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Sept 2003
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Iron Overload and Treatment with a New Iron Chelator
Morey Blinder
5/21/04
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Andrews NC. N Engl J Med. 1999;341:1986-1995.
Body Iron Distribution and StorageDietary iron
Utilization UtilizationDuodenum
(average, 1 - 2 mgper day)
Muscle(myoglobin)
(300 mg)
Liver(1,000 mg)
Bone marrow(300 mg)Circulating
erythrocytes(hemoglobin)
(1,800 mg)
Reticuloendothelialmacrophages
(600 mg)
Sloughed mucosal cellsDesquamation/Menstruation
Other blood loss(average, 1 - 2 mg per day)
Storageiron
Plasmatransferrin
(3 mg)
Iron loss
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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
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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.
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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.
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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
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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.
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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.
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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.
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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 worldwidePhotograph courtesy of A. Piga
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Monitoring Iron Overload by MRI
Clark PR, et al. Magn Reson Med. 2003;49:572-575. Image courtesy of T. St. Pierre
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.
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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
Iron Chelation Agents Approved or in Development
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13Deferoxamine: the Only Treatment for Transfusional Iron Overload
Available 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
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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.
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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)
O
OH
HOOH
N N
N
Fe
*
* **3 polar interaction sites in the binding pocket.Nick H, Current Medicinal Chemistry. 2003;10:1065-1076.
Clinical trial formulation or preparation
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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.
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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
ICL670 Phase I Safety Profile
Treatment-Related Adverse Events by Dose Level
Nisbet-Brown E, et al. Reprinted with permission from Elsevier (Lancet, 2003;361:1597-1602).
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Phase II Trial of ICL670 in Thalassemia:Objectives
• Primary– Safety and tolerability profile
• Secondary– Effects on LIC by SQUID– Pharmacokinetics
• Determine dose titration
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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.
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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.
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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
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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)
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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
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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
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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?