Dosage regimen of vidofludimus for use in the prevention or treatment of chronic inflammatory and / or autoimmune diseases - Patent Application 20070233633

Abstract

At high doses of bidofludimus (i.e., 70 mg / day or more or single doses of 210 mg or more), in very rare cases, a decrease in blood uric acid concentration and an increase in urinary red blood cell count have been observed, presenting as symptomatic hematuria during the first 7 days of treatment. The present invention provides a compound according to formula (I), 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid), JPEG2023057141000011.jpg2853(I) The present invention relates to novel dosing regimens and their use in the treatment of chronic inflammatory and / or autoimmune diseases. The compounds of formula (I) inhibit dihydroorotate dehydrogenase (DHODH) and are known for their use in the treatment and prevention of diseases, particularly diseases in which inhibiting dihydroorotate dehydrogenase (DHODH) is beneficial.

Description

[Technical field]

[0001] The present invention relates to a compound according to formula (I), CAS-No 717824-30-1, 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of the compound of formula (I) or its salt, and to novel administration regimes and their use in the prevention and / or treatment of diseases, in particular chronic inflammatory diseases and / or autoimmune diseases.

[0002] [ka] (I)

[0003] The compounds of formula (I) inhibit dihydroorotate dehydrogenase (DHODH) and are known for their use in the treatment and prevention of diseases, particularly diseases in which inhibiting dihydroorotate dehydrogenase (DHODH) is beneficial.

[0004] In the human body, DHODH catalyzes the synthesis of pyrimidines that are particularly necessary for cellular metabolism. Inhibition of DHODH leads to a block in the transcription of sensitive genes in metabolically activated cells, whereas cells with normal metabolic activity obtain the necessary pyrimidine building blocks from the pyrimidine salvage pathway and exhibit normal transcriptional activity. Disease-associated activated lymphocytes depend on de novo pyrimidine synthesis and are particularly sensitive to DHODH inhibition. Several substances that inhibit DHODH are important pharmaceuticals for use in the treatment of chronic inflammatory and autoimmune diseases.

[0005] A new compound with an inhibitory effect on DHODH, particularly human DHODH, has been found and described in European Patent Application Publication No. EP209314A1. Vidofludimus (CAS 717824-30-1) is the free acid of the compound of formula (I) and has been tested in human clinical trials. High doses of Vidofludimus in plasma have been shown to be beneficial, particularly for its use in the therapeutic treatment of patients with chronic inflammatory and autoimmune diseases, blocking DHODH by Vidofludimus. High doses refer to doses of Vidofludimus in humans that are more than 50 μmol once a day. However, doses of the compound of formula (I) that are more than 200 μmol once a day can cause undesirable side effects, such as the risk of increased red blood cell count (RBC) in urine (hematuria).

[0006] At higher doses of bidofludimus (i.e., 70 mg / day or more or single doses of 210 mg or more), very rare cases of decreased uric acid concentration in the blood and increased urinary red blood cell counts have been observed, with symptomatic hematuria during the first 7 days of treatment. Laboratory findings were consistent with post-renal events and de novo urinary precipitation. However, at a daily dose of 35 mg bidofludimus, no cases of symptomatic hematuria were seen.

[0007] Increased RBC and hematuria are associated with increased excretion of uric acid and may result from crystallization of uric acid or urate salts in the urinary tract. It is generally recognized that approximately 5-10% of all people have crystalline uric acid or urate salts in their urine [Pak, CYC The Journal of Urology 180, 813-819(2008)]. Increased hematuria rates are considered an undesirable side effect.

[0008] Therefore, the object of the present invention was to reduce or avoid side effects without substantially impairing the beneficial effect of treatment.Surprisingly, the present invention has found and provided a special dosing regimen that reduces or avoids side effects and / or provides a higher dose of the compound of formula (I) during its use in the prevention and / or treatment of the patient with the compound of formula (I), without substantially impairing the beneficial effect of the treatment of the patient who needs the prevention and / or treatment.

[0009] Side effects, which may also be referred to as adverse effects, are harmful and undesired effects resulting from dosing during the use of the compound (I) of the present invention in the prevention and / or treatment of a patient. The inventors have observed that, for example, hematuria can occur at the first dose of 70 mg or more of bidofludimus after administration of the compound of formula (I) of the present invention in the range of about 12 to about 168 hours after the start of treatment.

[0010] The evaluation of RBCs in urine, known techniques such as urinalysis, should be based only on findings from microscopic examination of the urinary sediment and not on dipstick readings alone [Grossfeld GD, et al., Am Fam Physician 2001;63(6):1145-54]. Therefore, microscopic examination of the urinary sediment should be performed after every significant dipstick reading.

[0011] According to embodiments of the dosing regimen of the present invention, the occurrence and / or extent of uric acid crystal buildup and / or RBC buildup in the urine and / or hematuria is reduced or prevented entirely.

[0012] The terms "increased" versus "normal" levels of uric acid crystals and / or "increased RBCs" refer to the patient's values ​​when not receiving the treatment of the present invention. Assessment of normal ranges of uric acid crystals and / or increased RBCs in the urine is within the capabilities of the attending physician.

[0013] A subject of the present invention is a compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) according to formula (I) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicine in a patient in need thereof, in which said compound or a salt thereof or a solvate of said compound or a salt thereof is administered to said patient initially for a period of at least 5 and at most 10 days in an initial daily dose of 14 to 130 μmol of the active moiety of the compound of formula (I), followed by a second dose which is 1.5 to 8.0 times higher than said initial daily dose.

[0014] [ka] (I)

[0015] The compound according to formula (I) is sometimes referred to as "vidofludimus" as an international nonproprietary name.

[0016] In the context of the present invention, "administration of" or "administering" or any other grammatical form thereof means that the present compounds of formula (I) are administered in the form of a pharmaceutical composition, optionally including a pharma- ceutically acceptable carrier.

[0017] Pharmaceutically acceptable carriers or excipients include diluents (fillers, bulking agents, e.g., lactose, microcrystalline cellulose), disintegrants (e.g., sodium starch glycolate, croscarmellose sodium), binders (e.g., PVP, HPMC), lubricants (e.g., magnesium stearate), glidants (e.g., colloidal SiO2), solvents / co-solvents (e.g., aqueous media, propylene glycol, glycerol), buffers (e.g., citrate, gluconate, butyrate), preservatives (e.g., sodium benzoate, parabens ( Me, Pr and Bu), BKC) antioxidants (e.g., BHT, BHA, ascorbic acid), humectants (e.g., polysorbates, sorbitan esters), thickeners (e.g., methylcellulose or hydroxyethylcellulose), sweeteners (e.g., sorbitol, saccharin, aspartame, acesulfame), flavoring agents (e.g., peppermint, lemon oil, butterscotch, etc.), humectants (e.g., propylene glycol, glycerol, sorbitol). Other suitable pharma- ceutically acceptable excipients include those described in Remington's Pharmaceutical Sciences, 15 th Ed., Mack Publishing Co., New Jersey (1991) and Bauer et al., Pharmazeutische Technologie, 5 th Ed., Govi-Verlag Frankfurt (1997).

[0018] Those skilled in the art are aware of suitable formulations for Bidofludimus. Bidofludimus may be formulated, for example, as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewables. Such solid formulations may include, for example, cellulose, microcrystalline cellulose, polyvidone, particularly FB polyvidone, magnesium stearate, etc.

[0019] A person skilled in the art would be able to readily select a suitable pharma- ceutically acceptable carrier or excipient depending on, for example, the formulation and route of administration of the pharmaceutical composition.

[0020] It should be understood that the pharmaceutical composition comprising the compound of the present invention is intended for use in administering to a human patient. The term "administer" in all grammatical forms means administration of a single therapeutic agent or administration in combination with another therapeutic agent. It is therefore envisaged that the pharmaceutical composition of the present invention is used in a combination therapy approach, i.e. in co-administration with other medicaments or drugs and / or any other therapeutic agent that may be beneficial in the context of the method of the present invention.

[0021] In some embodiments of the invention, the first dose is not therapeutically effective, i.e., it is a subtherapeutic dose, which means a dose of less than 20 mg of bidofludimus, which corresponds to 56 μmol of a compound according to formula (I). Without being strictly bound, for the purposes of the present invention, a dose of 56 μmol or less is considered to be subtherapeutic.

[0022] Such a "first dose" that is sub-therapeutic may include two or more doses. Thus, for example, two sub-therapeutic doses may be subsequently administered.

[0023] In a preferred embodiment of the invention, the second dose is therapeutically effective.

[0024] If multiple subtherapeutic doses are administered, the therapeutically effective dose may be the third or fourth dose, but in any case, is the first therapeutically effective dose after one or more subtherapeutic doses. The first therapeutically effective dose, which may hereafter be called a subsequent dose, is meant to be the first dose that is intended to be therapeutically effective. The therapeutically effective dose may be administered for an unterminated period of time, for example, one year or more.

[0025] The subject of the present invention is also a method for the prevention and / or treatment of a patient in need thereof, in which a compound 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) according to formula (I) or a salt thereof or a solvate of said compound or a salt thereof is first administered to said patient for a period of at least 5 and at most 10 days at an initial daily dose of 14 to 100 μmol of the active moiety of said compound, followed by a subsequent dose, for example a second dose, if only one pre-treatment dose was administered, in which said subsequent dose is 28 to 200 μmol of said active moiety of said compound per day. In one embodiment, the subsequent dose, for example the second dose, is 1.5 to 4.0 times higher than the initial daily dose.

[0026] [ka] (I)

[0027] The subject of the present invention is further the use of a compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) according to formula (I) or a salt thereof, or a solvate of said compound or a salt thereof, for the preparation of a medicament in a method for the prevention and / or treatment of a patient in need thereof, in which said compound or a salt thereof, or said solvate of said compound (I) or a salt thereof, is initially administered to said patient for a period of at least 5 to at most 10 days at an initial daily dose of 14 to 100 μmol of the active moiety of said compound (I), followed by a subsequent dose, for example a second dose, which is 1.8 to 2.2 times higher than the initial daily dose.

[0028] [ka] (I)

[0029] Suitable salts of the compounds according to formula (I) can be formed using the free acid 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) and an inorganic or organic acid or base. Examples of such salts are, for example, alkali metal salts, particularly sodium and potassium salts, or ammonium salts.

[0030] The solvates of 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) may be selected from the group comprising protic solvents such as alcohols and water. The alcohols may be selected from the group comprising ethanol, n-propanol, isopropanol, and butanol.

[0031] Solvates of the above salts may be selected from the group including water, ethanol, n-propanol, isopropanol, and butanol.

[0032] In one embodiment of the present invention, the first dose of the active moiety of Compound (I) is 14 to 130 μmol, preferably 14 to 64 μmol of the active moiety of Compound (I), more preferably 53 to 64 μmol of the active moiety of Compound (I).

[0033] In one embodiment of the present invention, the subsequent dose, e.g., the second dose, is 1.5 to 8.0 times higher than the initial daily dose (pretreatment dose), preferably 1.5 to 4.0 times higher than the initial daily dose, more preferably 1.5 to 3.0 times higher than the initial daily dose, even more preferably 1.5 to 2.5 times higher than the initial daily dose, and most preferably 2 times higher than the initial daily dose.

[0034] In one embodiment of the present invention, the subsequent dose, e.g. the second dose, has an active moiety of 28-200 μmol of compound (I) per day in its use for the method of prevention and / or treatment of a patient in need thereof. The subsequent dose, e.g. the second dose, has an active moiety of 56-200 μmol of compound (I) per day in its use for the method of treatment of a patient in need thereof, preferably an active moiety of 63-140 μmol of compound (I) per day in its use for the method of treatment of a patient in need thereof, and even more preferably an active moiety of 100-140 μmol of compound (I) per day in its use for the method of prevention and / or treatment of a patient in need thereof.

[0035] In one embodiment of the present invention, the patient in need of the method of prevention and / or treatment suffers from a chronic inflammatory disease and / or an autoimmune disease. In a preferred embodiment of the present invention, the patient suffers from a chronic inflammatory disease and / or an autoimmune disease selected from the group consisting of rheumatism, acute immune diseases, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, or athropathy. In one embodiment of the invention, the patient suffers from a chronic inflammatory and / or autoimmune disease selected from the group comprising graft-versus-host and host-versus-graft reactions, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, lupus erythematosus, lupus nephritis, inflammatory bowel disease, type 1 diabetes, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, and psoriasis. In a particular embodiment of the invention, the patient suffers from an inflammatory bowel disease, in particular ulcerative colitis and Crohn's disease.

[0036] In one embodiment of the invention, the compound 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a solvate thereof is administered, which may be selected from the group including water, ethanol, n-propanol, isopropanol, and butanol.

[0037] In another embodiment of the invention, the calcium salt of the compound is administered, which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) calcium (Example 2, CAS No. 1354012-90-0) or a solvate thereof. The solvate may be selected from the group including water, ethanol, n-propanol, isopropanol, and butanol.

[0038] In one embodiment of the invention, the first daily dose is 63.3 μmol and the subsequent dose is 126.6 μmol.

[0039] In one embodiment of the invention, the first daily dose has a duration of 5 to 10 days, and in one particular embodiment, the duration is 5, 6, 7, 8, 9 days, and in one particular embodiment, 7 days in duration.

[0040] In a particular embodiment, the duration of the second daily dose is at least 1 month, or at least 6 months. The phase of the second dose may or may not be indefinite, as long as the patient requires it.

[0041] In one embodiment of the invention, the solvate is an ethanol solvate or dehydrate of the compound 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) according to formula (I) or a salt thereof.

[0042] [ka] (I)

[0043] In the table below, the μmoles of active moiety of the compound are calculated based on the free acid of the compound of formula (I) and the calcium salt of the compound of formula (I). two Converted to mg of hydrate:

[0044] [Table 1]

[0045] In the above context, specific embodiments of the present invention are represented by the following sequentially numbered embodiments:

[0046] 1. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) according to formula (I) or a salt thereof, or a solvate of compound (I) or a salt thereof, for use as a medicine in a patient in need thereof, wherein said compound or a salt thereof, or a solvate of said compound or a salt thereof is administered to said patient initially for a period of a minimum of 5 to a maximum of 10 days at an initial daily dose of 14 to 130 μmol of the active moiety of said compound, followed by a second dose which is 1.5 to 8.0 times higher than said initial daily dose.

[0047] [ka] (I)

[0048] 2. The compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicament in a patient in need thereof according to embodiment 1, wherein the second dose is 28 to 200 μmol of the active moiety of said compound per day.

[0049] 3. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicament in a patient in need thereof according to embodiment 1 or 2, wherein said patient is suffering from a chronic inflammatory disease and / or an autoimmune disease.

[0050] 4. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicament in a patient in need thereof according to any one of embodiments 1 to 3, wherein said patient is suffering from a chronic inflammatory and / or autoimmune disease selected from the group consisting of rheumatism, acute immune diseases, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, or athropathy.

[0051] 5. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicament in a patient in need thereof according to any one of embodiments 1 to 4, wherein said patient is suffering from a chronic inflammatory disease and / or an autoimmune disease selected from the group comprising graft-versus-host and host-versus-graft reactions, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, inflammatory bowel disease, type 1 diabetes, and psoriasis.

[0052] 6. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicament in a patient in need thereof according to any one of embodiments 1 to 5, wherein said patient suffers from inflammatory bowel disease, in particular ulcerative colitis and Crohn's disease.

[0053] 7. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicament in a patient in need thereof according to any one of embodiments 1 to 6, wherein said compound 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a solvate thereof is administered.

[0054] 8. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or said salt, for use as a medicament in a patient in need thereof according to any one of embodiments 1 to 6, in which a calcium salt of said compound or a solvate thereof is administered.

[0055] 9. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicament in a patient in need thereof according to any one of embodiments 1 to 8, wherein the first daily dose is 63.3 μmol and the subsequent dose is 126.6 μmol.

[0056] 10. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicament in a patient in need thereof according to any one of embodiments 1 to 9, wherein the first daily dose is for 7 days.

[0057] 11. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for use as a medicament in a patient in need thereof according to any one of embodiments 1 to 10, wherein said solvate is an ethanol solvate or a dehydrate.

[0058] 12. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of the above compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof, comprising administering to the patient initially an initial daily dose of 14 to 130 μmol of the active moiety of the compound of formula (I) for a period of a minimum of 5 to a maximum of 10 days, followed by a second dose which is 1.5 to 8.0 times higher than the initial daily dose.

[0059] 13. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of the compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to embodiment 12, wherein the second dose is 28 to 200 μmol of the active moiety of the compound per day.

[0060] 14. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to embodiment 12 or 13, wherein said patient suffers from a chronic inflammatory disease and / or an autoimmune disease.

[0061] 15. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to any one of embodiments 12-14, wherein said patient suffers from a chronic inflammatory disease and / or an autoimmune disease selected from the group consisting of rheumatism, acute immune diseases, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, viral infections and diseases caused by Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, or athropathy.

[0062] 16. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to any one of embodiments 12-15, wherein said patient is suffering from a chronic inflammatory disease and / or an autoimmune disease selected from the group comprising graft-versus-host reaction and host-versus-graft reaction, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, inflammatory bowel disease, type 1 diabetes, and psoriasis.

[0063] 17. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to any one of embodiments 12 to 16, wherein said patient suffers from an inflammatory bowel disease, in particular ulcerative colitis and Crohn's disease.

[0064] 18. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of the compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to any one of embodiments 12 to 17, wherein the compound 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a solvate thereof is administered to the patient.

[0065] 19. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to any one of embodiments 12 to 18, in which a calcium salt of said compound or a solvate thereof is administered.

[0066] 20. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to any one of embodiments 12 to 19, wherein the first daily dose is 63.3 μmol and the subsequent dose is 126.6 μmol.

[0067] 21. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to any one of embodiments 12 to 20, wherein the first daily dose is for 7 days.

[0068] 22. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a salt thereof, or a solvate of said compound or a salt thereof, for the prevention and / or treatment of a disease in a patient in need thereof according to any one of embodiments 12 to 21, wherein said solvate is an ethanol solvate or a dehydrate.

[0069] Abbreviation / Definition DHODH - dihydroorotate dehydrogenase RBC - Red blood cell count IMU-838 = Bidofludimus calcium

[0070] As used throughout the Examples section, the terms "mean" and "median" of a data sample are each terms well known in statistics. Use of these terms in this application conforms to the corresponding definitions in general statistics textbooks. Generally, the mean is calculated by adding several quantities and dividing the sum by the number of said quantities. The median is the value that separates the upper half of a data sample from the lower half. [Brief description of the drawings]

[0071] [Figure 1] FIG. 1 shows blood uric acid concentrations in healthy subjects at various time points after receiving a single dose of 30 mg of IMU-838. [Figure 2a] Figure 2a shows the median urinary uric acid levels with 30 mg and 40 mg IMU-838 treatment at three time points: baseline (24 hours prior to treatment), day 1 of treatment, and day 14 of treatment. The figure shows the mean uric acid values ​​for each group. Each group consisted of 16 patients, 12 individuals receiving the active drug IMU-838 (either 30 or 40 mg per day) and 4 patients receiving placebo. [Figure 2b]Figure 2b shows the median % change in urinary uric acid levels in 20 healthy subjects. Eight were treated with 25 mg for 7 days followed by 50 mg once daily for 14 days. Another eight volunteers were treated with placebo (dose 1 = 0 mg) for 7 days followed by 50 mg of IMU-838. Four volunteers received placebo for the entire period. Figure 2c shows the mean change in urinary uric acid levels as % change at the four time points. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0072] Example 1 Effect of IMU-838 (bidofludimus calcium) on urinary uric acid concentration During the IMU-838 (bidofludim scalcim) Phase I SAD study (Immunic study number P1-IMU-838-SAD), urine was collected from all volunteers and tested for the amount of clinically relevant anions, including urate and oxalate. Additionally, the formation of anion crystals in urine was measured. In this study, IMU-838 was tested as a single dose administered to male healthy subjects. Five different dose regimens were tested, covering four different doses of IMU-838: 10 mg, 20 mg, 30 mg, and 40 mg in fasted patients. This means that there was no food intake 10 hours before treatment and 2 hours after dose administration. Additionally, one treatment group received 10 mg of IMU-838 in a fed state. This means that the 10 mg dose was administered after a high-fat breakfast. Each group consisted of six healthy subjects, except for the 40 mg dose group, which had only five healthy subjects. Maximum plasma concentrations (c max ) increased from 1.5772 μg / mL in fasted volunteers receiving 10 mg of IMU-838 to 7.8561 μg / mL in patients receiving a 40 mg dose of IMU-838.

[0073] Patients on the highest dose of 40 mg showed a higher increase in urinary uric acid levels of 50.1% compared to patients receiving 10 mg of IMU-838, who showed an average increase of 22.5%, as shown in Table 2. Pre-dose values ​​were obtained from urine collected 24 hours prior to administration of IMU-838 tablets. Post-dose values ​​were obtained from 24-hour urine collection 4 hours after IMU-838 inoculation.

[0074] [Table 2]

[0075] Increased urinary urate concentrations were seen in all patients, but urinary RBC (red blood cell count) did not increase at the doses tested.

[0076] Treatment of humans with IMU-838 leads to a dose-dependent increase in urinary uric acid excretion and thus to the formation of uric acid (micro)crystals. Doses of IMU-838 up to 40 mg did not produce dose-limiting side effects, such as hematuria.

[0077] In this example, the time course of uric acid concentration in blood was also examined. After a single dose of 30 mg, plasma uric acid concentration was minimally reduced after 4 hours and returned to baseline levels after 96 hours. This is shown in FIG. 2.

[0078] Example 2 Effect of IMU-838 (bidofludimus calcium) on urinary uric acid concentration after repeated administration without prior treatment In the randomized, double-blind, placebo-controlled Phase I MAD study (Immunic study number P1-IMU-838-MAD), IMU-838 was administered for 14 days to healthy volunteers to study the effects of IMU-838 on safety and biomarkers with repeated dosing once daily over 14 days.

[0079] In the first part of the study, 12 individuals were treated with 30 mg of IMU-838, 12 individuals were treated with 40 mg of IMU-838, and 8 individuals received placebo (4 individuals in each group). For all 32 individuals, urinary uric acid levels were quantified in three 24-h urine collections. The first collection was before dosing (day 0). The second urine collection began 4 hours after ingestion of the first dose (day 1, 4 to 28 hours). The third urine collection was performed on the last day of the 14-day treatment cycle (day 14, 4 to 28 hours). Uric acid levels at these time points are shown in Figure 2a.

[0080] Results: Surprisingly, the increase in uric acid measured in the urine was not linearly related to the dose administered. At the 30 mg dose, there was no increase on the first day of ingestion of IMU-838, but after 14 days of daily treatment, there was a 29% increase from 605.9 mg to 686.2 mg (Figure 2a). The amount of uric acid in the 40 mg group increased by 15.2% from 541.4 mg to 620.3 already on the first day (4-28 hours after ingestion of 40 mg of IMU-838), and then increased to 699.3 mg on the 14th day of the study. Thus, the increase in uric acid concentration was fast on the first day of treatment and gradual with a slow onset during the next 13 days. There was no further increase in the mean concentration of uric acid in the urine in the 40 mg dose group. The data are shown in Figure 2a.

[0081] Interestingly, despite the fact that subjects received different doses of IMU-838, volunteers showed a comparable increase in uric acid of about 30% after the entire 14-day treatment period compared to pre-treatment.

[0082] They also concluded that the rapid increase in urinary uric acid was dose-dependent: doses below 30 mg had little effect on uric acid levels on the first day of treatment with IMU-838.

[0083] Example 3 Effect of bidofludimus on urinary uric acid levels after the dose-in phase before repeated administration Based on the observation of a) the dose-dependent effect of IMU-838 on urinary uric acid levels and the formation of small crystals (Example 1) and b) the time course and dose-dependency of uric acid level changes in a single volunteer (Example 2), a new treatment scheme was devised. In this example, the treatment scheme was applied to a 3-week clinical phase I study consisting of two different doses, "Dose 1" at a daily dose of 25 mg and "Dose 2" at a daily dose of 50 mg. Eight subjects were administered the low dose 1 for 7 days, followed by the high (2x) dose 2 for another 14 days. Meanwhile, another eight subjects were administered placebo for 7 days, followed by treatment with the high dose (Dose 2) at 50 mg. Four subjects were administered placebo for the entire foll 3-week period. During this study, urine was collected at four different time points (before administration, day 1, day 7, day 14) and urate level / uric acid level was analyzed.

[0084] The mean increase in 24-hour urinary uric acid levels for all 20 patients, including those who received placebo, was 15% after one day (4-28 hours) of treatment, from 684.1 mg to 789.5 mg. Surprisingly, even when eight volunteers were not previously administered dose 1 and were immediately treated with the higher dose of 50 mg, the mean uric acid levels in urine collected on the first day of administration of dose 2 (day 7 of the entire study) did not increase (from 789.5 mg to 789.7 mg). After the entire 3-week period (day 21), there was a slight increase of 4% overall, from 789.7 mg to 815.9 mg.

[0085] Conclusion: Using a graded dosing of IMU-838 with a low first dose of 25 mg of IMU-838 followed by a higher second dose of 50 mg of IMU-838 reduced the increase in the average amount of uric acid in the urine, in this case over a time frame of 4 to 28 hours after taking 50 mg. The effect was clear even when the data was diluted with individuals who received a placebo.

[0086] We conclude that by starting with a low dose of treatment and then switching to a higher dose, increasing the dose in the second phase can increase the therapeutic efficacy of IMU-838 while avoiding the undesirable rapid and / or strong immediate excretion of large amounts of uric acid / urate. The results of the experiment resulted in an updosing scheme with a lower urate gradient compared to immediate dosing.

[0087] Example 4 Clinical trials comparing treatment with and without a pretreatment phase A double-blind, placebo-controlled, ascending dose clinical trial was conducted. The study has been reported (Study No. P1-IMU-838-MAD). Urinary excretion of uric acid increased after initiation of treatment with IMU-838 (bidofludimus calcium) in all groups except the 30 mg group. No dose-dependence was evident.

[0088] However, urinary uric acid excretion may be altered by the duration of pretreatment. Pretreatment with 25 mg of IMU-838 for 6 days in subjects receiving 50 mg of IMU-838 resulted in a smaller increase in urinary uric acid excreted on day 0 (the first day of administration of the 50 mg dose) compared with pretreatment with placebo (median 49.5 mg / 24 hours vs. 86.5 mg / 24 hours, respectively).

[0089] [Table 3]

[0090] Thus, the superiority of a treatment regimen including a pretreatment phase was demonstrated compared to treatment without such a pretreatment phase.

Claims

1. A compound which is 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) according to formula (I) for use in a method for reducing the risk of occurrence of hematuria in a subject in need thereof. 【Chemistry 1】 (I) or a salt thereof, or a solvate of said compound or salt thereof, wherein said pharmaceutical composition is administered to said subject at an initial daily dose of about 14 to about 64 μmol of an active moiety of said compound for a minimum of 5 days to a maximum of 10 days, followed by a subsequent dose of about 63 to about 140 μmol of the active moiety of said compound, said initial daily dose and subsequent doses being calculated based on the weight of 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid), and wherein said compound or salt thereof, or a solvate of said compound or salt thereof is a dihydrate of a calcium salt of said compound.

2. 2. The pharmaceutical composition of claim 1, wherein the initial daily dose is administered for a minimum of 6 days and a maximum of 8 days.

3. The pharmaceutical composition according to claim 1 or 2, wherein a salt of the compound 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a solvate thereof is administered.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the calcium salt of the compound 2-({3-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a solvate thereof is administered.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the solvate is a dihydrate.

6. The compound or a salt thereof, or a solvate of the compound or a salt thereof 【Chemistry 2】 The pharmaceutical composition according to any one of claims 1 to 5,

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