Darbepoetin Research Articles

Hematopoietic Recovery using Multi-Cytokine Therapy in 8 Patients Presenting Radiation-Induced Myelosuppression after Radiological Accidents.

Treatment of accidental radiation-induced myelosuppression is primarily based on supportive care and requires specific treatment based on hematopoietic growth factors injection or hematopoietic cell transplantation for the most severe cases. The cytokines used consisted of pegylated erythropoietin (darbepoetin alfa) 500 IU once per week, pegylated G-CSF (pegfilgrastim) 6 mg × 2 once, stem cell factor 20 µg.kg-1 for five days, and romiplostim (TPO analog) 10 µg.kg -1 once per week, with different combinations depending on the accidents. As the stem cell factor did not have regulatory approval for clinical use in France, the French regulatory authorities (ANSM, formerly, AFSSAPS) approved their compassionate use as an investigational drug "on a case-by-case basis". According to the evolution and clinical characteristics, each patient's treatment was adopted on an individual basis. Daily blood count allows initiating G-CSF and SCF delivery when granulocyte <1,000/mm3, TPO delivery when platelets <50,000/mm3, and EPO when Hb<80 g/L. The length of each treatment was based on blood cell recovery criteria. The concept of "stimulation strategy" is linked to each patient's residual hematopoiesis, which varies among them, depending on the radiation exposure's characteristics and heterogeneity. This paper reports the medical management of 8 overexposed patients to ionizing radiation. The recovery of bone marrow function after myelosuppression was accelerated using growth factors, optimized by multiple-line combinations. Particularly in the event of prolonged exposure to ionizing radiation in dose ranges inducing severe myelosuppression (in the order of 5 to 8 Gy), with no indication of hematopoietic stem cell transplantation.

Efficacy and Safety of Molidustat for Anemia in ESA-Naive Nondialysis Patients: A Randomized, Phase 3 Trial

Introduction: Molidustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that predominantly induces renal production of erythropoietin (EPO). Molidustat was evaluated for the treatment of anemia associated with chronic kidney disease (CKD) in the “Molidustat Once Daily Improves Renal Anemia by Inducing EPO” (MIYABI) program, which comprises 5 phase 3 clinical trials. The present MIYABI Non-Dialysis Correction (ND-C) study investigated the efficacy and safety of molidustat in Japanese patients with renal anemia who were not undergoing dialysis and were not receiving erythropoiesis-stimulating agent (ESA) treatment. Methods: This was a 52-week, randomized (1:1), open-label, active-control, parallel-group, multicenter, phase 3 study in Japanese patients with renal anemia associated with CKD (stages 3–5). Molidustat or the ESA darbepoetin alfa (hereinafter referred to as darbepoetin) were initiated at 25 mg once daily or 30 μg every 2 weeks, respectively, and doses were regularly titrated to correct and to maintain hemoglobin (Hb) levels in the target range of ≥11.0 g/dL and <13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30–36). The safety outcomes included evaluation of all adverse events. Results: In total, 162 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 80). Baseline characteristics were generally well balanced between treatment groups. The mean (standard deviation) Hb levels at baseline were 9.84 (0.64) g/dL for molidustat and 10.00 (0.61) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.28 [11.07, 11.50] g/dL) and darbepoetin (11.70 [11.50, 11.90] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin in the change in mean Hb level during the evaluation period from baseline; the least-squares mean (95% CI) difference (molidustat-darbepoetin) was −0.38 (−0.67, −0.08) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 93.9% for molidustat and 93.7% for darbepoetin. Most TEAEs were mild (54.9% for molidustat and 63.3% for darbepoetin) or moderate (22.0% for molidustat and 22.8% for darbepoetin) in intensity. There were 3 deaths in the molidustat group and 1 in the darbepoetin group. Discussion/Conclusion: In the MIYABI ND-C study, molidustat appeared to be an efficacious and generally well-tolerated alternative to darbepoetin for the treatment of renal anemia in Japanese patients who were not undergoing dialysis and were not receiving ESA treatment.

Molidustat for Renal Anemia in Nondialysis Patients Previously Treated with Erythropoiesis-Stimulating Agents: A Randomized, Open-Label, Phase 3 Study

Introduction: Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs. Methods: This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3–5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0–13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30–36). The safety outcomes included evaluation of all adverse events. Results: In total, 164 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48–11.85] g/dL) and darbepoetin (11.53 [11.31–11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (−0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively. Discussion/Conclusion: Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.

Variation in health plan coverage of ESAs for anemia due to chronic kidney disease.

BACKGROUND: Because health plans each issue their own policies, drug coverage can vary. This variation can result in patients having unequal access to treatment. In this study, we evaluate commercial health plans' coverage policies for erythropoiesis-stimulating agents (ESAs) for patients with anemia resulting from chronic kidney disease (CKD). OBJECTIVES: To assess how a set of US commercial health plans cover ESAs for patients with anemia due to CKD. Our second objective was to examine the evidence that the plans reviewed when formulating their coverage policies. METHODS: We used the Tufts Medical Center Specialty Drug and Evidence and Coverage Database to identify coverage policies issued by 17 of the largest US commercial health plans for ESAs. The following drugs were indicated for anemia due to CKD: darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, epoetin alfa (available as two brands), and epoetin alfa-epbx. Coverage policies were current as of May 2019. We determined whether the health plans applied any restrictions, such as step therapy protocols or patient subgroup restrictions, in their coverage policies. We categorized the evidence that plans cited to support their policies into seven categories: randomized controlled trials (RCTs), real-world evidence (RWE) studies (studies based on data collected in a real-world setting), other clinical studies (eg, single arm trials), systematic reviews and/or meta-analyses, clinical or treatment guidelines, health technology assessments, and economic evaluations. RESULTS: We categorized 72.5% of coverage policies (58/80 policies) as equivalent to the FDA label and 27.5% (22/80 policies) as more restrictive. In restricted policies, plans most often applied step therapy protocols (18/22 policies), followed by prescriber requirements (4/22 policies), and patient subgroup restrictions (3/22 policies). Five health plans applied restrictions in at least half of their coverage policies; seven plans did not apply restrictions in any policy. Plans that cited evidence reviewed an average of 10 citations across their ESA coverage policies, ranging from one to 29 studies. Plans varied with respect to the types of cited studies: at least 50% of evidence cited by five health plans was RCTs, while half or more of the evidence cited by four health plans was clinical or treatment guidelines. CONCLUSIONS: Health plans varied in how they covered ESAs for patients with anemia due to CKD and in the evidence cited in their coverage policies. Inconsistencies in plans' coverage policies may have implications for patients' access to ESAs. DISCLOSURES: This study was funded by Otsuka Pharmaceutical Development and Commercialization. Sanon, Redmond, and Mogahadam are employed by Otsuka Pharmaceutical. Michalopoulos was employed by Otsuka Pharmaceutical at the time of this study. Margaretos, Panzer, and Chambers are employed by Tufts Medical Center, Institute for Clinical Research and Health Policy Studies, Center for the Evaluation of Value and Risk in Health. Lai was with Tufts Medical Center, Institute for Clinical Research and Health Policy Studies, Center for the Evaluation of Value and Risk in Health at the time of this study.

MPN-280: Transfusion Independence Achieved with Combination Fedratinib and Luspatercept in an Elderly Male with Heavily Pretreated INT-2 Primary Myelofibrosis

Context: Myelofibrosis (MF)-associated anemia and transfusion dependency are associated with inferior quality of life and poor prognosis. Combination JAK2 inhibitors and TGF-β superfamily ligand traps are being explored as treatment options for MF-associated anemia. Objective: To demonstrate the efficacy and tolerability of combination fedratinib and luspatercept in transfusion-dependent MF. Design: Case report. Setting: Academic referral center. Patients or Other Participants: 66-year-old male was diagnosed with JAK2-positive PMF 8 years ago. IPSS at diagnosis was 0 (low-risk group). After 3 years of observation, he developed worsening anemia. Repeat bone marrow biopsy showed stable hypercellularity and reticulin fibrosis without increased myeloid blasts. DIPSS-PLUS score placed him in the INT-2 risk group. Interventions: Ruxolitinib yielded a 50% reduction in spleen size. However, it resulted in worsening anemia and transfusion dependence, leading to dose reduction, followed by discontinuation. The patient declined evaluation for bone marrow transplantation. He was then enrolled in a clinical trial for pacritinib, which resulted in the stabilization of splenomegaly without improvement in transfusion requirements. Pacritinib was discontinued after the development of empyema and drug-induced pneumonitis. Darbepoetin alfa was initiated without improvement in transfusion requirements. Ultimately, he was started on fedratinib 300 mg daily, then 400 mg daily, without significant side effects. Four months later, luspatercept 1 mg/kg every 3 weeks was added to fedratinib. Main Outcome Measures: Transfusion independence and spleen size. Results: Spleen size decreased from 20 cm to 12 cm by palpation 5 months after starting fedratinib. Hemoglobin increased from a baseline of 6 g/dL to 8.9 g/dL 18 days after the first dose of luspatercept. 8 months after the initiation of luspatercept, hemoglobin has stabilized around 11 g/dL. Luspatercept was held on several occasions due to hemoglobin >11.5 g/dL (highest 11.8 g/dL). The patient had significant improvement in his performance status and is now working full time. Conclusions: Combination fedratinib and luspatercept is a promising therapy for anemia in patients with transfusion-dependent INT-2 MF. Currently, 3 clinical trials are evaluating luspatercept alone (NCT03194542) or in combination with a JAK2 inhibitor (NCT04717414 and NCT03755518) for the treatment of MF-associated anemia. No grant was received for this article.

Uptake of evidence by physicians: De-adoption of erythropoiesis-stimulating agents after the TREAT trial

BackgroundVariation in de-adoption of ineffective or unsafe treatments is not well-understood. We examined de-adoption of erythropoiesis-stimulating agents (ESA) in anemia treatment among patients with chronic kidney disease (CKD) following new clinical evidence of harm and ineffectiveness (the TREAT trial) and the FDA’s revision of its safety warning.MethodWe used a segmented regression approach to estimate changes in use of epoetin alfa (EPO) and darbepoetin alfa (DPO) in the commercial, Medicare Advantage (MA) and Medicare fee-for-service (FFS) populations. We also examined how changes in both trends and levels of use were associated with physicians’ characteristics.ResultsUse of DPO and EPO declined over the study period. There were no consistent changes in DPO trend across insurance groups, but the level of DPO use decreased right after the FDA revision in all groups. The decline in EPO use trend was faster after the TREAT trial for all groups. Nephrologists were largely more responsive to evidence than primary care physicians. Differences by physician’s gender, and age were not consistent across insurance populations and types of ESA.ConclusionsPhysician specialty has a dominant role in prescribing decision, and that specializations with higher use of treatment (nephrologists) were more responsive to new evidence of unsafety and ineffectiveness.

Anemia in Cardiovascular Disease: Marker of Disease Severity or Disease-modifying Therapeutic Target?

In this review paper, we examine the latest evidence regarding the use of iron supplementation, erythropoiesis-stimulating agents (ESAs), and blood transfusions as therapeutic targets for anemia to mitigate morbidity and mortality in patients with cardiovascular disease. Intravenous ferric carboxymaltose (FC) injections in heart failure (HF) have resulted in improved self-reported patient symptoms; higher exercise capacity, as measured by 6-min walk test distance in anemic patients; and lower re-hospitalization rates in iron deficient patients. Darbepoetin alfa has shown evidence of improved Kansas City Cardiomyopathy Questionnaire scores. No mortality benefits have been noted thus far with FC injections or darbepoetin in HF, with an increase in adverse events with darbepoetin. Aggressive transfusions (Hg < 10g/dL) are not associated with improved outcomes in cardiovascular disease. Quality of life metrics, rather than mortality, appear to improve with IV FC and ESA use in HF. More studies are required to see if these treatments have a role in coronary artery disease. Current evidence suggests that anemia is a marker of underlying disease severity, with a limited role in disease modification. Further studies are required to solidify our understanding of this topic.

Institutional Usage of Ferric Pyrophosphate Citrate (FPC) Delivered Via Dialysate in Reducing Erythropoiesis Stimulating Agents (ESAs) and IV Iron Cost.

Dialysis patients are often iron deficient due to a multiple factors. Ferric pyrophosphate citrate is a complex iron salt that can be given via dialysate allowing maintenance of hemoglobin (Hgb) concentration and iron balance while reducing the need for IV iron. The purpose of this study is to perform a cost evaluation of FPC and the effect it has on lowering the dose/use of ESAs and IV iron therapy. This study reviewed the same 100 hemodialysis patient's charts before and after the use of FPC. The data points that were collected and analyzed are as follows: hemoglobin, ferritin levels, average weekly ESA dosing, and IV iron replacement therapy dose. Out of 100 patients, there was no statistical difference in the average hemoglobin, ferritin, and iron saturation levels observed in the patients before and after FPC use. The average weekly dose of darbepoetin alfa per patient was 52.74 μg before the FPC group compared to 39.27 μg in the post FPC group (P < .0001). The total dose of ferric gluconate per patient was 3290.01 mg in the before FPC group and 585.60 mg in the post FPC group (P < .0001). The average total iron sucrose dose per patient in the before FPC group was 3097.92 mg versus 1216.67 mg in the post FPC group (P < .1563). When comparing FPC's cost and implementation into both of our outpatient dialysis centers, this yielded a net savings of $296 751.49.

Safe and Effective Treatment for Anemic Patients With Chronic Kidney Disease: An Updated Systematic Review and Meta-Analysis on Roxadustat

Background: Roxadustat is a new oral drug for anemia in chronic kidney disease (CKD). This study aimed to synthesize the evidence from randomized controlled trial (RCT)-based studies that estimated the efficacy and safety of roxadustat in anemia patients with non-dialysis-dependent (NDD) and dialysis-dependent (DD) CKD. Methods: We searched the PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for related published studies. Moreover, we manually searched relevant pharmaceutical company websites and two international clinical trial registers to search for published and unpublished RCTs comparing roxadustat with erythropoietin-stimulating agents (ESAs) or placebo. Results: Fifteen RCTs (seven for DD-CKD patients, eight for NDD-CKD patients) were included in the meta-analysis, with 10,189 patients, 4,810 DD-CKD patients, and 5,379 NDD-CKD patients enrolled. Compared with ESAs (epoetin alfa or darbepoetin alfa) and placebo, roxadustat raised the hemoglobin level [weighted mean difference (WMD): 0.82 g/dL; 95% confidence interval (CI): 0.43–1.21], transferrin level (WMD: 0.5 g/L; 95% CI: 0.34–0.65), and TIBC level (WMD: 41.79 μg/dL; 95% CI: 38.67–44.92) and lowered the hepcidin level (WMD: −37.38 ng/ml; 95% CI: −46.63– −28.12) in both the DD-CKD and NDD-CKD patients with renal anemia. Roxadustat improved hemoglobin response and lowered the ferritin and TAST levels in the NDD-CKD patients but not in the DD-CKD patients. Furthermore, there was no difference between the treatment-emergent adverse events (TEAEs) of roxadustat and that of ESAs or placebo. But the incidence of serious TEAEs in the roxadustat group was significantly higher with NDD-CKD patients (OR: 1.15; 95% CI: 1.02–1.29). Conclusion: This study confirmed that roxadustat therapy could alleviate the anemia of DD-CKD and NDD-CKD patients by raising the hemoglobin level and regulating iron metabolism, but increased serious incidences of treatment-emergent adverse events (TEAEs) in NDD-CKD patients.

Phase 3 Randomized Study Comparing Vadadustat with Darbepoetin Alfa for Anemia in Japanese Patients with Nondialysis-Dependent CKD

Standard care for treating anemia in patients with CKD includes use of erythropoiesis-stimulating agents, which sometimes involves increased risks of cardiovascular morbidity and mortality. Previous studies in patients with anemia and nondialysis-dependent CKD (NDD-CKD) found significantly elevated hemoglobin levels with use of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, compared with placebo. In this phase 3, open-label, active-controlled noninferiority trial, we randomized 304 Japanese adults with anemia in NDD-CKD (including erythropoiesis-stimulating agent users and nonusers) to oral vadadustat or subcutaneous darbepoetin alfa for 52 weeks. The primary efficacy end point was average hemoglobin at weeks 20 and 24. Safety data included adverse events (AEs) and serious AEs. A total of 151 participants received vadadustat and 153 received darbepoetin alfa. Least squares mean of the average hemoglobin at weeks 20 and 24 was 11.66 (95% confidence interval [95% CI], 11.49 to 11.84) g/dl for vadadustat and 11.93 (95% CI, 11.76 to 12.10) g/dl for darbepoetin alfa. The 95% CIs for both treatments were within the target hemoglobin range (11.0-13.0 g/dl), and the lower 95% confidence limit for the difference between groups (-0.50 g/dl) was above the predefined noninferiority margin (-0.75 g/dl), demonstrating noninferiority of vadadustat to darbepoetin alfa. Similar proportions of patients in each group reported AEs and serious AEs. The most frequent AEs with vadadustat were nasopharyngitis, diarrhea, and constipation. In Japanese patients with NDD-CKD, vadadustat was noninferior to darbepoetin alfa, was effective up to week 52 in terms of average hemoglobin, and was generally well tolerated. These results suggest that vadadustat may be a potential treatment for anemia in this patient population.

The Clinical Efficacy of Epoetin Alfa and Darbepoetin Alfa in Patients with Low-Risk or Intermediate-1-Risk Myelodysplastic Syndrome: Retrospective Multi-center Real-Life Study.

The online version contains supplementary material available at 10.1007/s12288-021-01458-1.

An Integrated Analysis of Darbepoetin Alfa (DAR) in the Treatment of Anemia in Patients with Low- or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS)

An Integrated Analysis of Darbepoetin Alfa (DAR) in the Treatment of Anemia in Patients with Low- or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS)

Hypoxia-inducible factor prolyl hydroxylase domain inhibitor may maintain hemoglobin synthesis at lower serum ferritin and transferrin saturation levels than darbepoetin alfa.

BackgroundHypoxia-inducible factor (HIF) prolyl hydroxylase domain inhibitors, which have recently become clinically available for treating renal anemia, are attracting attention for their novel mechanisms of action.MethodsRelationships of reticulocyte hemoglobin content (CHr), which reflects recent Hb synthesis, with serum ferritin (s-ft) and transferrin saturation (TSAT) were examined in 30 patients on hemodialysis after switching from darbepoetin alfa (DA) to roxadustat (Rox). Iron deficiency was defined as CHr < 32.0 pg. Cutoff values of s-ft and TSAT were determined using receiver operating characteristic curves for the endpoint CHr ≥ 32.0 pg. Logistic analysis was performed with the reference group having s-ft or TSAT below the corresponding cutoff value (low vs high).ResultsWith the endpoint CHr ≥ 32.0 pg on Day 0, cutoff values for s-ft and TSAT were respectively 49.7 ng/mL and 21.6% on Day 0 and 35.5 ng/mL and 16.2% on Day 28. With the endpoint CHr ≥ 32.0 pg on Day 28, cutoff values for s-ft and TSAT on Day 0 were 81.6 ng/mL and 23.9%, respectively. According to multivariable logistic analysis, the odds ratios of CHr ≥ 32.0 pg on Day 0 were significantly higher for high TSAT on Day 0 [34.7 (95% CI 2.42–131.0), p<0.003] and Day 28 [24.8 (95% CI 2.75–224.0), p = 0.004]. There were no significant differences by s-ft. Odd ratios of CHr ≥ 32.0 pg on Day 28 were also significantly higher for high s-ft on Day 0 [16.0 (95% CI 1.57–163.0), p = 0.019] and high TSAT on Day 0 [13.5 (95% CI 1.24–147.0), p<0.033].ConclusionsOur results suggest Hb synthesis was maintained with lower TSAT and s-ft during Rox therapy compared with DA therapy. To avoid iron deficiency during the 4 weeks after switching DA to Rox, ideal s-ft and TSAT levels before the switch are 81.6 ng/mL and 23.9%, respectively.

Evaluating the utilisation and expenditure patterns of erythropoietin stimulating agents and immunosuppressants in Australian chronic kidney disease patients

Abstract Objectives This study aimed to characterise utilisation and expenditure patterns associated with erythropoietin stimulating agents (ESAs) (darbepoetin alfa, epoetin alfa, epoetin beta, epoetin lambda and methoxy polyethylene glycol-epoetin beta) and immunosuppressants (mycophenolate, tacrolimus, ciclosporine, sirolimus and everolimus) in the Australian chronic kidney disease (CKD) population from 2010–2018. Methods Utilisation and expenditure data for each drug were obtained from the Pharmaceutical Benefit Scheme and Highly Specialised Drugs program. Utilisation data were provided a number of dispensing per year, which was then converted to the daily defined dose per 1000 population per day for each year. Temporal trends were then analysed. Key findings Over the study period, utilisation of methoxy polyethylene glycol-epoetin beta and epoetin lambda rose by 13.7 and 81.4-fold, respectively. Contrastingly, the utilisation of darbepoetin alfa, epoetin alfa and epoetin beta declined by 6%, 42% and 70%, respectively. In 2018, tacrolimus, sirolimus, everolimus and mycophenolate utilisation was up 126%, 16.9%, 125% and 182% respectively; conversely, ciclosporine utilisation dropped 19%. Total Australian expenditure on all ESAs examined remained stable at around AUD 128 million over the study period, while total Australian expenditure across all immunosuppressants increased 1.1-fold reaching just over AUD 98 million. Conclusions It appears that immunosuppressant utilisation and expenditure are rising as transplantation rates in Australia continue to increase. Conversely, ESA utilisation and expenditure remained relatively unchanged over the study period. This may be due to increasing concerns around the safety of ESAs offsetting the increasing number of people with CKD.

Continuous optical in-line glucose monitoring and control in CHO cultures contributes to enhanced metabolic efficiency while maintaining darbepoetin alfa product quality.

Great efforts are directed towards improving productivity, consistency and quality of biopharmaceutical processes and products. One particular area is the development of new sensors for continuous monitoring of critical bioprocess parameters by using online or in-line monitoring systems. Recently, we developed a glucose biosensor applicable in single-use, in-line and long-term glucose monitoring in mammalian cell bioreactors. Now, we integrated this sensor in an automated glucose monitoring and feeding system capable of maintaining stable glucose levels, even at very low concentrations. We compared this fed-batch feedback system at both low (<1mM) and high (40mM) glucose levels with traditional batch culture methods, focusing on glycosylation and glycation of the recombinant protein darbepoetin alfa (DPO) produced by a CHO cell line. We evaluated cell growth, metabolite and product concentration under different glucose feeding strategies and show that continuous feeding, even at low glucose levels, has no harmful effects on DPO quantity and quality. We conclude that our system is capable of tight glucose level control throughout extended bioprocesses and has the potential to improve performance where constant maintenance of glucose levels is critical.

Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES).

BackgroundRoxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD).MethodsThis randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin (Hb) within 10.0–12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defined as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (non-inferiority margin, −15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous (IV) iron use, change in mean arterial pressure (MAP) and time to hypertension occurrence. Adverse events were assessed.ResultsOf 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval 5.66–17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first IV iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+ [MACE: 0.81 (0.52–1.25), P = 0.339; MACE+: 0.90 (0.61–1.32), P = 0.583].ConclusionsRoxadustat is a viable option to treat anaemia in NDD CKD patients maintaining Hb levels for up to 104 weeks.

FC 074POOLED EFFICACY AND CARDIOVASCULAR SAFETY RESULTS OF 3 PLACEBO-CONTROLLED AND 1 DARBEPOETIN ALFA-CONTROLLED STUDIES OF ROXADUSTAT FOR TREATMENT OF ANAEMIA IN PATIENTS WITH NON-DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE

Abstract Background and Aims Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, induces a coordinated erythropoietic response by increasing endogenous erythropoietin levels and improving iron metabolism. This analysis was performed to examine the consistency of efficacy and cardiovascular safety results for roxadustat vs placebo or darbepoetin alfa (DA) in patients with non-dialysis-dependent (NDD) chronic kidney disease (CKD). Method Results from three phase 3, double-blind studies comparing roxadustat with placebo (ALPS, ANDES, OLYMPUS) with anaemia and stage 3-5 NDD CKD were pooled and assessed for consistency with results of an open-label study comparing roxadustat with DA (DOLOMITES) in predominantly European patients. The primary efficacy endpoint was haemoglobin (Hb) response, defined as (a) Hb ≥11.0 g/dL that changed from baseline (CFB) by ≥1.0 g/dL in patients with Hb &amp;gt;8.0 g/dL or (b) Hb CFB by ≥2.0 g/dL in patients with Hb ≤8.0 g/dL irrespective of and without rescue therapy for placebo-controlled (assessed for superiority) and DA-controlled (assessed for non-inferiority) studies, respectively. The secondary efficacy endpoint was Hb CFB to Weeks 28-36 using least squares mean difference (LSMD) without rescue therapy. The key safety endpoints of major adverse cardiovascular event (MACE, comprising death, myocardial infarction, and stroke) and MACE+ (MACE plus hospitalization with heart failure or unstable angina) were adjudicated in all studies. MACE and MACE+ for roxadustat vs placebo or DA were compared in the intention-to-treat sample using a Cox proportional hazards model. Results In total, 4886 patients were randomised in placebo-controlled (2386 roxadustat, 1884 placebo) and DA-controlled (323 roxadustat, 293 DA) studies. Baseline characteristics of patients treated with roxadustat vs placebo and roxadustat vs DA were similar: baseline Hb (placebo, 9.10 vs 9.10 g/dL; DA, 9.55 vs 9.55 g/dL) and iron repletion (placebo, 59.9% vs 59.8%; DA, 56.3% vs 51.9%). Roxadustat was superior to placebo for Hb response without rescue therapy (80.2% vs 8.7%; difference of proportion [DOP], 71.50%; 95% CI, 69.40-73.51) and noninferior to DA (89.5% vs 78.0%; DOP, 11.51%; 95% CI, 5.66-17.36). Mean Hb CFB (Weeks 28-36) achieved superiority in pooled analysis vs placebo (LS mean, 1.91 vs 0.14; LSMD, 1.77; 95% CI, 1.69-1.84; P&amp;lt;0.0001) and noninferiority vs DA (LS mean, 1.85 vs 1.84; LSMD, 0.02; 95% CI, -0.13 to 0.16). Risk for MACE or MACE+ was similar for roxadustat vs placebo (MACE, 480 [20.1%] vs 350 [18.6%]; HR, 1.10; 95% CI, 0.96-1.27; MACE+, 578 [24.2%] vs 432 [22.9%]; HR, 1.07; 95% CI, 0.94-1.21) and vs DA (MACE, 38 [11.8%] vs 41 [14.0%]; HR, 0.81; 95% CI, 0.52-1.25; MACE+, 54 [16.7%] vs 43 [18.1%]; HR, 0.90; 95% CI, 0.61-1.32). Conclusion Roxadustat corrected Hb more effectively than placebo and comparably to DA in patients with anaemia and stage 3-5 NDD CKD. Cardiovascular safety was comparable between roxadustat and DA and placebo.

MO541HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH NON--DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylases under development to treat anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two phase 3, randomized trials (the PRO2TECT trials) in adult patients with non–dialysis-dependent (NDD) CKD and anemia, in which vadadustat met prespecified noninferiority criteria compared to darbepoetin alfa, with respect to hematologic efficacy (correction/maintenance of hemoglobin [Hb] target concentrations). Method The mean screening Hb level for the ESA-untreated NDD-CKD trial (NCT02648347) had to be &amp;lt;10.0 g/dL, and for the ESA-treated NDD-CKD trial (NCT02680574), the range had to be from 8.0-11.0 g/dL in the United States (US) and from 9.0-12.0 g/dL non-US. In the ESA-untreated trial, patients received no ESA within 8 weeks before randomization; in the ESA-treated trial, patients were maintained on ESA therapy, with ≥1 dose received within 6 weeks prior to or during screening. The vadadustat starting dose was 300 mg/day for all patients, whereas the initial darbepoetin alfa dose depended on each patient’s prior dose or the product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) both during the primary (PEP; weeks 24-36) and secondary (SEP; weeks 40-52) evaluation periods. Herein, we present topline results from the PEP and SEP endpoints, in addition to more detailed erythrocyte parameters. Results A total of 3,476 patients (1751 ESA-untreated and 1725 ESA-treated) were randomized 1:1 to vadadustat or darbepoetin alfa. In both trials, vadadustat was noninferior to darbepoetin alfa with regard to the difference of mean change in Hb concentrations between baseline and PEP, as well as between baseline and SEP. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 50.4% versus 50.2% and 43.1% versus 43.5% in the ESA-untreated trial and 60.1% versus 60.7% and 50.7% versus 49.0% in the ESA-treated trial. The proportion of patients (vadadustat vs darbepoetin alfa) who achieved an Hb increase &amp;gt;1.0 g/dL from baseline to week 52 was assessed only for the ESA-untreated trial and was 87.7% (95% CI: 85.4%, 89.8%) for vadadustat versus 88.0% (95% CI: 85.6%, 90.0%) for darbepoetin alfa. Hematologic parameters at time points within the PEP and SEP are presented in Table 1. In both the ESA-untreated and ESA-treated trials, the reticulocyte count trended up from baseline through week 52 for vadadustat and trended down from baseline for darbepoetin alfa. Trends in erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb were largely unremarkable by week 52 in both treatment groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of adults with anemia in CKD not on dialysis, whether ESA-untreated or ESA-treated at study entry.

MO539HEMATOLOGIC EFFICACY OF VADADUSTAT FOR ANEMIA IN PATIENTS WITH KIDNEY FAILURE ON DIALYSIS

Abstract Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase being developed for treatment of anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two of the four phase 3, randomized, open-label, sponsor-blind trials (the INNO2VATE trials) in adult patients with dialysis-dependent (DD) CKD and anemia, where vadadustat met prespecified noninferiority criteria compared with darbepoetin alfa with respect to cardiovascular safety and correction/maintenance of hemoglobin (Hb) target concentrations. Method The mean screening Hb range for the incident DD-CKD trial (NCT02865850) was 8.0-11.0 g/dL; for the prevalent DD-CKD trial (NCT02892149), it was 8.0-11.0 g/dL in the United States (US) and 9.0-12.0 g/dL for non-US. Patients in the incident and prevalent DD-CKD trials had initiated dialysis within &amp;lt;16 weeks with limited or no prior ESA exposure and &amp;gt;12 weeks with established ESA treatment prior to screening, respectively. Vadadustat starting dose was 300 mg/day for all patients, whereas initial darbepoetin alfa dose depended on each patient’s prior dose or product label. Both vadadustat and darbepoetin alfa doses were titrated according to prespecified dosing algorithms to achieve target Hb concentrations (US: 10-11 g/dL; non-US: 10-12 g/dL) during the primary evaluation period (PEP; weeks 24-36) and the secondary evaluation period (SEP; weeks 40-52). Herein, we present topline results from PEP and SEP endpoints, as well as other, more detailed hematologic erythrocyte parameters. Results A total of 3923 patients (369 with incident DD-CKD and 3554 with prevalent DD-CKD) were randomized 1:1 to vadadustat or darbepoetin alfa. Vadadustat was noninferior to darbepoetin alfa in achieving target-range Hb concentrations (primary efficacy endpoint) among patients who were new to, or established on, dialysis. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 43.6% versus 56.9% and 39.8% versus 41.0% in the incident trial and 49.2% versus 53.2% and 44.3% versus 50.9% in the prevalent dialysis trial. The proportion of patients who achieved an Hb increase &amp;gt;1.0 g/dL from baseline to week 52 was assessed only for the incident trial and was 84.0% (95% CI: 77.8%, 89.0%) for vadadustat versus 89.9% (95% CI: 84.7%, 93.8%) for darbepoetin alfa. Hematologic erythrocyte parameters at time points within the PEP and SEP are presented in Table 1. In the incident trial, reticulocyte count was slightly increased from baseline at 28 and 52 weeks for vadadustat, whereas for darbepoetin alfa, reticulocyte count was slightly decreased or unchanged in both trials. Erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb showed increases by week 52 for both groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of anemia associated with CKD in adults in both incident dialysis and prevalent dialysis settings.

MO559ASCEND-ND: STUDY DESIGN AND BASELINE CHARACTERISTICS

Abstract Background and Aims The Anemia Study in Chronic kidney disease (CKD): Erythropoiesis via a Novel prolyl hydroxylase inhibitor (PHI) Daprodustat-Non-Dialysis (ASCEND-ND; NCT02876835) trial is evaluating the efficacy and safety of daprodustat when compared with darbepoetin alfa in CKD patients with anaemia not requiring dialysis. We report the trial design as well as key baseline characteristics of participants. Method Eligible patients from 39 countries were adults with CKD stages 3–5 who were able to provide informed consent and demonstrated adherence to daprodustat placebo tablets and study procedures during the run-in period. Patients were eligible if (1) they were not using erythropoiesis stimulating agents (ESAs) and had a screening haemoglobin (Hb) 8 to 10 g/dL or if (2) they were receiving ESAs with screening Hb of 8 to 12 g/dL. Patients were required to be iron replete [transferrin saturation (TSAT) &amp;gt;20% and serum ferritin &amp;gt;100 ng/mL] at screening. Participants were randomised to daprodustat or darbepoetin alfa (1:1) in an open-label (sponsor-blind) trial design with blinded endpoint assessment. An IDMC conducts regular reviews of unblinded safety and efficacy data and makes recommendations for additions or adjustments. An external, independent and blinded Clinical Events Classification (CEC) group, led by the Duke Clinical Research Institute, in collaboration with George Clinical, adjudicate predefined events. During the study, both groups had randomised treatment adjusted using a protocol-defined algorithm targeting a Hb range of 10 to 11 g/dL. Participants also followed protocol-defined iron management criteria to ensure they remained iron replete. Additionally, an anaemia rescue algorithm was in place to minimise the risk of extended periods of inadequate Hb response and to ensure consistent application of rescue therapy across the study. The co-primary endpoints are mean change in Hb between baseline and Evaluation Period (EP; Weeks 28 to 52, inclusive) and time to first adjudicated major adverse cardiovascular event (MACE; composite of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke). The study has more than 99% power for the Hb non-inferiority (NI) test with an NI margin of -0.75 g/dL for the treatment difference of mean change in Hb between baseline and EP, and approximately 90% power to exclude the NI margin of 1.25 for time to first adjudicated MACE, for daprodustat compared with darbepoetin alfa. Conditional on both co-primary endpoints achieving NI at the one-sided 2.5% level, statistical testing will progress to evaluate MACE and the principal secondary endpoint of CKD progression for superiority. These tests will be multiplicity adjusted. Results A total of 3872 patients were randomised (median age 67 years, 56% female; 55% white, 28% Asian, and 10% black). The median baseline Hb was 9.8 g/dL, serum ferritin was 274 ng/mL, TSAT 30%, and eGFR 18 mL/min/1.73 m2. Among randomised patients, 54% were ESA non-users, 57% reported a history of diabetes mellitus and 36% a history of cardiovascular disease. Median blood pressure was 135/74 mmHg. Sixty percent of participants were taking angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, while 57% were taking lipid modifying agents at baseline. The trial is expected to complete during 2021. Conclusion ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not requiring dialysis.