Methoxy polyethylene glycol-epoetin beta 250micrograms/0.3ml solution for injection pre-filled syringes

Background. Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly. Methods. Haemodialysis patients (n = 490) on stable once-weekly intravenous darbepoetin alfa were randomized to methoxy polyethylene glycol-epoetin beta once monthly or darbepoetin alfa every 2 weeks for 26 weeks, with dose adjustment for individual haemoglobin target (11–13 g/dL; maximum decrease from baseline 1 g/dL). Subsequently, patients entered a second 26-week period of once-monthly methoxy polyethylene glycol-epoetin beta and darbepoetin alfa. The primary endpoint was the proportion of patients who maintained average haemoglobin ≥10.5 g/dL, with a decrease from baseline ≤1 g/dL, in Weeks 50–53; the secondary endpoint was dose change over time. The trial is registered at www.ClinicalTrials.gov, number NCT00394953. Results. Baseline characteristics were similar between groups. One hundred and fifty-seven of 245 patients treated with methoxy polyethylene glycol-epoetin beta and 99 of 245 patients with darbepoetin alfa met the response definition (64.1% and 40.4%; P < 0.0001). Doses increased by 6.8% with methoxy polyethylene glycol-epoetin beta and 58.8% with darbepoetin alfa during once-monthly treatment. Death rates were equal between treatments (5.7%). Most common adverse events included hypertension, procedural hypotension, nasopharyngitis and muscle spasms, with no differences between groups. Conclusions. Methoxy polyethylene glycol-epoetin beta maintained target haemoglobin more successfully than darbepoetin alfa at once-monthly dosing intervals despite dose increases with darbepoetin alfa.

Abstract licence: CC BY-NC 2.5

BackgroundAnemia is a common complication in patients with chronic kidney disease (CKD), for which recombinant human erythropoietin (rhEPO) is the standard treatment. UB-851 is a biosimilar rhEPO developed as an alternative to epoetin alfa (Eprex ® ). This study evaluated the clinical equivalence, safety, and immunogenicity of UB-851 compared with epoetin alfa in patients with anemia due to CKD receiving hemodialysis.MethodsIn this 52-week, multicenter, randomized, parallel-group, phase III trial, patients with anemic CKD undergoing maintenance hemodialysis were assigned to receive either UB-851 or epoetin alfa. Part I (weeks 1-24) included dose titration and hemoglobin (Hb) maintenance. Part II (weeks 25-52) focused on long-term safety and immunogenicity. The primary endpoint was the change in Hb levels from baseline to the efficacy evaluation period (weeks 21-24). The secondary endpoints included epoetin dose, adverse events (AEs), and anti-drug antibody formation.ResultsA total of 201 participants were randomized, and the mean change in Hb levels during the efficacy period was within the predefined equivalence margin (±0.6 g/dL) in both the intention-to-treat and per-protocol populations. Differences in weekly epoetin dose changes between the groups also fell within the predefined equivalence range (±45 IU/kg/wk). No significant differences were observed in the laboratory parameters, electrocardiograms, or vital signs. No anti-epoetin antibodies were detected in the UB-851 group. Regarding AEs, the UB-851 appears to be biosimilar to epoetin alfa.ConclusionUB-851 demonstrated clinical equivalence with epoetin alfa in maintaining Hb levels in patients with anemic CKD undergoing hemodialysis. The safety and immunogenicity profiles were comparable, supporting UB-851 as a biosimilar to epoetin alfa.

Abstract licence: CC BY-NC-ND

The covalent attachment of polyethylene glycol (PEG) to therapeutic agents, termed PEGylation, is a well-established and clinically proven drug delivery approach to improve the pharmacokinetics and pharmacodynamics of drugs. Specifically, PEGylation can improve the parent drug's solubility, extend its circulation time, and reduce its immunogenicity, with minimal undesirable properties. PEGylation technology has been applied to various therapeutic modalities including small molecules, aptamers, peptides, and proteins, leading to over 30 PEGylated drugs currently used in the clinic and many investigational PEGylated agents under clinical trials. Here, we summarize the diverse types of PEGylation strategies, the key advantages of PEGylated therapeutics over their parent drugs, and the broad applications and impacts of PEGylation in clinical settings. A particular focus has been given to the size, topology, and functionalities of PEG molecules utilized in clinically used PEGylated drugs, as well as those under clinical trials. An additional section has been dedicated to analyzing some representative PEGylated drugs that were discontinued at different stages of clinical studies. Finally, we critically discuss the current challenges faced in the development and clinical translation of PEGylated agents.

Abstract licence: CC BY

BackgroundThe monthly continuous erythropoietin receptor activator (CERA) utilization maintains stable hemoglobin (Hb) after conversion from weekly epoetin-β (EB); however, how the different pharmacologic properties affect the red blood cell (RBC) size determined by RBC distribution width (RDW) has not been evaluated yet. We assess the potential differences in iron metabolism, plasma erythropoietin (EPO), hepcidin, and soluble α-Klotho (α-Klotho) levels as an emergent hematopoiesis factor.MethodsThirty-seven chronic hemodialysis patients were included from January 2010 to November 2011 and randomized (1:1) to continue with EB or to convert to monthly CERA. Primary outcome was the mean change in Hb between groups at months 0, 3 and 6, and the percentage of patients who maintained stable Hb (Hb ± 1 g/dL from baseline level to month 6). Secondary outcomes were the influence on the erythropoietic process and iron metabolism markers. Thirty-one patients completed the study (CERA: n = 15, EB: n = 16).ResultsThe mean (95% confidence interval (CI)) Hb difference between groups was 0.28 g/dL (-0.36 to 0.93). There was no difference between the percentages of patients with stable Hb levels. In the CERA group RDW values increased progressively (interaction erythropoietin-stimulating agent (ESA) type and time on RDW values, F (1.57, 45.60) = 17.17, P 2 = 0.37) and the mean corpuscular volume changed at the different time points, (F (2, 28) = 29.12, P = 0.03, partial η2 = 0.23). During the evaluation period, in the CERA group, EPO was higher, and hepcidin and ferritin decreased significantly. α-Klotho decreased in both groups and correlated negatively with the changes on the RDW and positively with transferrin and serum iron. The number of serious adverse events was higher at the CERA group.ConclusionsMonthly CERA maintained Hb concentrations; however, it showed a significant effect on RDW, probably due to its impact on the EPO and hepcidin levels. α-Klotho decreased significantly in both groups, and its changes correlated with the changes in iron metabolism. Whether the RDW evolution was associated with the serious adverse events (SAEs) is a feasible hypothesis that needs to be confirmed in large studies.

Abstract licence: CC BY-NC