iron chelation, quo vadis?

Iron chelation, quo vadis?Hanspeter Nick

Orally bioavailable chelators for transfusional iron overload

have been sought since the introduction of deferoxamine

(Desferal1) in 1962. Despite tremendous efforts, to date, only

deferiprone (Ferriprox1) and deferasirox (Exjade1) have

successfully reached the market, reflecting the difficulty to

combine oral activity and safety. Owing to the risk of failure, few

new oral chelators can be expected in the future for the

treatment of transfusional iron overload. As iron is involved in

many disease processes, deferiprone and deferasirox have

been proposed to be potentially useful in a variety of indications

not characterized by general iron overload. Although it may be

possible to obtain clinical benefit from current compounds,

more selective chelators tailored to the particular target are

needed for successful intervention in these indications.

Addresses

Novartis Pharma AG, Lichtstrasse 35, CH-4002 Basel, Switzerland

Corresponding author: Nick, Hanspeter ([email protected])

Current Opinion in Chemical Biology 2007, 11:419–423

This review comes from a themed issue on

Orphan Diseases

Edited by Kip Guy

Available online 23rd July 2007

1367-5931/$ – see front matter

# 2007 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.cbpa.2007.04.025

IntroductionSeveral recent reviews describe the properties of the pre-

sently available iron chelators, the status of iron chelation,

and the many potential uses of iron chelators in different

disease areas [1�,2�]. Given the topic of the present paper,

inevitably, there will be overlap with statements already

made by those authors. In addition, radically new concepts

and views cannot be expected in such an ‘old field’ in which

many eminent individuals have given their opinions.

Rather, this paper illuminates the known scene from a

slightly different angle by firstly, placing the search for iron

chelators in a historical context, providing a notion of the

difficulty to develop iron chelators with an adequate safety

profile; secondly, assessing the likelihood of new chelators

emerging for use in transfusional iron overload; and thirdly,

discussing the use of iron chelators that have been devel-

oped for transfusional iron overload in other indications

characterized by moderate or no iron overload.

In summary, touching on various aspects of iron chelation,

the intention is to emphasize the difficulty in developing

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iron chelators and to provide the author’s view on the

potential usefulness of iron chelators in various diseases.

Transfusional iron overloadFor many patients, regular red blood cell transfusions

represent life-saving therapy. In thalassemia major, a dis-

ease that was usually fatal by the age of 5, transfusion

therapy has eliminated compensatory bone marrow expan-

sion, permitting normal or near-normal growth and de-

velopment [3]. However, iron overload is an inevitable

consequence in transfusion-dependent patients who do

not receive effective iron chelation therapy because iron,

once in the human body, is virtually retained. Each unit of

blood contains approximately 200 mg of iron and often two

to three units have to be given each month, which amounts

to an average daily iron influx of 13–20 mg. This may be

compared with a daily iron uptake from the diet of 1–2 mg,

which approximately equates the daily loss through cell

shedding and/or bleeding. In 1964, the initiation of a high

transfusion regimen to keep hemoglobin levels at about

12 g/dl [4] resulted in a dramatic improvement of childrens’

quality of life, but left iron overload as the outstanding

clinical problem. Complications due to iron overload in-

clude hematologic, cardiac, hepatic, endocrine and derma-

tologic disorders [5]. Prevention of iron overload is possible

by the use of selective and high affinity iron chelators,

which mobilize body iron and are excreted as iron chelate.

DeferoxamineDeferoxamine (Desferal1, DFO) was introduced into the

market in 1962, just one-and-a-half years after the first

studies in humans. DFO therapy constituted a quantum

leap for the treatment of transfusional iron overload

in thalassemia major patients. However, it took another

14 years of data collection and analysis to propose an

administration protocol with optimized drug efficacy [6], a

protocol that, in essence, is still used today: slow subcu-

taneous infusion of DFO over 8–12 hours, 5–7 days per

week for life. Survival of patients greatly increased [7];

however, it was shown to be highly dependent on com-

pliance with this harsh regimen. The need for an orally

active iron chelator was apparent from the very beginning

of chelation therapy.

Orally active iron chelatorsDespite major efforts in many laboratories, few iron

chelators progressed to an advanced clinical stage. 2,3-

Dihydroxybenzoic acid was initially found to be interest-

ing [8] but was later reported to be clinically ineffective

[9]; cholylhydroxamic acid [10], pyridoxal isonicotinoyl

hydrazone [11], and analogs [12] as well as desferrithiocin

[13] were investigated preclinically and later abandoned.


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http://dx.doi.org/10.1016/j.cbpa.2007.04.025

420 Orphan Diseases

The reasons for these and many other failures are

certainly multifaceted, a major one being the difficulty

to separate the pharmacologic effect of iron removal from

toxicity, probably a direct consequence of the fact that

orally active chelators are more likely to penetrate tissues

and to indiscriminately chelate ubiquitously needed iron.

Deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one, L1,

CP20, Ferriprox1), a low molecular weight, bidentate,

orally active iron chelator, was first described in 1982 [14].

This compound took a very unusual course of develop-

ment and initially was given to patients despite incom-

plete preclinical evaluation [15,16]. Deferiprone was

approved in August 1999 by the European Regulatory

Authority as a second-line therapy for thalassemia

patients who are unable to take DFO. This approval of

the first orally active iron chelator constituted an ad-

vancement in chelation therapy, although it was clear

that improvements with regard to side effects and efficacy

of deferiprone were desirable.

In 1994, an extraordinarily large chemistry program started

at CIBA (now Novartis) that allowed work on virtually all

known chemical classes of iron chelators. Approximately,

700 compounds were synthesized and subjected to a rig-

orousfiltering process,which includedthedetermination of

iron binding, testing of oral activity and, importantly, test-

ing of subchronic tolerability in animals at a very early stage

in research. The latter was a measure to avoid past negative

experience with ‘promising’ compounds that had to be

abandoned at a relatively advanced stage because of unac-

ceptable side effects in animals when used chronically.

Deferasirox (4-[(3,5-bis-(2-hydroxyphenyl)-1,2,4)triazol-1-

yl]-benzoic acid) — the basic structure of this tridentate

chelator was proposed through computational methods [17]

— emerged as the compound best combining high iron

affinity and selectivity, oral activity, and tolerability [18].

Following extensive clinical studies [19��,20], in Novem-

ber 2005 the Food and Drug Administration and the Swiss

Health Authorities approved deferasirox (Exjade1) for use

in transfusional iron overload for individuals>2 years of age

[21]. It has since been registered in more than 75 countries.

Forty-five years after the introduction of DFO, there are

now three options for patients with transfusional iron over-

load. Too few from a patient’s perspective, but realistically

Desferrioxamine mesylate is the active

substance of Desferal1 Mw 656.8

Deferasirox is t

Exjade1 Mw 37


reflecting the difficulty to devise a chelator that is able to

remove iron from the body without causing unwanted side

effects. The profile of an iron chelator has a number of

important requirements. In transfusional iron overload, it

must possess high affinity and selective iron binding, and

be orally available. Additionally, it must be able to remove

iron from the liver (storage iron), as well as from critical sites

such as the heart and endocrine organs, maintain low levels

of nontransferrin-bound iron to prevent uptake by par-

enchymal cells, and accomplish this without compromising

its safety and efficacy profile. From a medicinal chemistry

and designing perspective, such a ‘soft’ target is extremely

challenging as there is no simple strategy to ‘improve’ an

iron chelator. For transfusional iron overload, few new

compounds can be expected in the future because of

the considerable expense and a high risk of failure.

A possibility to potentially expand the limited armamen-

tarium of iron chelators for transfusional iron overload is to

combine chelators. Combination of iron chelators could

increase iron mobilization and excretion as a result of

differential access of iron pools and may also allow dose

reduction while maintaining efficacy. The DFO/deferi-

prone combination [22] is increasingly used and, predic-

tably, the DFO/deferasirox combination will be tried in

the future. Although deferasirox as a single agent given at

clinical doses is present in the circulation for 24 hours at

clinically relevant plasma levels, under special circum-

stances (e.g. when fast removal of iron is required), the

DFO/deferasirox combination may be useful. However,

these regimens come at the cost of requiring slow sub-

cutaneous or intravenous infusion of DFO. It is important

to note that these combination regimens do not fall within

the current approved labeling of the compounds.

The combination of the two orally active chelators defer-

asirox and deferiprone has been suggested. However,

unlike with the DFO/deferiprone and DFO/deferasirox

combinations where a hexadentate chelator is combined

with a bidentate (deferiprone) or tridentate (deferasirox)

chelator, one has to expect formation of mixed [defer-

iprone–Fe–deferasirox] complexes. Accordingly, this may

raise new safety concerns.

Molecular structure of marketed chelatorsand distribution characteristics

he active substance of

3.4

Deferiprone is the active

substance of Ferriprox1 Mw 139.2


Iron chelation, quo vadis? Nick 421

Volume of distribution is small indicating

that blood is the main compartment.

Promotes iron excretion into urine

(macrophage iron and iron collected in the

circulation) and bile (liver iron). Mobilization

of liver iron indicates that the liver is

an important target organ. BBB did

not cross a significant extent [23]

The small volume of distribution and the

high protein binding indicate that blood is

an important compartment. All iron

(macrophage, circulation, hepatocytes) is

excreted into bile [24]. Mobilization of liver

iron indicates that the liver is an important

target organ [20,24]. Animal data indicate that

the BBB did not cross a significant extent

[in preparation]

Volume of distribution is

relatively large indicating

exposure of various tissues

Crosses the BBB (extent

unknown, possibly limited due

to short half-life). Preliminary

clinical data indicate effect in

Friedreich’s ataxia [25]

Iron chelation in hemochromatosisHemochromatosis occurs because of gene mutations in the

hemochromatosis, hemojuvelin, hepcidin, transferrin-receptor 2,

or ferroportin gene [26]. The ‘unifying pathogenetic cause’

[27��] is hepcidin as, except for ferroportin, mutations in the

various genes cause a lowering of hepcidin levels, promot-

ing increased uptake of dietary iron from enterocytes and

increased flux of iron from red blood cell processing macro-

phages into the circulation. This leads to the characteristic

iron deposition pattern in hemochromatosis: comparatively

low iron contents in macrophages and highly iron-laden

hepatocytes. Commonly, hemochromatosis is associated

with disorders of the liver, whereas in the very rare types of

juvenile hemochromatosis (hemojuvelin and hepcidin gene

mutations) the first disease manifestations are of endocrine

and cardiac nature due to much faster iron loading.

As hemochromatosis patients are not anemic, iron over-

load is generally treated by phlebotomy. Despite this

generally safe and effective mode of iron removal, not

all patients are candidates for phlebotomy because of

underlying anemia, heart disease, or poor venous access,

and compliance with regular phlebotomy may be an issue.

Thus, there is a need for an alternative [28], and this need

may be met by iron chelators. In view of the differing iron

loading patterns of transfusional iron overload (macro-

phages and hepatocytes) and hemochromatosis (mainly

hepatocytes), the side effect profile of any one chelator

may differ in the two indications, mandating additional

safety evaluation.

Deferasirox has proven to be very efficacious in removing

liver iron [18,29] and constitutes a viable candidate to

explore the value of chelation therapy in the hemochro-

matosis indication. Because of the unmet medical needs

defined above, a phase I/II trial is underway to assess the

safety and efficacy of deferasirox in patients with iron

overload secondary to hereditary hemochromatosis.

Other uses of chelatorsIron depletion by using chelators has been proposed as a

strategy to interfere with the progression of a multitude of

diseases such as cancer [30], liver [31], infectious [32] and

neurologic [33] diseases, and atherosclerosis. Although

there is often no systemic iron overload associated with

many disorders, individual organs may have increased iron

levels. Although iron is not regarded as the cause of the


disease, it may play a rather important role in disease

progression, be it as an element to promote cellular growth

and proliferation, or an element to increase oxidative stress

by catalytic radical formation.

It is logical to test the approved chelators such as defer-

iprone and deferasirox in cell and animal models for the

above proposed conditions and often, in a first attempt,

results obtained from such models look surprisingly

positive. However, realistically what is shown in most

cases is that iron is important and that part of the disease

mechanism may involve iron. On the contrary, surprising

clinically relevant effects are sometimes seen: a recent

case report is strongly indicative of a dramatic, life-saving,

effect of deferasirox in rhinocerebral mucormycosis, a

deadly fungal infection [34��]. In the reported case,

standard therapy combined with short-term adminis-

tration of deferasirox eradicated the infection, an effect

that is most likely based on the strong iron dependency of

the micro-organism.

Although it may be possible to obtain clinical benefits for

these diseases from current compounds, what is really

needed are more selective chelators tailored to specifi-

cally act on the particular targets for successful interven-

tion in these indications. Targets may include individual

organs, parts of organs, macromolecular structures, or

relevant iron-dependent enzymes.

Iron has been associated with neurologic diseases; hence,

iron chelators that could access the brain are high on the

wish-list of investigators with an interest in Parkinson’s

disease (PD), Alzheimer’s disease (AD), and Friedreich’s

ataxia (FA) [35�] among others. However, again, once the

chelator has crossed the blood–brain barrier, what is

needed is selective targeting to specific brain areas or

to specific supramolecular structures whose formation is

believed to be supported by the presence of iron (e.g. in

AD). It cannot be excluded that a nontargeted chelator

might be useful in some instances, perhaps when a highly

iron-loaded brain area merely needs to be ‘iron diluted’ to

regain function. For both targeted and nontargeted che-

lators, the question remains as to what would be the fate

of chelated brain iron. Ideally, the iron complex is brought

back into the peripheral circulation and excreted. How-

ever, for the moment, availability of well brain-penetrat-

ing iron chelators that could be used as tools to scrutinize


422 Orphan Diseases

the various concepts in animal models would already be a

great advancement.

ConclusionsOrally active iron chelators for the use in transfusional

iron overload with an adequate safety profile have proven

challenging to develop, and the failure rate has been high.

Iron chelators developed for transfusional iron overload

could be valuable for the treatment of hemochromatosis,

and a clinical trial of deferasirox is currently underway to

explore this.

Iron has been implicated in many diseases; however, use

of chelators that have been developed for systemic iron-

overload conditions in cases of low or no iron overload

needs to be carefully studied because there exists the risk

of iron depletion and anemia. The value of chelation

therapy may be improved by the design of very selective

iron chelators, which show regional selectivity or selec-

tivity for the targeted iron-containing structures.

Iron is considered to be a very important factor for disease

progression in PD, AD, and FA. Therefore, availability of

central nervous system penetrating chelators is highly

desirable as a first step to investigate preclinical proof

of concept in animal disease models.

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest�� of outstanding interest

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Iron chelation, quo vadis? Nick 423

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35.�

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iron chelation, quo vadis?

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