RESUMO
BACKGROUND: Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD. METHODS: A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability. RESULTS: Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo-treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration. CONCLUSIONS: Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis-dependent and dialysis-dependent patients.
Assuntos
Anemia/tratamento farmacológico , Glicina/análogos & derivados , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Ácidos Picolínicos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Anemia/sangue , Anemia/etiologia , Biomarcadores/sangue , Proteína C-Reativa/análise , Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eritropoetina/sangue , Feminino , Ferritinas/sangue , Ferritinas/metabolismo , Glicina/farmacologia , Glicina/uso terapêutico , Hemoglobinas/análise , Hepcidinas/sangue , Hepcidinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Picolínicos/farmacologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD. METHODS: A total of 2584 participants were randomized to two doses of FCM 750 mg in one week, or iron sucrose 200 mg administered in up to five infusions in 14 days. The primary efficacy endpoint was the mean change to highest hemoglobin from baseline to Day 56. The primary composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, congestive heart failure, arrhythmias and hyper- and hypotensive events. RESULTS: The mean hemoglobin increase was 1.13 g/dL in the FCM group and 0.92 g/dL in the iron sucrose group (95% CI, 0.13-0.28). Similar results were observed across all subgroups, except Stage 2 CKD. More subjects in the FCM group achieved a hemoglobin increase of ≥ 1.0 g/dL between baseline and Day 56 (48.6 versus 41.0%; 95% CI, 3.6-11.6%). There was no significant difference between FCM and iron sucrose recipients with respect to the primary composite safety endpoint, including the major adverse cardiac events of death, myocardial infarction, or stroke. A significant difference in the number of protocol-defined, predominantly transient hypertensive episodes was observed in the FCM group. CONCLUSIONS: Two 750-mg infusions of FCM are a safe and effective alternative to multiple lower dose iron sucrose infusions in NDD-CKD patients with iron-deficiency anemia.
Assuntos
Anemia Ferropriva/terapia , Compostos Férricos/administração & dosagem , Taxa de Filtração Glomerular/fisiologia , Ácido Glucárico/administração & dosagem , Ferro/sangue , Maltose/análogos & derivados , Insuficiência Renal Crônica/fisiopatologia , Idoso , Anemia Ferropriva/sangue , Anemia Ferropriva/etiologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Óxido de Ferro Sacarado , Hematínicos/administração & dosagem , Hemoglobinas/metabolismo , Humanos , Infusões Intravenosas , Masculino , Maltose/administração & dosagem , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Resultado do TratamentoRESUMO
BACKGROUND: Peginesatide is a peptide-based erythropoiesis-stimulating agent that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. The primary objective of this phase 2 dose-finding study was to determine the once-monthly peginesatide dosing strategy that would maintain hemoglobin within ±1.0 g/dL of baseline values after conversion from epoetin alfa; the safety of peginesatide was evaluated concurrently. METHODS: Chronic hemodialysis patients on stable regimens of epoetin alfa were sequentially assigned to cohorts that differed on (1) how the peginesatide starting dose was determined (using a single epoetin alfa-to-peginesatide dose conversion ratio or a tiered, weight-based or absolute-dose conversion table) and on (2) whether or not a 1-week erythropoiesis-stimulating agent-free interval was used. Peginesatide doses were titrated to maintain hemoglobin levels within ±1.0 g/dL from baseline. RESULTS: A total of 164 patients were enrolled and received intravenous peginesatide every 4 weeks for up to 6 doses; the duration of the study including follow-up was ≤29 weeks. Overall, the proportion of patients with hemoglobin levels within ±1.0 g/dL of baseline increased over the course of the study from 39% (Weeks 2-13) to 54% (Weeks 18-25). Cohorts that used tiered dose conversion tables trended towards having more stable peginesatide doses than did those cohorts that used a single dose conversion ratio. Moreover, cohorts that used an erythropoiesis-stimulating agent-free interval did not have the substantial initial increase in hemoglobin levels that was seen in those cohorts that did not use such an interval. In this study, the safety profile of peginesatide was consistent with those of marketed erythropoiesis-stimulating agents. CONCLUSIONS: The results of this study were used to guide the dosing regimens used subsequently in phase 3 studies. Once-monthly peginesatide is feasible in hemodialysis patients. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT00228449.