Hepcidin as a predictor of response to epoetin therapy in anemic cancer patients.

BACKGROUND: Hepcidin is thought to be the central regulator of iron metabolism. Iron deficiency is associated with low hepcidin concentrations, and anemia in patients with cancer is associated with high concentrations of hepcidin. STUDY OBJECTIVES: Our main objective was to assess the potential role of hepcidin for predicting response to epoetin therapy in anemic cancer patients. We also aimed to identify a cutoff value for hepcidin as a potential predictive marker for response to epoetin therapy. METHODS: Using data from 525 anemic cancer patients enrolled in 5 studies, we assessed serum hepcidin concentrations in 408 of these patients at baseline and analyzed pooled data from the 408 patients. The analysis population was separated into 2 categories using a threshold hepcidin concentration of 13 nmol/L: low hepcidin (< 13 nmol/L) and high hepcidin (> or = 13 nmol/L). RESULTS: A significantly higher percentage of responders (defined as hemoglobin increase > or = 10 g/L or > or = 20 g/L from baseline) was observed in the low hepcidin group compared with the high hepcidin group (P = 0.04 for > or = 10 g/L increase and P = 0.009 for > or = 20 g/L from baseline). There was also a statistically significant difference between the 2 groups for hematopoietic response (hemoglobin rise at least once > or = 20 g/L from baseline or at least once > or = 120 g/L) to epoetin therapy (P = 0.0004). CONCLUSIONS: The results of this analysis suggest a potential role of hepcidin serum concentrations in predicting the response to epoetin therapy.

Intravenous human recombinant tumor necrosis factor receptor p55-Fc IgG1 fusion protein, Ro 45-2081 (lenercept): results of a dose-finding study in rheumatoid arthritis.

OBJECTIVE: To determine the optimal dose regimen of intravenous (IV) Ro 45-2081 (lenercept), a tumor necrosis factor receptor p55-Fc IgG1 fusion protein, in patients with active rheumatoid arthritis (RA) METHODS: In a double-blind, placebo-controlled, parallel-group, multicenter trial, adult patients with long-standing active RA stabilized on conventional therapy were randomly assigned to receive 3 IV infusions, one every 4 weeks, of one of the following: (a) placebo, (b) lenercept 0.01 mg/kg (maximum 1 mg), (c) lenercept 0.05 mg/kg (maximum 5 mg), (d) lenercept 0.2 mg/kg (maximum 20 mg), or (e) lenercept 0.5 mg/kg (maximum 50 mg). The material utilized in the study had a lower relative bioavailability [lower area under the time-concentration curve (AUC) per mg infused] than that used in a recent similar trial. Efficacy variables included change from baseline in number of swollen joints and tender joints, scores on physician and patient assessments of disease activity, and patient assessment of pain. RESULTS: Patients treated with lenercept exhibited improvement as early as one day after the first IV infusion. The treatment benefit, however, was modest, maximized by 2 weeks and then diminished or vanished as non-neutralizing anti-lenercept antibody concentrations increased. The majority of adverse experiences were mild or moderate and not considered related to study drug. CONCLUSION: Our results showed that lenercept administered by IV infusion every 4 weeks is well tolerated, but only transiently effective in patients with long-standing RA, likely due to both the low relative bioavailability of the material used in the study and the formation of non-neutralizing anti-lenercept antibodies.

Intravenous human recombinant tumor necrosis factor receptor p55-Fc IgG1 fusion protein Ro 45-2081 (lenercept): a double blind, placebo controlled dose-finding study in rheumatoid arthritis.

OBJECTIVE: To determine the optimal dose regimen for intravenous Ro 45-2081 (lenercept) in patients with rheumatoid arthritis (RA) by evaluating efficacy, safety, tolerability, and pharmacokinetic and pharmacodynamic characteristics. METHODS: Adult patients with longstanding RA who were taking stable doses of nonsteroidal antiinflammatory drug and/or low dose corticosteroids but who had stopped their previous disease-modifying antirheumatic drug were randomly assigned to receive 3 intravenous infusions, one every 4 weeks, of placebo or Ro 45-2081 in a double blind, placebo controlled, parallel group multicenter trial. Patients received one of the following: (1) placebo, (2) low dose Ro 45-2081 (0.05 mg/kg, maximum 5 mg), (3) middle dose (mid-dose) Ro 45-2081 (0.2 mg/kg, maximum 20 mg), or (4) high dose Ro 45-2081 (0.5 mg/kg, maximum 50 mg). Efficacy measures included change from baseline in number of swollen joints and tender joints, scores on physician and patient assessments of disease activity, and patient assessment of pain, as well as acute phase reactants. RESULTS: Patients treated with Ro 45-2081 exhibited improvement after one day of the first intravenous infusion. This treatment benefit maximized by 2 weeks but diminished thereafter. After the second and third infusion, improvement was of shorter duration as non-neutralizing anti-Ro 45-2081 antibodies developed and accelerated clearance of Ro 45-2081. There were no antibodies after the first infusion. This made efficacy transient in the mid-dose group and modest in the low and high dose groups at 12 weeks of treatment, resulting in no statistical differences at most time points or doses of Ro 45-2081. The majority of adverse experiences were mild or moderate, and were not related or only remotely related to study drug. No clinically relevant changes in mean laboratory values were reported. The third dose pharmacokinetic measurements showed that the average Ro 45-2081 clearance rate more than doubled compared with the first dosing interval, thus reducing the average Ro 45-2081 AUC by 36%. CONCLUSION: Intravenous Ro 45-2081 every 4 weeks proved to be well tolerated and transiently effective in the mid-dose group and modestly effective in the low and high dose groups in patients with longstanding RA. The interactions between Ro 45-2081, its non-neutralizing anti-Ro 45-2081 antibody, and the clinical benefit remain complex, but affected efficacy over the 12 weeks of treatment as Ro 45-2081 concentrations fell.