METHOD OF TREATMENT OF HEREDITARY HEMOCHROMATOSIS

The present invention relates to the use of Compound I in the treatment of hereditary hemochromatosis and to a commercial package comprising Compound I together with instructions for the treatment of hereditary hemochromatosis. The present invention relates to the use of Compound I for the treatment of iron overload in hereditary hemochromatosis patients.

BACKGROUND OF THE INVENTION

Hereditary hemochromatosis, abbreviated as HH, is the most common inherited single-gene disorder in the Caucasian population. HFE gene is the name of the hemochromatosis gene. The HFE gene mutation is most frequently associated with hereditary hemochromatosis, and is located on the short arm of chromosome 6. Approximately one in 250 to 300 white persons is homozygous for the C282Y HFE gene mutation and at least one in 10 persons is a carrier, i.e. the mutation replaces cysteine with tyrosine at position 282 in the protein's chain of amino acids, also written as C282Y or Cys282Tyr. Another common mutation in the HFE gene that can lead to iron overload is the H63D mutation, i.e. the mutation replaces histidine with aspartic acid at position 63, written as H63D or His63Asp. The risk of iron overload is higher in person who are homozygous for the C282Y mutation, compared to C282Y/H63D compound heterozygotes or H63D homozygotes. Another mutation in the HFE gene, S65C accounts for nearly 8% of hemochromatosis mutations that are neither C282Y nor H63D. The exact function of the HFE gene product is not known however it appears to take part in the regulation of hepcidin expression.

HJV, Juvenile hemochromatosis is due to mutations in the HJV gene coding for hemojuvelin and HAMP gene coding for hepcidin. With juvenile hemochromatosis, iron accumulation begins early in life, and symptoms are present before the age of 30 years. Men and women are affected equally. The signs and symptoms of juvenile hemochromatosis are more severe than those of the HFE type and complications involving endocrine glands and, clinically most relevant, the heart. The disease, Juvenile hemochromatosis due to mutations of HJV and HAMP is very rare but it has been reported in several different ethnic groups. Mutations in the HAMP and HFE2 genes cause HJV. The HAMP and HFE2 genes appear to play a role in regulating iron absorption during digestion. The HAMP gene instructs cells to manufacture a small protein called hepcidin, which was originally identified as having antimicrobial properties. Recent evidence indicates that hepcidin levels are important in determining the amount of iron absorbed from the diet. Low levels of hepcidin, e.g. due to HAMP mutation, increases the iron influx from the intestinal mucosa. Hemojuvelin acts upstream of hepcidin and co-determines the amount of hepcidin expression. Researchers recently discovered that hepcidin level plays a role in maintaining iron balance in humans.

Generally, the various types of hereditary hemochromatosis are characterized by increased intestinal absorption of iron, which leads to deposition of iron in the body, i.e. in multiple organs such as liver, pancreas, heart and other organs. Excess iron deposition, if left untreated, causes tissue damage and fibrosis with irreversible damage to various organs, e.g. iron overloaded organs, e.g. endocrine dysfunction or hepatic cirrhosis.

Initiation of treatment of hereditary hemochromatosis is indicated for patients with evidence of iron overload based on elevated iron parameters or markers, e.g. serum ferritin and transferrin saturation. Phlebotomy is the current standard of care because it is simple, effective and safe. Phlebotomy entails removal of up to two units of blood, e.g. 800 to 1000 ml corresponding to approximately 500 mg of iron per week, for information a unit of blood, e.g. approximately 500 ml removes about 250 mg iron. The aim is to remove excess body iron and lower the ferritin value to 50 mcg/L (microgram per liter) or less. This phase, which takes to 1-3 years rarely more, corresponds to the so called “induction phase”. Once iron depletion is accomplished, most patients require four to eight phlebotomies per year to keep the serum ferritin concentration below 50 mcg/L, this corresponds to the so called “maintenance phase”.

However 5 to 10% of patients are ineligible for, inadequately treated by, e.g. due to poor compliance, or unwilling to have phlebotomies due to poor venous access, anemia, congestive heart failure/left ventricular dysfunction, or “needlephobia”.

An alternative to phlebotomy is the use of iron chelation. Iron chelator can bind iron and promote its secretion. During this procedure, a drug that binds to excess free iron is administered.

Therefore, there is a need to provide an alternative treatment for hereditary hemochromatosis patients, e.g. for hemochromatosis patients unwilling or unable to undergo a phlebotomy regimen. As the amount of iron removed per phlebotomy is limited, and the number of phlebotomies an individual is able to tolerate is also limited, there is also a need for an alternative treatment to be used in combination with standard care, i.e. phlebotomy, to shorten the duration of iron removal in patients with modestly elevated ferritin levels, in order to prevent progression of end-organ damage.

The treatment of iron overload by subcutaneous desferrioxamine (abbreviated as DFO), i.e. Desferal®, was studied in 3 patients with HH in which phlebotomy was not, or transiently not possible because of their serious clinical conditions or the lack of peripheral venous access. DFO treatment was shown to be as effective as weekly phlebotomy, e.g. 500 ml (Nielsen P. et al, Br. J. Haematol 2003, 123(5):952-3). However available data reporting the use of desferrioxamine in this patient population is very limited.

Moreover, despite the merits of DFO, DFO cannot be administered orally and its half life within the bloodstream is short. DFO is administered via intravenous or subcutaneous infusion 8-12 h/day at least 5 days per week and leads to poor patient compliance.

Compound of formula I as disclosed below is known to be used in the treatment of iron overload in blood-transfused patients, e.g. in beta-thalassemia patients. However, no or very little information is available on the safety of Compound I at low ferritin levels, e.g. ferritin levels below 500 mcg/L, e.g. 100 mcg/L, e.g. 50 mcg/L. Therefore, there was a need to determine the safety of Compound I at such low ferritin values, e.g. in order to determine a suitable treatment schedule for the use of Compound I in the removal of iron in hereditary hemochromatosis patients. Surprisingly, the inventors have found that Compound I is suitable and safe for hereditary hemochromatosis patients.

DETAILED DESCRIPTION OF THE INVENTION

Compound I is a 3,5-diphenyl-1,2,4-triazoles of the following formula: 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid and can be administered orally.

Compound I has the following formula:

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Compound I in the free acid form, salts thereof and its crystalline forms are disclosed in the International Patent Publication WO 97/49395, which is hereby incorporated by reference (published on Dec. 31, 1997).

Compound I and its process of preparation is described, e.g. in U.S. Pat. No. 6,465,504 B1.

Pharmaceutical preparation comprising Compound I are described in the International Patent Application WO 97/49395.

However U.S. Pat. No. 6,465,504 does not disclose that Compound I is suitable to treat the iron overload due to hereditary hemochromatosis. U.S. Pat. No. 6,465,504 does not disclose either the particular dosage, nor the treatment schedule as described herein after.

Within the scope of the present invention by “treatment of hereditary hemochromatosis” is meant the control of the body iron balance of the HH patient.

An HH patient is to be understood to be a patient having hereditary hemochromatosis or juvenile hemochromatosis. Hereditary hemochromatosis and juvenile hemochromatosis being defined as in the background of the invention.

The treatment of hereditary hemochromatosis can be performed according to an intermittent regimen, i.e. Compound I is administered until the serum ferritin reaches a defined value, e.g. of about 100 mcg/L or below, e.g. of 100 mcg/L or below, e.g. of about 50 mcg/L and the treatment is resumed as soon as the serum ferritin level exceeds another defined value, e.g. of about 300 mcg/L or above, e.g. of 300 mcg/L or above, e.g. of about 200 mcg/L or above, e.g. of about 200 mcg/L or above for female patients, e.g. of about 300 mcg/L or above for male patients.

The present invention pertains to the treatment of iron overload in hereditary hemochromatosis patients according to the intermittent treatment described above.

The treatment of hereditary hemochromatosis can be performed in two consecutive steps according to a second regimen, i.e. in a first phase, e.g. called the induction phase, Compound I is administered at a daily dose of 5 to 40 mg/kg of body weight, e.g. 5 to 20 mg/kg of body weight, e.g. 20 to 40 mg/kg body weight, with or without concomitant phlebotomy, e.g. until the serum ferritin level reaches a value of about 100 mcg/L or below, e.g. of 100 mcg/L, e.g. of about 50 mcg/L or below. The daily dose of Compound I administered during the induction phase can be determined based on the measured serum ferritin level of the HH patient. For example, for iron overloaded patients, e.g. with a serum ferritin level above 1500 mcg/L, or e.g. with a serum ferritin level above 200 mcg/L for the female patient and above 300 mcg/L for the male patient, concomitant administration of Compound I, e.g. at an appropriate dosage and phlebotomy can be performed. This combination has surprising advantage benefit also for e.g. hereditary hemochromatosis patients suffering from arthropathy. For example for patients having a serum ferritin level of about or above 300 mcg/L, e.g. of about or above 200 mcg/L for women, e.g. or about or above 300 mcg/L for men, the patients can be administered Compound I, e.g. at a daily dose of 5 to 20 mg/kg of body weight, e.g. until the serum ferritin level falls below, e.g. 100 mcg/L, e.g. 50 mcg/L. The patient is switched to the maintenance phase, e.g. at a daily or intermittent dose of 1 to 20 mg/kg of body weight, e.g. of 2 to 20 mg/kg of body weight, e.g. 5 to 20 mg/day per kg of body weight, e.g. as soon as the patient's serum ferritin level exceeds a defined value, e.g. of about 300 mcg/L, e.g. of 300 mcg/L, e.g. of about 200 mcg/L, e.g. 200 mcg/L for female patients, e.g. of about 300 mcg/L for male patients. Alternatively, after the induction phase, the patient is switched to the intermittent regimen.

Alternatively, after the induction phase is completed, the patient iron overload is managed by phlebotomy, e.g. 3 or 4 times per year.

Alternatively, the patient is treated in the maintenance phase following an induction phase using phlebotomy only.

For the treatment of hereditary hemochromatosis, the dosage of Compound I within the maintenance phase can depend on various factors, such as for example, the age, the body weight and/or the individual condition of the warm-blooded animal, e.g. human to be treated.

The oral daily dose of Compound I to be administered to a patient with hereditary hemochromatosis during the maintenance phase is from, e.g. 1 to 10 mg/kg of body weight per day, e.g. 1 to 5 mg/kg of body weight per day, in particular from 2 to 4 mg/kg of body weight per day. For a warm-blooded animal, e.g. a human having a body weight of approximately 40 kg, the oral daily dose of Compound I is approximately of from 40 to 200 mg/day for the maintenance phase of hereditary hemochromatosis.

Compound I has a plasma half life of approximately 8 to 16 hours, e.g. 12 to 13 hours within the human body. Therefore, alternatively, the dose of Compound I to be administered can be taken every other day, e.g. for a person of a body weight of 40 kg, one tablet of 80 to 400 mg can be taken every other day, e.g. on for two consecutive weeks on days 1, 3, 5, 7 for the first week and on days 2,4, and 6 for the subsequent week. Alternatively the dose of Compound I as mentioned above can daily divided, e.g. the daily dose as mentioned above can be split and given as two administrations.

The present invention relates to the use of for the preparation of a medicament for the control of the body iron content in patients having HH.