[(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid (rosaxostat) for treatment of chemotherapy-induced anemia (CIA)

Abstract

The present application relates to a method of using [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) amino] acetic acid (rosaxostat) for the treatment of chemotherapy-induced anemia (CIA), for the treatment of anemia associated with cancer chemotherapy in a subject undergoing chemotherapy with a chemotherapeutic agent, comprising orally administering to the subject a therapeutically effective amount of rosaxostat, wherein the anemia is treated.

Description

[0001] This application is a divisional application of the invention patent application with the application date of November 3, 2023, application number 202311457714.0, and invention name “[(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid (rosuvastatin) for the treatment of chemotherapy-induced anemia (CIA)”. Background of the Invention

[0003] Chemotherapy-induced anemia (CIA) is the result of the reduction of the red blood cells (RBC) produced by the bone marrow due to the bone marrow suppression of chemotherapeutic agents, thereby reducing the hemoglobin (Hb) level. Although some chemotherapeutic drugs, such as cisplatin and ifosfamide, may also produce nephrotoxicity, resulting in a reduction in the production of endogenous erythropoietin, most CIA patients have active kidneys that can generate erythropoietin in response to the RBC reduction caused by chemotherapeutic drugs. Although these patients are anemic, they often show already high serum erythropoietin circulation levels, which shows that only increasing the production of endogenous erythropoietin is usually not enough to treat CIA. Therefore, unlike the erythropoietin deficiency anemia caused by CKD, chemotherapy-induced anemia is mainly caused by the erythroid progenitor proliferation defect in the bone marrow.

[0004] The prevalence of CIA in patients with solid tumors receiving myelosuppressive chemotherapy has been reported to be 86-98%, with higher rates in patients with advanced disease and those receiving multiple cycles of treatment (Xu et al. (2016) Clin Epidemiol 8:61-71). CIA is a significant health burden associated with increased morbidity, mortality, and healthcare costs, as well as decreased quality of life (Xu et al., supra; Busti et al. (2018) Pharmaceuticals (Basel, Switzerland) 11:94). Current management options for CIA include erythropoietin-stimulating agents (ESAs), red blood cell (RBC) transfusions, and iron supplementation (Escobar et al. (2021) Clin Transl Oncol 23:931–939). However, because ESAs are associated with venous thromboembolism and low or slow Hb response rates, they are recommended for symptomatic anemia treatment only at the lowest dose required to avoid RBC transfusions (Escobar et al., supra; Abdel-Razeq and Hashem (2020) Crit Rev Oncol Hematol 145:102837; Samaras and Bennett (2008) Am J Hematol Oncol 7:327–332). In addition, iron supplementation should be avoided in patients receiving cytotoxic chemotherapy (Escobar et al., supra).

[0005] Roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, promotes coordinated erythropoiesis by increasing endogenous erythropoietin, improving iron utilization and reducing hepcidin. In multiple subgroups of patients with chronic kidney disease (CKD), it has been demonstrated that the administration of roxadustat increases erythropoiesis while maintaining plasma erythropoietin levels within or close to the normal physiological range, including in the presence of inflammation, and does not require supplemental intravenous iron. Anemia in CKD patients is essentially due to reduced production of endogenous erythropoietin in the diseased kidneys, i.e., CKD causes erythropoietin deficiency anemia. Although erythropoietin is almost entirely produced by the kidneys, roxadustat surprisingly demonstrates the ability to increase endogenous erythropoietin production, even in patients with advanced renal disease.

[0006] Roxadustat is approved in China, Europe, Japan, and many other countries for the treatment of anemia in patients with CKD who are receiving dialysis and those who are not. In an open-label phase 2 study of roxadustat for anemia in patients with non-myeloid malignancies receiving chemotherapy in the United States, roxadustat was reported to be effective in patients regardless of tumor type and chemotherapy regimen (Glaspy et al. (2023) Am J Hematol 98(5):703-711). However, the study did not compare roxadustat with erythropoietin-stimulating agents (ESAs) or attempt to determine which patients would benefit from roxadustat rather than ESAs. The study was also limited by the demographic characteristics of the subjects involved, limiting the conclusions that could be drawn regarding unrepresented or underrepresented categories.

[0007] Therefore, there is a need for improved therapeutic options for managing anemia in patients receiving myelosuppressive chemotherapy. Summary of the invention

[0008] Disclosed herein is the use of rosuvastat in the preparation of a drug for treating chemotherapy-induced anemia in a subject receiving multi-cycle platinum or non-platinum myelosuppressive chemotherapy for non-myeloid malignancies, wherein the subject has a hemoglobin level of ≤100g / L before treatment, and the subject's blood hemoglobin level is reduced by at least 10g / L after the start of chemotherapy. In some embodiments, the subject has a transferrin saturation (TSAT) of ≥20% and a ferritin of ≥100ng / mL before rosuvastat treatment. In some embodiments, the subject has a C-reactive protein (CRP) level of ≤ULN (upper limit of normal) before rosuvastat treatment. In some embodiments, the subject has a TSAT of ≥20%, a ferritin of ≥100ng / mL, and a CRP of ≤ULN before rosuvastat treatment. In some embodiments, the subject has a serum erythropoietin (Epo) level of ≥200U / L before rosuvastat treatment. In some embodiments, the subject has a blood pressure of ≥60 mL / min / 1.73 m prior to roxadustat treatment. 2 In some embodiments, the subject has an Epo level of ≥200 U / L and an Epo level of ≥60 mL / min / 1.73 m prior to rosuvastatin treatment. 2 In some embodiments, the subject has an Epo level of ≥200 U / L, an eGFR of ≥60 mL / min / 1.73 m 2 eGFR of ≥20%, TSAT of ≥20%, ferritin of ≥100 ng / mL, and CRP of ≤ULN.

[0009] In some embodiments, the subject is receiving multiple cycles of platinum-based myelosuppressive chemotherapy. In some embodiments, the subject is receiving multiple cycles of non-platinum-based myelosuppressive chemotherapy. In some embodiments, the non-myeloid malignancy is selected from breast cancer, lung cancer, gastrointestinal cancer, gynecological cancer, pancreatic cancer, and head and neck cancer. In some embodiments, the subject receives chemotherapy for at least 8 weeks after the start of treatment.

[0010] In some embodiments, the subject is ≥18 years old before treatment. In some embodiments, the subject weighs ≥40 kg before treatment. In some embodiments, the subject has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2 before treatment. In some embodiments, the subject has a life expectancy of ≥6 months at the start of treatment. In some embodiments, the subject is over 18 years old, diagnosed with a non-myeloid malignancy, weighs more than 40 kg, has an ECOGPS of 0, 1 or 2; and has a life expectancy of ≥6 months before roxadustat treatment.

[0011] In some embodiments, the drug is described as being administered to the patient based on a dose of roxadustat relative to the subject's body weight. In some embodiments, the subject has a body weight of 40 to <50 kg, and the roxadustat dose is 50-150 mg, particularly about 100 mg. In some embodiments, the subject has a body weight of 50 to 60 kg, and the roxadustat dose is 70-200 mg, particularly about 120 mg. In some embodiments, the subject has a body weight of> 60 kg, and the roxadustat dose is 100-250 mg, particularly about 150 mg. In some embodiments, the subject has a body weight of> 60 to <80 kg, and the roxadustat dose is 100-200 mg, particularly about 150 mg. In some embodiments, the subject has a body weight of ≥ 80 kg, and the roxadustat dose is 150-250 mg, particularly about 200 mg. In some embodiments, the dose is about 1 to 4 mg roxadustat per kilogram of the subject's body weight. In some embodiments, the dosage is about 1 to 3.5 mg of rosuvastat per kilogram of the subject's body weight. In some embodiments, the dosage is about 1.5 to 3.5 mg of rosuvastat per kilogram of the subject's body weight. In some embodiments, the dosage is about 2.0 to 3.5 mg of rosuvastat per kilogram of the subject's body weight. In some embodiments, the dosage is about 2.0 to 2.5 mg of rosuvastat per kilogram of the subject's body weight, particularly about 2.15 ± 0.33 mg / kg.

[0012] In some embodiments, the drug is described as administering a dose of roxadustat three times a week. In some embodiments, the subject has a body weight of 40 to <50 kg, and the roxadustat is administered three times a week at 50-150 mg, particularly about 100 mg. In some embodiments, the subject has a body weight of 50 to 60 kg, and the roxadustat is administered three times a week at 70-200 mg, particularly about 120 mg. In some embodiments, the subject has a body weight of> 60 kg, and the roxadustat is administered three times a week at 100-250 mg, particularly about 150 mg. In some embodiments, the subject has a body weight of> 60 to <80 kg, and the roxadustat is administered three times a week at 100-200 mg, particularly about 150 mg. In some embodiments, the subject has a body weight of ≥ 80 kg, and the roxadustat is administered three times a week at 150-250 mg, particularly about 200 mg.

[0013] In some embodiments, the rosuvastatin is a crystalline form A, characterized in that the X-ray powder diffraction pattern includes peaks at 8.5, 12.8, 16.2, 21.6, 22.9 and 27.4 ° 2θ ± 0.2 ° 2θ. In some embodiments, the rosuvastatin is a solid having a unimodal particle size distribution of D90 of 21 μm to 29 μm, D50 of 12 μm to 17 μm and D10 of 6 μm to 10 μm. In some embodiments, the drug is formulated for oral administration. In some embodiments, the drug also includes a pharmaceutically acceptable excipient. In some embodiments, the drug is formulated in a capsule. In some embodiments, the capsule contains 20 mg rosuvastatin. In some embodiments, the capsule contains 50 mg rosuvastatin. In some embodiments, the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg of rosuvastat and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, yellow iron oxide, and gelatin. In some embodiments, the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 50 mg of rosuvastat and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising allura red AC, titanium dioxide, yellow iron oxide, and gelatin.

[0014] In some embodiments, the drug is intended to increase the blood hemoglobin level in the subject after administration compared to the hemoglobin level of the subject before the drug is administered. In some embodiments, the subject reaches and maintains a hemoglobin level of>100g / L up to 130g / L during treatment. In some embodiments, the blood hemoglobin level of the subject after administration of the drug increases by ≥10g / L compared to the hemoglobin level of the subject before the drug is administered, provided that the blood hemoglobin level does not exceed 130g / L. In some embodiments, the blood hemoglobin level of the subject after administration of the drug increases by ≥15g / L compared to the hemoglobin level of the subject before the drug is administered, provided that the blood hemoglobin level does not exceed 130g / L. In some embodiments, the blood hemoglobin level of the subject after administration of the drug increases by ≥20g / L compared to the hemoglobin level of the subject before the drug is administered, provided that the blood hemoglobin level does not exceed 130g / L. In some embodiments, the subject has a blood hemoglobin level of ≤100 g / L prior to treatment, and the subject achieves a hemoglobin level of ≥100 g / L up to 130 g / L after treatment.

[0015] In a specific embodiment, the medicament is described for use in treating anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for a non-myeloid malignancy, wherein the subject has a blood hemoglobin level of ≤100 g / L prior to treatment, and comprises administering 100 mg to 150 mg of roxadustat orally to the subject three times per week, wherein the subject achieves a hemoglobin level of ≥110 g / L to 130 g / L during treatment. In some embodiments, the drug is formulated in a capsule, wherein the capsule comprises a capsule fill and a capsule shell; wherein the capsule fill comprises 20 mg rosuvastatin, 101.84 mg lactose monohydrate 310, 9.36 mg microcrystalline cellulose PH101, 6.48 mg povidone K30, 5.76 mg cross-linked carboxymethyl cellulose sodium and 0.56 mg magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, yellow iron oxide and gelatin, wherein the titanium dioxide accounts for 1% of the capsule shell by weight and the yellow iron oxide accounts for 2% of the capsule shell by weight. In some embodiments, the drug is formulated in a capsule, wherein the capsule comprises a capsule fill and a capsule shell; wherein the capsule fill comprises 50 mg rosuvastatin, 254.6 mg lactose monohydrate (310), 23.4 mg microcrystalline cellulose PH101, 16.20 mg povidone K30, 14.40 mg croscarmellose sodium, and 1.4 mg magnesium stearate; and the capsule shell is a gelatin shell comprising allura red AC, titanium dioxide, yellow iron oxide, and gelatin, wherein the allura red AC accounts for 1% by weight of the capsule shell, the titanium dioxide accounts for 1% by weight of the capsule shell, and the yellow iron oxide accounts for 1% by weight of the capsule shell. In some embodiments, the rosuvastatin is in crystalline form A, characterized in that the X-ray powder diffraction pattern includes peaks at 8.5, 12.8, 16.2, 21.6, 22.9, and 27.4°2θ±0.2°2θ. In some embodiments, the roxadustat has a unimodal particle size distribution with a D90 of 21 μm to 29 μm, a D50 of 12 μm to 17 μm, and a D10 of 6 μm to 10 μm.

[0016] In a specific embodiment, the medicament is described as being used to treat anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for a non-myeloid malignancy, wherein the subject has a blood hemoglobin level of ≤100 g / L prior to treatment, and comprises administering to the subject orally 50 mg to 400 mg of roxadustat three times per week, wherein the blood hemoglobin level in the subject increases after the administration of roxadustat compared to the subject's hemoglobin level prior to the administration of roxadustat, provided that the blood hemoglobin level does not exceed 130 g / L; provided that the roxadustat is administered at least 2 days apart and no more than 4 days apart; and if the subject is receiving paclitaxel as part of the myelosuppressive chemotherapy, provided that the roxadustat dose is maintained for 24 hours before or after the subject receives the paclitaxel. In multiple embodiments, the medicament is described as providing an amount of roxadustat administered to the subject based on the subject's weight as disclosed herein.

[0017] In a specific embodiment, the medicament is described for use in treating anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for a non-myeloid malignancy, wherein the subject has a blood hemoglobin level of <100 g / L prior to treatment, and comprises orally administering to the subject 2.0 to 3.5 mg of roxadustat per kg of the subject's body weight three times per week, wherein the blood hemoglobin level in the subject increases after the administration of roxadustat compared to the subject's hemoglobin level before the administration of roxadustat, provided that the blood hemoglobin level does not exceed 130 g / L; provided that the roxadustat is administered at least 2 days apart and no more than 4 days apart; provided that the dose does not exceed 400 mg; and if the subject is receiving paclitaxel as part of the myelosuppressive chemotherapy, provided that the roxadustat dose is maintained for 24 hours before or after the subject receives the paclitaxel.

[0018] In a specific embodiment, the drug is further described as optionally increasing or decreasing the rosuvastat dose until the subject achieves and maintains a blood hemoglobin level of 100 to 120 g / L, provided that the dose does not exceed 400 mg. In some embodiments, the increase or decrease in the rosuvastat dose results in a dose of 50 mg, 70 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The study design described in Example 1 is represented schematically.

[0020] Figure 2A and2B Shown are changes in hemoglobin (Hb) levels from baseline to mean levels during Weeks 9-13. Figure 2A Shown are the mean (SE) of absolute Hb relative to baseline at scheduled visits in the per-protocol set (PPS). Figure 2B Means (SE) of absolute Hb relative to baseline at scheduled visits in the full analysis set (FAS) are shown.

[0021] Figure 3 Forest plots of the primary efficacy results in subgroups are shown. DETAILED DESCRIPTION

[0022] definition

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. Although any method and material similar or equivalent to that described herein may be used in the practice or testing of the present invention, preferred methods, equipment and materials are now described. To describe and disclose the methodology, reagents and tools reported in the publications that can be used in connection with the present invention, all the publications cited herein are incorporated herein by reference in their entirety. This article should be interpreted as the present invention having the right to advance the disclosure due to prior inventions.

[0024] Unless otherwise stated, the articles “a” and “an” used herein mean “one or more” or “at least one.” That is, referring to any element of the present invention by the indefinite article “a” and “an” does not exclude the possibility that more than one of the element is present.

[0025] When the term "about" is used before a numerical designation (eg, temperature, time, amount, and concentration, including ranges), it indicates an approximate value that may vary by ±10%, ±5%, or ±1%.

[0026] "Administering" refers to the introduction of a medicament or drug into a patient. For the drugs of the present invention, oral administration is preferred. The related terms and phrases "administering" and "administering of" when used in conjunction with a medicament or drug (and grammatical equivalents thereof) refer to direct administration (which can be administered to a patient by a medical professional or self-administered by the patient) and / or indirect administration (which can be the act of prescribing a drug). For example, a physician who instructs a patient to self-administer a drug and / or provides a drug prescription to a patient is administering the drug to the patient. In any case, administration requires delivery of the drug to the patient.

[0027] The term "anemia" as used herein refers to a decrease in the number of red blood cells and / or hemoglobin levels in the blood relative to normal blood levels. For example, a subject is considered to be anemic when his hematocrit is less than 36% and / or blood hemoglobin is less than 100 g / L. Anemia may develop in cancer patients undergoing chemotherapy (e.g., chemotherapy with or without cisplatin). Anemia may also be caused by disorders in iron transport, processing, and utilization.

[0028] The phrase "chemotherapy" refers to the use of various cytotoxic agents to treat cancer.

[0029] The term / phrase "chemotherapy-induced anemia" or "CIA" or "anemia associated with cancer chemotherapy" is used interchangeably and refers to anemia that develops in association with the chemotherapy regimen in a subject who is undergoing treatment with a chemotherapeutic agent or a subject who has undergone or is expected to undergo such treatment. Anemia associated with chemotherapy can be determined by anemia that develops after and as a result of the administration of the chemotherapeutic agent. In some embodiments, CIA is determined as a subject having a hemoglobin level of ≤100 g / L, and the subject's blood hemoglobin level decreases by at least 10 g / L after the start of chemotherapy.

[0030] The phrase "multi-cycle chemotherapy" is a term well known in the art and refers to multiple cycles of chemotherapy. A subject undergoing chemotherapy receives the chemotherapeutic agent for a period of time and then has a rest period. The treatment period and the rest period constitute a treatment cycle. A series of cycles is called a course of treatment. A course of treatment has multiple cycles.

[0031] “Myelosuppressive chemotherapy” is chemotherapy that slows the growth of blood-forming cells in the bone marrow. Myelosuppressive chemotherapy kills normal cells in the bone marrow, thereby lowering the number of normal red blood cells, white blood cells, and platelets in the blood and bone marrow.

[0032] "Non-myeloid malignancies" refers to all malignancies except myeloid leukemias. Non-myeloid malignancies include all types of carcinomas, sarcomas, melanomas, lymphomas, lymphoid leukemias, and multiple myeloma.

[0033] The term "pharmaceutically acceptable" means that the material does not have properties that would cause a person skilled in the art to avoid administering the material to a patient, taking into account the disease or condition to be treated and the corresponding route of administration. In addition, the material is considered safe for human or animal administration.

[0034] The "P value" or "probability value" is the probability of obtaining the same or more extreme result as the actual observed result under the assumption of no effect or no difference (null hypothesis).

[0035] The terms "subject", "individual" or "patient" are used interchangeably and, as used herein, are intended to include humans and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cattle, horses, chickens, amphibians and reptiles, but mammals (e.g., non-human primates, sheep, dogs, cats, cattle and horses) are preferred. The medicament is particularly suitable for treating a human patient suffering from a disease or condition described herein.

[0036] "Roxadustat strength", "API strength" or "strength" refers to the amount of roxadustat (compound of Formula (I)) in a particular drug. It is also understood that when referring to "x mg tablet" or "x mg capsule", x is the amount of roxadustat in the tablet or capsule. For example, a 20 mg capsule means that there are 20 mg of roxadustat in the capsule formulation.

[0037] "Treatment," "treating," and "treat" are defined as the action of an agent on a disease, disorder, or condition to alleviate or ameliorate the harmful or any undesirable effect of the disease, disorder, or condition and / or its symptoms. As used herein, treatment encompasses the treatment of human patients and includes: (a) reducing the risk of developing the condition in a patient determined to be susceptible to the disease but not yet diagnosed as having the condition, (b) arresting the progression of the condition, and / or (c) relieving the condition, i.e., causing regression of the condition and / or relieving one or more symptoms of the condition.

[0038] Rosuvastatin, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, is a compound of formula (I):

[0039]

[0040] Also known as [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid. Rosuvastatin has been disclosed in International Publication No. WO2004 / 108681, US Patent No. 7323475 and Chinese Patent Publication No. 102977016.

[0041] Roxadustat promotes coordinated erythropoiesis by increasing endogenous erythropoietin, improving iron utilization and reducing hepcidin. In multiple subgroups of patients with chronic kidney disease (CKD), it has been demonstrated that the administration of roxadustat increases erythropoiesis while maintaining plasma erythropoietin levels within or close to the normal physiological range, including in the presence of inflammation, and does not require supplementary intravenous iron. Anemia in CKD patients is essentially due to the reduction in endogenous erythropoietin production in the diseased kidney, that is, CKD causes erythropoietin deficiency anemia. Although erythropoietin is almost completely produced by the kidney, roxadustat surprisingly demonstrates the ability to increase endogenous erythropoietin production, even in patients with advanced renal disease. Roxadustat is approved for the treatment of anemia in CKD patients receiving dialysis and not receiving dialysis in China, Europe, Japan and many other countries.

[0042] Chemotherapy-induced anemia (CIA) is the result of the red blood cell (RBC) that the bone marrow produces due to the bone marrow suppression of chemotherapeutics reduces, thereby reduces hemoglobin (Hb) level. Although some chemotherapeutics, such as cisplatin and ifosfamide, may also produce nephrotoxicity, causing the generation of endogenous erythropoietin to reduce, most CIA patients have the viable kidney that can generate erythropoietin in response to the RBC that chemotherapeutics causes to reduce. These patients often show already high serum erythropoietin circulation level, although they are anemic, this shows that only increasing endogenous erythropoietin produces and is usually not enough to treat CIA. Therefore, unlike the erythropoietin deficiency anemia caused by CKD, chemotherapy-induced anemia is mainly caused by the erythroid progenitor cell proliferation defect in the bone marrow.

[0043] The present invention provides the use of roxadustat in the preparation of a drug for the treatment of CIA. In some embodiments, the present invention provides the use of roxadustat in the preparation of a drug for the treatment of anemia in a subject receiving multi-cycle platinum or non-platinum myelosuppressive chemotherapy for non-myeloid malignancies, wherein the subject has a hemoglobin level of ≤100g / L before treatment, and the blood hemoglobin level of the subject is reduced by at least 10g / L after the start of chemotherapy. In some embodiments, the subject has a transferrin saturation (TSAT) of ≥20% and a ferritin of ≥100ng / mL before treatment. In some embodiments, the subject has a C-reactive protein (CRP) level of ≤ULN (upper limit of normal) before treatment. In some embodiments, the subject has a TSAT of ≥20%, a ferritin of ≥100ng / mL, and a CRP of ≤ULN before treatment. In some embodiments, the subject has a serum erythropoietin (Epo) level of ≥200U / L before treatment. In some embodiments, the subject has ≥60 mL / min / 1.73 m 2 In some embodiments, the subject has an Epo level of ≥200 U / L and an estimated glomerular filtration rate (eGFR) of ≥60 mL / min / 1.73 m 2 In some embodiments, the subject has an Epo level of ≥200 U / L, an eGFR of ≥60 mL / min / 1.73 m 2 eGFR of ≥20%, TSAT of ≥20%, ferritin of ≥100 ng / mL, and CRP of ≤ULN.

[0044] Transferrin is a plasma glycoprotein, used for iron ions to be transported to various tissues, such as liver, spleen and bone marrow by blood. Each transferrin molecule contains two binding sites for ferric iron, and the degree to which all complements of these binding sites on transferrin in the blood are occupied by ferric iron is called transferrin saturation (TSAT). On the other hand, ferritin is the main intracellular iron storage protein, which keeps iron in a soluble and non-toxic form. It is found that ferritin is a cytoplasmic protein in most tissues, but is secreted in serum in small quantities, and in serum, the plasma ferritin is used as an indirect marker for the total amount of iron stored in the body. This iron regulatory system is usually destroyed during inflammation, resulting in an increase in the chelation of iron in storage and a reduction in circulating iron. High serum ferritin and low TSAT levels may suggest the presence of iron chelation conditions.

[0045] C-reactive protein (CRP) is an acute phase reactant protein found in plasma, whose circulating concentrations are elevated during the acute phase of inflammatory / infectious processes. Therefore, elevated CRP levels are also an indication of underlying inflammation and resulting iron chelation. In subjects with TSAT ≥ 20%, ferritin ≥ 100 ng / mL, and CRP ≤ ULN, anemia due to iron chelation and inflammation is unlikely. Therefore, the anemia in these subjects may have alternative causes.

[0046] Erythropoietin (Epo) is a glycoprotein cytokine that is primarily secreted by the kidney in response to cellular hypoxia, which stimulates red blood cell production in the bone marrow. Low levels of Epo (about 10 mU / mL) continue to secrete enough to compensate for normal red blood cell turnover, but elevated EPO levels (up to 10,000 mU / mL) occur due to renal hypoxia, usually caused by anemia or pulmonary dysfunction. In patients with chronic kidney disease (CKD), Epo deficiency may cause normochromic normocytic anemia. When the glomerular filtration rate (GFR) drops to 60 mL / min / 1.73 m 2 Below 3a (stage CKD), renal Epo production decreases and leads to anemia due to CKD. Recombinant human erythropoietin injection (hereinafter referred to as “SEPO”, Shenyang 3SBio Pharmaceutical Group, Shenyang, China) and roxadustat have both been approved for the treatment of anemia caused by CKD. 2 CKD and resulting anemia are unlikely in subjects with CKD. Therefore, the anemia in these subjects may have other causes.

[0047] In a direct comparison of ESAs and roxadustat in subjects receiving multiple cycles of platinum-based or non-platinum myelosuppressive chemotherapy for non-myeloid malignancies, roxadustat generally performed better than ESAs in the subgroup with TSAT ≥ 20% and ferritin ≥ 100 ng / mL, CRP ≤ ULN, and / or Epo levels ≥ 200 U / L. These subjects may be the most representative of those with anemia caused primarily, if not entirely, by the administration of myelosuppressive chemotherapy agents. Therefore, roxadustat is surprisingly beneficial in the treatment of CIA.

[0048] Therefore, the present invention provides roxadustat for preparing a drug for treating CIA anemia in a subject receiving multi-cycle platinum or non-platinum myelosuppressive chemotherapy for non-myeloid malignancies. The effectiveness of roxadustat does not depend on the type of non-myeloid malignancies in the subject or the chemotherapeutic drugs used. In addition, compared with the treatment using ESA, the ratio of Hb increase of ≥10, 15 and 20g / L in the subject treated with roxadustat is numerically higher, and the time required for roxadustat group to achieve ≥15 and 20g / L Hb increase is shorter than that of ESA group (hemoglobin increase of ≥15 grams / liter is 42.0 days and 52.0 days respectively, and hemoglobin increase of ≥20 grams / liter is 57.0 days and 77.0 days respectively). In patients receiving conventional chemotherapy (e.g., 3-week regimen), the difference of 20 days between roxadustat and ESA in the time of reaching ≥20g / L increase may be clinically significant, because when treated with roxadustat instead of ESA, the patient can reach the required Hb level in advance by about one cycle.

[0049] In one aspect, the present invention provides the use of roxadustat in the preparation of a medicament for treating anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for non-myeloid malignancies, wherein the medicament is administered to the subject at a dose of 50 to 400 mg of roxadustat, wherein the anemia is treated. More specifically, the present invention provides the use of roxadustat in the preparation of a medicament for treating anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for non-myeloid malignancies, wherein the medicament is administered to the subject at a dose of 100 to 150 mg of roxadustat 2 to 3 times per week, wherein the anemia is treated.

[0050] In one aspect, the present invention provides the use of roxadustat in the preparation of a medicament for treating anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for non-myeloid malignancies, wherein the medicament is administered to the subject at a dose of about 1 to 4 mg of roxadustat per kilogram of subject body weight, wherein the anemia is treated. More specifically, the present invention provides the use of roxadustat in the preparation of a medicament for treating anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for non-myeloid malignancies, wherein the medicament is administered to the subject at a dose of about 2.0 to 3.5 mg of roxadustat per kilogram of subject body weight 2 to 3 times per week, wherein the anemia is treated.

[0051] Rosuvastatin

[0052] In some embodiments, roxadustat according to any embodiment described herein is amorphous, anhydrous polymorph, solvate, hydrate or hemihydrate. In some embodiments, roxadustat according to any embodiment described herein is as described in WO2014 / 014835 International Patent Publication, U.S. Patent No. 8883823 and Chinese Patent Publication No. 107382859; each of which is incorporated herein by reference in its entirety. In some embodiments, roxadustat according to any embodiment described herein is amorphous, Form A, Form B, Form C or Form D, as described in WO2014 / 014835. In some embodiments, roxadustat according to any embodiment described herein is an amorphous solid. In some embodiments, roxadustat according to any embodiment described herein is Form A or Form B. In some embodiments, roxadustat according to any embodiment described herein is in Form A, characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 16.2, and 27.4°2θ±0.2°2θ. In some embodiments, roxadustat according to any embodiment described herein is in Form A, characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9, and 27.4°2θ±0.2°2θ. In some embodiments, roxadustat according to any embodiment described herein is in Form A, characterized by an X-ray powder diffraction pattern as shown in Table 1.

[0053] Table 1: X-ray powder diffraction pattern of rosuvastatin Form A

[0054]

[0055]

[0056] In some embodiments, rosuvastatin according to any embodiment described herein has a particle size distribution as described in Chinese Patent Publication No. 116199628. In some embodiments, rosuvastatin is a solid having a unimodal particle size distribution of D90 of 21 μm to 29 μm, D50 of 12 μm to 17 μm, and D10 of 6 μm to 10 μm. In some embodiments, rosuvastatin is a crystalline form A having a unimodal particle size distribution of D90 of 21 μm to 29 μm, D50 of 12 μm to 17 μm, and D10 of 6 μm to 10 μm.

[0057] Roxadustat

[0058] In one aspect, the drug comprises only rosuvastatin. On the other hand, the drug comprises rosuvastatin and at least one pharmaceutically acceptable excipient. In some embodiments, the drug comprises rosuvastatin and at least one pharmaceutically acceptable excipient formulated for oral administration. In some embodiments, the drug formulated for oral administration is described in International Patent Application Publication No. WO2014 / 197660, U.S. Patent No. 10765672, Chinese Patent Application Publication No. 111728951 and / or Chinese Patent Application No. 116199628.

[0059] In some embodiments, the medicament according to any embodiment described herein is an oral pharmaceutical composition, wherein the excipient of the rosuvastat oral pharmaceutical composition is selected from a diluent, a binder, a disintegrant and a lubricant or a combination thereof. In some embodiments, the rosuvastat oral pharmaceutical composition according to any embodiment described herein further comprises a light stabilizer. In some embodiments, the light stabilizer is selected from one or more of allura red AC, titanium dioxide and yellow iron oxide. In some embodiments, the light stabilizer comprises titanium dioxide and yellow iron oxide. In some embodiments, the light stabilizer comprises allura red AC, titanium dioxide and yellow iron oxide.

[0060] In some embodiments, the medicine according to any embodiment described herein is a tablet or capsule. In some embodiments, the medicine according to any embodiment described herein is a capsule. In some embodiments, the medicine according to any embodiment described herein is a capsule containing 20 mg of rosuvastat and at least one suitable excipient for oral capsule delivery. In some embodiments, the medicine according to any embodiment described herein is a capsule containing 50 mg of rosuvastat and at least one suitable excipient for oral capsule delivery.

[0061] In some embodiments, the drug according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 20 mg of rosuvastat according to any embodiment described herein and a pharmaceutically acceptable excipient, the pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, cross-linked carboxymethyl cellulose sodium and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, yellow iron oxide and gelatin. In some embodiments, the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, cross-linked carboxymethyl cellulose sodium and magnesium stearate. In some embodiments, the capsule fill comprises 101.84 mg lactose monohydrate 310, 9.36 mg microcrystalline cellulose PH101, 6.48 mg povidone K30, 5.76 mg cross-linked carboxymethyl cellulose sodium and 0.56 mg magnesium stearate. In some embodiments, titanium dioxide and yellow iron oxide account for 3% of the capsule shell by weight. In some embodiments, titanium dioxide comprises 1% by weight of the capsule shell and yellow iron oxide comprises 2% by weight of the capsule shell.

[0062] In some embodiments, the drug according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 20 mg of solid rosuvastatin, wherein the solid rosuvastatin has a unimodal particle size distribution of D90 of 21 μm to 29 μm, D50 of 12 μm to 17 μm, and D10 of 6 μm to 10 μm; and a pharmaceutically acceptable excipient, the pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, cross-linked carboxymethyl cellulose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, yellow iron oxide, and gelatin. In some embodiments, the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, cross-linked carboxymethyl cellulose sodium, and magnesium stearate. In some embodiments, the capsule fill comprises 101.84 mg lactose monohydrate 310, 9.36 mg microcrystalline cellulose PH101, 6.48 mg povidone K30, 5.76 mg cross-linked carboxymethyl cellulose sodium and 0.56 mg magnesium stearate. In some embodiments, titanium dioxide and yellow iron oxide account for 3% of the capsule shell by weight. In some embodiments, titanium dioxide accounts for 1% of the capsule shell by weight and yellow iron oxide accounts for 2% of the capsule shell by weight.

[0063] In some embodiments, the medicament according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 20 mg of solid rosuvastatin, wherein the rosuvastatin is rosuvastatin Form A characterized by an X-ray powder diffraction pattern including peaks at 8.5, 12.8, 16.2, 21.6, 22.9 and 27.4°2θ±0.2°2θ; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, cross-linked carboxymethyl cellulose sodium and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, yellow iron oxide and gelatin. In some embodiments, the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, cross-linked carboxymethyl cellulose sodium and magnesium stearate. In some embodiments, the capsule fill comprises 101.84 mg lactose monohydrate 310, 9.36 mg microcrystalline cellulose PH101, 6.48 mg povidone K30, 5.76 mg cross-linked carboxymethyl cellulose sodium and 0.56 mg magnesium stearate. In some embodiments, titanium dioxide and yellow iron oxide account for 3% of the capsule shell by weight. In some embodiments, titanium dioxide accounts for 1% of the capsule shell by weight and yellow iron oxide accounts for 2% of the capsule shell by weight.

[0064] In some embodiments, the medicament according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 20 mg of solid rosuvastatin, wherein the rosuvastatin is rosuvastatin Form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9 and 27.4°2θ±0.2°2θ; and has a unimodal particle size distribution of D90 of 21 μm to 29 μm, D50 of 12 μm to 17 μm, and D10 of 6 μm to 10 μm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, yellow iron oxide, and gelatin. In some embodiments, the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, cross-linked carboxymethyl cellulose sodium and magnesium stearate. In some embodiments, the capsule fill comprises 101.84 mg lactose monohydrate 310, 9.36 mg microcrystalline cellulose PH101, 6.48 mg povidone K30, 5.76 mg cross-linked carboxymethyl cellulose sodium and 0.56 mg magnesium stearate. In some embodiments, titanium dioxide and yellow iron oxide account for 3% of the capsule shell by weight. In some embodiments, titanium dioxide accounts for 1% of the capsule shell by weight and yellow iron oxide accounts for 2% of the capsule shell by weight.

[0065] In some embodiments, the medicament according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 20 mg of solid roxadustat, wherein the roxadustat is roxadustat Form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9, and 27.4° 2θ ± 0.2° 2θ; and having a D90 of 21 μm to 29 μm, a D50 of 12 μm to 17 μm, and a D20 of 6 μm to 10 μm. 10 μm; and a pharmaceutically acceptable excipient comprising 101.84 mg lactose monohydrate 310, 9.36 mg microcrystalline cellulose PH101, 6.48 mg povidone K30, 5.76 mg cross-linked carboxymethyl cellulose sodium and 0.56 mg magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, yellow iron oxide and gelatin; wherein the titanium dioxide accounts for 1% of the capsule shell by weight and the yellow iron oxide accounts for 2% of the capsule shell by weight.

[0066] In some embodiments, the drug according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 50 mg of rosuvastatin and a pharmaceutically acceptable excipient, the pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, cross-linked carboxymethyl cellulose sodium and magnesium stearate; and the capsule shell is a gelatin shell comprising allura red AC, titanium dioxide, yellow iron oxide and gelatin. In some embodiments, the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, cross-linked carboxymethyl cellulose sodium and magnesium stearate. In some embodiments, the capsule fill comprises 254.6 mg lactose monohydrate (310), 23.4 mg microcrystalline cellulose PH101, 16.20 mg povidone K30, 14.40 mg cross-linked carboxymethyl cellulose sodium and 1.4 mg magnesium stearate. In some embodiments, allura red AC, titanium dioxide and yellow iron oxide account for 3% of the capsule shell by weight. In some embodiments, Allura Red AC comprises 1% by weight of the capsule shell, titanium dioxide comprises 1% by weight of the capsule shell, and yellow iron oxide comprises 1% by weight of the capsule shell.

[0067] In some embodiments, the drug according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 50 mg of solid rosuvastatin, wherein the rosuvastatin has a unimodal particle distribution of D90 of about 21 μm to 29 μm, D50 of about 12 μm to 17 μm, and D10 of about 6 μm to 10 μm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, cross-linked carboxymethyl cellulose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising allura red AC, titanium dioxide, yellow iron oxide, and gelatin. In some embodiments, the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, cross-linked carboxymethyl cellulose sodium, and magnesium stearate. In some embodiments, the capsule fill comprises 254.6 mg lactose monohydrate (310), 23.4 mg microcrystalline cellulose PH101, 16.20 mg povidone K30, 14.40 mg croscarmellose sodium, and 1.4 mg magnesium stearate. In some embodiments, allura red AC, titanium dioxide, and yellow iron oxide account for 3% of the capsule shell by weight. In some embodiments, allura red AC accounts for 1% of the capsule shell by weight, titanium dioxide accounts for 1% of the capsule shell by weight, and yellow iron oxide accounts for 1% of the capsule shell by weight.

[0068] In some embodiments, the medicament according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 50 mg solid rosuvastatin, wherein the rosuvastatin is rosuvastatin Form A characterized by an X-ray powder diffraction pattern including peaks at 8.5, 12.8, 16.2, 21.6, 22.9 and 27.4°2θ±0.2°2θ; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, cross-linked carboxymethyl cellulose sodium and magnesium stearate; and the capsule shell is a gelatin shell comprising allura red AC, titanium dioxide, yellow iron oxide and gelatin. In some embodiments, the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, cross-linked carboxymethyl cellulose sodium and magnesium stearate. In some embodiments, the capsule fill comprises 254.6 mg lactose monohydrate (310), 23.4 mg microcrystalline cellulose PH101, 16.20 mg povidone K30, 14.40 mg croscarmellose sodium, and 1.4 mg magnesium stearate. In some embodiments, allura red AC, titanium dioxide, and yellow iron oxide account for 3% of the capsule shell by weight. In some embodiments, allura red AC accounts for 1% of the capsule shell by weight, titanium dioxide accounts for 1% of the capsule shell by weight, and yellow iron oxide accounts for 1% of the capsule shell by weight.

[0069] In some embodiments, the medicament according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 50 mg of solid rosuvastatin, wherein the rosuvastatin is rosuvastatin Form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9 and 27.4°2θ±0.2°2θ; and has a unimodal particle size distribution of D90 of 21 μm to 29 μm, D50 of 12 μm to 17 μm, and D10 of 6 μm to 10 μm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and the capsule shell is a gelatin shell comprising allura red AC, titanium dioxide, yellow iron oxide, and gelatin. In some embodiments, the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, cross-linked carboxymethyl cellulose sodium and magnesium stearate. In some embodiments, the capsule fill comprises 254.6 mg lactose monohydrate (310), 23.4 mg microcrystalline cellulose PH101, 16.20 mg povidone K30, 14.40 mg cross-linked carboxymethyl cellulose sodium and 1.4 mg magnesium stearate. In some embodiments, allura red AC, titanium dioxide and yellow iron oxide account for 3% of the capsule shell by weight. In some embodiments, allura red AC accounts for 1% of the capsule shell by weight, titanium dioxide accounts for 1% of the capsule shell by weight and yellow iron oxide accounts for 1% of the capsule shell by weight.

[0070] In some embodiments, the medicament according to any embodiment described herein is a capsule comprising a capsule fill and a capsule shell, wherein: the capsule fill comprises 50 mg of solid roxadustat, wherein the roxadustat is roxadustat Form A characterized by an X-ray powder diffraction pattern comprising peaks at 8.5, 12.8, 16.2, 21.6, 22.9 and 27.4° 2θ ± 0.2° 2θ; and having a unimodal particle size of D90 of 21 μm to 29 μm, D50 of 12 μm to 17 μm and D10 of 6 μm to 10 μm distribution; and a pharmaceutically acceptable excipient, the pharmaceutically acceptable excipient comprising 254.6 mg lactose monohydrate (310), 23.4 mg microcrystalline cellulose PH101, 16.20 mg povidone K30, 14.40 mg cross-linked carboxymethyl cellulose sodium and 1.4 mg magnesium stearate; and the capsule shell is a gelatin shell comprising allura red AC, titanium dioxide, yellow iron oxide and gelatin; wherein allura red AC accounts for 1% of the capsule shell by weight, titanium dioxide accounts for 1% of the capsule shell by weight and yellow iron oxide accounts for 1% of the capsule shell by weight.

[0071] Those skilled in the art will appreciate that more than one roxadustat drug may be administered to a subject to achieve the desired dose. For example, if a subject requires a 100 mg dose of roxadustat, that dose may be achieved by taking two 50 mg capsules or tablets simultaneously, or, a 100 mg dose may be achieved by administering five 20 mg tablets or capsules. For example, a 120 mg dose of roxadustat may be achieved by administering one 70 mg tablet or capsule and one 50 mg tablet or capsule; by administering six 20 mg tablets or capsules; or by administering two 50 mg tablets or capsules and one 20 mg tablet or capsule. For example, a 150 mg dose may be achieved by administering one 150 mg tablet or capsule; by administering three 50 mg tablets or capsules; by administering one 100 mg tablet or capsule and one 50 mg tablet or capsule; or by administering one 50 mg tablet or capsule and five 20 mg tablets or capsules.

[0072] Subjects

[0073] In some embodiments, the subject according to any embodiment described herein is a patient who is undergoing chemotherapy and suffers from anemia associated with chemotherapy treatment. In some embodiments, the subject according to any embodiment described herein has been diagnosed with a non-myeloid malignancy, and anemia is associated with myelosuppressive chemotherapy. In some embodiments, the subject according to any embodiment described herein has a hemoglobin level of ≤100g / L before rosuvastat treatment. In some embodiments, the subject according to any embodiment described herein has a hemoglobin level of ≤100g / L before rosuvastat treatment, and the subject's blood hemoglobin level is reduced by at least 10g / L after the start of chemotherapy.

[0074] In some embodiments, the subject according to any embodiment described herein has a transferrin saturation (TSAT) of ≥20% and a ferritin of ≥100ng / mL before roxadustat treatment. In some embodiments, the subject according to any embodiment described herein has a C-reactive protein (CRP) level of ≤ULN (upper limit of normal) before roxadustat treatment. In some embodiments, the subject according to any embodiment described herein has a serum erythropoietin (Epo) level of ≥200U / L before roxadustat treatment. In some embodiments, the subject according to any embodiment described herein has a serum erythropoietin (Epo) level of ≥60mL / min / 1.73m before roxadustat treatment. 2 In some embodiments, the subject according to any embodiment described herein has an Epo level of ≥200 U / L, ≥60 mL / min / 1.73 m 2eGFR of ≥20%, TSAT of ≥20%, ferritin of ≥100 ng / mL, and CRP of ≤ULN.

[0075] In some embodiments, the subject according to any embodiment described herein is ≥18 years old. In some embodiments, the subject according to any embodiment described herein weighs ≥40 kg. In some embodiments, the subject according to any embodiment described herein has an Eastern Cooperative Oncology Group performance status (ECOGPS) of 0, 1 or 2. In some embodiments, the subject according to any embodiment described herein has a life expectancy of ≥6 months at the start of roxadustat treatment.

[0076] In some embodiments, the subject according to any embodiment as described herein has one or more of the aforementioned conditions. In some embodiments, the subject according to any embodiment as described herein has two or more of the aforementioned conditions. In some embodiments, the subject according to any embodiment as described herein has three or more of the aforementioned conditions. In some embodiments, the subject according to any embodiment as described herein has four or more of the aforementioned conditions. In some embodiments, the subject according to any embodiment as described herein has five or more of the aforementioned conditions. In some embodiments, the subject according to any embodiment as described herein has six or more of the aforementioned conditions. In some embodiments, the subject according to any embodiment as described herein has seven or more of the aforementioned conditions. In some embodiments, the subject according to any embodiment as described herein has eight or more of the aforementioned conditions. In some embodiments, the subject according to any embodiment as described herein has all of the aforementioned conditions.

[0077] In some embodiments, the subject according to any embodiment described herein is a patient as described below:

[0078] Over 18 years old;

[0079] Weight exceeds 40kg;

[0080] Diagnosed with non-myeloid malignancy;

[0081] Have an Eastern Cooperative Oncology Group performance status (ECOGPS) of 0, 1, or 2;

[0082] Have a life expectancy of ≥ 6 months at the start of roxadustat treatment; and

[0083] Anemia (defined as Hb ≤ 100 g / L) associated with myelosuppressive chemotherapy before rosuvastatin treatment, and a decrease in blood hemoglobin level of at least 10 g / L after the start of chemotherapy.

[0084] In some embodiments, the subject according to any embodiment described herein is a patient who, prior to roxadustat treatment:

[0085] Have an Epo level ≥200 U / L;

[0086] Have a TSAT of ≥ 20%;

[0087] · Have ferritin ≥100 ng / mL;

[0088] CRP ≤ ULN

[0089] Anemia (defined as Hb ≤ 100 g / L) associated with myelosuppressive chemotherapy before rosuvastatin treatment, and a decrease in blood hemoglobin level of at least 10 g / L after the start of chemotherapy.

[0090] In some embodiments of the invention, roxadustat increases blood hemoglobin levels in a subject after administration, compared to the subject's hemoglobin level before roxadustat administration. In some embodiments of the invention, the subject reaches and maintains a hemoglobin level of>100 g / L during the remainder of roxadustat treatment. In some embodiments, the subject reaches a hemoglobin level of>100 g / L 5-9 weeks after the start of treatment, and maintains a hemoglobin level of>100 g / L during the remainder of treatment. In some embodiments, the subject reaches and maintains a hemoglobin level of>100 g / L up to 130 g / L during treatment.

[0091] Chemotherapy and Non-Myeloid Malignancies

[0092] In some embodiments, the chemotherapeutic agent according to any embodiment described herein is a myelosuppressive chemotherapeutic agent. In some embodiments, the chemotherapeutic agent according to any embodiment described herein is a platinum or non-platinum chemotherapeutic agent. In some embodiments, the chemotherapeutic agent according to any embodiment described herein is a platinum chemotherapeutic agent. In some embodiments, the chemotherapeutic agent according to any embodiment described herein is a platinum chemotherapeutic agent selected from cisplatin, carboplatin, dicycloplatin, oxaliplatin, nedaplatin and satraplatin. In some embodiments, the chemotherapeutic agent according to any embodiment described herein is a non-platinum chemotherapeutic agent. In some embodiments, the chemotherapeutic agent according to any embodiment described herein is selected from albumin-bound paclitaxel (abraxane), actinomycin, alitretinoin, all-trans retinoic acid, hexamethylmelamine, azacitidine, azathioprine, belotecan, bendamustine, bexarotene, bleomycin, bortezomib, busulfan, cabazitaxel, camptothecin, carboquinone, carmustine, capecitabine, chlorambucil, nitrogen mustard, chlorozotocin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, etoposide, exotecan, fluorouracil, fotemustine, gefitinib, gemcitabine, gematine, hydroxyurea, idarubicin, isothiocyanate, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, erlotinib, etoposide, exotecan, fluorouracil, fotemustine, gefitinib, gemcitabine, gematine, hydroxyurea, idarubicin, isothiocyanate, Non-platinum chemotherapy agents of cyclophosphamide, imatinib, irinotecan, ixabepilone, lalotaxel, lomustine, melphalan, melphalan flufenamide, mercaptopurine, methotrexate, dibromomannitol, mitomycin C, mitoxantrone, nimustine, nitrosoureas, paclitaxel, pemetrexed, pipobroman, panimustine, pomedesin, pemustine, streptozotocin, tafoside, docetaxel, temozolomide, tesetaxel, teniposide, thiotepa, thioguanine, topotecan, treosulfan, tretinoin, triazinequinone, triethylene melamine, valrubicin, vemurafenib, vinblastine, vincristine, vindesine, vinorelbine, vismodegib, and vorinostat.

[0093] In some embodiments, other chemotherapeutic agents may be used in addition, wherein the class of chemotherapeutic agents is selected from antimetabolites, plant alkaloids or other natural products, alkylating agents, cytotoxic antibiotics and related substances, hormone antagonists, monoclonal antibodies or antibody drug conjugates, drugs that affect bone structure and calcification, protein kinase inhibitors and other tumor chemotherapeutic agents. In some embodiments, the chemotherapeutic agent according to any embodiment described herein is selected from abemaciclib, astragalus root, atezolizumab, bevacizumab, calcium folinate, calcium levulinate, carrelizumab, capecitabine, carboplatin, cabitinib, cabitinib hydrochloride, cetuximab, cisplatin, cyclophosphamide, denosumab, sodium cantharidate, docetaxel, durvalumab, Acanthopanax root and underground stem, endostatin, envolizumab, epirubicin hydrochloride, eribulin, eribulin mesylate, etoposide, fluorouracil, fulvestrant, gefitinib, gemcitabine , gemcitabine hydrochloride, gemcitabine, inituzumab, irinotecan, irinotecan hydrochloride, liposome doxorubicin, lobaplatin, cantharides, nedaplatin, oteracil potassium, oxaliplatin, paclitaxel, liposome paclitaxel, paclitaxel nanoparticle albumin-bound, ginseng root, pegaspargase, pembrolizumab, pemetrexed, pemetrexed disodium, pemetrexed disodium heptahydrate, penampalimab, pyridoxine hydrochloride, pyrotinib maleate, apatinib mesylate, sintilimab, tamoxifen, tegafur, tislelizumab, toripalimab, and vinorelbine tartrate.

[0094] In some embodiments, the chemotherapeutic agent according to any embodiment described herein is used to treat non-myeloid cancer. In some embodiments, the chemotherapeutic agent according to any embodiment described herein is used to treat lung cancer, breast cancer, head and neck cancer, gastrointestinal malignancies, gynecological malignancies, lymphomas, metastases, bile duct cancer, malignant mesothelioma, esophageal cancer, esophageal squamous cell carcinoma and / or pancreatic cancer. In some embodiments, the chemotherapeutic agent according to any embodiment described herein is used to treat breast cancer, lung cancer, gastrointestinal cancer, gynecological cancer, pancreatic cancer and head and neck cancer.

[0095] In some embodiments, the chemotherapeutic agent according to any embodiment described herein is used to treat gastric adenocarcinoma, cervical adenocarcinoma, adenolymphoma, angiocentric lymphoma, bile duct carcinoma, bladder transitional cell carcinoma, breast cancer, cervical cancer, colon cancer, diffuse large B-cell lymphoma, endometrial cancer, gastric cancer, hepatobiliary carcinoma, invasive breast cancer, invasive ductal breast cancer, nasopharyngeal keratinizing squamous cell carcinoma, lung adenocarcinoma, lung adenocarcinoma stage IV, malignant lung tumor, lung squamous cell carcinoma stage IV, malignant mesothelioma, abdominal metastasis, adrenal Glandular metastasis, bone metastasis, central nervous system metastasis, chest wall metastasis, heart metastasis, liver metastasis, lung metastasis, lymph node metastasis, pancreatic metastasis, pelvic metastasis, peritoneal metastasis, pharyngeal metastasis, pleural metastasis, spinal metastasis, spleen metastasis, nasopharyngeal carcinoma, lung neuroendocrine tumor, esophageal cancer, esophageal squamous cell carcinoma, pancreatic cancer, ovarian cancer, ovarian cancer stage III, papillary thyroid cancer, peritoneal malignant mesothelioma, rectal cancer, pulmonary sarcomatoid carcinoma, small cell lung cancer, lung squamous cell carcinoma, tongue squamous cell carcinoma, laryngeal cancer and / or uterine cancer.

[0096] Roxadustat medication can be started at any time point during chemotherapy. For example, roxadustat medication can be started during the treatment period of a chemotherapy cycle, during the rest period of a chemotherapy cycle, or during both the treatment period and the rest period of a chemotherapy cycle. Roxadustat medication can be administered in any cycle of a chemotherapy process, in more than one cycle of a chemotherapy process, or in all cycles of a chemotherapy process. Roxadustat medication can be administered at the start of a chemotherapy cycle.

[0097] dose

[0098] According to any embodiment described herein, the therapeutically effective dose of the rosuvastatin drug refers to an amount that allows the subject to achieve a hemoglobin level of ≥110 g / L. In some embodiments, the therapeutically effective dose refers to an amount that allows the subject to achieve a hemoglobin level of ≥110 g / L to 130 g / L. In some embodiments, the therapeutically effective dose refers to an amount that allows the subject to achieve a hemoglobin level of 100 to 130 g / L. In some embodiments, the therapeutically effective dose refers to an amount that allows the subject to achieve a hemoglobin level of>100 g / L to 120 g / L.

[0099] In some embodiments, the therapeutically effective dose of the rosuvastat drug according to any embodiment described herein refers to an amount that increases the hemoglobin level of the subject compared to the hemoglobin level before treatment. In some embodiments, the therapeutically effective dose refers to an amount that increases the hemoglobin level of the subject by ≥10 g / L compared to the hemoglobin level before treatment. In some embodiments, the therapeutically effective dose refers to an amount that increases the hemoglobin level of the subject by ≥10 g / L compared to the hemoglobin level before treatment, provided that the blood hemoglobin level does not exceed 130 g / L. In some embodiments, the therapeutically effective dose refers to an amount that increases the hemoglobin level of the subject by ≥15 g / L compared to the hemoglobin level before treatment, provided that the blood hemoglobin level does not exceed 130 g / L. In some embodiments, the therapeutically effective dose refers to an amount that increases the hemoglobin level of the subject by ≥15 g / L compared to the hemoglobin level before treatment, provided that the blood hemoglobin level does not exceed 130 g / L. In some embodiments, a therapeutically effective dose refers to an amount that increases the subject's hemoglobin level by ≥20 g / L compared to the hemoglobin level before treatment. In some embodiments, a therapeutically effective dose refers to an amount that increases the subject's hemoglobin level by ≥20 g / L compared to the hemoglobin level before treatment, provided that the blood hemoglobin level does not exceed 130 g / L.

[0100] In some embodiments, the therapeutically effective dose of the roxadustat drug according to any embodiment described herein is a dose of about 50 to 400 mg of roxadustat provided to the subject. In some embodiments, the therapeutically effective dose according to any embodiment described herein provides about 50 to 250 mg of roxadustat. In some embodiments, the therapeutically effective dose according to any embodiment described herein provides about 100 to 400 mg of roxadustat. In some embodiments, the therapeutically effective dose according to any embodiment described herein provides about 100 to 150 mg of roxadustat. In some embodiments, the therapeutically effective dose according to any embodiment described herein provides an amount of roxadustat selected from 100 mg, 120 mg, and 150 mg. In some embodiments, the therapeutically effective dose according to any embodiment described herein provides about 100 mg of roxadustat. In some embodiments, the therapeutically effective dose according to any embodiment described herein provides about 120 mg of roxadustat. In some embodiments, the therapeutically effective dose according to any embodiment described herein provides about 150 mg of roxadustat.

[0101] In some embodiments, the therapeutically effective dose of the roxadustat drug according to any embodiment described herein is based on the subject's body weight. In some embodiments, the subject has a body weight of 40 to <50kg, and the roxadustat dosage is 50-150mg, particularly about 100mg. In some embodiments, the subject has a body weight of 50 to 60kg, and the roxadustat dosage is 70-200mg, particularly about 120mg. In some embodiments, the subject has a body weight of>60kg, and the roxadustat dosage is 100-250mg, particularly about 150mg. In some embodiments, the subject has a body weight of>60 to <80kg, and the roxadustat dosage is 100-200mg, particularly about 150mg. In some embodiments, the subject has a body weight of ≥80kg, and the roxadustat dosage is 150-250mg, particularly about 200mg.

[0102] In some embodiments, the therapeutically effective dose of the roxadustat drug according to any embodiment described herein is about 1 to 4 mg roxadustat per kilogram of subject body weight, provided that the maximum dose does not exceed 400 mg roxadustat. In some embodiments, the therapeutically effective dose of the roxadustat drug according to any embodiment described herein is about 1 to 3.5 mg roxadustat per kilogram of subject body weight, provided that the maximum dose does not exceed 400 mg roxadustat. In some embodiments, the therapeutically effective dose of the roxadustat drug according to any embodiment described herein is about 1.5 to 3.5 mg roxadustat per kilogram of subject body weight, provided that the maximum dose does not exceed 400 mg roxadustat. In some embodiments, the therapeutically effective dose of the roxadustat drug according to any embodiment described herein is about 2 to 3.5 mg roxadustat per kilogram of subject body weight, provided that the maximum dose does not exceed 400 mg roxadustat. In some embodiments, the therapeutically effective dose of the roxadustat drug according to any embodiment described herein is about 2 to 2.5 mg roxadustat per kilogram of subject body weight, provided that the maximum dose does not exceed 400 mg roxadustat. In some embodiments, the therapeutically effective dose of the roxadustat drug according to any embodiment described herein is about 2 to 2.5 mg roxadustat per kilogram of subject body weight, particularly about 2.15 ± 0.33 mg / kg.

[0103] In some embodiments, roxadustat medicine is described as being used for administering about 1 to 4 mg roxadustat / kilogram of subject body weight (1-4 mg / kg) to a subject two to three times per week. In some embodiments, roxadustat medicine is described as being used for administering about 1-3.5 mg / kg to a subject two to three times per week. In some embodiments, roxadustat medicine is described as being used for administering about 1.5-3.5 mg / kg to a subject two to three times per week. In some embodiments, roxadustat medicine is described as being used for administering about 2-3.5 mg / kg to a subject two to three times per week. In some embodiments, roxadustat medicine is described as being used for administering about 2-2.5 mg / kg to a subject two to three times per week.

[0104] In some embodiments, the roxadustat drug is described as being used to administer about 50 to 400 mg roxadustat to a subject two to three times per week. In some embodiments, the roxadustat drug is described as being used to administer about 50 to 250 mg roxadustat to a subject two to three times per week. In some embodiments, the roxadustat drug is described as being used to administer about 70 to 200 mg roxadustat to a subject two to three times per week. In some embodiments, the roxadustat drug is described as being used to administer about 100 to 150 mg roxadustat to a subject two to three times per week. In some embodiments, the roxadustat drug is described as being used to administer a subject selected from 100 mg, 120 mg, and 150 mg roxadustat two to three times per week.

[0105] In some embodiments, roxadustat drugs are described as being used to administer about 1 to 4 mg roxadustat / kg of subject body weight (1-4 mg / kg) to a subject three times a week. In some embodiments, roxadustat drugs are described as being used to administer about 1-3.5 mg / kg to a subject three times a week. In some embodiments, roxadustat drugs are described as being used to administer about 1.5-3.5 mg / kg to a subject three times a week. In some embodiments, roxadustat drugs are described as being used to administer about 2-3.5 mg / kg to a subject three times a week. In some embodiments, roxadustat drugs are described as being used to administer about 2-2.5 mg / kg to a subject three times a week.

[0106] In some embodiments, the roxadustat drug is described as being used to administer about 50 to 400 mg of roxadustat to a subject three times a week. In some embodiments, the roxadustat drug is described as being used to administer about 50 to 250 mg of roxadustat to a subject three times a week. In some embodiments, the roxadustat drug is described as being used to administer about 70 to 200 mg of roxadustat to a subject three times a week. In some embodiments, the roxadustat drug is described as being used to administer about 100 to 150 mg of roxadustat to a subject three times a week. In some embodiments, the roxadustat drug is described as being used to administer 100 mg, 120 mg, and 150 mg of roxadustat to a subject three times a week.

[0107] In some embodiments, the roxadustat drug is described as being used to administer about 50 to 150 mg of roxadustat to a subject having a body weight of 40 to ≤50 kg. In a specific embodiment, the subject has a body weight of 40 to <50 kg, and roxadustat is administered three times per week at 50 to 150 mg. In a specific embodiment, the subject has a body weight of 40 to <50 kg, and roxadustat is administered three times per week at about 100 mg.

[0108] In some embodiments, the roxadustat drug is described as being used to administer about 70 to 200 mg of roxadustat to a subject having a body weight of 50 to 60 kg. In a specific embodiment, the subject has a body weight of 50 to 60 kg, and roxadustat is administered three times per week at 70 to 200 mg. In a specific embodiment, the subject has a body weight of 50 to 60 kg, and roxadustat is administered three times per week at about 120 mg.

[0109] In some embodiments, the roxadustat drug is described as being used to administer about 100 to 250 mg of roxadustat to a subject with a body weight of>60 kg. In a specific embodiment, the subject has a body weight of>60 kg, and roxadustat is administered three times per week at 100 to 250 mg. In a specific embodiment, the subject has a body weight of>60 kg, and roxadustat is administered three times per week at about 150 mg. In other embodiments, the subject has a body weight of>60 to≤80 kg, and roxadustat is administered three times per week at about 100 to 200 mg. In other embodiments, the subject has a body weight of>60 to<80 kg, and roxadustat is administered three times per week at about 150 mg.

[0110] In some embodiments, the roxadustat medication is described as being used to administer about 150 to 250 mg of roxadustat to a subject having a body weight of ≥80 kg. In a specific embodiment, the subject has a body weight of ≥80 kg, and roxadustat is administered three times per week at 150 to 250 mg. In a specific embodiment, the subject has a body weight of ≥80 kg, and roxadustat is administered three times per week at 200 mg.

[0111] In some embodiments, the roxadustat drug is indicated for administration two to three times per week at a dosage according to any embodiment described herein. In specific embodiments, the roxadustat drug is indicated for administration three times per week at a dosage according to any embodiment described herein.

[0112] In some embodiments, the roxadustat medication is indicated for administering about 50 mg, about 70 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 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 370 mg, about 380 mg, about 390 mg, or about 400 mg of roxadustat to a subject two to three times per week. In some embodiments, the roxadustat medication is indicated for administering about 50 mg, about 70 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, or about 250 mg of roxadustat to a subject three times per week.

[0113] Those skilled in the art understand that symptoms and results may vary with age, sex, and disease burden. Based on Hb levels, the rosuvastatin dosage may be titrated to achieve and maintain an Hb level of 100 to 130 g / L and minimize the need for blood transfusion. By considering the current Hb level and the change in the Hb level during this time period (e.g., within the first 4 weeks), dosage adjustments may be made periodically, e.g., once every 4 weeks.

[0114] In some embodiments, the roxadustat is administered at least 2 days apart and no more than 4 days apart. In some embodiments, roxadustat is administered before or after chemotherapy, but the timing should be consistent throughout the treatment. In some embodiments, if paclitaxel (e.g., TAXOL or ABRAXANE) is given as part of myelosuppressive chemotherapy, the roxadustat dose is maintained for 24 hours before or after paclitaxel treatment (time 0 = infusion time).

[0115] Other Implementations

[0116] The implementation plan includes the following:

[0117] Embodiment 1. Use of roxadustat in the preparation of a medicament for treating chemotherapy-induced anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for non-myeloid malignancies, wherein the subject has a hemoglobin level of ≤100 g / L before treatment and the subject's blood hemoglobin level decreases by at least 10 g / L after the start of chemotherapy.

[0118] Embodiment 2. The use according to embodiment 1, wherein the subject has a serum erythropoietin (Epo) level of ≥200 U / L before treatment.

[0119] Embodiment 3. The use according to embodiment 1 or 2, wherein the subject has ≥60 mL / min / 1.73 m 2 The estimated glomerular filtration rate (eGFR).

[0120] Embodiment 4. The use of any one of embodiments 1 to 3, wherein the subject has a transferrin saturation (TSAT) of ≥20% and a ferritin of ≥100 ng / mL before treatment.

[0121] Embodiment 5. The use of any one of embodiments 1 to 4, wherein the subject has a C-reactive protein (CRP) level of ≤ ULN (upper limit of normal) before treatment.

[0122] Embodiment 6. The use according to any one of Embodiments 1 to 5, wherein the subject is receiving multiple cycles of platinum-based myelosuppressive chemotherapy.

[0123] Embodiment 7. The use according to any one of Embodiments 1 to 5, wherein the subject is receiving multiple cycles of non-platinum myelosuppressive chemotherapy.

[0124] Embodiment 8. The use as described in any one of embodiments 1 to 5, wherein the bone marrow suppressive chemotherapy is selected from abemaciclib, astragalus root, atezolizumab, bevacizumab, leucovorin, leucovorin, capecitabine, carboplatin, cabitinib, cabitinib hydrochloride, cetuximab, cisplatin, cyclophosphamide, denosumab, sodium cantharidate, docetaxel, durvalumab, Acanthopanax senticosus root and rhizome, endostatin, envolimab, epirubicin hydrochloride, eribulin, eribulin mesylate, etoposide, fluorouracil, fulvestrant, gefitinib, Gemcitabine, gemcitabine hydrochloride, gemeriturin, inituzumab, irinotecan, irinotecan hydrochloride, liposome doxorubicin, lobaplatin, cantharides, nedaplatin, oteracil potassium, oxaliplatin, paclitaxel, liposome paclitaxel, paclitaxel nanoparticle albumin-bound, ginseng root, pegaspargase, pembrolizumab, pemetrexed, pemetrexed disodium, pemetrexed disodium heptahydrate, penampalimumab, pyridoxine hydrochloride, pyrotinib maleate, apatinib mesylate, sintilimab, tamoxifen, tegafur, tislelizumab, toripalimumab, and vinorelbine tartrate.

[0125] Embodiment 9. The use according to any one of embodiments 1 to 8, wherein the non-myeloid malignancy is selected from breast cancer, lung cancer, gastrointestinal cancer, gynecological cancer, pancreatic cancer and head and neck cancer.

[0126] Embodiment 10. The use as described in any one of embodiments 1 to 8, wherein the non-myeloid malignancy is selected from gastric adenocarcinoma, cervical adenocarcinoma, adenolymphoma, angiocentric lymphoma, bile duct carcinoma, bladder transitional cell carcinoma, breast cancer, cervical cancer, colon cancer, diffuse large B-cell lymphoma, endometrial cancer, gastric cancer, hepatobiliary carcinoma, invasive breast cancer, invasive ductal breast cancer, nasopharyngeal keratinizing squamous cell carcinoma, lung adenocarcinoma, lung adenocarcinoma stage IV, malignant lung tumor, lung squamous cell carcinoma stage IV, malignant mesothelioma, abdominal cavity metastasis, adrenal metastasis, bone metastasis, central nervous system metastasis, chest wall metastasis, heart metastasis, liver metastasis, lung metastasis, lymph node metastasis, pancreatic metastasis, pelvic metastasis, peritoneal metastasis, pharyngeal metastasis, pleural metastasis, spinal metastasis, spleen metastasis, nasopharyngeal carcinoma, lung neuroendocrine tumor, esophageal cancer, esophageal squamous cell carcinoma, pancreatic cancer, ovarian cancer, ovarian cancer stage III, papillary thyroid cancer, peritoneal malignant mesothelioma, rectal cancer, pulmonary sarcomatoid carcinoma, small cell lung cancer, lung squamous cell carcinoma, tongue squamous cell carcinoma, laryngeal cancer and uterine cancer.

[0127] Embodiment 11. The use of any one of Embodiments 1 to 10, wherein the subject receives chemotherapy for at least 8 weeks after the start of treatment.

[0128] Embodiment 12. The use of any one of embodiments 1 to 11, wherein the subject is ≥ 18 years old before treatment.

[0129] Embodiment 13. The use according to any one of embodiments 1 to 12, wherein the subject weighs ≥ 40 kg before treatment.

[0130] Embodiment 14. The use of any one of Embodiments 1 to 13, wherein the subject has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2 before treatment.

[0131] Embodiment 15. The use of any one of embodiments 1 to 14, wherein the subject has a life expectancy of ≥ 6 months at the start of treatment.

[0132] Embodiment 16. The use according to any one of embodiments 1 to 15, wherein the rosuvastatin is in crystalline Form A, characterized in that the X-ray powder diffraction pattern comprises peaks at 8.5, 12.8, 16.2, 21.6, 22.9 and 27.4° 2θ ± 0.2° 2θ.

[0133] Embodiment 17. The use according to any one of embodiments 1 to 16, wherein the roxadustat is a solid having a unimodal particle size distribution of D90 of 21 μm to 29 μm, D50 of 12 μm to 17 μm, and D10 of 6 μm to 10 μm.

[0134] Embodiment 18. The use according to any one of embodiments 1 to 17, wherein the medicament is formulated for oral administration.

[0135] Embodiment 19. The use according to any one of embodiments 1 to 18, wherein the medicament further comprises a pharmaceutically acceptable excipient.

[0136] Embodiment 20. The use according to any one of embodiments 1 to 19, wherein the medicament is formulated in a capsule.

[0137] Embodiment 21. The use according to embodiment 20, wherein the capsule comprises 20 mg of roxadustat.

[0138] Embodiment 22. The use according to embodiment 20, wherein the capsule comprises 50 mg of roxadustat.

[0139] Embodiment 23. The use according to embodiment 20, wherein the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg of roxadustat and a pharmaceutically acceptable excipient, the pharmaceutically acceptable excipient comprises lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, yellow iron oxide and gelatin.

[0140] Embodiment 24. The use as described in embodiment 20, wherein the drug is formulated in a capsule, wherein the capsule comprises a capsule fill and a capsule shell; wherein the capsule fill comprises 20 mg rosuvastatin, 101.84 mg lactose monohydrate 310, 9.36 mg microcrystalline cellulose PH101, 6.48 mg povidone K30, 5.76 mg croscarmellose sodium and 0.56 mg magnesium stearate; and the capsule shell is a gelatin shell comprising titanium dioxide, yellow iron oxide and gelatin, wherein the titanium dioxide accounts for 1% by weight of the capsule shell and the yellow iron oxide accounts for 2% by weight of the capsule shell.

[0141] Embodiment 25. The use as described in embodiment 20, wherein the capsule comprises a capsule fill and a capsule shell, wherein the capsule fill comprises 50 mg of rosuvastatin and a pharmaceutically acceptable excipient, the pharmaceutically acceptable excipient comprises lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate; and the capsule shell is a gelatin shell comprising Allura Red AC, titanium dioxide, yellow iron oxide and gelatin.

[0142] Embodiment 26. The use as described in embodiment 20, wherein the drug is formulated in a capsule, wherein the capsule comprises a capsule fill and a capsule shell; wherein the capsule fill comprises 50 mg rosuvastatin, 254.6 mg lactose monohydrate (310), 23.4 mg microcrystalline cellulose PH101, 16.20 mg povidone K30, 14.40 mg croscarmellose sodium and 1.4 mg magnesium stearate; and the capsule shell is a gelatin shell comprising Allura Red AC, titanium dioxide, yellow iron oxide and gelatin, wherein the Allura Red AC accounts for 1% by weight of the capsule shell, the titanium dioxide accounts for 1% by weight of the capsule shell and the yellow iron oxide accounts for 1% by weight of the capsule shell.

[0143] Embodiment 27. The use of any one of embodiments 1 to 26, wherein the drug increases the blood hemoglobin level in the subject after administration compared to the hemoglobin level of the subject before administration of the drug.

[0144] Embodiment 28. The use as described in embodiment 27, wherein the subject achieves and maintains a hemoglobin level of >100 g / L up to 130 g / L during treatment.

[0145] Embodiment 29. The use as described in Embodiment 27, wherein the blood hemoglobin level of the subject after administration of the drug increases by ≥10 g / L compared to the hemoglobin level of the subject before administration of the drug, provided that the blood hemoglobin level does not exceed 130 g / L.

[0146] Embodiment 30. The use as described in Embodiment 27, wherein the blood hemoglobin level of the subject after administration of the drug increases by ≥15 g / L compared to the hemoglobin level of the subject before administration of the drug, provided that the blood hemoglobin level does not exceed 130 g / L.

[0147] Embodiment 31. The use as described in Embodiment 27, wherein the blood hemoglobin level of the subject after administration of the drug is increased by ≥20 g / L compared to the hemoglobin level of the subject before administration of the drug, provided that the blood hemoglobin level does not exceed 130 g / L.

[0148] Embodiment 32. The use of any one of embodiments 1 to 31, wherein the medicament is indicated for administration to the patient on a roxadustat dosage basis relative to the subject's body weight.

[0149] Embodiment 33. The use according to embodiment 32, wherein the subject has a body weight of 40 to <50 kg and the roxadustat dose is 50-150 mg, in particular about 100 mg.

[0150] Embodiment 34. The use according to embodiment 32, wherein the subject has a body weight of 50 to 60 kg and the roxadustat dose is 70-200 mg, in particular about 120 mg.

[0151] Embodiment 35. The use according to embodiment 32, wherein the subject has a body weight > 60 kg and the roxadustat dose is 100-250 mg, in particular about 150 mg.

[0152] Embodiment 36. The use according to embodiment 32, wherein the subject has a body weight of >60 to <80 kg and the roxadustat dose is 100-200 mg, in particular about 150 mg.

[0153] Embodiment 37. The use according to embodiment 32, wherein the subject has a body weight of ≥80 kg and the roxadustat dose is 150-250 mg, in particular about 200 mg.

[0154] Embodiment 38. The use according to embodiment 32, wherein the dosage is about 1 to 4 mg of roxadustat per kg of body weight of the subject.

[0155] Embodiment 39. The use according to embodiment 32, wherein the dosage is about 1 to 3.5 mg of roxadustat per kg of body weight of the subject.

[0156] Embodiment 40. The use according to embodiment 32, wherein the dosage is about 1.5 to 3.5 mg of roxadustat per kg of body weight of the subject.

[0157] Embodiment 41. The use according to embodiment 32, wherein the dosage is about 2.0 to 3.5 mg of roxadustat per kg of body weight of the subject.

[0158] Embodiment 42. The use according to embodiment 32, wherein the dosage is about 2.0 to 2.5 mg rosuvastatin per kg body weight of the subject, in particular about 2.15±0.33 mg / kg.

[0159] Embodiment 43. The use of any one of embodiments 1 to 42, wherein the medicament is indicated for administration of roxadustat doses three times per week.

[0160] Embodiment 44. The use of any one of Embodiments 1 to 26, wherein the medicament is indicated for treating anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for a non-myeloid malignancy, wherein the subject has a blood hemoglobin level of ≤100 g / L prior to treatment, and comprising orally administering to the subject 100 mg to 150 mg of roxadustat three times per week, wherein the subject achieves a hemoglobin level of ≥110 g / L to 130 g / L during treatment.

[0161] Embodiment 45. The use of any one of Embodiments 1 to 26, wherein the medicament is indicated for treating anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for a non-myeloid malignancy, wherein the subject has a blood hemoglobin level of ≤100 g / L prior to treatment, and comprises orally administering to the subject 50 mg to 400 mg of roxadustat three times per week, wherein the blood hemoglobin level in the subject increases after the administration of roxadustat compared to the subject's hemoglobin level before the administration of roxadustat, provided that the blood hemoglobin level does not exceed 130 g / L; provided that the roxadustat is administered at least 2 days apart and no more than 4 days apart; and if the subject is receiving paclitaxel as part of the myelosuppressive chemotherapy, provided that the roxadustat dose is maintained for 24 hours before or after the subject receives the paclitaxel.

[0162] Embodiment 46. The use of any one of Embodiments 1 to 26, wherein the medicament is indicated for treating anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for a non-myeloid malignancy, wherein the subject has a blood hemoglobin level of <100 g / L prior to treatment, and comprises administering orally to the subject 2.0 to 3.5 mg of roxadustat per kg of the subject's body weight three times per week, wherein the blood hemoglobin level in the subject increases after the administration of roxadustat compared to the subject's hemoglobin level before the administration of roxadustat, provided that the blood hemoglobin level does not exceed 130 g / L; provided that the roxadustat is administered at least 2 days apart and no more than 4 days apart; provided that the dose does not exceed 400 mg; and if the subject is receiving paclitaxel as part of the myelosuppressive chemotherapy, provided that the roxadustat dose is maintained for 24 hours before or after the subject receives the paclitaxel.

[0163] Embodiment 47. The use of any one of embodiments 1 to 46, wherein the medicament is further described to optionally increase or decrease the roxadustat dose until the subject achieves and maintains a blood hemoglobin level of 100 to 120 g / L, provided that the dose does not exceed 400 mg.

[0164] Embodiment 48. The use of embodiment 47, wherein said increasing or decreasing said roxadustat dose results in a dose of 50 mg, 70 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg or 400 mg.

[0165] Example

[0166] Example 1: A randomized, open-label, active-controlled, multicenter phase 3 study to investigate the use of rosuvastatin in Efficacy and safety of treating anemia in subjects receiving chemotherapy for non-myeloid malignancies

[0167] Study Design

[0168] The study consisted of a screening period of up to 4 weeks, followed by a 12-week treatment period and a subsequent 4-week follow-up period ( Figure 1 ).

[0169] Screening Period (up to 4 weeks): All screening procedures were completed prior to Study Day 1 to determine eligibility for participation in this study.

[0170] Treatment period (12 weeks): Eligible subjects were randomized in a 1:1 ratio to receive rosuvastatin and (recombinant human erythropoietin-α [rHuEPO-α]) and were stratified by screening Hb levels (<90 g / L or ≥90 g / L), tumor type (lung, breast cancer, or other), and chemotherapy regimen (i.e., platinum vs. non-platinum) on study day 1. Subjects underwent 12 weeks of study treatment. Study visits were scheduled every two weeks to regularly assess the clinical status and safety of the subjects.

[0171] Follow-up period (4-week visit after early termination [ET] / end of treatment [EOT]): All patients who completed 12 weeks of rosuvastatin or Treated subjects underwent a 4-week follow-up period. Subjects who discontinued treatment early were encouraged to complete the EOT visit and the 4-week follow-up visit and continue to complete study visits until the Week 17 visit was completed.

[0172] The enrolled subjects are receiving best supportive care. If the subject's condition changes and the subject requires a blood transfusion, the subject may receive a blood transfusion while participating in this study.

[0173] In addition, an independent data monitoring committee was established to review efficacy and safety data regularly during the study. Particular attention was paid to subjects who experienced thromboembolic events.

[0174] Target subject population and sample size

[0175] Subjects aged 18 years or older, with a histologically or cytologically confirmed diagnosis of non-myeloid malignancies, weighing more than 40 kg, with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2, an estimated life expectancy of ≥6 months at enrollment, ferritin ≥50 ng / mL, and transferrin saturation (TSAT) ≥10% were included in the study. Subjects must also have anemia associated with myelosuppressive chemotherapy (defined as Hb ≤100 g / L at screening and a recorded decrease in the subject's Hb level of no less than 10 g / L after the start of chemotherapy as determined by the investigator) and plan to receive at least 8 additional weeks of concurrent cancer treatment (myelosuppressive chemotherapy) after enrollment (study day 1).

[0176] The study was conducted at 44 centers, with a total of 159 subjects (82 roxadustat subjects and 77 SEPO subjects) enrolled, and 155 subjects were treated (81 subjects in the roxadustat group and 74 subjects in the SEPO group). Among the randomized subjects, 102 (64.2%) subjects completed the study treatment according to the protocol (60 subjects in the roxadustat group and 42 subjects in the SEPO group). All 155 treated subjects were included in the Safety Analysis Set, 144 (90.6%) subjects were included in the Full Analysis Set (FAS), and 140 (88.1%) subjects were included in the Per Protocol Set (PPS).

[0177] The FAS was defined as all randomized subjects who received at least one dose of study drug and had at least one non-missing post-baseline Hb value. FAS analyses were performed on the basis of randomized treatment, even if subjects did not receive the correct treatment. The PPS included all FAS subjects with no major protocol deviations that affected the evaluation of the primary endpoint. The Safety Analysis Set (SAF) was defined as all subjects who took at least one dose of study drug. SAF population analyses were performed on the basis of treatment received.

[0178] The key demographics and baseline characteristics of the full analysis set (FAS) are shown in Table 2. The baseline stratification and tumor stage of the FAS are shown in Table 3.

[0179] Table 2FAS demographics

[0180]

[0181] Table 3 FAS baseline stratification and tumor stage

[0182]

[0183] Treatment of subjects

[0184] Rosuvastatin:

[0185] Rosuvastat was administered orally 3 times per week (TIW) to achieve an Hb level of 100-120 g / L. The starting dose of rosuvastat was based on the subject's weight group (Table 4). The maximum dose for a single subject could not exceed 3.5 mg / kg or 400 mg TIW, whichever was lower. Dose modification / adjustment assessments were performed every 4 weeks and the dose was adjusted based on Hb levels and Hb rate of change. However, if the subject received an RBC transfusion, the timing of the next dose adjustment should be discussed with the medical monitor.

[0186] Table 4 Starting dose of roxadustat

[0187]

[0188]

[0189] TIW subcutaneous injection and avoid hematocrit (HCT) > 36% to achieve Hb levels of 100-120 g / L. The starting dose is 150 IU / kg. Dose modifications / adjustments may be evaluated at any time during the study based on the subject's local Hb and HCT values.

[0190] Chemotherapy:

[0191] The dose, route and schedule of administration of any chemotherapeutic agent is determined and administered by the treating physician according to standard treatment algorithms.

[0192] Rosuvastatin or It can be given before or after chemotherapy, but the timing should be consistent throughout the study.

[0193] Treatment compliance:

[0194] Rosuvastatin or Dosing history and study treatment reconciliation were recorded on the corresponding case report forms (CRFs).

[0195] Study objectives and end points

[0196]

[0197]

[0198]

[0199] Recombinant erythropoietin alpha Compared with rosuvastatin, rosuvastatin showed non-inferiority in terms of the primary endpoint, which was defined as the change in mean hemoglobin (Hb) level from baseline to week 9-13 ( Figure 2A-2B ). Based on the mixed model repeated measures (MMRM) analysis for the primary endpoint, the lower limit of the one-sided 97.5% confidence interval (CI) of the treatment difference (-3.39 g / L) in the mean change of Hb from baseline between the rosuvastatin group and the SEPO group in the per-protocol set (PPS) was >-6.6 g / L (predefined non-inferiority limit). The results of the FAS analysis also supported this conclusion, with the lower limit of the one-sided 97.5% CI of the treatment difference being (-2.53 g / L) g / L.

[0200] As shown in Table 5, the changes in mean levels of Hb from baseline to weeks 9–13 across tumor types were generally consistent with the primary endpoint.

[0201] Table 5 Hb increase in different tumor types

[0202]

[0203] As shown in Table 6, Roxadustat also demonstrated noninferiority in the percentage of subjects with an increase in hemoglobin of ≥10 g / L from baseline to week 13. In the PPS, the lower limit of the one-sided 97.5% CI for the difference between the roxadustat and SEPO groups was -6.4%, which was >-15% (the predefined noninferiority margin), indicating that the proportion of subjects with an increase in Hb of ≥10 g / L from baseline during treatment was comparable in the roxadustat and SEPO groups.

[0204] Table 6 Percentage of subjects with Hb increase ≥ 10 g / L

[0205]

[0206] As shown in Table 7, the proportion of subjects achieving an increase in hemoglobin ≥10 g / L from baseline to Week 13 (per-protocol set; PPS) across tumor type and chemotherapy regimen subgroups was also generally consistent with findings in the overall population.

[0207] Table 7 Subgroup analysis of the percentage of subjects with Hb increase ≥ 10 g / L

[0208]

[0209] Figure 3 A forest plot of the primary efficacy results in the subgroups is shown. The difference in LSM between the rosuvastatin group and the SEPO group is shown with a 95% two-sided confidence interval by comparison with -6.6 (the predefined non-inferiority margin). Figure 3 As shown in the results of the current study, the various subgroup analyses were also generally consistent with the primary analysis. Of note, rosuvastatin generally performed better in subjects with initial serum erythropoietin (Epo) levels ≥200 U / L. These subjects showed normal kidney function in terms of erythropoietin response, indicating that their anemia was caused by the myelosuppressive chemotherapy rather than Epo deficiency.

[0210] Roxadustat was originally used to treat renal anemia, a chronic inflammatory anemia that affects the erythropoiesis process by inhibiting EPO production. It was also found that roxadustat could temporarily increase the patient's endogenous EPO level to within the physiological range or close to the physiological range. Figure 3The lower limit of the LSM difference was -2.30, which was higher than -6.6 (the predefined non-inferiority margin) in subjects with initial serum erythropoietin (Epo) levels ≥200 U / L, while subjects with initial serum erythropoietin (Epo) levels <200 U / L did not show the same trend. This result is quite surprising, indicating that rosuvastatin seems to provide more benefits in CIA patients with higher Epo levels. Similar trends were also observed in subjects with TSAT ≥20% and ferritin ≥100 ng / mL.

[0211] As shown in Table 8, noninferiority between the rosuvastatin and SEPO groups was established for the three patient-reported outcome (PRO) endpoints, and the lower limit of the one-sided CI of the difference was greater than the predefined noninferiority (NI) margin.

[0212] Table 8 Improvement in PRO (Per-Protocol Set, PPS)

[0213]

[0214]

[0215] *CFB: change from baseline; bold indicates inferiority or noninferiority of association.

[0216] As shown in Table 9, the proportions of subjects who achieved increases in Hb ≥ 110 g / L, Hb ≥ 110 g / L or ≥ 15 g / L, or Hb ≥ 100 g / L were numerically higher in the rosuvastatin group than in the SEPO group.

[0217] Table 9 Proportion of subjects achieving ≥100 / 110 g / L ≥110 g / L or ≥15 g / L Hb increase

[0218]

[0219] As shown in Table 10, the proportion of subjects in the FAS data set that achieved an increase in Hb ≥ 10, ≥ 15, or ≥ 20 g / L was numerically higher for patients in the roxadustat group. As shown in Table 10, the proportion of subjects in the FAS data set that achieved an increase in Hb ≥ 10, ≥ 15, or ≥ 20 g / L was numerically higher for patients in the roxadustat group. In addition, the time required to achieve an increase in ≥ 15 or ≥ 20 g / L Hb was shorter (≥ 15 g / L Hb increase was 42 days and 52 days, respectively, and ≥ 20 g / L Hb increase was 57 days and 77 days, respectively), which may have clinical significance.

[0220] Table 10 Proportion of subjects achieving ≥10 / 15 / 20 g / L Hb increase and time to increase (FAS)

[0221]

[0222] The percentages of nonresponders, defined as any subject requiring RBC transfusion or Hb < 60 g / L from Week 5 to Week 13, are shown in Table 11. The upper limit of the one-sided CI for the 7.4% difference in % treatment nonresponders between the roxadustat and SEPO groups was < 12.5% ​​(predefined NI limit), indicating that the roxadustat and SEPO groups were equivalent. PPS was the primary analysis for the primary endpoint and all secondary endpoints for noninferiority testing.

[0223] Table 11 Percentage of non-responders in PPS and FAS

[0224]

[0225] The proportion of subjects (PPS) requiring RBC transfusion or Hb < 60 g / L from week 5 to week 13 in the tumor type and chemotherapy regimen subgroups is shown in Table 12. Subgroup analyses of key secondary endpoints were generally consistent with the findings for the overall population.

[0226] Table 12 Percentage of non-responders in PPS subgroups

[0227]

[0228] The proportion of subjects requiring RBC transfusion or ESA rescue is shown in Table 13. The proportion of subjects receiving RBC transfusion was numerically lower in the roxadustat group. The incidence of RBC transfusion (number of times per week) was lower in the roxadustat group (frequency ratio 0.225, 95% CI 0.084, 0.603), and the hazard ratio of RBC transfusion between the 2 groups was 0.622 (95% CI 0.208, 1.861).

[0229] Table 13 Proportion of subjects requiring RBC transfusion or ESA rescue

[0230]

[0231] Responses among subjects based on baseline erythropoietin levels are shown in Table 14. Responses were similar in subjects treated with roxadustat regardless of baseline erythropoietin levels, whereas SEPO was less effective in subjects with baseline erythropoietin levels ≥ 200 U / L.

[0232] Table 14 Changes from baseline in erythropoietin test results (full analysis set)

[0233]

[0234] Safety Summary

[0235] The incidence of any treatment-emergent adverse event (TEAE) was similar between treatment groups, and the exposure-adjusted incidence was lower in the roxadustat group. The proportion of patients with drug-related TEAEs and TEAEs leading to discontinuation was lower in the roxadustat group compared with the SEPO group. The proportion of patients with TEAEs of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 was numerically slightly higher in the roxadustat group compared with the SEPO group.

[0236] The proportion of patients experiencing treatment-emergent serious adverse events (TESAEs) was numerically higher in the roxadustat group compared to the SEPO group (29.6% vs. 21.6%). Most SAEs were sporadic reports. For TESAEs reported in ≥2 subjects, the preferred terms (PT) are "myelosuppression" and "neutrophil count decreased". These are common conditions in patients undergoing chemotherapy for cancer.

[0237] For common TEAEs (reported ≥5% in any treatment group), AST increased, ALT increased, blood LDH increased, back pain, cancer pain, and dizziness were reported 2-fold more often in the roxadustat group than in the SEPO group. Vertigo and insomnia were reported 2-fold more often in the SEPO group than in the roxadustat group.

[0238] For adverse events of special interest (AESI) - deep vein thrombosis (DVT) and pulmonary embolism (PE), there were 2 subjects in the rosuvastatin group (PE, leg vein thrombosis) and 1 subject in the SEPO group (DVT).

[0239] The proportion of patients whose TEAEs led to death was numerically higher in the roxadustat group than in the SEOP group (11.1% vs. 2.7%). All fatal events were assessed as unrelated to study drug. Some cases were questionable. The patient exposure years (PEY) were approximately 31% higher in the roxadustat group compared with SEPO, which may have affected the ascertainment of events. Overall, adverse events in the study were similar to those observed in TEAEs.

Claims

1. Use of rosuvastatin in the preparation of a medicament for treating chemotherapy-induced anemia in a subject receiving multiple cycles of platinum-based or non-platinum-based myelosuppressive chemotherapy for non-myeloid malignancies, wherein the subject has a hemoglobin level of ≤100 g / L before treatment, and the subject's blood hemoglobin level decreases by at least 10 g / L after the start of chemotherapy.

2. The method of claim 1, wherein the subject receives chemotherapy for at least 8 weeks after the start of treatment.

3. The method of claim 1 or 2, wherein the subject is ≥18 years old before treatment.

4. The method of any one of claims 1 to 3, wherein the subject weighs ≥ 40 kg before treatment.

5. The use of any one of claims 1 to 4, wherein the subject has an Eastern Cooperative Oncology Group performance status (ECOGPS) of 0, 1 or 2 before treatment.

6. The use according to any one of claims 1 to 5, wherein the subject has a life expectancy of ≥ 6 months at the start of treatment.

7. The use according to any one of claims 1 to 6, wherein the rosuvastatin is in crystalline form A, characterized in that The X-ray powder diffraction pattern includes peaks at 8.5, 12.8, 16.2, 21.6, 22.9 and 27.4° 2θ ± 0.2° 2θ.

8. The use according to any one of claims 1 to 7, wherein the roxadustat is a solid having a unimodal particle size distribution of D90 of 21 to 29 μm, D50 of 12 to 17 μm, and D10 of 6 to 10 μm.

9. The use according to any one of claims 1 to 8, wherein the medicament is formulated for oral administration.

10. The use according to any one of claims 1 to 9, wherein the medicament further comprises a pharmaceutically acceptable excipient.

Images