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Iron Chelator Basics: Emerging Data Beyond Transfusion-Dependent Iron Overload

Iron Chelator Basics: Emerging Data Beyond Transfusion-Dependent Iron Overload. Antonello Pietrangelo, MD, PhD Professor of Internal Medicine Center for Hemochromatosis University Hospital of Modena Modena, Italy

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Iron Chelator Basics: Emerging Data Beyond Transfusion-Dependent Iron Overload

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  1. Iron Chelator Basics: Emerging DataBeyond Transfusion-Dependent Iron Overload Antonello Pietrangelo, MD, PhDProfessor of Internal MedicineCenter for Hemochromatosis University Hospital of Modena Modena, Italy Alberto Piperno, MDProfessor of Internal MedicineDepartment of ClinicalMedicine and PreventionUniversity of Milano-BicoccaMonza, Italy

  2. Beyond Transfusion-Dependent Iron Overload • Hereditary haemochromatosis • Chronic liver diseases • Chronic hepatitis C • Chronic hepatitis B • Nonalcoholic fatty liver disease and metabolic syndrome • Other

  3. Antonello Pietrangelo, MD, PhD Beyond Transfusion-Dependent Iron Overload Hereditary Haemochromatosis

  4. Iron Overload in Hereditary Haemochromatosis1,2 • Autosomal recessive disorder characterized by excessive iron uptake through intestinal absorption • If untreated, tissue iron overload may lead to toxicity and disease in an appreciable proportion of patients • Liver cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy, arthropathy, and hypogonadism are common clinical features of fully expressed disease • The paradigmatic and most common form is associated with homozygosity for the C282Y polymorphism of HFE • Phlebotomy is the standard of care in Hereditary Haemochromotosis • Reduces iron burden and prevents clinical complications 1. Pietrangelo A. N Engl J Med.2004;350:2383-2397. 2. Beutler E, et al. Annu Rev Med. 2006.57:331-347.

  5. Phlebotomy in HH—Limitations • Some patients may: • Not be able to tolerate the induced mild anaemic state (eg, elderly patients) • Be poor candidates due to underlying medical conditions (eg, severe heart disease or anaemia) and/or poor venous access • Experience hypovolaemia • Experience discomfort of needle puncture • Low acceptance of the procedure may lead to a decline in compliance over time and treatment failure

  6. Iron Chelation in HH—An Option 1. Franchini M, et al. Blood. 2000;95:2776-2779. 2. Barton JC, et al. Am J Hematol. 2005;78:83. 3. Polo-Romero FJ. Am J Hematol. 2006;81:225-226. 4. Nielsen P, et al. Br J Haematol. 2003;123:952-953. The use of iron chelators in HH has only been reported in case studies1–4 Despite approval of iron chelators for posttransfusional iron overload,the extent and rate of iron accumulation in HH is substantially different, which may affect safety and efficacy Deferoxamine is approved in the European Union for use in HH but rarely used due to very low patient acceptance

  7. Iron Chelation Therapy with Deferasirox in HH • A phase I/II dose-escalation trial with deferasirox is the first trial of iron chelation in a nontransfusional iron overloaded population1 • Deferasirox is a once-daily oral iron chelator under investigation as a possible additional treatment option • Deferasirox is approved for the treatment of transfusional hemosiderosis in patients >2 years of age2 • Daily therapy results in dose-dependent reduction in iron load as indicated by liver iron concentration and serum ferritin2 • Efficacy and safety in a variety of transfusion-dependent anaemias3–7 1. Pietrangelo A, et al. Blood. 2007; 110:2680. 2 Exjade. Summary of Product Characteristics. West Sussex, UK: Novartis Europharm Ltd; 2006. 3. Galanello R, et al. Haematologica. 2006;91:1343-1351. 4. Piga A, et al. Haematologica. 2006;91:873-880. 5. Cappellini MD, et al. Blood. 2006;107:3455-3462. 6. Porter J, et al. Eur J Haematol. 2008;80:168-176. 7. Vichinsky E, et al. Br J Haematol. 2007;136:501-508.

  8. Deferasirox in HFE-Related HHA Phase I/II, Open-Label, Dose-Escalation Trial • Primary objective: To explore the safety of deferasirox in iron-overloaded adult patients with HFE C282Y homozygosity • Secondary objective: To explore the effect of deferasirox on serum ferritin • 2-part study • Core study: 24-weeks duration • Extension study: patients completing the core study were eligible to continue receiving deferasirox for a further 24 weeks with appropriate dose adjustments Pietrangelo A, et al. Blood. 2007; 110:2680.

  9. Key Inclusion/Exclusion Criteria • Inclusion criteria • Male and female patients aged ≥18 years with HFE C282Y homozygous HH documented by molecular diagnostic testing • Serum ferritin levels of 300 ng/mL to 2000 ng/mL with transferrin saturation ≥45% • Exclusion criteria • Haemoglobin <13 g/dL for males and <12 g/dL for females • History of blood transfusion during the 6 months prior to study entry • Serum creatinine > the upper limit of normal (ULN) • Alanine aminotransferase (ALT) levels of ≥2 x ULN Pietrangelo A, et al. Blood. 2007; 110:2680.

  10. Study Design1,2 • 49 patients enrolled • Doses explored • 5 mg/kg/day • 10 mg/kg/day • 15 mg/kg/day 1. Pietrangelo A, et al. Blood. 2007; 110:2680. 2. Pietrangelo A, et al. J Hepatol. 2009;50:S4.

  11. Most Common Adverse Events (AE) (>10%) No deaths or serious AEs occurred during the course of this study Pietrangelo A, et al. J Hepatol. 2009;50:S4. Graphic courtesy of Dr. Antonello Pietrangelo.

  12. Serum Ferritin by Visit and Dose Cohort 859 634 512 356 322 205 Abbreviation: SF, seum ferritin.Pietrangelo A, et al. J Hepatol. 2009;50:S4. Graphic courtesy of Dr. Antonello Pietrangelo. BL, baseline

  13. Conclusions of the Core Trial—Safety The results from the core trial suggest that deferasirox has an acceptable safety profile in patients with HH Adverse events are consistent with the known safety profile of deferasirox and previous data acquired in transfusion-dependent iron overload Pietrangelo A, et al. J Hepatol. 2009;50:S4.

  14. Conclusions of the Core Trial—Efficacy 1. Pietrangelo A, et al. J Hepatol. 2009;50:S4. 2. Phatak PD, et al. Presented at: 2009 ASH Annual Meeting. New Orleans, LA; December 5-8, 2009. Abstract 1514. Deferasirox doses of 5, 10, and 15 mg/kg/day effectively reduced serum ferritin in HH (nontransfusional iron overload population)1 Efficacy was demonstrated at lower doses of deferasirox in this population compared with doses in the current label for the transfusional overload population1 The 6-month extension phase to the trial is now complete and data will be presented at the 2009 ASH Annual Meeting2

  15. Alberto Piperno, MD Beyond Transfusion-Dependent Iron Overload Iron Overload and Chronic Liver Disease Iron Overload and Chronic HCV Iron Overload and Insulin Resistance

  16. NAFLD DIOS Viral hepatitis Liver Iron Overload Alcoholic liver disease Porphyria cutanea tarda End-stage liver disease Local Iron Overload—The Liver • The liver is the central regulator of iron homeostasis and the main site of iron storage • Probably more exposed to iron accumulation because of the first-pass effect of the portal circulation • Beyond systemic forms of iron overload, there are many other disorders associated with mild-moderate hepatic iron overload Abbreviation: DIOS, dismetabolic iron overload syndrome; NAFLD, nonalcoholic fatty liver disease. Graphic courtesy of Dr. Alberto Piperno.

  17. Iron Overload in Chronic Liver Diseases1-4 • Many patients with chronic liver diseases (CLD) have increased serum iron indices • Mild-moderate amount of haemosiderin iron is present in a significant proportion of liver biopsies of patients with CLD • The amount of iron associated with these conditions would be generally considered to be at nontoxic levels, certainly much lower than in hereditary haemochromatosis or in thalassaemia • What are the mechanisms of iron accumulation in CLD? • May the combination of slightly-moderately increased iron with an added insult act synergistically to increase the risk of progression of liver damage? • Consequently, may iron removal be useful in the management of CLD and in improving the natural history of these disorders? 1. Chapman RW, et al. Dig Dis Sci. 1982;27:909-916. 2. Martinelli AL, et al. J Gastroenterol Hepatol. 2004;19:1036-1041. 3. Bugianesi E, et al. Hepatology. 2004;39:179-187. 4 Piperno A, et al. Hepatology. 1998;28:1105-1109

  18. Fe Fe Hepatocyte Mechanisms of Iron Accumulation in CLD Hepatic Iron Overload Chronic Liver Disease Increased iron absorption Hepatocyte damage and inflammation • Genetic background • Mutations of HH genes • Phagocytosis of damaged hepatocytes • Cytokine-mediated iron retention in macrophages • Increased iron and ferritin release to extracellular fluid and plasma • Increased NTBI Macrophage Abbreviations: HH; hereditary haemochromatosis; NTBI, nontransferrin-bound iron. Graphics courtesy of Dr. Alberto Piperno.

  19. ‘Labile’ or ‘free’ iron Oxidative Stress at the Interface of Iron- and Other Hepatoxin-Induced Liver Damage • Oxidative stress in the liver can be induced by alcohol, hepatitis C virus (HCV) or insulin resistance associated with obesity1-3 • Excess iron in the liver may exacerbate this oxidative stress and promote liver injury and fibrosis and, in some cases, carcinogenesis • Oxidative stress can depress hepcidin expression in hepatocytes via reduced activity of C/EBP-, as shown in animal models of HCV infection and alcoholic liver disease1,4,5 • This may increase iron absorption and accumulation in the liver, contributing further to oxidative stress. Insulin resistance Obesity Alcohol HCV Oxidative stress Cell death Carcinogenesis Liver fibrosis Abbreviation: C/EBPa, CCAAT/enhancer binding protein-alpha; PCT, porphyria cutanea tarda; UROD, uroporphyrinogen decarboxylase.1. Wallace DF, et al. Biochim Biophys Acta. 2009;1790:663-670. 2. Harrison-Findik DD. World J Gastroenterol. 2007;13:4925-4930. 3. Miura K, et al. Hepatology. 2008;48:1420-1429. 4. Girelli D, et al. J Hepatol. 2009;51:845-852. 5. Nishina S, et al. Gastroenterology. 2008;134:226-238. Graphic courtesy of Dr. Alberto Piperno.

  20. Chronic Liver Diseases, Iron, and Progression to Liver Damage + Marked Iron Overload Chronic Liver Disease Synergistic Effect Liver Damage (fibrosis, cirrhosis, HCC) • Alcohol intake promotes liver damage in patients with haemochromatosis1-3 • Chronic HCV and HBV infection promotes liver damage in patients with haemochromatosis and thalassaemia4-6 • NAFLD promotes liver damage in patients with haemochromatosis7 1. Adams PC, et al. Hepatology. 1996;23:724-727. 2. Powell EE, et al. Gastroenterology. 2005;129:1937-1943. 3. Fletcher LM, et al. Gastroenterology. 2002;122:281-289. 4. Piperno A, et al. J Hepatol. 1992;16:364-368. 5. Diwakaran HH, et al. J Hepatol. 2002;36:687-691. 6. Angelucci E, et al. Blood. 2002;100:17-21. 7. Fargion S, et al. Hepatology. 1992;15:655-659. Graphic courtesy of Dr. Alberto Piperno.

  21. Iron, Chronic HCV Infection, and Disease Progression—A Controversial Issue The effect of iron on HCV replication • Iron has been shown to either increase expression of HCV genes, suppress HCV replication, or to have no effect on HCV transgene expression in vitro1-3 • Clinical data indicate that iron status does not significantly influence HCV replication in vivo3 The effect of iron on disease progression • Phlebotomies significantly decrease serum ALT4,5 • In small pilot studies, phlebotomies improve markers of hepatic fibrosis and liver histology in untreated patients with chronic HCV5 • Phlebotomies may improve the response rate to interferon alone4 • Uncertain whether it may improve response rate to interferon-ribavirin combination therapy6,7 1. Theurl I, et al. J Infect Dis. 2004;190:819-825. 2. Fillebeen C, et al. J Biol Chem. 2005;280:9049-9057. 3. Mueller S, et al. Gastroenterology. 2006;130:2229-2234. 4. Alexander J, et al. Liver Int. 2007;27:268-273. 5. Kato J, et al. Cancer Res. 2001;61:8697-8702. 6. Rulyak SJ, et al. Am J Gastroenterol. 2005;100:332-337. 7. Sievert W, et al. Am J Gastroenterol. 2002;97:982-987.

  22. Chronic Hepatitis B Virus (HBV) Infection and Hepatic Iron Overload There are very few data available on iron metabolism in patients with chronic HBV infection1-5 A relationship between serum iron indices and outcome of HBV infection and clearance of virus was reported in the past but has not been confirmed1,2 Mild abnormalities in serum iron indices and increased liver iron deposits have been described in about 30% of HBV-infected patients3 In contrast with chronic HCV, hepatic oxidative damage in chronic HBV is not related to body iron4 Reduction of ferritin by iron depletion therapy improved the likelihood of response to interferon therapy in a single small study Iron depletion inhibits HBV secretion in HBV stably-transfected cells5 This may not reflect a decrease of viral replicative form, but could be associated with active viral DNA synthesis 1. Felton C, et al. Proc Natl Acad Sci U S A. 1979;76:2438-2441. 2. Blumberg BS, et al. Proc Natl AcadSci U S A. 1981;78:3222-3224. 3. Martinelli AL, et al. J Gastroenterol Hepatol. 2004;19:1036-1041. 4. Fujita N, et al. J Viral Hepat. 2008;15:498-507. 5. Chouteau P, et al. J Hepatol. 2001;34:108-113.

  23. Severe Fibrosis/Cirrhosis Is More Frequent in Chronic HCV with Hepatic Iron Overload1-5 60 85/659 (12.9%) 68/287 (23.7%) P <.001 • Some studies report an association between HFE mutations and iron overload, and between HFE mutations and fibrosis • Others have found no such association • Some studies however, found an association between hepatic iron or increased serum iron indices and more severe disease independent of HFE mutations 50 40 Patients with Severe Fibrosis/Cirrhosis (%) 293 30 23.12 20 171 163 9.62 10 3.31 No Iron Deposits With Iron Deposits 1. Hézode C, et al. J Hepatol. 1999;31:979-984. 2. Corengia C, et al. Am J Clin Pathol. 2005;124:846-853. 3. Guyader D, et al. J Hepatol. 2007;46:587-95. 4. Tung BY, et al. Gastroenterology. 2003;124:318-326. 5. Negro F, et al. J Med Virol. 2000;60:21-27. Graphic courtesy of Dr. Alberto Piperno; data from unpublished meta-analysis of references 1, 2, and 3.

  24. HSC Interactions Between Hepatic Iron Overload and Cirrhosis1-4 Iron Overload Hepatic Cirrhosis Mechanisms of Fibrogenesis Mechanisms of Iron Load • Hepatocellular necrosis (sideronecrosis) • Amplification and propagation of fibrogenesis in concert with other hepatotoxins • Induction of fibrogenesis through activation of hepatic stellate cells • Decreased transferrin synthesis • Spontaneous porto-systemic shunts • Ineffective erythropoiesis • Chronic hemolysis • Reduced hepcidin synthesis Injured Hepatocyte Liver Fibrosis IRON Hepatotoxins Activated HSC Activated Kupffer cell 1. Deugnier Y, et al. Am J Surg Pathol. 1997;21:669-675. 2. Ludwig J, et al. Gastroenterology. 1997;112:882-888. 3. Guyader D, et al. J Hepatol. 2007;46:587-595. 4. Tsukamoto H, et al. Am J Physiol. 1999;277(6 Pt 1):G1240-G1250. Graphic courtesy of Dr. Alberto Piperno.

  25. NASH—An Emerging Cause of Cirrhosis Proportion of Liver Transplants for Specific Etiologies; US, 1992 to 2007 • Nonalcoholic steato-hepatitis (NASH) is the predominant cause of cryptogenic cirrosis • Represents the severe end of the NAFLD spectrum • Associated with metabolic syndrome and insulin resistance O'Leary JG, et al. Gastroenterology. 2008;134:1764-1776.

  26. NAFLD/NASH and Iron Overload—An Intriguing and Controversial Association1-6 • Increased serum ferritin is frequent in patients with NAFLD, not always associated with hepatic iron overload • In fact, hepatic iron is generally present in not more than half of patients with hyperferritinaemia • Some studies have shown that increased ferritin levels, but not iron overload, are markers of severe histologic damage and that iron burden does not contribute to hepatic fibrosis in patients with NAFLD • Others studies have shown that hyperferritinemia or hepatic iron concentration are associated with increased risk of fibrosis in NASH, or increased risk of NASH • Some studies demonstrated an association between HFE mutations, fibrosis and iron overload in NASH, but others failed to find this association 1. Trombini P, et al. J Hepatol. 2007;46:549-552. 2. Bugianesi E, et al. Hepatology. 2004;39:179-187. 3. Fargion S, et al. Am J Gastroenterol. 2001;96:2448-2455. 4. George DK, et al. Gastroenterology. 1998;114:311-318. 5. Nelson JE, et al. Hepatology. 2007;46:723-729. 6. Chitturi S, et al. Hepatology. 2002;36:142-149.

  27. NAFLD/NASH and Iron Overload—The Dismetabolic Iron Overload Syndrome • A new syndrome termed insulin resistance hepatic iron overload (IR-HIO) or dismetabolic iron overload (DIOS)1-4 • Mild to moderate hepatic iron overload is associated with features of insulin resistance or metabolic syndrome • Most common form of iron overload in Western countries (at least 10 times more common than haemochromatosis) • Increased prevalence of HFE mutations and of NAFLD or NASH have been observed in DIOS5 • Physiopathologic mechanism of iron overload in DIOS is unclear6 • A link between iron and the progression of NAFLD have been supported by the observation that iron removal by phlebotomy can improve insulin resistance, metabolic indices, and liver function in patients with NAFLD or DIOS7,8 1. Mendler MH, et al. Gastroenterology. 1999;117:1155-1163. 2. Riva A, et al. World J Gastroenterol. 2008;14:4745-4752. 3. Facchini FS, et al. Gastroenterology. 2002;122:931-939. 4. Le Guenno G, et al. Diabetes Res Clin Pract. 2007;77:363-370. 5. Barisani D, et al. J Hepatol. 2008;49:123-133. 6. Ruivard M, et al. J Hepatol. 2009;50:1219-1225. 7. Valenti L, et al. Am J Gastroenterol. 2007;102:1251-1258. 8. Piperno A, et al. Liver Int. 2004;24:471-476.

  28. Iron and Hepatocellular Carcinoma • Patients with haemochromatosis have significantly increased risk for Hepatocellular Carcinima (HCC)1-3 • HCC has been reported in the absence of cirrhosis and after reversal of cirrhosis, suggesting iron might be direct carcinogen4,5 • In transgenic mice expressing HCV poliprotein, iron overload increases risk of HCC by potentiating mitochrondrial injury via oxidative stress6 • Recent data suggest that, in patients with alcoholic cirrhosis, but not HCV-related cirrhosis, liver iron overload (whatever its cause) is major risk factor for HCC7 1. Niederau C, et al. N Engl J Med. 1985;313:1256-1262. 2. Bradbear RA, et al. J Natl Cancer Inst. 1985;75:81-84. 3. Hsing AW, et al. Int J Cancer. 1995;60:160-162. 4. Kew MD. Hepatology. 1990;11:1086-1087. 5. Blumberg RS, et al. Gastroenterology. 1988;95:1399-1402. 6. Nishina S, et al. Gastroenterology. 2008;134:226-238. 7. Nahon P, et al. Gastroenterology. 2008;134:102-110.

  29. Iron Removal Therapy in CLD—Reality, Myth, and Perspectives • In patients with CLD for whom there is a suspicion of hepatic iron overload, the decision to remove iron should rely firstly on demonstration of hepatic iron overload • Noninvasive (quantitative MR, SQUID) or invasive (liver biopsy) methods • There is some evidence that the association of CLD and high levels of hepatic iron contribute to more rapid progression to hepatic fibrosis and cirrhosis • iron removal is recommended as part of the therapeutic options • If hepatic iron is mildly/moderately increased, treatment to reduce excessive iron burden can be considered before, together, or after specific therapies (antiviral, alcohol abstinence, lifestyle modification) • However, at this time there is insufficient evidence to elevate iron removal therapies to the status of a proven therapy in these scenarios • The availability of new iron chelators (ie, able to remove iron from specific sites) may open new perspectives in this exiting area of research • This issue needs to be addressed in large cohorts of patients in carefully designed studies

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