Transcript Document

1
Iron Overload and Treatment with a
New Iron Chelator
Morey Blinder
5/21/04
Sept 2003
Body Iron Distribution and Storage
Dietary iron
Utilization
Duodenum
(average, 1 - 2 mg
per day)
Plasma
transferrin
(3 mg)
Muscle
(myoglobin)
(300 mg)
Circulating
erythrocytes
(hemoglobin)
(1,800 mg)
Storage
iron
Liver
(1,000 mg)
Utilization
Sloughed mucosal cells
Desquamation/Menstruation
Other blood loss
(average, 1 - 2 mg per day)
Iron loss
Andrews NC. N Engl J Med. 1999;341:1986-1995.
Bone
marrow
(300 mg)
Reticuloendothelial
macrophages
(600 mg)
2
3
Major Iron Compartments
• Metabolic
– Hemoglobin
– Myoglobin
• Storage
– Iron storage
• Transit
– Serum iron
• Total
2000-2500 mg
300-500 mg
0-1000 mg
3 mg
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 With
Transfusional 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
Agent
Deferoxamine
(Novartis)
Route
T½,
hours
Schedule
Clearance
Toxicity
Slow
infusion
0.5
8 - 24 hours
5 - 7 days
per week
Renal
and
hepatic
Infusion site rxns,
allergic rxns,
ocular, auditory
Deferiprone
(Apotex)
Oral
2-3
3 daily
Renal
Nausea/vomiting,
arthropathy,
neutropenia,
agranulocytosis,
 liver fibrosis (?)
ICL670
(Novartis)
Oral
12 - 16
1 daily
Hepatobiliary
Transient nausea,
diarrhea, rash
Deferoxamine: the Only Treatment for
Transfusional Iron Overload
Available in the US
13
• 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
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
OH
O
• Chelated iron excreted mainly
in feces (< 10% in urine)
Clinical trial formulation
or preparation
N
N
N
*
OH
* Fe*
*3 polar interaction sites in the binding pocket.
Nick H, Current Medicinal Chemistry. 2003;10:1065-1076.
HO
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
Severity
10 mg/kg
(n = 5)
20 mg/kg
(n = 6)
Nausea
Mild
–
2
1
Nausea
Moderate
–
–
1
Diarrhea
Mild
–
1
3
Abdominal pain
Mild
–
–
1
Preferred term
40 mg/kg
(n = 7)
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 Trial
Adult 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?