1 / 25

Iron Overload and Treatment with a New Iron Chelator

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).

arleen
Download Presentation

Iron Overload and Treatment with a New Iron Chelator

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Iron Overload and Treatment with a New Iron Chelator Morey Blinder 5/21/04

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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).

  18. Phase II Trial of ICL670 in Thalassemia:Objectives • Primary • Safety and tolerability profile • Secondary • Effects on LIC by SQUID • Pharmacokinetics • Determine dose titration

  19. 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.

  20. 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.

  21. 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

  22. 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)

  23. 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

  24. 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

  25. 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?

More Related