Dataset Information

First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis.

ABSTRACT: In chronic kidney disease both renal insufficiency and chronic inflammation trigger elevated hepcidin levels, which impairs iron uptake, availability. and erythropoiesis. Here we report the two first-in-human phase 1 trials of PRS-080#22, a novel, rationally engineered Anticalin protein that targets and antagonizes hepcidin. A single intravenous infusion of placebo or PRS-080#22 was administered to 48 healthy volunteers (phase 1a) and 24 patients with end stage chronic kidney disease (CKD) on hemodialysis (phase 1b) at different doses (0.08-16mg/kg for the phase 1a study and 2-8mg/kg for the phase 1b study) in successive dosing cohorts. The primary endpoint for both randomized, double-blind, phase 1 trials was safety and tolerability. Following treatment, all subjects were evaluable, with none experiencing dose limiting toxicities. Most adverse events were mild. One serious adverse event occurred in the phase 1b (CKD patient) study. There were no clinically significant changes in safety laboratory values or vital signs. PRS-080#22 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately three days in healthy volunteers and 10 to 12 days in CKD patients. Serum hepcidin levels were suppressed in a dose dependent manner and remained low for up to 48 hours after dosing. PRS-080#22 dose-dependently mobilized serum iron with increases in both serum iron concentration and transferrin saturation. No consistent changes were observed with regard to ferritin, reticulocytes, hemoglobin, and reticulocyte hemoglobin. Low titer anti-drug-antibodies were detected in five healthy volunteers but in none of the CKD patients. PRS-080#22, a novel Anticalin protein with picomolar affinity for hepcidin, was safe and well-tolerated when administered to healthy volunteers and CKD patients at all doses tested. The drug exhibited linear pharmacokinetics, longer half-life in CKD patients in comparison to healthy volunteers as well as expected pharmacodynamic effects which hold promise for further clinical studies.

SUBMITTER: Renders L

PROVIDER: S-EPMC6436791 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis.

Renders Lutz L Budde Klemens K Rosenberger Christian C van Swelm Rachel R Swinkels Dorine D Dellanna Frank F Feuerer Werner W Wen Ming M Erley Christiane C Bader Birgit B Sommerer Claudia C Schaier Matthias M Meurer Karoline K Matis Louis L

PloS one 20190327 3

In chronic kidney disease both renal insufficiency and chronic inflammation trigger elevated hepcidin levels, which impairs iron uptake, availability. and erythropoiesis. Here we report the two first-in-human phase 1 trials of PRS-080#22, a novel, rationally engineered Anticalin protein that targets and antagonizes hepcidin. A single intravenous infusion of placebo or PRS-080#22 was administered to 48 healthy volunteers (phase 1a) and 24 patients with end stage chronic kidney disease (CKD) on he ...[more]

PMID: 30917125

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Project description:BACKGROUND: Aim of this study was to evaluate whether the A736V TMPRSS6 polymorphism, a major genetic determinant of iron metabolism in healthy subjects, influences serum levels of hepcidin, the hormone regulating iron metabolism, and erythropoiesis in chronic hemodialysis (CHD). METHODS: To this end, we considered 199 CHD patients from Northern Italy (157 with hepcidin evaluation), and 188 healthy controls without iron deficiency, matched for age and gender. Genetic polymorphisms were evaluated by allele specific polymerase chain reaction assays, and hepcidin quantified by mass spectrometry. RESULTS: Serum hepcidin levels were not different between the whole CHD population and controls (median 7.1, interquartile range (IQR) 0.55-17.1 vs. 7.4, 4.5-17.9 nM, respectively), but were higher in the CHD subgroup after exclusion of subjects with relative iron deficiency (p?=?0.04). In CHD patients, the A736V TMPRSS6 polymorphism influenced serum hepcidin levels in individuals positive for mutations in the HFE gene of hereditary hemochromatosis (p?<?0.0001). In particular, the TMPRSS6 736 V variant was associated with higher hepcidin levels (p?=?0.017). At multivariate analysis, HFE and A736V TMPRSS6 genotypes predicted serum hepcidin independently of ferritin and C reactive protein (p?=?0.048). In patients without acute inflammation and overt iron deficiency (C reactive protein <1 mg/dl and ferritin >30 ng/ml; n?=?86), hepcidin was associated with lower mean corpuscular volume (p?=?0.002), suggesting that it contributed to iron-restricted erythropoiesis. In line with previous results, in patients without acute inflammation and severe iron deficiency the "high hepcidin" 736 V TMPRSS6 variant was associated with higher erythropoietin maintenance dose (p?=?0.016), independently of subclinical inflammation (p?=?0.02). CONCLUSIONS: The A736V TMPRSS6 genotype influences hepcidin levels, erythropoiesis, and anemia management in CHD patients. Evaluation of the effect of TMPRSS6 genotype on clinical outcomes in prospective studies in CHD may be useful to predict the outcomes of hepcidin manipulation, and to guide treatment personalization by optimizing anemia management.

Project description:To compare the mortality of elderly adults with end-stage renal disease (ESRD) treated with home hemodialysis (HD) with that of those receiving a kidney transplant (KTx).Prospective cohort.Pertinent data for the two groups were obtained from electronic medical records from a large dialysis provider and the U.S. Renal Data System.Using data from elderly adults (aged ?65) who started home HD and underwent KTx in the US between 2007 and 2011, a 1:1 propensity score (PS)-matched cohort of 960 elderly adults was created, and the association between treatment modality and all-cause mortality was examined using Cox proportional hazards and competing risk regression survival models using modality failure as a competing event.Modality of renal replacement therapy.The baseline mean age ± standard deviation of the PS-matched individuals undergoing home HD was 71 ± 6, and that of KTx recipients was 71 ± 5, 69% of both groups were male, 81% of those undergoing home HD and 79% of KTx recipients were white, and 11% and 12%, respectively, were African American. Median follow-up time was 205 days (interquartile range (IQR) 78-364 days) for those undergoing home HD and 795 days (IQR 366-1,221 days) for KTx recipients. There were 97 deaths (20%, 253/1,000 patient-years, 95% confidence interval (CI) = 207-309/1,000 patient-years) in the home HD group and 48 deaths (10%, 45/1,000 patient-years, 95% CI = 34-60/1,000 patient-years) in the KTx group. Elderly adults undergoing home HD had a risk of mortality that was almost five times as high as that of KTx recipients (hazard ratio = 4.74, 95% CI = 3.25-6.91). Similar results were seen in competing risk regression analyses (subhazard ratio = 4.71, 95% CI = 3.27-6.79). Results were consistent across different types of kidney donors and subgroups divided according to various recipient characteristics.Elderly adults with ESRD who receive a KTx have greater survival than those who undergo home HD. Further studies are needed to assess whether KTx receipt is associated with other benefits such as better quality of life and lower hospitalization rates.

Project description:Background and objectivesA preference-based health utility score (PROPr) can be calculated using Patient-Reported Outcomes Measurement Information System domain scores. We assessed the construct validity of PROPr among patients treated with KRT (hemodialysis or kidney transplant).Design, setting, participants, & measurementsWe performed a secondary analysis of data collected in multicenter, cross-sectional studies of adults treated with KRT, recruited between April 2016 to March 2020 in Toronto, Canada. All participants provided informed consent. The outcome was the PROPr score. Coadministered outcome variables included the Short-Form Six-Domain (SF-6D) and EuroQol Five-Domain Five-Level (EQ-5D-5L) scores. Socioeconomic and clinical variables included age, sex, diabetes, eGFR, serum albumin, hemoglobin, KRT, and Charlson Comorbidity Index. Construct validity was assessed through correlations between PROPr and SF-6D or EQ-5D-5L, and associations between PROPr and other exposure variables. Health-condition impact estimates (coefficients for health conditions compared with a referent category, e.g., dialysis versus kidney transplant) were calculated using multivariable linear regression.ResultsThe mean (SD) age of the 524 participants was 57 (17) years, 58% were male, and 45% were White. Median (interquartile range) score was 0.39 (0.24-0.58) for PROPr, 0.69 (0.58-0.86) for SF-6D, and 0.85 (0.70-0.91) for EQ-5D-5L. Large correlations were observed between PROPr versus SF-6D (0.79; 95% confidence interval [95% CI], 0.76 to 0.82) and EQ-5D-5L (0.71; 95% CI, 0.66 to 0.75). Both PROPr and the other utility indices demonstrated health-condition impact in the expected direction. For example, the estimate for PROPr was -0.17 (95% CI, -0.13 to -0.21) for dialysis (versus kidney transplant), -0.05 (95% CI, -0.11 to 0.01; P=0.08) for kidney transplant recipients with an eGFR of <45 versus ≥45 ml/min per 1.73 m2, and -0.28 (95% CI, -0.22 to -0.33) for moderate/severe versus no/mild depressive symptoms.ConclusionsOur results support the validity of PROPr among patients treated with KRT.

Dataset Information

First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis.

Publications

First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis.

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