Purpose: This report describes the Food and Drug Administration's review of data and analyses leading to the approval of the oral iron chelator, deferasirox for the treatment of chronic iron overload due to transfusional hemosiderosis.
Experimental Design: The FDA reviewed findings of a controlled, open-label, randomized multicenter phase III study of deferasirox vs deferoxamine in 586 patients with beta-thalessemia and transfusional hemosiderosis. The study results as well as the results of the FDA review of chemistry, preclinical pharmacology, and supportive studies are described.
Results: Following 48 weeks of treatment in the phase III study, patients' liver iron concentrations (a key endpoint variable) had decreased an average of 2.4 mg of iron (Fe)/g dry weight (dw) and 2.9 mg Fe/g dw in the deferasirox and deferoxamine groups, respectively, despite continued blood transfusions in both cohorts. Deferasirox was associated with serum creatinine increases in approximately a third of patients. Common adverse events included gastrointestinal symptoms and skin rash. Other data provided supportive evidence of deferasirox safety and efficacy.
Conclusions: The FDA granted deferasirox accelerated approval on November 2, 2005, for use in treating chronic iron overload due to transfusional hemosiderosis in patients ≥ 2 years of age. The sponsor must obtain clinical data demonstrating the drug's long-term safety and effectiveness.
The clinical development of deferasirox was based on results of preclinical studies documenting the drug's iron chelation bioactivity and on results of early-phase clinical studies that showed pharmacokinetics and iron chelation pharmacodynamics sufficient to justify oral, once-daily dose administration.
Phase I and II Studies: Overview
Exploratory studies examined deferasirox pharmacokinetics and bioactivity in healthy volunteers and patients over a period of ≤ 2 weeks. Longer exposure times were examined in four phase II clinical studies that explored a range of deferasirox dosages in patients who had a broad variety of anemias associated with transfusional hemosiderosis.
Two phase II studies compared various deferasirox doses to deferoxamine. One of these studies randomized 71 adult patients with beta-thalessemia and transfusion dependence to one of three treatment cohorts: 10 mg/kg/d or 20 mg/kg/d deferasirox or 40 mg/kg deferoxamine injected subcutaneously 5 consecutive days each week. The findings from this 48-week study suggested that a deferasirox dose of 20 mg/kg/d decreased LIC to the same approximate degree as the deferoxamine regimen did, whereas 10 mg/kg/d deferasirox maintained LIC at a stable value. As a result, in most subsequent clinical studies, including the confirmatory study, baseline LIC was the determining factor in selection of a deferasirox dose regimen.
The other comparative phase II study randomized 195 adult and pediatric patients with sickle cell disease and transfusional iron overload to one of several deferasirox dosages (dose range: 5-30 mg/kg daily) or to deferoxamine at 20-60 mg/kg. Preliminary safety data from 6 months of dosing (submitted in the marketing application) were similar to those for patients with other types of anemia.
Two noncomparative phase II studies were performed to obtain deferasirox safety and bioactivity data for specific populations. These populations and underlying conditions consisted of the following: pediatric patients with beta-thalassemia previously treated with deferoxamine (n = 40), other beta-thalessemia patients (n = 85), myelodysplastic syndrome patients (n = 47), Diamond Blackfan syndrome patients (n = 30), and patients with a variety of rare anemias such as aplastic, sideroblastic, autoimmune hemolytic, and Fanconi's anemias, alpha-thalassemia, myelofibrosis, pure red cell aplasia, and pyruvate kinase deficiency (n = 22). Overall, changes in LIC and serum ferritin were similar to the confirmatory study's findings.
These phase I and II studies provided important safety and bioactivity assessments for patients with a variety of anemic conditions. The findings suggested that deferasirox's activity (lowering of LIC) and safety profiles were similar regardless of a patient's underlying condition.
Phase III Confirmatory Clinical Study
• Patients and Methods—A single phase III clinical study (Study 0107) provided the definitive evidence of deferasirox safety and efficacy. This multicenter, multinational study, initiated in 2003, enrolled subjects from 12 countries, including the United States. The majority (68%) of subjects were from Greece, Italy, Turkey, and Tunisia.
Eligible subjects were adult and pediatric patients with transfusional hemosiderosis who could have received prior treatment with deferoxamine. Patients with abnormal serum creatinine levels or serologic evidence of human immunodeficiency viral infection were excluded. Multiple other exclusion criteria limited enrollment to patients who were likely to comply with drug and study protocols.
The study was a randomized, open-label study in which deferasirox was compared to deferoxamine in patients ≥ 2 years old with beta-thalassemia and transfusional hemosiderosis. Patients had baseline assessments of LIC by biopsy or SQUID, with the assessment repeated (using the same methodology) at the end of the 1-year treatment period. Other major evaluations during the study—some limited to study population subgroups—were assessments of serum ferritin, growth velocity, clinical laboratory values, iron balance measurements, ocular and auditory examinations, and echocardiography.
The dosages of deferasirox and deferoxamine were protocol-specified based on certain criteria (Table 1). Deferasirox dosages were determined by patients' baseline LICs, which were stratified by value, with each value range assigned a dosage level in an attempt to tailor the deferasirox dose according to the baseline need for chelation therapy. Deferoxamine assigned dosages were also tailored (by protocol-specified categorization) to the perceived need for chelation. However, certain patients who had previously received deferoxamine were allowed to continue the prior dosage regardless of baseline LIC. Deferoxamine was subcutaneously infused via an automated pump over ≥ 8 hours for 5 consecutive days each week.
Dose adjustments were permitted for both study agents based on safety findings and evidence of over or underchelation. Blood transfusion therapy was to continue throughout the study to maintain blood hemoglobin concentrations ≥ 9.0 g/dL.
The study's primary endpoint was a comparison of "success" between the two study groups according to the protocol-specified definition of success (Table 2), an outcome based on the change in LIC from baseline to end of study. The protocol specified that deferasirox would be considered noninferior to deferoxamine if the two-sided 95% confidence interval (CI) of the difference in success rates between the two study groups was above 15%.
The primary endpoint variable, LIC, was assessed at baseline by liver biopsy in most patients. Some pediatric patients had LIC determined noninvasively using SQUID methodology, an investigational technique with limited performance characterization. Liver biopsy samples were analyzed at a single center using well-accepted methodologies. SQUID determinations were conducted at three centers (Turin, Italy; Hamburg, Germany; Oakland, USA). For each patient, LIC was reassessed after 1 year using the same methodology used at baseline.
The key secondary efficacy endpoint outcomes were a comparison between the cohorts of the change from baseline in LIC among patients whose baseline LICs were ≥ 7 mg Fe/g dw and a comparison within the deferasirox cohort of LICs at baseline and 1 year later.
In interpreting the study findings, FDA reviewers noted that limited data supported the selection of the primary endpoint's noninferiority margin. Consequently, the FDA focused on analyses of the change in LIC from baseline among subjects receiving deferasirox. A clinically meaningful change (decrement) from baseline was considered substantial evidence of efficacy in light of the continuing blood transfusion therapy administered during the treatment period.
• Results: Randomization and Compliance—Overall, 591 beta-thalessemia patients were randomized (1:1) to receive either deferasirox (n = 297) or deferoxamine (n = 294). Before initiation of treatment, one patient in the deferasirox group and four in the deferoxamine group withdrew consent and were not treated. Patients' baseline characteristics are shown in Table 3. The treatment groups were generally balanced with respect to important baseline and demographic characteristics.
Table 4 summarizes the protocol-assigned doses of the study drugs and the average doses actually administered to enrolled subjects. In general, the average deferasirox doses administered were consistent with the assigned doses, whereas the administered deferoxamine doses in patients with LIC < 7 mg Fe/g dw were somewhat higher than the assigned doses because the protocol allowed patients previously treated with deferoxamine to receive prestudy dose levels.
The frequency and characteristics of dosing interruptions were similar for the two cohorts. However, dose adjustments owing to adverse events or laboratory abnormalities were twice as common in the deferasirox group as in the deferoxamine group, mostly because of protocol-mandated changes in response to elevations in serum creatinine values.
• Results: Efficacy—The primary analysis (comparison of success rates between the two cohorts) did not meet the prespecified boundary for noninferiority (Table 5). Post hoc subset analyses as well as the secondary endpoint results suggested that deferasirox's failure to achieve the prespecified noninferiority margin was related predominantly to the maintenance of relatively high, prestudy deferoxamine doses and to the disproportionately low dosing of deferasirox (5 and 10 mg/kg/d) compared with deferoxamine. In a prespecified subset analysis that excluded patients receiving the two lowest deferasirox and deferoxamine dosages (ie, patients with baseline LIC ≥ 7 mg Fe/g dw; n = 381), the difference in success rates between the cohorts was -0.3 (95% CI = -10.2, 9.6), a finding that would have fulfilled the primary endpoint goal of demonstrating deferasirox's noninferiority.
Other secondary endpoints included assessments of changes in serum ferritin concentration and changes in iron balance (Table 6 and Figure 2). Dose-dependent effects on serum ferritin concentrations over time that generally paralleled the changes in LIC were observed in both deferasirox- and deferoxamine-treated patients.
Iron balance is assessed as the calculated ratio of iron excretion to iron intake. Negative iron balance (corresponding to an iron excretion:iron intake ratio > 1) indicates removal of iron in excess of that received from transfusion. In this confirmatory study, the ratios of iron excretion to iron intake in the overall population across all LIC values were similar for deferasirox- and deferoxamine-treated patients. Importantly, the iron excretion:iron intake ratio was observed to be closely dose related in deferasirox-treated patients (ratio < 1 at doses of 5 and 10 mg/kg/d, ≈1 at 20 mg/kg/d, and > 1 at 30 mg/kg/d).
• Results: Safety—Approximately 33% of deferasirox-treated patients had an increase in serum creatinine, although those increases frequently remained within normal limits. Dose reduction or interruption of deferasirox administration was usually associated with a fall in serum creatinine to the baseline value. The changes in renal function were not progressive despite resumption or continuation of deferasirox at lower dosages.
Deferasirox administration was also associated with an increase in the urinary protein:urinary creatinine ratio in a minority of patients. In 17 deferasirox-treated patients, serum liver enzyme concentrations (serum glutamic pyruvic transaminase/alanine aminotransferase) increased to more than five times the upper limit of normal on two consecutive assessments, whereas five deferoxamine-treated patients experienced these abnormalities. Two patients had liver biopsy-confirmed drug-induced hepatitis, and both discontinued deferasirox. Increases in liver enzyme concentrations did not appear to be dose-related.
Integrated Safety Results From All Clinical Studies
Overall, 700 adult and pediatric patients (including those with beta-thalassemia [n = 469], sickle cell disease [n = 132], and various rare anemias [n = 99]) were administered deferasirox in clinical studies lasting at least 48 weeks. The most frequently occurring adverse events in these patients were diarrhea, vomiting, nausea, headache, abdominal pain, pyrexia, cough, and increase in serum creatinine. In general, rates of gastrointestinal symptoms, increases in serum creatinine, and skin rash suggested a deferasirox dose relationship. With the exception of increases in serum creatinine, the pattern of adverse events was similar for patients receiving deferasirox and those receiving deferoxamine (Table 7).
Adverse events leading to discontinuation of deferasirox, as well as serious adverse events assessed as drug-related, occurred in 3% of the 700 deferasirox-treated patients. The most common events prompting deferasirox discontinuation were gastrointestinal disorders, skin rash, increase in liver enzymes/drug-induced hepatitis, renal abnormalities, cataract development, and hyperactivity. Serious adverse events were skin rashes, gastrointestinal disorders, and increases in serum liver enzyme concentrations.
Among 700 deferasirox-treated patients, 6 deaths were recorded. In the beta-thalassemia population, one unexplained sudden death occurred in a 3-year-old child who had complicating risks and who received 31 mg/kg/d deferasirox for 84 days. Five patients with other chronic anemias died—three with sepsis in the setting of neutropenia that was present at baseline or developed in association with the use of chemotherapeutic drugs, one with recurrent thromboembolism, and one with cardiopulmonary arrest and known cardiac disease.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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