Methoxy Polyethylene Glycol-epoetin Beta Research Articles

#1171 Effect of methoxy polyethylene glycol-epoetin beta on delaying dialysis in anemic patients with Stage 4-5 chronic kidney disease

Abstract Background and Aims The optimal hemoglobin (Hb) target for treating anemia in pre-dialysis chronic kidney disease (CKD) remains controversial. This study investigates the efficacy and safety of methoxy polyethylene glycol-epoetin beta, in delaying the initiation of kidney replacement therapy (KRT), all-cause mortality, CKD progression, and quality of life in stage 4-5 CKD patients. It compares outcomes between patients targeting an Hb level of 10.5-11.5 g/dL versus 8.5-9.5 g/dL. Method This was a single-center, open-label, parallel-group randomized controlled trial. Patients with estimated glomerular filtration rates (eGFR) of 8-15 ml/min/1.73 m2, who had not yet started dialysis, were randomized into two groups based on different Hb targets (Group A: 10.5-11.5 g/dL, Group B: 8.5-9.5 g/dL). Methoxy polyethylene glycol-epoetin beta (MIRCERA®) was prescribed by a pre-specified protocol to achieve these Hb targets. Iron supplements were administered to maintain transferrin saturation >20% or serum ferritin >200 ng/ml. Primary outcomes included a composite of all-cause death and KRT initiation, with secondary outcomes encompassing eGFR slope, hospitalization incidence, blood transfusion necessity, and quality of life measured by the 36-Item Short Form Health Survey (SF-36). Results A total of 62 participants were randomized. The mean age was 64.0 years (SD ±16.0), with 51.6% being female. The mean estimated Glomerular Filtration Rate (eGFR) at enrollment was 12.1 ml/min/1.73 m2 (SD ±3.1). Group A had a significantly higher time-averaged Hemoglobin (Hb) level (10.5 g/dL, SD ±1.2) compared to 8.5 g/dL (SD ±0.9) in the control group (p < 0.001). There was no significant difference in the composite endpoint of all-cause death and Kidney Replacement Therapy (KRT) initiation between the two groups (Hazard Ratio [HR] 0.69; 95% Confidence Interval [CI] 0.32-1.50; p = 0.35, as shown in the Figure). The eGFR slope was similar in both groups (−2.54 vs. −2.53 ml/min/1.73 m2 per year, p = 0.9). Time-averaged ferritin, transferrin saturation, blood pressure, and dietary sodium/protein intake showed no significant differences. Participants in the lower Hb target group required more blood transfusions (11 vs 1 unit, Incidence Rate Ratio [IRR] = 0.075, 95% CI 0.002-0.517, p = 0.001). Rates of hospital admissions, and changes in SF-36 quality of life domains were comparable between the groups, as detailed in the Table. Conclusion The study indicates that using methoxy polyethylene glycol-epoetin beta to maintain a higher Hb target in anemic patients with stage 4-5 CKD does not significantly alter the rate of all-cause mortality, the initiation of KRT, and rate of eGFR decline compared to a lower Hb target. However, a higher Hb target may reduce the need for blood transfusions without adversely affecting the progression of CKD, hospitalization rates, or quality of life. These findings suggest that while higher Hb targets may not dramatically alter key clinical outcomes, they could offer benefits in reducing transfusion requirements, thus providing a more nuanced approach to managing anemia in late-stage CKD.

Continuous Erythropoietin Receptor Activator for the Treatment of Chronic Dialysis Patients with Renal Anemia in Daily Clinical Practice in Poland: A Non-Interventional, Multi-Center, Pragmatic NAVIGO Trial

Background: Renal anemia is one of the most common complications of chronic kidney disease (CKD). This real-life study assessed the effectiveness of methoxy polyethylene glycol-epoetin beta, a continuous erythropoietin receptor activator (C.E.R.A.), for the treatment of CKD-associated anemia in patients receiving dialysis in daily clinical practice. Methods: 247 patients receiving chronic intermitted dialysis in 26 centers in Poland with CKD-associated symptomatic anemia, ESA-naïve, and with balanced iron stores in the investigators’ opinion were enrolled this real-life study. Over 12 months, the following data were collected: hemoglobin (Hb) concentration and dosage, route of administration and dosing scheme of C.E.R.A., dialysis adequacy, adverse events, iron therapy, and blood transfusions. Results: During the treatment, a Hb concentration of ≥10 g/dL was noted in 90.9% of hemodialysis patients (n = 224) and 96.0% of peritoneal dialysis patients (n = 23). At baseline, 7.8% of patients had a Hb concentration of 10–12 g/dL, which increased to 63.3% after 12 months. The median time when Hb concentration was maintained within 10–12 g/dL was 115.2 (interquartile range 49.1–188.7) days. A Hb concentration ≥12 g/dL was observed after 7 months of treatment in a maximum of 24.1% of hemodialysis patients, and 31.8% of peritoneal dialysis patients. The median time elapsed between the start of treatment and the first Hb concentration >10 g/dL was 42.0 (21.0–78.2) days. C.E.R.A. was well tolerated. Conclusions: C.E.R.A. corrects CKD-associated anemia in dialysis patients, and maintains Hb levels within the recommended target range. The study also confirmed the acceptable safety profile of the drug.

Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis.

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events.This is an update of a Cochrane review first published in 2014. To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD. In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion. Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence)andepoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects onpreventing blood transfusion compared to placebo.The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain forepoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence),methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence),a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) anda biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) comparedto placebo. There was probably no difference between darbepoetin alfa andplacebo on the odds of death (any cause)(OR 0.99, 95% CI 0.81 to 1.21; moderatecertainty evidence). The comparative effects of ESAs compared with another ESAon death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderatecertainty evidence). Compared to placebo,epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa(OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin(OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence)and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension.The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data. AUTHORS' CONCLUSIONS: The comparative effects of different ESAson blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessnesswere uncertain.

The resistance to methoxy polyethylene glycol-epoetin beta in anemic patients of end-stage renal disease

BackgroundChronic kidney disease (CKD) is a global disease, and the number of people affected is increasing due to driving factors such as diabetes, obesity, and hypertension, as well as increased life expectancy. Many patients with CKD suffer anemia throughout the period of their disease. AimThis research aimed to investigate the relation between resistance to the methoxy polyethylene glycol-epoetin beta (ME-β) and angiotensin-converting enzyme (ACE) gene polymorphism. MethodsSeventy Iraqi patients with CKD on hemodialysis treatment for at least six months and receiving a subcutaneous injection of ME-β were selected to enroll in this current study. In addition to these patients, the control group of 20 healthy subjects. Baseline samples (Three blood samples) were obtained and withdrawn from each participant, then 3 and 6 months following the starting sample. In addition, a unique blood sample was taken from each participant in the control group in the early morning hours following 8 h of fasting and before dialysis (for the patients' group). ResultsACE polymorphism did not demonstrate a significant (p ˃ 0.05) relation with changing the dose of ME-β. Furthermore, there was a negative relationship between ME-β dose and hemoglobin (Hb) in CKD patients. Comparing ACE polymorphism between good and hypo-response groups shows no significant effect (p ˃ 0.05) on ME-β therapy. Moreover, the erythropoietin resistance index (ERI) was significantly (p < 0.001) lower in good responders to ME-β therapy compared to the hypo-response group. Finally, comparing the ERI of the patient, the good response group to the hypo-response group showed no significant association (p ˃ 0.05) with ACE gene polymorphism in response to ME-β therapy. ConclusionNo relation was determined between the polymorphism ACE gene and the resistance to the ME-β administration in CKD Iraqi patients.

P8.155: Current Trends in Anemia Treatment in Kidney Transplant Recipients

Background and Aims: The topic of management of chronic kidney disease (CKD) anemia has constantly been improving. This study aimed to assess the prevalence and current trends in anemia treatment in real-world kidney transplant recipients (KTR). Methods: This cross-section study included 509 KTR patients, mean age – of 53 years, 51.5% male, with functioning grafts in the late post-transplant period in the last quarter of 2021, in an average of 9,4 years post-transplantation. Data were analyzed using SPSS Statistics 27.0. Student’s t-test, Chi-squared test, Pearson correlation tests were used. According to the Kidney Disease: Improving Global Outcomes (KDIGO) definition, anemia was determined as a hemoglobin (Hb) level of <120 g/L for women and <130 g/L for men. CKD stage was determined by the estimated glomerular filtration rate (eGFR) calculated using creatinine in the CKD-EPI equation. Results: The prevalence of anemia in the KTR population was 35% (n=178), increasing from 13% to 96% by progressing CKD from stage 1 to 5 in a transplant (Table 1: The prevalence of anemia depends on the stage of CKD in a transplant.).A moderately strong Pearson correlation was recognized between the stage of CKD and anemia (r=0.441; p<0.001). A statistically significant association (p<0.001) was detected between anemia and the female gender (n=107; 60% of all anemic patients). We found no significant association between anemia and the use of mycophenolate or calcineurin inhibitors. Still, there was a statistically significant association between steroid use and anemia (p=0.041), with a 31% (Odds Ratio = 0.69) less chance of anemia in a group that received steroid therapy. 90% of anemic patients had normochromic, normocytic anemia, 7,8% hypochromic, microcytic, and 2,2% hyperchromic, macrocytic anemia. The treatment involved iron replacement in 29% (n=51) of patients, of whom 92.2% had oral medication and 7.8% intravenous. 54% (n=96) of anemic KTR received treatment with erythropoiesis-stimulating agents (ESAs): 27,1% with darbepoetin alfa and 72,9% with methoxy polyethylene glycol-epoetin beta. Anemia was corrected up to Hb level >110 g/L in 69.7% (n=67) of ESAs receiving KTR. A statistically significant correlation was not detected between the ESAs dosage (µg/kg) and the correction of the anemia (p=0.217). Conclusion: Like in the general CKD population, the prevalence of anemia in KTR increases as CKD progress in a transplant. The extent of anemia correction seems insufficient, although it includes both major components: iron replacement and ESAs. We found anemia more prevalent in female patients and those not receiving steroids in the immunosuppressive regimen. This last unexpected finding needs further exploration. Darja Golubeva for data collection. Ieva Evelina Stolcere for data collection. Liana Linda Lice for data collection.

FC037: A Study to Ascertain the Optimum Starting Dose of Subcutaneous (SC) C.E.R.A. for Maintenance Treatment of Anemia in Pediatric Patients with Chronic Kidney Disease (CKD) on Dialysis or not yet on Dialysis

Abstract BACKGROUND AND AIMS The Phase II study DOLPHIN (NH19707; NCT00717366) demonstrated that pediatric patients with chronic kidney disease (CKD) on hemodialysis can be safely and effectively switched from maintenance treatment with epoetin alfa/beta or darbepoetin alfa to intravenous continuous erythropoietin receptor activator (C.E.R.A.)—methoxy polyethylene glycol-epoetin beta, using defined conversion factors [1]. This study (NH19708; NCT03552393; SKIPPER) was conducted to ascertain the optimum starting dose of C.E.R.A. administered subcutaneously for maintenance treatment of anemia in pediatric patients with CKD on dialysis, or those not yet on dialysis, using the same conversion factors. Methods This Phase II, open-label, single-arm, multicentre study included a 3-week screening period, 16-week dose-titration period, 4-week evaluation period and 24-week optional safety extension (for patients who completed the 20 weeks of treatment with hemoglobin [Hb] within ± 1 g/dL of their baseline Hb and within the target range of 10–12 g/dL). Patients aged 3 months to 17 years with stable chronic renal anemia and a baseline Hb concentration of 10.0–12.0 g/dL were switched from epoetin alfa/beta or darbepoetin to subcutaneous (SC) C.E.R.A. every 4 weeks using the previously determined conversion factors. The primary endpoint was change in Hb concentration (g/dL) between baseline and the evaluation period. Secondary endpoints included the number of patients with a mean Hb concentration within a target range of 10.0–12.0 g/dL and/or ± 1 g/dL of baseline during the evaluation period and change in C.E.R.A. SC dose over time. Safety/tolerability and the pharmacokinetics/pharmacodynamics profile of C.E.R.A. SC were also assessed. RESULTS Forty patients were enrolled, with 38 completing the core study period and 25 entering the safety extension period. Six patients withdrew from the study, mainly due to kidney transplantation (5/6; 83.3%). The mean age of patients was 10 years; 12 (30%) aged &amp;lt;5 years, 11 (27.5%) aged 5–11 years and 17 (42.5%) aged 12–17 years. Eighteen patients (45.0%) were on peritoneal dialysis, 5 (12.5%) were on hemodialysis and 17 (42.5%) were not on dialysis. The mean Hb level at baseline was 11.02 g/dL (range: 10.1–12.2 g/dL). Mean change in Hb between baseline and the evaluation period was 0.48 g/dL (standard deviation: 1.03; 90% confidence interval 0.20–0.76). Results were consistent based on sub-analyses by age groups (&amp;lt;5, 5–11, 12–17 years), dialysis status (no dialysis, hemodialysis or peritoneal dialysis) and previous type of erythropoiesis-stimulating agent treatment. Mean Hb concentration levels were maintained within 10–12 g/dL and within ± 1 g/dL of baseline throughout the entire core period and safety extension period. During the evaluation period, 24/38 patients (63.2%) maintained Hb within 10–12 g/dL, 19 (50%) maintained Hb within 1 g/dL of baseline and 18 (47.4%) fulfilled both criteria. The median ratio of C.E.R.A. dose between Week 1 (median dose of 75 μg) and Week 17 (50 μg) was 1.44, indicating a decrease relative to the initial dose. Safety results were consistent with the known safety profile for C.E.R.A. in adults and pediatric patients aged 6–17 years on hemodialysis and IV administration of C.E.R.A [1], with no unexpected safety signals detected. CONCLUSION In this study, the primary endpoint was met and provided evidence that pediatric patients with CKD on dialysis, or those not yet on dialysis, can be safely and effectively switched from previous treatment with epoetin alfa/beta or darbepoetin to C.E.R.A. SC every 4 weeks for maintenance treatment of anemia.

MO1041: C.E.R.A. (Continuous Erythropoietin Receptor Activator—Methoxy Polyethylene Glycol Epoetin Beta) In Paediatric Dialysis Patients with Anaemia of Chronic Kidney Disease: Real-World Evidence from the IPDN and IPHN Registries

Abstract BACKGROUND AND AIMS Continuous erythropoietin receptor activator—methoxy polyethylene glycol epoetin beta (C.E.R.A.) is a long-acting erythropoiesis-stimulating agent (ESA) approved for the treatment of anaemia associated with chronic kidney disease (CKD) in adults. In June 2018, the Food and Drug Administration approved the use of C.E.R.A. administered intravenously in patients on haemodialysis aged 5–&amp;lt;18 years switching from another ESA. This observational real-world study (MH40258) assessed the safety, dosing and haemoglobin (Hb) levels associated with C.E.R.A. in paediatric patients with CKD on dialysis. METHOD This was a non-interventional real-world study of patients from the International Paediatric Peritoneal Dialysis Network (IPPN) and the International Paediatric Hemodialysis Network (IPHN) registries. Demographics, clinical characteristics, dialysis information, treatment, laboratory parameters, number and causes of hospitalization events and deaths were reported in patients treated with C.E.R.A. from both registries (IPPN: 2007–2021; IPHN: 2013–2021). RESULTS Overall, 229 patients had at least one observation while being treated with C.E.R.A. and were analysed in this study; 177 on peritoneal dialysis (PD) (median age 10.6 years, interquartile range [IQR] 4.2–14.6) and 52 on haemodialysis (HD) (median age 14.1 years, IQR 10.4-16.2). The median observation time under C.E.R.A. exposure was 6 months (IQR 0–12.5) for PD patients and 12 months (0–18) for HD patients. 121 PD patients (68%) and 36 HD patients (69%) had ≥ 1 hospitalization, of whom 102/121 (84%) and 32/36 (89%), respectively, had non-elective hospitalizations. Median hospitalization surveillance time/patient was 13.5 months in the PD and 18.3 months in the HD cohorts. The most frequent causes for non-elective hospitalization were infections, reported as a cause in 56/177 (32%) patients in the PD cohort and 14/52 (27%) in the HD cohort and technique complications, in 41/177 (23%) patients in the PD cohort and 20/52 (38%) in the HD cohort. There were seven deaths (PD: 5 patients; HD: 2 patients), corresponding to an overall mortality rate of 19.8 cases per 1000 observation years. Causes of death were infections (n = 2), intracranial bleeding (n = 2), congestive heart failure (n = 2) and one case of sudden death at home. Hb levels remained stable over time with 47% of PD patients and 48% of HD patients having a Hb value within the range of 10–12 g/dL at their last observation. Mean [standard deviation (SD)] Hb levels at last observation were 10.9 (1.7) g/dL in the PD and 10.4 (1.7) g/dL in the HD cohort. The median monthly dose of C.E.R.A. at first visit was 100 (IQR 50–120) µg in the PD and 107 (80–129) µg in the HD cohort, while at last visit it was 100 (50–150) µg (PD) and 80 (54–129) µg (HD). While absolute C.E.R.A. dose increased with age, weight-related doses decreased substantially with age in both cohorts: in groups aged &amp;lt; 2, 2–&amp;lt;5, 5–&amp;lt;12 and 12–&amp;lt;18 years, respectively, the median monthly dose was 7.9, 5.4, 3.2 and 2.6 µg/kg at first observation and 5.1, 5.2, 3.0 and 3.0 µg/kg at last observation in the PD cohort. The age-related dosing differences were smaller when doses were normalized to body surface area (BSA) rather than body weight, with median doses at last visit of 114, 121, 87 and 98 µg/m2/month, respectively in the PD cohort. In the HD cohort, a similar pattern wasobserved regarding weight and BSA-based dosing, but overall C.E.R.A.dosing was generally lower over the course of the study in HD compared with PD patients. The median monthly C.E.R.A. dose at last observation was 3.5 (IQR 2.3– 5.1) µg/kg, or 95 (62–145) µg/m2 in the PD cohort and 2.1 (1.2–3.4) µg/kg, or 63 (40–98) µg/m2 in the HD cohort (Table). CONCLUSION Real-world data from the IPPN and IPHN registries indicated that C.E.R.A. treatment is associated with efficient maintenance of Hb levels in paediatric patients with CKD on dialysis. C.E.R.A. appeared to have a favourable safety profile; analysis of hospitalization rate and causes as well as patient mortality did not reveal any safety signals.

Impact of anti-PEG antibody affinity on accelerated blood clearance of pegylated epoetin beta in mice

Antibodies that bind polyethylene glycol (PEG) can be induced by pegylated biomolecules and also exist in a significant fraction of healthy individuals who have never received pegylated medicines. The binding affinity of antibodies against PEG (anti-PEG antibodies) likely varies depending on if they are induced or naturally occurring. Anti-PEG antibodies can accelerate the clearance of pegylated medicines from the circulation, resulting in loss of drug efficacy, but it is unknown how accelerated blood clearance is affected by anti-PEG antibody affinity. We identified a panel of anti-PEG IgG and IgM antibodies with binding avidities ranging over several orders of magnitude to methoxy polyethylene glycol-epoetin beta (PEG-EPO), which is used to treat patients suffering from anemia. Formation of in vitro immune complexes between PEG-EPO and anti-PEG IgG or IgM antibodies was more obvious as antibody affinity increased. Likewise, high affinity anti-PEG antibodies produced greater accelerated blood clearance of PEG-EPO as compared to low affinity antibodies. The molar ratio of anti-PEG antibody to PEG-EPO that accelerates drug clearance in mice correlates with antibody binding avidity. Our study indicates that the bioactivity of PEG-EPO may be reduced due to rapid clearance in patients with either high concentrations of low affinity or low concentrations of high affinity anti-PEG IgG and IgM antibodies.

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.

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.

Daprodustat Compared with Epoetin Beta Pegol for Anemia in Japanese Patients Not on Dialysis: A 52-Week Randomized Open-Label Phase 3 Trial

Background: Daprodustat is an oral agent that stimulates erythropoiesis by inhibiting the prolyl hydroxylases which mark hypoxia-inducible factor for degradation through hydroxylation. Its safety and efficacy (noninferiority) were assessed in this 52-week, open-label study. Methods: Japanese patients not on dialysis (ND) (N = 299) with anemia of CKD (stages G3, G4, and G5) with iron parameters of ferritin >100 ng/mL or transferrin saturation >20% at screening were randomized to daprodustat or epoetin beta pegol (continuous erythropoietin receptor activator [CERA], also known as methoxy polyethylene glycol-epoetin beta). After initiation of the study, the daprodustat starting dose for erythropoiesis-stimulating agent (ESA)-naïve participants was revised, and daprodustat was started at 2 or 4 mg once daily depending on baseline hemoglobin. ESA users switched to daprodustat 4 mg once daily. CERA was started at 25 μg every 2 weeks for ESA-naïve patients and 25–250 μg every 4 weeks for ESA users based on previous ESA dose. In both treatment groups, dose was adjusted every 4 weeks based on hemoglobin level and changed according to a prespecified algorithm. The primary endpoint was mean hemoglobin level during weeks 40–52 in the intention-to-treat (ITT) population. ESA-naïve patients who entered before the protocol amendment revising the daprodustat starting dose were excluded from the ITT population. Results: Mean hemoglobin levels during weeks 40–52 were 12.0 g/dL in the daprodustat group (n = 108; 95% confidence interval [CI], 11.8–12.1) and 11.9 g/dL for CERA (n = 109; 95% CI 11.7–12.0); the difference between the groups was 0.1 g/dL (95% CI −0.1 to 0.3 g/dL). The lower limit of the 95% CI of the difference was greater than the prespecified margin of −1.0 g/dL. The mean hemoglobin level was within the target range (11.0–13.0 g/dL) during weeks 40–52 for 92% of participants in both groups. There was no meaningful difference in the frequencies of adverse events. Conclusions: Oral daprodustat was noninferior to CERA in achieving and maintaining target hemoglobin levels in Japanese ND patients. Daprodustat was well tolerated, with no new safety concerns identified.

The efficiency and safety of methoxy polyethylene glycol-epoetin beta usage in patients with dialysis, who are transitioning from short-acting epoethins

INTRODUCTION . Methoxy polyethylene glycol-epoetin beta (PEG-EPO) is a representative of a third-generation erythropoiesis-stimulating agent with a continuous erythropoietin receptor activator (CERA). Although the effectiveness of methoxy polyethylene glycol-epoetin beta has been confirmed in multicenter randomized clinical trials, research continues to examine the safety and tolerability in patients with chronic renal anemia previously treated with recombinant human erythropoietins (rhEpo) of the first generation. AIMS . Evaluation of the efficacy and safety during the transition from rhEpo of first generation epoetin alpha (Epocrin, Aeprin, Eralfon) to third generation continuous activator erythropoietin receptor (CERA), methoxy polyethyleneglycol-epoetin beta (Mircera) administered intravenously every 4 weeks to maintain a stable hemoglobin (Hb) in patients with EPO-dependent anemia in programed hemodialysis (PhD). P ATIENTS AND METHODS . A retrospective study was conducted enrolling 116 patients with terminal stage renal failure. They all were undergoing the renal replacement therapy with programmed hemodialysis, and were all being transferred from rhEpo of the first generation (months from -12 to -1) to CERA (Mircera) (months from1 to 12). As rhEpo first generation drugs with epoetin alpha (Alpha-EPO) were used Epocrin, Aeprin, Eralfon. RESULTS . 1. The use of CERA allows one to maintain a stable level of hemoglobin, with smooth dynamics. In sharp contrast, the short-acting epoetins induce drastic fluctuations. 2. The dose modification in the CERA (Mircera) therapy was half as frequent, compared to the frequency of dose modification in the alpha-EPO therapy (1.4±0.15 and 2.1 ± 0.3 episodes/year, respectively). 3. Adverse events associated with the use of CERA (Mircera) were rare. An increase in blood pressure indicators was revealed in CERA (Mircera) therapy, compared with the use of alpha-EPO. CONCLUSION . The use of CERA (Mircera) allows for the effective and safe maintaince of stable hemoglobin level in patients receiving treatment with program hemodialysis.

Model-based approach for methoxy polyethylene glycol-epoetin beta drug development in paediatric patients with anaemia of chronic kidney disease.

Methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator, C.E.R.A.) is used for the treatment of anaemia in adults with chronic kidney disease (CKD). Patients treated with shorter-acting erythropoiesis-stimulating agents up to three times weekly can be switched to once-monthly C.E.R.A.. Doses can be adjusted on a monthly basis based on haemoglobin (Hb) levels during the preceding period. A model-based approach was applied to optimise C.E.R.A. development, more specifically the confirmatory trial of the paediatric plan. Pharmacokinetic and pharmacodynamic data from a phase II paediatric study and phase II and III adult studies were analysed together using modelling and simulation to determine the pharmacokinetic/pharmacodynamic characteristics of C.E.R.A. in a broad population. Model-based simulations of C.E.R.A. treatment outcomes in paediatric patients were performed, notably when administered subcutaneously and compared to clinical and real-world data. Age and body weight explained differences in pharmacokinetics, while the pharmacodynamic characteristics of C.E.R.A. were similar between adult and paediatric populations. Simulated Hb levels (mean and 95% prediction interval 10.9 [10.6, 11.2] g dL-1 ) and C.E.R.A. doses (median and 95% prediction interval 105 [72, 159] μg) 20 weeks after switching to subcutaneous C.E.R.A. were confirmed by observed real-world data from International Pediatric Dialysis Network registries (mean Hb was 10.8 g dL-1 and median C.E.R.A. dose was 100 μg). These analyses have facilitated optimisation of the C.E.R.A. development programme in paediatric patients with anaemia of CKD to provide this patient population with faster access to the drug while avoiding unnecessary clinical trial exposure and related monitoring burden in children.

Safety and Efficacy of Methoxy Polyethylene Glycol-epoetin Beta in Anemia Treatment in Patients on Hemodialysis: a Macedonian Experience.

Introduction:Anemia in patients with chronic kidney disease (CKD) is present in about 50% in pre-dialysis and over 90% of patients on hemodialysis. Erythropoiesis-stimulating agent (ESA) is a standard therapy for renal anemia, but management of anemia in CKD still remains a challenge from the treatment point of view.Aim:To evaluate safety and efficacy of methoxy polyethylene glycol-epoetin beta as continuous erythropoietin receptor activator (C.E.R.A.) in maintenance of haemoglobin (Hb) concentrations in patients with chronic renal anemia in the routine clinical practice.Methods:National, multicenter, observational, prospective study in patients with CKD on hemodialysis for maintenance of Hb levels with once-monthly therapy with C.E.R.A. In 8 dialysis centers 184 adult patients were observed and followed up every month during one year. Total number of enrolled patients was 185 from whom 184 patients were observed and 147 patients were followed for 12 months as 37 dropped out from the study earlier.Results:Overall mean dose of C.E.R.A. was 115.2 μg with average 4.99 dose modifications per patient. Among 184 patients observed, total number of 121 adverse events (AEs) were identified in 49 of the patients. The most of the AEs were of mild or moderate severity. A few serious AEs were assessed and reported as not related to the drug administration. Mean Hb levels during the study varied but were maintained stable in the range of 100-120 g/l.Conclusion:Safety and tolerability of C.E.R.A. was as expected as the frequency and type of AEs was similar to the known pattern from the studies done in other countries and relevant literature. Hb levels as the primary efficacy parameter of C.E.R.A. treatment were maintained stable within the target range during the study.

Both IgM and IgG Antibodies Against Polyethylene Glycol Can Alter the Biological Activity of Methoxy Polyethylene Glycol-Epoetin Beta in Mice.

Pre-existing antibodies that bind polyethylene glycol are present in about 40% of healthy individuals. It is currently unknown if pre-existing anti-polyethylene glycol (PEG) antibodies can alter the bioactivity of pegylated drugs with a single long PEG chain, which represents the majority of newly developed pegylated medicines. Methoxy polyethylene glycol-epoetin beta (PEG-EPO) contains a single 30 kDa PEG chain and is used to treat patients suffering from anemia. We find that the pre-existing human anti-PEG IgM and IgG antibodies from normal donors can bind to PEG-EPO. The prevalence and concentrations of anti-PEG IgM and IgG antibodies were also higher in patients that responded poorly to PEG-EPO. Monoclonal anti-PEG IgM and IgG antibodies at concentrations found in normal donors blocked the biological activity of PEG-EPO to stimulate the production of new erythrocytes in mice and accelerated the clearance of 125I-PEG-EPO, resulting in PEG-EPO accumulation primarily in the liver and spleen. Accelerated clearance by the anti-PEG IgG antibody was mediated by the Fc portion of the antibody. Importantly, infusing higher doses of PEG-EPO could compensate for the inhibitory effects of anti-PEG antibodies, suggesting that pre-existing anti-PEG antibodies can be “dosed through.” Our study indicates that the bioactivity and therapeutic activity of PEG-EPO may be reduced in patients with elevated levels of pre-existing anti-PEG antibodies. New pegylated medicines with a single long PEG chain may also be affected in patients with high levels of anti-PEG antibodies.

Toward confirmation of the safety and efficacy of methoxy polyethylene glycol-epoetin beta in anemia treatment in patients on hemodialysis: a Macedonian experience

Toward confirmation of the safety and efficacy of methoxy polyethylene glycol-epoetin beta in anemia treatment in patients on hemodialysis: a Macedonian experience

Cardiovascular Safety and All-Cause Mortality of Methoxy Polyethylene Glycol-Epoetin Beta and Other Erythropoiesis-Stimulating Agents in Anemia of CKD: A Randomized Noninferiority Trial.

Erythropoiesis-stimulating agents correct anemia of CKD but may increase cardiovascular risk. We compared cardiovascular outcomes and all-cause mortality associated with monthly methoxy polyethylene glycol-epoetin beta with those of the shorter-acting agents epoetin alfa/beta and darbepoetin alfa in patients with anemia of CKD. We conducted a multicenter, open-label, noninferiority trial in which patients were randomized to receive methoxy polyethylene glycol-epoetin beta or reference erythropoiesis-stimulating agents, stratified by maintenance or correction treatment status and C-reactive protein level. The trial had a prespecified noninferiority margin of 1.20 for the hazard ratio (HR) for the primary end point (a composite of all-cause mortality, nonfatal myocardial infarction or stroke, adjudicated by an independent blinded committee). This trial is registered with ClinicalTrials.gov, number NCT00773513. In total, 2818 patients underwent randomization, received methoxy polyethylene glycol-epoetin beta or a reference agent, and were followed for a median of 3.4 years (maximum, 8.4 years). In the modified intention-to-treat analysis, a primary end point event occurred in 640 (45.4%) patients in the methoxy polyethylene glycol-epoetin beta arm, and 644 (45.7%) in the reference arm (HR 1.03; 95% confidence interval [95% CI], 0.93 to 1.15, P=0.004 for noninferiority). All-cause mortality was not different between treatment groups (HR 1.06; 95% CI, 0.94 to 1.19). Results in patient subgroups on dialysis or treated in the correction or maintenance settings were comparable to the primary analysis. In patients with anemia of CKD, once-monthly methoxy polyethylene glycol-epoetin beta was noninferior to conventional, shorter-acting erythropoiesis-stimulating agents with respect to rates of major adverse cardiovascular events or all-cause mortality.

Time spent on erythropoietin stimulating agents administration in hemodialysis centers in Panama: a time and motion study

Objectives: There is a lack of data in Panama on the potential differences in total healthcare professional (HCP) time between routine administrations of short-acting erythropoietin simulating agents (ESAs) (i.e. epoetin alfa) and continuous erythropoietin receptor activator (CERA) (i.e. methoxy polyethylene glycol–epoetin beta). This study aimed to quantify the HCP time associated with a single administration of epoetin alfa and CERA for the treatment of anemic patients with chronic kidney disease (CKD) on hemodialysis. Methods: This was a multi-center, cross-sectional study, using a time-and-motion methodology. Costs related to HCP time and consumables usage associated with administration of epoetin alfa and CERA were estimated. Results: Based on 60 administrations of either CERA or epoetin alfa, the estimated savings in mean total active HCP time were 2.34 (95% confidence interval = 1.87–2.81) min (–30%) per administration. When extrapolating to a full year’s treatment with intravenous ESA, it would require a total of 20.3 (95% CI = 19.90–20.71) h of HCP time for epoetin alfa vs 1.1 (95% CI = 1.01–1.19) h for CERA per patient per year. Estimated savings in active HCP time per patient per year were 19.20 (95% CI = 19.20–19.21) h (–95%). This, in turn, translates into staff cost efficiency that favors Mircera with an estimated annual saving of $78.24 (95% CI = 78.24–78.28) (–95%) per patient. Conclusions: Data from a real-world setting showed that the adoption of CERA could potentially lead to a reduction in active HCP time. Highlights Few comparative data have explored the costs and potential savings of using long-acting erythropoietin–stimulating agents (ESA) instead of short-acting ESAs to treat anemia in CKD patients on hemodialysis. This time-and-motion study shows that use of CERA reduces total healthcare professional time and could represent a save for an institution in a real-world setting in Panama.

Role of erythropoietin and its receptor in the development of endometriosis in rats

Objective:Besides its hematopoietic function, erythropoietin (EPO) may protect tissues from degenerative disorders. As such, EPO and its receptors were revealed in nonhematopoietic cells, including stromal and endometrial epithelial cells. However, the role of EPO in endometrial disorders is still unknown. Here, we aimed to examine the role of EPO and its receptor activation in the development of endometriosis in rats.Material and Methods:Animals were treated with EPO, darbepoietin (the synthetic form of EPO) or EPO’s receptor activator, methoxy polyethylene glycol-epoetin beta (MIRCERA), after development of endometriosis. Endometriosis was induced by estrogen-administration following surgical attachment of endometrial surface on the inner abdominal wall. Treatments were started 3 weeks after induction of endometriosis and continued for the following 3 weeks. For the analysis of recurrence of endometriosis, additional analyses were conducted 3 weeks after cessation of treatments.Results:As compared with vehicle-treated animals, lesion size was reduced significantly and recurrence of endometriosis was not observed in all treatment groups. Histopathologic examination revealed that EPO and darbepoietin were more effective than MIRCERA- and vehicle-treated animals.Conclusion:Here we provide evidence that EPO is a promising candidate for the treatment of endometriosis. Our histopathologic results in particular indicate that EPO is more effective than its receptor activator MIRCERA in the development endometriosis.

Patterns of Erythropoiesis-Stimulating Agent Use in European Hemodialysis Patients: The Dialysis Outcomes and Practice Patterns Study

Background: Clinicians providing dialysis care have numerous erythropoiesis-stimulating agents (ESAs) available for treating anemia. We sought to provide a contemporary description of ESA types used in hemodialysis (HD) settings in nine European countries. Methods: Our study uses Dialysis Outcomes and Practice Patterns Study phase 5 (2012–2015) data from nine European countries (Belgium, France, ­Germany, Italy, Russia, Spain, Sweden, Turkey, and the United Kingdom). A total of 164 facilities and 3,281 patients contributed cross-sectional data. ESA types captured included short-acting epoetins (e.g., epoetin alfa, beta, etc., including biosimilars), darbepoetin alfa, and continuous erythropoietin receptor agonist (CERA; methoxy polyethylene glycol-epoetin beta). Results: We observed broad variability across countries in prescription of ESA types: prescription of epoetin alfa or epoetin beta ranged from 22% (France) to 78% (Russia), darbepoetin alfa prescription ranged from 13% (Russia) to 53% (UK), and CERA prescription ranged from <3% (Sweden) to 26% (France). Prescription of different ESA types varied substantially within some European countries from 2012–2015 but not across all countries in aggregate. Number of ESA types prescribed by a facility varied from 1, 2, 3, or 4 different ESA types in 32, 40, 21, and 8% of facilities, respectively. No differences were seen in the unadjusted distributions of achieved hemoglobin values by ESA type. Conclusion: A variety of short- and long-acting ESAs are commonly used in European HD facilities to maintain hemoglobin at remarkably similar levels with each ESA type. The availability of numerous ESA options for managing anemia has allowed European providers to optimize anemia management according to the particular circumstances of each patient.