Download - Current status of iron overload and chelation with deferasirox

Indian Journal of Pediatrics, Volume 74—August, 2007 759

Special Article

Correspondence and Reprint requests : Dr. V.P. Choudhry, DirectorSunflag Pahuja Centre for Blood Disorders Sunflag Hospital, Sector16A Faridabad, Haryana-121002, Ph: 01294075184, 9811073904

[Received October 26, 2006; Accepted March 12, 2007]

Current Status of Iron Overload and Chelation withDeferasirox

V.P. Choudhry and Rahul Naithani

Department of Hematology, All India Institute of Medical Sciences, New Delhi.

ABSTRACT

A large number of complications in thalassemia major are due mainly to iron overload. Deferoxamine in iron-overloaded patientshas established that chelation therapy, when given at an adequate dose, reduces iron-related complications. Parenteraladministration and the daily nuisance of an infusion pump hinder the optimal compliance. Deferiprone is moderately effectiveoral iron chelator. Arthralgia and cytopenias constitute the main side effects. Deferasirox is a new orally effective iron chelatorwhich has been shown to be non-inferior to deferoxamine in clinical trials. Further clinical trials especially in Indian children willtell if it stands the test of time. [Indian J Pediatr 2007; 74 (8) : 759-764] E-mail : [email protected]

Key words : Thalassemia; Iron overload; Deferasirox

Patients with chronic anemias such as thalassemia, sicklecell disease, congenital rare anemias and myelodysplasticsyndromes who require regular blood transfusions fortheir survival and/or to improve the quality of life. Thereis no system to eliminate the iron released from thebreakdown of transfused red blood cells.1,2 The excessiron in the body gets deposited in various tissues of thebody, particularly the liver, heart, and endocrine organs.3

Once the body’s storage capacity is exceeded, free ironcatalyzes the formation of highly reactive hydroxylradicals, which leads to membrane damage anddenaturation of proteins. This process leads to tissuedamage and ultimately to significant morbidity andmortality.4 chronic iron overload progresses to multipleorgan failure and is a major cause of death in patientswho receive blood transfusions regularly withoutappropriate chelation therapy.5

In children with thalassemia major, within 2 to 3 yr ofinitiation of regular blood transfusions, evidence of ironoverload is manifest as elevated liver iron concentration(LIC) and elevated serum ferritin levels. An increased riskof iron-induced cardiac disease is observed in thalassemiapatients with LIC values above 15 mg of iron per gram ofdry weight of liver (15 mg Fe/g/dw), and in patientswith serum ferritin values above 2500 μg/L.6 Patientswith a number of other congenital and acquired anemias

who may receive frequent blood transfusions are alsosusceptible to the adverse effects of iron loading.7

LIC values greater than 7 mg Fe/g dw have beenreported in the literature to be associated with anincreased morbidity and mortality. Maintenance orreduction of LIC values to less than 7 mg Fe/g dw isdesirable as an endpoint.

Measurement of iron overload

Limitations of serum ferritin as a marker of iron overloadare well known but is important measurement inresource poor settings. Liver biopsy has been the “goldstandard” for iron balance studies, but the technique isinvasive, expensive, and subject to variability within andbetween research subjects.8

To avoid the need for invasive liver biopsy, liver ironconcentration (LIC) has been measured non-invasively bybiomagnetic susceptometry using a low criticaltemperature (low-TC) superconducting quantuminterference device (SQUID) biomagnetometer, whichallows the measurement of the paramagneticsusceptibility of the iron stored in the liver ashemosiderin and ferritin.1 In patients with iron overload,the results of biomagnetic susceptometry measurementsof hepatic non-heme iron have been reported to bestrongly correlated with those obtained by conventionalanalysis of liver biopsy.9 LIC values derived frommagnetic susceptometry as milligrams of iron per gram ofliver tissue (wet weight) were multiplied by a factor of3.33 to provide values per gram of liver tissue dry weight(mg Fe/g dw; the conventional units used for LIC).10

V.P. Choudhry and R. Naithani

760 Indian Journal of Pediatrics, Volume 74—August, 2007

Another technique used is a T2* imaging of heart. LowT2* values {< 8 ms compared with normal (> 20 ms)} arerelated to risk of heart failure and death in iron-overloaded thalassemia patients.11 T2* reports initiallyraised concerns about whether it is a good surrogate forcardiac iron concentration for technical reasons as well asthe paradox that liver iron correlated poorly with cardiacT2*. The poor correlation of T2* with hepatic iron is nowunderstood on a kinetic basis. The liver can be readilyunloaded by aggressive chelation much more rapidlythan can the heart, giving rise to patients with low T2*values (heart still iron loaded) while the liver has beenunloaded to values previously thought of as “safe.”12

Iron chelators

More than 40 yr of clinical experience with deferoxamine(Desferal, DFO) in iron-overloaded patients hasestablished that chelation therapy, when given at anadequate dose, reduces iron-related complications andthereby improves quality of life and overall survival.6Ahexadentate chelator, it binds iron tightly, and the iron-DFO complex is excreted in both urine and stool. Thestandard regimen to remove excess iron is bysubcutaneous (sc) infusion of DFO over 8-12 hours, on 3to 7 days each week because the plasma half-life is short(minutes).13 The DFO-iron chelate is charged and does notreadily enter and leave cells.8 Parenteral administrationand the daily nuisance of an infusion pump hinder theoptimal compliance.

Deferiprone is a bidentate chelator (3 moleculessurround one iron ion). An advantage of this compoundis that the iron (III) chelate of deferiprone carries no netcharge and therefore, can penetrate membranes easily,allowing removal of potentially toxic iron from tissues.6

Deferiprone often causes gastrointestinal symptoms,idiosyncratic side effects that are potentially severe

include erosive arthritis (5% to > 20%) and neutropenia(up to 5% of patients), including severe agranulocytosis(up to 0.5% of patients). Therefore close monitoring isrequired.

An expert group of the International Conference onOral Chelators (ICOC) committee have recommended theICOC combination protocol, which involves the use ofdeferiprone during the day (80-110 mg/Kg/day) anddeferoxamine (40-60 mg/Kg) of a minimum of threenights per week for rapid, safe and effective depletion ofexcess body iron. Following the depletion of excesscardiac and liver iron load deferiprone monotherapy atdoses exceeding 80 mg/Kg/day has also been suggestedfor preventing the reaccumulation of excess iron in theheart and other organs.14

Deferasirox (Exjade®, ICL670) is an N-substituted bis-hydroxyphenyl-triazole 1 that was selected from morethan 700 compounds as part of a rational drugdevelopment program. It represents a new class oftridentate iron chelators with a high specificity for iron.15

With a plasma half-life of 8 to 16 hours, it is practical toadminister the drug once a day and to maintain effectiveplasma level of the drug. It is able to scavenge non–transferrin-bound “labile plasma iron, the chemicalspecies responsible for tissue damage in iron-overloadedsubjects, by means of toxic oxygen intermediaries.16

Over the years it is now clear what should be theproperties of an ideal chelator. Unfortunately, in spite ofcontinuous work over four decades an ideal iron chelatorhas not been developed, possibly as it is required only bylimited number of patients and many researchlaboratories or pharmaceuticals are not inclined in thisarea. Essential characteristics of an ideal chelator alongwith those of DFO, deferiprone and deferasirox are

TABLE 1. Comparision of the Three Iron Chelators

Ideal chelator Deferoxamine Deferiprone Deferasirox

Molar iron chelating efficiency; High High (hexadentate Low (bidentate) Moderate (tridentate)Iron binding (drug: iron) 1:1 1:1 3:1 2:1Charge of iron (III) complex Uncharged Charged Uncharged UnchargedRoute of administration Oral Iv or subcutaneous Oral OralPlasma half-life Long enough to give Short (minutes) Moderate (< 2 hours) Long, 8-16 hours;

constant protection from remains in plasma atlabile plasma iron 24 h

Dosing schedule Once a day Continuous infusion Thrice a day Once a dayTherapeutic index High High Idiosyncratic side Probably high

effects are mostimportant

Important side effects None or only in iron- Local skin reactions at Abdominal discom- Abdominal discomfort;depleted subjects infusion sites; Auditory fort; erosive arthritis; rash or mild diarrhea

and retinal toxicity; Rare but severe upon initiation ofeffects on bones and agranulocytosis; therapy; mildgrowth; all at high doses; mild neutropenia increased creatinine

levelAbility to chelate intracellular High Probably lower than High in clinical Insufficient clinicalcardiac and other tissue deferiprone and and in vitro studies datairon in humans deferasirox

Current Status of Iron overload and Chelation with Deferasirox


summarized in Table 1 (adapted from Neufeld J).17

Mechanism of action

Deferasirox mobilize tissue iron by forming soluble,stable complexes that are then excreted in the feces.1 It isa tridentate iron chelator requiring 2 molecules of thedrug (as ferric iron has 6 coordination sites) to form thestable complex. Iron is chelated, both from the reticulo-endothelial cells (RE cells) as well as various parenchymaltissues. The chelated iron is cleared by the liver andexcreted through the bile. It also has the ability to preventmyocardial cell iron uptake, remove iron directly frommyocardial cells. In fact, ICL 670 readily yields iron toDFO.18 In animal models, on molar basis, it has beenshown to be 5 times more potent than DFO (hexadentate)and 10 times more potent than deferiprone (bidentate).19

Iron removal also depends on plasma concentration, hostfactors, degree of loading, and rate of accessibility ofstored iron to chelator.

Pharmacokinetics

Drug is orally effective with bioavailability being close to70%.20 The median time to reach the maximalconcentrations of deferasirox ranged from 1 to 2 hours inboth the 10 and 20 mg/Kg/day dose groups and levelspersisted at detectable amounts for at least 24 hours (h)after one dose. Mean elimination half-life of ICL670 inplasma was between 12 and 16 h after multiple doseadministration. Pharmacokinetic steady state wasreached after 3 days of treatment based on trough plasmaconcentrations gathered over the study. It accords withthe expected time to steady state on the basis of half life ofthe drug in plasma.1,20 The fact that UIBC showedsustained increase after one oral dose of ICL670 suggeststhat the drug might eliminate or reduce serum non-transferrin bound iron thought to be a particularlycardiotoxic moiety of the expanded iron pool ofchronically transfused patients with thalassemia.20

The continuous presence of significant plasma levelseven 24 hours after oral intake of DSX over the timecourse of 360 days is one of the most promisingproperties found for this drug. This may narrow thepathway for iron from sequestered red blood cells inmacrophages into organs and glands susceptible to ironcatalyzed toxicity effects such as the heart, pituitarygland, or pancreas.21

Iron excretion occurs almost entirely in the feces and is

dose-dependent, averaging 0.13, 0.34 and 0.56 mg/kg/day at deferasirox doses of 10, 20 and 40 mg/Kg/day,respectively.16 ICL670 produced a linear dose-dependentrise in net iron excretion, with wide variation seen at 40-mg/Kg/day. At the mid-dose range (20 mg Kg–1 day–1)variation was much less.16 It is highly selective for ironand does not induce the excretion of zinc or copper.19

Clinical Trials

Deferasirox (ICL670, Exjade) belongs to a new class oforal tridentate chelator, N-substituted bis-hydroxyphenyltriazoles. Deferasirox underwent extensivesafety testing and clinical trials including preclinicalstudies.22 Initial phase 1 and iron balance studies,16 phase2 efficacy studies in adult23 and pediatric24 thalassemiapatients, patients with a variety of anemias or unable/noncompliant with DFO,25 and the phase 3 clinical trialhave been conducted.8

The largest clinical trial8 showed that patientsreceiving 5 mg/Kg deferasirox and the majority ofpatients receiving 10 mg/Kg deferasirox (those withbaseline LIC values ≤ 7 mg Fe/g dw), all 3 parameters i.e.LIC, serum ferritin and net body iron balance indicated anincrease in iron burden. In patients receiving 20 mg/Kgdeferasirox (those with baseline LIC values LIC between7 and ≤ 14 mg Fe/g dw), the iron burden was essentiallyunchanged; while the patients recieving 30 mg/Kg(corresponding to an LIC > 14 mg Fe/g dw), the ironburden was reduced. In frequently transfused patients,defined as individuals receiving 2 to 4 units per month (or7-14 mL/Kg/mo) of packed RBCs, oral deferasirox at aonce-daily dose of 20 mg/Kg led to maintenance of LIC,neutral iron balance, and stable serum ferritin levels. Theresults obtained are consistent with a previouslypublished short-term study examining the ability ofdeferasirox to remove iron from the body.16

Another large phase 2 study1, patients wererandomized to receive once-daily deferasirox (10 or 20mg/Kg; n=24 in both groups) or DFO (40 mg/Kg, 5days/week; n=23) for 48 weeks. Decreases in liver ironconcentration (LIC) were comparable in the deferasirox20 mg/Kg/day and DFO groups; baseline values of 8.5and 7.9 mg Fe/g dw fell to 6.6 and 5.9 mg Fe/g dw,respectively, by week 48.

Nisbet et al concluded that ICL 670 given once daily at20 mg/kg seems to be an effective orally active ironchelator and is reasonably well tolerated.16

TABLE 2. Clinical Studies of Deferasirox

Reference Phase Number of patients Dose (mg/kg) Outcome

Nisbet-Brown E (2003)11 II 24 10,20,40 Safe, Effective at 20 and 40 mg/kg/dayGalanello R* (2006)26 II 40 20 Safe, not effectivePiga (2006)1 II 48 10 and 20 Effective and safeCappellini MD (2006)18 III 296 5,10,20,30 Safe, Effective at 20 and 30 mg/kg/day

*Pediatric study



The one pediatric study published so far has howeverfailed to document clinical efficacy in 40 children at 20mg/kg/day doses used. The drug however was welltolerated and safe.26 Table 2 summarizes the clinicalstudies done.

In initial pharmacokinetics it was suggested thatdeferasirox can lead to iron deposition in myocardiumbecause of its lipophilicity and long half-life.27 However,in small clinical studies, it has improved cardiac function.Porter et al showed improved myocardial T2* from 18 msto 23.1 milliseconds in a cohort of 23 patients treated withdesferasirox though there was no difference in leftventricular ejection fraction.28 This observation needs tobe confirmed on large multicentric studies.

Adverse reactions

The most common adverse events with an apparentrelationship to deferasirox were transient gastrointestinalevents in 15.2% of patients that included abdominal pain,nausea and vomiting, diarrhea, and constipation, as wellas skin rash in 10.8% of patients. The gastrointestinalevents lasted a median of 8 days or less. These symptomsrarely required dose adjustment or discontinuation ofdeferasirox. Mild, dose-dependent increases in serumcreatinine were observed in 38% of patients receivingdeferasirox, most frequently at doses of 20 and 30 mg/Kgin the population of patients having the most dramaticdecrease in LIC and serum ferritin. These increases weresometimes transient and generally within the normalrange, and they never exceeded 2 times the upper limit ofnormal. Similar increases in serum creatinine occurred in14% of patients receiving deferoxamine.1,8

Deafness, neurosensory deafness, or hypoacusis werereported as adverse events in 1 patient on deferasirox(0.3%). Cataracts or lenticular opacities were reported asadverse events in 1 (0.3%) patient on deferasirox.9 Noretinal findings, lens abnormalities or hearing losses weredetected during regular ophthalmological and auditorytesting in another study.1

Zinc and copper levels at the end of the study withdeferasirox were comparable with those observed inpatients receiving deferoxamine.1,8 Cardiac toxicity of anyform was not identified. A similar percentage of patientsreceiving deferasirox and deferoxamine experiencedcardiac adverse events (deferasirox 5.1%, deferoxamine6.9%) and serious adverse events (deferasirox 0.7%,deferoxamine 1.0%).8

There were no episodes of neutropenia,agranulocytosis or thrombocytopenia in any of thetreatment groups. No adverse effects on growth ordevelopment in pediatric patients were observed. Itshould also facilitate patient compliance, a critical factorin effective patient management, and thereby helpmaintain low iron burdens in patients requiring frequentblood transfusions.1,8

There were no episodes of arthralgia in patientsrandomized to deferasirox.1,8 Elevations of urinary β-2microglobulin were detected in all treatment groups butwere more frequent in patients receiving deferasirox 20mg/kg/day. The elevations were transient and low-grade (<10-fold above the upper limit of normal) andtended to normalize despite continuation of the studydrug.1

Precautions

In patients with hepatic dysfunction (transaminases upto5 times upper limit of normal), the drug was usedwithout any adverse outcome. There has been a dosedependent increase in serum creatinine values. Dataregarding safety of drug in renal dysfunction is lacking.Regular monitoring of hepatic and renal functions isdesirable till more data is generated. Drug is safe inchildren over 2 years. Data for safety in pregnancy,lactating mothers and children below 2 years is notavailable.

Dose, formulations and cost

Initially the drug is started at 20 mg/Kg/day orally oncea day. Dose is gradually increased in 5-10 mg/Kg/dayevery 3-6 months depending upon the serum ferritin, LICor T2* values. In view of lack of clinical data, themaximum dose is 30 mg/Kg/day. The drug is suppliedin strength of 125, 250 and 500 mg of tablets. The correctnumbers of tablets are dispersed in a glass of non-carbonated mineral water, stirred and ingested 30minutes before breakfast.

ICL 670 (Exjade) was approved in November 2005under the FDA’s accelerated approval program, whichallows the agency to approve products for serious or life-threatening diseases based on early evidence of theproduct’s effectiveness.29 Companies are required to dofurther studies to verify the clinical benefits. Exjade alsoreceived Orphan Drug Designation, which is granted toproducts that treat diseases affecting fewer than 200,000people in the United States. The Orphan Drug Actprovides a seven-year period of exclusive U.S. marketingto the first sponsor that obtains marketing approval for adesignated orphan drug.

Future developments

A number of experimental iron chelators such as DMDFT(structure activity related compund of desferrithiocin) areunder clinical evaluation.30 This is highly active oral ironchelator and promotes iron excretion in the primatemodel at 3 times that of subcutaneous DFO. No toxiceffects have been noted so far. The drug is ready forphase I trials.

Hydroxypyridone ester analogs of deferiprone withfavorable in vivo drug metabolism have been designed tospecifically target low molecular weight iron pool in liverin experimental studies. Toxic effects similar to

Current Status of Iron overload and Chelation with Deferasirox


deferiprone have been observed in small study.Increasing the pFe(III) values allows the chelator toeffectively scavenge iron at lower concentration and alsodissociate less easily.30

Another highly effective oral iron chelator 4’-(OH)-DAFT is a desferrithiocin analogue. It is orally active andpromotes iron excretion almost 3 times that of DFO.Preclinical studies have demonstrated no toxic effects.30

Hydroxypyridinone ester drugs have also beendeveloped and its analogue CP502 has been selected forpreclinical development by the pharmaceutical companyApotex Inc. (Canada).31

Pyridoxal isonicotinoyl hydrazone (PIH) is an orallyactive tridentate iron chelator which binds ironoctahedrally. No toxicity has been noted and whenadministered in doses of 30 mg/Kg three times a day for3 weeks resulted in negative iron balance in non-transfused subjects. However, this dose may not besufficient in transfusion dependent patients.32

Another class of drugs, which has been effective, is 2-pyridylcarboxaldehyde isonicotinoyl hydrazoneanalogues. A dose dependent fecal iron excretion wasobserved and no signs of toxicity were seen in micetreated with 50-100 mg/Kg/day for 3 weeks. This agentmay be a future candidate in treatment of iron overload.30

Development of an ideal iron chelator has been amajor challenge. DFO since its development has been thegold standard in spite of various odds such as parenteralcontinuous administration, high cost, poor compliance,poor chelation from myocardium etc. It was only afterthree decades that deferiprone was developed which isan effective oral iron chelator but has toxicity in the formof arthropathy, agranulocytosis etc. Over the last decadedeferasirox has been developed which appears quitepromising based upon various clinical trials (Table 2).FDA has recently approved the drug so that the largernumber of patients could be benefited. Only time will tellwhether it will replace DFO as a gold standard drug.However, there is need for continuous research onchelating agents as no agent till now fulfills all theessentials of an ideal iron chelator. Deferasirox, however,is expected to improve the long-term survival and qualityof life for iron overloaded patients all over the world.

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