Oral Hypoxia-inducible Factor Prolyl Hydroxylase Research Articles

#708 Retrospective analysis of the real-world experience of desidustat in the treatment of chronic kidney disease induced anemia

Abstract Background and Aims Chronic kidney disease (CKD) is commonly associated with an increased risk of anemia, which significantly impacts patients' quality of life and increases morbidity and mortality. Current treatment options for anemia in CKD, such as injectable erythropoiesis-stimulating agents (ESAs) have limitations and safety concerns. Desidustat, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) has shown promise in stimulating endogenous erythropoiesis and addressing anemia in CKD. Therefore, the present study assesses the real-world clinical efficacy and safety of the desidustat treatment for a short duration of 6 months (24 weeks) in CKD patients with anemia. Method This is a retrospective analysis of 140 patients at our center who received Desidustat as a treatment for CKD anemia. Desidustat was initiated in all patients at 100 mg three times a week. Dose adjustment was done every 4 weeks as per the Hb level of the patient. The duration of the study was 6 months. The primary endpoint of the present study was a change in Hb from baseline with desidustat therapy and the secondary endpoint was safety of the treatment. Results The majority of the patients were Pre-dialysis 74.28% (n = 104) and 25.72% (n = 36) were dialysis-dependent patients. Of 36 dialysis-dependent patients; 75% (n = 27) were on dialysis three times a week, rest were on twice-a-week dialysis. In the current study, the majority of patients had Hypertension (95.7%) and diabetes (68.57%) as co-morbidities. All the patients in the current study were maintained with 100 mg Desidustat, however, 9.2% (n = 13) required dose reduction, and 11.42% (n = 16) required an increased dose of desidustat on the follow-up visit. In both Pre-Dialysis and dialysis-dependent patients, there was a sustainable rise in the mean Hb levels at the end of 24 weeks from baseline (1.05 g/dL; p < 0.05) All the patients tolerated desidustat well. In the present study, we didn't observe significant side effects related to the therapy apart from 2.41% (n = 3) cases of Diarrhoea and Vomiting. Conclusion Desidustat is effective in increasing Hb in CKD Anemia patients in the short run. However, Long-term studies are required to establish the efficacy and safety of this novel therapy.

#2063 Safety and efficacy of vadadustat vs darbepoetin alfa in patients on maintenance dialysis by prespecified subgroups of baseline ESA dose

Abstract Background and Aims Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in Europe, Australia, Japan for the treatment of anemia in patients with dialysis-dependent (DD)-CKD. In the INNO2VATE global phase 3 trials in patients with DD-CKD, including 2 separate trials in patients new to dialysis [NCT02865850] and on maintenance dialysis [NCT02892149], vadadustat was noninferior to the erythropoiesis -stimulating agent (ESA) darbepoetin alfa for cardiovascular safety and hemoglobin efficacy. Among patients with DD-CKD, high ESA dose requirements have been associated with an increased risk of cardiovascular complications. In this secondary analysis, we compared cardiovascular safety and hematological efficacy of vadadustat and darbepoetin alfa across baseline ESA dose categories. Method In the INNO2VATE trials, 3554 patients on maintenance dialysis were randomized 1:1 to vadadustat or darbepoetin alfa, stratified according to geographic region, New York Heart Association heart failure classification, and hemoglobin concentration at trial entry. Data were analyzed for prespecified subgroups of patients categorized by their baseline ESA (epoetin alfa/equivalents) dose: low (<90 U/kg/week), intermediate (90-299 U/kg/week), or high (≥300 U/kg/week). Within these dose subgroups, the key safety endpoint was the first occurrence of an adjudicated major adverse cardiovascular event (MACE: first occurrence of all-cause mortality, nonfatal myocardial infarction [MI], or nonfatal stroke) using a time-to-event analysis. Primary and secondary efficacy endpoints were mean change in hemoglobin concentration from baseline during the primary (weeks 24-36) and secondary (weeks 40-52) evaluation periods, respectively. Results More participants were in the low (vadadustat: n = 916 [53%], darbepoetin alfa: n = 968 [55%]) and intermediate (vadadustat: n = 724 [42%], darbepoetin alfa: n = 693 [39%]) than in the high (vadadustat: n = 102 [6%], darbepoetin alfa: n = 98 [6%]) baseline ESA dose subgroups. Hazard ratios for the occurrence of first MACE between vadadustat and darbepoetin alfa in the 3 baseline ESA dose subgroups were as follows: low dose, 0.99 (95% CI, 0.81 to 1.23); intermediate dose, 0.93 (95% CI, 0.74 to 1.18); and high dose, 0.62 (95% CI, 0.34 to 1.14) (Fig.). Similar results were observed for other key MACE-related endpoints, including all-cause mortality, MACE plus hospitalizations for heart failure or thromboembolic events, cardiovascular MACE (first occurrence of cardiovascular mortality, nonfatal MI, or nonfatal stroke), and cardiovascular death. Mean hemoglobin concentrations increased in both treatment groups throughout the trial period. The least squares mean treatment difference (vadadustat compared to darbepoetin alfa) for change in hemoglobin concentration from baseline to the primary efficacy period was –0.10 g/dL (95% CI, –0.19 to –0.02), –0.20 g/dL (95% CI, –0.30 to –0.09), and –0.39 g/dL (95% CI, –0.67 to –0.11) for the low, intermediate, and high baseline ESA dose subgroups, respectively. Similar results were observed for the secondary efficacy period. Across baseline ESA dose subgroups, the proportion of patients whose average hemoglobin concentration was within target range was similar between the vadadustat and darbepoetin alfa arms during the primary efficacy period (low: odds ratio [OR], 0.89; 95% CI, 0.74, 1.08; intermediate: OR, 0.87; 95% CI, 0.70, 1.09; high: OR, 0.90; 95% CI 0.49, 1.64). Similar results were observed during the secondary efficacy period. Conclusion The cardiovascular safety and efficacy of vadadustat was similar to darbepoetin alfa in patients with DD-CKD irrespective of baseline ESA dose. In patients requiring higher ESA doses at baseline, the risk of MACE was numerically (but not significantly) lower in vadadustat-treated patients. Further investigation is required to confirm or refute this trend.

#2815 Single center, single arm, prospective, observational study of desidustat in chronic kidney disease-induced anemia

Abstract Background and Aims Anemia in chronic kidney disease (CKD) is multifactorial. Relative deficiency of erythropoietin is one of the key reasons for decreased RBC production. This anemia is associated with poor quality of life and increases morbidity in CKD patients. Injectable erythropoietin is the standard of care for CKD-anemia, which has safety concerns. Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), stimulates endogenous erythropoiesis and is approved for CKD anemia treatment. Hence, the present study identifies the real-world clinical efficacy and safety of the desidustat treatment for a short duration in CKD anemia. Method This is an open-label, single-center, prospective study. We analyzed the data of 130 patients who are currently in follow-up and received Desidustat as treatment for CKD-anemia. The study is for the duration of 24 weeks. We followed up on patent at 1 month, 3 months, and the end of the study (6 months). Patients were given a 100-mg Desidustat tablet orally three times in a week. The primary outcome is to assess the change in Hb from baseline, and the secondary outcome is the safety of the therapy. Results In this study, we enrolled 130 patients. Of these 130 patients, 58.4% (n = 76) were male and 41.5% (n = 54) were female. The mean age of the study population was 53.6 ± 12.3 years. The majority of the study population was in the pre-dialysis category; 80% (n = 104) and 20% (n = 26) were on dialysis. All the dialysis patients were on three times per week on Dialysis. Diabetes (68%) and hypertension (75%) are the most common co-morbid conditions in patients with CKD anemia. All the patients received desidustat at a 100 mg, three-weekly dose. During each follow-up visit, a significant rise in hemoglobin was observed (p<0.001), as shown in the figure. With desidustat therapy, adverse drug reactions were seen in 5.3% (n = 7) cases: three cases of abdominal pain, two cases of vomiting, and two cases of diarrhea. Conclusion Oral HIF-PHIs and Desidustat showed significant improvement in hemoglobin in CKD anemia patients. More studies require for safety and efficacy in Dialysis dependent CKD - Anemia patients.

#2898 Exposure response model describing hematologic changes with chronic treatment of CKD anemia with vadadustat

Abstract Background and Aims Vadadustat (VADA) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate endogenous erythropoietin production, increasing iron mobilization and red blood cell production. VADA is approved in 36 countries globally and is indicated in the European Union for the treatment of symptomatic anaemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis and is an alternative to treatment with erythropoiesis-stimulating agents (ESAs). The aim of this work was to develop a predictive, semi-mechanistic model to understand the effects of VADA and erythropoiesis-stimulating agents (ESAs) on hemoglobin response and to evaluate the impact of intrinsic and extrinsic patient characteristics on that response for non-dialysis dependent (NDD) and dialysis-dependent (DD) patient populations. Method A predictive semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for VADA and ESA treatment was developed using nonlinear mixed effects methods. The model describes changes in reticulocyte count (RETICs), mature erythrocytes (RBCs) and hemoglobin (Hb) as a function of drug exposure and subject-specific characteristics. The dataset was based on data from 7 Phase 1 to Phase 3 studies (Table 1; N = 894 for VADA; N = 560 for ESA modeling) in healthy volunteers and subjects with NDD- or DD-CKD who were either ESA-naïve or ESA experienced but not receiving treatment at screening. Prior population PK modeling of VADA provided estimated drug exposures for VADA-treated subjects, while dose normalized to standard units (IU/kg/wk) was used as the exposure metric for subjects on ESA. Each of these exposure metrics could vary with time, as the dose was adjusted according to observed Hb response. This work evaluated alternative model structures, as well as covariate effects affecting Hb individual response. Results A predictive semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for VADA and ESA treatment was developed using nonlinear mixed effects methods. The model describes changes in reticulocyte count (RETICs), mature erythrocytes (RBCs) and hemoglobin (Hb) as a function of drug exposure and subject-specific characteristics. The dataset was based on data from 7 Phase 1 to Phase 3 studies (Table 1; N = 894 for VADA; N = 560 for ESA modeling) in healthy volunteers and subjects with NDD- or DD-CKD who were either ESA-naïve or ESA experienced but not receiving treatment at screening. Prior population PK modeling of VADA provided estimated drug exposures for VADA-treated subjects, while dose normalized to standard units (IU/kg/wk) was used as the exposure metric for subjects on ESA. Each of these exposure metrics could vary with time, as the dose was adjusted according to observed Hb response. This work evaluated alternative model structures, as well as covariate effects affecting Hb individual response. A similar model structure was found to describe early changes in RETICs and longer-term changes in Hb for both VADA and ESAs. In each case, the magnitude of response increases with increased drug exposure up to a maximum value (Emax), and the Emax values were similar between VADA and ESAs. Subject intrinsic predictors of response included eGFR, subject age, BMI, and serum albumin, while extrinsic factors affecting response included geographic region, limits on acceptable Hb values (which also differ by geographic region) and the presence of previous ESA treatment. Interestingly, Hb responses were also correlated with changes in serum hepcidin, a key regulator of iron homeostasis, following both VADA and ESA treatment. Differences between the response to VADA and ESA were also described, including differences in temporal changes in RETICs and Hb. Conclusion This model showed an exposure-response relationship between VADA or ESA treatment and changes in RETICs and Hb for ESA naïve or ESA-experienced CKD subjects. The model will be used to inform dosage recommendations for VADA based on patient characteristics.

The Efficacy and Safety of Roxadustat for the Treatment of Posttransplantation Anemia: A Randomized Study

IntroductionRoxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, can stimulate erythropoiesis. Our objective was to evaluate the efficacy and safety of roxadustat for the treatment of post-transplantation anemia (PTA). MethodsA total of 150 adult renal transplant recipients who underwent PTA were randomized to either the experimental group or the control group. During the 12-week randomized phase, the experimental group was randomized to oral iron and roxadustat treatment, and the control group was randomized to oral iron treatment only. The randomized phase was followed by a 12-week extended treatment period in which all participants were prescribed roxadustat treatment according to hemoglobin (Hb) levels. All the participants were followed up every 4 weeks. The primary endpoints were the change in Hb levels and response rate throughout the randomized period. ResultsA total of 128 participants completed the randomized treatment period (90 in the experimental group and 38 in the control group). The mean Hb concentration at week 12 was 12.20 g/dL in the experimental group and 11.19 g/dL in the control group. A significantly higher proportion of participants who achieved Hb responses were in the experimental group than in the control group. Differences in serum iron, total iron-binding capacity (TIBC) and transferrin from baseline to week 8-12 were significant between the two groups. The adverse event profiles were comparable between the two groups. ConclusionsRoxadustat increased Hb in adult renal transplant recipients who underwent PTA, with an adverse event profile comparable to that of the control group.

Factors affecting responsiveness of vadadustat in patients with anemia associated with chronic kidney disease: a post-hoc subgroup analysis of Japanese phase 3 randomized studies

BackgroundVadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed for treating anemia in chronic kidney disease (CKD). The purpose of this post-hoc analysis was to investigate the factors affecting the responsiveness to vadadustat in anemia patients with nondialysis-dependent (NDD) or hemodialysis-dependent (HDD) CKD in two Japanese phase 3 studies.MethodsOf 151 and 162 patients enrolled in NDD-CKD and HDD-CKD studies, 136 and 140 patients, respectively, were included and divided into subgroups for the analysis. To assess vadadustat responsiveness, the resistance index was defined as the mean body weight-adjusted dose of vadadustat (mg/kg) at weeks 20–24 divided by the mean hemoglobin (g/dL) at weeks 20–24. Multivariate analysis was performed to identify the variables affecting the resistance index.ResultsIndependent factors identified as determinants for better response to vadadustat were as follows: high baseline hemoglobin, low baseline eGFR, high week-20–24 ferritin, and CKD not caused by autoimmune disease/glomerulonephritis/vasculitis in NDD-CKD; and male sex, high baseline C-reactive protein, and low baseline erythropoiesis-stimulating agent resistance index (ERI) in HDD-CKD.ConclusionsIn this post-hoc analysis, several factors were identified as affecting the response to vadadustat. These results may provide useful information leading to an appropriate dose modification for vadadustat.Clinical trial registrationNCT03329196 (MT-6548-J01) and NCT03439137 (MT-6548-J03).

Mechanistic Determinants of Daprodustat Drug-Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B-CYP2C8 Interplay.

Daprodustat is the first oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B-mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically-based PK (PBPK) modeling of its drug-drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by OATP1B1/1B3 in the transfected cell systems and primary human and monkey hepatocytes. A single-dose oral rifampin (OATP1B inhibitor) reduced daprodustat intravenous clearance by a notable9.9 ± 1.2-fold (P < 0.05) in cynomolgus monkeys. Correspondingly, volume of distribution at steady-state was also reduced by 5.0 ± 1.1-fold, whereas the half-life change was minimal (1.5-fold), corroborating daprodustat hepatic uptake inhibition by rifampin. A PBPK model accounting for OATP1B-CYP2C8 interplay was developed, which well described daprodustat PK and DDIs with gemfibrozil (CYP2C8 and OATP1B inhibitor) and trimethoprim (weak CYP2C8 inhibitor) within 25% error of the observed data in healthy subjects. About 18-fold increase in daprodustat area under the curve (AUC) following gemfibrozil treatment was found to be associated with strong CYP2C8 inhibition and moderate OATP1B inhibition. Moreover, PK modulation in hepatic dysfunction and subjects with CKD, in comparison to healthy control, was well-captured by the model. CYP2C8 and/or OATP1B inhibitor drugs (e.g., gemfibrozil, clopidogrel, rifampin, and cyclosporine) were predicted to perpetrate moderate-to-strong DDIs in healthy subjects, as well as, in target CKD population. Daprodustat can be used as a sensitive CYP2C8 index substrate in the absence of OATP1B modulation.

Roxadustat treatment for erythropoiesis-stimulating agent-hyporesponsive anemia in maintenance hemodialysis patients.

Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is a prevalent problem affecting hemodialysis (HD) patients. Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. We explored the ability of roxadustat to increase the hemoglobin (Hb) concentration in ESA-hyporesponsive patients undergoing HD and assessed its effect on iron metabolism and inflammation. This prospective study included 30 patients with ESA-hyporesponsive anemia who had been undergoing stable dialysis. All patients received roxadustat three times per week for 24 weeks. The primary endpoint was the mean change in Hb from baseline to the average level over weeks 20 to 24. Iron metabolism markers, C-reactive protein, interleukin (IL)-6, and safety were also assessed. At week 24, roxadustat treatment resulted in a 2.5 ± 1.3 g/dL increase in the Hb level. In total, 28 of 30 patients (93.3%) had an Hb level increase of more than 1.0 g/dL from baseline. Seventeen patients (56.7%) met the endpoint, with a mean Hb level of at least 10.0 g/dL. Iron metabolism and IL-6 levels were also improved. Oral roxadustat is effective for ESA-hyporesponsive anemia in maintenance HD patients and may also improve iron metabolism and IL-6 levels.

Evaluation of the Carcinogenic Potential of Enarodustat (JTZ-951), a Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor, in 26-Week Tg.rasH2 Mouse Study and 2-Year Sprague-Dawley Rat Study.

Enarodustat (JTZ-951) is an oral hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor for the treatment of anemia with chronic kidney disease. Carcinogenicity of enarodustat was evaluated in a 26-week repeated oral dose study in Transgenic rasH2 (Tg.rasH2) mice and a 2-year repeated oral dose study in Sprague-Dawley (SD) rats. The highest dose levels were set at 6mg/kg in the Tg.rasH2 mouse study and at 1mg/kg in the SD rat study based on the maximum tolerated doses in the 3-month and 6-month dose-range finding studies, respectively. Enarodustat did not increase the incidence of any tumors or affect survival in these carcinogenicity studies. Pharmacology-related findings including increases in blood RBC parameters were observed at the highest dose levels for each study. The AUC-based exposure margins as protein-unbound drug base are 16.3-/26.0-fold multiple (males/females) for Tg.rasH2 mice and 1.6-/1.1-fold multiple for SD rats when compared with the estimated exposure in human with chronic kidney disease at 8mg/day (maximum recommended human dose). In conclusion, enarodustat was considered to have no carcinogenic potential at the clinical dose.

Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non–Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Naïve Patients

Prespecified analyses of the PRO2TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO2TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents. Phase 3, global, open-label, randomized, active-controlled clinical trial. Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD. Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa. The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACEplus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis). In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of≤10mL/min/1.73m2 in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of≤10mL/min/1.73m2 and who may not have had access to dialysis. Different regional treatment patterns of patients with NDD-CKD. The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.

Effect of Roxadustat versus erythropoietin (EPO) for treating anemia in patients with diabetic kidney disease: a retrospective cohort study

Renal anemia of diabetic kidney disease (DKD) shows higher incidence rate, earlier onset and higher severity than other chronic kidney disease (CKD). Roxadustat, an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor, improves CKD anemia. This retrospective cohort study evaluates if Roxadustat could effectively treat DKD anemia. DKD anemia patients treated with either Roxadustat or erythropoietin (EPO) for 3 months in two hospitals were enrolled. EPO group were matched 1:1 to Roxadustat group based on age, gender and baseline Hb. Baseline data include age, sex, dialysis, height, weight, hemoglobin (Hb), hematocrit (Hct), serum albumin (ALB), serum creatinine (Scr), eGFR, C-reactive protein (CRP), and intact parathyroid hormone (iPTH). Primary and secondary outcomes were change of Hb (ΔHb) and Hct (ΔHct), Hb response rate and Hb qualified rate. Sensitivity analyses were performed and the effect size were calculated. No significant differences were observed in body mass index (BMI), Scr, eGFR, Hct, CRP, and dialysis between the 2 groups (61 subjects each). ALB, iPTH, and DKD stage differed between the 2 groups. After 3-month treatment, Roxadustat significantly increased patients' Hb and Hct. Although ΔHb and ΔHct of the Roxadustat group was higher than those of EPO group, difference in the least-square mean changes (95% CI) were 4.9 (-2.4, 12.1) and 1.2 (-1.1, 3.4), while Cohen's d were 0.18 and 0.14, suggesting that Roxadustat's ability to increase Hb within 3-month was similar to EPO. 78.7% and 54.1% of the patients responded to anti-anemia therapy in the Roxadustat and EPO group, respectively. Logistic regression analysis showed the Hb response rate of Roxadustat was 3.30 (1.20, 9.94) times higher than that of EPO. Subgroup analysis suggested that Roxadustat might have better efficacy in treating patients in the advanced stage, with high CRP and iPTH, and low ALB levels. In DKD patients, Roxadustat improves renal anemia. Effect of Roxadustat is similar to that of EPO.

MO536: Cardiovascular Events in Patients With Anemia Associated With Non–Dialysis-Dependent Chronic Kidney Disease: Regional Analysis of Patients not Previously Treated With Erythropoiesis-Stimulating Agents in The PRO2TECT Trial

Abstract BACKGROUND AND AIMS Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being investigated for treatment of anemia due to chronic kidney disease (CKD). In global phase 3 trials, vadadustat has demonstrated non-inferiority to darbepoetin alfa for time to major adverse cardiovascular event (MACE) in patients with dialysis-dependent CKD (INNO2VATE trials), but not with non–dialysis-dependent CKD (NDD-CKD; PRO2TECT trials) [1,2]. In a prespecified subgroup analysis of the PRO2TECT trials, no difference in cardiovascular safety was observed in the USA, but a higher risk of MACE was found for patients treated with vadadustat outside the USA.1 We investigated regional differences in MACE in patients previously untreated with erythropoietin-stimulating agents (ESAs) in the PRO2TECT trial. METHOD Two phase 3, open-label, randomized, active-controlled clinical trials comparing vadadustat with darbepoetin alfa were conducted in North America, Latin America, Europe, Africa, and the Asia-Pacific region. This post hoc analysis evaluated MACE in patients in the PRO2TECT trial not treated with ESAs within 8 weeks of enrollment (correction trial; NCT02648347) and who received ≥1 dose of trial drug, stratified by region (USA versus Europe versus non-USA/non-Europe). MACE was defined as a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. Expanded MACE was defined as MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access failure. RESULTS A total of 1748 ESA-untreated patients receiving ≥1 dose of study drug were enrolled in the PRO2TECT trial, including 1058 patients in the USA, 139 in Europe and 551 outside the USA and Europe. Patients in the non-USA/non-European countries were younger and had a lower mean eGFR than patients in the USA or Europe. Furthermore, 34.7% of patients randomized to vadadustat had a baseline eGFR &amp;lt;10 mL/min/1.73 m2 versus 24.0% of patients randomized to darbepoetin alfa in the non-USA/non-European countries. The hazard ratio for MACE in the overall population for vadadustat versus darbepoetin alfa was 1.16 [95% confidence interval (CI) 0.96–1.41]. When analyzed by region, higher event rate for MACE was observed in the vadadustat arm in the non-USA/non-European countries compared with the USA and Europe (Table 1). The higher event rates for MACE in the non-USA/non-European countries were driven by 21 excess MACEs reported in the vadadustat group. Many deaths in the non-USA/non-European countries were related to kidney failure (n = 25/43 in the vadadustat group; n = 20/30 in the darbepoetin alfa group; Table 2), and were concentrated in Brazil and South Africa, countries that enrolled a higher proportion of patients with end-stage kidney failure who may not have had access to dialysis. The adverse event profiles for vadadustat and darbepoetin alfa were similar across regions. CONCLUSION Regional differences in time to first MACE were observed in patients with NDD-CKD who were not previously treated with ESAs and randomized to receive vadadustat or darbepoetin alfa as part of the PRO2TECT trial. The higher event rate in the vadadustat group in non-USA/non-European countries may have been related to randomization imbalances and/or design and methodological issues. These findings should help inform care providers as they assess the overall safety of vadadustat for the treatment of anemia associated with NDD-CKD.

MO532: Cardiovascular Events in Patients With Non–Dialysis-Dependent Chronic Kidney Disease and Anemia: Regional Analysis of Patients Previously Treated With Erythropoiesis-Stimulating Agents in the PRO2TECT Trial

Abstract BACKGROUND AND AIMS Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being investigated for the treatment of anemia due to chronic kidney disease (CKD). In global phase 3 trials, vadadustat has demonstrated non-inferiority to darbepoetin alfa for time to major adverse cardiovascular event (MACE) in patients with dialysis-dependent CKD (INNO2VATE trials), but not with non–dialysis-dependent CKD (NDD-CKD; PRO2TECT trials) [1, 2]. In a prespecified subgroup analysis of the PRO2TECT trials, a difference in the relative safety between vadadustat and darbepoetin alfa was observed between the US and non-US regions [1]. We investigated regional differences in MACE in patients with NDD-CKD-administered vadadustat and darbepoetin alfa who were previously treated with erythropoietin-stimulating agents (ESAs) in the PRO2TECT trials. METHOD Two phase 3, open-label, randomized, active-controlled clinical trials comparing vadadustat with darbepoetin alfa were conducted in North America, Latin America, Europe, Africa, and the Asia-Pacific region. This post hoc analysis evaluated MACE in patients in the PRO2TECT trial who were actively maintained on ESAs at study entry with ≥1 dose received within 6 weeks before or during screening (Conversion trial; NCT02680574) and who received ≥1 dose of trial drug, stratified by region (USA versus Europe versus non-US/non-Europe). MACE was defined as a composite of death from any cause, nonfatal myocardial infarction or nonfatal stroke. Expanded MACE was defined as MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access failure. RESULTS A total of 1723 ESA-treated patients were randomized in the conversion trial of the PRO2TECT program and received ≥1 dose of study drug, including 665 patients in the USA, 444 in Europe, and 614 outside the USA and Europe. Europe had a lower proportion of patients with diabetes and more patients who had received intravenous (IV) iron, while patients in the non-US/non-European region were younger and had a lower prevalence of cardiovascular (CV) disease. A higher proportion of patients in Europe were using darbepoetin alfa at baseline than in other regions (59%–63% versus 14%–28%), though ESA dose was lower (57–61 versus 93–149 IV epoetin equivalent U/kg/week). The hazard ratio for MACE in the overall population for vadadustat versus darbepoetin alfa was 1.16 (95% CI 0.93–1.45). Across regions, event rates were similar in the vadadustat groups, but event rates in the darbepoetin alfa group were lower in Europe compared with the US and non-US/non-Europe (Table 1), which was driven by fewer total deaths (non-CV and CV) reported in Europe in the darbepoetin alfa arm (n = 24/220) compared with the vadadustat arm (n = 38/224) (Table 2). Additional post hoc analyses of MACE accounting for several baseline characteristics, including ESA dose, did not alter the outcomes of the study. CONCLUSION Regional differences in time to first MACE were observed in patients with NDD-CKD who were treated with ESA and randomized to receive vadadustat or darbepoetin alfa as part of the PRO2TECT program. It remains unclear if the lower risk of MACE observed in Europe with the darbepoetin alfa group was related to differences in unobserved baseline characteristics, regional treatment practices, methodological reasons or chance.

Clinical parameters among patients in Japan with anemia and non-dialysis-dependent chronic kidney disease with and without diabetes mellitus who received roxadustat

BackgroundRoxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in patients with non-dialysis-dependent (NDD) CKD evaluated disease state–related parameters among patients with and without diabetes mellitus who received roxadustat. In the 1517-CL-0310 study (NCT02988973), roxadustat was noninferior to darbepoetin alfa for change in average hemoglobin levels at Weeks 18–24 from baseline who received roxadustat.MethodsPatients enrolled in the 1517-CL-0310 study who received roxadustat were included in this post hoc analysis. Hematologic (hemoglobin, reticulocyte/erythrocyte ratio, mean corpuscular volume [MCV], and mean corpuscular hemoglobin [MCH]), iron-related (ferritin, total iron-binding capacity, transferrin, ceruloplasmin, and hepcidin), metabolic (HbA1c, glycated albumin, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), and renal (eGFR) parameters were summarized descriptively by visit through Week 52.ResultsAmong 201 included patients, 105 (52.2%) and 96 (47.8%) were in the Diabetes and No Diabetes subgroups, respectively. There were no clinically meaningful differences through Week 52 for most hematologic, iron-related, metabolic, or renal parameters between patients in the Diabetes and No Diabetes subgroups. MCV and MCH remained lower and HbA1c and glycated albumin remained higher in patients in the Diabetes subgroup through Week 52. Both subgroups experienced a similar benefit from roxadustat in maintaining hemoglobin levels in the target range of 10–12 g/dL.ConclusionRoxadustat maintained hemoglobin levels in the target range with similar clinical parameters irrespective of diabetes mellitus presence at baseline.

Desidustat in Anemia due to Non-Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-ND)

Background: Desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being developed to treat anemia in patients with chronic kidney disease (CKD) without dialysis dependency. Methods: In total, 588 patients with a clinical diagnosis of anemia due to CKD without dialysis need and with baseline hemoglobin of 7.0–10.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either desidustat 100 mg oral tablets thrice a week for 24 weeks or biosimilar darbepoetin subcutaneous injection 0.75 μg/kg once in 2 weeks for 24 weeks. The primary outcome was the change from baseline in hemoglobin to evaluation period of Weeks 16–24. Key secondary outcomes included the number of patients with hemoglobin response, changes in the hepcidin levels, changes in the vascular endothelial growth factor (VEGF) levels, and changes in the lipid and lipoprotein profiles. Results: Hemoglobin change from baseline to Weeks 16–24 was 1.95 g/dL in the desidustat group and 1.83 g/dL in the darbepoetin group (difference: 0.11 g/dL; 95% CI: −0.12, 0.34), which met prespecified non-inferiority margin (−0.75 g/dL). The hemoglobin responders were significantly higher (p = 0.0181) in the desidustat group (196 [77.78%]) compared to the darbepoetin group (176 [68.48%]). The difference of change in hepcidin from baseline to Week 12 and Week 24 (p = 0.0032 at Week 12, p = 0.0016 at Week 24) and the difference of change in low-density lipoprotein from baseline to Week 24 (p value = 0.0269) between the two groups was statistically significant. The difference of change from baseline in VEGF to Weeks 12 and 24 between the two groups was not statistically significant. Conclusion: Desidustat is non-inferior to darbepoetin in the treatment of anemia due to non-dialysis dependent CKD and it is well-tolerated.

Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D)

Background: A phase 3 study to assess the efficacy and safety of the desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, against the epoetin alfa for the treatment of anemia in patients with chronic kidney disease (CKD) with dialysis dependency. Methods: DREAM-D was a phase 3, multicenter, open-label, randomized, active-controlled clinical study conducted across 38 centers in India. A total of 392 patients with clinical diagnosis of anemia due to CKD with dialysis need (Erythrocyte Stimulating Agent [ESA] naïve or prior ESA users) and with baseline hemoglobin levels of 8.0–11.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either desidustat oral tablets (thrice a week) or epoetin alfa subcutaneous injection for 24 weeks to maintain a hemoglobin level of 10–12 g/dL. The primary endpoint was to assess the change in the hemoglobin level between the desidustat and the epoetin alfa groups from the baseline to evaluation period week 16–24. The key secondary efficacy endpoint was the number of patients with hemoglobin response. Results: The least square mean (standard error) change in hemoglobin from the baseline to week 16–24 was 0.95 (0.09) g/dL in the desidustat group and 0.80 (0.09) g/dL in the epoetin alfa group (difference: 0.14 [0.14] g/dL; 95% confidence interval: −0.1304, 0.4202), which met the prespecified noninferiority margin. The number of hemoglobin responders was significantly higher in the desidustat group (106 [59.22%]) when compared to the epoetin alfa group (89 [48.37%]) (p = 0.0382). The safety profile of the desidustat oral tablet was comparable with the epoetin alfa injection. There were no new risks or no increased risks seen with the use of desidustat compared to epoetin alfa. Conclusion: In this study, desidustat was found to be noninferior to epoetin in the treatment of anemia in CKD patients on dialysis and it was well-tolerated. Clinical Trial Registry Identifier: CTRI/2019/12/022312 (India).

Treatment of Renal Anemia in Patients With Hemodialysis Using Hypoxia-inducible Factor (HIF) Stabilizer, Roxadustat: A Short-term Clinical Study

Renal anemia is a major complication in patients with chronic kidney disease (CKD) and hemodialysis, increasing morbidity and mortality. Roxadustat is a novel oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), which is administrated for renal anemia. Different from erythropoiesis-stimulating agents (ESAs), Roxadustat could increase erythropoietin physiologically, improving the therapeutic effects. It has not been so long since Roxadustat was approved by the U.S. Food and Drug Administration (FDA). Thus, only a few studies have reported on the treatment of renal anemia using Roxadustat. In this study, we evaluated the efficacy of Roxadustat in patients undergoing hemodialysis (HD). Nine patients under HD (72±10 years old) were enrolled in this study. Patients received Roxadustat first time or changed from ESAs (5-10 mg, 3 times a week after HD). Observation period was 5.3±2.9 months. Roxadustat treatment effectively increased and maintained hemoglobin levels. Levels of ferritin and C-reactive protein tended to decrease, but the difference was not statistically significant. No significant adverse effects were observed in all patients during the study. Roxadustat is effective and relatively tolerant for treating renal anemia in patients subjected to hemodialysis.

Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis

BackgroundDaprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown.MethodsIn this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke).ResultsOverall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of −0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups.ConclusionsAmong patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.)

Clinical Pharmacokinetics of Daprodustat: Results of an Absorption, Distribution, and Excretion Study With Intravenous Microtracer and Concomitant Oral Doses for Bioavailability Determination.

Daprodustat, an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor, is being investigated for treatment of anemia in chronic kidney disease. This phase 1, nonrandomized, 2‐period, crossover study in 6 healthy men characterized the absorption, distribution, and excretion of daprodustat when administered as oral and intravenous (IV) doses of unlabeled and radiolabeled daprodustat ([14C]‐GSK1278863). Tolerability and pharmacokinetic properties of daprodustat, and its 6 metabolites in the systemic circulation, were also evaluated. The mean recovery of radiolabeled daprodustat was ≈95% by day 5, with the majority in feces and minor renal elimination, indicating that daprodustat and metabolites are primarily eliminated via hepatobiliary and fecal routes. Approximately 40% of total circulating radioactivity in plasma following both IV and oral administration was daprodustat; thus, 60% was attributed to metabolites. It was estimated that ≈80% of daprodustat was absorbed across the gastrointestinal tract, and ≈18% cleared by hepatic extraction. Pharmacokinetics were essentially dose proportional, with moderate (≈66%) oral tablet bioavailability. Following IV administration, daprodustat plasma clearance (19.3 L/h) and volume of distribution (14.6 L) were low, suggesting low tissue distribution outside systemic circulation with likely low penetration into tissues. Daprodustat was generally well tolerated, with no deaths or serious or significant adverse events reported.

Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness. Methods: Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18–24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated. Results: Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m² were associated with requiring higher DA but not roxadustat doses. Discussion/Conclusion: The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.