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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).

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body iron distribution and storage
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
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
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
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 with transfusional iron overload
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
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
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
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
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
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
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 overload available in the us
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
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.

icl670 a new oral iron chelator

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
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
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
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
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
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
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 trial adult and pediatric sickle cell disease
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
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
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
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?