Highlights from

EHA 2019

European Hematology Association

Amsterdam 13-16 June 2019

Early trial data shows positive results for treating anaemia in patients with end-stage renal failure

This multicentre, randomised, double-blind, placebo-controlled, multiple ascending dose, pilot phase 2a study in anaemic stage 5 chronic kidney disease patients requiring haemodialysis determined that PRS-080 is safe. A haemoglobin (Hb) response with clear separation of Hb values between placebo and PRS-080 in the 8mg/kg cohort during the treatment period showed early efficacy, consisting of an increase of Hb in drug-treated patients and a decline in placebo patients, potentially related to the withdrawal of iron treatment [1].

In an oral presentation, nephrologist Dr Lutz Renders (Klinikum Rechts der Isar, Germany) explained that patients with chronic kidney disease (CKD) commonly present with anaemia. Current treatment regimens consist of iron, erythropoietin stimulating agents (ESAs), or both, but a significant proportion of patients remain anaemic despite these therapies. Hepcidin, a liver-derived hormone, is a central regulator of iron homeostasis, frequently elevated in CKD patients and thought to represent a root cause of the hypoferremia. Therefore, hepcidin inhibition has the potential to ameliorate functional iron deficiency anaemia in CKD patients. PRS-080 is a pegylated hepcidin protein antagonist that has been shown to induce dose-dependent serum iron mobilisation and increased transferrin saturation (TSAT) in single ascending dose phase 1 clinical studies, both in healthy male volunteers and dialysis-dependent CKD patients [2].

The study authors aimed to determine the safety and tolerability of 5 repeated intravenous administrations of PRS-080 at doses of 4 and 8 mg/kg body weight compared with placebo, in anaemic, haemodialysis dependent stage 5 CKD patients, as well as to assess pharmacokinetics, pharmacodynamics, and immunogenicity. Using a standard 4+2 design, 4 patients in each cohort were randomised to PRS-080 and 2 patients in each cohort will be randomised to placebo. The decision to escalate the dose was based on an interim analysis of clinical and laboratory safety as well on a comparison with pharmacokinetic data.

Twelve patients were enrolled. Four patients per cohort each received PRS 080 at a dose of 4 or 8 mg/kg, with 2 patients per cohort receiving placebo. The study included a screening period of 4 weeks; the mean of 3 Hb values during the screening period, each obtained at least 7 days apart, was required to be ≤10.5 g/dL with a difference of ≤1.0 g/dL between the lowest and highest values. Additional inclusion criteria included ferritin > 300 ng/mL and TSAT ≤30%. The ESA dose had to remain stable for at least 4 weeks prior to screening, as well as through the treatment period, and iron therapy had to be withdrawn 1 week before randomisation. Study medication was administered by infusion over 60 minutes using an infusion pump on day 0, 7, 14, 21, and 28. Patients were observed with regard to safety up until day 112. Safety was monitored continuously by a data safety monitoring board (DSMB), including prior to dose escalation.

The study results indicated that there were no treatment-related adverse events or serious adverse events. Robust iron mobilisation with increases in both serum iron and TSAT were consistently observed following each weekly dose in both dose cohorts. Peak iron concentrations were higher in the 8 mg/kg cohort than in the 4 mg/kg cohort.

Whereas no clear difference was observed in Hb values between placebo and PRS-080 patients in the 4 mg/kg cohort over the course of treatment, evidence of a Hb response with clear separation of Hb values between placebo and PRS-080 could be shown in the 8 mg/kg cohort during the treatment period, consisting of an increase of Hb in drug-treated patients and a decline in placebo patients, potentially related to the withdrawal of iron treatment.

  1. Renders L, et al. A phase IIA study to evaluate the safety, PK and PD of repeated administrations of the hepcidin antagonist PRS-080 in anemic chronic kidney disease patients undergoing hemodialysis. Abstract S1630, 24th Congress of the European Hematology Association, 13-16 June 2019, Amsterdam, the Netherlands.
  2. Renders L et al. 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.

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.