Sustained Protection from Labile Plasma Iron (LPI) with the Once-Daily, Oral Iron Chelator Deferasirox (Exjade®, ICL670) in Iron-Overloaded β-Thalassemia Patients

Excess iron leads to the appearance of NTBI in the blood, which has been hypothesized to increase the risk for developing co-morbidities. LPI, one form of NTBI, is redox-active and can produce harmful reactive oxygen species. LPI is readily taken up by cells, resulting in expansion of the cellular iron pool. As LPI is produced 24 hours per day, the constant presence of an iron chelator in the plasma may help avoid accumulation of excess iron. Due to its long t½, clinically significant levels of deferasirox are present in the plasma for 24 hours following once-daily administration. This 1-year substudy has evaluated whether deferasirox treatment produced a sustained reduction in LPI. LPI, liver iron concentration (LIC; by biopsy) and serum ferritin (SF) levels over 1 year of treatment with deferasirox 20–30 mg/kg/day have been analyzed in a subgroup of 14 β-thalassemia patients from the ESCALATOR trial, all of whom had previously received DFO/deferiprone combination therapy. Blood samples for LPI and PK assessments were taken pre dose (predicted LPI daily peak) and 2 hours post dose (predicted daily LPI nadir), at baseline and following repeat dosing at weeks 4, 16, 28, 40 and 52. Efficacy and safety were assessed monthly, primarily by evaluating SF and the incidence and type of adverse events (AEs). LIC was measured at baseline and study end. The subgroup comprised 6 males and 8 females with a mean age of 17.5 years (range 12–27). Mean baseline iron parameters were: LPI 0.99 ± 0.82 μmol/L, LIC 28.6 ± 10.3 mg Fe/g dw, SF 7122 ± 3282 ng/mL. Baseline LPI levels were well correlated with LIC (R=0.66). Median deferasirox dose was 27.5 mg/kg/day. Mean steady-state deferasirox trough plasma levels at week 4 were 22.4 ± 18.5 μM (pre dose). Significant LPI reductions were observed post versus pre dose at baseline and week 4 (P LPI, pre and post deferasirox dose (corresponding to nadir and Cmax, respectively), at baseline and after repeat doses* LPI, μmol/L Week Mean ± SD Baseline vs repeat pre *As 1 pt died between wks 4–16, LPI data are taken from 13 pts, except †n=11 and ‡n=12 due to lost samples Baseline Pre 0.99 ± 0.82 Post 0.12 ± 0.16 4 Pre 0.45 ± 0.58 P=0.0735 Post 0.08 ± 0.20 16 Pre 0.21 ± 0.27 P=0.0015 Post 0.02 ± 0.06 28 Pre 0.15 ± 0.18 P=0.0006 Post 0.04 ± 0.05 40† Pre 0.11 ± 0.15 P=0.0007 Post 0.30 ± 0.36 52‡ Pre 0.27 ± 0.74 P=0.0070 Post 0.08 ± 0.21 During the study, LIC decreased by 6.8 ± 6.2 mg Fe/g dw, while SF decreased by 752 ± 1500 ng/mL. Deferasirox treatment was well tolerated, with no discontinuations due to AEs. The most common AEs were mild nausea (n=4) and vomiting (n=3). Conclusions: Despite a high baseline iron burden in these patients, these results highlight the ability of once-daily deferasirox 20–30 mg/kg/day to reduce levels of toxic LPI and maintain them within normal limits. Deferasirox daily trough levels were within the therapeutic range, demonstrating constant 24-hour chelation coverage. Decreases in LPI were accompanied by decreases in mean LIC and SF, indicating effective iron removal by deferasirox.