RESUMO
INTRODUCTION: Hyporesponsiveness to recombinant human erythropoietin (rhEPO) is a major problem affecting some patients with chronic kidney disease (CKD), predominantly those on hemodialysis (HD). Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase inhibitor that is being investigated as a treatment for anemia of CKD. METHODS: This phase 2a, exploratory, multicenter, single-arm study assessed the ability of daprodustat to increase or maintain hemoglobin concentrations within the target range (10.0-11.5 g/dl) over 16 weeks in subjects with anemia who were on HD and who had a high erythropoietin resistance index (ERI). All included subjects met the criteria for chronic rhEPO hyporesponsiveness (i.e., an ERI based on a series of contiguous strata of patients' hemoglobin-by-epoetin alfa for a minimum of 12 weeks). Eligible adults were on a stable HD regimen 3 to 4 times per week. Markers of iron utilization and safety were also assessed. All subjects initially received oral daprodustat 12 mg once daily. RESULTS: Of the 60 participants screened, 15 were enrolled, and 7 (47%) completed 16 weeks of treatment. At week 16, 2 of 7 subjects (29%) had >1 g/dl increases in hemoglobin from baseline. Daprodustat had minimal effects on markers of iron metabolism and utilization. Fourteen subjects (93%) experienced ≥1 adverse event (AE). The most common AEs included nausea, pneumonia, pleural effusion, and urinary tract infection. The majority of on-therapy AEs were mild or moderate in intensity. CONCLUSION: Daprodustat increased hemoglobin concentrations within the target range in 29% of chronic rhEPO-hyporesponsive subjects. No new safety concerns were identified in this short exploratory study.
RESUMO
Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar D-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer's disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and D-serine increases following administration of low oral doses.