Explore the vast range of titles available.

Background Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treatment of anemia in dialysis-dependent chronic kidney disease (CKD) with a starting dose of 300 mg once daily (dose adjustments up to 600 mg). A recent phase 1b study evaluated the pharmacokinetics, pharmacodynamics, and safety of higher vadadustat doses (500–900 mg) in healthy volunteers. Here we report the pharmacokinetic (PK), pharmacodynamic (PD), and safety characterization of higher doses of vadadustat in patients with CKD receiving dialysis. Methods This phase 1b, randomized, open-label study evaluated the pharmacokinetics and pharmacodynamics of vadadustat (600, 750, or 900 mg) in patients with CKD-related anemia receiving hemodialysis over a 10-day treatment period. Forty-six eligible patients were randomized to vadadustat 600, 750, or 900 mg daily or an intravenous erythropoiesis-stimulating agent. For vadadustat groups, blood samples for PK and PD analyses were collected on Day 1 and Day 8. PK analyses included area under the plasma concentration time curve (AUC) from dosing to last quantifiable concentration and to infinity, and to maximum plasma concentration (C max ). PD analyses measured serum erythropoietin (EPO), hemoglobin, and red blood cells (RBCs). Safety assessments included adverse events in the safety population (patients who received ≥ 1 dose of study drug). Patients underwent a 30-day safety follow-up period after the last dose of study drug. Results In the vadadustat groups, a dose-dependent increase in plasma exposure of vadadustat (C max and AUC) with modest accumulation was observed on Day 1 and Day 8. Vadadustat increased plasma EPO concentrations, with a variable EPO response observed in each group. Relative to baseline, mean hemoglobin and RBC levels remained unchanged, with no significant changes observed in any treatment group. Vadadustat was welltolerated. Conclusions The current study characterized the PK and PD response (EPO and reticulocytes) and safety profile of vadadustat at doses of 600, 750, and 900 mg in patients with CKD receiving dialysis. Overall, vadadustat was well tolerated. These findings will contribute to the development of higher-dose regimens for further investigation in phase 3 studies. Trial Registration ClinicalTrials.gov ID NCT03992066; https://clinicaltrials.gov/study/NCT03992066 ; Retrospectively registered on June 18, 2019. Accessed January 13, 2025.

Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Agios Pharmaceuticals.

This randomized, phase 3 trial compared the effectiveness of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, with epoetin alfa in patients undergoing hemodialysis or peritoneal dialysis in China. Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia.

This phase 3, randomized trial in China compared the efficacy and safety of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, with placebo for anemia in patients with CKD who were not undergoing dialysis. Roxadustat was superior to placebo in increasing and maintaining hemoglobin levels.

The sea cucumber Apostichopus japonicus is an important aquatic invertebrate, which has high nutritional and medicinal value. Kisspeptins are neuropeptides encoded by the kiss1 gene, and little is known about them outside of the vertebrate lineage. In this study, we investigated the effect of KPs on locomotor behavior in one control group and two treatment groups (AjK1 and AjK2). We found that AjK1 had a significant dose effect, mainly by reducing the stride length and duration of movement to decrease the movement distance of sea cucumbers, whereas AjK2 had little inhibitory effect at the same dose. The levels of phosphatidylethanolamine (PE), phosphatidylcholine (PC),uridine, glycine, and L-serine in the longitudinal muscle of A. japonicus treated with AjK1 differed significantly from those of the control, which may explain the observed changes in locomotor behavior. Kisspeptins are neuropeptides encoded by the kiss1 gene, and little is known about them outside the vertebrate lineage. Two kisspeptin-type neuropeptides (KPs) have been discovered in Apostichopus japonicus (AjK1 and AjK2), an edible sea cucumber, and have been linked to reproductive and metabolic regulation. In this study, we evaluated how KPs affected locomotor behavior in one control group and two treatment groups (AjK1 and AjK2). We discovered that AjK1 had a significant dose effect, primarily by shortening the stride length and duration of movement to reduce the sea cucumber movement distance, whereas AjK2 had little inhibitory effect at the same dose. The levels of phosphatidylethanolamine (PE), phosphatidylcholine (PC), uridine, glycine, and L-serine in the longitudinal muscle of A. japonicus treated with AjK1 differed significantly from those of the control, which may explain the observed changes in locomotor behavior. Treatment with AjK2 induced changes in aspartate levels. Our results imply that AjK1 is more likely than AjK2 to have a role in the regulation of A. japonicus locomotion.

PurposeReport pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.MethodsPatients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 − 2, pre-dose and 2 h post-dose on D15 of C1 − 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously.ResultsPK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease).ConclusionOnce-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma.Clinical trial registrationNCT02989857 Registered February 20, 2017.

This randomized trial compared daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, with darbepoetin alfa for the treatment of anemia in patients with chronic kidney disease who were not undergoing dialysis. Daprodustat was noninferior to darbepoetin alfa with respect to the change in hemoglobin level and cardiovascular outcomes.

Two randomized, phase 3, open-label noninferiority trials compared vadadustat with darbepoetin alfa in patients with non–dialysis-dependent chronic kidney disease. Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not for cardiovascular safety.

The addition of the oral proteasome inhibitor ixazomib to a regimen of lenalidomide plus dexamethasone led to a significant prolongation of progression-free survival of almost 6 months, as compared with placebo, with a small increase in the risk of thrombocytopenia. Outcomes of multiple myeloma have improved substantially over the past 15 years with the introduction of proteasome inhibitors and immunomodulatory drugs, 1 , 2 and these agents now form the backbone of therapy for multiple myeloma. 3 In phase 3 studies, triplet regimens based on these agents were shown to be more efficacious than doublet regimens when these regimens were used as a first-line treatment 4 – 6 and in relapsed disease. 7 , 8 In addition, there has been a shift in treatment patterns toward the use of extended treatment to further improve long-term outcomes, 9 and this shift highlights the need for additional effective agents with . . .

The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders, including autism and hyperekplexia. Understanding of molecular mechanisms and pharmacology of glycine receptors has been hindered by a lack of high-resolution structures. Here we report electron cryo-microscopy structures of the zebrafish α1 GlyR with strychnine, glycine, or glycine and ivermectin (glycine/ivermectin). Strychnine arrests the receptor in an antagonist-bound closed ion channel state, glycine stabilizes the receptor in an agonist-bound open channel state, and the glycine/ivermectin complex adopts a potentially desensitized or partially open state. Relative to the glycine-bound state, strychnine expands the agonist-binding pocket via outward movement of the C loop, promotes rearrangement of the extracellular and transmembrane domain ‘wrist’ interface, and leads to rotation of the transmembrane domain towards the pore axis, occluding the ion conduction pathway. These structures illuminate the GlyR mechanism and define a rubric to interpret structures of Cys-loop receptors. A high-resolution electron cryo-microscopy structure of the zebrafish α1 glycine receptor bound to agonists or antagonists reveals the conformational changes that take place when the channel transitions from closed to open state. Glycine receptor mechanism Eric Gouaux and colleagues have determined the high-resolution electron cryo-microscopy structure of strychnine-sensitive glycine receptor (GlyR) from zebrafish, bound to agonists or antagonists to reveal the conformational changes that take place when the channel opens. GlyRs mediate neurotransmission throughout the spinal cord and brainstem and their dysfunction is linked to multiple neurological disorders, including autism and hyperekplexia. Also in this issue of Nature , Xin Huang et al . report the X-ray crystal structure of the human GlyR in the presence of the antagonist strychnine.