Prolyl Hydroxylase Inhibitor Research Articles

Integrated Longitudinal Population Dose-Hemoglobin Response of Daprodustat Following Dose Titration in Patients With Anemia in Chronic Kidney Disease.

Daprodustat, a novel oral hypoxia-inducible factor prolyl hydroxylase inhibitor is approved in the United States for the treatment of anemia due to chronic kidney disease (CKD) in adults receiving dialysis for at least 4 months. Pharmacodynamic dose-hemoglobin (Dose-Hgb) models were developed as daprodustat progressed through development. To support global phase III development, a dose-titration algorithm, guided by simulations from the initial Dose-Hgb model based on phase II clinical data, was implemented. This work was to update and re-calibrate this model to support the dose titration algorithm. Data from five pivotal phase III studies in CKD patients with anemia treated with daprodustat once daily (q.d.) and/or three times a week (t.i.w.) using a titration dosing schedule were included. The data comprised 2,770 CKD patients with anemia providing 53,535 Hgb observations over a period of 6 months up to 4 years. This final Dose-Hgb model consisted of a precursor cell compartment and 12 transit compartments to describe the red blood cell (RBC) lifespan. Treatment increased the precursor cell production rate (Kin) by a power of allometrically scaled dose. Disease progression, as an exponential decline of Hgb production rate over time, varied with dialysis status. The dose-titration algorithm resulted in comparable response for t.i.w. dosing relative to q.d. dosing. Titration-based visual predictive checks for Hgb target criteria for the analysis dataset and the prediction dataset showed that the model adequately predicted the observed data. This re-calibrated Dose-Hgb model will provide further support for the individualized dosing strategy in CKD patients with anemia treated with daprodustat.

Bioanalysis, Analysis, Chemistry, and Pharmacological Aspects of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors.

The development of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors (HIFPHIs), such as Roxadustat (ROX), Enarodustat (ENA), Desidustat (DES), Vadadustat (VAD), Molidustat (MOL), and Daprodustat (DAP), has significant effects on anemia in chronic kidney disease. This review presents comprehensive information about the synthesis, pharmacology, and analysis of HIF-PHIs across several matrices. The literature has presented several approaches for quantifying HIF-PHIs in diverse sample matrices. Furthermore, HIF-PHIs exhibit similar modes of action, demonstrating distinct pharmacokinetic parameters. The pharmacological insights encompass their half-life, mechanism of action, absorption, distribution, metabolism, excretion, and therapeutic uses. Research indicates that most studies concentrate on hyphenated methodologies for drug estimation in various biological fluids. Consequently, this study assesses the biological efficacy of HIF-PHIs and elucidates the analytical methodologies currently employed for measurement across various matrices.

Inhibition of HIF-prolyl hydroxylase promotes renal tubule regeneration via the reprogramming of renal proximal tubular cells.

The ability of the mammalian kidney to repair or regenerate after acute kidney injury (AKI) is very limited. The maladaptive repair of AKI promotes progression to chronic kidney disease (CKD). Therefore, new strategies to promote the repair/regeneration of injured renal tubules after AKI are urgently needed. Hypoxia has been shown to induce heart regeneration in adult mice. However, it is unknown whether hypoxia can induce kidney regeneration after AKI. In this study, we used a prolyl hydroxylase domain inhibitor (PHDI), MK-8617, to mimic hypoxic conditions and found that MK-8617 significantly ameliorated ischemia reperfusion injury (IRI)-induced AKI. We also showed that MK-8617 dramatically facilitated renal tubule regeneration by promoting the proliferation of renal proximal tubular cells (RPTCs) after IRI-induced AKI. We then performed bulk mRNA sequencing and discovered that multiple nephrogenesis-related genes were significantly upregulated with MK-8617 pretreatment. We also showed that MK-8617 may alleviate proximal tubule injury by stabilizing the HIF-1α protein specifically in renal proximal tubular cells. Furthermore, we demonstrated that MK-8617 promotes the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells and the regeneration of renal proximal tubules. In summary, we report that the inhibition of prolyl hydroxylase improves renal proximal tubule regeneration after IRI-induced AKI by promoting the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells.

Efficacy of Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors in Renal Anemia: Enhancing Erythropoiesis and Long-Term Outcomes in Patients with Chronic Kidney Disease.

Renal anemia is one of the major complications associated with chronic kidney disease (CKD). Erythropoietin-stimulating agents (ESAs) are commonly used; however, some patients exhibit resistance. Hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) have emerged as a novel treatment for renal anemia, enhancing erythropoiesis and iron metabolism. We retrospectively analyzed laboratory data related to erythropoiesis from 105 patients with CKD before and after treatment with HIF-PHI or ESA. The dialysis initiation and mortality rates were also assessed over a median follow-up of 614 days. HIF-PHI and ESA significantly increased the hemoglobin levels within 6 months of treatment (9.5 ± 1.0 to 10.7 ± 1.1, p < 0.01, and 9.9 ± 1.5 to 10.7 ± 1.2 g/dL, p < 0.01, respectively). The HIF-PHI group demonstrated a significant decrease in red cell distribution width (14.5 ± 1.9% to 13.8 ± 1.4%, p < 0.01), suggesting improved erythropoiesis, and exhibited a lower cumulative incidence of outcomes. The aged-adjusted multivariate analysis confirmed the independent association between HIF-PHI treatment and reduced risk of cumulative outcome (p = 0.042). HIF-PHIs can serve as an alternative to ESA for managing renal anemia in CKD, improving both hematological parameters and long-term outcomes.

Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor.

Hypoxia-inducible factor prolyl hydroxylase (PHD) inhibitors have been approved for treating renal anemia yet have failed clinical testing for inflammatory bowel disease because of a lack of efficacy. Here we used a multimodel multimodal generative artificial intelligence platform to design an orally gut-restricted selective PHD1 and PHD2 inhibitor that exhibits favorable safety and pharmacokinetic profiles in preclinical studies. ISM012-042 restores intestinal barrier function and alleviates gut inflammation in multiple experimental colitis models.

Hypoxia-inducible factor prolyl hydroxylase inhibitor-induced thrombosis leading to transcatheter aortic valve dysfunction: a case report

Abstract Background Transcatheter aortic valve replacement (TAVR) is a well-established treatment option for patients with severe aortic valve stenosis; however, clinical valve thrombosis is a major challenge. Case summary A 92-year-old woman underwent TAVR for severe aortic stenosis. One month later, the patient developed acute heart failure. As the progression of anaemia due to renal anaemia seemed to cause acute heart failure exacerbation, we started an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor. After 2 weeks, the patient redeveloped shortness of breath. Transthoracic echocardiography revealed that the mean aortic valve pressure gradient (ΔP) increased from 9 to 54 mmHg, and the aortic valve area decreased from 1.93 to 0.86 cm2. Blood work revealed a markedly elevated haemoglobin level from 8.0 to 13.2 g/dL, and transoesophageal echocardiography revealed markedly decreased left coronary and non-coronary cusp mobility. We diagnosed that the rapid increase in the haemoglobin level caused by the HIF-PH inhibitor was related to valve thrombosis and bioprosthetic dysfunction of the transcatheter aortic valve. The HIF-PH inhibitor was discontinued, and anticoagulation therapy was started. Transthoracic echocardiography at 16 days later revealed that the mean aortic valve ΔP improved by 15 mmHg, and the subjective symptoms resolved. Discussion This is the first report on a successful treatment of TAVR thrombosis formation associated with HIF-PH inhibitor use. When treating renal anaemia in patients undergoing TAVR, care should be taken to avoid rapid anaemia resolution and valve thrombosis development.

Effects of Roxadustat on Thyroid Profiles in Patients and Animals with Chronic Kidney Disease

Introduction: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor used in renal anemia treatment, has been associated with thyroid hormone suppression. This study investigated the patterns of thyroid profile changes following roxadustat administration and their clinical implications. Methods: In this retrospective study (2019–2023) at Shenzhen Second People’s Hospital, patients were categorized based on thyroid-stimulating hormone (TSH) reduction during follow-up (≥50% decrease vs. <50% decrease). Thyroid profiles, clinical symptoms, and laboratory indicators were analyzed. Quality of life was assessed using EQ-5D-3L and ThyPRO questionnaires. Complementary animal experiments were conducted to verify the effects of roxadustat on thyroid function. Results: A total of 118 patients were finally enrolled in our study. Among patients with initially normal thyroid function, 31 developed euthyroid sick syndrome post-roxadustat treatment. Treatment significantly decreased TT3, FT3, FT4, and TSH levels, with TSH showing marked reduction within the first 10 weeks. Contrastingly, animal models exhibited decreased T3 but increased TSH levels, regardless of renal status. Blood lipid levels decreased in all patients, particularly in those with substantial TSH reduction. Despite thyroid alterations, quality-of-life scores remained unchanged between roxadustat-treated and untreated patients, with no overt clinical symptoms in either humans or animals. Conclusion: While roxadustat induces significant thyroid hormone suppression in patients, these alterations rarely manifest as clinical symptoms. Euthyroid sick syndrome is the predominant thyroid dysfunction pattern observed. Regular thyroid function monitoring is recommended during roxadustat therapy, particularly during the initial treatment phase when TSH changes are most pronounced.

Anemia, iron metabolism, and anemia medication habits in patients undergoing maintenance hemodialysis and peritoneal dialysis are different: a multicenter investigation.

This study aimed to investigate anemia, iron metabolism status, and treatment in patients undergoing maintenance hemodialysis (HD) and peritoneal dialysis (PD). Patients aged ≥ 18years undergoing HD and PD were surveyed using a case report form to collect information. Data were collected from 1071 patients undergoing HD and 630 undergoing PD at eight centers. Anemia was observed in 96.2% of the patients (96.7% for HD vs. 95.2% for PD, P = 0.121). Of these, 38.3% had hemoglobin (Hb) levels between 110 and 130g/L (41.2% for HD vs. 33.3% for PD, P < 0.001), 22.8% had absolute iron deficiency (ID) (31.2% for HD vs. 8.4% for PD, P < 0.001), and 5.8% had functional ID (4.7% for HD vs. 7.6% for PD, P = 0.012). Among patients with Hb < 110g/L, 13.0% received no treatment with erythropoiesis-stimulating agents (ESAs, all recombinant human erythropoietin) or hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI, all roxadustat) (12.6% for HD vs. 13.6% for PD, P = 0.667), while 64.6% had no iron treatment (69.4% for HD vs. 57.4% for PD, P < 0.001). Logistic regression was used to explore the relationship between dialysis mode and hemoglobin target achievement, suggesting that the attainment of hemoglobin targets may be associated with the use of ESAs or HIF-PHI. Anemia, iron metabolism, and medication habits have distinct characteristics in patients undergoing HD and PD. Iron deficiency is prevalent, and achieving hemoglobin targets is suboptimal, possibly influenced by the administration of ESAs or HIF-PHI. Therefore, timely adjustments of medication habits are necessary to prevent anemia exacerbation.

Hypoxia-inducible factor activators: a novel class of oral drugs for the treatment of anemia of chronic kidney disease.

Anemia is a hallmark of chronic kidney disease (CKD), worsens with disease progression, and profoundly affects a patient's well-being. Major pathogenic factors are inadequate kidney erythropoietin (EPO) production and absolute and functional iron deficiency. The 2 mainstays of current anemia treatment are a) replacement therapy with recombinant EPO or 1 of its glycosylated derivatives, administered subcutaneously or intravenously, and b) intravenous (IV) iron injections. Over the past 5 years, hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitors (HIF-PHIs) have been approved in many countries for the management of anemia in both nondialysis and dialysis-dependent patients with CKD. Due to cardiovascular safety concerns, only 2 HIF-PHIs, daprodustat and vadadustat, have been approved for marketing in the United States, and only for patients on maintenance dialysis. HIF-PHIs are oral agents that are effective at improving and maintaining hemoglobin levels by activating HIF signaling in anemic patients with CKD. They stimulate the production of endogenous EPO, increase total iron-binding capacity through their direct effects on transferrin gene transcription, lower plasma hepcidin indirectly, and have beneficial effects on red blood cell parameters. Here, we discuss the mechanisms of action and pharmacologic properties of different HIF-PHIs. We discuss unwanted on-target and off-target effects, review cardiovascular and other safety concerns, and provide a benefit/risk-based perspective on how this new class of oral drugs might impact current anemia management in CKD. A clinical case is presented that highlights the clinical complexities and therapeutic challenges in managing anemia in CKD.

Successful treatment of low-risk myelodysplastic syndrome-related anemia in patients with chronic kidney disease with daprodustat: A report of two cases.

Anemia is a major clinical manifestation seen in myelodysplastic syndromes (MDS). Treatment options for anemia in low-risk MDS are limited. Especially, oral medication which is uniformly effective for anemia in low-risk MDS is required. Hypoxia-inducible factor (HIF) prolyl hydroxylase (HIF-PH) inhibitors, such as daprodustat, are oral tablets effective for renal anemia. Pharmacological restoration of HIF activity by HIF-PH inhibitors may be beneficial for MDS-related anemia as well. Yet, their efficacy and safety against low-risk MDS are unclear. Here, we report two cases of low-risk MDS complicated with chronic kidney disease whose anemia responded to daprodustat treatment.

Erythrocyte indices and response to hypoxia-inducible factor prolyl hydroxylase inhibitors in chronic kidney disease patients with renal anemia: a retrospective study

BackgroundAlthough erythropoiesis-stimulating agents (ESAs) have been the standard treatment for renal anemia, ESA hyporesponsiveness remains a concern. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of agents indicated for renal anemia. Several lines of evidence indicate that HIF-PHIs affect erythrocyte indices; nonetheless, their clinical significance remains unclear.MethodsWe retrospectively analyzed data from 233 non-dialysis-dependent chronic kidney disease patients who initiated either ESA (darbepoetin) or HIF-PHI for the treatment of anemia. We analyzed the changes in hemoglobin levels three months after the initiation of anti-anemic treatments, examining their association with changes in erythrocyte indices.ResultsBoth ESA and HIF-PHIs significantly increased hemoglobin levels after three months of treatment. In the HIF-PHI group, the increase in hemoglobin levels was positively correlated with the increase in mean corpuscular volume (MCV) levels, a finding that was not observed in the ESA group. In a subgroup analysis based on the mean reference range value for MCV (90.9 fL), a significant difference in the proportion of patients with improved anemia was observed between ESA and HIF-PHIs in patients with lower MCV values. Logistic regression and interaction analyses confirmed that there was a significant interaction between baseline MCV values and the effectiveness of anti-anemic drugs, independently of other covariates.ConclusionsAn increase in hemoglobin levels is associated with an increase in MCV in patients treated with HIF-PHIs. The anti-anemic effects of ESA and HIF-PHIs may be influenced by baseline MCV values. However, long-term consequences need further evaluation.

Inhibition of alternative complement system and prolyl hydroxylase ameliorates anaemia of inflammation.

Chronic diseases associated with inflammation cause early destruction of RBCs. Complement system, part of innate immunity, is involved in such RBC destruction. Persistent inflammation causes kidney injury, leading to reduced erythropoietin release and functional iron deficiency, causing anaemia. We have investigated effect of iptacopan, a factor B inhibitor, and desidustat, a prolyl hydroxylase inhibitor in anaemia induced by peptidoglycan polysaccharide (PGPS) treatment in rats. Inflammation, haemolysis and its diagnostic markers (LDH, total bilirubin, and RBC lifespan) were evaluated after three days of PGPS challenge. Haemoglobin, RBC, iron homeostasis, and RBC destruction were evaluated fourteen days after PGPS challenge. Desidustat (15mg/kg) and iptacopan (20mg/kg) were given along with PGPS and continued for two weeks. Iptacopan and its combination with desidustat prevented LDH, total bilirubin, complement protein-C3a and haemolysis. Combination treatment caused an early normalization of haemoglobin and RBC. Combination also reduced WBC, alkaline phosphatase, aspartate aminotransferase, and rat paw volume. Serum iron was increased by desidustat and its combination treatment. Spleen weight, tissue iron, and serum hepcidin were reduced by combination treatment. Effect of desidustat alone was prominent on iron (serum and tissue) and hepcidin. Thus, combination of iptacopan and desidustat can be a potentially useful therapeutic option for treatment of anaemia of inflammation.

Efficacy and safety of daprodustat in patients on peritoneal dialysis in the ASCEND-D trial.

Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is approved for treatment of anemia in dialysis patients with CKD in some parts of the world. This subgroup analysis examined the efficacy and safety of daprodustat versus darbepoetin alfa in patients with anemia of CKD undergoing peritoneal dialysis (PD). ASCEND-D (NCT02879305) was an open-label, Phase 3 trial; patients with CKD were randomized to daprodustat daily and epoetin alfa (HD patients) or darbepoetin alfa (PD patients). In PD patients, prespecified analyses of the co-primary endpoints of mean change in hemoglobin from baseline to Weeks 28-52 using an ANOVA model and first occurrence of a major cardiovascular event (MACE) using a Cox proportional hazards model were conducted. The secondary endpoints were average monthly intravenous iron dose to Week 52 and treatment-emergent adverse events. Additional post hoc analyses were conducted. Overall, 340 PD patients (daprodustat n=171, darbepoetin alfa n=169) were randomized. Mean age was 53.6 years (±14 SD), 55% male, 56% White. For daprodustat and darbepoetin alfa groups respectively, mean change in hemoglobin was 0.38 and 0.23g/dL [adjusted mean difference 0.15, 95% confidence interval (CI), -0.04, 0.34], and first occurrence of adjudicated MACE occurred in 40 (23.4%) and 46 (27.2%) patients (HR 0.84; 95% CI, 0.55-1.28). No heterogeneity was observed between PD and HD patients for these endpoints in ASCEND-D. Serum hepcidin was lower with daprodustat; there was no difference in other iron parameters, intravenous iron usage, transfusion requirement, blood pressure, or quality of life. There were no differences in adverse events or incidence of peritonitis between the groups. This subgroup analysis of the ASCEND-D trial demonstrated comparable efficacy and safety of daprodustat versus darbepoetin alfa in PD patients, supporting its use in the treatment of anemia in these patients.

Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat.

Prolyl hydroxylase domain-containing proteins 1-3 (PHD1-3) are 2-oxoglutarate (2OG)-dependent oxygenases catalysing C-4 hydroxylation of prolyl residues in α-subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF), modifications that promote HIF-α degradation via the ubiquitin-proteasome pathway. Pharmacological inhibition of the PHDs induces HIF-α stabilisation, so promoting HIF target gene transcription. PHD inhibitors are used to treat anaemia caused by chronic kidney disease (CKD) due to their ability to stimulate erythropoietin (EPO) production. We report studies on the effects of the approved PHD inhibitors Desidustat and Enarodustat, and the clinical candidate TP0463518, on activities of a representative set of isolated recombinant human 2OG oxygenases. The three molecules manifest selectivity for PHD inhibition over that of the other 2OG oxygenases evaluated. We obtained crystal structures of Desidustat and Enarodustat in complex with the human 2OG oxygenase factor inhibiting hypoxia-inducible factor-α (FIH), which, together with modelling studies, inform on the binding modes of Desidustat and Enarodustat to active site Fe(II) in 2OG oxygenases, including PHD1-3. The results will help in the design of selective inhibitors of both the PHDs and other 2OG oxygenases, which are of medicinal interest due to their involvement inter alia in metabolic regulation, epigenetic signalling, DNA-damage repair, and agrochemical resistance.

Roxadustat Efficacy and Safety in Patients Receiving Peritoneal Dialysis: Pooled Analysis of Four Phase 3 Studies.

Background/Objectives: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved to treat anemia of chronic kidney disease (CKD). The efficacy and safety of roxadustat compared with parenteral erythropoiesis-stimulating agents (ESAs) were evaluated in patients with anemia of CKD receiving peritoneal dialysis (PD). Methods: This analysis pooled data from four phase 3, multicenter, randomized, open-label, active-comparator studies (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES). The primary endpoints evaluated were hemoglobin change from baseline (CFB) to Weeks 28-36 without rescue therapy and hemoglobin CFB to Weeks 28-52 regardless of rescue therapy use. Safety data were reported. Results: This analysis included 422 patients (215 roxadustat, 207 ESA). Hemoglobin CFB to Weeks 28-36 without rescue therapy and hemoglobin CFB to Weeks 28-52 regardless of rescue therapy achieved non-inferiority for roxadustat vs. ESAs. The mean weekly dose of roxadustat was maintained over time (Weeks 1-4, 3.86 mg/kg/week; Weeks 101-104, 3.27 mg/kg/week), whereas the mean weekly ESA dose increased by 24% (Weeks 1-4, 115.70 IU/kg/week; Weeks 101-104, 143.40 IU/kg/week). Fewer patients treated with roxadustat received intravenous iron supplementation and rescue therapy, and patients treated with an ESA required blood transfusions sooner. Roxadustat-treated patients experienced a greater decrease in low-density lipoprotein cholesterol levels relative to baseline vs. ESA-treated patients. Treatment-emergent adverse events were similar in both treatment groups. Major adverse cardiovascular event (MACE), MACE plus unstable angina or congestive heart failure, and all-cause mortality hazard ratios were <1; the lower limit of the 95% CIs was <0.6, and the upper limit was >1.3. Conclusions: Roxadustat was non-inferior to ESAs in correcting and maintaining hemoglobin levels, with stable dosing and a comparable safety profile, in anemic patients receiving PD.

Hypertension Induced by Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Treating Anemia in Patients With Chronic Kidney Disease: A Mini-Review.

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of agents for the treatment of anemia in chronic kidney disease (CKD). Unlike traditional treatments such as erythropoiesis-stimulating agents (ESAs), HIF-PH inhibitors are orally administered drugs and may increase endogenous erythropoietin and improve iron homeostasis. However, a significant concern is their possible side effect on blood pressure. The current mini-review summarizes the data of 26 randomized controlled (placebo or ESAs) trials on six different HIF-PH inhibitors with regard to their potential influence on blood pressure and hypertension in the management of anemia in CKD. Overall, the use of HIF-PH inhibitors was associated with a higher risk of hypertension than placebo (pooled risk ratio 1.36, 95% confidence interval [CI] 1.16-1.59), but a lower risk of hypertension than ESA treatment (pooled risk ratio 0.92, 95% CI 0.86-0.98), especially in CKD patients not undergoing dialysis (pooled risk ratio 0.85, 95% CI 0.73-0.98). This review highlights the importance of blood pressure monitoring during the treatment of HIF-PH inhibitors, especially out-of-office blood pressure measurement.

Oxygen sensing in the kidney.

The kidneys fulfil several essential homeostatic functions for the body. One of them is the maintenance of sufficient oxygen supply to the organs. For this purpose, the kidneys control the formation of red blood cells by the production of the hormone erythropoietin. This control of red cell formation is not only relevant to prevent states of oxygen deficiency but also to prevent an unwanted increase of red cell numbers causing thromboembolic risks. The adequate production of erythropoietin requires a sensing of the arterial oxygen content and transduction to hormone production. This oxygen sensing is a two-step process which includes a translation of the arterial oxygen content to respective oxygen tension in the tubulointerstitium and a perception of the resulting local interstitial oxygen tension to translate them into specific cellular responses such as the production of erythropoietin. This contribution will describe these steps of oxygen sensing for the healthy kidney and for the changes occurring during states of chronic renal disease, which are commonly associated with anemia. In this context a special focus will also be set on intrarenal hypoxia and oxygen sensing in the diabetic kidney including the treatment with tubular glucose transport (SGLT-2) inhibitors which might influence the oxygen sensing in the kidney. Finally, we will consider the effects of prolylhydroxylase inhibitors (PHD-I), which fundamentally interfere with the cellular oxygen sensing and which are meanwhile treatment options in renal anemia.

Vadadustat Three Times Weekly in Patients With Anemia Due to Dialysis-Dependent CKD

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) may offer an alternative erythropoiesis-stimulating agents (ESA) for the treatment of anemia in the setting of CKD. To investigate the efficacy and safety of conversion from long-acting erythropoiesis-stimulating agent (ESA) methoxy polyethylene glycol-epoetin beta (MPG-EPO) to the oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) vadadustat 3-times-weekly versus maintenance on MPG-EPO. Phase 3b, open-label, noninferiority trial. Multicenter study in United States; 456 patients adults with anemia and dialysis-dependent chronic kidney disease. Participants were randomized 1:1:1 either to vadadustat (starting dose: 600 mg thrice weekly), vadadustat (starting dose: 900 mg thrice weekly), or MPG-EPO, for up to 52 treatment weeks and 4 safety follow-up weeks after the end of treatment or early termination. Primary and secondary efficacy endpoints were the mean change in hemoglobin from baseline during primary (weeks 20-26) and secondary (weeks 46-52) evaluation periods, respectively. Noninferiority was specified as a lower bound of the 95% CI above -0.75 g/dL for the difference in mean change in hemoglobin from baseline. Other efficacy endpoints were the proportion of participants with hemoglobin levels within the target range and the proportions of participants requiring ESA or red blood cell transfusion rescue for anemia during the evaluation periods. Transfusion rates were low and occurred at similar rates across treatment groups (2.7% and 4.0% in the combined vadadustat and MPG-EPO groups, respectively). Primary safety endpoints were any treatment-emergent and serious adverse events (AEs). After combining the vadadustat groups (600 mg and 900 mg thrice weekly, n=304), vadadustat was noninferior to MPG-EPO (n=152) for both primary (least squares mean treatment difference, -0.33; 95% CI, -0.53 to -0.13) and secondary efficacy endpoints (-0.33; -0.56 to -0.09). Mean hemoglobin concentrations were stable for all groups, except for an initial slight decline in the vadadustat 600 mg group, which stabilized by week 12. ESA rescue for anemia was more frequent in the MPG-EPO group (primary evaluation period, 27.7%; secondary evaluation period, 16.2%) than in the combined vadadustat (14.2%; 7.3%) groups. The incidences of any treatment-emergent and serious treatment-emergent AEs were similar across treatment groups. Potential errors in attribution of AEs as drug related. Three-times-weekly vadadustat was noninferior to MPG-EPO on their effect on hemoglobin levels without detectable differences in AEs.

Safety and Efficacy of Vadadustat Once Daily and Three Times Weekly in Patients With Dialysis-Dependent CKD With Anemia.

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia in chronic kidney disease (CKD). This study investigated safety and efficacy of once-daily and 3-times-weekly dosing in patients with dialysis-dependent (DD)-CKD compared with darbepoetin alfa (DA). This phase 3b, randomized (1:1:1; vadadustat once-daily [starting dose: 300 or 450 mg], vadadustat 3-times-weekly [starting dose: 600 or 750 mg], DA), open-label, active-controlled, noninferiority trial included conversion (weeks 0-20) and maintenance (weeks 20-52) periods. Primary and secondary efficacy endpoints were mean change in hemoglobin from baseline during the primary (PEP, weeks 20-26) and secondary (SEP, weeks 46-52) evaluation periods. Other endpoints included proportion of patients requiring ESA rescue (hemoglobin <9.5 g/dL or with increases in dose ≥50% or ≥100% in DA group). Safety endpoints included treatment-emergent adverse events (TEAEs) and serious AEs (SAEs). Least squares (LS) mean treatment difference between vadadustat once-daily and DA from baseline to PEP was -0.27 g/dL (95% CI, -0.55 to 0.01); the lower bound met the noninferiority threshold (-0.75 g/dL). The LS mean treatment difference between vadadustat 3-times-weekly and DA from baseline to PEP was -0.53 g/dL (95% CI, -0.80 to -0.25), which did not meet the lower bound noninferiority threshold. The LS mean change from baseline to the SEP between DA and vadadustat once-daily was -0.40 (95% CI, -0.79 to -0.02), and for vadadustat 3-times-weekly was -0.42 (95% CI, -0.81 to -0.02). Proportion of patients who received ESA rescue during weeks 2-52 was higher in the DA group than vadadustat groups. Similar TEAEs and treatment-emergent SAEs were observed across groups. Vadadustat once-daily, but not 3-times-weekly, was noninferior to DA in the correction and maintenance of hemoglobin in patients with DD-CKD converted from an ESA; safety profiles were similar across groups. EudraCT 2019-004851-36/ClinicalTrials.gov identifier: NCT04313153.

Chemistry, Analysis, and Biological Aspects of Daprodustat, A New Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitor: A Comprehensive Review.

The National Health and Nutrition Examination Survey (NHANES) carried out a survey between 2007-10 and found that as compared to the general population, the prevalence of anemia in chronic kidney disease (CKD) patients was twice high. Daprodustat is an investigational novel drug for the treatment of renal anemia. The objective of this study is to provide a comprehensive review of chemistry, synthesis, pharmacology, pharmacokinetic, and bioanalytical methods for the analysis of Daprodustat. To improve understanding, a review was carried out by creating a database of relevant prior research from electronic sources such as ScienceDirect and PubMed. The methodology is shown in the flowchart of the literature selection process. The drug was approved in 2020 for therapeutic purposes in Japan. It is a novel drug approved for the treatment of anemia in chronic kidney disease for oral administration. It is intended for adults who have undergone dialysis for a minimum of four months and are experiencing anemia as a result of chronic kidney disease. This review examines therapeutic, pharmacological, and analytical aspects related to the novel drug Daprodustat.