Prolyl Hydroxylase Inhibitor Research Articles

Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2.

The hypoxia-inducible factor (HIF) prolyl-hydroxylases (human PHD1-3) catalyze prolyl hydroxylation in oxygen-dependent degradation (ODD) domains of HIFα isoforms, modifications that signal for HIFα proteasomal degradation in an oxygen-dependent manner. PHD inhibitors are used for treatment of anemia in kidney disease. Increased erythropoietin (EPO) in patients with familial/idiopathic erythrocytosis and pulmonary hypertension is associated with mutations in EGLN1 (PHD2) and EPAS1 (HIF2α); a drug inhibiting HIF2α activity is used for clear cell renal cell carcinoma (ccRCC) treatment. We report crystal structures of PHD2 complexed with the C-terminal HIF2α-ODD in the presence of its 2-oxoglutarate cosubstrate or N-oxalylglycine inhibitor. Combined with the reported PHD2.HIFα-ODD structures and biochemical studies, the results inform on the different PHD.HIFα-ODD binding modes and the potential effects of clinically observed mutations in HIFα and PHD2 genes. They may help enable new therapeutic avenues, including PHD isoform-selective inhibitors and sequestration of HIF2α by the PHDs for ccRCC treatment.

MYC overrides HIF-1α to regulate proliferating primary cell metabolism in hypoxia

Hypoxia requires metabolic adaptations to sustain energetically demanding cellular activities. While the metabolic consequences of hypoxia have been studied extensively in cancer cell models, comparatively little is known about how primary cell metabolism responds to hypoxia. Thus, we developed metabolic flux models for human lung fibroblast and pulmonary artery smooth muscle cells proliferating in hypoxia. Unexpectedly, we found that hypoxia decreased glycolysis despite activation of hypoxia-inducible factor 1α (HIF-1α) and increased glycolytic enzyme expression. While HIF-1α activation in normoxia by prolyl hydroxylase (PHD) inhibition did increase glycolysis, hypoxia blocked this effect. Multi-omic profiling revealed distinct molecular responses to hypoxia and PHD inhibition, and suggested a critical role for MYC in modulating HIF-1α responses to hypoxia. Consistent with this hypothesis, MYC knockdown in hypoxia increased glycolysis and MYC over-expression in normoxia decreased glycolysis stimulated by PHD inhibition. These data suggest that MYC signaling in hypoxia uncouples an increase in HIF-dependent glycolytic gene transcription from glycolytic flux.

Anemia Treatment, Hemoglobin Variability, and Clinical Events in Patients With Nondialysis-Dependent CKD in Japan.

Anemia management in patients with non-dialysis-dependent chronic kidney disease has attracted attention with the introduction of novel therapeutic agents; however, few studies have provided comprehensive epidemiologic information. A retrospective cohort study was conducted in adult patients with stage ≥3a non-dialysis-dependent chronic kidney disease and hemoglobin <11 g/dL (January 2013-November 2021; N=26,626) to assess longitudinal treatment patterns, hemoglobin, and iron parameters (ferritin and transferrin saturation) for anemia management. Time-dependent Cox proportional hazard models were applied to assess the risk of clinical events, including death, cardiovascular events, dialysis introduction, and red-blood-cell transfusion, associated with temporal fluctuation patterns of hemoglobin levels. The cumulative incidence of anemia treatment initiation within 12 months was 37.1%, including erythropoiesis-stimulating agents 26.5%, iron oral 16.8%, iron intravenous 5.1%, and hypoxia-inducible factor prolyl hydroxylase inhibitor 0.2%. The mean (±standard deviation) hemoglobin levels were improved from 9.9±1.2 g/dL to 10.9±1.6 g/dL at 12 months. Despite erythropoiesis-stimulating agents or hypoxia-inducible factor prolyl hydroxylase inhibitor therapy, 30.1% of patients remained hemoglobin <10 g/dL. The risks of premature death, cardiovascular events, dialysis introduction, and red-blood-cell transfusion were significantly higher in groups with consistently low hemoglobin or low-amplitude hemoglobin fluctuation around the lower limit of target hemoglobin range than in patients with target hemoglobin range (p <0.05). Likewise, significantly higher risks for dialysis introduction and red-blood-cell transfusion were associated with high-amplitude hemoglobin fluctuation across target hemoglobin range were observed. The findings underscore the importance of stable hemoglobin control within the target range to reduce the mortality and morbidity risks in patients with non-dialysis-dependent chronic kidney disease while highlighting the suboptimal and heterogeneous treatment of anemia in clinical practice.

No benefit of HIF prolyl hydroxylase inhibition for hypertensive renal damage in renovascular hypertensive rats.

Introduction: We previously reported that malignant hypertension is associated with impaired capillary density of target organs. Here, we tested the hypothesis that stabilization of hypoxia-inducible factor (HIF) in a modified "preconditioning" approach prevents the development of malignant hypertension. To stabilize HIF, we employed pharmacological inhibition of HIF prolyl hydroxylases (PHD), that profoundly affect HIF metabolism. Methods: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats; controls were sham operated. 2K1C rats received either intermittent injections of the PHD inhibitor ICA (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate) or placebo. Thirty-five days after clipping, the frequency of malignant hypertension was assessed (based on weight loss and the occurrence of characteristic vascular lesions). In addition, kidney injury was compared between all ICA treated versus all placebo treated 2K1C, regardless of the occurrence of malignant hypertension. HIF stabilization was evaluated by immunohistochemistry, and HIF target gene expression by RT-PCR. Results: Blood pressure was elevated to the same degree in ICA- and placebo-treated 2K1C compared to control rats. ICA treatment did not affect the frequency of malignant hypertension or the extent of kidney tissue fibrosis, inflammation, or capillary density. There was a trend towards higher mortality and worse kidney function in ICA-treated 2K1C rats. ICA increased the number of HIF-1α-positive renal tubular cell nuclei and induced several HIF-1 target genes. In contrast, expression of HIF-2α protein as well as HIF-2 target genes were markedly enhanced by 2K1C hypertension, irrespective of ICA treatment. Discussion: We conclude that intermittent PHD inhibition did not ameliorate severe renovascular hypertension in rats. We speculate that the unexpected strong renal accumulation of HIF-2α in renovascular hypertension, which could not be further augmented by ICA, may contribute to the lack of a benefit from PHD inhibition.

Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia in chronic kidney disease (CKD). We evaluated by meta-analysis and meta-regression the efficacy and safety of HIF-PHIs in patients with CKD-related anaemia. We selected phase 3 randomized clinical trials (RCTs) comparing HIF-PHIs and erythropoiesis-stimulating agents (ESAs) in dialysis and non-dialysis patients. Efficacy outcomes were the changes from baseline of haemoglobin, iron parameters (hepcidin, serum iron, TIBC, TSAT, ferritin) and intravenous iron dose; as safety outcomes we considered cancer, adjudicated major adverse cardiovascular events (MACE), MACE+ (MACE plus hospitalization for hearth failure or unstable angina or thromboembolic event), thrombotic events (deep vein thrombosis, pulmonary embolism), arterovenous fistula (AVF) thrombosis and death. We included 26 RCTs with 24387 patients. Random effect meta-analysis of the unstandardized mean difference between HIF-PHIs and ESAs showed a significant change in haemoglobin levels from baseline of 0.10g/dL (95% CI 0.02 to 0.17). Meta-regression analysis showed a significantly higher haemoglobin change for HIF-PHIs in younger patients and versus short-acting ESA (0.21g/dL, 95% CI 0.12 to 0.29 versus -0.01, 95% CI -0.09 to 0.07 in studies using long-acting ESA, P<.001). No significant effect on heterogeneity was found for type of HIF-PHIs. In comparison with ESAs, HIF-PHIs induced a significant decline in hepcidin and ferritin and a significant increase in serum iron and TIBC, while TSAT did not change; intravenous iron dose was lower with HIF-PHI (-3.1mg/week, 95% CI -5.6 to -0.6, P=.020). Rate ratio of cancer (0.93, 95% CI 0.76 to 1.13), MACE (1.00, 95% CI 0.94 to 1.07), MACE+ (1.01, 95% CI 0.95 to 1.06), thrombotic events (1.08, 95% CI 0.84 to 1.38), AVF thrombosis (1.02, 95% CI 0.93 to 1.13) and death (1.02, 95% CI 0.95 to 1.13) did not differ between HIF-PHIs and ESAs. HIF-PHIs at the doses selected for the comparisons are effective in correcting anaemia in comparison with ESA therapy with a significant impact on iron metabolism without notable difference among various agents. No safety signals emerge with use of HIF-PHIs.

#4140 DAPRODUSTAT VERSUS RECOMBINANT HUMAN ERYTHROPOIETIN FOR TREATING ANAEMIA OF CHRONIC KIDNEY DISEASE: COST EFFECTIVENESS MODEL METHODOLOGY AND FINDINGS

Abstract Background and Aims Anaemia is a common manifestation in patients with chronic kidney disease (CKD).1,2 Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, offers an alternative to conventional treatment with recombinant human erythropoietins (rhEPOs). This study reports the development of a cost-effectiveness analysis to support reimbursement discussions for daprodustat in Canada. Method A Markov model was developed to conduct a cost-utility analysis to compare expected costs and outcomes associated with daprodustat, vs two rhEPO treatment comparators (darbepoetin alfa [DA] or epoetin alfa [EA]), which represent standard of care. The model used a lifetime time horizon, and a publicly funded Canadian healthcare payer perspective for adults with anaemia of CKD (on/not on dialysis). Clinical inputs for the model were obtained from two Phase 3 clinical trials: ASCEND-D1 (daprodustat vs DA or EA in 2964 dialysis patients) and ASCEND-ND2 (daprodustat vs DA in 3872 non-dialysis patients). Efficacy and adverse event profiles of both rhEPOs were assumed equal. Patients entering the model (Figure) receive daprodustat, DA or EA. The model includes five health states informed by ASCEND-D and ASCEND-ND: non-dialysis, dialysis, kidney transplant, post-transplantation and terminal care. While in the dialysis or non-dialysis health state, costs and utilities are assigned based on three haemoglobin (Hb) levels: &amp;lt;10g/dL, 10–11.5g/dL or &amp;gt;11.5g/dL. A monthly cycle length is utilised and aligned with the ASCEND study visits and observations up to Week 52. Hb concentrations from ASCEND-D and ASCEND-ND are used to estimate proportions of patients in the target Hb range of 10–11.5g/dL, and non-target Hb levels. They were assumed to have different utility values. Patients could transition from non-dialysis to dialysis; in the latter state, patients could die or receive a kidney transplant, and transition to a post-transplantation state. Transition probabilities were derived from ASCEND-D and ASCEND-ND data and the literature. The median follow-up durations in ASCEND-D and ASCEND-ND were 2.5 and 1.9 years, respectively, necessitating extrapolation to the model time horizon; increases over time in the transition probabilities were applied. It is assumed that patients cannot transition back to non-dialysis from the dialysis state. Patients may transition to death from any health state, with mortality risks informed by the ASCEND trials and Canadian all-cause mortality data. Costs in the model included treatment acquisition and administration, cold-chain storage, dialysis, kidney transplant, transfusions of red blood cells and iron, and adverse events (AEs). All costs were sourced from fee schedules (2022 $CAD) or the literature. Utilities for health states and Hb levels were obtained from the ASCEND trials; AE-associated utility decrements could not be estimated from ASCEND data due to low event rates – hence, disutilities were sourced from the literature. Results In the probabilistic reference case analysis, daprodustat was less costly (comparison with DA: −$8763; EA:−$13,864) and produced more quality-adjusted life years (DA: +0.012; EA: +0.018; Table). The incremental savings with daprodustat versus DA and EA were −$860 and −$1033, respectively, in the non-dialysis state, and −$7904 and −$12,831 in the dialysis state. Contributors to the cost savings with daprodustat include an absence of cold-chain storage costs and reduced administration costs. Conclusion This study indicates that daprodustat is less costly and originates more QALYs than DA and EA in the treatment of anaemia due to CKD. In this setting, daprodustat may provide cost savings from a Canadian public payer perspective. The model described here could be adapted to other perspectives, including European countries.

#3704 EU REGION-SPECIFIC CARDIOVASCULAR EVENT DATA FOR DAPRODUSTAT IN ASCEND-D AND ASCEND-ND

Abstract Background and Aims Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase inhibitor under investigation for the treatment of anaemia of chronic kidney disease. Phase 3 studies in dialysis (ASCEND-D) and non-dialysis (ASCEND-ND) patients demonstrated the non-inferiority of daprodustat vs recombinant human erythropoietin (rhEPO) control (in ASCEND-D) or darbepoetin alfa (ASCEND-ND) control in terms of the mean change in haemoglobin levels between Weeks 28 and 52 versus baseline and the first occurrence of a composite major adverse cardiovascular (CV) event (MACE) [1, 2]. Post-hoc analyses were conducted to evaluate prespecified CV endpoints for patients enrolled in these studies from participating countries in Europe (EU patients) versus elsewhere (non-EU patients). Method Post-hoc time to the first adjudicated MACE (death from any cause, non-fatal myocardial infarction or non-fatal stroke), time to the first adjudicated MACE or thromboembolic event (TEE; deep vein thrombosis, pulmonary embolism or vascular access thrombosis), and time to the first adjudicated MACE or hospitalisation for heart failure (HHF) were analysed for EU (enrolled from Austria, Belgium, Bulgaria, Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Romania, Spain, Sweden and the UK; not all countries participated in both studies) and non-EU (all other participating countries) patients. Hazard ratios (HRs) and associated 95% confidence intervals were calculated to evaluate the likelihood of CV events with daprodustat versus alternative therapy in both studies. HRs for EU and non-EU patients were compared for each endpoint in each study and p-values were calculated to assess the statistical significance of observed differences. Significance was defined at the 10% level (interaction p-value &amp;lt;0.1). Results ASCEND-D included 415 EU patients and 1072 non-EU patients randomised to daprodustat, and 440 EU and 1037 non-EU patients randomised to rhEPO. ASCEND-ND included 410 EU patients and 1527 non-EU patients randomised to daprodustat, and 407 EU and 1528 non-EU patients randomised to darbepoetin alfa. No significant heterogeneity was observed between EU and non-EU patients in terms of the prespecified CV endpoints (p≥0.1979). In ASCEND-D and ASCEND-ND, the results for MACE, MACE+TEE and MACE+HHF for the EU subgroup were consistent with the non-EU subgroup (Table), as well as with the co-primary analysis [1, 2]. Efficacy and additional safety data for EU versus non-EU patients are being explored and will be included in the subsequent presentation. Conclusion Non-inferiority in terms of the first occurrence of MACE was demonstrated for daprodustat versus rhEPO in ASCEND-D and versus darbepoetin alfa in ASCEND-ND.1,2 Results for EU and non-EU patients in the current analysis were consistent with the global outcomes from both studies.

#2959 EFFICACY AND SAFETY OF ROXADUSTAT IN PATIENTS WITH ANEMIA OF DIALYSIS-DEPENDENT CKD WITH OR WITHOUT INFLAMMATION: A POOLED ANALYSIS OF 4 PHASE 3 STUDIES

Abstract Background and Aims Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia of chronic kidney disease (CKD). ESA hyporesponsiveness is prevalent in a significant portion of patients with CKD, especially those with end-stage renal disease on dialysis. Inflammation has been reported to contribute to ESA hyporesponsiveness and is associated with poor outcomes in patients with CKD. Roxadustat, an oral medication, is a hypoxia-inducible factor prolyl hydroxylase inhibitor that has previously demonstrated efficacy in patients with anemia of CKD. This pooled analysis evaluated the efficacy and safety of roxadustat in correcting hemoglobin (Hb) levels in subgroups of patients with dialysis-dependent (DD) CKD with or without inflammation at baseline. Method Data for this analysis were pooled from four phase 3, randomized, open-label, active comparator−controlled studies (HIMALAYAS [NCT02052310], ROCKIES [NCT02174731], PYRENEES [NCT02278341], SIERRAS [NCT02273726]) in patients with DD CKD. Outcomes evaluated were mean Hb change from baseline to Weeks 28−52 and mean weekly roxadustat dose (mg/kg) at Week 24 in patients with or without baseline inflammation (as determined by high-sensitivity C-reactive protein [hsCRP] level, divided into quintiles). Data were analyzed with an analysis of covariance model with baseline Hb as a covariate. Adjusted least-squares means, their difference, and corresponding confidence intervals were generated from datasets where missing data were imputed using missing at random-based multiple imputation, by treatment group, with baseline Hb, cardiovascular/cerebrovascular/thromboembolic history, geographical region (United States vs non-United States) and incident vs stable dialysis (≤4 vs &amp;gt;4 months) as predictor variables. Safety data were summarized descriptively. Results In total, 4072 patients with DD CKD (roxadustat N = 2022; ESA N = 2050) were evaluated. At baseline, mean Hb levels (g/dL [SD]) were similar in the roxadustat (9.80 [1.29]) and ESA (9.83 [1.29]) groups, regardless of baseline hsCRP levels (roxadustat hsCRP quintiles 1−5: 9.72 [1.43], 9.78 [1.27], 9.80 [1.32], 9.90 [1.18], and 9.79 [1.23], respectively; ESA hsCRP quintiles 1−5: 9.75 [1.34], 9.92 [1.23], 9.90 [1.23], 9.96 [1.23], and 9.62 [1.38], respectively). Hb change from baseline was greater in patients treated with roxadustat compared with ESA, regardless of baseline hsCRP levels (Fig. 1). At Week 24, patients with higher baseline hsCRP levels did not require higher doses of roxadustat compared to patients with lower baseline hsCRP levels (Fig. 2). The overall percentages of patients with at least one treatment-emergent adverse event were similar for patients treated with roxadustat (hsCRP quintiles 1−5: 86.7, 88.1, 86.6, 88.7, and 90.0, respectively) or ESA (hsCRP quintiles 1−5: 83.5, 84.6, 90.5, 88.2, and 87.9, respectively) across hsCRP quintiles. Conclusion In patients with anemia of DD CKD, roxadustat increased Hb levels without requiring increased doses of roxadustat in patients with or without baseline inflammation. Results from the current analysis suggest that roxadustat is effective, with a comparable safety profile to ESA, regardless of inflammation status.

#4026 ECONOMIC EVALUATION OF ANAEMIA OF CHRONIC KIDNEY DISEASE (CKD): A SYSTEMATIC LITERATURE REVIEW AND MODEL CONCEPTUALISATION

Abstract Background and Aims Anaemia is a common complication of chronic kidney disease (CKD), affecting up to 53.4% of patients with Stage 5 CKD compared to 8.4% of patients with Stage 1 CKD [1]. Anaemia of CKD is associated with increased risk of cardiovascular events and death, increased healthcare resource utilisation (HRU), and reduced health-related quality of life (HRQoL) [2]. Established treatments for anaemia of CKD include erythropoiesis-stimulating agents (ESAs) [1,2]; however, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), targeting both erythropoietin production and iron metabolism (the two key mechanisms of anaemia of CKD), are an emerging class of agents in this indication [3]. The cost and HRQoL burden associated with anaemia of CKD treatment is not well characterised.1 Thus, we conducted a systematic literature review (SLR) to evaluate published economic models (including the cost inputs, time horizon, subgroups, and clinical assumptions used) and HRU data in patients with anaemia of CKD. Findings of the SLR will help guide future economic model development and inform economic evaluation strategies as part of health technology assessment submissions to support daprodustat, an HIF-PHI under development for use in both dialysis-dependent and non-dialysis-dependent patients. Method Relevant publications were identified using structured searching of MEDLINE, Embase, MEDLINE In-Process, Cochrane Controlled Trials Register, and the Cochrane Database of Systematic Reviews from database inception to 10 April 2022 using disease- (e.g. CKD, chronic kidney failure, anaemia) and economic-associated (e.g. economics, economic evaluation, quality-adjusted life-years, model structure) search terms. Additional supplemental searches (conference proceedings [2016–2021], grey literature, and bibliographies) were conducted. Studies were assessed for inclusion or exclusion by two independent reviewers, with any discrepancies resolved by a third reviewer. Objectives were to determine the structure of any published economic models and the availability of health utility data in patients with anaemia and additional complications of CKD, and to examine what cost inputs, time horizons, subgroups, and clinical assumptions are used to inform economic modelling. Results From 1397 citations identified in the searches, 40 primary studies were included in the final analysis. Review of the data revealed an established approach for modelling the ESA cost-effectiveness (i.e. a Markov model with health states defined according to CKD treatment received or anaemia status): most studies were conducted from a North American or European perspective, time horizons varied, and reporting of cycle length was poor. Only one economic evaluation included an HIF-PHI model: given the different mechanisms of action of ESAs and newer treatments, a modelling strategy focused mainly on a Markov approach may not be the most optimal way of assessing cost-effectiveness in anaemia of CKD where HIF-PHIs are used. Considerations of modelling factors that could influence cost-effectiveness of HIF-PHIs are shown in Fig. 1. While existing models typically only stratified patient populations according to age (&amp;lt;65 vs &amp;gt;65 years), for appropriate modelling of treatment effectiveness, the impact of prior treatments (including response to prior ESAs) was also considered. As in every model, comorbidities may also have a role in effect modification and this impact will need to be considered in economic models of anaemia of CKD treatment. Due to the natural history of anaemia in CKD, innovative modelling techniques that retain the Markov approach and which account for respective haemoglobin levels, CKD stage, and potential kidney transplantation should be incorporated into the economic evaluation (Fig. 2). Conclusion Adjustment of existing models using the approaches described may provide more reliable estimates of treatment efficacy in a highly heterogenous population of patients with anaemia of CKD.

#5534 HIFS AND BUTS: A NETWORK META-ANALYSIS OF HIF-PH INHIBITORS AND ESAS IN NDD-CKD PATIENTS WITH ANEMIA COMPARING THEIR SAFETY AND EFFICACY

Abstract Background and Aims Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of oral medicines for the management of anemia in CKD patients. These agents are found to be efficacious in the management of renal anemia, however safety is still under scrutiny. While, ESAs (Erythropoietin stimulating agents) are available since long with a well-established clinical profile. This network meta-analysis aimed to compare the safety and efficacy of HIF-PHI vs ESA in CKD patients with anemia not undergoing dialysis. Method An electronic database search was carried out in EBM (Evidence Based Medicine) Reviews, Cochrane Library and PubMed from inception to July 2022 for phase III clinical trials comparing six different HIF-PHIs and ESA for treating anemia in non-dialysis-dependent (NDD) CKD patients. The outcomes included the serious adverse events (SAEs) and change in hemoglobin (Hb) levels. Results Total 163 records were identified out of which 6 studies involving a total of 6847 patients were eligible for analysis. Compared to ESA, all HIF-PHIs increased risk for SAEs (daprodustat of RR, 1.21[95% CI, 0.825–1.77]; desidustat, 1.38[95% CI, 0.695–2.76]; enarodustat, 1.29[95% CI, 0.568–3.02]; molidustat, 1.02[95% CI, 0.585–1.74]; roxadustat, 1.29[95% CI, 0.674–2.57] and vadadustat, 1.01[95% CI, 0.693–1.47]) although these differences were statistically non-significant. When change in Hb was analyzed, there was no statistically significant difference between the two groups. The mean difference in change in HB with various HIFs as compared to ESA were: daprodustat (MD: 0.0796, 95% CI −0.676–0.838), desidustat (MD: 0.120, 95% CI: −0.626–0.883), enarodustat (MD: -0.600, 95% CI: −1.36–0.157), molidustat (MD: -0.309, 95% CI: −1.07–0.449), roxadustat (MD: -0.0702, 95% CI: −0.831–0.692) and vadadustat (MD: -0.0402, 95% CI: −0.802–0.720). Conclusion In terms of safety, HIF PHIs were associated with more SAEs compared to ESA although these differences are not statistically significant. Comparing efficacy, HIF-PHIs and ESA both effectively increase Hb level in NDD-CKD patients without any significant difference. Results of our network meta-analysis suggest the need for larger and long-term studies comparing HIF-PHIs with ESAs to have better understanding of their comparative efficacy and safety profiles.

#2962 EFFICACY AND SAFETY OF ROXADUSTAT IN NON-DIALYSIS-DEPENDENT CKD PATIENTS WITH OR WITHOUT INFLAMMATION: A POOLED ANALYSIS OF FOUR PHASE 3 STUDIES

Abstract Background and Aims Chronic kidney disease (CKD)-associated anemia is commonly treated with erythropoiesis-stimulating agents (ESAs); however, some patients respond inadequately to ESAs. Inflammation may be a cause of ESA hyporesponsiveness. Roxadustat, an oral medication, is a hypoxia-inducible factor prolyl hydroxylase inhibitor that has shown efficacy in patients with anemia of CKD. This pooled analysis examined the efficacy and safety of roxadustat in correcting hemoglobin (Hb) levels in subgroups of patients with non−dialysis-dependent (NDD) CKD with or without inflammation at baseline. Method Data from four phase 3, randomized, placebo-controlled (OLYMPUS [NCT02174627], ALPS [NCT01887600], ANDES [NCT01750190]) or erythropoiesis-stimulating agent−controlled (ESA; DOLOMITES [NCT02021318]) studies in patients with NDD CKD were pooled for this analysis. Mean Hb change from baseline to Weeks 28−52 and mean weekly total roxadustat dose (mg/kg body weight) at Week 24 in patients with or without inflammation at baseline (as determined by high-sensitivity C-reactive protein [hsCRP] levels divided into quintiles) were evaluated with an analysis of covariance model with baseline Hb and baseline estimated glomerular filtration rate as covariates. Safety data were summarized descriptively. Results In total, 3573 patients with NDD-CKD (roxadustat N = 2068; placebo = 1212; ESA N = 293) were evaluated. At baseline, the mean [SD] Hb levels (g/dL) for roxadustat (hsCRP quintiles 1−5: 9.17 [0.82], 9.26 [0.68], 9.18 [0.75], 9.15 [0.74], 9.08 [0.82]), placebo (hsCRP quintiles 1−5: 9.09 [0.74], 9.20 [0.71], 9.15 [0.69], 9.09 [0.71], 9.01 [0.76]), and ESA (hsCRP quintiles 1−5: 9.53 [0.69], 9.53 [0.64], 9.54 [0.73], 9.60 [0.66], 9.53 [0.71]) were similar across hsCRP quintiles. The mean Hb change from baseline to Weeks 28–52 was greater with roxadustat than with placebo, and comparable between roxadustat and ESA, regardless of inflammation at baseline (Fig. 1). At Week 24, roxadustat dose was not increased in patients across hsCRP quintiles (hsCRP quintiles 1−5: 3.3, 3.0, 2.7, 3.1, 3.1 mg/kg, respectively). Roxadustat dose was not significantly higher at Week 24 for patients with moderate-to-high baseline hsCRP levels (quintile 4, &amp;gt;3.48 to ≤8.67 mg/L; least squares mean [LSM], 3.05; 95% CI, 2.80−3.30; quintile 5, &amp;gt;8.67 mg/L; LSM, 3.10; 95% CI, 2.83−3.36) compared with patients with low baseline hsCRP levels (quintile 1, ≤0.71 mg/L; LSM, 3.30; 95% CI, 3.04−3.56; treatment comparison between quintile 1 and quintile 4: LSM difference, 0.25; 95% CI, −0.11 to 0.61; treatment comparison between quintile 1 and quintile 5: LSM difference, 0.20; 95% CI, −0.17 to 0.57; Fig. 2), indicating that patients with increased inflammation at baseline did not consistently require a higher roxadustat dose. The overall percentages of patients with at least one treatment-emergent adverse event were similar across hsCRP quintiles for patients treated with roxadustat (hsCRP quintiles 1−5: 88.7, 91.4, 90.3, 90.7, 90.5), placebo (hsCRP quintiles 1−5: 88.2, 84.5, 89.4, 88.5, 87.9), and ESA (hsCRP quintiles 1−5: 89.1, 90.9, 91.4, 94.1, 94.8). The most common treatment-emergent adverse events were hypertension (hsCRP quintiles 1−5 [%]; roxadustat: 16.8, 16.5, 17.4, 22.2, 18.9; placebo: 7.9, 9.5, 11.8, 9.3, 8.5; ESA: 45.7, 36.4, 39.7, 22.1, 31.2), end-stage renal disease (hsCRP quintiles 1−5 [%]; roxadustat: 21.3, 22.7, 21.1, 24.6, 23.1; placebo: 13.8, 15.9, 15.3, 18.1, 16.5; ESA: 32.6, 36.4, 34.5, 39.7, 36.4), and decreased glomerular filtration rate (hsCRP quintiles 1−5 [%]; roxadustat: 4.6, 5.0, 4.5, 5.3, 5.1; placebo: 2.0, 2.0, 2.4, 1.3, 3.1; ESA: 13.0, 22.7, 19.0, 13.2, 16.9). Conclusion Independent of baseline inflammation status, roxadustat increased Hb levels greater than placebo and comparable to ESA with a similar safety profile. Patients with high baseline hsCRP did not require increased roxadustat doses to maintain Hb levels up to Week 24. These data suggest that roxadustat is effective in patients with anemia of NDD CKD regardless of inflammation status.

#4471 CHARACTERISTICS OF PATIENTS WITH CKD WHO USE HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS: A JAPAN MEDICAL DATA CENTER DATABASE STUDY

Abstract Background and Aims Anemia is common among patients with chronic kidney disease (CKD) and is reported to be associated with increased cardiovascular disease and all-cause mortality, as well as reduced quality of life. The incidence of anemia increases as kidney function declines and affects approximately 32% of Japanese patients with stage 3–5 CKD [1]. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been approved in the Japan since Sept 2019 for patients with anemia of chronic kidney disease. Available HIF-PHIs include roxadustat (approved Sept 2019), daprodustat (approved June 2020), vadadustat (approved June 2020), enarodustat (approved Sept 2020) and molidustat (approved Jan 2021). This analysis aims to provide a real-world account of patient characteristics of those initiating HIF-PHIs since the approval of HIF-PHIs in Japan, overall and by individual treatments. Method This retrospective cohort study leveraged data from the Japan Medical Data Center (JMDC) database from Nov 2018 – May 2022 and included patients over 18 years of age with documented CKD who initiated any HIF-PHI from Nov 2019 – Nov 2021. JMDC is a health insurance database aggregating administrative claims data, medical examination data, and ledger information of patients who are on employer-based insurance and &amp;lt;75 years of age. The study index date was defined as the first observed claim for any HIF-PHI during the identification period. Patients were required to have baseline period of 1 year prior to the index date and a minimum of six months of follow-up after the index date, with continuous insurance enrollment. This study assessed patient demographics, clinical characteristics, and previous anemia of CKD treatment in the baseline period. Results Overall, 500 patients initiated HIF-PHIs, with 47.8% (n = 239) patients initiating daprodustat, 40.8% (n = 204) patients initiating roxadustat, and 11.4% (n = 57) patients initiating other HIF-PHIs. Table 1 illustrates the patient demographic characteristics overall and by index HIF-PHI. Overall, 60.2% (n = 301) of patients were male; the mean age was 55.7 years (SD = 10.8). More than a third (37.2%) of overall patients received dialysis in the baseline period. Within the 184 patients on specified types of dialysis, 67.9% (n = 125) had received hemodialysis and 32.1% (n = 59) had received peritoneal dialysis. In terms of prior anemia of CKD treatments, 61.8% (n = 309) of patients had any rhEPO use in the baseline period. Further break down is in Table 2. Nearly a third (31.6%, n = 158) of patients received any iron treatment in the baseline period, with 19.2% (n = 96) receiving oral iron and 13.8% (n = 69) receiving injectable iron. At baseline, almost all of patients initiating on HIF-PHIs had baseline comorbidities of hypertension (95.8%; n = 479) and diabetes (77.0%; n = 385). Conclusion Evaluating a real-world database for patients initiating HIF-PHIs within Japan allows for a more comprehensive picture of patient clinical and demographic characteristics. Our analysis found most patients initiating on HIF-PHIs were male, had previous rhEPO use, and had history of hypertension and diabetes. Understanding patient profiles in a real-world setting may guide treatment decisions in clinical practice.

#3777 ACTIVATION OF HYPOXIA-INDUCIBLE FACTORS IN ERYTHROID PROGENITOR CELLS RESULTS IN DEFECTIVE ERYTHROPOIESIS

Abstract Background and Aims Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) activates HIF in renal pericytes and fibroblasts to promote erythropoietin production and erythropoiesis. However, the effects of HIF stabilization in the erythroid lineage are not clear. We aim to study the effects of erythroid lineage-specific stabilization of HIF on erythropoiesis by preclinical models. Method EporGFP-Cre/+;VhlF/F mice were used to achieve erythroid lineage-specific stabilization of HIF. Surface expression of TER-119, CD44, and forward scatter (FSC) were used to define erythroblast, reticulocyte, and red blood cell in the bone marrow. Expression of propidium iodide and surface annexin V were used to define apoptosis. Stress erythropoiesis was induced by subcutaneous administration of phenylhydrazine. Results Compared with littermate VhlF/F mice, EporGFP-Cre/+;VhlF/F mice had decreased hematocrit, decreased percentage of erythroblasts in the bone marrow, and increased apoptosis of erythroblasts in the bone marrow under steady state. These phenotypes of defective erythropoiesis were normalized in mice harboring concomitant Vhl, Hif1a, and Hif2a deletion (EporGFP-Cre/+;VhlF/F;Hif1aF/F;Hif2aF/Fmice). Although macrophages in the bone marrow also express Epor, macrophage-specific Vhl deletion in either Tg(Csf1r-CreESR1);VhlF/F or Lyz2Cre/+;VhlF/F mice did not result in defective erythropoiesis. During stress erythropoiesis, compared with littermate VhlF/F mice, EporGFP-Cre/+;VhlF/F mice had similar hematocrit, lower percentage of erythroblast in the bone marrow, and increased percentage of erythroblast in the spleen. Conclusion Vhl deletion in erythroid progenitor cells impairs erythropoiesis in murine bone marrow in the steady state. The phenotypes of defective erythropoiesis were partially reversed during stress erythropoiesis.

#3676 EVALUATION OF HAEMOGLOBIN RESPONSE IN PATIENTS WITH CKD-RELATED ANAEMIA NOT ON DIALYSIS RECEIVING DAPRODUSTAT OR CONTROL IN ASCEND-ND

Abstract Background and Aims Daprodustat (Dapro) is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor being investigated in anaemia of chronic kidney disease (CKD). ASCEND-ND1 achieved non-inferiority (NI) for Dapro vs darbepoetin alfa (Darbe) in both coprimary endpoints, mean change in haemoglobin (Hb) levels from baseline to the evaluation period (EP; Week [Wk] 28–Wk 52) and first occurrence of a composite major adverse cardiovascular event, in patients (pts) with anaemia of CKD not on dialysis. Here, we present key Hb efficacy data and evaluate differences in Hb response within ASCEND-ND subgroups. Method Pts with Stages 3–5 CKD (not on erythropoiesis stimulating agents [ESAs]: Hb 8–10g/dL; on ESAs: Hb 8–11g/dL) were randomised 1:1 to Dapro or Darbe. Statistical analysis methods for the coprimary endpoint have been published.1 Secondary endpoints evaluated during the EP included: 1) the percentage of Hb responders (pts with mean evaluable Hb within the analysis range [10–11.5g/dL]); 2) the percentage of time Hb was within the analysis range; 3) analysis of Hb change from baseline to Wk 52. Secondary endpoints were analysed as follows: 1) Cochran-Mantel-Haenszel test adjusted for ESA use and region; 2) Rosendaal method (evaluable Hb values) and Hodges-Lehmann and stratified Mann-Whitney estimates of treatment effect, analysed with a van Elteren's test stratified by ESA use and region; 3) mixed model repeated measures analysis (on-/off-treatment, observed Hb values from Wks 28–52) with factors for ESA use, region, baseline Hb (by time), treatment by time interactions. Secondary and subgroup analyses were not multiplicity adjusted. Results Of 3872 pts in ASCEND-ND (Dapro n = 1937; Darbe n = 1935), mean baseline Hb levels were similar for both treatment arms and mean change in the EP Hb level for Dapro and Darbe met the prespecified NI margin of ‒0.75 g/dL (difference = 0.08g/dL; 95% confidence interval [CI] = 0.03, 0.13).1 Subgroup analyses were consistent with coprimary analyses (Table), with little or no heterogeneity between most groups: 7/22 subgroups (ethnicity, high-level race, region, ESA use at randomisation, prior ESA dose group, history of stroke, and hospitalisation 6 months prior to screening) had interaction p values &amp;lt;0.1; however, all subgroups met the NI criterion with between-group differences that were not clinically meaningful. Proportions of pts within the Hb analysis range were higher for Dapro than Darbe in the EP overall and regardless of baseline ESA use and similar for region (Table). The median (interquartile range) percentage of time Hb was in the analysis range during the EP was 70.5% (45.3%–93.2%) for Dapro vs 63.2% (33.7%–88.9%) for Darbe. Dapro was associated with a nominally NI (margin of ‒15%) and significant increase in percentage time in analysis range during the EP (estimate of median difference [95% CI] = 4.57% [2.04%, 7.11%]; one-sided p&amp;lt;0.0001). The estimate (95% CI) for the probability that Dapro had a greater percentage of time Hb within the analysis range than Darbe was 0.55 (0.53, 0.57); the lower boundary of the 95% CI exceeded 0.50, representing equal probability between the two treatment arms. Results by region were similar for Dapro vs Darbe (treatment effect): Asia Pacific = 0.56; Eastern Europe/South Africa = 0.51; Western Europe/Canada/Australia/New Zealand/Israel, 0.58; Latin America, 0.58; USA, 0.55). In mixed-model repeated measures analysis, g/dL Hb change (standard error) at Wk 52 was 0.76 (0.029) with Dapro and 0.73 (0.029) with Darbe (difference [95% CI] = 0.03 [−0.05, 0.11]). Hb efficacy was similar regardless of ESA use (Figure). Conclusion Dapro was effective and NI to Darbe for maintaining Hb in non-dialysis pts with anaemia of CKD, and results of subgroup analyses were consistent with the coprimary analyses. Additionally, Dapro raised and maintained Hb within the analysis range regardless of baseline ESA use or region. These preliminary analyses indicated a nominal NI showcasing greater Hb time in range with Dapro vs Darbe; further analyses will be presented to fully characterise this interaction.

Long-term treatment of chronic kidney disease patients with anemia using hypoxia-inducible factor prolyl hydroxylase inhibitors: potential concerns.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been approved in several countries as a supplement or even an alternative to the clinical treatment of anemia in patients with chronic kidney disease (CKD). Activation of HIF by HIF-PHIs effectively increases hemoglobin (Hb) level in CKD patients by inducing multiple HIF downstream signaling pathways. This indicates that HIF-PHIs have effects beyond erythropoietin, while their potential benefits and risks should be necessarily assessed. Multiple clinical trials have largely demonstrated the efficacy and safety of HIF-PHIs in the short-term treatment of anemia. However, in terms of long-term administration, especially over 1year, the benefits and risks of HIF-PHIs still need to be assessed. Particular attention should be paid to the risk of kidney disease progression, cardiovascular events, retinal diseases, and tumor risk. This review aims to summarize the current potential risks and benefits of HIF-PHIs in CKD patients with anemia and further discuss the mechanism of action and pharmacological properties of HIF-PHIs, in order to provide direction and theoretical support for future studies.

Relationship Between the Effect of Roxadustat and Comorbid Diabetes in Non-dialyzed Chronic Kidney Disease Patients: A Retrospective Observational Study.

Introduction The dose of roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, required to treat anemia, the hemoglobin level and the rate of hemoglobin target achievement were retrospectively investigated in non-dialyzed chronic kidney disease (CKD) patients with and without type 2 diabetes. Methods As the full analysis set, 25 subjects (10 with diabetes and 15 without diabetes) were observed over six months among 44 non-dialyzed CKD patients who received roxadustat. The target hemoglobin level was set at 110-130 g/L. Results The comorbidities of diabetes and body weight at baseline were significantly associated with each dose of roxadustat at six months and the change in each dose of roxadustat from the initiation of roxadustat treatment. There was no significant difference in the amount of increase in the hemoglobin level (14±11 g/L vs. 15±8 g/L) and the rate of hemoglobin target achievement (70% vs. 67%) between patients with and without diabetes. Each dose of roxadustat gradually decreased in patients without diabetes, whereas it increased in those with diabetes. Each dose of roxadustat was significantly higher in patients with diabetes than in those without diabetes at 3 (60±21 mg vs. 42±14 mg) and 6 (61±22 mg vs. 41±14 mg) months after the initiation of roxadustat treatment. Conclusion Roxadustat is useful for the treatment of anemia in both CKD patients with and without diabetes. However, the dose required to achieve the target hemoglobin level may be higher in patients with diabetes than in those without diabetes.

Chronic kidney disease and anemia: updated management issues

Anemia is common in patients with chronic kidney diseases (CKD). It is a common complication of advanced CKD. Its prevalence in CKD stage 5 populations is over 50%. The hormone “erythropoetin” (EPO) secreted by the kidneys is essential in the maintenance of adequate hemoglobin in human body. Scientific Presentation BJM Vol. 34 No. 2(1) Suppliment 2023 177 Apart from failure of EPO secretion, many other factors including chronic inflammation, uremic bone marrow suppression, hyperparathyroidism, poor absorption of substrates from the uremic gastrointestinal tract etc. contribute to development of anemia in patients living with advanced kidney failure and dialysis. Iron deficiency state due to absolute or relative iron deficiency is common in CKD population. Furthermore, nutritional anemia is common in general population in our part of the world. Majority of this is also a result of iron deficiency. Replenishing iron stores in the body is the first strategy in the management of this condition. Besides the use of iron, deficiencies of other substrates like vitamin B12 should also be taken into account while managing anemia in CKD. Ferric citrate can be used as an hematinic and phosphate binder as well. Blood transfusion was invariable treatment strategy in the remote past. Though oral and parenteral iron and other hematinics are routinely used in the management of CKD, various erythropoesis stimulating agents (ESAs) used as injectable solutions lead the current therapeutic strategy in the treatment of anemia in patients with end stage renal disease (ESRD) and renal replacement therapies. More recently newer agents, the prolylhydroxylase inhibitors (PHI) like roxadustat which act as hypoxic ischemic factor (HIF) stabilizers have been more appealing to the patients and the clinicians. In contrast to the parenteral administration of ESAs, these new agents can be administered orally. While anemia is common, ideal treatment for anemia in CKD is still unsolved riddle and demands further research. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 177-178

First detection/quantification of roxadustat in hair with a new liquid chromatography with tandem mass spectrometry method: Application to a treated patient

Roxadustat is an oral inhibitor of hypoxia-inducible factor prolyl hydroxylase which increases erythropoiesis. It can therefore be used as a doping agent. No data are available on how to measure roxadustat in hair and on the concentration found in treated patients. The aim of this study was to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of roxadustat in hair and to apply it to a chronically treated patient.After decontamination with dichloromethane, testosterone-D3 used as an internal standard and phosphate buffer pH 5.0 were added to 20 mg of hair and incubated for 10 min at 95 °C. Four ml of dichloromethane were used for extraction and reconstituted into the mobile phase, 10 µL were injected into the chromatographic system.The method was linear in the range 0.5–200 pg/mg, accurate and precise (evaluated at 3 levels) and was successfully applied to measure roxadustat in a brown-haired patient treated pharmacologically with 100–120 mg 3 days a week. Results were stable between 41 and 57 pg/mg in the 6 proximal 1 cm segments.This first method describing the measurement of roxadustat in hair appears to be suitable for the quantification of this compound in clinical or doping control cases.

Quality of life: a crucial aspect for the patients, a neglected goal in the treatment of anemia in patients with CKD

The aim of any treatment should be to add life to years and not simply years to life. Surprisingly, the label of erythropoiesis-stimulating agents for anemia treatment in chronic kidney disease does not include the indication for improving quality of life. Merit of the placebo-controlled Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat in Non-Dialysis Subjects Evaluating Hemoglobin (Hgb) and Quality of Life (ASCEND-NHQ) trial was to address this issue by analyzing the effect of anemia treatment with daprodustat aimed at the hemoglobin target range of 11-12 g/dl; the trial demonstrates that partial anemia correction improved quality of life.

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.