Iron Overload and Treatment with a New Iron Chelator

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. 19993411986-1995.
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. 199613399-408. 2.
Porter JB. Br J Haematol. 2001115239-252.
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. 2001115239-252. 2.
Kushner JP, et al. Hematology. 200147-61.
6
Diseases Associated WithTransfusional Iron
Overload

• ?-thalassemia (major and intermedia)
• Sickle cell anemia
• Aplastic anemia
• Myelodysplastic syndromes
• Rare chronic anemias
• Fanconis 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. 19993411986-1995.
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. 200310115-19.
• Cook JD, et al. Blood. 20031013359-3364.

9
Limitations of Serum Ferritin

• Changes are confounded by
• Inflammation (acute phase reactant)
• Liver function abnormalities
• Serum ferritin concentration is not an accurate
  marker of increased body iron stores or iron
  toxicity
• LIC shows much better correlation with
• Total transfused iron
• Onset of morbidity
• Fatal iron accumulation

Brittenham GM, et al. Am J Hematol.
19934281-85. Olivieri NF, et al. Blood.
199789739-761.
10
LIC Accurately Reflects Body Iron Stores
300
r 0.98
250
25 patients with iron overload andcirrhosis ?
1-mg dry weight liver sample
200
Total body iron stores, mg/kg
150
100
50
0
0
5
10
15
20
25
Hepatic iron concentration, mg/g dry weight
LIC Liver iron content. Angelucci E, et al. N
Engl J Med. 2000343327-331.
11
LIC Correlates With Prognosis in
Thalassemia and Hemochromatosis
Approximate LIC, mg/g dry weight
liver Age, Hemochromatosis Thalassemiayrs Norma
l Heterozygous Homozygous major 5 lt 1.2 lt
1.2 gt 3.2 gt 1510 lt 1.2 lt 1.2 7 gt 15
15 lt 1.2 lt 1.2 gt 7 gt 1520 lt 1.2 1.2
15 gt 1525 lt 1.2 gt 1.2 gt 15 (Not
surviving)30 lt 1.2 3.2 gt 15 35 lt 1.2 gt
3.2 gt 15
3.2 - 7 (adequate iron chelation)
7 - 15 (increased risk of complications)
? 15 (cardiac disease and early death)
LIC changes are presented for patients without
phlebotomy or iron chelation therapy. Olivieri
NF, et al. Blood. 199789739-761.
12
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. 199789739-761.
13
Limitations of Liver Biopsy

• Invasive, painful procedure
• Risk of bleeding, infection, organ damage
• Risk of fatal complications (rare)
• Sampling error, especially in presence of
  cirrhosis
• Limited accuracy if lt 1-mg dry weight sample
  size

Harmatz P, et al. Blood. 20019676-79. Porter
JB. Br J Haematol. 2001115239-252.
14
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
15
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. 200349572-575.
Image courtesy of T. St. Pierre
16
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 Or
al 2 - 3 3 daily Renal Nausea/vomiting, (Apotex)
arthropathy, neutropenia, agranuloc
ytosis, ? liver fibrosis (?) ICL670 Oral 12
- 16 1 daily Hepato- Transient nausea,
(Novartis) biliary diarrhea, rash
17
Chemical Structures of Iron Chelators
Deferoxamine (Desferal) Hexadentate (11) high
MW
Deferiprone (Ferriprox, Kelfer)Bidentate
(31) low MW
Deferasirox (ICL670)Tridentate (21) low MW
Nick H. Curr Med Chem. 2003101065-1076.
18
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

19
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. 200310217-23.
20
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 (lt 10 in
  urine)

Clinical trial formulation or preparation
3 polar interaction sites in the binding
pocket. Nick H, Current Medicinal Chemistry.
2003101065-1076.
21
Two ICL670 Molecules Chelate One Iron Atom
22
Comparative Efficacy in Animal Studies
Iron-Overloaded Marmoset Model

• ICL670 preclinical results
• More effective than deferoxamine and deferiprone
  at clearing iron
• In iron-overloaded animals
• Reduced toxicity
• No effects on growth or reproduction
• No mutagenicity or teratogenicity

3,000
2,500
ICL670
2,000
Deferoxamine
Deferiprone
Fe excretion, µg/kg per 48 hours
1,500
1,000
500
0
All agents administered at 150 µmol iron-binding
equivalents/kg. Sergejew T, et al. Br J Haematol.
2000110985-992.
23
ICL670 Plasma Concentration is Proportional to
Dose
Galanello R, et al. J Clin Pharmacol.
200343565-572.
24
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. 20033611597-1602.
25
Summary of Phase I Results

• Dose-response relationship (10 to 40 mg/kg)
• Iron excretion within therapeutic range (0.1 to
  0.5 mg Fe/kg/day)
• Iron excreted mainly in feces
• Acceptable safety profile
• Dose recommendation 10 to 20 mg/kg

1.2
1.0
0.8
0.6
Net iron excretion, mg/kg/day
0.4
0.2
0
Placebo
10
20
40
ICL670, mg/kg/day
Nisbet-Brown E, et al. Lancet, 20033611597-1602)
.
26
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, 20033611597-1602).
27
Phase II Trial of ICL670 in ThalassemiaObjective
s

• Primary
• Safety and tolerability profile
• Secondary
• Effects on LIC by SQUID
• Pharmacokinetics
• Determine dose titration

28
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 gt 250 Units/L
• Creatinine clearance lt 80 mL/min
• Significant EKG irregularities

Cappellini M, et al. 16th Annual Meeting of the
International BioIron Society. 2003.
29
Phase II Efficacy and Safety of ICL670
Thalassemia Patients
Treatment ? 12 months
Wash-out(of DFO)
Extension
ICL670 10 mg/kg/day (ICL 10)
ICL670 20 mg/kg/day (ICL 20)
Switch to ICL670
Deferoxamine 40 mg/kg/day

• SQUID assessments and audiometry performed every
  3 months
• Safety assessments performed every 2 weeks
  initially and monthly thereafter

Cappellini M, et al. 16th Annual Meeting of the
International BioIron Society. 2003.
30
Changes From Baseline in LIC at 12 Months
Patients, Absolute, mg/kg dry
wtTreatment n Mean Range ICL670
10 24 0.4 (4.1 to 4.9)ICL670 20 22
2.1 (8.4 to 4.4) Deferoxamine 21
2.0 (6.1 to 2.4) Patients, Relative,
changeTreatment n Mean Range
ICL670 10 24 3.3 (61.5 to 65.3)ICL670
20 22 24.1 (75.0 to 40.7)Deferoxamine
21 26.2 (66.3 to 42.9)
Courtesy of Cappellini M, et al. 16th Annual
Meeting of the International BioIron Society.
2003.
31
Oral ICL670 Prevented Serum Ferritin Increases
Over 12 Months Comparable to Deferoxamine
8
Deferoxamine 40
ICL 10
ICL 20
7
6
5
Serum ferritin, mg/L
4
(Mean 2 SD)
3
2
1
0
Baseline
3 months
6 months
12 months
9 months
n
24
/
24
/
23
n
24
/
23
/
22
n
23
/
23
/
20
n
24
/
22
/
21
n
24
/
24
/
23
Courtesy of Cappellini M, et al. 16th Annual
Meeting of the International BioIron Society.
2003.
32
Oral ICL670 (20 mg/kg) Is Comparable to
Deferoxamine in Reducing LIC
ICL670 10 mg/kg ICL670 20 mg/kg
Deferoxamine 40 mg/kg
Time on study, months
3
6
9
12
Change in LIC, mg/g dry weight
? Standard deviation LIC determined by
SQUID.Cappellini M, et al. 16th Annual Meeting
of the International BioIron Society. 2003.
33
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.
34
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

35
Ongoing and Planned Trials

• Study N Indication Design Phase Comparator
• 0107 500 Thalassemia Randomized III Deferoxamine
  noninferiority
• 0108 175 Rare anemias Single arm II None
• n 75 Thalassemia n 100 Other anemias
  
• 0109 170 Adult and Randomized II Deferoxamine
  pediatric noninferiority sickle cell
  disease

36
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 21 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)

37
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

38
Patient Population (Exclusion criteria)

• Chronic anemia other than sickle cell disease
• Increased ALT 250 during the previous year
• Uncontrolled systemic hypertension
• History of MI, CHF or unstable cardiac disease
• Elevated serum creatinine
• Significant proteinuria or history of nephrotic
  syndrome
• 2nd or 3rd degree A-V block
• Fever with in 10 days before start of study
• Clinically significant cataract or ocular
  toxicity from chelation
• Psychiatric or addictive disorder
• Pregnancy or breast feeding
• Patients treated with other investigational drug
  with 4 weeks
• Patients requiring hydroxyurea
• Patients with documented poor response or
  toxicity to DFO
• Any disorder which would alter absorption,
  distribution or metabolism of drug
• HIV, Hepatitis B or C
• History of non-compliance to medical regimens
• History of drug or alcohol abuse
• Patients unable to undergo SQUID exam
  (pacemakers, metal devicers)

39
Study 0109 Phase II Comparative TrialAdult and
Pediatric Sickle Cell Disease
Deferoxamine-naiveor previously treated(N 170)
ICL670 10 mg/kg/day (n 60)
Screening
andRandomization(21)
Deferoxamine 40 mg/kg/day ? 5 days/week ( n 30)
1-year treatment and observation
LIC bySQUID
LIC bySQUID
LIC bySQUID
Serum ferritin monitored monthly Liver biopsy/MRI
at baseline and 1-year for LIC assessment
patients subset
Dosing escalated/reduced per SQUID results
throughout trial.
40
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

41
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?