Inpharma 1476 - 26 Feb 2005

Deferasirox a strong contender for iron overload in all ages– Suzanne Sullivan –

Deferasirox [Exjade, ICL 670], an oral once-daily iron chelator, was shown to be effective in the treatment of ironoverload in both adults and children in studies presented at the 46th Annual Meeting of the American Society ofHematology (ASH) [San Diego, US; December 2004]. In a phase III study involving almost 600 patients withthalassaemia, deferasirox produced dose-dependent reductions in liver iron concentration (LIC), to levelscomparable to those observed with the current standard therapy, deferoxamine. A phase II study showed thatdeferasirox reduced LIC in patients with myelodysplastic syndromes and Diamond-Blackfan syndrome, and inpatients with thalassaemia who had inadequate chelation with deferoxamine.

The current standard treatment for iron overload, groups; patients receiving deferasirox 5–20 mg/kg haddeferoxamine, involves a demanding regimen of increases from baseline in ferritin levels, while patientsparenteral infusions, leading to poor compliance and a who received deferasirox 30 mg/kg had a reduction fromnegative impact on patient outcomes. Deferasirox is an baseline in levels.oral iron chelator which is administered once daily,offering improved ease of use and convenience for the Table 1. Effects on iron levels in patients withpatient. Previous smaller studies indicated that thalassaemia, according to therapydeferasirox had promising activity in the treatment of

Deferoxamine Deferasiroxiron overload in patients with thalassaemia.*Success rates at 12 months (% of patients):Comparable to standard therapyOverall 66.4 52.9

Deferasirox was compared with the standard therapy, Baseline LICa of ≥ 7mg Fe/g 58.9 58.6deferoxamine, in a randomised open-label phase III dry weightstudy involving 591 patients at centres in Argentina, Mean change from baseline in LIC at 12 months (mg Fe/g dryBelgium, Brazil, Canada, Germany, Greece, France, weight):Italy, Turkey, Tunisia, the UK and the US.1 The study Overall –2.9* –2.4*included patients aged ≥ 2 years with thalassaemia who Baseline LIC of < 7mg Fe/g +0.13 +4required eight or more blood transfusions per year to dry weightmaintain haemoglobin levels of ≥ 9 g/dL. Patients were Baseline LIC of ≥ 7mg Fe/g –4.3* –5.3*

dry weightrequired to have an LIC of ≥ 2mg Fe/g dry weight, amean ALT level of < 250 U/L during the previous * p < 0.001 vs baseline12 months and a normal serum creatinine level. a Liver iron concentrationApproximately half of the patients (51%) were aged< 16 years, and 52% of patients were men.

Tolerated in all agesPatients were randomised to receive oral deferasiroxDeferasirox was well tolerated in adult and paediatric5–30 mg/kg once daily (n = 297), or SC infusions of

patients. Eight patients receiving deferasirox withdrewdeferoxamine ≥ 20 mg/kg/day for 5 days per week, forfrom the study due to adverse events or death,12 months; the initial doses of the study drugs werecompared with four patients in the deferoxamine group.assigned according to LIC at baseline.None of the deaths was considered to be related to theOne patient in the deferasirox group and four patientsstudy drug. Three of the withdrawals in the deferasiroxin the deferoxamine group withdrew from the studygroup were due to increases from baseline in ALT levels.prior to the initiation of treatment. The per-protocol-1Among the overall safety population,† patients receiving(PP-1) population included the patients who had LIClower doses of deferasirox had slight increases frommeasurements at baseline and study endpoint, andbaseline in ALT levels, while patients receivingthose who withdrew from the study due to adversedeferasirox 20 mg/kg or 30 mg/kg had stable ALT levelsevents; the per-protocol-2 (PP-2) population comprisedor a decrease from baseline; a similar trend waspatients who had LIC measurements at baseline andobserved in the deferoxamine group. There were nostudy endpoint.reports of agranulocytosis in either treatment group.Dose-dependent effects on LIC The investigators concluded that deferasirox "appears

Among the PP-1 population, the success rate in the to be a convenient, well-tolerated and effective once-deferasirox group was similar to that noted in daily oral iron chelator for the treatment of chronic irondeferoxamine recipients [see table 1].** Specifically, the overload in patients receiving blood transfusions".success rate with deferasirox was non-inferior to the rate

Effective in other anaemiasobserved with deferoxamine in patients who had an LICA second study presented at the ASH meetingof ≥ 7mg Fe/g dry weight at baseline.

evaluated the effects of deferasirox in patients withIn the PP-2 population, patients in both treatmentvarious chronic anaemias.2 This open-label phase IIgroups had significant reductions from baseline in thestudy involved 184 patients aged ≥ 2 years at centres inmean LIC at 12 months. Although patients receivingBelgium, Canada, France, Germany, Italy, the UK anddeferasirox 5 mg/kg and 10 mg/kg experienced dose-the US. Patients were included in the study if they haddependent increases from baseline in LIC, patientsreceived eight or more transfusions during the previoustreated with deferoxamine 20 mg/kg and 30 mg/kg had12 months, and had an LIC of ≥ 2mg Fe/g dry weight,stable or decreasing LIC over the 12-month studymean ALT levels of < 250 U/L in the previousperiod.12 months, normal serum creatinine levels and no activeA dose-dependent effect on the change from baselinehepatitis. The study included patients who hadin serum ferritin levels was observed in both treatment

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Inpharma 26 Feb 2005 No. 14761173-8324/10/1476-0001/$14.95 Adis © 2010 Springer International Publishing AG. All rights reserved

Single Article

Deferasirox a strong contender for iron overload – continuedthalassaemia (n = 85) and patients with other anaemias, ferritin levels; in contrast, patients treated with lowerincluding myelodysplastic syndromes (47) and doses had an increase from baseline.Diamond-Blackfan syndrome (30). To be eligible for Consistent tolerability profileinclusion, patients with thalassaemia were required to

The most common adverse events related to studyhave inadequate iron chelation during treatment withdrug included skin rash and mild and transientdeferoxamine due to intolerance or poor compliance, orgastrointestinal adverse events. A dose-dependent effecta contraindication to deferoxamine.on ALT levels was observed, in a similar pattern to thatPatients received oral deferasirox 5–30 mg/kg oncenoted in the changes from baseline in LIC and ferritindaily for 12 months. The initial dose of deferasirox waslevels. There were 18 patients who withdrew from theassigned according to baseline LIC; the most commonstudy due to adverse events or death; the majority ofstarting dose was 30 mg/kg (58% of patients). Equalthese, including the five deaths, were considered to beproportions of men and women were included in therelated to underlying disease.study, and 19% of patients were aged < 16 years.

There were no reports of agranulocytosis in patientsAt 12 months, the overall success rate was 56.4% inwith thalassaemia. Among the patients with otherthe PP-1 population. Among the PP-2 population, LICanaemias, treatment with deferasirox was notwas significantly reduced from baseline in patients withassociated with worsening of pre-existingthalassaemia and those who had other anaemias [seemyelosuppression.table 2]. Specifically, significant reductions from* See Inpharma 1376: 7, 1 Mar 2003; 800888686baseline in LIC were observed in patients who had a** The criteria for success was an LIC of 1 to < 7mg Fe/g dry weight atbaseline LIC of ≥ 7mg Fe/g dry weight and were12 months in patients who had a baseline LIC of 2 to < 10mg Fe/g dryreceiving deferasirox 20 mg/kg or 30 mg/kg.weight. For patients who had a baseline LIC of ≥ 10mg Fe/g dry weight,a success was defined as a reduction from baseline in LIC of ≥ 3mg Fe/g dry weight.Table 2. Effects on iron levels, according to

anaemia type † The safety population included all patients who had received at leastone dose of study drug.Thalassaemia Other1. Cappellini M, et al. Phase III evaluation of once-daily, oral therapy with ICL670anaemias

(Exjade Rm) versus deferoxamine in patients with beta-thalassemia andMean reduction from baseline in LICa at 12 months (mg Fe/g dry transfusional hemosiderosis. Blood 104: 984 (plus poster) abstr. 3619, No. 11,weight): Part 1, 16 Nov 2004.

2. Porter j, et al. A phase II study with ICL670 (Exjade Rm), a once-daily oral ironAll patients –4.7* –3.7*chelator, in patients with various transfusion-dependent anemias and iron

Baseline LIC of < 7mg Fe/g +6 +1.6 overload. Blood 104: 872 (plus poster) abstr. 3193, No. 11, Part 1, 16 Nov 2004.dry weight 800999204

Baseline LIC of ≥ 7mg Fe/g –6.1* 4.8* » Editorial comment: Deferasirox [Novartis] is in phase III ofdry weightclinical development for the treatment of iron overload in the EU

* p < 0.001 vs baseline and the US. Novartis announced in December 2004 that ita Liver iron concentration expects to submit deferasirox for registration worldwide for this

indication in the first half of 2005. The drug has been grantedfast-track status by the US FDA and has orphan drug status inA dose-dependent effect on serum ferritin levels wasthe EU and the US.noted in both disease groups. Patients receiving higher

doses of deferasirox had a reduction from baseline in

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