Single and Repeated Dose First-in-Human Study with the Anti-Hepcidin Spiegelmer Nox-H94.
Authors: Riecke Kai , Zöllner Stefan , Boyce Malcolm , Vauléon Stephanie , Swinkels Dorine W. , Dümmler Thomas , Summo Luciana , Laarakkers Coby , Schwoebel Frank , Fliegert Frank 
Published: October 2019

Abstract
Abstract 2342

Background:
NOX-H94, the first-in-class hepcidin inhibitor in development for treatment of anemia of chronic disease (ACD), is a PEGylated anti-hepcidin L-RNA oligonucleotide. ACD is caused by iron sequestration in the reticulo-endothelial macrophages with subsequent iron restricted erythropoiesis due to high hepcidin production and subsequent ferroportin degradation. The treatment of ACD is challenging: a significant number of ACD patients do not respond to erythropoiesis stimulating agents (ESAs), while repeated intravenous iron administrations bear a risk of iron overload. Targeting hepcidin may provide more efficacious and well tolerated treatment alternatives.

Methods:
This First-in-Human study investigated the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of escalating single and repeated doses of intravenous (i.v.) NOX-H94 in healthy men and women. The study protocol (ClinicalTrials.gov identifier NCT01372137) was approved by an independent ethics committee and conducted in accordance with the Declaration of Helsinki. Five successive cohorts of 8 healthy subjects, at least 3 men and women, were randomly assigned to i.v. doses of 0.3, 0.6, 1.2, 2.4, and 4.8 mg/kg of NOX-H94 (n=6) or placebo (n=2). Similarly, 2 cohorts of 8 male subjects randomly received 5 doses of either 0.6 or 1.2 mg/kg NOX-H94 or placebo every other day (q2d). Safety parameters, iron parameters, total hepcidin-25 (sum of free circulating hepcidin-25 and hepcidin-25 bound to NOX-H94), and PK were assessed during treatment and follow-up periods of ≥3 weeks. Data are given as means±SD.

Results:
One man, assigned to 5 i.v. doses of 0.6 mg/kg, withdrew consent after 4 administrations; all other 55 subjects completed the study as scheduled. Safety: Treatment with NOX-H94 was generally safe and well tolerated. No serious adverse event occurred; headache and fatigue were the only treatment related events that occurred more than once. Mild and transient increases in transaminases (<2×ULN) were noted in subjects treated with NOX-H94 at single doses ≥2.4 mg/kg or with repeated doses of 1.2 mg/kg (4.2 mg/kg weekly). PK: After escalating single i.v. administrations of 0.3 to 4.8 mg/kg of NOX-H94, peak plasma concentrations of NOX-H94 (Cmax) and systemic exposure (AUC) increased dose-proportionally. The elimination was bi-phasic with a terminal plasma half-life (t ½) in the range of 17 to 26 h. The systemic clearance (CL) was low (Table 1). After repeated q2d i.v. administrations, no appreciable plasma accumulation was found based on Cmax and AUC. No obvious gender-difference was observed. PD: The plasma concentration of total hepcidin-25 increased dose-dependently upon NOX-H94 treatment, without ever exceeding the plasma concentration of NOX-H94. The PD effects were assessed by analysis of the area under the data time curve above baseline (AUD) of various iron parameters. Single and repeated doses of NOX-H94 up to 0.6 mg/kg had no effect on serum iron, serum ferritin, and transferrin saturation (TSAT) in the healthy subjects studied. At doses ≥1.2 mg/kg NOX-H94, serum iron, serum ferritin, and TSAT increased dose dependently.

Conclusions:
Treatment with NOX-H94 was generally safe and well tolerated over all dose levels and schedules studied; for subsequent phase II studies in patients, twice weekly i.v. doses of 1.2 mg/kg are recommended. PK analyses showed a dose-linear systemic exposure. In these healthy subjects, only mild dose-dependent increases in iron parameters were observed which likely underestimate the effects that may be obtained in patients with iron-restricted anemia.

Disclosures:
Riecke: NOXXON Pharma AG: Employment. Zöllner:NOXXON Pharma AG: Employment. Vauléon:NOXXON Pharma AG: Employment. Swinkels:NOXXON Pharma AG: Research Funding. Dümmler:NOXXON Pharma AG: Employment. Summo:NOXXON Pharma AG: Employment. Schwoebel:NOXXON Pharma AG: Employment. Fliegert:NOXXON Pharma AG: Employment.