Abstract
Introduction:
The iron transporter ferroportin is a membrane protein expressed in enterocytes that absorb dietary iron, macrophages of the spleen and liver that recycle iron from old red blood cells (RBCs), and hepatocytes that store and release iron according to body needs. Hepcidin (HEPC) regulates the absorption, plasma concentrations, and tissue distribution of iron through interactions with ferroportin, leading to degradation of ferroportin.
LY2928057 (LY), a humanized immunoglobulin (IgG4) monoclonal antibody, binds to ferroportin and prevents the HEPC-mediated degradation of ferroportin without affecting iron efflux.
Objectives:
Objectives were to assess safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of LY in patients with chronic kidney disease (CKD) on hemodialysis (HD) after intravenous (IV) multiple doses of LY.
The study, compliant with Helsinki declaration, was approved by institutional ethic review board and subjects provided written informed consent prior to enrolment.
Methods:
CKD patients (N=21) received IV doses (300, 600, or 1000 mg every 2 weeks; total, 3 doses) of LY following discontinuation (when LY treatment was initiated) of erythropoiesis-stimulating agents (ESAs) and IV iron. Seven CKD patients received placebo.
Safety assessments included: standard laboratory safety tests, vital signs, ECGs, and anti-drug antibodies.
PD data comprised serum iron, transferrin saturation (TSAT), ferritin, HEPC, RBC count and hemoglobin (Hb).
PK samples (up to 3 months post last dose) were assayed using a validated enzyme-linked immunosorbent assay method.
LY PK data were analyzed using standard non-compartmental PK analysis. Summary statistics were used to describe LY PD data (parameters and ratios relative to baseline). A Bayesian analysis of the absolute change in Hb at week 6 relative to baseline was performed with the following success criterion: >60 % posterior probability of ≥0.8 g/dL difference between any LY dose group and placebo.
Results - Safety
CKD patients (19 of 28 were male), with mean (SD) age and weight of 53.6 (8) years and 87.35 (18) kg, participated. LY was well tolerated; serious adverse events (syncope, anemia, hypertension, respiratory failure/staphylococcal sepsis/pneumonia) were reported by 3 patients. These were not attributed to study drug.
Results - Pharmacokinetics
LY maximum concentrations were generally measured at the end of the 30-min infusion and concentrations decreased thereafter in a multiexponential manner. LY area under the concentration time curve (AUC or exposure) increased greater than dose proportionally from 300 to 600 mg and was roughly dose proportional from 600 to 1000 mg. This observation is consistent with binding, target-mediated clearance.
LY volume of distribution was small (mean 4L) and LY clearance was low (mean 0.09 L/h) in the 600 to 1000 mg dose range, leading to a mean terminal half-life of 8 days (ranging from 5.5 to 13 days).
The dosing of LY during HD did not significantly alter LY exposure.
Results - Pharmacodynamics
A dose-related increase in iron, with a maximum effect approximately 24 h after dose, was observed. Iron values returned to baseline in approximately 2-weeks post-LY dose. Concurrently, an increase in TSAT was observed (Figure 1).
In addition, a decrease in ferritin levels was observed (Figure 2, after third dose, approximately 12% and 20% decrease relative to baseline at the 600 and 1000 mg doses, respectively).
HEPC levels increased following LY administration. This is likely explained by the feed-back regulatory response of the body to the iron increase.
Figure 3 illustrates that RBC and Hb declined to a lesser extent with LY 600 mg and 1000 mg dose levels compared to 300 mg dose levels and placebo treatment. The Bayesian analysis determined a posterior probability of 58% (less than 60%), for a greater than 0.8 g/dL difference between LY treatment and placebo, in the absolute change in Hb at week 6 relative to baseline
Conclusion
LY in CKD patients was well tolerated; no safety signals or trends were identified.
Expected changes in PD markers (serum iron, HEPC, TSAT, ferritin, RBC, and Hb) were observed after LY administration; however, the effect on Hb did not meet the pre-defined success criterion. It is possible that co-administration of an ESA with LY is required for the increased iron to be optimally used for Hb synthesis in RBC.
Barrington:Eli Lilly and Company: Employment, Equity Ownership. Sheetz:Eli Lilly and Company: Employment, Equity Ownership. Callies:Eli Lilly and Company: Employment, Equity Ownership. Waters:Eli Lilly and Company: Employment. Berg:Eli Lilly and Company: Employment, Equity Ownership. Pappas:Eli Lilly and Company: Employment. Marbury:Olando Clinical Research Center: Employment, Equity Ownership. Berg:Davita Clinical Research: Employment, Other: Full time employee of Davita Clinical Research, one of the research sites.
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