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.

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

“…Another phase 1 clinical trial for PRS-080#22 displayed no adverse effects when given to healthy patients (16 mg/kg) and chronic kidney disease (CKD) patients undergoing haemodialysis (8 mg/kg). In addition, serum iron and transferrin saturation were both increased with PRS-808#22 treatment with the authors suggesting this indicates that the iron was transferrin bound and therefore highly functional [88].…”

Anemia of Inflammation with An Emphasis on Chronic Kidney Disease

“…An additional novel therapeutic strategy in the treatment of anemia in CKD is the development of engineered lipocalins called anticalins, which are able to bind small hydrophobic molecules such as hepcidin and thereby inhibit it from carrying out its function [144]. Anticalin PRS-080#22 has also been shown to sequester hepcidin in a Phase I clinical trial [145]. PRS-080#22 decreased hepcidin and increased serum iron and transferrin saturation in a dose-dependent manner.…”

“…PRS-080#22 decreased hepcidin and increased serum iron and transferrin saturation in a dose-dependent manner. In mice and in patients with deep vein thrombosis (DVT), administration of the anticoagulant, heparin, caused decreased hepcidin levels and increased mobilization of iron from splenic stores, thereby increasing the circulating iron level [145].…”

TGFβ2-Hepcidin Feed-Forward Loop in the Trabecular Meshwork Implicates Iron in Glaucomatous Pathology

“…The significance of these observations is two-fold; first, this study demonstrates a clear involvement of iron-catalyzed ROS in TGF-β2-associated POAG, and second, the involvement of hepcidin in this process provides an untapped opportunity for using hepcidin antagonists as adjuncts to ROCK inhibitors and other treatment options for POAG. 4 A range of hepcidin antagonists are currently undergoing clinical trials for systemic disorders, 54 , 55 and could be modified for ophthalmic use.…”