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

PLoS One. 2019 Mar 27;14(3):e0212023. doi: 10.1371/journal.pone.0212023. eCollection 2019.

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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Double-Blind Method
  • Female
  • Half-Life
  • Healthy Volunteers
  • Hepcidins / antagonists & inhibitors*
  • Humans
  • Infusions, Intravenous
  • Lipocalins / pharmacokinetics
  • Lipocalins / pharmacology*
  • Male
  • Middle Aged
  • Renal Dialysis / methods
  • Renal Insufficiency, Chronic / drug therapy*

Substances

  • Hepcidins
  • Lipocalins

Grants and funding

Both studies were funded by Pieris Pharmaceuticals GmbH (https://www.pieris.com/). The phase I study in healthy volunteers was supported financially by the Eurocalin fund FP7-HEALTH.2011.1.4.3 (EUROpean Consortium for antiCALINs as next generation high-affinity protein therapeutics, https://www.bio-m.org/en/news/news-detail/munich-and-europe-european-eurocalinconsortiumwith-a-strong-munich-hallmark.html). Pieris Pharmaceuticals GmbH provided the study protocols based on the input from the authors of this manuscript, and the sponsor oversight according to GCP guidelines. Volunteers/patients were recruited by the phase 1 unit of Nuvisan GmbH for the healthy volunteers study and by the clinical centers (authors affiliations) for the CKD study. MVZ DaVita as a dialysis unit also recruited patients in the CKD study (affiliation of Prof. Dellana). Pieris Pharmaceuticals GmbH paid the per patient costs. Data analysis was performed by a CRO (Nuvisan GmbH for the healthy volunteers study and FGK for the CKD study) based on the study protocol on behalf of Pieris Pharmaceuticals GmbH. Hepcidin analysis was performed by hepcidinanalysis.com on behalf of Pieris Pharmaceuticals GmbH. The data and study reports were reviewed and commented upon by the authors of this publication, who also participated in writing and reviewing the manuscript. The decision to publish was taken jointly by the authors. Administrative support was provided by Pieris. Administrative support was provided by Pieris. This does not alter our adherence to PLOS ONE policies on sharing data and materials.