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

Presented by
Prof. Lutz Renders, Klinikum Rechts der Isar, Germany
Conference
EHA 2019
A multicentre, randomised, double-blind, placebo-controlled, multiple ascending dose, pilot phase 2a study determined that PRS-080 is safe in anaemic stage 5 chronic kidney disease patients requiring haemodialysis. A haemoglobin (Hb) response with clear segregation of Hb values between placebo and PRS-080 in the 8 mg/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].

Nephrologist Prof. 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 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. The decision to escalate the dose was based on an interim analysis of clinical and laboratory safety as well as on a comparison with pharmacokinetic data.

Twelve patients were enrolled. Using a standard 4+2 design, 4 patients in each cohort were randomised to PRS-080, and 2 patients to 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, including prior to dose escalation.

The study results indicated 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. Abstract S1630, 24th Congress of the EHA, 13-16 June 2019, Amsterdam, the Netherlands.
    2. Renders L, et al. PLoS One. 2019 Mar 27;14(3):e0212023.




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