Drug evaluation: Deferitrin for iron overload disorders

Deferitrin (GT-56-252) is the first drug in a class of desferrithiocin-derived hexadentate iron chelators. Genzyme Corp is developing this compound as an oral drug for the treatment of severe iron overload in people who require repeated erythrocyte transfusion for management of chronic anemia such as beta-thalassemia major. In phase I clinical trials in adults with beta-thalassemia, deferitrin promoted iron excretion in a dose-related manner and was well tolerated as both a liquid and capsule in fed and fasted states. There were no serious adverse events or significant laboratory abnormalities. The author concludes that deferitrin may be useful as chelation monotherapy or as part of combination or doublet chelation therapy for the treatment of severe iron overload in patients with beta-thalassemia major if its favorable pharmacokinetic profile, efficacy, safety and tolerability are confirmed in more extensive clinical trials. A phase I/II clinical trial that began in September 2003 has reportedly completed recruitment.     

Iron chelator research: past,present, and future

The occurrence of in vivo iron toxicity in the human body can be categorized into iron overload and non-iron overload conditions. Iron overload conditions are common in beta-thalassemia and hereditary hemochromatosis patients, and anthracycline mediated cardiotoxicity is an example of a non-iron overload condition in cancer patients, in which the toxicity is iron-dependent. While hundreds of iron chelators have been evaluated in animal studies, only a few have been studied in humans. Examples of iron chelator drugs are desferrioxamine (DFO), deferiprone (L1), and dexrazoxane (ICRF 187). The compound ICL670 has completed phase II clinical trials and a phase III trial is planned in 2003. Triapine is currently in phase II clinical trial as an anticancer agent. CP502, GT56-252, NaHBED, and MPB0201 are examples of new chelators in preclinical/clinical development. In the past decade, many new viable utilities for iron chelators have been reported. This includes the use of iron chelators as antiviral, photoprotective, antiproliferative, and antifibrotic agents. This review will focus on the status of drug development for the treatment of iron overload in patients with beta-thalassemia and the potential use of iron chelators in the prevention and treatment of other diseases.     

Iron chelators as therapeutic iron depletion agents

The great promise of iron depletion as a therapeutic strategy for various diseases, including iron overload, cancers, Alzheimer’s disease, Parkinson’s disease, tuberculosis, HIV, and fungal and malaria infection, has stimulated research on the development of iron chelators as iron depletion agents. In November 2005, the FDA approved deferasirox (ICL670A; Exjade^®), the first once-daily oral drug for treatment of chronic iron overload. So far, five iron chelators, deferoxamine, deferiprone, deferasirox, dexrazorane and ciclopirox, have been approved for use in iron overload, anticancer or antifungal therapy. Triapine^® is in Phase I and II clinical trials for the treatment of various metastatic and solid cancers. A desferrithiocin analogue, deferitrin, is presently in a Phase I trial for the treatment of iron overload diseases. Among the iron chelators being evaluated in preclinical settings are the analogues of deferiprone, pyridoxal isonicotinoyl hydrazone, desferrithiocin, deferoxamine, thiosemicarbazone, tachpyridine, N,N′-bis(2-hydroxybenzyl)ethylenediamine-N,N′-diacetic acid and hydroxyquinoline. This review describes the comparative properties of iron chelators in clinical use and evaluates the patent status of the novel synthetic iron chelators in preclinical settings.     

Pharmacotherapy of iron overload in thalassaemic patients

The recommended treatment for thalassaemia major is regular blood transfusions, although these lead to the harmful accumulation of iron in the body. If untreated, iron overload is responsible for heart, liver and endocrine diseases. The only two iron chelating agents available for the treatment of iron overload are deferoxamine and deferiprone. The standard iron chelation therapy is based on the use of deferoxamine. Although this drug was introduced in the 1970s, it still remains the treatment of choice. Recently, another iron chelator, deferiprone, became available for clinical use in the European Community. Deferiprone is indicated as second-line treatment in patients with thalassaemia major, for whom deferoxamine therapy is contraindicated or in patients who present with serious toxicity to deferoxamine therapy. This paper examines this chelating agent and compares it with deferoxamine in order to ascertain the current and potential contribution of deferiprone to the treatment of thalassaemic patients.     

Pharmacotherapy of iron overload in thalassaemic patients

The recommended treatment for thalassaemia major is regular blood transfusions, although these lead to the harmful accumulation of iron in the body. If untreated, iron overload is responsible for heart, liver and endocrine diseases. The only two iron chelating agents available for the treatment of iron overload are deferoxamine and deferiprone. The standard iron chelation therapy is based on the use of deferoxamine. Although this drug was introduced in the 1970s, it still remains the treatment of choice. Recently, another iron chelator, deferiprone, became available for clinical use in the European Community. Deferiprone is indicated as second-line treatment in patients with thalassaemia major, for whom deferoxamine therapy is contraindicated or in patients who present with serious toxicity to deferoxamine therapy. This paper examines this chelating agent and compares it with deferoxamine in order to ascertain the current and potential contribution of deferiprone to the treatment of thalassaemic patients.     

Optimizing therapy for iron overload in the myelodysplastic syndromes: recent developments

The myelodysplastic syndromes (MDS) are characterized by cytopenias and risk of progression to acute myeloid leukaemia (AML). Most MDS patients eventually require transfusion of red blood cells for anaemia, placing them at risk of transfusional iron overload. In β-thalassaemia major, transfusional iron overload leads to organ dysfunction and death; however, with iron chelation therapy, organ function is improved, and survival improved to near normal and correlated with the degree of compliance with chelation. In lower-risk MDS, several nonrandomized studies suggest an adverse effect of iron overload on survival and that lowering iron with chelation may minimize this impact. Emerging data indicate that chelation may improve organ function, particularly hepatic function, and a minority of patients may have improvement in cell counts and decreased transfusion requirements. While guidelines for MDS generally recommend chelation in selected lower-risk patients, data from nonrandomized trials suggest iron overload may impact adversely on the outcome of higher-risk MDS and stem cell transplantation (SCT). This effect may be due to increased transplant-related mortality, infection and AML progression, and preliminary data suggest that lowering iron may be beneficial in this patient group. Other areas of active and future investigation include optimizing the monitoring of iron overload using imaging such as T2* MRI and measures of labile iron and oxidative stress; correlating new methods of measuring iron to clinical outcomes; clarifying the contribution of different cellular and extracellular iron pools to iron toxicity; optimizing chelation by using agents that access the appropriate iron pools to minimize the relevant clinical consequences in individual patients; and incorporating measures of quality of life and co-morbidities into clinical trials of chelation in MDS. It should be noted that chelation is costly and potentially toxic, and in MDS should be initiated after weighing potential risks and benefits for each patient until more definitive data are available. In this review, data on the impact of iron overload in MDS and SCT are discussed; for example, several noncontrolled studies show inferior survival in patients with iron overload in these clinical settings, including an increase in transplant-related mortality and infection risk. Possible mechanisms of iron toxicity include oxidative stress, which can damage cellular components, and the documented impact of lowering iron on organ function with measures such as iron chelation therapy includes an improvement in elevated liver transaminases. Lowering iron also appears to improve survival in both lower-risk MDS and SCT in nonrandomized studies. Selected aspects of iron metabolism, transport, storage and distribution that may be amenable to future intervention and improved removal of iron from important cellular sites are discussed, as are attempts to quantify quality of life and the importance of co-morbidities in measures to treat MDS, including chelation therapy.     

Optimal management strategies for chronic iron overload

Iron overload is characterised by excessive iron deposition and consequent injury and dysfunction of target organs, especially the heart, liver, anterior pituitary, pancreas and joints. Iron overload disorders are common worldwide and occur in most major race/ethnicity groups. Physiological mechanisms to excrete iron are very limited. Thus, all patients with iron overload need safe and effective treatment that is compatible with their co-existing medical conditions. Treatments for iron overload include phlebotomy and erythrocytapheresis that remove iron predominantly as haemoglobin, and chelation therapy with drugs that bind excess iron selectively and increase its excretion. The most important potential benefits of therapy are preventing deaths due to cardiac siderosis and hepatic cirrhosis. Preventing iron-related injury to endocrine organs is critical in children. Successful treatment or prevention of iron overload increases quality of life and survival in many patients. This article characterises the major categories of iron overload disorders, tabulates methods to evaluate and treat iron overload, and describes treatment options for iron overload disorders. Research needed to advance knowledge about treatment of iron overload is proposed.     

Deferasirox: An effective once-daily orally active iron chelator

Deferasirox (ICL670) in an orally absorbed tridentate chelator of iron (III), intended as a once-daily monotherapy for transfusional iron overload. Deferasirox was identified by Novartis from over 700 molecular entities in preclinical screening, comparing favorably with parenteral desferrioxamine or oral deferiprone. Clinical phase I and II studies demonstrated an exclusively fecal route of iron excretion, with a long plasma half-life, suitable for once-daily dosing and 24-hour protection from labile iron. Systematic large-scale prospective clinical trials have been completed in thalassemia major, sickle cell disease, and other transfusionally dependent anemias, such as myelodysplastic syndrome. These show dose-dependent reduction in body iron and have identified doses necessary either to stabilize or to decrease iron loading according to transfusion requirements. Tolerability after more than two years in phase III studies is good, with a low trial dropout rate and no drug-related arthropathy or agranulocytosis. An early, nonprogressive serum creatinine increase, remaining within normal ranges, was seen in about one-third of patients. Preliminary clinical findings using T2* as well as preclinical models suggest good drug access to myocardial iron. Deferasirox is currently registered as monotherapy for transfusional iron overload in more than 65 countries worldwide, including the United States and in the European Union.     

New chelation therapies and emerging chelating drugs for the treatment of iron overload

Iron chelation therapy using deferoxamine or deferiprone (L1) is effective for the treatment of most transfused iron-loaded patients. The combination administration of deferiprone in the daytime and deferoxamine in the night appears to be universally effective in rapidly achieving negative iron balance. The cardiac iron removal effect of deferiprone increases the prospects of longer survival in beta-thalassaemia patients. New chelators have reached the stage of clinical development such as deferitrin, 1-allyl-2-methyl-3-hydroxypyrid-4-one (L1NAll) and the starch deferoxamine polymers. Deferasirox has received a conditional approval in the US under the FDA-accelerated approval regulations, but needs further verification of its efficacy and safety. Future iron chelation therapies are likely to be based on combinations of chelating drugs.     

祛铁治疗对再生障碍性贫血患者造血恢复的作用

目的评价祛铁治疗对再生障碍性贫血患者造血恢复的作用。方法1例重型再生障碍性贫血患者经免疫抑制治疗11个月,外周血细胞水平无明显改善,并出现输血相关铁过载。加用祛铁胺规律祛铁治疗。结果祛铁治疗5个月后患者脱离血小板输注,7个月脱离红细胞输注,9个月停止祛铁治疗,13个月外周血细胞水平恢复正常,无不良反应发生。结论对输血依赖的骨髓衰竭患者,应密切监测血清铁蛋白水平变化,出现铁过载后及时进行祛铁治疗,有助于患者造血恢复。     

Effects of silymarin on the proliferation and glutathione levels of peripheral blood mononuclear cells from beta-thalassemia major patients

Iron toxicity in beta-thalassemia major is the main cause of oxidative stress and cell mediated immune deficiencies. Despite indicative signs of severe oxidative deficiencies associated with beta-thalassemia major, such as decreased level of plasma antioxidants and depletion of erythrocyte glutathione, little is known about intracellular redox status of immune cells. Since glutathione is a primary intracellular antioxidant and plays an essential role in several functions in T cells, in this study intracellular glutathione (GSH) levels as well as proliferation of PHA-activated peripheral blood mononuclear cells (PBMC) were investigated in 28 beta-thalassemia major patients and 28 healthy age-matched individuals. Considering the potential benefits of flavonoids in the therapy of oxidative stress, the effects of silymarin on the GSH levels and proliferation of PBMC from normal and thalassemia individuals were further examined. Quantitative determination of intracellular GSH and proliferative response of PBMC to PHA were performed before and after 72 h incubation of PBMC with various concentrations of silymarin (0, 5, 10, or 20 mug/ml). Results demonstrated a significant reduction of GSH and proliferation in beta-thalassemia major cells; however treatment with silymarin led to restoration of both GSH levels and PBMC proliferation in thalassemia patients. Considerably low levels of GSH and depressed proliferative response of PBMC in beta-thalassemia major may be responsible for the cell mediated immune abnormalities in iron overload conditions. Moreover, the GSH restoration and improvement of PBMC growth by silymarin is a possible explanation for its recently reported antioxidant and immunostimulatory activities. These data suggest the benefit of using flavonoids to normalize immune dysfunction in beta-thalassemia major. The immunomodulatory effects of silymarin in beta-thalassemia major are currently under further investigation in a double blind clinical trial.     

Deferasirox.

PURPOSE: The pharmacology, clinical efficacy, adverse effects and toxicities, and the economic issues that should be considered in using deferasirox are reviewed. SUMMARY: Iron overload is a complication of the chronic blood transfusions used to treat several hematologic disorders. To date, management of transfusional iron overload has consisted of chelation therapy with parenteral deferoxamine. Although survival rates improve with adequate chelation, an estimated one third to one half of patients are not compliant with deferoxamine therapy, largely because of the discomfort and demanding nature of the regimen. In 2005, the Food and Drug Administration approved the labeling for deferasirox for the treatment of chronic overload due to transfusional hemosiderosis. Deferasirox is an oral tridentate chelator that mobilizes iron stores by binding selectively to the ferric form of iron. Deferasirox has been studied in >700 adult and pediatric patients who had transfusion-related iron overload and underlying thalassemia, sickle cell anemia, myelodysplastic syndrome, Diamond-Blackfan syndrome, or another rare anemia. The largest clinical study to date demonstrated the noninferiority of deferasirox 20 or 30 mg/kg/day compared with subcutaneous infusions of deferoxamine >/=35 mg/kg/day administered five days weekly in a subgroup of patients with higher hepatic iron burdens. Deferasirox has been well tolerated in clinical trials. Nearly 97% of participants in a comparative study stated that they preferred deferasirox over their previous deferoxamine treatment. CONCLUSION: Deferasirox, a tridentate oral chelator approved for the treatment of chronic iron overload due to blood transfusions, offers a promising alternative for patients unwilling or unable to comply with deferoxamine therapy.     

Advances in iron overload therapies. prospects for effective use of deferiprone (L1), deferoxamine, the new experimental chelators ICL670, GT56-252, L1NA11 and their combinations

Effective new therapies and mechanisms have been developed for the targeting and prevention of iron overload and toxicity in thalassaemia and idiopathic haemochromatosis patients. A new era in the development of chelating drugs began with the introduction of deferiprone or L1, which as a monotherapy or in combination with deferoxamine can be used universally for effective chelation treatments, rapid iron removal, maintenance of low iron stores and prevention of heart and other organ damage caused by iron overload. Several experimental iron chelators such as deferasirox (4-[3,5-bis (2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid) or ICL670, deferitrin (4,5-dihydro-2- (2,4-dihydroxyphenyl)-4-methylthiazole-4 (S)-carboxylic acid) or GT56-252, 1-allyl-2-methyl-3-hydroxypyrid-4-one or L1NAll and starch deferoxamine polymers have reached different stages of clinical development. The lipophilic ICL670, which can only be administered once daily is generally ineffective in causing negative iron balance but is effective in reducing liver iron. It is suspected that it may increase iron absorption and the redistribution of iron from the liver to the heart and other organs. The experimental iron chelators do not appear to have significant advantages in efficacy and toxicity by comparison to deferiprone, deferoxamine or their combination. However, the prospect of combination therapies using deferiprone, deferoxamine and new chelators will provide new mechanisms of chelator interactions, which may lead to higher efficacy and lower toxicity by comparison to monotherapies. A major disadvantage of the experimental chelators is that even if they are approved for clinical use, they are unlikely to be as inexpensive as deferiprone and become available to the vast majority of thalassaemia patients, who live in developing countries.     

Development of tridentate iron chelators: from desferrithiocin to ICL670

Successful treatment of beta-thalassemia requires two key elements: blood transfusion and iron chelation. Regular blood transfusions considerably expand the lifespan of patients, however, without the removal of the consequential accumulation of body iron, few patients live beyond their second decade. In 1963, the introduction of desferrioxamine (DFO), a hexadentate chelator, marked a breakthrough in the treatment of beta-thalassemia. DFO significantly reduces body iron burden and iron-related morbidity and mortality. DFO is still the only drug for general use in the treatment of transfusion dependent iron overload. However, its very short plasma half-life and poor oral activity necessitate special modes of application (subcutaneous or intravenous infusion) which are inconvenient, can cause local reactions and are difficult to be accepted by many patients. Over the past four decades, many different laboratories have invested major efforts in the identification of orally active iron chelators from several hundreds of molecules of synthetic, microbial or plant origin. The discovery of ferrithiocin in 1980, followed by the synthesis of the tridentate chelator desferrithiocin and proof of its oral activity raised a lot of hope. However, the compound proved to be toxic in animals. Over a period of about fifteen years many desferrithiocin derivatives and molecules with broader alterations led to the discovery of numerous new compounds some of which were much better tolerated and were more efficacious than desferrithiocin in animals, however, none was safe enough to proceed to the clinical use. The discovery of a new chemical class of iron chelators: The bis-hydroxyphenyltriazoles re-energized the search for a safe tridentate chelator. The basic structure of this completely new chemical class of iron chelators was discovered by a combination of rational design, intuition and experience. More than forty derivatives of the triazole series were synthesized at Novartis. These compounds were evaluated, together with more than 700 chelators from various chemical classes. Using vigorous selection criteria with a focus on tolerability, the tridentate chelator 4-[(3,5-Bis-(2-hydroxyphenyl)-1,2,4)triazol-1-yl]-benzoic acid (ICL670) emerged as an entity which best combined high oral potency and tolerability in animals. ICL670 is presently being evaluated in the clinic.     

Safety issues of iron chelation therapy in patients with normal range iron stores including thalassaemia,neurodegenerative, renal and infectious diseases

An increased number of thalassaemia patients treated with effective chelation therapy protocols are achieving body iron levels similar to those of normal individuals. Iron chelation therapy has also been recently used in a number of other categories of patients with no excess body iron load such as neurodegenerative, renal and infectious diseases. Chelation therapy in the absence of iron overload in the latter conditions raises many safety issues including chelator overdose toxicity and toxicity related to iron and other essential metal deficiencies. Preliminary preclinical and clinical toxicity evidence suggest that deferoxamine and deferasirox can only be safely used for these non-iron loaded conditions for short-term treatments of a few weeks, whereas deferiprone can be used for longer term treatments of many months. The selection of the chelating drug and appropriate dose protocols for targeting specific organs and conditions is critical for the safety of patients with normal iron stores. Chelation therapy is likely to play a major role as adjuvant, alternative or main therapy in many non-iron loading conditions in the forthcoming years.     

去铁敏在脑出血治疗中的应用

脑出血是死亡率非常高的卒中亚型,实验已经表明：铁离子和血凝块在出血后脑损伤中起着重要的作用。在大鼠出血后的脑组织中发现铁离子超载。流入脑组织中的铁离子导致脑水肿和神经元死亡。铁螯合剂去铁敏是经食品和药物管理局（FDA）批准的,用来治疗急性铁中毒,和由于长期输血导致的慢性铁中毒。去铁敏能快速的通过血脑屏障,聚集在脑组织中。我们的研究已经说明,去铁敏能减少出血后导致的脑水肿,神经元死亡,脑萎缩和神经缺陷。铁螯合剂去铁敏可能成为脑出血后一种新的治疗方法。     

Deferasirox: for iron overload: only a third-line option

In patients with iron overload, oral deferasirox has a less favourable risk-benefit balance than subcutaneous deferoxamine: deferasirox appears to be less effective and also has more hepatic and renal adverse effects. In second-line situations it is better to first use deferiprone (another oral treatment, with which deferasirox has not been compared), a drug with which we have more experience. However, as iron chelation can be a lifelong necessity for some patients, deferasirox can be reserved as a third-line option which may be useful in some cases.     

Once-daily oral deferasirox for the treatment of transfusional iron overload

The increasing use of blood transfusions, combined with extended patient survival, has led to an increase in the number of patients at risk of developing transfusional iron overload. Clinical data have shown that the once-daily oral iron chelator deferasirox is effective in adults and children with various transfusion-dependent anemias, including β-thalassemia and the myelodysplastic syndromes. Deferasirox has a defined, clinically manageable safety profile. The most common treatment-related adverse events are mild gastrointestinal disorders, skin rash and mild, nonprogressive serum creatinine increases. The deferasirox clinical trial program is continuing in Phase II/III extension phases and Phase IV trials. Long-term data continue to support the efficacy and safety of deferasirox. Convenient, effective and tolerable chelation therapy with deferasirox is a significant development in the treatment of transfusional iron overload.     

Deferasirox : a review of its use in the management of transfusional chronic iron overload

Deferasirox (Exjade) is an oral, once-daily iron chelator widely approved for the treatment of transfusional chronic iron overload. In the EU, deferasirox is indicated in patients with beta-thalassaemia major aged > or =6 years and, in the US, in all transfusional chronic iron overload patients aged > or =2 years. Deferasirox is highly selective for iron as Fe3+. In approximately 1-year clinical trials of patients with transfusional chronic iron overload associated with beta-thalassaemia, sickle cell disease, myelodysplastic syndrome or other rare chronic anaemias, deferasirox 20 or 30 mg/kg/day had a beneficial effect on liver iron concentrations (LIC) and serum ferritin levels; tolerability issues were clinically manageable with regular patient monitoring. Although longer-term efficacy and tolerability data are required, in particular examining the prevention of iron overload-related complications and the effect of deferasirox on renal function, deferasirox is an easily administered iron chelator and is a valuable option in the management of transfusional chronic iron overload.     

Pathophysiological and clinical aspects of iron chelation therapy in MDS

The majority of patients with myelodysplastic syndromes (MDS) become transfusion-dependent during the course of disease and may thus develop transfusional iron overload. As a further contributor to iron overload there is increased absorption of dietary iron from the gut, as a consequence of ineffective erythropoiesis. Compared with thalassemia, it is less clear how frequent patients with MDS develop clinical complications of iron overload, and whether the accumulation of iron shortens their survival. This review aims to summarize our current knowledge of the detrimental effects of transfusional iron overload in MDS, point out the risks associated with iron-induced oxidative stress, describe the tools available for diagnosing iron overload, indicate the treatment options with currently available iron chelators, and discuss the measurement of labile plasma iron (LPI) as a tool to monitor the efficacy of iron chelation therapy.