Differences in efficacy found in animals between recombinant forms of erythropoietin will not necessarily translate into differences in humans

doi:10.1038/sj.bjc.6600503 www.bjcancer.co

Development of an erythropoietin prescription simulator to improve abilities for the prescription of erythropoietin stimulating agents: Is it feasible?

BACKGROUND: The increasing use of erythropoietins with long half-lives and the tendency to lengthen the administration interval to monthly injections call for raising awareness on the pharmacokinetics and risks of new erythropoietin stimulating agents (ESA). Their pharmacodynamic complexity and individual variability limit the possibility of attaining comprehensive clinical experience. In order to help physicians acquiring prescription abilities, we have built a prescription computer model to be used both as a simulator and education tool. METHODS: The pharmacokinetic computer model was developed using Visual Basic on Excel and tested with 3 different ESA half-lives (24, 48 and 138 hours) and 2 administration intervals (weekly vs. monthly). Two groups of 25 nephrologists were exposed to the six randomised combinations of half-life and administration interval. They were asked to achieve and maintain, as precisely as possible, the haemoglobin target of 11-12 g/dL in a simulated naïve patient. Each simulation was repeated twice, with or without randomly generated bleeding episodes. RESULTS: The simulation using an ESA with a half-life of 138 hours, administered monthly, compared to the other combinations of half-lives and administration intervals, showed an overshooting tendency (percentages of Hb values > 13 g/dL 15.8 ± 18.3 vs. 6.9 ± 12.2; P < 0.01), which was quickly corrected with experience. The prescription ability appeared to be optimal with a 24 hour half-life and weekly administration (ability score indexing values in the target 1.52 ± 0.70 vs. 1.24 ± 0.37; P < 0.05). The monthly prescription interval, as suggested in the literature, was accompanied by less therapeutic adjustments (4.9 ± 2.2 vs. 8.2 ± 4.9; P < 0.001); a direct correlation between haemoglobin variability and number of therapy modifications was found (P < 0.01). CONCLUSIONS: Computer-based simulations can be a useful tool for improving ESA prescription abilities among nephrologists by raising awareness about the pharmacokinetic characteristics of the various ESAs and recognizing the factors that influence haemoglobin variability

Phase II study of two dose schedules of C.E.R.A. (Continuous Erythropoietin Receptor Activator) in anemic patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy

BACKGROUND: C.E.R.A. (Continuous Erythropoietin Receptor Activator) is an innovative agent with unique erythropoietin receptor activity and prolonged half-life. This study evaluated C.E.R.A. once weekly (QW) or once every 3 weeks (Q3W) in patients with anemia and advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. METHODS: In this Phase II, randomized, open-label, multicenter, dose-finding study, patients (n = 218) with Stage IIIB or IV NSCLC and hemoglobin (Hb) ≤ 11 g/dL were randomized to one of six treatment groups of C.E.R.A. administered subcutaneously for 12 weeks: 0.7, 1.4, or 2.1 μg/kg QW or 2.1, 4.2, or 6.3 μg/kg Q3W. Primary endpoint was average Hb level between baseline and end of initial treatment (defined as last Hb measurement before dose reduction or transfusion, or the value at week 13). Hematopoietic response (Hb increase ≥ 2 g/dL or achievement of Hb ≥ 12 g/dL with no blood transfusion in the previous 28 days determined in two consecutive measurements within a 10-day interval) was also measured. RESULTS: Dose-dependent Hb increases were observed, although the magnitude of increase was moderate. Hematopoietic response rate was also dose dependent, achieved by 51% and 62% of patients in the 4.2 and 6.3 μg/kg Q3W groups, and 63% of the 2.1 μg/kg QW group. In the Q3W group, the proportion of early responders (defined as ≥ 1 g/dL increase in Hb from baseline during the first 22 days) increased with increasing C.E.R.A. dose, reaching 41% with the highest dose. In the 6.3 μg/kg Q3W group, 15% of patients received blood transfusion. There was an inclination for higher mean Hb increases and lower transfusion use in the Q3W groups than in the QW groups. C.E.R.A. was generally well tolerated. CONCLUSION: C.E.R.A. administered QW or Q3W showed clinical activity and safety in patients with NSCLC. There were dose-dependent increases in Hb responses. C.E.R.A. appeared to be more effective when the same dose over time was given Q3W than QW, with a suggestion that C.E.R.A. 6.3 μg/kg Q3W provided best efficacy in this study. However, further dose-finding studies using higher doses are required to determine the optimal C.E.R.A. dose regimen in cancer patients receiving chemotherapy

Darbepoetin alfa is more potent in vivo and can be administered less frequently than rHuEPO

doi:10.1038/sj.bjc.6600506 www.bjcancer.co

Potent and selective chemical probe of hypoxic signaling downstream of HIF-α hydroxylation via VHL inhibition

Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling

Long-term pulse wave velocity outcomes with aerobic and resistance training in kidney transplant recipients – A pilot randomised controlled trial

Supporting information: S1 Fig. study protocol.(available at https://doi.org/10.1371/journal.pone.0171063.s001 (DOCM)); S1 Table. supplementary raw data (available at: https://doi.org/10.1371/journal.pone.0171063.s002 (XLSX)); S2 Fig. Consort checklist (available at: https://doi.org/10.1371/journal.pone.0171063.s003 (DOC)).Copyright: © 2017 O’Connor et al. Background This pilot study examined long-term pulse wave velocity (PWV) and peak oxygen uptake (VO2peak) outcomes following a 12-week moderate-intensity aerobic or resistance training programme in kidney transplant recipients. Method Single-blind, bi-centre randomised controlled parallel trial. 42 out of 60 participants completed a 9-month follow-up assessment (Aerobic training = 12, Resistance training = 10 and usual care = 20). Participants completed 12 weeks of twice-weekly supervised aerobic or resistance training. Following the 12-week exercise intervention, participants were transitioned to self-managed community exercise activity using motivational interviewing techniques. Usual care participants received usual encouragement for physical activity during routine clinical appointments in the transplant clinic. PWV, VO2peak, blood pressure and body weight were assessed at 12 weeks and 12 months, and compared to baseline. Results ANCOVA analysis, covarying for baseline values, age, and length of time on dialysis pre-transplantation, revealed a significant mean between-group difference in PWV of -1.30 m/sec (95%CI -2.44 to -0.17, p = 0.03) between resistance training and usual care groups. When comparing the aerobic training and usual care groups at 9-month follow-up, there was a mean difference of -1.05 m/sec (95%CI -2.11 to 0.017, p = 0.05). A significant mean between-group difference in relative VO2peak values of 2.2 ml/kg/min (95% CI 0.37 to 4.03, p = 0.02) when comparing aerobic training with usual care was revealed. There was no significant between group differences in body weight or blood pressure. There were no significant adverse effects associated with the interventions. Conclusions Significant between-group differences in 9-month follow-up PWV existed when comparing resistance exercise intervention with usual care. A long-term between-group difference in VO2peak was only evident when comparing aerobic intervention with usual care. This pilot study, with a small sample size, did not aim to elucidate mechanistic mediators related to the exercise interventions. It is however suggested that a motivational interviewing approach, combined with appropriate transition to community training programmes, could maintain the improvements gained from the 12-week exercise interventions and further research in this area is therefore warranted. Trial registration study number: ISRCTN43892586.National Institute for Health Research (NIHR). The study was hosted in the KCH NIHR Clinical Research Facility. This paper presents independent research funded by the NIHR

Natural Form of Noncytolytic Flexible Human Fc as a Long-Acting Carrier of Agonistic Ligand, Erythropoietin

Human IgG1 Fc has been widely used as a bioconjugate, but exhibits shortcomings, such as antibody- and complement-mediated cytotoxicity as well as decreased bioactivity, when applied to agonistic proteins. Here, we constructed a nonimmunogenic, noncytolytic and flexible hybrid Fc (hyFc) consisting of IgD and IgG4, and tested its function using erythropoietin (EPO) conjugate, EPO-hyFc. Despite low amino acid homology (20.5%) between IgD Fc and IgG4 Fc, EPO-hyFc retained “Y-shaped” structure and repeated intravenous administrations of EPO-hyFc into monkeys did not generate EPO-hyFc-specific antibody responses. Furthermore, EPO-hyFc could not bind to FcγR I and C1q in contrast to EPO-IgG1 Fc. In addition, EPO-hyFc exhibited better in vitro bioactivity and in vivo bioactivity in rats than EPO-IgG1 Fc, presumably due to the high flexibility of IgD. Moreover, the mean serum half-life of EPO-hyFc(H), a high sialic acid content form of EPO-hyFc, was approximately 2-fold longer than that of the heavily glycosylated EPO, darbepoetin alfa, in rats. More importantly, subcutaneous injection of EPO-hyFc(H) not only induced a significantly greater elevation of serum hemoglobin levels than darbepoetin alfa in both normal rats and cisplatin-induced anemic rats, but also displayed a delayed time to maximal serum level and twice final area-under-the-curve (AUClast). Taken together, hyFc might be a more attractive Fc conjugate for agonistic proteins/peptides than IgG1 Fc due to its capability to elongate their half-lives without inducing host effector functions and hindering bioactivity of fused molecules. Additionally, a head-to-head comparison demonstrated that hyFc-fusion strategy more effectively improved the in vivo bioactivity of EPO than the hyperglycosylation approach

Heart Failure Hospitalization in Adults Receiving Hemodialysis and the Effect of Intravenous Iron Therapy

OBJECTIVES: This study sought to examine the effect of intravenous iron on heart failure events in hemodialysis patients. BACKGROUND: Heart failure is a common and deadly complication in patients receiving hemodialysis and is difficult to diagnose and treat. METHODS: The study analyzed heart failure events in the PIVOTAL (Proactive IV Iron Therapy in Hemodialysis Patients) trial, which compared intravenous iron administered proactively in a high-dose regimen with a low-dose regimen administered reactively. Heart failure hospitalization was an adjudicated outcome, a component of the primary composite outcome, and a prespecified secondary endpoint in the trial. RESULTS: Overall, 2,141 participants were followed for a median of 2.1 years. A first fatal or nonfatal heart failure event occurred in 51 (4.7%) of 1,093 patients in the high-dose iron group and in 70 (6.7%) of 1,048 patients in the low-dose group (HR: 0.66; 95% CI: 0.46-0.94; P = 0.023). There was a total of 63 heart failure events (including first and recurrent events) in the high-dose iron group and 98 in the low-dose group, giving a rate ratio of 0.59 (95% CI: 0.40-0.87; P = 0.0084). Most patients presented with pulmonary edema and were mainly treated by mechanical removal of fluid. History of heart failure and diabetes were independent predictors of a heart failure event. CONCLUSIONS: Compared with a lower-dose regimen, high-dose intravenous iron decreased the occurrence of first and recurrent heart failure events in patients undergoing hemodialysis, with large relative and absolute risk reductions. (UK Multicentre Open-label Randomised Controlled Trial Of IV Iron Therapy In Incident Haemodialysis Patients; 2013-002267-25)