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

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?