and surgery.

[0021] In embodiments, the anemia is associated with blood loss.

[0022] In embodiments, the anemia is associated with defects in iron transport, processing, absorption, or utilization.

[0023] In another aspect, the present invention provides herein a method of improving serum ferritin comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition. [0024] In another aspect, the present invention provides herein a method of improving (e.g., increasing) serum iron comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0025] In another aspect, the present invention provides herein a method of improving transferrin saturation comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0026] In another aspect, the present invention provides herein a method of decreasing total iron-binding capacity (TIBC) comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0027] In another aspect, the present invention provides herein a method of increasing iron absorption comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0028] In another aspect, the present invention provides herein a method of decreasing hepcidin expression comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition. [0029] In another aspect, the present invention provides herein a method of treating iron deficiency comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0030] In another aspect, the present invention provides herein a method of treating functional iron deficiency comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0031] In another aspect, the present invention provides herein a method of regulating expression of genes involved in iron mobilization comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0032] In embodiments, said genes are selected from Egln, Egln1, Egln2, Egln3, erythropoietin, ceruloplasmin, transferrin, ferritin mitochondrial, EPO Receptor, ferroportin 1, transferrin receptor, hepcidin, and HMOX1.

[0033] In embodiments, said genes are selected from HIF1α, HIF2, HIF3α, PHD1, PHD2, PHD3, and ARNT.

[0034] In embodiments, said genes are selected from ΗΙF1β, HIF2α, ΗΙF2β, and ΗΙF3β.

[0035] In another aspect, the present invention provides herein a method of regulating HIF1α gene expression comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition. [0036] In another aspect, the present invention provides herein a method of regulating HIF2 gene expression comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0037] In another aspect, the present invention provides herein a method of regulating HIF3α gene expression comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0038] In another aspect, the present invention provides herein a method of regulating PHD1 gene expression comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0039] In another aspect, the present invention provides herein a method of regulating PHD2 gene expression comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0040] In another aspect, the present invention provides herein a method of regulating PHD3 gene expression comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition. [0041] In another aspect, the present invention provides herein a method of regulating ARNT gene expression comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0042] In another aspect, the present invention provides herein a method of improving hematologic functions comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0043] In another aspect, the present invention provides herein a method of increasing hemoglobin (Hb) levels comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0044] In another aspect, the present invention provides herein a method of improving red blood cell quality comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0045] In embodiments, the improved red blood cell quality is characterized by increased red blood cell size.

[0046] In embodiments, the improved red blood cell quality is characterized by increased reticulocyte count.

[0047] In embodiments, the improved red blood cell quality is characterized by increased cell hemoglobin concentration. [0048] In another aspect, the present invention provides herein a method of increasing erythropoietin (EPO) levels comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0049] In another aspect, the present invention provides herein a method of inducing enhanced or complete erythropoiesis comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0050] In another aspect, the present invention provides herein a method of reducing systemic inflammation comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0051] In embodiments, the systemic inflammation is characterized by ankle diameter.

[0052] In embodiments, the systemic inflammation is characterized by relative organ weights.

[0053] In embodiments, the systemic inflammation is characterized by CRP (C-reactive protein).

[0054] In embodiments, the systemic inflammation is characterized by haptoglobin.

[0055] In embodiments, the systemic inflammation is characterized by serum cytokines.

[0056] In embodiments, the serum cytokine is IL-6 (lnterleukin-6), IL-15 (Interleukin-15) or LIF (Leukemia inhibitory factor).

[0057] In another aspect, the present invention provides herein a method of treating or preventing a disorder associated with cytokine activity comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0058] In another aspect, the present invention provides herein a method of overcoming or ameliorating cytokine-induced impairment of erythropoiesis comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0059] In embodiments, the serum cytokine is IL-6 (lnterleukin-6), IL-15 (Interleukin-15) or LIF (Leukemia inhibitory factor).

[0060] In another aspect, the present invention provides herein a method of improving kidney function comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0061] In embodiments, the kidney function is characterized by estimated glomerular filtration rate (eGFR).

[0062] In embodiments, the kidney function is characterized by creatinine clearance

(CLcr).

[0063] In embodiments, the kidney function is characterized by urine protein excretion.

[0064] In embodiments, the kidney function is characterized by dialysis status, and wherein the improved kidney function is characterized by avoiding or delaying dialysis.

[0065] In another aspect, the present invention provides herein a method of increasing glomerular filtration rate (GFR) comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition. [0066] In another aspect, the present invention provides herein a method of treating a hypoxic or ischemic disorder or condition comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0067] In another aspect, the present invention provides herein a method of stabilizing the alpha subunit of hypoxia inducible factor (HIFa) comprising administering to a patient in need thereof an effective amount of a first compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor; and a second compound that is an iron-containing composition.

[0068] In embodiments, said first compound is selected from vadadustat, roxadustat, daprodustat, molidustat, enarodustat, and desidustat, or a pharmaceutically acceptable salt thereof.

[0069] In embodiments, said first compound is vadadustat, or a pharmaceutically acceptable salt thereof.

[0070] In embodiments, said first compound is roxadustat, or a pharmaceutically acceptable salt thereof.

[0071] In embodiments, said first compound is daprodustat, or a pharmaceutically acceptable salt thereof.

[0072] In embodiments, said first compound is molidustat, or a pharmaceutically acceptable salt thereof.

[0073] In embodiments, said first compound is enarodustat, or a pharmaceutically acceptable salt thereof.

[0074] In embodiments, said first compound is desidustat, or a pharmaceutically acceptable salt thereof.

[0075] In embodiments, the method comprises administering a dose of said first compound daily.

[0076] In embodiments, the method comprises administering a dose of said first compound about three times per week. [0077] In embodiments, the method comprises administering a dose of said first compound about once per week.

[0078] In embodiments, said dose of said first compound is about 1 mg to about 24 mg daily, three times per week, or once per week.

[0079] In embodiments, said dose of said first compound is about 1 mg.

[0080] In embodiments, said dose of said first compound is about 2 mg.

[0081] In embodiments, said dose of said first compound is about 3 mg.

[0082] In embodiments, said dose of said first compound is about 4 mg.

[0083] In embodiments, said dose of said first compound is about 5 mg.

[0084] In embodiments, said dose of said first compound is about 6 mg.

[0085] In embodiments, said dose of said first compound is about 7 mg.

[0086] In embodiments, said dose of said first compound is about 8 mg.

[0087] In embodiments, said dose of said first compound is about 9 mg.

[0088] In embodiments, said dose of said first compound is about 10 mg.

[0089] In embodiments, said dose of said first compound is about 20 mg.

[0090] In embodiments, said dose of said first compound is about 24 mg.

[0091] In embodiments, said dose of said first compound is about 50 mg to about 120 mg daily, three times per week, or once per week.

[0092] In embodiments, said dose of said first compound is about 50 mg.

[0093] In embodiments, said dose of said first compound is about 70 mg.

[0094] In embodiments, said dose of said first compound is about 100 mg.

[0095] In embodiments, said dose of said first compound is about 110 mg.

[0096] In embodiments, said dose of said first compound is about 120 mg.

[0097] In embodiments, said dose of said first compound is about 75 mg to about 1200 mg daily, three times per week, or once per week.

[0098] In embodiments, said dose of said first compound is about 75 mg.

[0099] In embodiments, said dose of said first compound is about 150 mg.

[0100] In embodiments, said dose of said first compound is about 300 mg.

[0101] In embodiments, said dose of said first compound is about 450 mg.

[0102] In embodiments, said dose of said first compound is about 600 mg.

[0103] In embodiments, said dose of said first compound is about 750 mg. [0104] In embodiments, said dose of said first compound is about 900 mg.

[0105] In embodiments, said dose of said first compound is about 1050 mg.

[0106] In embodiments, said dose of said first compound is about 1200 mg.

[0107] In embodiments, said second compound is oral iron or an iron-containing phosphorus adsorbent.

[0108] In embodiments, said second compound is an iron-containing phosphorus adsorbent.

[0109] In embodiments, said second compound is selected from ferrous sulfate, sodium ferrous citrate, ferric citrate, or sucroferric oxyhydroxide.

[0110] In embodiments, said second compound is ferrous sulfate.

[0111] In embodiments, said second compound is sodium ferrous citrate.

[0112] In embodiments, said second compound is ferric citrate.

[0113] In embodiments, said second compound is sucroferric oxyhydroxide.

[0114] In embodiments, the method comprises administering a dose of said second compound three times a day.

[0115] In embodiments, the method comprises administering a dose of said second compound daily.

[0116] In embodiments, said dose of said second compound is about 300 mg to about 15 g daily. In embodiments, said dose of said second compound is given in divided doses of 1 to 3 times daily.

[0117] In embodiments, said dose of said second compound is about 300 mg.

[0118] In embodiments, said dose of said second compound is about 500 mg.

[0119] In embodiments, said dose of said second compound is about 600 mg.

[0120] In embodiments, said dose of said second compound is about 1 g.

[0121] In embodiments, said dose of said second compound is about 2 g.

[0122] In embodiments, said dose of said second compound is about 2.5 g.

[0123] In embodiments, said dose of said second compound is about 3g.

[0124] In embodiments, said dose of said second compound is about 4g.

[0125] In embodiments, said dose of said second compound is about 5g.

[0126] In embodiments, said dose of said second compound is about 6g.

[0127] In embodiments, said dose of said second compound is about 7g. [0128] In embodiments, said dose of said second compound is about 7.5 g.

[0129] In embodiments, said dose of said second compound is about 8g.

[0130] In embodiments, said dose of said second compound is about 9g.

[0131] In embodiments, said dose of said second compound is about lOg.

[0132] In embodiments, said dose of said second compound is about llg.

[0133] In embodiments, said dose of said second compound is about 12g.

[0134] In embodiments, said dose of said second compound is about 12.5 g.

[0135] In embodiments, said dose of said second compound is about 15 g.

[0136] In embodiments, said first compound is vadadustat, or a pharmaceutically acceptable salt thereof, administered at a total daily dose of about 75-1200 mg; and said second compound is ferric citrate, administered at a total daily dose of about 1-12 grams.

[0137] In embodiments, said first compound is vadadustat, or a pharmaceutically acceptable salt thereof, administered at a total daily dose of about 150-600 mg; and said second compound is ferric citrate, administered at a total daily dose of about 1-12 grams.

[0138] In embodiments, said first compound and said second compound are given sequentially.

[0139] In embodiments, said first compound is given at least 4 hours before and/or after taking said second compound.

[0140] In embodiments, said first compound is given at least 2 hours before and/or after taking said second compound.

[0141] In embodiments, said first compound is given at least 1 hour before and/or after taking said second compound.

[0142] In embodiments, said first compound and said second compound are given simultaneously.

[0143] In embodiments, administration of said first compound and administration of said second compound occur within a time period that is no more than about 1, 5, 10, 20, or 30 minutes.

[0144] In embodiments, said patient has iron deficiency anemia. [0145] In embodiments, said patient has anemia secondary to or associated with chronic kidney disease (renal anemia).

[0146] In embodiments, said patient has non-dialysis dependent chronic kidney disease (NDD-CKD).

[0147] In embodiments, said patient has dialysis dependent chronic kidney disease (DD- CKD).

BRIEF DESCRIPTION OF THE DRAWINGS

[0148] FIG. 1a shows mean serum iron levels at day -1, 4, 7, 14, and 21 in subjects with different treatments. Increased serum iron levels were observed in vadadustat group, Auryxia group, and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy groups (vadadustat group or Auryxia group).

[0149] FIG. 1b shows mean TIBC (total iron-binding capacity) levels at day -1, 4, 7, 14, and 21 in subjects with different treatments. Decreased TIBC levels were observed in vadadustat group, Auryxia group, and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy groups (vadadustat group or Auryxia group).

[0150] FIG. 1c shows mean TSAT (transferrin saturation) levels at day -1, 4, 7, 14, and 21 in subjects with different treatments. Increased TSAT levels were observed in vadadustat group, Auryxia group, and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy groups (vadadustat group or Auryxia group).

[0151] FIG. 2a shows mean serum iron AUC (area under the curve) during the study in subjects with different treatments. Increased serum iron AUC was observed in vadadustat group, Auryxia group, and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy groups (vadadustat group or Auryxia group).

[0152] FIG. 2b shows mean TIBC (total iron-binding capacity) AUC (area under the curve) during the study in subjects with different treatments. Decreased TIBC AUC was observed in vadadustat group, Auryxia group, and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy groups (vadadustat group or Auryxia group).

[0153] FIG. 2c shows mean TSAT (transferrin saturation) AUC (area under the curve) during the study in subjects with different treatments. Increased TSAT AUC was observed in vadadustat group, Auryxia group, and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy groups (vadadustat group or Auryxia group).

[0154] FIG. 3a shows mean EPO (erythropoietin) levels at day 4, 7, 14, and 21 in subjects with different treatments. Increased EPO levels were observed in vadadustat group, and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy group (vadadustat group).

[0155] FIG. 3b shows mean EPO (erythropoietin) AUC (area under the curve) during the study in subjects with different treatments. Increased EPO AUC was observed in vadadustat group, and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy group (vadadustat group).

[0156] FIG.4 shows mean ankle diameter measurements at day 19, 20, and 21 in subjects with different treatments. Decreased ankle diameters were observed in vadadustat group, and Auryxia/vadadustat group compared to the vehicle group. For each timepoint, the test groups as shown from left to right are: normal control, vehicle, Auryxia, Vadadustat, and the Auryxia + Vadadustat combination.

[0157] FIG. 5 shows mean relative organ weight measurements at day 21 in subjects with different treatments. Decreased relative organ weights were observed in vadadustat group, and Auryxia/vadadustat group compared to the vehicle group. For each timepoint, the test groups as shown from left to right are: normal control, vehicle, Auryxia, Vadadustat, and the Auryxia + Vadadustat combination.

[0158] FIG. 6 shows mean CRP (C-reactive protein) levels at day 21 in subjects with different treatments. Decreased CRP levels were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group. [0159] FIG. 7 shows mean haptoglobin levels at day 21 in subjects with different treatments. Decreased haptoglobin levels were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group.

[0160] FIG. 8a shows mean IL-15 (Interleukin 15) AUC (area under the curve) during the study in subjects with different treatments. Decreased IL-15 AUC was observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group.

[0161] FIG. 8b shows mean IL-6 (Interleukin 6) AUC (area under the curve) during the study in subjects with different treatments. Decreased IL-6 AUC was observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group.

[0162] FIG. 8c shows mean LIF (leukemia inhibitory factor) AUC (area under the curve) during the study in subjects with different treatments.

[0163] FIG. 9a shows mean immune cell parameter such as WBC (white blood cells) levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments. Decreased WBC levels were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group.

[0164] FIG. 9b show mean immune cell parameter such as Neutrophil levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments. Decreased Neutrophil levels were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group.

[0165] FIG. 9c show mean immune cell parameter such as Lymphocyte levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments. Decreased Lymphocyte levels were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group.

[0166] FIG. 9d show mean immune cell parameter such as Monocyte levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments.

[0167] FIG. 10a shows mean hematologic parameter such as HGB (Hb, or hemoglobin) levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments. Increased Hb levels were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group.

[0168] FIG. 10b shows mean hematologic parameter such as HCT (hematocrit) levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments. Increased HCT levels were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group.

[0169] FIG. 10c shows mean hematologic parameter such as % reticulocytes levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments. Increased % reticulocytes were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group.

[0170] FIG. 10d shows mean hematologic parameter such as MCV (mean corpuscular volume) levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments. Increased MCV levels were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy groups (vadadustat group).

[0171] FIG. 10e shows mean hematologic parameter such as MCH (mean corpuscular hemoglobin) levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments. Increased MCH levels were observed in vadadustat group and Auryxia/vadadustat group compared to the vehicle group, an improved effect was observed in the Auryxia/vadadustat group compared to the monotherapy groups (vadadustat group).

[0172] FIG. 10f shows mean hematologic parameter such as MCHC (mean corpuscular hemoglobin concentration) levels measured at day -1, 4, 7, 14, and 21 in subjects with different treatments.

[0173] FIG. 11a shows mean serum iron levels at day -2, 4, 7, and 14 in subjects with different treatments. FIG. 1ib shows mean serum iron AUC (area under the curve) during the study in subjects with different treatments. Increased serum iron levels were observed in the Auryxia/vadadustat simultaneous administration group compared to the vehicle group, monotherapy groups (vadadustat group or Auryxia group) or Auryxia/vadadustat non-simultaneous administration group.

[0174] FIG. 12a shows mean TIBC (total iron-binding capacity) levels at day -2, 4, 7, and 14 in subjects with different treatments. FIG. 12b shows mean TIBC (total iron-binding capacity) AUC (area under the curve) during the study in subjects with different treatments. Decreased TIBC levels were observed in vadadustat group and Auryxia/vadadustat groups (simultaneous administration and non-simultaneous administration) compared to the vehicle group.

[0175] FIG. 13a shows mean Fe saturation % levels at day -2, 4, 7, and 14 in subjects with different treatments. FIG. 13b shows mean Fe saturation % AUC (area under the curve) during the study in subjects with different treatments. Increased Fe saturation % levels were observed in vadadustat group and Auryxia/vadadustat groups (simultaneous administration and non-simultaneous administration) compared to the vehicle group.

[0176] FIG. 14a shows mean HGB (Hb, or hemoglobin) levels measured at day -2, 4, 7, 14, and 21 in subjects with different treatments. FIG. 14b shows mean HGB (Hb, or hemoglobin) AUC (area under the curve) during the study in subjects with different treatments. Increased Hb levels were observed in vadadustat group and Auryxia/vadadustat groups (simultaneous administration and non-simultaneous administration) compared to the vehicle group.

[0177] FIG. 15a shows mean serum iron levels at day 0, 12, 20, 28, and 35 in subjects with different treatments. FIG. 15b shows mean serum iron AUC (area under the curve) during the study in subjects with different treatments. Decreased serum iron levels were observed in the vehicle disease control group compared to the normal control diet group. Further decreases were observed in the vadadustat group. Subjects in the Auryxia/vadadustat group had increased serum iron as compared to the vehicle disease control group, monotherapy groups (Auryxia, vadadustat, or rhEPO group), and rhEPO/Auryxia group.

[0178] FIG. 16a shows mean TIBC (total iron-binding capacity) levels at day 0, 12, 20, 28, and 35 in subjects with different treatments. FIG. 16b shows mean TIBC (total iron - binding capacity) AUC (area under the curve) during the study in subjects with different treatments. Decreased TIBC levels were observed in the vehicle disease control group compared to the normal control diet group. Increased TIBC levels were observed in vadadustat group and Auryxia/vadadustat groups (simultaneous administration and non-simultaneous administration) compared to the vehicle disease control group.

[0179] FIG. 17a shows mean Fe saturation % levels at day 0, 12, 20, 28, and 35 in subjects with different treatments. FIG. 17b shows mean Fe saturation % AUC (area under the curve) during the study in subjects with different treatments. Decreased Fe saturation % levels were observed in the vehicle disease control group compared to the normal control diet group. Further decreases were observed in the vadadustat group. Subjects in the Auryxia/vadadustat group had increased serum iron as compared to the vehicle disease control group and monotherapy group (vadadustat group).

[0180] FIG. 18a shows mean HGB (Hb, or hemoglobin) levels measured at day 0, 12, 15, 18, 20, 28 and 35 in subjects with different treatments. FIG. 18b shows mean HGB (Hb, or hemoglobin) AUC (area under the curve) during the study in subjects with different treatments. Decreased HGB (Hb, or hemoglobin) levels were observed in the vehicle disease control group compared to the normal control diet group. Increased Hb levels were observed in vadadustat group and Auryxia/vadadustat group (simultaneous administration and non-simultaneous administration) compared to the vehicle disease control group.

DETAILED DESCRIPTION

[0181] Described herein are exemplary therapeutic methods comprising administering to a patient in need thereof (1) a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and (2) another agent that is an iron-containing composition. Such combinations and methods can result in unexpectedly improved (e.g., synergistic) therapeutic effects to said patients. In particular, therapeutic outcomes may be improved as compared to monotherapy using the HIF-PH inhibitor and/or the iron- containing composition. For example, methods described herein may result in unexpected improvement in iron parameters as compared to monotherapy, including increased improvement in said patient's iron mobilization, systemic iron, serum iron, and/or transferrin saturation (TSAT) as compared to monotherapy.

[0182] In embodiments, an increased serum iron and/or TSAT (transferrin saturation) may be observed in patients commenced with administration of both (1) and (2). In embodiments, a decreased TIBC (total iron-binding capacity) may be observed in patients commenced with administration of both (1) and (2). Methods described herein may also result in unexpected improvement in EPO levels as compared to monotherapy. In embodiments, an increased EPO level may be observed in patients commenced with administration of both (1) and (2). Methods described herein may also result in unexpected improvement in hematologic parameters as compared to monotherapy, including increased improvement in said patient's MCV (mean corpuscular volume) levels, and/or MCH (mean corpuscular hemoglobin) levels as compared to monotherapy. In embodiments, an increased MCV level may be observed in patients commenced with administration of both (1) and (2). In embodiments, an increased MCH level may be observed in patients commenced with administration of both (1) and (2).

[0183] For example, a beneficial outcome may be observed when treating is commenced with administration of both (1) and (2). Methods described herein may be particularly beneficial to patients having iron deficiency anemia and/or who are in need of iron supplementation at commencement of treatment, and/or who have limited iron absorption and/or uptake. Methods described herein may also be particularly beneficial to patients having anemia secondary to or associated with chronic kidney disease (renal anemia), patients having non-dialysis dependent chronic kidney disease (NDD-CKD) and/or patients having dialysis dependent chronic kidney disease (DD-CKD).

[0184] Exemplary methods, HIF-PH inhibitors, and iron-containing compositions are described herein.

Definitions

[0185] In order for the present invention to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference for all purposes.

[0186] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans, at any stage of development. In some embodiments, "animal" refers to non-human animals, at any stage of development. In embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and/or worms. In some embodiments, an animal may be a transgenic animal, genetically-engineered animal, and/or a clone. [0187] Approximately or about: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In embodiments, the term "approximately" or "about" refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%,

10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0188] Dose(s): As used herein, the term "dose(s)" means a quantity of the compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof to be administered at one time. A dose may comprise a single unit dosage form, or alternatively may comprise more than a single unit dosage form (e.g., a single dose may comprise two tablets), or even less than a single unit dosage form (e.g., a single dose may comprise half of a tablet).

[0189] Daily dose: As used herein, the term "daily dose" means a quantity of the compound, or a pharmaceutically acceptable salt, solvate, or hydrate thereof that is administered in a 24-hour period. Accordingly, a daily dose may be administered all at once [i.e., once daily dosing) or alternatively the daily dosing may be divided such that administration of the compound is twice daily, three times daily, or even four times daily.

[0190] Improve, increase, or reduce: As used herein, the terms "improve," "increase" or "reduce," or grammatical equivalents, indicate values that are relative to a baseline measurement, such as a measurement in the same individual prior to initiation of the treatment described herein, or a measurement in a control sample or subject (or multiple control samples or subjects) in the absence of the treatment described herein.

A "control subject" is a subject afflicted with the same form of disease as the subject being treated, who is about the same age as the subject being treated.

[0191] In Vitro: As used herein, the term "in vitro" refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.

[0192] In Vivo: As used herein, the term "in vivo" refers to events that occur within a multi-cellular organism, such as a human and a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems).

[0193] Patient: As used herein, the term "patient" or "subject" refers to any organism to which a provided composition may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. A human includes pre- and post-natal forms.

[0194] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine, sheep, horse or primate). A human includes pre- and post-natal forms. In many embodiments, a subject is a human being. A subject can be a patient, which refers to a human presenting to a medical provider for diagnosis or treatment of a disease. The term "subject" is used herein interchangeably with "individual" or "patient." A subject can be afflicted with or is susceptible to a disease or disorder but may or may not display symptoms of the disease or disorder.

[0195] Pharmaceutically acceptable: The term "pharmaceutically acceptable", as used herein, refers to substances that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0196] Pharmaceutically acceptable salt: Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge etal., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 - alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate, and aryl sulfonate. Further pharmaceutically acceptable salts include salts formed from the quarternization of an amine using an appropriate electrophile, e.g., an alkyl halide, to form a quarternized alkylated amino salt.

[0197] Substantially. As used herein, the term "substantially" refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term "substantially" is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0198] Therapeutically effective amount. As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the symptom(s) of the disease, disorder, and/or condition. It will be appreciated by those of ordinary skill in the art that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one-unit dose. [0199] Preventing : The term "prevent," "preventing," or "prevention," as used herein refers to an effect that mitigates an undesired effect, e.g., an undesirable drug-drug interaction or the formation of a drug-iron chelate. Prevention does not require the 100% elimination of the possibility of an event. Rather, it denotes that the likelihood of the occurrence of the event has been reduced by the compound or method.

[0200] Treating: As used herein, the term "treat," "treatment," or "treating" refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, delay onset of, reduce severity of and/or reduce incidence of one or more symptoms or features of a particular disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and/or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.

[0201] As used herein, the term "HIF prolyl hydroxylase" is art-recognized and may be abbreviated as "PHD". HIF prolyl hydroxylase is also known as "prolyl hydroxylase domain-containing protein" which may be abbreviated as "PHD". In this regard, there are three different PHD isoforms, PHD1, PHD2, and PHD3, also referred to as EGLN2, EGLN1, and EGLN3, or HPH3, HPH2, and HPH1, respectively.

[0202] As used herein, the term "unit dosage form(s)" includes tablets; caplets; capsules, such as soft elastic gelatin capsules; sachets; cachets; troches; lozenges; dispersions; powders; solutions; gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions), emulsions (e.g., oil-in-water emulsions, or a water-in-oil liquid emulsion), solutions, and elixirs; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for oral or parenteral administration to a patient. The unit dosage form does not necessarily have to be administered as a single dose nor does a single unit dosage form necessarily constitute an entire dose.

[0203] Alkyl: As used herein, the term "alkyl" means acyclic linear and branched hydrocarbon groups, e.g. "C ₁ -C ₂₀ alkyl" refers to alkyl groups having 1-20 carbons. An alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl tert-pentyl, hexyl, isohexyl, and the like. Other alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. An alkyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, an alkyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, haloalkyl (e.g., - CH ₂ F and -CH ₂ CI, as well as perhaloalkyl groups such as CF ₃ and CCI ₃ ), -CO ₂ R', -CN, -OH, - OR', -NH ₂ , -NHR', -N(R') ₂ , -SR' or-SO ₂ R', wherein each instance of R' independently is C ₁ - C ₃ alkyl. In embodiments, the alkyl is unsubstituted. In embodiments, the alkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein).

[0204] Alkoxy: The term "alkoxy," as used herein, a monovalent substituent which consists of a linear or branched, substituted or unsubstituted, acyclic or cyclic alkyl group linked through an ether oxygen and having its free valence bond from the ether oxygen such as, for example methoxy, ethoxy, 1- and 2-propoxy, 1-butoxy, 1,2- dimethylethoxy, 1- and 2-pentoxy-, 3-hexoxy- and the like.

[0205] Alkylene: The term "alkylene," as used herein, represents a saturated divalent straight or branched chain hydrocarbon group, e.g., a " C ₁ -C ₁₀ alkylene" group having 1- 10 carbons. Alkylene groups are exemplified by methylene, ethylene, isopropylene and the like. An alkylene may be unsubstituted or substituted with substituent groups as described herein. In embodiments, an alkylene group is unsubstituted

[0206] Aryl: The terms "aryl" and "ar-", used alone or as part of a larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl", refer to an optionally substituted C _6-14 aromatic hydrocarbon moiety comprising one to three aromatic rings. For example, the aryl group is a C _6-10 aryl group ( i.e ., phenyl and naphthyl). Aryl groups include, without limitation, optionally substituted phenyl, naphthyl, or anthracenyl. The terms "aryl" and "ar-", as used herein, also include groups in which an aryl ring is fused to one or more cycloaliphatic rings to form an optionally substituted cyclic structure such as a tetrahydronaphthyl, indenyl, or indanyl ring. The term "aryl" may be used interchangeably with the terms "aryl group", "aryl ring", and "aromatic ring".

[0207] Benzyloxy: As used herein, the term "benzyloxy" refers to a monovalent substituent which consists of a substituted or unsubstituted benzyl group linked through an ether oxygen and having its free valence bond from the ether oxygen. [0208] Cycloalkyl: As used herein, the term "cycloalkyl" means a nonaromatic, saturated, cyclic group, e.g. " C ₃ -C ₁₀ cycloalkyl." In embodiments, a heterocyclyl is monocyclic. In embodiments, a heterocyclyl is polycyclic (e.g., bicyclic or tricyclic). In polycyclic cycloalkyl groups, individual rings can be fused, bridged, or spirocyclic. Examples of a cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo[3.2.1]octanyl, octahydro-pentalenyl, and spiro[4.5]decanyl, and the like. The term "cycloalkyl" may be used interchangeably with the term "carbocycle". A cycloalkyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, a cycloalkyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -CO ₂ R', -CN, -OH, -OR', -NH ₂ , -NHR', -N(R') ₂ , -SR' or-SO ₂ R', wherein each instance of R' independently is C ₁ - C ₃ alkyl. In embodiments, the cycloalkyl is unsubstituted. In embodiments, the cycloalkyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein).

[0209] Halo or Halogen : As used herein, the term "halo" or "halogen" means fluorine, chlorine, bromine, or iodine.

[0210] Heterocyclyl: As used herein, the term "heterocyclyl" means a nonaromatic, cyclic structure having at least one of any type of heteroatom as ring atoms, having any degree of unsaturation, and excludes aromatic heterocyclic rings that are defined as "heteroaryl" herein. For example, a "3- to 10-membered heterocyclyl" refers to heterocyclics having 3-10 ring atoms that are carbon or heteroatoms as described herein. The one or more heteroatoms may be selected from nitrogen, sulfur, and oxygen. The term "heterocycle", "heterocyclyl", "heterocyclic", "heterocycloalkyl," and "heterocyclic ring" can be used interchangeably. A heterocyclyl group can be attached as a substituent via a carbon atom or a heteroatom (e.g. a nitrogen atom). In embodiments, a heterocyclyl is monocyclic. In embodiments, a heterocyclyl is polycyclic (e.g., bicyclic or tricyclic). Examples include 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2- thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- piperidinyl, l,3-oxazolidin-3-yl, isothiazolidinyl, 1,3- thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, 1,2- tetrahydrothiazin-2-yl, l,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, 1,2- tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperizin-2-onyl, piperizin-3-onyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4- dioxanyl, and 4-thiazolidinyl, and the like. A heterocyclyl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, a heterocyclyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, - CO ₂ FV, -CN, -OH, -OR', -NH ₂ , -NHR', -N(R') ₂ , -SR' or-SO ₂ R', wherein each instance of R' independently is C ₁ -C ₃ alkyl. In embodiments, the heterocyclyl is unsubstituted. In embodiments, the heterocyclyl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein).

[0211] Heteroaryl: As used herein, the term "heteroaryl" means an aromatic moiety having at least one of any type of heteroatom as ring atoms. For example, a "5- to 14- membered heteroaryl" refers to heteroaryls having 5-14 ring atoms that are carbon or heteroatoms as described herein. The one or more heteroatoms may be selected from nitrogen, sulfur, and oxygen. A heteroaryl group can be attached as a substituent via a carbon atom or a heteroatom (e.g. a nitrogen atom). In embodiments, a heteroaryl is monocyclic. In embodiments, a heteroaryl is polycyclic ( e.g ., bicyclic or tricyclic). In embodiments, polycyclic heteroaryls comprise a cyclic group that is non-aromatic ( e.g ., a heteroaryl fused to a cycloalkyl or a heterocyclyl group as described herein). The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". Examples include 5-membered monocyclic rings such as pyrrolyl, imidazolyl, pyrazolyl, triazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, and the like; and 6-membered monocyclic rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. For further examples, see, e.g., Katritzky, Handbook of Heterocyclic Chemistry. Further specific examples of heteroaryl rings include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3- pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2- thienyl, 3-thienyl and carbazolyl. The term "heteroaryl" also refers to rings that are optionally substituted. A heteroaryl group may be optionally substituted with one or more functional groups discussed below. Still other examples include indolyl, azaindolyl, benzimidazolyl, indazolyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolyl, isoquinolyl, benzoxazolyl, benzathiazolyl, benzothiophenyl, benzofuranyl, and isobenzofuranyl, and the like. A heteroaryl group may be unsubstituted or substituted with one or more substituent groups as described herein. For example, a heteroaryl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -CO ₂ R', -CN, -OH, -OR', -NH ₂ , -NHR', -N(R') ₂ , -SR' or-SO ₂ R', wherein each instance of R' independently is C ₁ -C ₃ alkyl. In embodiments, the heteroaryl is unsubstituted. In embodiments, the heteroaryl is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituent groups as described herein).

[0212] Further abbreviations and acronyms are given in the table below.

Hypoxia-Inducible Factor-Prolyl Hydroxylase (HIF-PH) Inhibitors [0213] Described herein are therapeutic methods comprising administering to a subject in need thereof a compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF- PH) inhibitor or a pharmaceutically acceptable salt thereof. [0214] Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor consisting of an oxygen-sensitive HIF-α subunit and a constitutively expressed HIF-β subunit. In mammals, the alpha subunits are encoded by three genes: HIF1α, EPAS1 (also known as HIF2α), and HIF3α. The HIF1 beta subunits (HIF1B), also known as aryl hydrocarbon receptor nuclear translocators (ARNT), are encoded by two genes ARNT1 and ARNT2. Under normoxic conditions, the HIF-α subunit is produced and continuously degraded with a t½ of approximately 5 minutes. In response to hypoxic conditions, levels of HIFa are elevated in most cells because of a decrease in HIFa prolyl hydroxylation.

[0215] Prolyl hydroxylation of HIFa is accomplished by a family of proteins variously termed the prolyl hydroxylase domain-containing proteins (PHD1, 2, and 3), also known as HIF prolyl hydroxylases (HIF-PH-3, 2, and 1) or EGLN-2, 1, and 3, which use physiological levels of oxygen to hydroxylate specific proline residues of HIF-α, signaling proteasomal degradation of HIF-α (Ke et al. (2006) Mol. Pharmacol. 70 (5):1469-80). Under hypoxic conditions the activity of HIF-PHs is decreased, degradation of HIF-α is inhibited and cellular levels of HIF-α are increased. Stabilization of HIF-α allows it to translocate to the nucleus and dimerize with the HIF-β subunit where it binds to as- acting hypoxia-response elements and activates the transcription of target genes involved in erythropoiesis and iron homeostasis. The HIF-PHs thus function as critical sensors of cellular oxygen levels, and regulate oxygen homeostasis in response to hypoxia through inhibition of hydroxylation thus leading to stabilization of HIF-α, which in turn signals gene transcription and translation of proteins necessary for the cellular and organ responses to poor oxygenation (Myllylharju et al. (2013) Acta Physiol 208 (2):148-65).

[0216] HIF Prolyl 4-Hydroxylases (HIF-PH), are 2-oxoglutarate-dependent dioxygenases that require oxygen for hydroxylation of proline residues in the oxygen-dependent degradation domain of HIF α, and also require Fe ²⁺ and ascorbate as essential cofactors. Each of the 3 known HIF-PHs regulate HIF la and HIF 2α in a non-redundant manner that is dependent upon the degree of hypoxia and the relative abundance of the specific HIF-PH in different tissues. PHD2 is the abundant isoform present in most cells during normoxia (Appelhoff 2004). During hypoxia, messenger ribonucleic acid (mRNA) and protein for PHD2 and 3 were shown to increase with marked upregulation of PHD3 (Appelhoff 2004). Although all 3 HIF-PHs contribute to the regulation of HIF la and HIF 2α, PHD2 was shown to preferentially interact with HIF-1α, while PHD3 and PHD1 preferentially inhibit HIF 2α (Appelhoff et al. (2004) J. Biol. Chem. 279 (37):38458-65).

Exemplary HIF-PH inhibitor compounds

[0217] Provided herein are exemplary HIF-PH inhibitor compounds for use in methods for treating, preventing, regulating, and/or controlling a disease or condition, wherein the disease or condition is as described anywhere herein.

[0218] Non-limiting examples of HIF-PH inhibitors include but are not limited to vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof, and compounds described in U.S. Patent Nos. 8,759,345, 8,937,078, 8,796,263, 9,273,034, 8,530,404, 7,696,223, 7,629,357, 8,927,591, 8,269,008, 8,952,160, 8,952,160, 8,927,591, 8,921,389, 8,916,585, 8,703,795, 8,921,389, 7,662,854, and 9,040,522; in International Publication No. WO2020/072645; in U.S. Provisional Patent Application Nos. 63/125,661, 63/125,642, 62/992,585, 62/992,606, 62/992,616, 63/081,005, and 63/065,642; and in "Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and Their Therapeutic Implications" (Kim et al. Molecules 2015, 20, 20551-20568; see, e.g., any of the compounds described therein, including any of the compounds described in any of Tables 2, 3, or 4), each of which is hereby incorporated by reference in its entirety. In embodiments, a suitable compound is described in any of International Publication No. WO2020/072645; and in U.S. Provisional Patent Application Nos. 63/125,661, 63/125,642, 62/992,585, 62/992,606, 62/992,616, 63/081,005, and 63/065,642.

Formula (I): Vadadustat and Related Compounds [0219] Exemplary HIF-PH inhibitor compounds that can be used in any of the methods described herein include those described in U.S. Patent Nos. 7,811,595, 8,343,952, 8,323,671, 8,598,210, 8,722,895, 8,940,773, and 9,598,370; and in U.S. Publication No. US 20190192494A1, each of which is incorporated by reference in its entirety. In embodiments, a compound, or pharmaceutically acceptable salt thereof, is described in any of claims 1-32 of U.S. Patent No. 7,811,595. [0220] In embodiments, suitable compounds include a compound having a structure according to Formula (I), Formula (I), or a pharmaceutically acceptable salt thereof, wherein,

R and R ¹ are each independently:

(i) hydrogen

(ii) substituted or unsubstituted phenyl;

(iii) substituted or unsubstituted heteroaryl; or

(iv) substituted or unsubstituted alkyl; said substitution selected from:

(i) C ₁ -C ₄ alkyl;

(ii) C ₃ -C ₄ cycloalkyl;

(iii) C ₁ -C ₄ alkoxy;

(iv) C ₃ -C ₄ cycloalkoxy;

(v) C ₁ -C ₄ haloalkyl;

(vi) C ₃ -C ₄ halocycloalkyl;

(vii) halogen;

(viii) cyano;

(ix) NHC(O)R ⁴ ;

(x) C(O)NR ^5a R ^5b ;

(xi) phenyl; and

(xii) heteroaryl; or

(xiii) two substituents are taken together to form a fused ring having from 5 to 7 atoms;

R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl; R ^5a and R ^5b are each independently selected from:

(i) hydrogen;

(ii) C ₁ -C ₄ alkyl;

(iii) C ₃ -C ₄ cycloalkyl; or (iv) R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms; R ² is selected from:

(i) OR ⁶

(ii) NR ^7a R ^7b ; and

R ⁶ is selected from hydrogen and C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl;

R ^7a and R ^7b are each independently selected from:

(i) hydrogen;

(ii) C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl; or

(iii) R ^7a and R ^7b are taken together to form a ring having from 3 to 7 atoms; R ³ is selected from hydrogen, methyl, and ethyl;

L is a linking unit having a structure -[C(R ^8a R ^8b )] _n - R ^8a and R ^8b are each independently selected from hydrogen, methyl and ethyl; n is an integer from 1 to 3; and

R ⁹ is selected from hydrogen and methyl.

[0221] In embodiments, R is hydrogen.

[0222] In embodiments, R is unsubstituted phenyl. In embodiments, R is substituted phenyl. In embodiments, R is phenyl substituted with C ₁ -C ₄ alkyl. In embodiments, R is phenyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R is phenyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R is phenyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R is phenyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R is phenyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R is phenyl substituted with halogen. In embodiments, R is phenyl substituted with cyano. In embodiments, R is phenyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R is phenyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R is phenyl substituted with phenyl. In embodiments, R is phenyl substituted with heteroaryl. In embodiments, R is phenyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0223] In embodiments, R is unsubstituted heteroaryl. In embodiments, R is substituted heteroaryl. In embodiments, R is heteroaryl substituted with C ₁ -C ₄ alkyl. In embodiments, R is heteroaryl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R is heteroaryl substituted with C ₁ -C ₄ alkoxy. In embodiments, R is heteroaryl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R is heteroaryl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R is heteroaryl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments,

R is heteroaryl substituted with halogen. In embodiments, R is heteroaryl substituted with cyano. In embodiments, R is heteroaryl substituted with NHC(O)R ⁴ wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R is heteroaryl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R is heteroaryl substituted with phenyl. In embodiments, R is heteroaryl substituted with heteroaryl. In embodiments, R is heteroaryl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0224] In embodiments, R is unsubstituted alkyl. In embodiments, R is substituted alkyl.

In embodiments, R is alkyl substituted with C ₁ -C ₄ alkyl. In embodiments, R is alkyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R is alkyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R is alkyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R is alkyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R is alkyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R is alkyl substituted with halogen. In embodiments, R is alkyl substituted with cyano. In embodiments, R is alkyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R is alkyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R is alkyl substituted with phenyl. In embodiments, R is alkyl substituted with heteroaryl. In embodiments, R is alkyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0225] In embodiments, R is substituted or unsubstituted phenyl. In embodiments, R is chosen from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, and 4-chlorophenyl. In embodiments, R is chosen from 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-iso-propoxyphenyl, 3-iso-propoxyphenyl, 4-iso-propoxyphenyl, 2-cyanophenyl, 3- cyanophenyl, and 4-cyanophenyl.

[0226] In embodiments, R is a unit having the formula: where exemplary groups for R ¹⁰ are as described herein.

[0227] In embodiments, R ¹⁰ has the formula — C(O)NR ^5a R ^5b ; R ^5a and R ^5b are each hydrogen or R ^5a and R ^5b are taken together to from a ring having 5 or 6 atoms. In embodiments, R ^5a and R ^5b are taken together to form a pyrrolidin-1-yl ring.

[0228] In embodiments, R ¹⁰ has the formula — NHC(O)R ⁴ ; R ⁴ is a unit chosen from methyl, ethyl, n-propyl, iso-propyl, and cyclopropyl.

[0229] In embodiments, R ¹⁰ is a heteroaryl unit chosen from 1,2,3,4-tetrazol-5-yl,

[1,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, and thiophene-3- yl. [0230] In embodiments, R is substituted or unsubstituted heteroaryl. In embodiments, R is a unit chosen from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4- yl, pyrimidin-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.

[0231] In embodiments, R is a unit chosen from thiazol-2-yl, thiazol-4-yl, 1,2,3,4-tetrazol- 5-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, and thiophene-3-yl.

[0232] In embodiments, R ¹ is hydrogen.

[0233] In embodiments, R ¹ is unsubstituted phenyl. In embodiments, R ¹ is substituted phenyl. In embodiments, R ¹ is phenyl substituted with C ₁ -C ₄ alkyl. In embodiments, R ¹ is phenyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is phenyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R ¹ is phenyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R ¹ is phenyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R ¹ is phenyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R ¹ is phenyl substituted with halogen. In embodiments, R ¹ is phenyl substituted with cyano. In embodiments, R ¹ is phenyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is phenyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R ¹ is phenyl substituted with phenyl. In embodiments, R ¹ is phenyl substituted with heteroaryl. In embodiments, R ¹ is phenyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0234] In embodiments, R ¹ is unsubstituted heteroaryl. In embodiments, R ¹ is substituted heteroaryl. In embodiments, R ¹ is heteroaryl substituted with C ₁ -C ₄ alkyl. In embodiments, R ¹ is heteroaryl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is heteroaryl substituted with C ₁ -C ₄ alkoxy. In embodiments, R ¹ is heteroaryl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R ¹ is heteroaryl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R ¹ is heteroaryl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R ¹ is heteroaryl substituted with halogen. In embodiments, R ¹ is heteroaryl substituted with cyano. In embodiments, R ¹ is heteroaryl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is heteroaryl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R ¹ is heteroaryl substituted with phenyl. In embodiments, R ¹ is heteroaryl substituted with heteroaryl. In embodiments, R ¹ is heteroaryl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0235] In embodiments, R ¹ is unsubstituted alkyl. In embodiments, R ¹ is substituted alkyl. In embodiments, R ¹ is alkyl substituted with C ₁ -C ₄ alkyl. In embodiments, R ¹ is alkyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is alkyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R ¹ is alkyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R ¹ is alkyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R ¹ is alkyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R ¹ is alkyl substituted with halogen. In embodiments, R ¹ is alkyl substituted with cyano. In embodiments, R ¹ is alkyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is alkyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R ¹ is alkyl substituted with phenyl. In embodiments, R ¹ is alkyl substituted with heteroaryl. In embodiments, R ¹ is alkyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0236] In embodiments, R ¹ is chosen from 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-iso-propoxyphenyl, 3-iso-propoxyphenyl, 4-iso-propoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, and 4- cyanophenyl.

[0237] In embodiments, R ² is OR ⁶ , wherein R ⁶ is hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ² is NR ^7a R ^7b , wherein R ^7a and R ^7b are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^7a and R ^7b are taken together to form a ring having from 3 to 7 atoms.

[0238] In embodiments, R ⁶ is hydrogen. In embodiments, R ⁶ is methyl.

[0239] In embodiments, R ² is — NR ^7a R ^7b ; R ^7a and R ^7b are each independently hydrogen, methyl, or ethyl. In embodiments, R ² is chosen from -NH ₂ , -NHCH ₃ , and -N(CH ₃ ) ₂ .

[0240] In embodiments, R ³ is hydrogen. In embodiments, R ³ is methyl. In embodiments, R ³ is ethyl.

[0241] In embodiments, L is a linking unit having a structure -[C(R ^8a R ^8b )] _n -, wherein R ^8a and R ^8b are each independently selected from the group consisting of hydrogen, methyl and ethyl.

[0242] In embodiments, L is chosen from -CH ₂ -, -CH ₂ CH ₂ -, and -C(CH ₃ ) ₂ -. In embodiments, L is -CH ₂ -. In embodiments, L is -CH ₂ CH ₂ -. In embodiments, L is -C(CH ₃ ) ₂ -.

[0243] In embodiments, n is an integer from 1 to 3. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0244] In embodiments, R ⁹ is hydrogen. In embodiments, R ⁹ is methyl.

[0245] In embodiments, a compound according to Formula (I) has the following structure: Formula (la), or a pharmaceutically acceptable salt thereof, wherein R is as defined anywhere herein.

[0246] In embodiments, a compound according to Formula (I) has the following structure: Formula (lb), or a pharmaceutically acceptable salt thereof, wherein R is as defined anywhere herein.

[0247] In embodiments, a compound according to Formula (I) has the following structure: Formula (lc), or a pharmaceutically acceptable salt thereof, wherein R is as defined anywhere herein.

[0248] In embodiments, R is a heteroaryl unit chosen from thiazol-2-yl, thiazol-4-yl, 1,2,3,4-tetrazol-5-yl, [1,2,4]triazol-5-yl, imidazol-2-yl, furan-2-yl, furan-3-yl, thiophene-2- yl, thiophene-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, isoquinolin-1-yl, isoquinolin-3-yl, and isoquinolin-4-yl.

[0249] In embodiments, a compound according to Formula (I) has the following structure:

Formula (Id), or a pharmaceutically acceptable salt thereof, wherein R is selected from 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-cyanophenyl, 3- cyanophenyl, and 4-cyanophenyl; and

R ⁶ is selected from hydrogen, methyl, and ethyl.

[0250] In embodiments, a compound is selected from the group consisting of:

{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amin o}-acetic acid methyl ester;

{[5-(4-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amin o}-acetic acid methyl ester;

{[5-(2-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amin o}-acetic acid methyl ester;

{[5-(4-Fluoro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amin o}-acetic acid methyl ester;

[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino ]-acetic acid methyl ester;

{[3-Hydroxy-5-(4-isopropyl-phenyl)-pyridine-2-carbonyl]-a mino}-acetic acid methyl ester;

{[5-(4-Ethyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino }-acetic acid methyl ester;

{[3-Hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbo nyl]-amino}-acetic acid methyl ester;

{[5-(4-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino }-acetic acid methyl ester;

{[5-(3-Cyano-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino }-acetic acid methyl ester;

{[5-(3-Carbamoyl-phenyl)-3-hydroxy-pyridine-2-carbonyl]-a mino}-acetic acid methyl ester;

({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)-phenyl]-pyridin e-2-carbonyl}- amino)-acetic acid methyl ester;

({5-[3-(Cyclopropanecarbonyl-amino)-phenyl]-3-hydroxy-pyr idine-2- carbonyl}-amino)-acetic acid methyl ester; ({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)-phenyl]-pyridine-2-carbo nyl}-amino)- acetic acid methyl ester;

[(5-Hydroxy-[3,3']bipyridinyl-6-carbonyl)-amino]-acetic acid methyl ester [(5'-Hydroxy-[2,3']bipyridinyl-6'-carbonyl)-amino]-acetic acid methyl ester; [(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-ace tic acid methyl ester;

[(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino ]-acetic acid methyl ester;

[(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-ac etic acid methyl ester;

{[5-(3-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}- acetic acid; {[5-(4-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-ace tic acid; {[5-(2-Chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-ace tic acid; {[5-(4-Fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}-ace tic acid; [(3-Hydroxy-5-(4-methylphenyl)pyridine-2-carbonyl)amino]-ace tic acid; {[5-(4-Ethylphenyl)-3-hydroxypyridine-2-carbonyl]amino}-acet ic acid; {[3-Hydroxy-5-(4-isopropylphenyl)pyridine-2-carbonyl]amino}- acetic acid; {[3-Hydroxy-5-(3-trifluoromethylphenyl)pyridine-2-carbonyl]a mino}-acetic acid;

{[5-(4-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-a cetic acid; {[5-(3-Cyanophenyl)-3-hydroxypyridine-2-carbonyl]amino}-acet ic acid; {[5-(5-Chloro-2-methylphenyl)-3-hydroxypyridine-2-carbonyl]a mino}-acetic acid;

{[3-Hydroxy-5-(4-isopropoxyphenyl)pyridine-2-carbonyl]ami no}-acetic acid; ({5-[3-(Cyclopropanecarbonylamino)phenyl]-3-hydroxy-pyridine -2-carbonyl}- amino)-acetic acid;

({3-Hydroxy-5-[3-(pyrrolidine-1-carbonyl)phenyl]-pyridine -2-carbonyl}amino)- acetic acid;

({3-Hydroxy-5-[3-(2H-tetrazol-5-yl)phenyl]-pyridine-2-car bonyl}-amino)-acetic acid;

[(5'-Hydroxy-[2,3']bipyridinyl-6'-carbonyl)-amino]-acetic acid; [(5-Hydroxy-[3,3']bipyridinyl-6-carbonyl)-amino]-acetic acid; [(3-Hydroxy-5-pyrimidin-5-yl-pyridine-2-carbonyl)-amino]-ace tic acid; [(3-Hydroxy-5-isoquinolin-4-yl-pyridine-2-carbonyl)-amino]-a cetic acid; [(3-Hydroxy-5-thiazol-2-yl-pyridine-2-carbonyl)-amino]-aceti c acid; {[5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-3-hydroxy-pyridine-2 -carbonyl]- amino}-acetic acid;

5-(Chlorophenyl)-N-(2-amino-2-oxo-l,l-dimethylethyl)-3-hy droxylpyridin-2-yl amide;

5-(Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin -2-yl amide; 5-(Chlorophenyl)-N-(2-amino-2-oxo-1-methylethyl)-3-hydroxylp yridin-2-yl amide;

5-(4-Methylphenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxy lpyridin-2-yl amide;

5-(3-Chlorophenyl)-N-(2-methylamino-2-oxoethyl)-3-hydroxy lpyridin-2-yl amide;

2-{[5-(3-Chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-am ino}-2-methyl- propionic acid methyl ester;

2-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-ami no}-2-methyl- propionic acid

3-[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-ami no]-propionic acid ethyl ester;

3-[(3-Hydroxy-5-(3-chlorophenyl)-pyridine-2-carbonyl)-ami no]-propionic acid ethyl ester;

3-{[5-(3-Chlorophenyl)-3-hydroxy-pyridine-2-carbonyl]-ami no}-propionic acid; 3-[(3-Hydroxy-5-(4-methylphenyl)-pyridine-2-carbonyl)-amino] -propionic acid;

5-(Chlorophenyl)-N-(3-amino-3-oxo-1,1-dimethylpropyl)-3-h ydroxylpyridin-2- yl amide; and

5-(3-Chlorophenyl)-N-(2-dimethylamino-2-oxoethyl)-3-hydro xylpyridin-2-yl amide; or a pharmaceutically acceptable salt thereof. [0251] In embodiments, compounds are salts comprising anions chosen from chloride, bromide, iodide, sulfate, bisulfate, carbonate, bicarbonate, phosphate, formate, acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate, fumarate, and citrate.

[0252] In embodiments, compounds are salts comprising cations chosen from sodium, lithium, potassium, calcium, magnesium, and bismuth.

[0253] In embodiments, a compound (e.g., a first compound) that is a HIF-PH inhibitor is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acet ic acid (Compound 1), or a pharmaceutically acceptable salt thereof. Compound 1, also referred to as vadadustat or AKB-6548, has the following structure:

Compound 1 (vadadustat, or AKB-6548)

Formula (II): Roxadustat and Related Compounds [0254] Still other HIF-PH inhibitor compounds that can be useful in the methods described herein include those described in U.S. Patent No. 7,323,475, which is incorporated by reference in its entirety. In embodiments, a compound, or a pharmaceutically acceptable salt thereof, is described in any of claims 1-46 of U.S. Patent No. 7,323,475.

[0255] In embodiments, suitable compounds include a compound having a structure according to Formula (II), Formula (II), or a pharmaceutically acceptable salt thereof, wherein q is zero or one; R ^a1 is selected from the group consisting of hydrogen, alkyl, Substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, halo, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted hetero cyclic, and R ^a7 is hydrogen, alkyl or aryl or, when X is — NR ^a7 — , then R ^a7 and R ^a6 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group;

R ^a2 and R ^a3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano. -S(O) _n -N(R ^a6 )-R ^a6 where n is 0, 1, or 2, — NR ^a6 C(O)NR ^a6 R ^a6 , -XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, each R ^a6 is independently selected from the group consisting of hydrogen, alkyl, Substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic provided that when when X is —SO— or — SO ₂ — , then R ^a6 is not hydrogen, and R ^a7 is selected from the group consisting of hydrogen, alkyl, aryl, or R ^a2 , R ^a3 together with the carbon atom pendent thereto, form an aryl substituted aryl, heteroaryl, or substituted heteroaryl;

R ^a4 and R ^a5 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, Substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl or, when X is — NR ^a7 — , then R ^a7 and R ^a6 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or Substituted heterocyclic group;

R ^a" is selected from the group consisting of hydrogen, alkyl and substituted alkyl;

R ^a"' is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, — S(O) — R ^a10 wherein R ^a10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl and n is zero, one or two; or a pharmaceutically acceptable salt, ester, or prodrug thereof; with the proviso that when R ^a" is hydrogen and q is zero, then at least one of the following occurs:

1) R ^a1 is fluoro, bromo, iodo, alkyl, substituted alkyl, alkoxy, aminoacyl, Substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl; or

2) R ^a2 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, fluoro, bromo, iodo, cyano, — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl provided that: a) when R ^a2 is substituted alkyl such a substituent does not include trifluoromethyl; b) — XR ^a6 is not alkoxy; and c) when — XR ^a6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C ₁ -C ₅ ) alkyl and (C ₁ -C ₅ ) alkoxy or does not include a fluoroalkoxy substituent of the formula:

— O— [CH ₂ ] _x — C _f H _(2f+1-g) F _g where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); or

3) R ^a3 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, bromo, iodo, — XR ^a6 where X is oxygen— S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl provided that: a) when R ^a3 is substituted alkyl such a substituent does not include trifluoromethyl; b) — XR ^a6 is not alkoxy; and c) when XR ^a6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C ₁ -C ₅ ) alkyl and (C-C) alkoxy or does not include a fluoroalkoxy substituent of the formula:

— O— [CH ₂ ] _x — C _f H _(2f+1-g) F _g where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); or

4) R ^a4 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, — XR ^a6 where X is oxygen— S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl provided that: a) when R ^a4 is substituted alkyl such a substituent does not include trifluoromethyl; b) — XR ^a6 is not alkoxy; and c) when XR ^a6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C ₁ -C ₅ ) alkyl and (C-C) alkoxy or does not include a fluoroalkoxy substituent of the formula: — O— [CH ₂ ] _x — C _f H _(2f+1-g) F _g where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); or

5) R ^a5 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, — XR ^a6 where X is oxygen, — S(O) _n — , or —NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl provided that: a) when R ^a5 is substituted alkyl such a substituent does not include trifluoromethyl; b) — XR ^a6 is not alkoxy; and c) when XR ^a6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C ₁ -C ₅ ) alkyl and (C-C) alkoxy or does not include a fluoroalkoxy substituent of the formula:

— O— [CH ₂ ] _x — C _f H _(2f+1-g) F _g where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); and with the further following proviso: that when R ^a1 , R ^a3 , R ^a4 , and R ^a5 are hydrogen, then R ^a2 is not bromo.

[0256] In embodiments, a compound according to Formula (II) has the following structure: Formula (lla), or a pharmaceutically acceptable salt thereof, wherein q is zero or one;

R ^a" is selected from hydrogen and alkyl: R ^a1 is selected from the group consisting of hydrogen, alkyl, Substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, halo, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, Substituted alkyl, aryl, sub stituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl;

R ^a2 and R ^a3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl;

R ^a4 and R ^a5 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, Substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl; or a pharmaceutically acceptable salt or prodrug thereof.

[0257] In embodiments, a compound according to Formula (II) has the following structure: Formula (IIb), or a pharmaceutically acceptable salt thereof, wherein R ^a1 is selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl or, when X is — NR ^a7 — , then R ^a7 and R ^a6 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group; and R ^a2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, — S(O) _n — N(R ^a6 )— R ^a6 where n is 0, 1 or 2, — NR ^a6 C(O)NR ^a6 R ^a6 , XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, each R ^a6 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that when X is —SO— or —SO ² — , then R ^a6 is not hydrogen, and R ^a7 is selected from the group consisting of hydrogen, alkyl, aryl, or R ^a2 , R ^a3 together with the carbon atom pendent thereto, form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or a pharmaceutically acceptable salt, ester, or prodrug thereof; with the proviso that at least one of the following occurs:

1) R ^a1 is fluoro, bromo, iodo, alkyl, substituted alkyl, alkoxy, aminoacyl, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl; or

2) R ^a2 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, fluoro, bromo, iodo, cyano, — XR ^a6 where X is oxygen, — S(O) _n — , or — NR ^a7 — where n is zero, one or two, R ^a6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R ^a7 is hydrogen, alkyl or aryl provided that: a) when R ^a2 is substituted alkyl such a substituent does not include trifluoromethyl; b) — XR ^a6 is not alkoxy; and c) when — XR ^a6 is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C ₁ -C ₅ ) alkyl and (C ₁ -C ₅ ) alkoxy or does not include a fluoroalkoxy substituent of the formula:

— O— [CH ₂ ] _x — C _f H _(2f+1-g) F _g where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1).

[0258] In embodiments, a compound (e.g., a first compound) that is a HIF-PH inhibitor is (1-methyl -4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino-acetic acid (Compound 2), or a pharmaceutically acceptable salt thereof. Compound 2, also referred to as roxadustat, or FG-4592, has the following structure:

Compound 2 (roxadustat, or FG-4592)

Formula (III): Daprodustat and Related Compounds [0259] Still other HIF-PH inhibitor compounds that can be useful in the methods described herein include those described in U.S. Patent No. 8,324,208, which is incorporated by reference in its entirety. In embodiments, a compound, or a pharmaceutically acceptable salt thereof, is described in any of claims 1-16 of U.S. Patent No. 8,324,208. [0260] In embodiments, suitable compounds include a compound having a structure according to Formula (III), Formula (III), or a pharmaceutically acceptable salt thereof, wherein

R ^b1 and R ^b4 are each independently selected from the group consisting of hydrogen, — NR ^b5 R ^b6 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₁₀ alkyl, C ₅ -C ₈ cycloalkenyl, C ₅ -C ₈ cycloalkenyl- C ₁ -C ₁₀ alkyl, C ₃ -C ₈ heterocycloalkyl, C ₃ -C ₈ heterocycloalkyl-C ₁ -C ₁₀ alkyl, aryl, aryl- C ₁ -C ₁₀ alkyl, heteroaryl and heteroaryl- C ₁ -C ₁₀ alkyl;

R ^b2 is — NR ^b7 R ^b8 or -OR ^{b 9} ;

R ^b3 is H or C ₁ -C ₄ alkyl; where R ^b5 and R ^b6 are each independently selected from the group consisting of hydrogen, C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₁₀ alkyl, C ₃ -C ₈ heterocycloalkyl, C ₃ -C ₈ heterocycloalkyl-C ₁ -C ₁₀ alkyl, aryl, aryl- C ₁ -C ₁₀ alkyl, heteroaryl and heteroaryl- C ₁ -C ₁₀ alkyl, — C(O)C ₁ -C ₄ alkyl, — C(O)C ₃ -C ₆ cycloalkyl, — C(O)C ₃ -C ₆ heterocycloalkyl, — C(O)aryl, — C(O)heteroaryl and —S(O) ₂ C ₁ -C ₄ alkyl, or, when R ^b5 and R ^b6 are attached to the same nitrogen, R ^b5 and R ^b6 taken together with the nitrogen to which they are attached forma 5- or 6- or 7-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen and sulphur,

R ^b7 and R ^b8 are each independently selected from the group consisting of hydrogen, C ₁ - C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ heterocycloalkyl, aryl, and heteroaryl, and

R ^b9 is H or a cation, or C ₁ -C ₁₀ alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C ₃ -C ₆ cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

X ^b is O or S; and

Y is O or S; where any carbon or heteroatom of R ^b1 , R ^b2 , R ^b3 , R ^b4 , R ^b5 , R ^b6 , R ^b7 , R ^b8 , R ^b9 is unsubstituted or is substituted with one or more substituents independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, halogen, — OR ^b10 , — NR ^b5 R ^b6 , oxo, cyano, nitro, — C(O)R ^b10 , — C(O)OR ^b10 , — SR ^b10 , — S(O)R ^b10 , — S(O) ₂ R ^b10 , — CONR ^b5 R ^b6 , -N(R ^b5 )C(O)R ^b10 , - N(R ^b5 )C(O)OR ^b10 ,

— OC(O)NR ^b5 R ^b6 ', — N(R ^b5 )C(O)NR ^b5 R ^b6 , -SO ₂ NR ^b5 R ^b6 , -N(R ^b5 )SO ₂ R ^b10 , C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl, aryl, C ₁ -C ₆ alkyl-aryl, heteroaryl and C ₁ -C ₆ alkyl-heteroaryl, wherein R ^b5 and R ^b6 are the same as defined above and R ^b10 is selected from hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl. — C(O)C ₁ -C ₄ alkyl, — C(O)aryl,

— C(O)heteroaryl, — C(O)C ₃ -C ₆ cycloalkyl, — C(O)C ₃ -C ₆ heterocycloalkyl, — S(O) ₂ C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ heterocycloalkyl, C ₆ -C ₁ 4 aryl, aryl-C ₁ -C ₁₀ alkyl, heteroaryl and heteroaryl -C ₁ -C ₁₀ alkyl;

[0261] In embodiments, X ^b is O. In embodiments, Y is O.

[0262] In embodiments, R ^b1 and R ^b4 are each independently selected from the group consisting of hydrogen, — NR ^b5 R ^b6 , C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl -C ₁ -C ₁₀ alkyl, C ₅ -C ₈ cycloalkenyl, C ₅ -C ₈ cycloalkenyl- C ₁ -C ₁₀ alkyl, C ₃ -C ₈ heterocycloalkyl, C ₃ -C ₈ heterocycloalkyl-C ₁ -C ₁₀ alkyl, aryl, aryl- C ₁ -C ₁₀ alkyl, heteroaryl and heteroaryl- C ₁ -C ₁₀ alkyl. In embodiments, R ^b1 is C ₃ -C ₈ cycloalkyl. In embodiments, R ^b4 is C ₃ -C ₈ cycloalkyl.

[0263] In embodiments, R ^b2 is —OR ^b9 , wherein R ^b9 is H or a cation. In embodiments, R ^b2 is

OH.

[0264] In embodiments, R ^b3 is H.

[0265] In embodiments, a compound (e.g., a first compound) that is a HIF-PH inhibitor is N-(l,3-Dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5 - pyrimidinyl)carbonylglycine (Compound 3), or a pharmaceutically acceptable salt thereof. Compound 3, also referred to as daprodustat, or GSK-12788363, has the following structure:

Compound 3 ( daprodustat, or GSK-12788363)

Formula (IV): Molldustat and Related Compounds [0266] Still other HIF-PH inhibitor compounds that can be useful in the methods described herein include those described in U.S. Patent No. 8,389,520, which is incorporated by reference in its entirety. In embodiments, a compound, or a pharmaceutically acceptable salt thereof, is described in any of claims 1-10 of U.S. Patent No. 8,389,520.

[0267] In embodiments, suitable compounds include a compound having a structure according to Formula (IV), Formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^c1 represents a heteroaryl group of the formula , wherein

* denotes the linkage point with the dihydropyrazolone ring and R ^c4 denotes hydrogen, fluorine, chlorine, bromine, cyano, C ₁ -C ₄ alkyl, trifluoromethyl, hydroxymethyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, hydroxycarbonyl or C ₁ -C ₄ alkoxycarbonyl; R ^c2 represents a heteroaryl group of the formula

, wherein

# denotes the linkage point with the dihydropyrazolone ring and R ^c6 , R ^c6a and R ^c6b are identical or different and independently of one another denote hydrogen or a substituent chosen from the group consisting of fluorine, chlorine, bromine, cyano, C ₁ -C ₆ alkyl, trifluoromethyl, hydroxyl, C ₁ -C ₆ alkoxy, trifluoromethoxy, amino, mono- C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ alkylamino, hydroxycarbonyl, C ₁ -C ₄ alkoxycarbonyl, 4-to 6- membered heterocycloalkyl, phenyl and 5-or 6-membered heteroaryl, wherein C ₁ -C ₆ alkyl in its turn can be substituted by hydroxyl, C ₁ -C ₄ alkoxy or amino and 4-to 6-membered heterocycloalkyl, phenyl and 5-or 6-membered heteroaryl in their turn can in each case be substituted once or twice in an identical or different manner by fluorine, chlorine, bromine, cyano, C ₁ -C ₄ alkyl, trifluoromethyl, hydroxyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, oxo, amino, mono- C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ alkylamino, hydroxycarbonyl or C ₁ -C ₄ alkoxycarbonyl, and

R ^c3 represents hydrogen, or a salt thereof.

[0268] In embodiments, R ^c1 is a heteroaryl group of the formula or , wherein * denotes the linkage point with the dihydropyrazolone ring, and wherein R ^c4 is hydrogen, fluorine, chlorine, bromine, cyano, C ₁ -C ₄ alkyl, trifluoromethyl, hydroxymethyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, hydroxycarbonyl or C ₁ -C ₄ alkoxycarbonyl.

[0269] In embodiments, R ^c2 is a heteroaryl group of the formula or , wherein # denotes the linkage point with the dihydropyrazolone ring and wherein R ^c6 , R ^c6a and R ^c6b are identical or different and independently of one another denote hydrogen or a substituent chosen from the group consisting of fluorine, chlorine, bromine, cyano, C ₁ -C ₆ alkyl, trifluoromethyl, hydroxyl, C ₁ -C ₆ alkoxy, trifluoromethoxy, amino, mono-C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ alkylamino, hydroxycarbonyl, C ₁ -C ₄ alkoxycarbonyl, 4-to 6-membered heterocycloalkyl, phenyl and 5-or 6-membered heteroaryl. In embodiments, a C ₁ -C ₆ alkyl is unsubstituted C ₁ -C ₆ alkyl. In embodiments, a C ₁ -C ₆ alkyl is substituted C ₁ -C ₆ alkyl. In embodiments, a C ₁ -C ₆ alkyl is substituted with hydroxyl, C ₁ -C ₄ alkoxy or amino. In embodiments, a 4-to 6-membered heterocycloalkyl is unsubstituted. In embodiments, a 4-to 6-membered heterocycloalkyl is substituted. In embodiments, a 4-to 6-membered heterocycloalkyl is substituted with once or twice in an identical or different manner by fluorine, chlorine, bromine, cyano, C ₁ -C ₄ alkyl, trifluoromethyl, hydroxyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, oxo, amino, mono-C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ alkylamino, hydroxycarbonyl or C ₁ -C ₄ alkoxycarbonyl. In embodiments, a phenyl is unsubstituted. In embodiments, a phenyl is substituted. In embodiments, a phenyl is substituted with once or twice in an identical or different manner by fluorine, chlorine, bromine, cyano, C ₁ -C ₄ alkyl, trifluoromethyl, hydroxyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, oxo, amino, mono-C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ alkylamino, hydroxycarbonyl or C ₁ -C ₄ alkoxycarbonyl. In embodiments, a 5-or 6-membered heteroaryl is unsubstituted. In embodiments, a 5-or 6-membered heteroaryl is substituted. In embodiments, a 5-or 6-membered heteroaryl is substituted with once or twice in an identical or different manner by fluorine, chlorine, bromine, cyano, C ₁ -C ₄ alkyl, trifluoromethyl, hydroxyl, C ₁ -C ₄ alkoxy, trifluoromethoxy, oxo, amino, mono-C ₁ -C ₄ alkylamino, di-C ₁ -C ₄ alkylamino, hydroxycarbonyl or C ₁ -C ₄ alkoxycarbonyl.

[0270] In embodiments, R ^c3 is hydrogen.

[0271] In embodiments, a compound (e.g., a first compound) that is a HIF-PH inhibitor is 2-(6-Morpholin-4-ylpyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl) -1,2-dihydro-3H-pyrazol-3- one (Compound 4), or a pharmaceutically acceptable salt thereof. Compound 4, also referred to as molidustat, or BAY 85-3934, has the following structure:

Compound 4 (molidustat, or BAY 85-3934)

Formula (V): Enarodustat and Related Compounds [0272] Exemplary HIF-PH compounds that can be used in any of the methods described herein include those described in U.S. Patent No. 8,283,465, U.S. Publication No. US20160145254A1, and U.S. Publication No. US20200017492A1, each of which is incorporated by reference in its entirety. In embodiments, a compound, or pharmaceutically acceptable salt thereof, is described in any of claims 1-30 of U.S. Patent No. 8,283,465.

[0273] In embodiments, suitable compounds include a compound having a structure according to Formula (V), Formula (V), or a pharmaceutically acceptable salt thereof, wherein R and R ¹ are each independently:

(i) hydrogen

(ii) substituted or unsubstituted phenyl;

(iii) substituted or unsubstituted heteroaryl; or

(iv) substituted or unsubstituted alkyl; said substitution selected from:

(i) C ₁ -C ₄ alkyl;

(ii) C ₃ -C ₄ cycloalkyl;

(iii) C ₁ -C ₄ alkoxy;

(iv) C ₃ -C ₄ cycloalkoxy; (v) C ₁ -C ₄ haloalkyl;

(vi) C ₃ -C ₄ halocycloalkyl;

(vii) halogen;

(viii) cyano;

(ix) NHC(O)R ⁴ ;

(x) C(O)NR ^5a R ^5b ;

(xi) phenyl; and

(xii) heteroaryl; or

(xiii) two substituents are taken together to form a fused ring having from 5 to 7 atoms;

R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl;

R ^5a and R ^5b are each independently selected from:

(i) hydrogen;

(ii) C ₁ -C ₄ alkyl;

(ill) C ₃ -C ₄ cycloalkyl; or

(iv) R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms;

R ² is selected from:

(i) OR ⁶

(ii) NR ^7a R ^7b ; and

R ⁶ is selected from hydrogen and C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl;

R ^7a and R ^7b are each independently selected from:

(i) hydrogen;

(ii) C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl; or

(ill) R ^7a and R ^7b are taken together to form a ring having from 3 to 7 atoms;

R ³ is selected from hydrogen, methyl, and ethyl;

L is a linking unit having a structure -[C(R ^8a R ^8b )] _n -

R ^8a and R ^8b are each independently selected from hydrogen, methyl and ethyl; n is an integer from 1 to 3; and

R ⁹ is selected from hydrogen and methyl.

[0274] In embodiments, R is hydrogen. [0275] In embodiments, R is unsubstituted phenyl. In embodiments, R is substituted phenyl. In embodiments, R is phenyl substituted with C ₁ -C ₄ alkyl. In embodiments, R is phenyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R is phenyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R is phenyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R is phenyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R is phenyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R is phenyl substituted with halogen. In embodiments, R is phenyl substituted with cyano. In embodiments, R is phenyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R is phenyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R is phenyl substituted with phenyl. In embodiments, R is phenyl substituted with heteroaryl. In embodiments, R is phenyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0276] In embodiments, R is unsubstituted heteroaryl. In embodiments, R is substituted heteroaryl. In embodiments, R is heteroaryl substituted with C ₁ -C ₄ alkyl. In embodiments, R is heteroaryl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R is heteroaryl substituted with C ₁ -C ₄ alkoxy. In embodiments, R is heteroaryl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R is heteroaryl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R is heteroaryl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R is heteroaryl substituted with halogen. In embodiments, R is heteroaryl substituted with cyano. In embodiments, R is heteroaryl substituted with NHC(O)R ⁴ wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R is heteroaryl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R is heteroaryl substituted with phenyl. In embodiments, R is heteroaryl substituted with heteroaryl. In embodiments, R is heteroaryl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0277] In embodiments, R is unsubstituted alkyl. In embodiments, R is substituted alkyl.

In embodiments, R is alkyl substituted with C ₁ -C ₄ alkyl. In embodiments, R is alkyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R is alkyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R is alkyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R is alkyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R is alkyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R is alkyl substituted with halogen. In embodiments, R is alkyl substituted with cyano. In embodiments, R is alkyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R is alkyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R is alkyl substituted with phenyl. In embodiments, R is alkyl substituted with heteroaryl. In embodiments, R is alkyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0278] In embodiments, R is substituted or unsubstituted alkyl. In embodiments, R is a C ₁ -C ₆ alkyl. In embodiments, R is a C ₃ -C ₈ cycloalkyl. In embodiments, R is a C ₆ -C ₁₄ aryl. In embodiments, R is a C ₆ -C ₁₄ aryl. In embodiments, R is a C ₆ -C ₁₄ aryl-C ₁ -C ₆ alkyl group.

[0279] In embodiments, R ¹ is hydrogen. [0280] In embodiments, R ¹ is unsubstituted phenyl. In embodiments, R ¹ is substituted phenyl. In embodiments, R ¹ is phenyl substituted with C ₁ -C ₄ alkyl. In embodiments, R ¹ is phenyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is phenyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R ¹ is phenyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R ¹ is phenyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R ¹ is phenyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R ¹ is phenyl substituted with halogen. In embodiments, R ¹ is phenyl substituted with cyano. In embodiments, R ¹ is phenyl substituted with NHC(O)R ⁴ wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is phenyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R ¹ is phenyl substituted with phenyl. In embodiments, R ¹ is phenyl substituted with heteroaryl. In embodiments, R ¹ is phenyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0281] In embodiments, R ¹ is unsubstituted heteroaryl. In embodiments, R ¹ is substituted heteroaryl. In embodiments, R ¹ is heteroaryl substituted with C ₁ -C ₄ alkyl. In embodiments, R ¹ is heteroaryl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is heteroaryl substituted with C ₁ -C ₄ alkoxy. In embodiments, R ¹ is heteroaryl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R ¹ is heteroaryl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R ¹ is heteroaryl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R ¹ is heteroaryl substituted with halogen. In embodiments, R ¹ is heteroaryl substituted with cyano. In embodiments, R ¹ is heteroaryl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is heteroaryl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R ¹ is heteroaryl substituted with phenyl. In embodiments, R ¹ is heteroaryl substituted with heteroaryl. In embodiments, R ¹ is heteroaryl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0282] In embodiments, R ¹ is unsubstituted alkyl. In embodiments, R ¹ is substituted alkyl. In embodiments, R ¹ is alkyl substituted with C ₁ -C ₄ alkyl. In embodiments, R ¹ is alkyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is alkyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R ¹ is alkyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R ¹ is alkyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R ¹ is alkyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R ¹ is alkyl substituted with halogen. In embodiments, R ¹ is alkyl substituted with cyano. In embodiments, R ¹ is alkyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is alkyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R ¹ is alkyl substituted with phenyl. In embodiments, R ¹ is alkyl substituted with heteroaryl. In embodiments, R ¹ is alkyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0283] In embodiments, R ¹ is C ₁ -C ₁₀ alkyl. In embodiments, R ¹ is C ₃ -C ₈ unsubstituted cycloalkyl. In embodiments, R ¹ is substituted C ₃ -C ₈ cycloalkyl. In embodiments, R ¹ is C ₃ -C ₈ cycloalkyl substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, cyano, and C ₁ -C ₆ haloalkyl. In embodiments, R ¹ is unsubstituted C ₃ -C ₈ cycloalkenyl. In embodiments, R ¹ is substituted C ₃ -C ₈ cycloalkenyl. In embodiments, R ¹ is C ₃ -C ₈ cycloalkenyl substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, cyano, and C ₁ -C ₆ haloalkyl.

[0284] In embodiments, R ¹ is unsubstituted C ₆ -C ₁₄ aryl. In embodiments, R ¹ is substituted C ₆ -C ₁₄ aryl. In embodiments, R ¹ is C ₆ -C ₁₄ aryl substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, cyano, and C ₁ -C ₆ haloalkyl. In embodiments, R ¹ is unsubstituted heteroaryl, wherein the heteroaryl has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom. In embodiments, R ¹ is substituted C ₆ -C ₁₄ heteroaryl, wherein the heteroaryl has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom. In embodiments, R ¹ is heteroaryl substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, cyano, and C ₁ -C ₆ haloalkyl, and wherein the heteroaryl has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom.

[0285] In embodiments, R ¹ is a C ₆ -C ₁₄ aryl-C ₁ -C ₆ alkyl group, wherein C ₆ -C ₁₄ aryl is optionally substituted by the same or different 1 to 5 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, cyano, and C ₁ -C ₆ haloalkyl. In embodiments, R ¹ is a C ₃ -C ₈ cycloalkyl-C ₁ -C ₆ alkyl group, wherein C ₃ -C ₈ cycloalkyl is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, cyano, and C ₁ -C ₆ haloalkyl. In embodiments, R ¹ is a phenyl-C ₁ -C ₆ alkyl group.

[0286] In embodiments, R ² is OR ⁶ , wherein R ⁶ is hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ² is NR ^7a R ^7b , wherein R ^7a and R ^7b are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^7a and R ^7b are taken together to form a ring having from 3 to 7 atoms.

[0287] In embodiments, R ³ is hydrogen. In embodiments, R ³ is methyl. In embodiments, R ³ is ethyl. [0288] In embodiments, L is a linking unit having a structure -[C(R ^8a R ^8b )] _n -, wherein R ^8a and R ^8b are each independently selected from the group consisting of hydrogen, methyl and ethyl.

[0289] In embodiments, n is an integer from 1 to 3. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0290] In embodiments, R ⁹ is hydrogen. In embodiments, R ⁹ is methyl.

[0291] In embodiments, a compound (e.g., a first compound) that is a HIF-PH inhibitor is [(7-hydroxy-5-phenethyl [1,2,4] triazolo [1,5-a] pyridine-8-carbonyl)aminoacetic acid (Compound 5), or a pharmaceutically acceptable salt thereof. Compound 5, also referred to as enarodustat, or JTZ-951, has the following structure:

Compound 5 (enarodustat, or JTZ-951)

Formula (VI): Desldustat and Related Compounds [0292] Exemplary HIF-PH inhibitor compounds that can be used in any of the methods described herein include those described in U.S. Patent No. 9,394,300, and U.S. Publication No. US 20190359574A1, each of which is incorporated by reference in its entirety. In embodiments, a compound, or pharmaceutically acceptable salt thereof, is described in any of claims 1-10 of U.S. Patent No. 9,394,300.

[0293] In embodiments, suitable compounds include a compound having a structure according to Formula (VI), Formula (VI), or a pharmaceutically acceptable salt thereof, wherein, R and R ¹ are each independently:

(i) hydrogen

(ii) substituted or unsubstituted phenyl;

(iii) substituted or unsubstituted heteroaryl; or

(iv) substituted or unsubstituted alkyl; said substitution selected from:

(i) C ₁ -C ₄ alkyl;

(ii) C ₃ -C ₄ cycloalkyl;

(iii) C ₁ -C ₄ alkoxy;

(iv) C ₃ -C ₄ cycloalkoxy;

(v) C ₁ -C ₄ haloalkyl;

(vi) C ₃ -C ₄ halocycloalkyl;

(vii) halogen;

(viii) cyano;

(ix) NHC(O)R ⁴ ;

(x) C(O)NR ^5a R ^5b ;

(xi) phenyl; and

(xii) heteroaryl; or

(xiii) two substituents are taken together to form a fused ring having from 5 to 7 atoms;

R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl; R ^5a and R ^5b are each independently selected from:

(i) hydrogen;

(ii) C ₁ -C ₄ alkyl;

(iii) C ₃ -C ₄ cycloalkyl; or

(iv) R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms;

R ² is selected from:

(i) OR ⁶

(ii) NR ^7a R ^7b ; and

R ⁶ is selected from hydrogen and C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl; R ^7a and R ^7b are each independently selected from: (i) hydrogen;

(ii) C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl; or

(iii) R ^7a and R ^7b are taken together to form a ring having from 3 to 7 atoms; R ³ is selected from hydrogen, methyl, and ethyl;

L is a linking unit having a structure -[C( R ^8a R ^8b )] _n -

R ^8a and R ^8b are each independently selected from hydrogen, methyl and ethyl; n is an integer from 1 to 3; and

R ⁹ is selected from hydrogen and methyl.

[0294] In embodiments, R is hydrogen.

[0295] In embodiments, R is unsubstituted phenyl. In embodiments, R is substituted phenyl. In embodiments, R is phenyl substituted with C ₁ -C ₄ alkyl. In embodiments, R is phenyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R is phenyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R is phenyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R is phenyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R is phenyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R is phenyl substituted with halogen. In embodiments, R is phenyl substituted with cyano. In embodiments, R is phenyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R is phenyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R is phenyl substituted with phenyl. In embodiments, R is phenyl substituted with heteroaryl. In embodiments, R is phenyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0296] In embodiments, R is unsubstituted heteroaryl. In embodiments, R is substituted heteroaryl. In embodiments, R is heteroaryl substituted with C ₁ -C ₄ alkyl. In embodiments, R is heteroaryl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R is heteroaryl substituted with C ₁ -C ₄ alkoxy. In embodiments, R is heteroaryl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R is heteroaryl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R is heteroaryl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments,

R is heteroaryl substituted with halogen. In embodiments, R is heteroaryl substituted with cyano. In embodiments, R is heteroaryl substituted with NHC(O)R ⁴ wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R is heteroaryl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R is heteroaryl substituted with phenyl. In embodiments, R is heteroaryl substituted with heteroaryl. In embodiments, R is heteroaryl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0297] In embodiments, R is unsubstituted alkyl. In embodiments, R is substituted alkyl.

In embodiments, R is alkyl substituted with C ₁ -C ₄ alkyl. In embodiments, R is alkyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R is alkyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R is alkyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R is alkyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R is alkyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R is alkyl substituted with halogen. In embodiments, R is alkyl substituted with cyano. In embodiments, R is alkyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R is alkyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R is alkyl substituted with phenyl. In embodiments, R is alkyl substituted with heteroaryl. In embodiments, R is alkyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0298] In embodiments, R ¹ is hydrogen.

[0299] In embodiments, R ¹ is unsubstituted phenyl. In embodiments, R ¹ is substituted phenyl. In embodiments, R ¹ is phenyl substituted with C ₁ -C ₄ alkyl. In embodiments, R ¹ is phenyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is phenyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R ¹ is phenyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R ¹ is phenyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R ¹ is phenyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R ¹ is phenyl substituted with halogen. In embodiments, R ¹ is phenyl substituted with cyano. In embodiments, R ¹ is phenyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is phenyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R ¹ is phenyl substituted with phenyl. In embodiments, R ¹ is phenyl substituted with heteroaryl. In embodiments, R ¹ is phenyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0300] In embodiments, R ¹ is unsubstituted heteroaryl. In embodiments, R ¹ is substituted heteroaryl. In embodiments, R ¹ is heteroaryl substituted with C ₁ -C ₄ alkyl. In embodiments, R ¹ is heteroaryl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is heteroaryl substituted with C ₁ -C ₄ alkoxy. In embodiments, R ¹ is heteroaryl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R ¹ is heteroaryl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R ¹ is heteroaryl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R ¹ is heteroaryl substituted with halogen. In embodiments, R ¹ is heteroaryl substituted with cyano. In embodiments, R ¹ is heteroaryl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is heteroaryl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R ¹ is heteroaryl substituted with phenyl. In embodiments, R ¹ is heteroaryl substituted with heteroaryl. In embodiments, R ¹ is heteroaryl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0301] In embodiments, R ¹ is unsubstituted alkyl. In embodiments, R ¹ is substituted alkyl. In embodiments, R ¹ is alkyl substituted with C ₁ -C ₄ alkyl. In embodiments, R ¹ is alkyl substituted with C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is alkyl substituted with C ₁ -C ₄ alkoxy. In embodiments, R ¹ is alkyl substituted with C ₃ -C ₄ cycloalkoxy. In embodiments, R ¹ is alkyl substituted with C ₁ -C ₄ haloalkyl. In embodiments, R ¹ is alkyl substituted with C ₃ -C ₄ halocycloalkyl. In embodiments, R ¹ is alkyl substituted with halogen. In embodiments, R ¹ is alkyl substituted with cyano. In embodiments, R ¹ is alkyl substituted with NHC(O)R ⁴ , wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ¹ is alkyl substituted with C(O)NR ^5a R ^5b , wherein R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl; or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms. In embodiments, R ¹ is alkyl substituted with phenyl. In embodiments, R ¹ is alkyl substituted with heteroaryl. In embodiments, R ¹ is alkyl substituted with two substituents independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₄ cycloalkoxy, C ₁ -C ₄ haloalkyl, C ₃ -C ₄ halocycloalkyl, NHC(O)R ⁴ , C(O)NR ^5a R ^5b , phenyl and heteroaryl, wherein the two substituents are taken together to form a fused ring having from 5 to 7 atoms, and wherein R ⁴ is a C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl, R ^5a and R ^5b are each independently selected from hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^5a and R ^5b are taken together to form a ring having from 3 to 7 atoms.

[0302] In embodiments, R and R ¹ are taken together to form a fused ring having from 5 to 7 atoms. In embodiments, R and R ¹ are taken together to form a fused ring that is an aryl. In embodiments, R and R ¹ are taken together to form a fused ring that is a phenyl.

[0303] In embodiments, R ² is OR ⁶ , wherein R ⁶ is hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₄ cycloalkyl. In embodiments, R ² is N R ^7a R ^7b , wherein R ^7a and R ^7b are each independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl, or R ^7a and R ^7b are taken together to form a ring having from 3 to 7 atoms.

[0304] In embodiments, R ³ is hydrogen. In embodiments, R ³ is methyl. In embodiments,

R ³ is ethyl.

[0305] In embodiments, L is a linking unit having a structure -[C(R ^8a R ^8b )] _n -, wherein R ^8a and R ^8b are each independently selected from the group consisting of hydrogen, methyl and ethyl.

[0306] In embodiments, n is an integer from 1 to 3. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.

[0307] In embodiments, R ⁹ is hydrogen. In embodiments, R ⁹ is methyl.

[0308] In embodiments, a compound (e.g., a first compound) that is a HIF-PH inhibitor is 2-(l-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoli ne-3-carboxamido) acetic acid (Compound 6), or a pharmaceutically acceptable salt thereof. Compound 6, also referred to as enarodustat, or ZYAN1, has the following structure:

Compound 6 (desidustat, or ZYAN1)

[0309] Compounds described herein can be used with the compositions and formulations provided herein. Diseases Associated with HIF Prolyl Hydroxylase Modulation

[0310] In certain embodiments, methods described herein may be beneficial to treat or prevent diseases ameliorated by modulation of HIF-PH. Diseases associated with HIF prolyl hydroxylase modulation include Peripheral Vascular Disease (PVD); Coronary Artery Disease (CAD); heart failure; ischemia; anemia; wound healing; ulcers; ischemic ulcers; inadequate blood supply; poor capillary circulation; small artery atherosclerosis; venous stasis; atherosclerotic lesions (e.g., in coronary arteries); angina; myocardial infarction; diabetes; hypertension; Buerger's disease; diseases associated with abnormal levels of VEGF, GAPDH, and/or EPO; Crohn's disease; ulcerative colitis; psoriasis; sarcoidosis; rheumatoid arthritis; hemangiomas; Osler-Weber-vasculitis disease; hereditary hemorrhagic telangiectasia; solid or blood borne tumors and acquired immune deficiency syndrome; atrial arrhythmias; ischemic tissue damage in tissues such as: cardiac tissue, such as myocardium and cardiac ventricles, skeletal muscle, neurological tissue, such as from the cerebellum, internal organs, such as the stomach, intestine, pancreas, liver, spleen, and lung; and distal appendages such as fingers and toes.

[0311] For example, the methods provided herein include administering a HIF-PH inhibitor and an iron-containing composition to a subject having, inter alia, Peripheral Vascular Disease (PVD); Coronary Artery Disease (CAD); heart failure; ischemia; anemia; wound healing; ulcers; ischemic ulcers; inadequate blood supply; poor capillary circulation; small artery atherosclerosis; venous stasis; atherosclerotic lesions (e.g., in coronary arteries); angina; myocardial infarction; diabetes; hypertension; Buerger's disease; diseases associated with abnormal levels of VEGF, GAPDH, and/or EPO; Crohn's disease; ulcerative colitis; psoriasis; sarcoidosis; rheumatoid arthritis; hemangiomas; Osler-Weber-vasculitis disease; hereditary hemorrhagic telangiectasia; solid or blood borne tumors and acquired immune deficiency syndrome; atrial arrhythmias; ischemic tissue damage in tissues such as: cardiac tissue, such as myocardium and cardiac ventricles, skeletal muscle, neurological tissue, such as from the cerebellum, internal organs, such as the stomach, intestine, pancreas, liver, spleen, and lung; and distal appendages such as fingers and toes. [0312] In certain embodiments, the methods provided herein include administering a HIF prolyl hydroxylase inhibitor (e.g., vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), or desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof) and an iron- containing composition (e.g., oral iron or an iron-containing phosphorus adsorbent) to a subject having anemia, including anemia described herein.

[0313] In embodiments, a subject has anemia. In embodiments, anemia includes (but is not limited to) anemia of chronic disease, anemia secondary to or associated with chronic kidney disease (renal anemia), anemia associated with or resulting from chemotherapy (chemo-induced anemia), anemia associated with AIDS, anemia secondary to congestive heart failure, idiopathic anemia of aging, sickle cell anemia, iron deficiency anemia, anemia associated with or resulting from elevated hepcidin, anemia associated with abnormal hemoglobin or erythrocytes, anemia associated with diabetes, anemia associated with cancer, anemia associated with ulcers, anemia associated with kidney disease, anemia associated with immunosuppressive disease, anemia associated with infection, anemia associated with inflammation, anemia associated with a procedure or treatment (e.g., radiation therapy, chemotherapy, dialysis, or surgery), anemia associated with blood loss, and anemia associated with defects in iron transport, processing, absorption, or utilization.

[0314] In embodiments, a subject has anemia secondary to or associated with chronic kidney disease (renal anemia).

[0315] In certain embodiments, the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease. In embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. In embodiments, the chronic kidney disease is non-dialysis dependent chronic kidney disease. In embodiments, the chronic kidney disease is dialysis dependent chronic kidney disease. In still other embodiments, the subject has not been previously treated for anemia (e.g., anemia secondary to or associated with chronic kidney disease). In alternative embodiments, the subject has been previously treated for anemia (e.g., anemia secondary to or associated with chronic kidney disease). In another embodiments, the subject has been previously treated for anemia with a HIF-PH inhibitor, erythropoiesis stimulating agent (ESA), or both. Iron-Containing Compositions

[0316] An iron-containing composition can be administered to a subject for treating or preventing diseases or conditions including low blood levels of iron, iron deficiency, functional iron deficiency, hyperphosphatemia, chronic kidney disease, hypocalcemia (e.g., hypocalcemia associated with or caused by hyperphosphatemia), and anemia (e.g., iron deficiency anemia or anemia associated with or secondary to chronic kidney disease/failure); or for lowering high blood phosphate levels (e.g., in a subject on dialysis).

[0317] In embodiments, a subject receiving an iron-containing composition receives the iron-containing composition for treating or preventing low levels of red blood cells.

[0318] In embodiments, a subject receiving an iron-containing composition receives the iron-containing composition for treating or preventing low levels of healthy red blood cells due to iron deficiency.

[0319] In embodiments, a subject receiving an iron-containing composition receives the iron-containing composition for treating or preventing iron-deficiency anemia.

[0320] In embodiments, a subject receiving an iron-containing composition receives the iron-containing composition for treating or preventing low iron levels.

[0321] In embodiments, a subject receiving an iron-containing composition receives the iron-containing composition for treating or preventing high blood phosphate levels (hyperphosphatemia). In embodiments, a subject is on dialysis due to severe kidney disease.

[0322] In embodiments, a subject receiving an iron-containing composition receives the iron-containing composition for treating or preventing hypocalcemia. In embodiments, hypocalcemia is associated with or caused by hyperphosphatemia.

[0323] In embodiments, the iron-containing composition is administered in an amount such that ferritin is maintained at a level of between about 50 ng/mL and about 300 ng/mL

[0324] An iron-containing composition can also be administered to a subject in combination with other therapeutic agents in a combination therapy.

[0325] For example, therapeutic methods for patients having anemia (e.g., anemia associated with or secondary to chronic kidney disease) comprising administration of a HIF-PH inhibitor can also comprise the administration of one or more additional therapeutic agents such as an iron-containing composition. Such iron-containing composition can be useful for treating one or more co-morbid conditions, such as those pre-existing at the time of commencement of the anemia therapy and/or arising during the period of anemia treatment. Such co-morbid conditions include, but are not limited to, thrombosis, sleep disorders, somnolence, retinal hemorrhage, rotational vertigo, high blood pressure, palpitations, diarrhea, nausea, abdominal discomfort, vomiting, soft stool, gastroenteritis, stomatitis, liver dysfunction, AST elevation, rash, pruritus, eczema, erythema, alopecia, cold sweats, frequent urination, serum ferritin reduction, trans ferritin saturation reduction, fatigue, chest pain, bilirubin rise, and/or ALT rise. Other co-morbid conditions include, but are not limited to gout, gouty arthritis, hyperuricemia, high cholesterol, triglyceride levels, hypervolemia, edema, and/or other swelling related to, e.g., congestive heart failure, liver disease, kidney disease.

[0326] In embodiments, an iron-containing composition is formulated for oral administration (oral iron).

[0327] In embodiments, the iron-containing composition is administered continuously and/or indefinitely, such as for about 20 to about 25 consecutive days (e.g, about 21 consecutive days) or more than 25 consecutive days. In certain alternative embodiments, the iron-containing composition is administered on an as needed basis.

[0328] In embodiments, a compound (e.g., a second compound) that is an iron- containing composition is oral iron or an iron-containing phosphorus adsorbent.

[0329] In embodiments, a compound (e.g., a second compound) that is an iron- containing composition comprises ferrous sulfate (also referred to as iron sulfate or iron(ll) sulfate), ferrous citrate (e.g., sodium ferrous citrate), ferric citrate (including ferric citrate hydrate), or sucroferric oxyhydroxide.

[0330] In embodiments, a compound (e.g., a second compound) that is an iron- containing composition is ferric citrate.

[0331] An iron-containing composition can further comprise any of the excipients described herein (e.g., as described for formulations of a HIF-PH inhibitor), as well as any combinations thereof. Ferrous Sulfate

[0332] In embodiments, an iron-containing composition comprises ferrous sulfate (also known as iron sulfate or iron (II) sulfate).

[0333] In embodiments, a subject receives ferrous sulfate for treating or preventing low blood levels of iron. In embodiments, a subject who receives ferrous sulfate is at risk of low blood levels of iron.

[0334] In embodiments, a subject receives ferrous sulfate in a dose of about 300 mg to about 325 mg daily. In embodiments, a subject receives ferrous sulfate in a dose of about 300 mg to about 325 mg one to four times a day (e.g., once a day, twice a day, three times a day, or four times a day). In embodiments, a subject receives ferrous sulfate in a dose equivalent to about 40-300 mg elemental iron. In embodiments, a subject receives ferrous sulfate in a dose equivalent to about 40-100 mg elemental iron (e.g., about 45 mg elemental iron or about 65 mg elemental iron). In embodiments, a subject receives ferrous sulfate in a dose equivalent to about 200-300 mg elemental iron (e.g., about 210 mg elemental iron). In embodiments, a subject receives ferrous sulfate as an oral solution (e.g., as a dose equivalent to about 40-100 mg elemental iron such as about 45 or about 60 mg elemental iron). In embodiments, a subject receives ferrous sulfate as oral liquid drops (e.g., as a dose equivalent to about 50-100 mg elemental iron such as about 75 mg elemental iron). In embodiments, a subject receives ferrous sulfate as a tablet (e.g., as a dose equivalent to about 40-100 mg elemental iron such as about 45 mg, about 50 mg, about 60 mg, or about 65 mg elemental iron or as a dose equivalent to about 200 to about 300 mg elemental iron such as about 215 mg elemental iron). In embodiments, a subject receives a dose of ferrous sulfate once daily, two times a day, three times a day, or four times a day. In embodiments, a subject receives ferrous sulfate as an immediate release formulation (e.g., as a tablet). In embodiments, a subject receives ferrous sulfate as an extended or delayed release formulation (e.g., as a tablet).

Ferrous Citrate

[0335] In embodiments, an iron-containing composition comprises ferrous citrate. In embodiments, a subject receives ferrous citrate for treating or preventing low blood levels of iron. In embodiments, a subject who receives ferrous citrate is at risk of low blood levels of iron. In embodiments, a subject receives ferrous citrate for treating or preventing anemia. In embodiments, a subject receives ferrous citrate for treating or preventing iron deficiency.

[0336] In embodiments, a subject receives ferrous citrate as a dose equivalent to about 150 mg to about 300 mg elemental iron (e.g., about 200 mg elemental iron). In embodiments, a subject receives a dose of ferrous citrate once a day, two times a day, three times a day, or four times a day.

Ferric Citrate

[0337] In embodiments, an iron-containing composition comprises ferric citrate. In embodiments, a subject receives ferric citrate for treating or preventing hyperphosphatemia. In embodiments, a subject receives ferric citrate for lowering high blood phosphate levels (e.g., in a subject on dialysis). In embodiments, a subject receives ferric citrate for treating or preventing anemia (e.g., iron deficiency anemia or anemia associated with or secondary to chronic kidney failure).

[0338] In embodiments, a subject receives a dose of about 250 mg to about 12 g ferric citrate (e.g., about 250 mg, about 500 mg, about 750 mg, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 11 g, or about 12 g ferric citrate) daily. In embodiments, a subject receives about 250 mg to about 12 g of ferric citrate in divided doses of 1 to 3 times daily. In embodiments, a subject receives ferric citrate in a dose equivalent to about 50 mg to about 300 mg elemental iron (e.g., about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg). In embodiments, a subject receives ferric citrate in a dose equivalent to about 300 mg to about 3000 mg elemental iron (e.g., about 630 mg, about 840 mg, about 1050 mg, about 1260, about 1470 mg, about 1680 mg, about 1890 mg, about 2100 mg, about 2310 mg, or about 2520 mg elemental iron). In embodiments, a subject receives a dose of ferric citrate once a day, two times a day, three times a day, or four times a day.

Sucroferric Oxyhydroxide

[0339] In embodiments, an iron-containing composition comprises sucroferric oxyhydroxide. In embodiments, a subject receives sucroferric oxyhydride for treating or preventing hyperphosphatemia. In embodiments, a subject receives sucroferric oxyhydride for lowering high blood phosphate levels (e.g., in a subject on dialysis). In embodiments, a subject receives sucroferric oxyhydride for treating patients with chronic kidney disease. In embodiments, a subject receives sucroferric oxyhydride for treating or preventing hypocalcemia (e.g., hypocalcemia associated with or caused by hyperphosphatemia).

[0340] In embodiments, a subject receives sucroferric oxyhydroxide in a dose of about 2500 mg to about 15000 mg (e.g., about 2500 mg, about 5000 mg, about 7500 mg, about 10000 mg, about 12500 mg, about 15000 mg) daily. In embodiments, a subject receives about 2500 mg to about 15000 mg sucroferric oxyhydroxide in divided doses of one to three times daily. In embodiments, a subject receives sucroferric oxyhydroxide in a dose equivalent to about 500 to about 3000 mg elemental iron (e.g., about 500 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, or about 3000 mg elemental iron). In embodiments a subject receives sucroferric oxyhydroxide in a dose equivalent to about 500 to about 3000 mg elemental iron daily.

Administration of a HIF-PH Inhibitor and an Iron-Containing Compositions

[0341] In embodiments, a subject receiving a compound that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor may also be administered a compound that is an iron-containing composition.

[0342] In embodiments, a subject receiving a compound that is an iron-containing composition may also be administered a compound that is a hypoxia-inducible factor- prolyl hydroxylase (HIF-PH) inhibitor.

[0343] In embodiments, a subject is receiving an iron-containing composition prior to commencement of therapy with a HIF-PH inhibitor. In embodiments, a subject receives an iron-containing composition after commencing therapy with a HIF-PH inhibitor.

[0344] In embodiments, a patient's treatment with a HIF-PH inhibitor is initiated at the same time as said patient's treatment with an iron-containing composition.

[0345] In embodiments, a subject is administered an iron-containing composition for treating a disease or condition in the patient that was present at the time treatment with a HIF-PH inhibitor was commenced. In embodiments, a subject is administered an iron-containing composition for treating or preventing a disease or condition in the patient that was not present at the time treatment with a HIF-PH inhibitor was commenced (e.g., the disease or condition developed after treatment with the first compound was commenced). In embodiments, a subject is administered an iron- containing composition for treating or preventing a disease or condition in the patient induced by treatment with a HIF-PH inhibitor. In embodiments, a subject is administered an iron-containing composition for treating or preventing a disease or condition in the patient that arises independently of treatment with a HIF-PH inhibitor.

[0346] In embodiments, a subject is administered a HIF-PH inhibitor for treating a disease or condition in the patient that was present at the time treatment with an iron- containing composition was commenced. In embodiments, a subject is administered a HIF-PH inhibitor for treating or preventing a disease or condition in the patient that was not present at the time treatment with an iron-containing composition was commenced (e.g., the disease or condition developed after treatment with the first compound was commenced). In embodiments, a subject is administered a HIF-PH inhibitor for treating or preventing a disease or condition in the patient induced by treatment with an iron- containing composition. In embodiments, a subject is administered a HIF-PH inhibitor for treating or preventing a disease or condition in the patient that arises independently of treatment with an iron-containing composition.

[0347] In embodiments, an iron-containing composition is administered before (e.g., at least about four hours after) the administration of a HIF-PH inhibitor. In embodiments, an iron-containing composition is administered after (e.g., at least about four hours after) the administration of a HIF-PH inhibitor.

[0348] Exemplary protocols for the administration of a HIF-PH inhibitor in combination with an iron-containing composition that can result in unexpected therapeutic effects are described herein.

Methods of Treatment

[0349] Described herein are therapeutic methods comprising administering a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor (e.g., vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK- 12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), or desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof), in combination with a compound (e.g., a second compound) that is an iron-containing composition (e.g., oral iron or an iron- containing phosphorus adsorbent) in subjects in need thereof. Methods described herein can be useful for treating, preventing, regulating, and/or controlling a disease or condition (e.g., a disease or condition as described here).

[0350] In embodiments, methods described herein can result in improved (e.g., synergistic) therapeutic effects. For example, an improved therapeutic effect may be observed when compared to a therapeutic effect obtained from administration of a single compound in monotherapy (e.g., administration of a HIF-PH inhibitor only or administration of an iron-containing composition only) or a therapeutic effect that is more than additive of multiple compounds (i.e., synergistic). For example, an improved therapeutic effect allows for administration of a lower dose of a first compound and/or a lower dose of a second compound relative to a dose of the first compound or a dose of the second compound in monotherapy. In embodiments, methods described herein can result in an improved therapeutic effect that allows for administration of dose of a first compound that is lower than a dose of a first compound in monotherapy. In embodiments, methods described herein can result in an improved therapeutic effect that allows for administration of a dose of a second compound that is lower than a dose of a second compound in monotherapy.

[0351] In embodiments, an improved effect (e.g., a synergistically improved effect) is observed in iron parameters (e.g., serum iron, TIBC, or TSAT levels), including as compared to monotherapy. In embodiments, an improved effect is observed in serum iron levels. In embodiments, an improved effect is observed in TIBC levels. In embodiments, an improved effect is observed in TSAT levels. In embodiments, an improved effect is observed in EPO levels.

[0352] In embodiments, an improved effect (e.g., a synergistically improved effect) is observed in the level of certain hematologic parameters, including as compared to monotherapy. In embodiments, an improved effect is observed in hemoglobin (HGB/Hb), hematocrit (HCT), reticulocytes, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), or mean corpuscular hemoglobin concentration (MCHC). In embodiments, an improved effect in MCV. In embodiments, an improved effect is observed in MCH. [0353] In embodiments, an improved effect (e.g., a synergistically improved effect) is observed in the level of certain immune cell parameters, including as compared to monotherapy. In embodiments, an improved effect is observed in white blood cell (WBC), Neutrophil, Lymphocyte, or Monocyte levels. In embodiments, an improved effect is observed in reducing systemic inflammation, including as compared to monotherapy. In embodiments, systemic inflammation is characterized by e.g., ankle diameter measurement, relative organ weights, C-reactive protein (CRP), haptoglobin, and/or serum cytokines such as IL-6, IL-15 or leukemia inhibitory factor (LIF). In embodiments, systemic inflammation is characterized by CRP. In embodiments, systemic inflammation is characterized by serum cytokines. In embodiments, systemic inflammation is characterized by a serum cytokine that is IL-6. In embodiments, systemic inflammation is characterized by a serum cytokine that is IL-15.

[0354] Suitable HIF-PH inhibitors include (but are not limited to) those described herein, including but not limited to vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or any pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is daprodustat, roxadustat, or vadadustat. In embodiments, a HIF-PH inhibitor is vadadustat.

[0355] Exemplary methods are described herein.

Patient Populations

[0356] In embodiments, methods described herein can be useful for a patient having a condition (e.g., a disease or disorder) as described herein. In embodiments, an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor (e.g., vadadustat), and a compound (e.g., a second compound) that is an iron-containing composition are administered to a patient having a condition (e.g., a disease or disorder) as described herein.

[0357] In embodiments, a patient has a condition (e.g., a disease or disorder) that can be treated (and/or prevented) by administering an HIF-PH inhibitor (e.g., vadadustat). In embodiments, a patient does not have a condition (e.g., a disease or disorder) that can be treated (and/or prevented) by administering an HIF-PH inhibitor (e.g., vadadustat) in monotherapy (e.g., administration of a HIF-PH inhibitor only).

[0358] In embodiments, a patient has a condition (e.g., a disease or disorder) that can be treated (and/or prevented) by administering an iron-containing composition (e.g., oral iron or an iron-containing phosphorus adsorbent). In embodiments, a patient does not have a condition (e.g., a disease or disorder) that can be treated (and/or prevented) by administering an iron-containing composition in monotherapy (e.g., administration of an iron-containing composition only).

[0359] In embodiments, a patient has anemia (e.g., anemia as described herein).

[0360] In embodiments, a patient has impaired iron mobilization (e.g., has a decreased serum iron and/or TSAT (transferrin saturation) compared to normal; and/or has an increased TIBC (total iron-binding capacity) compared to normal). In embodiments, a patient has iron deficiency and/or functional iron deficiency.

[0361] In embodiments, a patient has impaired hematologic functions (e.g., has a decreased HGB/Hb (hemoglobin), HCT (hematocrit), % reticulocytes, MCV (mean corpuscular volume), and/or MCH (mean corpuscular hemoglobin) compared to normal).

[0362] In embodiments, a patient has decreased erythropoietin (EPO) levels compared to normal.

[0363] In embodiments, a patient has systemic inflammation (e.g., has an increased WBC (white blood cell), neutrophil, lymphocyte, ankle diameter, relative organ weights, CRP (C-Reactive Protein), haptoglobin, and/or serum cytokines compared to normal).

[0364] In embodiments, a patient has impaired kidney functions (e.g., has chronic kidney disease such as non-dialysis dependent chronic kidney disease or dialysis dependent chronic kidney disease).

[0365] In embodiments, a patient has a hypoxic or ischemic disorder.

[0366] Other exemplary characteristics of patients that can benefit from the exemplary therapeutic methods are further described herein. Anemia

[0367] Methods described herein can be useful for treating, regulating, preventing, and/or controlling anemia in a patient in need thereof. In embodiments, methods described herein can result in improved (e.g., synergistic) therapeutic effects as compared to monotherapy (e.g., administration of a HIF-PH inhibitor or an iron- containing composition alone). For example, an increased EPO level may be observed, and methods described herein may be particularly beneficial to a patient having anemia (e.g., anemia secondary to or associated with chronic kidney disease (renal anemia)) at commencement treatment according to methods described herein. In addition, an increased serum iron, an increased TSAT (transferrin saturation), and/or a decreased TIBC (total iron-binding capacity) may also be observed, and thus methods described herein may be particularly beneficial to a patient having iron deficiency anemia at commencement treatment according to methods described herein.

[0368] Anemia may be characterized by hemoglobin threshold as follows:

[0369] In embodiments, provided herein is a method of treating anemia comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition (e.g., oral iron or an iron-containing phosphorus adsorbent). In embodiments, a treatment is commenced with administration of both a first and a second compounds. In embodiments, a patient has iron deficiency anemia and/or is in need of iron supplementation at commencement of treatment. In embodiments, a patient has limited iron absorption and/or uptake (e.g., a lower iron absorption and/or uptake rate compared to normal). In embodiments, a treatment can result in increased improvement in the patient's iron mobilization, systemic iron, serum iron, and/or transferrin saturation (TSAT) as compared to monotherapy.

[0370] In embodiments, provided herein is a method of regulating anemia comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition (e.g., oral iron or an iron-containing phosphorus adsorbent). In embodiments, a treatment is commenced with administration of both a first and a second compounds. In embodiments, a patient has iron deficiency anemia and/or is in need of iron supplementation at commencement of treatment. In embodiments, a patient has limited iron absorption and/or uptake (e.g., a lower iron absorption and/or uptake rate compared to normal). In embodiments, a treatment can result in increased improvement in the patient's iron mobilization, systemic iron, serum iron, and/or transferrin saturation (TSAT) as compared to monotherapy.

[0371] In embodiments, provided herein is a method of preventing anemia comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition (e.g., oral iron or an iron-containing phosphorus adsorbent). In embodiments, a treatment is commenced with administration of both a first and a second compounds. In embodiments, a patient has iron deficiency anemia and/or is in need of iron supplementation at commencement of treatment. In embodiments, a patient has limited iron absorption and/or uptake (e.g., a lower iron absorption and/or uptake rate compared to normal). In embodiments, a treatment can result in increased improvement in the patient's iron mobilization, systemic iron, serum iron, and/or transferrin saturation (TSAT) as compared to monotherapy.

[0372] In embodiments, provided herein is a method of controlling anemia comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition (e.g., oral iron or an iron-containing phosphorus adsorbent). In embodiments, a treatment is commenced with administration of both a first and a second compounds. In embodiments, a patient has iron deficiency anemia and/or is in need of iron supplementation at commencement of treatment. In embodiments, a patient has limited iron absorption and/or uptake (e.g., a lower iron absorption and/or uptake rate compared to normal). In embodiments, a treatment can result in increased improvement in the patient's iron mobilization, systemic iron, serum iron, and/or transferrin saturation (TSAT) as compared to monotherapy.

[0373] In embodiments, anemia includes (but is not limited to) anemia of chronic disease, anemia secondary to or associated with chronic kidney disease (renal anemia), anemia associated with or resulting from chemotherapy, anemia associated with AIDS, anemia secondary to congestive heart failure, idiopathic anemia of aging, sickle cell anemia, iron deficiency anemia, anemia associated with or resulting from elevated hepcidin, anemia associated with abnormal hemoglobin or erythrocytes, anemia associated with diabetes, anemia associated with cancer, anemia associated with ulcers, anemia associated with kidney disease, anemia associated with immunosuppressive disease, anemia associated with infection, anemia associated with inflammation, anemia associated with a procedure or treatment (e.g., radiation therapy, chemotherapy, dialysis, or surgery), anemia associated with blood loss, and anemia associated with defects in iron transport, processing, absorption, or utilization. Accordingly, methods described herein may be suitable for treating a patient in need thereof having any of these anemias, or any combination thereof.

[0374] In embodiments, HIF-PH inhibitors include (but are not limited to) vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85- 3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is daprodustat, roxadustat, or vadadustat. In embodiments, a HIF-PH inhibitor is vadadustat.

[0375] In embodiments, an iron-containing composition is oral iron or an iron-containing phosphorus adsorbent. In embodiments, iron-containing compositions include (but are not limited to) ferrous sulfate, sodium ferrous citrate, ferric citrate, and sucroferric oxyhydroxide. In embodiments, an iron-containing composition is ferric citrate. [0376] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs concomitantly (concomitant administration). In embodiments, concomitant administration of a compound (e.g., a first compound) and administration of the other compound (e.g., a second compound) occur within a time period that is no more than one about hour (e.g., no more than about 1, 5, 10, 15, 20, 25 or 30 minutes). In embodiments, concomitant administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs simultaneously (simultaneous administration) where both compounds are administered at the same time. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0377] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs sequentially (sequential administration). In embodiments, a first compound is given at least about 1, 2, or 4 hours before and/or after taking a second compound. In embodiments, a first compound is given at least about 4 hours before and/or after taking a second compound. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0378] In embodiments, a first compound is a HIF-PH inhibitor that is vadadustat and is administered at a total daily dose of about 150-600 mg. In embodiments, a second compound is an iron-containing composition that is ferric citrate and is administered at a total daily dose of about 1-12 grams. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed about 5, 10, 15, or 20 days after commencement of the treatment. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed for about 5, 10, 15, 20, or more than 20 days during the treatment.

[0379] In embodiments, a patient has iron deficiency anemia (e.g., a patient may have iron deficiency anemia at commencement of treatment according to methods described herein). In embodiments, a patient has anemia secondary to or associated with chronic kidney disease (renal anemia). In embodiments, a patient has non-dialysis dependent chronic kidney disease (NDD-CKD). In embodiments, a patient has dialysis dependent chronic kidney disease (DD-CKD).

Dialysis Status

[0380] The methods described herein can be beneficial to patients of different dialysis status, including the statuses described herein.

[0381] In embodiments, the patient is non-dialysis dependent. For example, in some embodiments, the patient with chronic kidney disease is non-dialysis dependent (a NDD- CKD patient).

[0382] In embodiments, the patient is dialysis-dependent. For example, in embodiments, the patient with chronic kidney disease is dialysis-dependent (a DD-CKD patient).

[0383] In embodiments, the patient receives or previously has received dialysis. In embodiments, the patient receives dialysis. In embodiments, the patient previously received dialysis.

[0384] In embodiments, dialysis is hemodialysis (HD). In embodiments, the patient with chronic kidney disease receives or previously received hemodialysis. In embodiments, the patient with chronic kidney disease receives hemodialysis. In embodiments, the patient with chronic kidney disease previously received hemodialysis.

[0385] In embodiments, dialysis is peritoneal dialysis (PD). In embodiments, the patient with chronic kidney disease receives or previously received peritoneal dialysis. In embodiments, the patient with chronic kidney disease receives peritoneal dialysis. In embodiments, the patient with chronic kidney disease previously received peritoneal dialysis.

Iron Mobilization

[0386] Methods described herein can be useful for improving iron mobilization in patients in need thereof. In embodiments, methods described herein can result in improved (e.g., synergistic) therapeutic effects as compared to monotherapy (e.g., administration of a HIF-PH inhibitor or an iron-containing composition alone).

[0387] In particular, the effects on iron mobilization may be improved as compared to monotherapy: for example, the observed effects may be synergistic. For example, an increased serum iron, an increased TSAT (transferrin saturation), and/or a decreased TIBC (total iron-binding capacity) may be observed, and thus methods described herein may be particularly beneficial to a patient having iron deficiency and/or functional iron deficiency at commencement treatment according to methods described herein.

[0388] In embodiments, provided herein is a method of improving serum ferritin comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0389] In embodiments, provided herein is a method of improving (e.g., increasing) serum iron comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0390] In embodiments, provided herein is a method of improving transferrin saturation comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0391] In embodiments, provided herein is a method of decreasing total iron-binding capacity (TIBC) comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0392] In embodiments, provided herein is a method of increasing iron absorption comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0393] In embodiments, provided herein is a method of decreasing hepcidin expression comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0394] In embodiments, provided herein is a method of treating iron deficiency comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0395] In embodiments, provided herein is a method of treating functional iron deficiency comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0396] In embodiments, provided herein is a method of regulating gene expression involved in iron mobilization, comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition. In embodiments, a gene involved in iron mobilization is selected from the group consisting of Egln, Egln1, Egln2, Egln3, erythropoietin, ceruloplasmin, transferrin, ferritin mitochondrial, EPO Receptor, ferroportin 1, transferrin receptor, hepcidin, and HMOX1 gene. In embodiments, a gene involved in iron mobilization is selected from the group consisting of HIF1α, HIF2, HIF3α, PHD1, PHD2, PHD3, and ARNT gene. In embodiments, a gene involved in iron mobilization is selected from the group consisting of ΗΙF1β, HIF2a, ΗΙF2β, and ΗΙF3β gene.

[0397] In embodiments, HIF-PH inhibitors include (but are not limited to) vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85- 3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is daprodustat, roxadustat, or vadadustat. In embodiments, a HIF-PH inhibitor is vadadustat.

[0398] In embodiments, an iron-containing composition is oral iron or an iron-containing phosphorus adsorbent. In embodiments, iron-containing compositions include (but are not limited to) ferrous sulfate, sodium ferrous citrate, ferric citrate, and sucroferric oxyhydroxide. In embodiments, an iron-containing composition is ferric citrate.

[0399] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs concomitantly (concomitant administration). In embodiments, concomitant administration of a compound (e.g., a first compound) and administration of the other compound (e.g., a second compound) occur within a time period that is no more than one about hour (e.g., no more than about 1, 5, 10, 15, 20, 25 or 30 minutes). In embodiments, concomitant administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs simultaneously (simultaneous administration) where both compounds are administered at the same time. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0400] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs sequentially (sequential administration). In embodiments, a first compound is given at least about 1, 2, or 4 hours before and/or after taking a second compound. In embodiments, a first compound is given at least about 4 hours before and/or after taking a second compound. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0401] In embodiments, a first compound is a HIF-PH inhibitor that is vadadustat and is administered at a total daily dose of about 150-600 mg. In embodiments, a second compound is an iron-containing composition that is ferric citrate and is administered at a total daily dose of about 1-12 grams. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed about 5, 10, 15, or 20 days after commencement of the treatment. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed for about 5, 10, 15, 20, or more than 20 days during the treatment.

[0402] In embodiments, a patient has iron deficiency anemia (e.g., a patient may have iron deficiency anemia at commencement of treatment according to methods described herein). In embodiments, a patient has anemia secondary to or associated with chronic kidney disease (renal anemia). In embodiments, a patient has non-dialysis dependent chronic kidney disease (NDD-CKD). In embodiments, a patient has dialysis dependent chronic kidney disease (DD-CKD).

Hematologic Functions

[0403] Methods described herein can be useful for improving hematologic functions in patients in need thereof. For example, an increased HGB/Hb (hemoglobin), HCT (hematocrit), % reticulocytes, MCV (mean corpuscular volume), and/or MCH (mean corpuscular hemoglobin) may be observed. In embodiments, methods described herein can result in improved (e.g., synergistic) therapeutic effects as compared to monotherapy (e.g., administration of a HIF-PH inhibitor or an iron-containing composition alone). In particular, the effects on hematologic functions may be improved as compared to monotherapy: for example, the observed effects may be synergistic. For example, an increased MCV (mean corpuscular volume), and/or an increased MCH (mean corpuscular hemoglobin) may be observed, and thus methods described herein may be particularly beneficial to a patient having a disease as described herein.

[0404] In embodiments, provided herein is a method of improving hematologic functions comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0405] In embodiments, provided herein is a method of increasing hemoglobin (Hb) levels comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0406] In embodiments, provided herein is a method of improving red blood cell quality comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition. In embodiments, improved red blood cell quality is characterized by increased red blood cell size (e.g., measured by mean corpuscular volume (MCV)). In embodiments, the improved red blood cell quality is characterized by increased reticulocyte count. In embodiments, improved red blood cell quality is characterized by increased cell hemoglobin concentration (e.g., measured by mean corpuscular hemoglobin (MCH)).

[0407] In embodiments, HIF-PH inhibitors include (but are not limited to) vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85- 3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is daprodustat, roxadustat, or vadadustat. In embodiments, a HIF-PH inhibitor is vadadustat.

[0408] In embodiments, an iron-containing composition is oral iron or an iron-containing phosphorus adsorbent. In embodiments, iron-containing compositions include (but are not limited to) ferrous sulfate, sodium ferrous citrate, ferric citrate, and sucroferric oxyhydroxide. In embodiments, an iron-containing composition is ferric citrate.

[0409] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs concomitantly (concomitant administration). In embodiments, concomitant administration of a compound (e.g., a first compound) and administration of the other compound (e.g., a second compound) occur within a time period that is no more than one about hour (e.g., no more than about 1, 5, 10, 15, 20, 25 or 30 minutes). In embodiments, concomitant administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs simultaneously (simultaneous administration) where both compounds are administered at the same time. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0410] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs sequentially (sequential administration). In embodiments, a first compound is given at least about 1, 2, or 4 hours before and/or after taking a second compound. In embodiments, a first compound is given at least about 4 hours before and/or after taking a second compound. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof. [0411] In embodiments, a first compound is a HIF-PH inhibitor that is vadadustat and is administered at a total daily dose of about 150-600 mg. In embodiments, a second compound is an iron-containing composition that is ferric citrate and is administered at a total daily dose of about 1-12 grams. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed about 5, 10, 15, or 20 days after commencement of the treatment. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed for about 5, 10, 15, 20, or more than 20 days during the treatment.

[0412] In embodiments, a patient has iron deficiency anemia (e.g., a patient may have iron deficiency anemia at commencement of treatment according to methods described herein). In embodiments, a patient has anemia secondary to or associated with chronic kidney disease (renal anemia). In embodiments, a patient has non-dialysis dependent chronic kidney disease (NDD-CKD). In embodiments, a patient has dialysis dependent chronic kidney disease (DD-CKD).

EPO Level

[0413] Methods described herein can be useful for increasing erythropoietin (EPO) level in patients in need thereof. In embodiments, methods described herein can result in improved (e.g., synergistic) therapeutic effects as compared to monotherapy (e.g., administration of a HIF-PH inhibitor or an iron-containing composition alone). In particular, the effects on EPO levels may be improved as compared to monotherapy: for example, the observed effects may be synergistic. For example, an increased EPO level may be observed, and thus methods described herein may be particularly beneficial to a patient having anemia (e.g., anemia secondary to or associated with chronic kidney disease (renal anemia)), and/or chronic kidney disease at commencement treatment according to methods described herein.

[0414] In embodiments, provided herein is a method of increasing erythropoietin (EPO) comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition. [0415] In embodiments, provided herein is a method of inducing enhanced or complete erythropoiesis comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0416] In embodiments, HIF-PH inhibitors include (but are not limited to) vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85- 3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is daprodustat, roxadustat, or vadadustat. In embodiments, a HIF-PH inhibitor is vadadustat.

[0417] In embodiments, an iron-containing composition is oral iron or an iron-containing phosphorus adsorbent. In embodiments, iron-containing compositions include (but are not limited to) ferrous sulfate, sodium ferrous citrate, ferric citrate, and sucroferric oxyhydroxide. In embodiments, an iron-containing composition is ferric citrate.

[0418] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs concomitantly (concomitant administration). In embodiments, concomitant administration of a compound (e.g., a first compound) and administration of the other compound (e.g., a second compound) occur within a time period that is no more than one about hour (e.g., no more than about 1, 5, 10, 15, 20, 25 or 30 minutes). In embodiments, concomitant administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs simultaneously (simultaneous administration) where both compounds are administered at the same time. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0419] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs sequentially (sequential administration). In embodiments, a first compound is given at least about 1, 2, or 4 hours before and/or after taking a second compound. In embodiments, a first compound is given at least about 4 hours before and/or after taking a second compound. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof. [0420] In embodiments, a first compound is a HIF-PH inhibitor that is vadadustat and is administered at a total daily dose of about 150-600 mg. In embodiments, a second compound is an iron-containing composition that is ferric citrate and is administered at a total daily dose of about 1-12 grams. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed about 5, 10, 15, or 20 days after commencement of the treatment. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed for about 5, 10, 15, 20, or more than 20 days during the treatment.

[0421] In embodiments, a patient has iron deficiency anemia (e.g., a patient may have iron deficiency anemia at commencement of treatment according to methods described herein). In embodiments, a patient has anemia secondary to or associated with chronic kidney disease (renal anemia). In embodiments, a patient has non-dialysis dependent chronic kidney disease (NDD-CKD). In embodiments, a patient has dialysis dependent chronic kidney disease (DD-CKD).

Systemic Inflammation

[0422] Methods described herein can be useful for reducing systemic inflammation in patients in need thereof. For example, a decreased WBC (white blood cell), neutrophil, lymphocyte, ankle diameter, relative organ weights, CRP (C-Reactive Protein), haptoglobin, and/or serum cytokines (e.g., Interleukin-15 (IL-15), or lnterleukin-6 (IL-6)) may be observed. In embodiments, methods described herein can result in improved (e.g., synergistic) therapeutic effects as compared to monotherapy (e.g., administration of a HIF-PH inhibitor or an iron-containing composition alone). In particular, the effects on systemic inflammation may be improved as compared to monotherapy: for example, the observed effects may be synergistic.

[0423] In embodiments, provided herein is a method of reducing systemic inflammation comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition. [0424] In embodiments, systemic inflammation is characterized by ankle diameter. In embodiments, systemic inflammation is characterized by relative organ weights. In embodiments, systemic inflammation is characterized by CRP (C-reactive protein). In embodiments, systemic inflammation is characterized by haptoglobin. In embodiments, systemic inflammation is characterized by serum cytokines (e.g., IL-6 (lnterleukin-6), IL- 15 (Interleukin-15) or LIF (Leukemia inhibitory factor)).

[0425] In embodiments, reducing of systemic inflammation is characterized by a reduced ankle diameter, and the invention relates to a method for reducing ankle diameter comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0426] In embodiments, reducing of systemic inflammation is characterized by a reduced relative organ weight, and the invention relates to a method for reducing relative organ weight comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0427] In embodiments, systemic inflammation is characterized by a reduced CRP (C- reactive protein) level, and the invention relates to a method for reducing CRP level comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0428] In embodiments, systemic inflammation is characterized by a reduced haptoglobin level, and the invention relates to a method for reducing haptoglobin level comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition. [0429] In embodiments, systemic inflammation is characterized by reduced serum cytokines (e.g., IL-6 (lnterleukin-6), IL-15 (Interleukin- 15) or LIF (Leukemia inhibitory factor)), and the invention relates to a method for reducing serum cytokines comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0430] In embodiments, provided herein is a method of treating or preventing a disorder associated with cytokine activity comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition. In embodiments, cytokines include (but are not limited to) IL-6 (lnterleukin-6), IL-15 (Interleukin-15) and LIF (Leukemia inhibitory factor).

[0431] In embodiments, provided herein is a method of overcoming or ameliorating cytokine-induced impairment of erythropoiesis comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition. In embodiments, cytokines include (but are not limited to) IL-6 (lnterleukin-6), IL-15 (Interleukin-15) and LIF (Leukemia inhibitory factor).

[0432] In embodiments, HIF-PH inhibitors include (but are not limited to) vadadustat

(AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85- 3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is daprodustat, roxadustat, or vadadustat. In embodiments, a HIF-PH inhibitor is vadadustat.

[0433] In embodiments, an iron-containing composition is oral iron or an iron-containing phosphorus adsorbent. In embodiments, iron-containing compositions include (but are not limited to) ferrous sulfate, sodium ferrous citrate, ferric citrate, and sucroferric oxyhydroxide. In embodiments, an iron-containing composition is ferric citrate.

[0434] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs concomitantly (concomitant administration). In embodiments, concomitant administration of a compound (e.g., a first compound) and administration of the other compound (e.g., a second compound) occur within a time period that is no more than one about hour (e.g., no more than about 1, 5, 10, 15, 20, 25 or 30 minutes). In embodiments, concomitant administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs simultaneously (simultaneous administration) where both compounds are administered at the same time. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0435] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs sequentially (sequential administration). In embodiments, a first compound is given at least about 1, 2, or 4 hours before and/or after taking a second compound. In embodiments, a first compound is given at least about 4 hours before and/or after taking a second compound. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0436] In embodiments, a first compound is a HIF-PH inhibitor that is vadadustat and is administered at a total daily dose of about 150-600 mg. In embodiments, a second compound is an iron-containing composition that is ferric citrate and is administered at a total daily dose of about 1-12 grams. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed about 5, 10, 15, or 20 days after commencement of the treatment. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed for about 5, 10, 15, 20, or more than 20 days during the treatment. In embodiments, a patient has iron deficiency anemia (e.g., a patient may have iron deficiency anemia at commencement of treatment according to methods described herein). In embodiments, a patient has anemia secondary to or associated with chronic kidney disease (renal anemia). In embodiments, a patient has non-dialysis dependent chronic kidney disease (NDD-CKD). In embodiments, a patient has dialysis dependent chronic kidney disease (DD-CKD).

Kidney Function

[0437] Methods described herein can be useful for improving kidney function in patients in need thereof. In embodiments, methods described herein can result in improved (e.g., synergistic) therapeutic effects as compared to monotherapy (e.g., administration of a HIF-PH inhibitor or an iron-containing composition alone). In particular, the effects on kidney function may be improved as compared to monotherapy: for example, the observed effects may be synergistic. For example, an increased EPO level may be observed, and thus methods described herein may be particularly beneficial to a patient having chronic kidney disease (e.g., non-dialysis dependent chronic kidney disease or dialysis dependent chronic kidney disease) at commencement treatment according to methods described herein.

[0438] In embodiments, provided herein is a method of improving kidney function comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0439] In embodiments, kidney function is characterized by estimated glomerular filtration rate (eGFR). In embodiments, kidney function is characterized by creatinine clearance (CLcr). In embodiments, kidney function is characterized by urine protein excretion. In embodiments, kidney function is characterized by dialysis status. In embodiments, improved kidney function is characterized by avoiding or delaying dialysis.

[0440] In embodiments, provided herein is a method of increasing glomerular filtration rate (GFR) comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0441] In embodiments, HIF-PH inhibitors include (but are not limited to) vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85- 3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is daprodustat, roxadustat, or vadadustat. In embodiments, a HIF-PH inhibitor is vadadustat.

[0442] In embodiments, an iron-containing composition is oral iron or an iron-containing phosphorus adsorbent. In embodiments, iron-containing compositions include (but are not limited to) ferrous sulfate, sodium ferrous citrate, ferric citrate, and sucroferric oxyhydroxide. In embodiments, an iron-containing composition is ferric citrate.

[0443] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs concomitantly (concomitant administration). In embodiments, concomitant administration of a compound (e.g., a first compound) and administration of the other compound (e.g., a second compound) occur within a time period that is no more than one about hour (e.g., no more than about 1, 5, 10, 15, 20, 25 or 30 minutes). In embodiments, concomitant administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs simultaneously (simultaneous administration) where both compounds are administered at the same time. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0444] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs sequentially (sequential administration). In embodiments, a first compound is given at least about 1, 2, or 4 hours before and/or after taking a second compound. In embodiments, a first compound is given at least about 4 hours before and/or after taking a second compound. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0445] In embodiments, a first compound is a HIF-PH inhibitor that is vadadustat and is administered at a total daily dose of about 150-600 mg. In embodiments, a second compound is an iron-containing composition that is ferric citrate and is administered at a total daily dose of about 1-12 grams. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed about 5, 10, 15, or 20 days after commencement of the treatment. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed for about 5, 10, 15, 20, or more than 20 days during the treatment.

[0446] In embodiments, a patient has iron deficiency anemia (e.g., a patient may have iron deficiency anemia at commencement of treatment according to methods described herein). In embodiments, a patient has anemia secondary to or associated with chronic kidney disease (renal anemia). In embodiments, a patient has non-dialysis dependent chronic kidney disease (NDD-CKD). In embodiments, a patient has dialysis dependent chronic kidney disease (DD-CKD).

Other Diseases

[0447] Methods described herein can be useful for, e.g., treating a hypoxic or ischemic disorder, or stabilizing the alpha subunit of hypoxia inducible factor (HIFa), in patients in need thereof. In embodiments, methods described herein can result in improved (e.g., synergistic) therapeutic effects as compared to monotherapy (e.g., administration of a HIF-PH inhibitor or an iron-containing composition alone). In particular, the effects on treating a hypoxic or ischemic disorder, or stabilizing HIFa may be improved as compared to monotherapy: for example, the observed effects may be synergistic.

[0448] In embodiments, provided herein is a method of treating a hypoxic or ischemic disorder or condition comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0449] In embodiments, provided herein is a method of stabilizing the alpha subunit of hypoxia inducible factor (HIFa) comprising administering to a patient in need thereof an effective amount of a compound (e.g., a first compound) that is a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, and a compound (e.g., a second compound) that is an iron-containing composition.

[0450] In embodiments, HIF-PH inhibitors include (but are not limited to) vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85- 3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is daprodustat, roxadustat, or vadadustat. In embodiments, a HIF-PH inhibitor is vadadustat.

[0451] In embodiments, an iron-containing composition is oral iron or an iron-containing phosphorus adsorbent. In embodiments, iron-containing compositions include (but are not limited to) ferrous sulfate, sodium ferrous citrate, ferric citrate, and sucroferric oxyhydroxide. In embodiments, an iron-containing composition is ferric citrate. [0452] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs concomitantly (concomitant administration). In embodiments, concomitant administration of a compound (e.g., a first compound) and administration of the other compound (e.g., a second compound) occur within a time period that is no more than one about hour (e.g., no more than about 1, 5, 10, 15, 20, 25 or 30 minutes). In embodiments, concomitant administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs simultaneously (simultaneous administration) where both compounds are administered at the same time. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0453] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs sequentially (sequential administration). In embodiments, a first compound is given at least about 1, 2, or 4 hours before and/or after taking a second compound. In embodiments, a first compound is given at least about 4 hours before and/or after taking a second compound. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof.

[0454] In embodiments, a first compound is a HIF-PH inhibitor that is vadadustat and is administered at a total daily dose of about 150-600 mg. In embodiments, a second compound is an iron-containing composition that is ferric citrate and is administered at a total daily dose of about 1-12 grams. In embodiments, the combination therapy is administered for at least 7, 14, 21, or 28 days to a patient in need thereof. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed about 5, 10, 15, or 20 days after commencement of the treatment. In embodiments, an improved (e.g., synergistic) therapeutic effect can be observed for about 5, 10, 15, 20, or more than 20 days during the treatment.

[0455] In embodiments, a patient has iron deficiency anemia (e.g., a patient may have iron deficiency anemia at commencement of treatment according to methods described herein). In embodiments, a patient has anemia secondary to or associated with chronic kidney disease (renal anemia). In embodiments, a patient has non-dialysis dependent chronic kidney disease (NDD-CKD). In embodiments, a patient has dialysis dependent chronic kidney disease (DD-CKD).

Timing of administration

[0456] In embodiments of methods described herein, administration of a compound (e.g., a first compound) that is a HIF-PH inhibitor (e.g., vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), or desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof) and a compound (e.g., a second compound) that is an iron-containing composition (oral iron or iron-containing phosphorus adsorbents) occurs simultaneously (simultaneous administration).

[0457] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs concomitantly (concomitant administration). In embodiments, concomitant administration of a compound (e.g., a first compound) and administration of the other compound (e.g., a second compound) occur within a time period that is no more than one about hour (e.g., no more than about 1, 5, 10, 15, 20, 25 or 30 minutes). In embodiments, concomitant administration of a compound (e.g., a first compound) and administration of the other compound (e.g., a second compound) occur within a time period that is at least about 30 minutes but no more than about one hour. In embodiments, concomitant administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs simultaneously (simultaneous administration) where both compounds are administered at the same time.

[0458] In embodiments of methods described herein, administration of a compound (e.g., a first compound) that is a HIF-PH inhibitor (e.g., vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), or desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof) and a compound (e.g., a second compound) that is an iron-containing composition (oral iron or iron-containing phosphorus adsorbents) occurs sequentially. In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) is separated by a time period. In embodiments, a compound (e.g., a first compound) is administered before administration of the other compound (e.g., a second compound). In embodiments, a compound (e.g., a first compound) is administered after administration of the other compound (e.g., a second compound).

[0459] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs sequentially (sequential administration).

[0460] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) occurs in a time period that is separated by at least about 1 hour to about 6 hours, at least about 2 hours to about 6 hours, at least about 2 hours to about 4 hours, at least about 3 hours to about 6 hours, at least about 4 hours to about 6 hours, at least about 1 hour to about 12 hours, at least about 2 hours to about 12 hours, at least about 3 hours to about 12 hours, at least about 4 hours to about 12 hours, at least about 6 hours to about 12 hours, or at least about 12 hours to about 24 hours.

[0461] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) is separated by a time period that is at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours.

[0462] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) is separated by a time period that is no more than about 12 hours or about 24 hours. In embodiments, administration of a first compound and a second compound is separated by a time period that is no more than about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours.

[0463] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) is separated by a time period that is about 1 hour to about 6 hours, about 2 hours to about 6 hours, about 2 hours to about 4 hours, about 3 hours to about 6 hours, about 4 hours to about 6 hours, about 1 hour to about 12 hours, about 2 hours to about 12 hours, about 3 hours to about 12 hours, about 4 hours to about 12 hours, about 6 hours to about 12 hours, or about 12 hours to about 24 hours.

[0464] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) is separated by a time period that is at least about 1 hour. In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) is separated by a time period that is at least about 2 hours. In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) is separated by a time period that is at least about 4 hours.

[0465] In embodiments, administration of a compound (e.g., a first compound) and the other compound (e.g., a second compound) is separated by a time period that is at least about 4 hours.

[0466] In embodiments, a compound (e.g., a first compound) is administered at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours before the other compound (e.g., a second compound). In other embodiments, a compound (e.g., a first compound) is administered at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after the other compound (e.g., a second compound).

[0467] In embodiments, a compound (e.g., a first compound) is administered at least about 1 hour to about 6 hours, about 2 hours to about 6 hours, about 2 hours to about 4 hours, about 3 hours to about 6 hours, about 4 hours to about 6 hours, about 1 hour to about 12 hours, about 2 hours to about 12 hours, about 3 hours to about 12 hours, about 4 hours to about 12 hours, about 6 hours to about 12 hours, or about 12 hours to about 24 hours before the other compound (e.g., a second compound). In embodiments, a compound (e.g., a first compound) is administered at least about 1 hour to about 6 hours, about 2 hours to about 6 hours, about 2 hours to about 4 hours, about 3 hours to about 6 hours, about 4 hours to about 6 hours, about 1 hour to about 12 hours, about 2 hours to about 12 hours, about 3 hours to about 12 hours, about 4 hours to about 12 hours, about 6 hours to about 12 hours, or about 12 hours to about 24 hours after the other compound (e.g., a second compound).

[0468] In embodiments, a compound (e.g., a first compound) is administered at least about 1 hour before administration of the other compound (e.g., a second compound). In embodiments, a compound (e.g., a first compound) is administered at least about 2 hours before administration of the other compound (e.g., a second compound). In embodiments, a compound (e.g., a first compound) is administered about 4 hours before administration of the other compound (e.g., a second compound).

[0469] In embodiments, a compound (e.g., a first compound is administered at least about 1 hour after administration of the other compound (e.g., a second compound). In embodiments, a compound (e.g., a first compound is administered at least about 2 hours after administration of the other compound (e.g., a second compound). In embodiments, a compound (e.g., a first compound is administered at least about 4 hours after administration of the other compound (e.g., a second compound).

[0470] In embodiments, a compound that is a HIF-PH inhibitor is the first compound administered to the patient. In embodiments, a compound that is a HIF-PH inhibitor is not the first compound administered to the patient. In embodiments, a compound that is a HIF-PH inhibitor is the second compound administered to the patient. Suitable HIF- PH inhibitor include (but are not limited to) those described herein, including compounds such as vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK- 12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof.

[0471] In embodiments, a compound that is an iron-containing composition is the first compound administered to the patient. In embodiments, a compound that is an iron- containing composition is not the first compound administered to the patient. In embodiments, a compound that is an iron-containing composition is the second compound administered to the patient. Suitable iron-containing composition include (but are not limited to) those described herein, including ferrous sulfate, sodium ferrous citrate, ferric citrate, and sucroferric oxyhydroxide. Pharmaceutical Compositions

Formulation (Pharmaceutical Compositions) of HIF-PH Inhibitors

[0472] Pharmaceutical compositions may be used in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms provided herein comprise a HIF prolyl hydroxylase inhibitor, such as a compound described herein ( e.g., vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), or desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof). Pharmaceutical compositions and dosage forms can further comprise one or more excipients. Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors including, but not limited to, the route by which it is to be administered to patients.

[0473] Exemplary formulations of vadadustat are described in WO 2014/200773 and WO/2016/161094, which are incorporated by reference in their entirety. Still further exemplary formulations are described herein.

[0474] In embodiments, a HIF-PH inhibitor may be administered by oral or parenteral route. As used herein, the term "parenteral" includes but not limited to subcutaneous, intradermal, intravascular injections, such as intravenous, intramuscular and any another similar injection or infusion technique; transdermal route; inhalation, and rectal route. In embodiments, a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer may be administered orally, such as in a tablet or capsule formulation. Examples of HIF-PH inhibitors include compounds such as vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is vadadustat or a pharmaceutically acceptable salt thereof.

Oral Formulations

[0475] Pharmaceutical compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. [0476] Oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[0477] In one embodiment, oral dosage forms are tablets or capsules, in which case solid excipients are employed. In another embodiment, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

[0478] For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.

[0479] Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. [0480] Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM. Other suitable forms of microcrystalline cellulose include, but are not limited to, silicified microcrystalline cellulose, such as the materials sold as PROSOLV 50, PROSOLV 90, PROSOLV HD90, PROSOLV 90 LM, and mixtures thereof.

[0481] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is, in one embodiment, present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[0482] In embodiments, fillers may include, but are not limited to block copolymers of ethylene oxide and propylene oxide. Such block copolymers may be sold as POLOXAMER or PLURONIC, and include, but are not limited to POLOXAMER 188 NF, POLOXAMER 237 NF, POLOXAMER 338 NF, POLOXAMER 437 NF, and mixtures thereof.

[0483] In embodiments, fillers may include, but are not limited to isomalt, lactose, lactitol, mannitol, sorbitol xylitol, erythritol, and mixtures thereof.

[0484] Disintegrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients may be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In one embodiment, pharmaceutical compositions comprise from about 0.5 weight percent to about 15 weight percent of disintegrant, or from about 1 to about 5 weight percent of disintegrant.

[0485] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre- gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0486] Glidants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional glidants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB-O-SIL (a pyrogenic colloidal silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, glidants may be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

[0487] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof. [0488] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0489] Suspensions, in addition to the active inhibitor(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulation (Pharmaceutical Compositions) of Iron-Containing Composition

[0490] Exemplary formulations of an iron-containing composition are described in WO 2011/011541 and WO 2013/192565, which are incorporated by reference in their entirety. Still further exemplary formulations are described herein.

[0491] In embodiments, an iron-containing composition is formulated for oral administration (oral iron). In embodiments, an iron-containing composition is formulated for intravenous administration.

[0492] An iron-containing composition can further comprise any of the excipients described herein (e.g., as described for formulations of a HIF-PH inhibitor), as well as any combinations thereof.

[0493] In one embodiment, an iron-containing composition is in the form of a tablet.

Such tablets may be produced by tableting, e.g., direct compressing, the iron-containing composition as a pure powder, i.e., without containing any excipient. In other embodiments, suitable excipients may be added. Such as excipients include antiadherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, vehicles, and mixtures thereof.

[0494] In other embodiments, the tablet is obtained by compression of the granulated powders (i.e. the "inner phase") together with further excipients (the "outer phase"). The inner phase of the iron-containing composition may comprise the phosphate adsorbent, and at least one excipient. The outer phase of the pharmaceutical composition according to the invention may comprise at least one excipient.

[0495] The pharmaceutical compositions according to the present invention may comprise a filler to provide processability. [0496] Suitable filler materials are well-known to the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990), Mack Publishing Co., Easton, Pa., pp. 1635- 1636), and include microcrystalline cellulose, lactose and other carbohydrates, starch, pregelatinized starch, e.g., starch 1500R (Colorcon Corp.), corn starch, dicalcium phosphate, potassium bicarbonate, sodium bicarbonate, cellulose, calcium phosphate dibasic anhydrous, sugars, sodium chloride, and mixtures thereof, of which lactose, micro-crystalline cellulose, pregelatinized starch, and mixtures thereof, are preferred. Owing to its superior disintegration and compression properties, microcrystalline cellulose (Avicel grades, FMC Corp.), and mixtures comprising microcrystalline cellulose and one or more additional fillers, e.g., corn starch or pregelatinized starch, are particularly useful.

[0497] In certain embodiments, the iron-containing composition is a tablet that is formulated to be a slow-release tablet.

[0498] In other embodiments, the iron-containing composition is a tablet that is formulated to be a chewable tablet.

Doses and Dosing Regimens

Doses and Dosing Regimens of a HIF-PH Inhibitor

[0499] The specific doses for uses of a HIF-PH inhibitor as described herein can be administered in any manner known to the skilled artisan. Exemplary doses are provided herein, including in the Examples.

[0500] In embodiments, a disease or condition as described herein, may be treated by administering a HIF-PH inhibitor to a patient in need thereof. In embodiments, the dose of a HIF-PH inhibitor is about 1 mg to about 1500 mg. In embodiments, the dose of a HIF-PH inhibitor is about 1 mg to about 1800 mg. In embodiments, the dose of a HIF-PH inhibitor is about 1 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 600 mg, about 60 mg to about 800 mg, about 800 mg to about 1000 mg, about 1000 mg to about 1200 mg, about 1200 mg to about 1500 mg, about 1500 mg to about 1800 mg. [0501] In embodiments, the dose of a HIF-PH inhibitor is about 1 mg to about 6 mg, about 1 mg to about 10 mg, or about 1 mg to about 20 mg. In embodiments, the dose of a HIF-PH inhibitor is at least about 1 mg to about 6 mg, about 1 mg to about 10 mg, or about 1 mg to about 20 mg. In embodiments, the dose of a HIF-PH inhibitor is no more than about 1 mg to about 6 mg, about 1 mg to about 10 mg, or about 1 mg to about 20 mg.

[0502] In embodiments, the dose of a HIF-PH inhibitor is about 20 mg to about 100 mg, about 20 mg to about 200 mg, or about 20 mg to about 400 mg. In embodiments, the dose of a HIF-PH inhibitor is at least about 20 mg to about 100 mg, about 20 mg to about 200 mg, or about 20 mg to about 400 mg. In embodiments, the dose of a HIF- PH inhibitor is no more than about 20 mg to about 100 mg, about 20 mg to about 200 mg, or about 20 mg to about 400 mg.

[0503] In embodiments, the dose of a HIF-PH inhibitor is about 150 mg to about 600 mg, about 150 mg to about 750 mg, about 150 mg to about 900 mg, about 150 mg to about 1200 mg, about 150 mg to about 1500 mg, about 75 mg to about 1200 mg, about 75 mg to about 1500 mg, or about 75 mg to about 1800 mg. In embodiments, the dose of a HIF-PH inhibitor is at least about 150 mg to about 600 mg, about 150 mg to about 750 mg, about 150 mg to about 900 mg, about 150 mg to about 1200 mg, about 150 mg to about 1500 mg, about 75 mg to about 1200 mg, about 75 mg to about 1500 mg, or about 75 mg to about 1800 mg. In embodiments, the dose of a HIF-PH inhibitor is no more than about 150 mg to about 600 mg, about 150 mg to about 750 mg, about 150 mg to about 900 mg, about 150 mg to about 1200 mg, about 150 mg to about 1500 mg, about 75 mg to about 1200 mg, about 75 mg to about 1500 mg, or about 75 mg to about 1800 mg..

[0504] In embodiments, the dose of a HIF-PH inhibitor is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 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, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg,.

[0505] In embodiments, the dose of a HIF-PH inhibitor is at least about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 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, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg,.

[0506] In embodiments, the dose of a HIF-PH inhibitor is no more than about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 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, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg.

[0507] In embodiments, doses may be administered orally, doses of a HIF-PH inhibitor may be taken while fasting, together with fluids, or together with food of any kind. In specific embodiments, doses of a HIF-PH inhibitor may be taken or 1, 2, 3, 4, 5, 6, 7, 8, 9,

10, 11, or 12 hours after a meal, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours before a meal. Doses of a HIF-PH inhibitor may be taken at any time of day. In certain embodiments, repeat doses are administered at the same time during the day. In certain embodiments, the dose doses are administered in the morning, around mid-day, or in the evening. In certain embodiments, the doses are administered between 4:00 am and 2:00 pm. In certain embodiments, the doses are administered between 5:00 am and 1:00 pm. In certain embodiments, the doses are administered between 6:00 am and 12:00 noon. In certain embodiments, the doses are administered between 7:00 am and 11:00 am. In certain embodiments, the doses are administered between 8:00 am and 10:00 am. In certain embodiments, the doses are administered before, during, or after breakfast. Administration and dosing regimens may be adjusted as described herein.

[0508] In embodiments, a HIF-PH inhibitor is administered to a patient for at least about 1 week to about 260 weeks, about 1 week to about 4 weeks, about 4 weeks to about 52 weeks, or about 52 weeks to about 260 weeks. In embodiments, a HIF-PH inhibitor is administered to a patient for at least about 1 week, for at least about 4 weeks, for at least about 8 weeks, for at least about 12 weeks, for at least about 24 weeks, for at least about 28 weeks, for at least about 32 weeks, for at least about 36 weeks, for at least about 40 weeks, for at least about 44 weeks, for at least about 48 weeks, for at least about 52 weeks, for at least about 64 weeks, for at least about 76 weeks, for at least about 88 weeks, for at least about 104 weeks, for at least about 116 weeks, for at least about 128 weeks, for at least about 140 weeks, for at least about 156 weeks, for at least about 168 weeks, for at least about 180 weeks, for at least about 192 weeks, for at least about 208 weeks, or for at least about 260 weeks.

[0509] In embodiments, such doses may be administered orally, once daily, twice daily, three times daily, three times per week, or once per week.

[0510] In embodiments, HIF-PH inhibitors include (but are not limited to) compounds such as vadadustat (AKB-6548), roxadustat (FG-4592), daprodustat (GSK-12788363), molidustat (BAY 85-3934), enarodustat (JTZ-951), and desidustat (ZYAN1), or a pharmaceutically acceptable salt thereof. In embodiments, a HIF-PH inhibitor is daprodustat, roxadustat, or vadadustat. In embodiments, a HIF-PH inhibitor is vadadustat.

[0511] In embodiments, a HIF-PH inhibitor is daprodustat. In certain embodiments, the dose of daprodustat is about 1 mg to about 6 mg, about 1 mg to 10 mg, or about 1 mg to 20 mg. In certain embodiments, the dose of the compound is about 1 mg to about 10 mg. In embodiments, the dose of daprodustat is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In embodiments, the dose of daprodustat is at least about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In embodiments, the dose of daprodustat is no more than about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg.

[0512] In embodiments, a HIF-PH inhibitor is roxadustat. In embodiments, the dose of roxadustat is about 20 mg to about 100 mg, about 20 mg to about 200 mg, or about 20 mg to about 400 mg. In embodiments, the dose of roxadustat is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 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. In embodiments, the dose of roxadustat is at least about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 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. In embodiments, the dose of roxadustat is no more than about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 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.

[0513] In embodiments, a HIF-PH inhibitor is vadadustat. In embodiments, the dose of vadadustat is about 150 mg to about 600 mg, about 150 mg to 750 mg, about 150 mg to 900 mg, about 150 mg to 1200 mg, about 150 mg to 1500 mg, about 75 mg to 1200 mg, about 75 mg to 1500 mg, or about 75 mg to 1800 mg. In embodiments, the dose of vadadustat is about 75 mg to about 1200 mg, about 150 mg to about 600 mg, or about 150 mg to about 750 mg. In embodiments, the dose of vadadustat is about 75 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg. In embodiments, the dose of vadadustat is at least about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg. In embodiments, the dose of vadadustat is no more than about 75 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg.

[0514] This section provides several exemplary doses for a HIF-PH inhibitor. In certain embodiments, such a dose is the initial dose at the beginning of a treatment. In other embodiments, such a dose is the adjusted dose at a later time during the course of treatment.

Doses and Dosing Regimens of an Iron-Containing Composition

[0515] In embodiments, an iron-containing composition suitable for the methods described herein is a composition formulated for oral administration. [0516] In embodiments, an iron-containing composition suitable for the methods described herein is a composition formulated for intravenous administration.

[0517] In embodiments, an iron-containing composition is administered orally at a dose of at least about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3200 mg, about 3400 mg, about 3600 mg, about 3800 mg, about 4000 mg of elemental iron.

[0518] In embodiments, an iron-containing composition is administered orally at a dose of no more than about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3200 mg, about 3400 mg, about 3600 mg, about 3800 mg, about 4000 mg of elemental iron.

[0519] In embodiments, an iron-containing composition is administered orally at a dose of at least about 0 to 50 mg, 50 mg to 200 mg, 200 mg to 500 mg, 500 mg to 1000 mg, 1000 mg to 1500 mg, 1500 mg to 2000 mg, 2000 mg to 2500 mg, 2500 mg to 3000 mg, 3000 mg to 3500 mg, 3500 mg to 4000 mg of elemental iron.

[0520] In embodiments, an iron-containing composition is administered orally at a dose of no more than about 0 to 50 mg, 50 mg to 200 mg, 200 mg to 500 mg, 500 mg to 1000 mg, 1000 mg to 1500 mg, 1500 mg to 2000 mg, 2000 mg to 2500 mg, 2500 mg to 3000 mg, 3000 mg to 3500 mg, 3500 mg to 4000 mg of elemental iron. In embodiments, a dose is a daily dose. [0521] In embodiments, an iron-containing composition is administered orally at a dose of about 360 mg, 840 mg, 1050 mg, 1260 mg, 1470 mg, 1680 mg, 1890 mg, 2100 mg, 2300 mg, or 2520 mg of elemental iron.

[0522] In embodiments, an iron-containing composition comprises one or more iron (II) salts (ferrous salts). In embodiments, the iron-containing composition is formulated for oral administration.

[0523] In embodiments, an iron-containing composition comprises one or more iron (III) salts (ferric salts). In embodiments, the iron-containing composition is formulated for oral administration.

[0524] In embodiments, an iron-containing composition comprises ferrous sulfate (also known as iron sulfate or iron (II) sulfate), sodium ferrous citrate, ferric citrate, or sucroferric oxyhydroxide.

[0525] In embodiments, an iron-containing composition comprises ferric citrate.

[0526] In embodiments, an iron-containing composition is administered orally at a dose of at least about 250 mg, about 300 mg, about 500 mg, about 600 mg, about 1 g, about

1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, about 10 g, about 10.5 g, about 11 g, about 11.5 g, about 12 g, about

12.5 g, about 13 g, about 13.5 g, about 14 g, about 14.5 g, or about 15 g of ferric citrate. In embodiments, an iron-containing composition is administered orally at a dose of no more than about 250 mg, about 300 mg, about 500 mg, about 600 mg, about 1 g, about

1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, about 10 g, about 10.5 g, about 11 g, about 11.5 g, about 12 g, about

12.5 g, about 13 g, about 13.5 g, about 14 g, about 14.5 g, or about 15 g of ferric citrate. In embodiments, an iron-containing composition is administered orally at a dose of at least about 250 mg to about 1 g, about 1 g to about 3 g, about 3 g to about 5g, about 5g to about 8 g, about 8 g to about 12 g, or about 12 g to about 15 g of ferric citrate. In embodiments, an iron-containing composition is administered orally at a dose of no more than about 250 mg to about 1 g, about 1 g to about 3 g, about 3 g to about 5g, about 5g to about 8 g, about 8 g to about 12 g, or about 12 g to about 15 g of ferric citrate.

[0527] In embodiments, an iron-containing composition is administered continuously and/or indefinitely. In certain embodiments, an iron-containing composition is administered 3 times per days. In certain embodiments, an iron-containing composition is administered once daily. In certain embodiments, an iron-containing composition is administered three times per week. In certain alternative embodiments, the iron- containing composition is administered on an as needed basis.

Exemplification

Examole 1: Administration of vadadustat and Aurvxia (Ferric Citrate) - PGPS model

[0528] A study of the therapeutic effects of test articles (vadadustat and Auryxia) on PGPS (peptidoglycan-polysaccharide) induced model of anemia was undertaken in 45 female Lewis rats.

[0529] Preparation of study subjects: on day -14, the animals had food switched out with a 50 PPM iron limited diet. On study day -7, animals were administered an IP injection of saline or PG-PAS at 7.5 μg/g to induce disease. On study day -1, animals were bled for baseline clinical pathology parameters. On study day 0, animals were randomized into treatment groups (Table 1) based on hemoglobin values and then dosing would begin as described herein.

[0530] Treatment of study subjects: treatment groups received one of the following once daily from day 0 to day 20: vehicle only; Auryxia only; vadadustat only; or a combination of Auryxia and vadadustat, as described in Table 1.

Table 1. Group Designations

[0531] Blood collections were carried out on study day 4, 7, 14, and 21 for CBC (complete blood count), clinical chemistry and serum cytokine analysis. Ankle diameters were measured and corresponding results are summarized herein. Necropsy was carried out on study day 21, and organs were weighted.

[0532] Iron mobilization parameters such as serum iron level, TIBC level, and TSAT level were measured at time points: day -1, 4, 7, 14, and 21 (FIGs. 1a-1c and 2a-2c). Statistical analysis results are summarized in Tables 2-4 below.

Table 2. Serum Iron level

Table 3. TIBC Level

Table 4. TSAT Level

[0533] EPO level was measured at time points: day 4, 7, 14, and 21 (FIGs. 3a and 3b). Statistical analysis results are summarized in Table 5 below.

Table 5. EPO Level

[0534] Serum cytokines (IL-15, IL-6, LIF) were measured at time points: day 4, 7, 14, and 21 (FIGs. 8a-8c). Statistical analysis results are summarized in Tables 6-8 below.

Table 6. IL-15 Level

Table 7. IL-6 Level

Table 8. LIF Level

[0535] Systemic inflammatory parameters (CRP (C-Reactive Protein), haptoglobin) were measured (FIGs. 6 and 7), and statistical analysis results (at day 21) are summarized in Table 9 below.

Table 9. Systemic inflammatory parameters

[0536] Ankle diameter were measured at day 19, 20, and 21 (FIG. 4). Statistical analysis results are summarized in Table 10 below.

Table 10. Ankle Diameter

[0537] Relative organ weights were measured at day 21 (FIG. 5). Statistical analysis results are summarized in Table 11 below.

Table 11. Relative Organ Weights

[0538] Immune cell parameters were measured at day -1, 4, 7, 14, and 21 (FIGs. 9a-9d). Statistical analysis results are summarized in Tables 12-15 below.

Table 12. WBC (White blood cells) Table 13. Neutrophil

Table 14. Lymphocyte

Table 15. Monocyte

[0539] Hematologic parameters were measured at day -1, 4, 7, 14, and 21 (FIGs. 10a- lOf). Statistical analysis results are summarized in Tables 16-21 below.

Table 16. HGB/Hb

Table 17. HCT

Table 18. Reticulocyte

Table 19. MCV Table 20. MCH

Table 21. MCHC

[0540] Thus, administration of vadadustat and Auryxia can lead to improvements in the inflammatory components, such as leading to reduced systemic inflammation. For example, administration of vadadustat and Auryxia resulted in decreased CRP (Table 9 and FIG. 6), haptoglobin (Table 9 and FIG. 7), IL-15 (Table 6 and FIG. 8a), or IL-6 (Table 7 and FIG. 8b), as well as reduced ankle diameter (Table 10 and FIG. 4) and relative organ weight (Table 11 and FIG. 5). Administration of vadadustat and Auryxia also led to improvements in immune cell parameters such as decreased WBC, neutrophil, and/or lymphocyte levels (Tables 12-14 and FIGs. 9a-9c).

[0541] In addition, administration of vadadustat and Auryxia led to improvements in hematologic parameter such as increased HGB/Hb (Table 16 and FIG. 10a), HCT (Table 17 and FIG. 10b), reticulocyte (Table 18 and FIG. 10c), MCV (Table 19 and FIG. 10d), and MCH (Table 20 and FIG. 10e). Improved (e.g., synergistic) effects were observed for MCV (Table 19 and FIG. 10d) and MCH (Table 20 and FIG. 10e) in the combination therapy of vadadustat and Auryxia. [0542] Moreover, administration of vadadustat and Auryxia can lead to improved (e.g., synergistic) therapeutic effects compared to monotherapy (administration of either vadadustat or Auryxia alone). For example, a combination therapy of vadadustat and Auryxia improved iron mobilization compared to monotherapy (administration of either vadadustat or Auryxia alone), Tables 2-4 and FIGs. 1a-1c, 2a-2c. In addition, a combination therapy of vadadustat and Auryxia improved EPO levels and EPO AUC compared to monotherapy (administration of either vadadustat or Auryxia alone), Table 5 and FIGs. 3a, 3b.

Example 2: Administration of vadadustat and Aurvxia (Ferric Citrate) - PGPS model

[0543] A study of the therapeutic effects of test articles (vadadustat and Auryxia) on PGPS (peptidoglycan-polysaccharide) induced model of anemia was undertaken in female Lewis rats.

[0544] Preparation of study subjects: on day -14, the animals had food switched out with a 50 PPM iron limited diet. On study day -7, animals were administered an IP injection of saline or PG-PAS at 7.5 μg/g to induce disease. On study day -1, animals were bled for baseline clinical pathology parameters. On study day 0, animals were randomized into treatment groups (Table 22) and then dosing would begin as described herein.

[0545] Treatment of study subjects: treatment groups received one of the following once daily from day 0 to day 20: vehicle only; Auryxia only; vadadustat only; or a combination of Auryxia and vadadustat, as described in Table 22.

Table 22. Group Designations

[0546] Blood collections were carried out on study day 4, 7, 14, and 21; necropsy was carried out on study day 21. Corresponding results are summarized herein.

[0547] Iron mobilization parameters such as serum iron level, TIBC level, and Fe saturation % were measured at time points: day -2, 4, 7, and 14 (FIGs. 11-13). Statistical analysis results are summarized in Tables 23-25 below.

Table 23. Serum iron level

Table 24. TIBC Level

Table 25. Fe Saturation Level

[0548] Hemoglobin levels were measured at day -2, 4, 7, 14, and 21 (FIGs. 14a-14b). Statistical analysis results are summarized in Table 26 below.

Table 26. HGB/Hb

[0549] As described herein, administration of vadadustat and Auryxia led to improvements in e.g., iron mobilization (Tables 23-25 and FIGs. 11-13) and HGB/Hb levels (Table 26 and FIG. 14a-b). Moreover, administration of vadadustat and Auryxia can lead to improved (e.g., synergistic) therapeutic effects compared to monotherapy (administration of either vadadustat or Auryxia alone). For example, a combination therapy of vadadustat and Auryxia improved iron mobilization compared to monotherapy (administration of either vadadustat or Auryxia alone), Tables 23-25 and FIGs. 11-13. In addition, concomitant administration of vadadustat and Auryxia led to increased serum iron levels compared to sequential administration (administration of vadadustat and Auryxia is separated by a time period), Table 23 and FIGs. 11a-b. Example 3: Administration of vadadustat and Aurvxia (Ferric Citrate) - adenine model

[0550] A study was conducted to determine the effects of test articles (vadadustat and Auryxia) on chronic kidney disease and associated anemia induced by adenine diet in male Wistar rats.

[0551] Preparation of study subjects: on day 0, the animals were bled for baseline clinical pathology, and groups 2 through 7 were placed on a 0.75% adenine diet. On study day

12, the animals were gently heated, and blood was drawn for clinical pathology. On day

13, animals in groups 2 through 7 were randomized into treatment groups (Table 27) based on hemoglobin (HGB) and blood urea nitrogen (BUN) concentrations. Following randomization, these groups were placed on a 0.2% adenine diet for the remainder of the study.

[0552] Treatment of study subjects: as described in Table 27, the rats were treated daily (QD) on study days 14 through 34 by the oral (PO) route with vehicle, ferric citrate (Auryxia°, 650 mg/kg), or vadadustat (90 mg/kg), or by the subcutaneous (SC) route with recombinant human erythropoietin (rhEPO, 30 U/kg). Combination therapy groups received treatment with vadadustat (90 mg/kg, PO) and Auryxia (650 mg/kg, PO) or rhEPO (30 U/kg, SC) and Auryxia (650 mg/kg, PO). Rats in group 1 (normal diet controls) were treated PO with vehicle and remained on standard chow for the entire study.

Table 27. Group and Treatment Information

[0553] Whole blood for CBCs and reticulocyte counts was collected on study days 0, 12, 15, 18, 20, and 28. Serum for evaluation of iron concentration, iron saturation, and TIBC was collected on study days 0, 12, 20, and 28. Necropsy was carried out on study day 35.

[0554] Iron mobilization parameters such as serum iron level, TIBC level, and TSAT level were measured at time points: day 0, 12, 20, 28, and 35 (FIGs. 15-17). Statistical analysis results are summarized in Tables 28-30 below.

Table 28. Serum Iron level

[0555] Vehicle disease control rats had serum iron levels that differed statistically from normal control diet rats over time. Rats dosed singly with vadadustat (90 mg/kg) had significant reduction in serum iron levels as compared to the vehicle disease control group. Rats treated with vadadustat (90 mg/kg) in combination with Auryxia (650 mg/kg) had significantly increased serum iron as compared to the vehicle disease control group (Figures 15a-15b, Table 28).

Table 29. TIBC Level

[0556] Vehicle disease control rats had TIBC that was statistically reduced as compared to normal diet control rats. Rats dosed singly with vadadustat (90 mg/kg) or with vadadustat (90 mg/kg) in combination with Auryxia (650 mg/kg) had significant increases in serum TIBC as compared to the vehicle disease control group Figures 16a- 16b, Table 29).

Table 30. Fe Saturation Level

[0557] Vehicle disease control rats had serum iron saturation that was statistically reduced as compared to normal diet control rats. Rats dosed singly with vadadustat (90 mg/kg) had serum iron saturation that was significantly reduced as compared to the vehicle disease control group. Rats treated with vadadustat (90 mg/kg) in combination with Auryxia (650 mg/kg) had serum iron saturation that was significantly increased as compared to the vehicle disease control group (Figures 17a-17b, Table 30).

[0558] Hemoglobin levels were measured at day 0, 12, 15, 18, 20, 28 and 35 (FIGs. 18a-

18b). Statistical analysis results are summarized in Table 31 below.

Table 31. HGB/Hb

[0559] Hemoglobin concentrations in vehicle disease control rats were statistically reduced as compared to normal diet control rats with a correspondingly significant reduction in AUC. Hemoglobin concentrations were significantly increased in rats treated with vadadustat (90 mg/kg) dosed alone or in combination with Auryxia (650 mg/kg) and in rats treated with rhEPO (30 U/kg) dosed alone or in combination with Auryxia (650 mg/kg) as compared to the vehicle disease control group (Figures 18a-b, Table 31).

[0560] While a number of embodiments of this invention have been described, it is apparent that the basic examples may be altered to provide other embodiments that utilize the compounds, methods, and processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example herein.

[0561] From the ongoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

[0562] All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls.