New Use

Abstract

The present invention relates to daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a specific population of non-dialysis subjects with anemia associated with chronic kidney disease, characterized by baseline hepcidin and hsCRP levels.

Description

[Technical Field]

[0001] The present invention relates to daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a specific population of non-dialysis subjects with anemia associated with chronic kidney disease, characterized by baseline hepcidin and hsCRP levels. [Background technology]

[0002] Instruments used to assess health-related quality of life (HRQoL) include both patient-reported and clinician-measured outcomes. The value of patient-reported outcomes, as opposed to clinician-assessed outcomes, is underscored by well-documented discrepancies in patient- and provider-reported ratings of problems and difficulties. As a result, some researchers in this field have emphasized the importance of patient assessments, suggesting that patients are the experts when it comes to assessing their own quality of life. These researchers focus on eliciting patient domains and concerns that may be specific to their condition, rather than relying on general categories included in standardized HR-QoL instruments (for a review, see Finkelstein et al., 2009, Kidney International, 76(9):946-952). Nevertheless, the 36-item short-form questionnaire (SF-36) is currently the most widely used HR-QoL instrument in patients with chronic kidney disease (CKD). It is not disease-specific and includes 36 items resulting in an 8-dimensional profile scored out of 100, with higher scores indicating better perception of health status. The reliability, validity, and responsiveness of the SF-36 scale in patients with chronic renal anemia have been demonstrated (Finkelstein et al., Health Qual Life Outcomes, 2018;16:111).

[0003] Using the SF-36, Pagels et al. reported that all HRQoL dimensions significantly worsened across CKD stages, with the lowest scores observed in CKD stage 5. The greatest declines compared with matched controls were observed in physical functioning, role functioning (physical), general health, and the physical QOL summary score (PCS). The smallest differences were observed in mental health and pain. Patients with CKD stages 2–3 had significantly worse HRQoL compared with matched controls, with significant differences in general health and PCS. Patients with CKD stage 4 showed significantly worse physical functioning, general health, and PCS scores compared with patients with CKD stages 2–3. Pagels also reported that C-reactive protein (CRP) levels of 5 mg / L or higher were the most significant predictor of impaired HRQoL (Pagels et al. Health and Quality of Life Outcomes 2012, 10:71).

[0004] Anemia is a common complication of CKD. Common symptoms of anemia include decreased energy, fatigue, weakness, shortness of breath, dizziness, decreased exercise tolerance, cognitive impairment, and decreased mental acuity. Furthermore, anemia is associated with decreased HR-QoL. Treatment of anemia with erythropoiesis-stimulating agents (ESAs) increases hemoglobin levels, potentially reducing anemia symptoms and improving the associated HR-QoL domains of "vitality" and "physical function." Numerous studies have assessed HR-QoL in patients treated with ESAs using the SF-36 questionnaire. Early studies are reviewed in Gandra et al. (American Journal of Kidney Diseases, Vol. 55, No. 3 (March), 2010: pp. 519-534). These studies vary in design, with most being open-label studies or studies comparing two management strategies, potentially introducing bias. Of the 11 studies reviewed, only one reported a clinically meaningful improvement in "vitality," eight reported a statistically significant improvement from baseline in "vitality," one reported a non-significant improvement from baseline in "vitality," and one study did not report energy or fatigue as a study outcome. In light of these data, the FDA removed quality of life claims from ESA labels. This recommendation was based on the lack of controlled studies demonstrating improvements in health-related quality of life measures.

[0005] The more recent CHOIR study did not include a placebo control and observed similar changes in the vitality domain of the SF-36 as observed in the earlier study (Singh et al., 2006, N. Engl. J. Med. 355 (20): 2085). Another recent study, with a smaller difference in hemoglobin concentrations between the treatment and control groups, showed a smaller benefit that may not be clinically relevant (Drueke et al., 2006, N Engl J Med 355 (20): 2071). The TREAT study was a large, double-blind trial randomizing patients with type 2 diabetes, nondialysis-dependent chronic kidney disease, and anemia to receive darbepoetin alfa or placebo. HRQoL was measured using multiple instruments, including the SF-36. At week 25, there was no significant difference in the mean change in the "energy" domain of the SF-36 (5.3 ± 20 vs. 4.2 ± 19 for darbepoetin alfa and placebo, P = 0.196), but the proportion of responders with a 5-point or greater increase in the "energy" domain of the SF-36 was 54% in patients receiving darbepoetin alfa compared with 49% in patients receiving placebo (nominal P = 0.027; Lewis et al., Clin J Am Soc Nephrol. 2011 Apr;6(4): 845-855).

[0006] HIF-prolyl hydroxylase inhibitors are a newer class of medications developed to treat anemia associated with CKD. Clinical trial reports of the PHI inhibitor vadadustat did not include HRQoL outcomes. However, placebo-controlled trials of the PHI inhibitor roxadustat assessed HRQoL outcomes. In a pooled analysis of the OLYMPUS, ANDES, and ALPS studies, patients treated with roxadustat experienced a small but statistically significant least-squares mean difference of 0.96 points (95% CI 0.44–1.47) in SF-36 "vitality" scores (scored 0–100) compared with patients receiving placebo over 12 weeks. Although statistically significant, this improvement is unlikely to be clinically relevant (Coyne et al., 2020, Health-Realized Quality of Life in Roxadustat-Treated Patients with Anemia and Non-Dialysis Dependent Chronic Kidney Disease, Oral presentation at the American Society of Nephrology Kidney Week, October 22-25, 2020).

[0007] In summary, reports of changes in vitality present a confusing picture in which improvements may depend on the medication used and study design, including the degree of proposed correction of anemia.

[0008] An effective treatment for anemia of chronic kidney disease that also beneficially impacts the vitality of non-dialysis patients is highly desirable. Summary of the Invention

[0009] In a first aspect, the present invention provides daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject with anemia associated with chronic kidney disease who is not undergoing dialysis, wherein the subject has a baseline hepcidin level of 75 μg / L or greater. In certain embodiments, the subject is further characterized by a baseline level of hsCRP.

[0010] In a second aspect, the present invention provides daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject with anemia associated with chronic kidney disease who is not undergoing dialysis, wherein the subject: (a) baseline hepcidin <75 μg / L; and (b) baseline hsCRP ≥ 2.60 mg / L; Daprodustat or a pharmaceutically acceptable salt thereof to provide.

[0011] CRP, or C-reactive protein, is a human protein typically considered a marker of inflammation. Conventional CRP assays can only detect CRP in the range of 10 to 1000 mg / L. High-sensitivity CRP, or hsCRP, is a highly sensitive assay that detects CRP in blood samples at 0.5 to 10 mg / L. Baseline hsCRP levels, as used herein, refer to CRP levels in a blood sample at baseline measured using a highly sensitive assay. Baseline hepcidin levels refer to hepcidin levels in a blood sample at baseline (measured using methods known in the art). [Brief explanation of the drawings]

[0012] [Figure 1]

[0023] Figure 1 is a line graph of mean hemoglobin concentration (g / dL) by treatment and visit. Daprodustat data are represented by circles / dotted line and placebo data are represented by triangles / solid line. [Figure 2]1 is a line graph of mean SF-36 Vitality subscore values ​​by treatment and visit. Daprodustat data are represented by circles / dotted line and placebo data are represented by triangles / solid line. [Figure 3] Forest plot of adjusted means from hsCRP subgroup analysis of hemoglobin change from baseline to the evaluation period. [Figure 4] Forest plot of adjusted means from the analysis of change from baseline in on-treatment SF-36 vitality at week 28 by hsCRP subgroup. [Figure 5] Forest plot of adjusted means from the analysis of change from baseline in on-treatment SF-36 vitality at week 28 by hemoglobin subgroup. Specific Description of the Invention

[0013] Fatigue is a patient-reported outcome and cannot be measured directly. Rather, it can be estimated by various means. The vitality domain of the short-form SF-36 questionnaire (e.g., readily available from several sources, e.g., https: / / www.rand.org / health-care / surveys_tools / mos / 36-item-short-form / survey-instrument.html) provides a validated measure of fatigue. It is scored from 0 to 100, with higher scores indicating reduced fatigue. The Chronic Amemia Disease Anemia Questionnaire (CKD-AQ) is a patient-reported outcome measure developed specifically for subjects with anemia of chronic kidney disease (Mathias et al. Journal of Patient-Reported Outcomes (2020) 4:64). The "Fatigue / Low Energy / Weakness" domain question of the CKD-AQ is shown in Example 5. The "Fatigue / Low Energy / Weakness domain" of the CKD-AQ provides a measure of fatigue, with higher scores indicating decreased fatigue.

[0014] As explained in the "Background Art" section, treating anemia does not necessarily result in clinically meaningful improvements in vitality (reduced fatigue). Rather, improvement is thought to depend on other factors, including the medication used to treat anemia and the degree of anemia correction. A post-hoc analysis of the clinical study described in Example 1 demonstrates a very weak correlation between changes in hemoglobin concentration and improvements in vitality (reduced fatigue) measured by either the SF-36 vitality domain subscore or the "fatigue / low energy / weakness domain" of the CKD-AQ (see Example 3). This confirms that treating anemia does not necessarily result in clinically meaningful improvements in vitality (reduced fatigue). Nevertheless, it was surprisingly found that daprodustat significantly reduced fatigue in non-dialysis subjects with anemia associated with chronic kidney disease (see Example 1).

[0015] Thus, daprodustat or a pharmaceutically acceptable salt thereof may be used to reduce fatigue in subjects with anemia associated with chronic kidney disease who are not undergoing dialysis. In one embodiment, fatigue is reduced at the end of the treatment period compared to baseline. In one embodiment, reduced fatigue is observed when subjects are treated to maintain hemoglobin levels in the range of 10-12 g / dL. In a more specific embodiment, reduced fatigue is observed when subjects are treated to maintain hemoglobin levels in the range of 11-12 g / dL.

[0016] In one embodiment, fatigue reduction refers to the situation where the subject's score in the vitality domain of the SF-36 questionnaire increases compared to baseline at the end of the treatment period.In a specific embodiment, the duration of treatment is at least 12 weeks.Example 3 describes a literature search to identify the threshold of meaningful change (minimum clinically important difference or MCID) in the SF-36 vitality domain.It concludes (conservatively) that an increase of 6 points or less in the SF-36 vitality domain within a subject is clinically relevant.

[0017] Thus, in one embodiment, fatigue reduction refers to a situation in which a subject's score on the vitality domain of the SF-36 questionnaire increases by 6 points at the end of the treatment period compared to baseline. In another embodiment, fatigue reduction refers to a situation in which the mean increase in the vitality domain of the SF-36 questionnaire is at least 6 points at the end of the treatment period compared to baseline in a population of subjects. In one embodiment, the population comprises at least 30 subjects. In the clinical study reported in Example 1, the adjusted mean change (within treatment difference) from baseline in the SF-36 vitality domain was 7.29 (standard error = 1.121) in subjects treated with daprodustat compared to 1.93 (standard error = 1.161) in subjects randomized to placebo tablets.

[0018] In another embodiment, fatigue reduction refers to a situation in which the mean score of the vitality domain of the SF-36 questionnaire increases in a subject population at the end of the treatment period compared to baseline. In one embodiment, the population comprises at least 30 subjects. In one embodiment, the increase is at least a 6-point increase.

[0019] In an alternative embodiment, fatigue reduction is achieved when a higher rate of responders achieving at least a 6-point increase in the SF-36 Vitality domain is observed in subjects treated with daprodustat compared to placebo. In one embodiment, the difference in responder rates between daprodustat-treated and placebo-treated subjects is nominally significant with a one-sided p-value of less than 0.025. In another embodiment, fatigue reduction is achieved when a greater than 50% proportion of subjects treated with daprodustat achieves an increase of at least 6 points in the Vitality domain of the SF-36 questionnaire. In Clinical Study Example 1, 58% of study participants treated with daprodustat demonstrated a 6.0-point or greater change from baseline to week 28 in the SF-36 Vitality domain. The difference in response rates (Dapro vs. placebo) was nominally significant (one-sided p-value = 0.0049).

[0020] In another embodiment, fatigue reduction refers to a situation in which the subject's score in the fatigue / low energy / weakness domain of the CKD-Anemia Questionnaire increases at the end of the treatment period compared to baseline. In a specific embodiment, the duration of treatment is at least 12 weeks. In one embodiment, fatigue reduction refers to a situation in which the subject's score in the fatigue / low energy / weakness domain of the CKD-AQ increases by at least 5 points at the end of the treatment period compared to baseline. In another embodiment, the subject's score in the fatigue / low energy / weakness domain of the CKD-AQ increases by at least 8 points at the end of the treatment period compared to baseline. In another embodiment, the subject's score in the fatigue / low energy / weakness domain of the CKD-AQ increases by at least 11 points at the end of the treatment period compared to baseline.

[0021] In another embodiment, reduced fatigue refers to a situation in which the mean increase in the fatigue / low energy / weakness domain of the CKDAQ is at least 5 points in a subject population at the end of the treatment period compared to baseline. In a more specific embodiment, reduced fatigue refers to a situation in which the mean increase in the fatigue / low energy / weakness domain of the CKDAQ is at least 8 points in a subject population at the end of the treatment period compared to baseline. In a more specific embodiment, reduced fatigue refers to a situation in which the mean increase in the fatigue / low energy / weakness domain of the CKDAQ is at least 11 points in a subject population at the end of the treatment period compared to baseline. In a particular embodiment, the population comprises at least 30 subjects. In the clinical study reported in Example 1, the adjusted mean change during the treatment period in the "fatigue / low energy / weakness" domain of the CKD-AQ was 8.72 (standard error = 1.086) in subjects treated with daprodustat compared to 2.81 (standard error 1.132) in subjects randomized to placebo tablets.

[0022] In yet another embodiment, fatigue reduction refers to a situation in which the mean score of the fatigue / low energy / weakness domain of the CKD-AQ increases in a subject population at the end of the treatment period compared to baseline. In one embodiment, the population comprises at least 30 subjects. In one embodiment, the increase is at least a 5-point increase. In a more specific embodiment, the increase is at least an 8-point increase. In one embodiment, the increase is at least an 11-point increase.

[0023] Although a post-hoc analysis (Example 3) demonstrated a very weak correlation between changes in hemoglobin concentration and improvements in vitality (reduced fatigue) as measured by either the SF-36 vitality domain subscore or the fatigue / low energy / weakness domain of the CKD-AQ, the fatigue reduction reported in Example 1 was accompanied by correction of anemia. This indicates that the dosing schedule used to treat anemia is also adequate for reducing fatigue, resulting in clinically relevant reductions of the magnitude described above. In one embodiment, fatigue reduction is observed when subjects are treated to maintain hemoglobin concentrations in the range of 10-12 g / dL. In a more specific embodiment, fatigue reduction is observed when subjects are treated to maintain hemoglobin concentrations in the range of 11-12 g / dL.

[0024] Given the weak correlation between changes in hemoglobin concentration and improved vitality (reduced fatigue), it is likely that certain subject groups with relatively modest changes in hemoglobin will experience greater reductions in fatigue.

[0025] Subgroup analysis of hemoglobin change and SF-36 vitality domain subscore identified a population of subjects with baseline hsCRP ≥ 6.60 mg / L who responded to Produstat and experienced a relatively modest mean hemoglobin increase (the adjusted mean treatment difference in hemoglobin concentration was 1.25 g / dL (CI 0.92, 1.58) for subjects with hsCRP ≥ 6.60 mg / L), but a relatively large increase in SF-36 vitality subscore (the adjusted mean treatment difference in SF-36 vitality domain subscore during the treatment period was 7.71 (CI 1.62, 13.80) for subjects with hsCRP ≥ 6.60 mg / L). Table 8 shows that there was a significant decrease in hsCRP levels in this group, suggesting that increased vitality may be associated with a decrease in hsCRP. However, as explained in Example 1, no firm conclusions can be drawn because a) similar reductions in hsCRP levels were observed in the placebo group with higher baseline hsCRP (Table 8), and b) the observed reductions may be due (at least in part) to subjects with the highest CRP levels not being evaluated at week 28 / end of treatment, presumably because these subjects were rescued.

[0026] Baseline hepcidin levels also influenced the energy response to daprodustat. Table 9 shows that greater improvements in patient-reported fatigue measures were observed in patients with baseline hepcidin levels of 74.58 μg / L or higher (which may be rounded to 75 μg / L or higher). This was likely accompanied by a decrease in hepcidin levels during treatment (in the overall population, daprodustat treatment resulted in a 37.40% decrease in hepcidin (nmol / L) at week 28 compared to baseline). Table 11 shows that among patients with baseline hepcidin ≥ 74.85 μg / L (which can be rounded to ≥ 75 μg / L), superior improvements in SF-36 Vitality scores from baseline to week 28 were observed in two distinct populations: patients with baseline hsCRP < 0.9 mg / L and patients with hsCRP ≥ 2.60 mg / L (e.g., patients with hsCRP ≥ 6.60 mg / L).

[0027] Among patients without elevated hepcidin at baseline, only those with elevated hsCRP at baseline (≥2.60 mg / L, especially ≥6.60 mg / L) demonstrated superior improvement in SF-36 vitality score from baseline to week 28, as shown in Table 10.

[0028] Thus, in one aspect, the present invention provides daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject with anemia associated with chronic kidney disease who is not undergoing dialysis, wherein the subject has a hepcidin level of 75 μg / L or greater at baseline.

[0029] In certain embodiments, the subject has a baseline hepcidin level in the range of 75 μg / L or greater to less than 121 μg / L, or the subject has a baseline hepcidin level of 121 μg / L or greater. In another embodiment, the subject has a baseline hsCRP level of less than 0.9 mg / L. In a further embodiment, the subject has a baseline hsCRP level of 2.60 mg / L or greater.

[0030] In a second aspect, the present invention provides daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject who is not undergoing dialysis and has anemia associated with chronic kidney disease, wherein the subject has: (a) hepcidin less than 75 μg / L at baseline, and (b) hsCRP greater than or equal to 2.60 mg / L at baseline.

[0031] Example 1 also discusses the effect of hemoglobin concentration on the adjusted mean treatment change in the SF-36 vitality domain subscore. Although the study design and the small number of subjects with baseline hemoglobin levels above 11 g / dL prevent firm conclusions, it appears likely that increases in the SF-36 vitality domain score are most pronounced in subjects with baseline hemoglobin levels of 11 g / dL or less. Thus, in one embodiment, the subject is further characterized by a baseline hemoglobin level of 11 g / dL or less. In more specific embodiments, the subject's hemoglobin level is 10 g / dL or less or 9 g / dL or less. It is noted that subjects with a baseline hemoglobin less than 9 g / dL had an adjusted mean treatment difference in the SF-36 Vitality domain subscore of 7.44 (confidence interval 1.86, 16.73), subjects with a baseline hemoglobin of 9 to less than 10 g / dL had an adjusted mean treatment difference in the SF-36 Vitality domain subscore of 5.25 (confidence interval 0.85, 9.65), and subjects with a baseline hemoglobin of 10 to 11 g / dL had an adjusted mean treatment difference in the SF-36 Vitality domain subscore of 6.01 (confidence interval 0.83, 11.20). In certain embodiments, the invention provides daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject with anemia associated with chronic kidney disease, wherein the subject's hemoglobin concentration at baseline is in the range of 10 to 11 g / dL.

[0032] The study of Example 1 recruited subjects with CKD stages 3, 4, and 5. In one embodiment, the subjects have CKD stage 3 or 4. In one embodiment, the subjects' GFR (or eGFR) is 60 ml / min / 1.73 m 2 In more specific embodiments, the subject's GFR (or eGFR) is less than 45 ml / min / 1.73 m 2Thus, in one embodiment, the present invention provides daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject with anemia associated with chronic kidney disease, wherein the subject has CKD stages 4 and 5. In a particular embodiment, the subject has CKD stage 3 or 4. In another embodiment, the present invention provides a method for reducing fatigue in a subject with a GFR (or eGFR) of 60 ml / min / 1.73 m 2 In a more specific embodiment, the subject's GFR (or eGFR) is less than or equal to 45 ml / min / 1.73 m. 2 is less than.

[0033] In one embodiment, the subject does not have a history of heart failure based on a review of the subject's clinical history. In one embodiment, the patient has a history of heart failure if the patient has New York Heart Association (NYHA) class II, III, or IV symptoms, and if the patient has a plasma concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) of 400 pg / mL or more. In another embodiment, the patient has a history of heart failure if, based on a review of the patient's clinical history, the patient has been hospitalized for heart failure within the previous 12 months. Hospitalization for heart failure is considered to be due to one or more of the following symptoms consistent with heart failure: a) Increased dyspnea; b) worsening orthopnea; c) Paroxysmal nocturnal dyspnea; d) increased fatigue / decreased exercise tolerance; e) worsening edema / anazarca; and two or more of the following symptoms compatible with heart failure: a) Rapid weight gain; b) pulmonary edema or rales; c) Increased jugular venous pressure; d) radiological signs of heart failure; e) peripheral edema; f) abdominal distension or increased ascites; g) S3 Gallop h) hepatoduodenal reflux; i) elevated brain natriuretic peptide (BNP) or N-terminal proBNP (≥400 pg / mL); j) congestive hepatomegaly (i.e., not associated with any underlying liver disease); k) Invasive / non-invasive tests showing cardiac filling pressures or low cardiac output; means hospitalization due to

[0034] The present invention also contemplates narrower patient populations. For example, the present invention provides daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject not undergoing dialysis and having anemia associated with chronic kidney disease, wherein the subject has a hepcidin level of 75 μg / L or greater at baseline, and the subject has one or more of the following: a) hsCRP <0.9 mg / L at baseline; b) hsCRP ≥ 2.60 mg / L at baseline; c) hsCRP ≥ 6.60 mg / L at baseline; d) baseline hemoglobin concentration ≤11 g / dL (e.g., <9 g / dL, ≥9 g / dL and <10 g / dL, <10 g / dL, or ≥10 g / dL and ≤11 g / dL); e)45ml / min / 1.73m 2 aGFR (or eGFR); f) CKD stage 3; g) CKD stage 4; and h) no history of heart failure; i) hepcidin ≥ 121 μg / L at baseline; However, the subject cannot have both a) and either b) or c), or both f) and g).

[0035] In certain embodiments, the subject is a patient having: a) and d); c) and d); a) and h); c) and h); a), d) and h); c), d) and h); a) and i); and c) and i) It has.

[0036] The present invention provides daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject with anemia associated with chronic kidney disease who is not undergoing dialysis, wherein the subject has: hepcidin less than 75 μg / L at baseline and hsCRP greater than or equal to 2.60 mg / L at baseline, wherein the subject has one or more of the following: a) baseline hsCRP ≥ 6.60 mg / L; b) baseline hemoglobin concentration ≤11 g / dL (e.g., <9 g / dL, ≥9 but <10 g / dL, <10 g / dL, or ≥10 but <11 g / dL); c) GFR (or eGFR) of 45 ml / min / 1.73 m 2 less than; d) CKD stage 3; e) CKD stage 4; and f) no history of heart failure; However, the above subject cannot have both d) and e).

[0037] In certain embodiments, the subject has: a) and b); b) and c); a) and f); b) and f); a), b) and f); and b), c) and f).

[0038] In the above embodiments, the term GFR refers to glomerular filtration rate, and eGFR refers to estimated glomerular filtration rate. GFR may be measured by methods known in the art, or in the case of eGFR, may be estimated by methods known in the art.

[0039] Daprodustat Daprodustat is the USAN, INN, and JAN name for the compound N-((1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl)glycine. (The IUPAC name for this compound is N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine.) Daprodustat exhibits keto / enol tautomerism and can also be named N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine. Where a claim refers to N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine, all tautomers of N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine are intended to be encompassed within the scope of the invention, including mixtures thereof.

[0040] In one embodiment, daprodustat or a pharmaceutically acceptable salt thereof is used in the methods of the invention. In one embodiment, a pharmaceutically acceptable salt of daprodustat is used. In another embodiment, daprodustat free acid is used.

[0041] In one embodiment, the daprodustat free acid is in a crystalline form.

[0042] In certain embodiments, daprodustat free acid is a nonsolvated crystalline form designated CS1. The X-ray powder diffraction pattern of Form CS1 has characteristic peaks at 2θ values ​​of 6.4°±0.2°, 7.5°±0.2°, and 7.9°±0.2° using CuKα radiation. In more specific embodiments, the X-ray powder diffraction pattern of Form CS1 has one or more additional characteristic peaks at 2θ values ​​of 17.2°±0.2°, 21.0°±0.2°, 24.0°±0.2°, and 19.3°±0.2° using CuKα radiation. Form CS1 has an endothermic peak near 242°C as measured by differential scanning calorimetry using a heating rate of 10°C min and a nitrogen purge gas.

[0043] In another embodiment, daprodustat free acid is in a non-solvated crystalline form designated CS9. The X-ray powder diffraction pattern of form CS9 has characteristic peaks at 4.6°±0.2°, 6.6°±0.2°, and 21.1°±0.2° 2θ using CuKα radiation. In a more specific embodiment, the X-ray powder diffraction pattern of CS9 has one or more additional characteristic peaks at 9.4°±0.2°, 20.2°±0.2°, and 24.2°±0.2° 2θ using CuKα radiation.

[0044] Forms CS1 and CS9 may be prepared from the free acid according to the process described in WO 2019 / 052133.

[0045] In another embodiment, daprodustat free acid is in a crystalline form designated Form 3. Form 3 has an X-ray powder diffraction pattern with peaks at 2-theta values ​​of 4.5°±0.2°, 5.6°±0.2°, 9.0°±0.2°, and 16.8°±0.2° using CuKα radiation. In a more specific embodiment, the X-ray powder diffraction pattern of Form 3 has one or more additional characteristic peaks at 2-theta values ​​selected from 8.5°±0.2°, 11.2°±0.2°, 20.6°±0.2°, and 24.7°±0.2° using CuKα radiation, and / or has a DSC endothermic peak with a T onset around 245.3°C.

[0046] In another embodiment, daprodustat free acid is in a crystalline form designated Form 4. Form 4 has an X-ray powder diffraction pattern with peaks at 2-theta values ​​of 7.2°±0.2°, 11.5°±0.2°, 21.7°±0.2°, 22.9°±0.2°, 23.3°±0.2°, and 25.8°±0.2° using CuKα radiation. In a more specific embodiment, the X-ray powder diffraction pattern of Form 4 has one or more additional characteristic peaks at 2-theta values ​​selected from 6.3°±0.2°, 12.9°±0.2°, 16.5°±0.2°, 18.1°±0.2°, and 19.7°±0.2° using CuKα radiation, and / or has a DSC endothermic peak with a T onset around 243.9°C.

[0047] Forms 3 and 4 may be prepared as described in WO 2020 / 102302.

[0048] In another embodiment, daprodustat free acid is in a crystalline form designated Form M. The X-ray powder diffraction pattern of Form M has characteristic peaks at 2θ values ​​of 4.7°±0.2°, 6.5°±0.2°, and 6.8°±0.2° using CuKα radiation. Form M may be prepared as described in WO 2021 / 031102.

[0049] In another embodiment, daprodustat free acid is a co-crystal with isoniazid, wherein the molar ratio of daprodustat to isoniazid is 2:1. In a more particular embodiment, the co-crystal has an X-ray powder diffraction pattern with diffraction peaks at 5.5, 8.1, 16.5, and 20.7 degrees 2θ. The co-crystal may be prepared as described in Chinese Patent No. 115260108.

[0050] In a further embodiment, daprodustat or a pharmaceutically acceptable salt thereof is a tromethamine salt of daprodustat, wherein the molar ratio of daprodustat to tromethamine is 1:1. In a more specific embodiment, the tromethamine salt of daprodustat is in a crystalline form and has an X-ray diffraction pattern with four or more peaks at 2θ values ​​selected from the group consisting of 2, 6.7, 9.7, 14.1, 15.8, 16.3, 16.8, 18.2, 20.4, 21.0, 24.4, 25.9, and 26.7. The tromethamine salt of daprodustat may be prepared as described in Chinese Patent No. 115260108.

[0051] Pharmaceutical Composition In one embodiment, daprodustat or a pharmaceutically acceptable salt thereof is administered as an immediate release formulation, such as an immediate release tablet.

[0052] In more particular embodiments, the immediate release tablet of daprodustat or a pharmaceutically acceptable salt thereof is a formulation comprising 1 to 8 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof that meets the following dissolution criteria: 1. An average of 85% or more (based on at least 12 tablets) of the free acid of N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine contained in the tablets is measured using a United States Pharmacopeia (USP) Apparatus 2 at a rotation speed of 50 ± 2 rpm in a pH 6.8 buffer or enzyme-free simulated intestinal fluid, USP, and is measured at a rotation speed of 50 ± 2 rpm. and 900±9 mL for tablets containing 2 mg or more of N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically acceptable salt thereof (measured as the free acid), within 45 minutes.

[0053] In one embodiment, the dissolution profile of an immediate-release tablet comprising 1 to 8 mg (measured as the free acid) of N-[(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, using United States Pharmacopeia (USP) Apparatus 2 under the conditions specified above, must further exhibit an f2 value of 50 or greater compared to the tablet described in Example 4 containing the same dose of active pharmaceutical ingredient. In one embodiment, the tablet of Example 4 was compressed using a main compression pressure of 200 to 290 MPa, more particularly 240 to 260 MPa, and even more particularly about 250 MPa.

[0054] In certain embodiments, immediate-release tablets of the present invention can comprise 1 to 10 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof, and the tensile strength of the tablet is 1.7 MPa or greater after compression of the tablet core at a pressure ranging from 200 to 290 MPa. In more specific embodiments, the tensile strength of the tablet is 1.75, 1.8, 1.9, or 2.0 MPa or greater after compression of the tablet core at a pressure ranging from 200 to 290 MPa. In certain embodiments, immediate-release tablets comprise 1 to 8 mg (measured as the free acid) of daprodustat or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, the immediate-release tablet comprises a compartment containing daprodustat or a pharmaceutically acceptable salt thereof in an amount of up to 5% by weight of the free acid, wherein the compartment does not contain a glidant. In one embodiment, the compartment contains a non-solvated crystalline form of daprodustat free acid.

[0056] In one embodiment, the tablet is a monolithic tablet consisting of a single compartment of uniform composition, optionally film coated. In one embodiment, the compartment is the tablet core. In another embodiment, the compartment is the entire tablet.

[0057] In an alternative embodiment, the tablet contains granules dispersed in the extragranular space, optionally film-coated. The granular and extragranular compositions may be different and form separate compartments. In one embodiment, the granular compartment is a glidant-free compartment containing daprodustat or a pharmaceutically acceptable salt thereof (e.g., a non-solvated crystalline form of daprodustat free acid).

[0058] In one embodiment, the intragranular compartment comprises the crystalline form of unsolvated daprodustat free acid, a diluent, a binder, and a disintegrant, but does not include a glidant. For the avoidance of doubt, more than one diluent, binder, and disintegrant may be included. In one embodiment, the intragranular compartment consists of the crystalline form of unsolvated daprodustat free acid, one or more diluents, binders, and disintegrants, but does not include a glidant.

[0059] In one embodiment, the extragranular compartment comprises a diluent, a disintegrant, a lubricant, and optionally a glidant. For the avoidance of doubt, more than one diluent, disintegrant, lubricant, or glidant may be included. In one embodiment, the extragranular compartment consists of one or more diluents, disintegrants, lubricants, and optionally a glidant.

[0060] Suitable diluents include lactose, sucrose, dextrose, mannitol, sorbitol, starches (e.g., corn starch, potato starch, and pregelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate, and dicalcium phosphate. In one embodiment, the diluent is not lactose.

[0061] Suitable binders include starch (e.g., corn starch, potato starch, and pregelatinized starch), hypromellose, gelatin, gum arabic, sodium alginate, alginic acid, gum tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g., microcrystalline cellulose).

[0062] Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose sodium, alginic acid, and sodium carboxymethyl cellulose.

[0063] Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

[0064] Glidants include colloidal silicon dioxide, talc, starch, and magnesium stearate. In one embodiment, the glidant is colloidal silicon dioxide or magnesium stearate. In one embodiment, the glidant is silica. In one embodiment, the glidant is colloidal silicon dioxide.

[0065] In one embodiment, the present invention provides an immediate release tablet, the tablet comprising: a) an intragranular component comprising a crystalline form of non-solvated daprodustat free acid, a diluent, a binder, and a disintegrant; and b) extragranular components comprising a diluent, a disintegrant, a lubricant, and optionally a glidant; The tablets are optionally coated.

[0066] In a more specific embodiment, the present invention provides an immediate release tablet, the tablet comprising: a) a crystalline form of non-solvated daprodustat free acid and an intragranular component consisting of one or more diluents, one or more binders, and one or more disintegrants; and b) extragranular components comprising a diluent, a disintegrant, a lubricant, and optionally a glidant; The tablets are optionally coated.

[0067] A coating may be applied to the tablet core. An example of a commercially available coating is "OPADRY OY-S-28876 WHITE". Colored coatings are also commercially available.

[0068] In one embodiment, the immediate-release tablet comprises up to 76% by weight of intragranular ingredients based on the weight of the uncoated tablet.

[0069] In one embodiment, the immediate-release tablet comprises an intragranular compartment and an extragranular compartment, wherein: a. The intragranular component comprises: i. 1 to 10 mg of a crystalline form of nonsolvated daprodustat free acid; ii. about 5% by weight of hypromellose; iii. about 1.5% by weight of croscarmellose sodium; and iv. mannitol and microcrystalline cellulose in a weight ratio of about 2.2 to about 3.6 (e.g., about 2.3 to about 3.5, or about 2.25); b. the extragranular component comprises, based on the total weight of the extragranular component: i. about 12% by weight of croscarmellose sodium; ii. about 4% by weight of magnesium stearate; iii. about 1.5% colloidal silica; and iv. Mannitol and microcrystalline cellulose in a weight ratio of about 0.3 to about 3 (e.g., about 2).

[0070] In certain embodiments, the tablet comprises about 1, 2, or 4 mg of daprodustat, and the core tablet weighs about 150 mg. In other embodiments, the tablet comprises about 6 or 8 mg of daprodustat, and the core tablet weighs about 300 mg. The tablets described herein may optionally be film coated.

[0071] In one embodiment, the immediate-release tablet is lactose-free.

[0072] medical use In one aspect, the present invention provides daprodustat, or a pharmaceutically acceptable salt thereof, for use in reducing fatigue in a subject as further defined herein.

[0073] In yet another embodiment, the present invention provides the use of daprodustat, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in reducing fatigue in a subject as further defined herein.

[0074] In another embodiment, the present invention provides a method for reducing fatigue in a subject having anemia associated with chronic kidney disease, the method comprising administering to the subject daprodustat or a pharmaceutically acceptable salt thereof, wherein the subject is further defined herein.

[0075] Preferably, the subject is a mammal, hi certain embodiments, the subject is a human.

[0076] In more specific embodiments, the subject may be iron deficient (TSAT≦20% and / or serum ferritin≦100 ng / ml) and may also be receiving iron replacement therapy.

[0077] In a further embodiment, the present invention provides a dosing regimen for treating fatigue in a subject as defined herein, aiming to maintain hemoglobin within the 10-12 g / dL range and gradually increasing hemoglobin levels if the hemoglobin level falls below the target range. Although the correlation between increases in either the SF-36 vitality domain or the CKD-AQ fatigue / low energy / weakness domain and hemoglobin increases is very weak, clinical studies in which doses were adjusted based on hemoglobin concentration have shown increases in both the SF-36 vitality domain subscore and the CKD-AQ fatigue / low energy / weakness domain scores. Dose modifications are based on hemoglobin concentrations measured at study visits. Hemoglobin concentrations can be measured by known methods, for example, by point-of-care analyzers such as HemoCue or standard laboratory-based tests.

[0078] In one aspect, the present invention provides a dosing regimen for treating fatigue in a subject as defined herein, wherein daprodustat or a pharmaceutically acceptable salt thereof is administered once daily at a dose of 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, 16 mg, or 24 mg (based on the daprodustat free acid), and the dose is increased or decreased by one dose step based on the subject's hemoglobin concentration to maintain the subject's hemoglobin concentration within the range of 10 to 12 g / dL. In one embodiment, the dose is increased or decreased by one dose step based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration within the range of 10 to 11 g / dL. In one embodiment, the dose is increased or decreased by one dose step based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration at a target of 10 g / dL. In another embodiment, the dose is increased or decreased in dose steps based on the patient's hemoglobin concentration to maintain the patient's hemoglobin concentration in the range of 11-12 g / dL.

[0079] In certain embodiments, a subject's hemoglobin concentration is monitored at least once every three months. In more specific embodiments, a subject's hemoglobin concentration is monitored monthly or every four weeks. One skilled in the art will appreciate that monitoring frequency increases when treatment is initiated and decreases once the subject's hemoglobin concentration stabilizes within the target range / value (10-12 g / dL, or 10-11 g / dL, 11-12 g / dL, or 10 g / dL). In one embodiment, reduced fatigue is observed when the hemoglobin concentration is treated to be maintained in the 10-12 g / dL range. In a more specific embodiment, reduced fatigue is observed when the hemoglobin concentration is treated to be maintained in the 11-12 g / dL range.

[0080] In embodiments where the patient's hemoglobin concentration rises rapidly (eg, above 2.0 g / dL within 4 weeks), the dose is reduced by one dose step or discontinued.

[0081] In embodiments where the patient's hemoglobin concentration is above the upper end of the target range, administration is interrupted and treatment resumed at a lower dose level until the hemoglobin concentration is within the target range.

[0082] Clinical judgment is also important when increasing or decreasing the dose. In embodiments where the patient is above the target range and at risk for thromboembolism (e.g., if the patient has had a stroke), administration is reduced by one dose step or discontinued. In embodiments where the patient exhibits symptoms of anemia, the dose is increased by one dose step.

[0083] In embodiments where the patient is not on dialysis and the patient has previously been treated with an erythropoiesis-stimulating agent (ESA), the starting dose is based on the previous ESA dose. In embodiments where the patient is not on dialysis and the patient has previously been treated with an erythropoiesis-stimulating agent (ESA), the starting dose is based on the patient's hemoglobin concentration. Table 1 shows suitable starting doses.

[0084] [Table 1]

[0085] The present invention provides a dosing regimen for the treatment of fatigue in a subject as defined herein to maintain hemoglobin levels in the range of 10-11 g / dL, wherein the immediate-release tablets of the present invention are administered once daily at one of the following doses: 1, 2, 4, 6, 8, 12, 16, and 24 mg (free acid dose), and further: a) If hemoglobin concentration is 12 g / dL or greater, daprodustat treatment is discontinued until hemoglobin concentration is less than 11.5 g / dL, and treatment is resumed at the next lower dose level; b) If the hemoglobin concentration is within the range of 9.5 to less than 11.5 g / dL, the dose is maintained; c) If the hemoglobin concentration at two consecutive clinic visits is within the range of greater than 11 and less than or equal to 11.5 g / dL and there is an increase or no change in hemoglobin concentration since the last visit, the dose will be reduced by one dose step; d) If the hemoglobin level is in the range of greater than 11.5 but less than 12 g / dL and the hemoglobin level has decreased since the last visit, the dose will be maintained; e) If the hemoglobin concentration is in the range of greater than 11.5 and less than 12 g / dL and there is an increase or no change in hemoglobin concentration since the last visit, the dose will be reduced by one dose step; f) If the hemoglobin concentration (concentation) at two consecutive clinic visits is in the range of 9.5 or greater but less than 10, and there is a decrease or no change in hemoglobin concentration since the last visit, the dose will be increased by one dose step; g) if hemoglobin concentration is in the range of 7.5 to less than 9.5 g / dL and there has been an increase in hemoglobin concentration of 0.5 g / dL or more since the last visit, the dose will be maintained; h) If the hemoglobin concentration is in the range of 7.5 to less than 9.5 g / dL and there has been a decrease, no change, or an increase of less than 0.5 g / dL in hemoglobin concentration since the last visit, the dose will be increased by one dose step; i) If the hemoglobin concentration is less than 7.5 g / dL, the dose is increased by one dose step; j) If there is an increase in hemoglobin concentration of more than 2 g / dL over a 4-week period or a decrease in hemoglobin concentration of more than 1 g / dL over a 2-week period, the dose will be reduced by one dose step; and k) If there is a decrease in hemoglobin concentration of more than 2 g / dL over a 4-week period or an increase in hemoglobin concentration of more than 1 g / dL over a 2-week period, the dose will be increased by one dose step.

[0086] In one embodiment, daprodustat or a pharmaceutically acceptable salt thereof is administered once daily at one of the following doses according to the dosing regimens described herein: 1, 2, 4, 6, 8, 12, 16, and 24 mg (free acid dose).

[0087] For the avoidance of doubt, it is noted that a particular dose may be administered in a single tablet or in multiple tablets, for example, an 8 mg dose may be administered as one 8 mg tablet, or two 4 mg tablets, or four 2 mg tablets, or eight 1 mg tablets, or a 6 mg and a 2 mg dosage form.

[0088] It will be apparent that a dose adjustment will result in the dose of daprodustat being increased or decreased one dose step at a time. Individuals requiring a dose increase and receiving the highest (maximum) dose of daprodustat will maintain the same dose, whereas individuals requiring a dose decrease and receiving the lowest dose of daprodustat will cease daprodustat treatment. [Example]

[0089] Example 1 Protocol A 28-week, randomized, double-blind, placebo-controlled clinical study was conducted in non-dialysis patients with anemia associated with chronic kidney disease. Participants were assessed for eligibility for inclusion in the study based on the following (non-exhaustive) inclusion and exclusion criteria:

[0090] Inclusion criteria - Be 18 years of age or older at the time of signing the informed consent Have stage 3, 4, or 5 chronic kidney disease as assessed against the Kidney Disease Outcomes Quality Initiative (KDOQI) Hemoglobin must be 8.5-10.5 g / dL at screening (4 weeks prior to randomization) and 8.5-10.0 g / dL on the day of randomization (Day 1). Maximum one dose of intravenous iron within 8 weeks prior to screening, with no intravenous iron use between screening and randomization If needed, oral iron supplementation for stable maintenance is permitted. There must be less than a 50% change in overall iron dose and no change in iron type in the 4 weeks prior to the Day 1 randomization visit. Female participants of childbearing potential, provided they are not pregnant or breastfeeding and agree to follow contraceptive instructions during treatment and for 4 weeks after the last dose of study treatment. Ability to obtain informed consent

[0091] Exclusion criteria -Currently on dialysis or have clinical evidence of an urgent need to start dialysis within 180 days of randomization - Plan to have a kidney transplant within 28 days of randomization Transferrin saturation <15% at screening Ferritin level at screening is less than 50ng / ml Use of recombinant erythropoietin within 8 weeks prior to screening or between screening and randomization

[0092] Enrolled participants were randomized 1:1 to receive either daprodustat tablets or matching placebo tablets administered once daily. The starting dose or matching placebo was assigned based on Hemocue hemoglobin level at randomization, such that participants with hemoglobin levels of 8.5 to less than 9 g / dL received a daily starting dose of 4 mg, and participants with hemoglobin levels of 9 to 10 g / dL received a daily starting dose of 2 mg.

[0093] Participants in both treatment groups received titrated treatment doses based on hemoglobin levels assessed by HemoCue. HemoCue assessments were performed on Day 1 and at Weeks 2, 4, 8, 12, 16, 20, 24, and 28. Available dose steps for daprodustat and placebo were 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, and 16 mg. Participants' dose modifications were performed according to the dose adjustment algorithm outlined in Table 2 to achieve and maintain hemoglobin levels within the target range of 11.0–12.0 g / dL.

[0094] [Table 2]

[0095] Participants' iron status was assessed on day 1 and at weeks 16 and 28. If ferritin was less than 50 ng / ml and / or transferrin saturation was less than 15%, iron therapy was administered, starting with oral iron, to reestablish participants' screening iron parameters. Participants who were intolerant to oral iron could receive intravenous iron; otherwise, intravenous iron was only administered to participants being evaluated for rescue.

[0096] A rescue algorithm was provided to minimize participants with prolonged inadequate response to anemia treatment. Starting at week 4, participants were assessed for iron status and rescue if their hemoglobin concentration, as assessed by HemoCue, was <7.5 g / dL, or <8.5 g / dL if the participant was symptomatic, or if it remained <8.5 g / dL for three consecutive visits. The initial intervention depended on iron status: if the participant's TSAT was <15% from the previous study visit and / or ferritin was <50 ng / ml, a single dose of up to 1000 mg of intravenous iron was administered in addition to iron administered according to iron management guidelines. If the patient was iron-replete (TSAT ≥15%, ferritin ≥50 ng / ml) or if the hemoglobin concentration at the next study visit remained <8.5 g / dL despite the use of intravenous iron, study treatment was discontinued and the participant should be rescued according to local clinical practice.

[0097] The primary objective of this trial was to compare the efficacy of daprodustat with placebo on the mean change in hemoglobin concentration. The primary endpoint was the mean change in hemoglobin concentration between baseline (Day 1) and the evaluation period (average of Weeks 24 through 28).

[0098] Several secondary and exploratory objectives were investigated. Secondary objectives included comparing daprodustat with placebo on health-related quality of life and comparing daprodustat with placebo on improving anemia symptoms in chronic kidney disease.

[0099] The short-form SF-36 questionnaire was completed by participants at day 1 and weeks 8, 12, and 28, and the CKD-AQ questionnaire was completed by participants at week -2 (i.e., during the screening period) and days 1 and weeks 8, 12, and 28.

[0100] Evaluation items included: Mean change in SF-36 vitality domain score (0-100) from baseline to week 28. This was the key secondary endpoint, and the study was adequately powered for this endpoint. · Mean change from baseline by domain on the CKD-AQ and global symptom score (the study was not powered for this secondary endpoint, so only nominal significance can be assessed).

[0101] In addition to analyzing the intention-to-treat population, several subgroup analyses were prespecified, including subgroups with baseline hsCRP quartiles of <0.9 mg / L, 0.9 to <2.6 mg / L, 2.60 to <6.60 mg / L, and ≥6.60 mg / L.

[0102] For the mean change endpoints of hemoglobin and SF-36 vitality domain, an analysis of covariance model was used, including covariates for baseline level, treatment, and domain. This model provided point estimates of treatment effect and two-sided 95% CIs, along with one-sided p-values. Significance was determined when one-sided p-values ​​were less than 0.025. The analysis population for the hemoglobin and SF-36 vitality domain endpoints was the intention-to-treat population. The analysis population for the fatigue / low energy / weakness domain endpoint of the Anemia of Chronic Kidney Disease Questionnaire was the on-treatment population, and the analysis was based on a mixed-model repeated measures model fitted from baseline to week 28 with factors for treatment, time, domain, baseline value, baseline value by time, and treatment by time interaction.

[0103] For the subgroup-specific endpoints of mean change in hemoglobin and SF-36 vitality domain, the same models were used as above, with the addition of subgroup covariates and subgroup x treatment interaction terms. The analysis population for these endpoints was the intention-to-treat population.

[0104] For the SF-36 vitality domain response rate difference endpoint, a Cochran-Mantel-Haenszel chi-square test adjusting for treatment, baseline level, and domain was used to compare between treatment groups. Significance was determined at a one-sided p-value of less than 0.025. The analysis population for these endpoints was the intention-to-treat population.

[0105] Analyses were calculated using SAS software, version 9.2 (or higher).

[0106] result In this study, daprodustat significantly increased the SF-36 Vitality subscore compared with placebo. As shown in Table 3, the adjusted mean SF-36 Vitality change during treatment was 7.29 for daprodustat in the intention-to-treat population (a 6-point change within subjects is conservatively estimated to be clinically relevant; see Example 3). The adjusted mean treatment difference (dapro-placebo) was 5.36. The one-sided superiority p-value (based on a test of the null hypothesis: (dapro-placebo) <= 0 vs. alternative: difference > 0) was 0.0005. 58% of participants treated with daprodustat demonstrated a change of 6.0 points or more in the SF-36 Vitality subscore from baseline to week 28, compared with 40% of participants treated with placebo. The adjusted difference in response rates (Dapro minus placebo) was 0.13 (0.04, 0.22), which was nominally significant (one-sided p-value = 0.0049). Note that missing or off-treatment SF36 data were imputed for completeness.

[0107] [Table 3]

[0108] Daprodustat increased the SF-36 Vitality subscore compared with placebo, regardless of baseline hsCRP levels. Subgroups with baseline hsCRP <0.9 mg / L, 0.9 to <2.6 mg / L, 2.60 to <6.60 mg / L, and ≥6.60 mg / L demonstrated adjusted mean SF-36 Vitality changes of 9.84, 4.98, 7.92, and 8.24, with adjusted mean treatment differences (CI) of 10.0 (3.53, 16.47), 1.09 (-4.86, 7.04), 4.38 (-1.77, 10.53), and 7.71 (1.62, 13.80), respectively.

[0109] Daprodustat also increased scores in the fatigue / low energy / weakness domain of the Chronic Kidney Disease-Anemia Questionnaire. As shown in Table 4, the adjusted mean change over the treatment period was 8.72 for daprodustat. The adjusted mean treatment difference (dapro-placebo) was 5.91. The one-sided p-value (based on a test of the null hypothesis: (dapro-placebo) <= 0 vs. alternative: difference > 0) was < 0.0001.

[0110] [Table 4]

[0111] These results demonstrate that daprodustat contributed to improvements in patient-reported fatigue measures during the treatment period, as measured by two separate instruments: the SF-36 vitality domain (statistically significant) and the CKD-AQ "fatigue / low energy / weakness domain" (nominal significance given the fact that the study was not powered for this endpoint).

[0112] Daprodustat also significantly increased hemoglobin concentrations during the treatment period compared with placebo (one-sided superiority p-value (based on a test of the null hypothesis: (dapro-placebo) <= 0 vs. alternative: difference > 0) < 0.0001). However, the time course of the increase in hemoglobin concentrations did not closely reflect the time course of the improvement in fatigue as measured by the SF-36 Vitality domain. Figures 1 and 2 show the change in hemoglobin concentrations (Figure 1) and SF-36 Vitality domain scores (Figure 2) in daprodustat- and placebo-treated patients. At week 12, there was a clear difference in hemoglobin response between daprodustat and placebo (see Figure 1). However, at week 12, SF-36 Vitality domain scores for daprodustat and placebo were indistinguishable, and the SF-36 Vitality domain score only reached a significant treatment difference at week 28 (see Figure 2). A post-hoc analysis (Example 3) was then used to examine the correlation between on-treatment change in hemoglobin concentration (g / dL) from baseline to week 28 and on-treatment change in patient-reported measures of fatigue (SF36 Vitality domain subscore and Fatigue / Low Energy / Weakness domain of the Chronic Kidney Disease-Anemia Questionnaire) from baseline to week 28. The results are shown in Example 3.

[0113] A patient population was identified in which fatigue reduction did not correlate closely with hemoglobin concentration. Figure 3 shows a forest plot of the on-treatment adjusted mean SF-36 vitality change for each hsCRP quartile. Figure 4 shows the corresponding forest plot showing the on-treatment adjusted mean hemoglobin change for each hsCRP quartile. This figure shows that the patient population with hsCRP levels of 6.60 mg / L or higher showed a large change in the SF-36 vitality domain subscore (adjusted mean treatment difference = 7.71, 95% confidence interval 1.62, 13.80), while a relatively modest hemoglobin increase (adjusted mean treatment difference = 1.25, 95% confidence interval 0.92, 1.58) would be expected to be clinically relevant (see Example 3). In this patient population, the observed clinically relevant fatigue reduction (improvement in vitality) correlated poorly with hemoglobin increases.

[0114] The change in hsCRP levels in each quartile is shown in Tables 5-8 below.

[0115] [Table 5]

[0116] [Table 6]

[0117] [Table 7]

[0118] [Table 8]

[0119] If the baseline hsCRP level was less than 6.60 mg / L, the change in hsCRP level was modest (see Tables 5-7). In subjects with high baseline hsCRP (≥6.60 mg / L), a significant decrease in hsCRP levels was observed in the daprodustat group, raising the possibility that increased vitality in this group was associated with the decrease in hsCRP (Table 8). However, no firm conclusions can be drawn due to the fact that a similar decrease in hsCRP levels was observed in the placebo group with high baseline hsCRP (Table 8). It is also possible that the observed decrease may be due (at least in part) to the fact that subjects with the highest CRP levels were not evaluated at week 28 / end of treatment, presumably because these subjects were rescued.

[0120] Baseline hsCRP levels appear to influence improvement in patient-reported measures of fatigue after daprodustat treatment. However, other factors may also contribute, and indeed, these factors may be interdependent. As shown in Table 9, baseline hepcidin levels also influence improvement in patient-reported measures of fatigue during treatment. Baseline SF-36 scores were similar across all quartiles.

[0121] [Table 9]

[0122] Patients with higher baseline hepcidin levels experienced greater improvements in patient-reported fatigue measures. This was particularly true for patients with baseline hepcidin levels of 74.58 μg / L or higher (which may be rounded to 75 μg / L or higher). The improvements appeared to be accompanied by a decrease in hepcidin levels. In the overall population, daprodustat treatment resulted in a 37.40% decrease in hepcidin (nmol / L) compared to baseline at 28 weeks. In contrast, the decrease observed with placebo over the same period was dramatically lower (9.54%).

[0123] The interaction between baseline hsCRP and hepcidin levels on patient response is complex. Tables 10 and 11 show that the mean change in SF-36 vitality at week 28 in patients with baseline hepcidin levels above or below the median (74.58 μg / L) was dependent on baseline hsCRP levels.

[0124] [Table 10]

[0125] [Table 11]

[0126] Baseline SF-36 values ​​were comparable for the populations in Tables 10 and 11. Among patients with baseline hepcidin <74.85 μg / L (which may be rounded to <75 μg / L), the greatest improvement in SF-36 Vitality score from baseline to week 28 was observed in patients with hsCRP ≥2.60 mg / L, especially in patients with baseline hsCRP ≥6.60 mg / L. Improvement in SF-36 Vitality score from baseline to week 28 was observed in all patients with baseline hepcidin ≥74.85 μg / L (which may be rounded to ≥75 μg / L). Within this group, more significant improvements in SF-36 Vitality score from baseline to week 28 were observed in two distinct populations: patients with baseline hsCRP <0.9 mg / L and patients ≥2.60 mg / L (especially in patients with baseline hsCRP ≥6.60 mg / L).

[0127] Furthermore, baseline hemoglobin concentration influences the adjusted mean treatment for the SF-36 Vitality subscore. Figure 5 shows a forest plot of the on-treatment adjusted mean SF-36 Vitality change for subjects with baseline hemoglobin concentrations of <9 g / dL, ≥9 but <10 g / dL, ≥10 but <11 g / dL, and >11 g / dL. While the small number of subjects with >11 g / dL complicates interpretation, it is noteworthy that the adjusted mean treatment difference for SF36 Vitality was reduced in this subgroup (adjusted mean treatment difference -7.13, confidence interval -26.23, 11.97). A smaller increase in hemoglobin concentration due to study design was also observed in this subgroup (adjusted mean treatment difference 0.76 g / dL, confidence interval -0.36, 1.88). Although the study design and the small number of subjects with baseline hemoglobin >11 g / dL preclude firm conclusions, the increase in SF36 vitality score appears to be most pronounced in subjects with baseline hemoglobin concentrations ≤11 g / dL.

[0128] Example 2 A post-hoc analysis was performed on data from the study described in Example 1 to determine the correlation between on-treatment change in hemoglobin concentration (g / dL) from baseline to week 28 and on-treatment change in the SF-36 vitality subscore from baseline to week 28, and between on-treatment change in hemoglobin concentration (g / dL) from baseline to week 28 and on-treatment change in the fatigue / low energy / weakness domain of the CKD-AQ from baseline to week 28. Correlations were calculated using SAS software, version 9.2 (or higher). Statistical outputs included the Pearson correlation coefficient, correlation estimates based on the Pearson correlation statistic (Fisher's z transformation) with bias adjustment, two-sided 95% CI, and one-sided p-values. The one-sided p-value was based on a test of the null hypothesis: Rho<=0.40 and the alternative hypothesis: Rho>0.40. Nominal significance is established when the one-sided p-value is less than 0.025.

[0129] The number of subjects with both baseline and week 28 hemoglobin and SF-36 vitality subscores was 188 (placebo) and 210 (Dapro). The Pearson correlation coefficient calculated for the on-treatment change in SF-36 vitality subscore from baseline to week 28 against the on-treatment change in hemoglobin concentration (g / dL) from baseline to week 28 was 0.0356, and the correlation estimate (based on the bias-adjusted Pearson correlation statistic (Fisher's z transformation)) was 0.0356 (two-sided 95% confidence interval: -0.06, 0.13). The one-sided p-value was >0.999.

[0130] Similarly, the number of subjects with both baseline and week 28 hemoglobin and CKD-AQ fatigue / low energy / weakness domain scores was 191 (placebo) and 212 (Dapro). The Pearson correlation coefficient calculated for the on-treatment change from baseline to week 28 in the CKD-AQ fatigue / low energy / weakness domain against the on-treatment change from baseline to week 28 in hemoglobin concentration (g / dL) was 0.0877, and the correlation estimate (based on the bias-adjusted Pearson correlation statistic (Fisher's z transformation)) was 0.0876 (two-sided 95% confidence interval: -0.01, 0.18). The one-sided p-value was >0.999.

[0131] These post-hoc analyses confirmed that the correlation between change in hemoglobin concentration and fatigue as measured by the SF-36 vitality subscore or the fatigue / low energy / weakness domain of the CKD-AQ was very weak.

[0132] Example 3 A targeted literature review was conducted to identify thresholds for meaningful change (minimal clinically important difference or MCID) for the SF-36 Vitality Scale (k = 4) and / or its four component items. Searches were conducted in MEDLINE (via PubMed) and Embase for articles and conference abstracts published in English between January 1, 1996, and January 26, 2018. A total of 56 citations were identified using search terms aimed at capturing literature on the minimal clinically important difference for the SF-36 Vitality Scale, and 33 were identified using search terms aimed at capturing literature on the minimal clinically important difference for the KDQOL (a measure of quality of life for patients with kidney disease) (because the SF-36 is incorporated within the KDQOL). Grey literature searches were also conducted to capture information available from various scientific conferences or websites from sources not indexed in MEDLINE or Embase. The grey literature search involved using common search engines (Google and Mozilla) to identify MCIDs for the SF-36 vitality scale not identified in MEDLINE or Embase. Additionally, the grey literature search involved searching conference abstracts and poster presentations (where available) from 2015–2017 meetings of the following conferences and meetings:

[0133] World Congress of Nephrology American Society of Nephrology (ASN) Annual Meeting ("Kidney Week") European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress National Kidney Foundation Clinical Conference International Society for Pharmacoeconomics and Outcomes Research International Society for Quality of Life Research

[0134] In addition to meeting the study inclusion criteria above, an additional requirement for a grey literature source to be included in the review was that it be citable in a format acceptable to regulatory agencies. The grey literature search did not yield any additional unique citations.

[0135] The following criteria were used to identify hits that warranted more critical review: Relevant to adult patients with chronic kidney disease Use approved treatments Outcomes include an empirical assessment of the minimal clinically important difference for the SF-36 Vitality subscale and / or its four components. Related to randomized controlled clinical trials, observational studies, or controlled or systematic literature reviews · Written in English (regardless of geographic region)

[0136] Screening of hits using this criteria was performed by reviewers using the following process. Level 1: Title / abstract review by one researcher Level 2: Full-text review. Rejected articles were reviewed by an independent researcher and any discrepancies were resolved. Level 3: Extraction of data including: Author and year country Study design Diseases studied Sample size Inclusion criteria o Exclusion criteria o Follow-up period (mean, median, or maximum) o Treatments investigated Patient demographic characteristics o Specific MCID methods oSF-36 scoring (comparison of norm-based and traditional 0-100 based) MCID results for the SF-36 Vitality Scale and / or its four component items

[0137] After data extraction and aggregation, MCID results for the SF-36 Vitality Scale and / or its four component items were displayed graphically and tabulated to allow triangulation between MCID methods.

[0138] For SF-36 citations: (1) 11 conference abstracts were screened, one for full-text extraction; (2) 45 general articles were screened, 10 for full-text extraction, and three were abstracted. For KDQOL citations: (1) 8 conference abstracts were screened, zero for full-text extraction; (2) 25 general articles were screened, 15 for full-text extraction, and two were abstracted. The reference lists of four systematic reviews / meta-analyses were reviewed to identify other relevant articles related to the MCID of the SF-36 Vitality Scale in CKD. The reference lists of all abstracted articles were also searched. A total of 16 additional studies were identified through these backward citation searches.

[0139] Four main methodological categories were derived to describe papers reporting thresholds of meaningful change for the SF-36 vitality scale in CKD: Within-group treatment studies - longitudinal studies involving one or more treatments for CKD anemia in which within-group change from baseline on the SF-36 vitality scale was reported A study investigating within-group changes in target hemoglobin levels (hemoglobin correction or normalization) and the SF-36 Vitality Scale Psychometric studies addressing distribution-based methods for deriving the MCID Psychometric studies addressing anchor-based methods for deriving the MCID

[0140] Considering the inclusion of distribution-based results, the overall thresholds for meaningful change in the SF-36 Vitality scale in CKD derived from 21 extracted studies are unweighted mean 5.8, weighted mean 5.3, unweighted median 5.6, and weighted median 4.5. Excluding distribution-based results, the overall thresholds for meaningful change in the SF-36 Vitality scale in CKD derived from 16 extracted studies are unweighted mean 6.1, weighted mean 5.7, unweighted median 5.8, and weighted median 4.9.

[0141] Based on this study, a literature-based threshold of 6.0 for meaningful change on the SF-36 Vitality scale applied in psychometric analyses is considered appropriate.

[0142] Example 4 Daprodustat free acid tablet formulations can be prepared as follows: The tablet core comprises granules and extragranular components. Granules are prepared by adding daprodustat, mannitol, microcrystalline cellulose, hypromellose 2910, and croscarmellose sodium to a high-shear granulator. The powders are blended under high shear for at least 5 minutes, and granulation is carried out while spraying at least 26 w / w% purified water over a water addition time of at least 7 minutes and a wet massing time of at least 2 minutes. The wet granules are dried in a fluidized bed dryer at a product temperature of at least 38°C to a target moisture content of not more than 2 w / w%, and the granules are dry-milled to normalize the granule size distribution. The milled granules are further blended with the extragranular components mannitol, microcrystalline cellulose, croscarmellose sodium, and the glidant colloidal silicon dioxide. Magnesium stearate is added and the resulting mixture is compressed into tablet cores using a rotary tablet press under the following conditions, using a compression pressure in the range of 180-370 MPa:

[0143] Tablet shape / size: Round, biconvex tablet / diameter 7 mm (4 mg or less), diameter 9 mm (6 mg or more) Compression speed is at least 40,000 tablets / hour

[0144] The composition of the tablets is shown in Table 12.

[0145] [Table 12]

[0146] The purified water used for granulation is removed during processing and does not remain in the tablets.

[0147] Example 5 The questions in the "Fatigue / Low Energy / Weakness" domain of the CKD-AQ are shown in Table 10:

[0148] [Table 13-1] [Table 13-2]

[0149] As mentioned above, the frequency items have a rating scale with five frequency categories: "never," "a little," "sometimes," "most of the time," and "always." The severity items have an 11-point numerical rating scale (0-10), with verbal descriptions at the extreme ends: 0 = "none / didn't exist" to 10 = "worst symptoms imaginable."

[0150] Due to the different rating scales, it was necessary to rescale the frequency and severity items to a 0–100 scale to ensure that "method factors" did not confound the analysis. Items were rescaled to a 0–100 scale using a simple linear transformation, as outlined in Tables 14 and 15.

[0151] [Table 14]

[0152] [Table 15]

[0153] To get a region score, the linearly transformed scores are summed and then divided by the number of items in the region. Region scores are always between 0 and 100.

Claims

1. 1. Daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject with anemia associated with chronic kidney disease who is not undergoing dialysis, wherein the subject has hepcidin levels of 75 μg / L or greater at baseline.

2. 1. A method of reducing fatigue in a subject with anemia associated with chronic kidney disease who is not undergoing dialysis, said method comprising administering to said subject daprodustat or a pharmaceutically acceptable salt thereof, wherein said subject has hepcidin ≧75 μg / L at baseline.

3. 3. The method of claim 2, wherein the subject has a hepcidin level in the range of greater than or equal to 75 μg / L to less than 121 μg / L at baseline.

4. 3. The use of daprodustat or a pharmaceutically acceptable salt thereof according to claim 1, or the method according to claim 2, wherein the subject has a hepcidin level of 121 μg / L or greater at baseline.

5. The use of daprodustat or a pharmaceutically acceptable salt thereof according to any one of claims 1, 3 and 4, or the method according to any one of claims 2 to 4, wherein the subject has an hsCRP of less than 0.9 mg / L at baseline.

6. The use of daprodustat or a pharmaceutically acceptable salt thereof according to any one of claims 1, 3 and 4, or the method according to any one of claims 2 to 4, wherein the subject has an hsCRP of 2.60 mg / L or greater at baseline.

7. 7. The use of daprodustat or a pharmaceutically acceptable salt thereof according to claim 6, or the method according to claim 6, wherein the subject has an hsCRP of 6.60 mg / L or greater at baseline.

8. 1. Daprodustat or a pharmaceutically acceptable salt thereof for use in reducing fatigue in a subject with anemia associated with chronic kidney disease who is not undergoing dialysis, wherein the subject: (a) hepcidin <75 μg / L at baseline; and (b) baseline hsCRP ≥ 2.60 mg / L; Daprodustat or a pharmaceutically acceptable salt thereof.

9. 1. A method for reducing fatigue in a subject with anemia associated with chronic kidney disease who is not undergoing dialysis, the method comprising administering to the subject daprodustat or a pharmaceutically acceptable salt thereof, wherein the subject: (a) hepcidin <75 μg / L at baseline; and (b) baseline hsCRP ≥ 2.60 mg / L; Daprodustat or a pharmaceutically acceptable salt thereof.

10. 10. The use of daprodustat or a pharmaceutically acceptable salt thereof according to claim 8, or the method according to claim 9, wherein the subject has an hsCRP of 6.60 mg / L or greater at baseline.

11. The use of daprodustat or a pharmaceutically acceptable salt thereof according to any one of claims 1, 3 to 8 and 10, or the method according to any one of claims 2 to 7 and 9 to 10, wherein the subject having anemia has a hemoglobin concentration of 10 g / dL or less at baseline.

12. 12. The use of daprodustat or a pharmaceutically acceptable salt thereof for use according to claim 11, or the method according to claim 11, wherein reduced fatigue is observed when the subject is treated to maintain a hemoglobin concentration in the range of 10 to 12 g / dL.

13. 12. The use of daprodustat or a pharmaceutically acceptable salt thereof for use according to claim 11, or the method according to claim 11, wherein reduced fatigue is observed when the subject is treated to maintain a hemoglobin concentration in the range of 11 to 12 g / dL.

14. The use of daprodustat or a pharmaceutically acceptable salt thereof according to any one of claims 1, 3 to 8 and 10 to 13, or the method according to any one of claims 2 to 7 and 9 to 13, wherein the subject with anemia has no history of heart failure.

15. Daprodustat or a pharmaceutically acceptable salt thereof for use according to any one of claims 1, 3 to 8 and 10 to 14, or the method according to any one of claims 2 to 7 and 9 to 14, wherein fatigue is reduced if the mean score on the Vitality subscale of the SF-36 questionnaire increases in the subject population at the end of the treatment period compared to baseline.

16. Daprodustat or a pharmaceutically acceptable salt thereof for use according to any one of claims 1, 3 to 8 and 10 to 14, or the method according to any one of claims 2 to 7 and 9 to 14, wherein fatigue is reduced if the mean increase in the Vitality subscale of the SF-36 questionnaire is at least 6 points in a subject population at the end of a treatment period compared to baseline.

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