Iron Overload and Treatment with a New Iron Chelator Morey Blinder 5/21/04
Body Iron Distribution and Storage Dietary iron Duodenum (average, 1 - 2 mg Utilization Utilization per day) Plasma transferrin (3 mg) Muscle Bone (myoglobin) marrow (300 mg) (300 mg) Circulating erythrocytes Storage (hemoglobin) iron (1,800 mg) Sloughed mucosal cells Desquamation/Menstruation Other blood loss (average, 1 - 2 mg per day) Reticuloendothelial Liver macrophages (1,000 mg) Iron loss (600 mg) Andrews NC. N Engl J Med. 1999;341:1986-1995.
Major Iron Compartments • Metabolic • Hemoglobin 2000-2500 mg • Myoglobin 300-500 mg • Storage • Iron storage 0-1000 mg • Transit • Serum iron 3 mg • Total 3000-4000 mg
Basic Causes of Iron Overload • Hereditary • HFE hemochromatosis • Homozygous C282Y mutation in HFE gene1 • Defective regulatory receptor in intestine • Other genetic mutations • Acquired (secondary) iron overload2 • Transfusional • Ineffective erythropoiesis • Toxic ingestion (rare) 1. Feder JN, et al. Nat Genet. 1996;13:399-408. 2. Porter JB. Br J Haematol. 2001;115:239-252.
Iron Loading From Blood Transfusions • 1 unit of blood contains approximately 200 to 250 mg of iron • Chronic transfusion-dependent patients have an iron excess of ~ 0.4 to 0.5 mg/kg/day (1g/month) • With repeated infusions, iron accumulates • Signs of iron overload can be seen anywhere between 10 and 20 transfusions • Unlike with hereditary hemochromatosis, phlebotomy to remove excess iron is usually not an option for patients with chronic anemias 1. Porter JB. Br J Haematol. 2001;115:239-252. 2. Kushner JP, et al. Hematology. 2001;47-61.
Diseases Associated WithTransfusional Iron Overload • -thalassemia (major and intermedia) • Sickle cell anemia • Aplastic anemia • Myelodysplastic syndromes • Rare chronic anemias • Fanconi’s anemia (hypoplastic anemia) • Blackfan-Diamond anemia (red cell aplasia) • Congenital dyserythropoietic anemias
Possible Complications of Iron Overload • Cardiac failure • Liver cirrhosis/fibrosis/cancer • Diabetes mellitus • Infertility • Arthritis Andrews NC. N Engl J Med. 1999;341:1986-1995.
Monitoring Iron Overload • Serum ferritin concentration • Noninvasive • Accuracy in iron overload questionable1 • Liver iron content (LIC)1 • Liver biopsy • Reference standard • SQUID • Noninvasive, availability limited • MRI • Noninvasive, investigational technique2 SQUID = Superconducting Quantum Interference Device Brittenham GM, et al. Blood. 2003;101:15-19. Cook JD, et al. Blood. 2003;101:3359-3364.
Advantages of Liver Biopsy • Historically, the reference method for measuring LIC • Quantitative, specific, and sensitive • Allows for measurement of non-heme storage iron • Provides insight into liver histology/pathology Olivieri NF, et al. Blood. 1997;89:739-761.
Monitoring LIC by SQUID • Superconducting QUantum Interference Device • High-power magnetic field • Iron interferes with the field • Changes in the field are detected • Noninvasive, sensitive, and accurate • Limited availability • Superconductor requires high maintenance • Only 4 machines worldwide Photograph courtesy of A. Piga
Monitoring Iron Overload by MRI An R2 image of an iron-overloaded human liver superimposed on a T-2 weighted image. Bright areas represent high iron concentration; dark areas represent low iron concentration. Clark PR, et al. Magn Reson Med. 2003;49:572-575. Image courtesy of T. St. Pierre
Iron Chelation Agents Approved or in Development T½, Agent Route hours Schedule Clearance Toxicity Deferoxamine Slow 0.5 8 - 24 hours Renal Infusion site rxns, (Novartis) infusion 5 - 7 days and allergic rxns, per week hepatic ocular, auditory Deferiprone Oral 2 - 3 3 daily Renal Nausea/vomiting, (Apotex) arthropathy, neutropenia, agranulocytosis, liver fibrosis (?) ICL670 Oral 12 - 16 1 daily Hepato- Transient nausea, (Novartis) biliary diarrhea, rash
Deferoxamine: the Only Treatment for Transfusional Iron OverloadAvailable in the US • Deferoxamine • Indicated for first-line treatment of iron overload • Reduces comorbidities, including fatal iron overload • The “gold-standard” therapy • Challenges of therapy • Subcutaneous slow infusion 5 to 7 nights/week • Infusion-site reactions and pain • High degree of noncompliance • Approximate cost $2000-4000/month
Deferiprone • Side effects • Nausea, vomiting, abdominal pain • Arthralgia • Neutropenia/Agranulocytosis • Weekly neutrophil count recommended • Efficacy • For second-line use in deferoxamine-intolerant patients with -thalassemia major • May be less effective than deferoxamine in reducing LIC1 • Reports of increased risk of liver fibrosis Ferriprox® [package insert]. Apotex Europe Ltd. 1999. Hoffbrand AV, et al. Blood. 2003;102:17-23.
OH O N N N * OH HO * * Fe ICL670: a New, Oral Iron Chelator • Selected from more than 700 compounds tested • Tridentate* iron chelator • An oral, dispersible tablet • Administered once daily • Highly specific for iron • Chelated iron excreted mainly in feces (< 10% in urine) Clinical trial formulation or preparation *3 polar interaction sites in the binding pocket. Nick H, Current Medicinal Chemistry. 2003;10:1065-1076.
Phase I Pharmacokinetic and Pharmacodynamic Study: Multiple Doses in Thalassemia Patients • Randomized, double-blind, placebo-controlled sequential trial to assess • Short-term safety (12-day exposure) • Efficacy (iron balance) • Pharmacokinetic/pharmacodynamic relationships • 3 cohorts of 7 patients with -thalassemia • 5 patients per cohort received active drug, 2 received placebo • Doses: 10, 20, 40 mg/kg Nisbet-Brown E, et al. Lancet. 2003;361:1597-1602.
ICL670 Phase I Safety Profile Treatment-Related Adverse Events by Dose Level ICL670 10 mg/kg 20 mg/kg 40 mg/kg Preferred term Severity (n = 5) (n = 6) (n = 7) Nausea Mild – 2 1 Nausea Moderate – – 1 Diarrhea Mild – 1 3 Abdominal pain Mild – – 1 Nisbet-Brown E, et al. Reprinted with permission from Elsevier (Lancet, 2003;361:1597-1602).
Phase II Trial of ICL670 in Thalassemia:Objectives • Primary • Safety and tolerability profile • Secondary • Effects on LIC by SQUID • Pharmacokinetics • Determine dose titration
Phase II Patient Selection Criteria • Inclusion • Transfusion-dependent -thalassemia • Age 18 years • Serum ferritin, 2,000 to 8,000 ng/mL • LIC, 5 to 15 mg/g dry weight • Exclusion • Alanine aminotransferase: > 250 Units/L • Creatinine clearance: < 80 mL/min • Significant EKG irregularities Cappellini M, et al. 16th Annual Meeting of the International BioIron Society.2003.
ICL670 Phase II Safety Profile • Mild transient gastrointestinal adverse events in some patients including dose-related nausea/vomiting • Resolved spontaneously • No myelosuppression • No clinically relevant toxicities in kidney, eye, ear, heart, or liver • Occasional elevations in urinary 2m and mild proteinuria of uncertain clinical significance Cappellini M, et al. 16th Annual Meeting of the International BioIron Society.2003.
Summary of Phase II Results • Results after 12 months of therapy with ICL670 in patients with -thalassemia and transfusional iron overload: • No serious adverse events • No clinically significant safety issues • Dose-dependent pharmacokinetics • ICL670 (20 mg/kg/day) demonstrated comparable efficacy to deferoxamine (40 mg/kg/day) in decreasing LIC over a 1-year treatment period
Study 0109: Phase II Comparative TrialAdult and Pediatric Sickle Cell Disease • Primary analysis • Safety and tolerability profile of ICL670 relative to that of deferoxamine in adult and pediatric patients with sickle cell disease • Study design • 1-year trial • 170 patients on transfusion programs • Randomized ~2:1 to ICL670 or deferoxamine • SQUID assessment of LIC • Doses adjusted according to SQUID results • Substudy of LIC assessed by MRI and liver biopsy (n = 30)
Patient Population (Eligiblity) • Common variant of sickle cell disease (Hgb SS, Sbeta°, Sbeta+, SC) • Evidence of iron overload from transfusion therapy • Chronic simple transfusions • Exchange transfusions • Intermittent simple transfusions with ≥20 units PRBCs • Adequate renal, hepatic and cardiac function • No pregnant patients • No patient requiring hydroxyurea • Age ≥ 2 years • Serum ferritin ≥ 1000 µg/L • Able to sign consent
Endpoints • Total duration of study will be 1 year • Absolute and relative change of liver iron concentraiton after 1 year of treatment will be analyzed as primary efficacy end point • All adverse events will be monitored and recorded
Conclusions • ICL670 has shown promise in phase II clinical trials in patients with transfusional iron overload • Efficacy after 1 year comparable to that of deferoxamine, the current reference standard • Once-daily oral chelation may lead to improved compliance in the treatment of iron overload • ICL670 is currently being studied in 12 countries and in more than 800 patients • Adults and children with -thalassemia, MDS, sickle cell disease, and other anemias • Will this lead to chelation euphoria?