COMPOUNDS AND DOSAGE REGIMEN FOR USE IN THE PREVENTION OR TREATMENT OF CHRONIC INFLAMMATORY AND/OR AUTOIMMUNE DISEASES

Abstract

The present invention refers to a 2-({3-fluoro-3′-methoxy-[1,1′-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) according to formula (I)

##STR00001##

and a novel dosage regimen as well as their uses in the treatment of chronic inflammatory and/or autoimmune diseases. The said compound of formula (I) inhibits dihydroorotate dehydrogenase (DHODH), and is known for the treatment and prevention of diseases, in particular their use in diseases where there is an advantage in inhibiting dihydroorotate dehydrogenase (DHODH).

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. (canceled)

10. (canceled)

11. (canceled)

12. A method of treatment comprising administering a compound that is 2-({3-fluoro-3′-methoxy-[1,1′-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) according to formula (I) ##STR00008## or salts thereof or solvates of the said compound (I) or the salts thereof to a patient in need thereof, wherein the compound (I) or salts thereof or solvates of the compound (I) or the salts thereof is initially administered to said patient in an initial daily dose of 14-130 μmol of the active moiety of the compound (I) for a period of minimum 5 and maximum 10 days and is thereafter administered in a subsequent dose that is 1.5 to 8.0-fold higher than the said initial daily dose.

13. A method of claim 12, wherein said subsequent dose provides a daily dose of the active moiety of the compound (I) of 28-200 μmol.

14. A method of claim 12 for treating a chronic inflammatory and/or autoimmune disease.

15. A method of claim 14, wherein the chronic inflammatory and/or autoimmune disease is selected from the group consisting of rheumatism, acute immunological disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases that are caused by protozoal infestations in humans and animals, diseases that are caused by viral infections and neumocystis carinii, fibrosis, uveitis, rhinitis, asthma or athropathy.

16. A method of claim 14, wherein the chronic inflammatory and/or autoimmune disease is selected from the group consisting of graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, inflammatory bowel disease, type 1 diabetes and psoriasis.

17. A method of claim 12 for the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease.

18. A method of claim 12, 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.

19. A method of claim 12, wherein the calcium salt of 2-({3-fluoro-3′-methoxy-[1,1′-biphenyl]-4-yl}carbamoyl)cyclopent-1-ene-1-carboxylic acid) or a solvate thereof is administered.

20. A method of claim 12, wherein the initial dose provides a daily dose of 60-70 μmol of the active moiety of the compound (I) and the subsequent dose provides a daily dose of the active moiety of the compound (I) of 120-140 μmol.

21. A method of claim 12, wherein initial daily dose is administered for a period of 6-8 days.

22. A method of claim 12, wherein the solvate of the compound (I) or the salts thereof that is administered is an ethanol solvate or a dehydrate.

23. A method of reducing the risk of occurrence of hematuria in a subject in need thereof, the method comprising administering to the subject: A) a first therapeutically-effective amount of a DHODH inhibitor according to formula (I) ##STR00009##  or salts thereof or solvates of a DHODH inhibitor according to formula (I) or the salts thereof, for a period of 5 to 10 days, and thereafter, B) a second therapeutically-effective amount of the DHODH inhibitor according to formula (I) or salts thereof or solvates of a DHODH inhibitor according to formula (I) or the salts thereof, wherein the first therapeutically-effective amount is about 1.5 to about 8 fold less than is the second therapeutically-effective amount.

24. The method of claim 23, wherein a human patient is administered: A) a first course of about 10 to 23 mg of the DHODH inhibitor according to formula (I) or salts thereof or solvates thereof daily for the period of 5 to 10 days, and thereafter, B) a second course of about 24 to 50 mg of the DHODH inhibitor according to formula (I) or salts thereof or solvates thereof.

Description

FIGURE DESCRIPTION

[0067] FIG. 1: FIG. 1 shows urate concentrations in the blood of healthy volunteers at different time points receiving a single dose of 30 mg of IMU-838.

[0068] FIG. 2a: FIG. 2a shows the median urate levels in urine with 30 mg and 40 mg IMU-838 treatment at three time points: baseline (24 hours before treatment), at day 1 of the treatment and at day 14 of the treatment. The figure shows the mean values of uric acid for each group. Each group consists of 16 patients with 12 individuals receiving active drug IMU-838 (either 30 or 40 mg per day) and 4 patients receiving placebo.

[0069] FIG. 2b: FIG. 2b shows the median change in % of uric acid levels in the urine of together 20 healthy volunteers. 8 individuals were treated with 25 mg for 7 days, followed by 14 day treatment with a dose of 50 mg once daily. Another 8 volunteers were treated with placebo (dose 1=0 mg) for 7 days followed by treatment of 50 mg IMU-838. 4 volunteers received placebo for the whole time. FIG. 2c shows the mean change of uric acid amount in urine at four time points in % change.

EXAMPLES

Example 1

[0070] Effect of IMU-838 (vidofludimus-calcium) on Uric Acid Levels in Urine

[0071] During the IMU-838 (vidofludimus-calcium) phase I SAD study (Immunic study number P1-IMU-838-SAD), urine was collected from all volunteers and tested with respect to the amount of clinical relevant anions, including urate and oxalate. In addition, formation of anion crystals in the urine was measured. In this study, IMU-838 was tested as a single dose applied to male healthy volunteers. Five different dose regimens were tested which covered four different doses of IMU-838: 10 mg, 20 mg, 30 mg and 40 mg of IMU-838 in fastened patients, which means no food intake 10 hours prior to the treatment and two hours after dose application. In addition, one dose group received 10 mg of IMU-838 in fed state which means that the 10 mg dose was applied after a high-fat breakfast. Each group consisted of six healthy volunteers, except for the 40 mg dose group with only five volunteers. The maximum plasma concentrations (c.sub.max) increased from 1.5772 μg/mL for fastened volunteers with 10 mg IMU-838 dose to 7.8561 μg/mL for patients who received 40 mg dose of IMU-838.

[0072] Patients with the highest dose of 40 mg showed a higher increase of uric acid amounts in urine of 50.1% compared with the patients who received 10 mg of IMU-838 which had a mean increase of 22.5%. This is shown in Table 2. The pre-dose value was derived from urine collected 24 hours before application of IMU-838 tablets. The post dose value was obtained by collecting 24 hours urine starting 4 hours after intake of IMU-838.

TABLE-US-00002 TABLE 2 Uric acid levels in 24 h collected urinein P1-IMU-838-SAD study - comparison of high dose (40 mg) with low dose (10 mg). 10 mg fasted 40 mg fasted Uric acid (mg/24 h) N = 6 N = 5 Pre dose (−24 h to 0) 520  489.sup.a Post dose (4 to 28 h) 637 734 Increase of mean uric acid levels 117 245 (22.5%) (50.1%) .sup.aN = 4; N = number of subjects

[0073] An increased concentration of urate in urine was found in all patients, however not leading to increase of RBC (red blood cell count) in urine at the doses tested.

[0074] Treatment of humans with IMU-838 leads to dose dependent increase of urate excretion through the urine and thus to formation of urate (micro)crystals. At the doses up to 40 mg of IMU-838 no dose limiting side effects like hematuria occurred.

[0075] In this example, also the time dependent change of uric acid levels in blood were tested. At 30 mg single dose, the plasma levels of uric acid drop after 4 hours to a minimum and go back to baseline levels after 96 hours. This is shown in FIG. 2.

Example 2

[0076] Effect of IMU-838 (vidofludimus-calcium) on Uric Acid Levels in Urine After Multiple Dosing without Predosing

[0077] In a randomized, placebo controlled double blind clinical Phase I MAD trial (Immunic study number P1-IMU-838-MAD), IMU-838 was applied to healthy volunteers for 14 days in order to test the effects of IMU-838 on safety and biomarkers for repeated once daily doses over 14 days. In the first part of this 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, urate levels in the urine was quantified in three periods of 24 hour urine collection. The first collection was at pre-dose (day 0). The second urine collection started four hours after intake of the first dose (day 1, 4 hours to 28 hours). The third collection of urine was performed on the last day of the 14 day treatment cycle (day 14, 4 hours to 28 hours). The amounts of uric acid at those timepoints is depicted in FIG. 2a.

[0078] Result: Surprisingly, the increase of uric acid measured in the urine was not related to the applied doses in a linear fashion. In the 30 mg dose there was no increase at day one of the intake of IMU-838 but a 29% increase from 605.9 mg to 686.2 mg (FIG. 2a) after 14 days of daily treatment. The amount of uric acid in the 40 mg group jumped by already 15.2% from 541.4 mg to 620.3 at the first day (4-28 hours after intake of 40 mg of IMU-838) and then rising to 699.3 mg at day 14 of the study. Therefore, the increase of uric acid levels was quick at the first day of treatment and only moderate with a slow onset during the next 13 days. In the 40 mg dose group, there was no further increase of the mean levels of uric acid in the urine. The data is shown in FIG. 2a.

[0079] Interestingly, despite the fact that the subjects received different doses of IMU-838, the volunteers showed a comparable increase of uric acid of around 30% compared with pre-treatment after the full 14 days treatment time.

[0080] We also conclude that the rapid increase of urate in the urine is dose dependent. Doses of 30 mg or lower have a low effect on urate levels at the first day of treatment with IMU-838.

Example 3

Effect of Vidofludimus on Uric Acid Levels in Urine After a Dose-In Phase Before Multiple Dosing

[0081] Based on the observations on a) dose dependent effect of IMU-838 on urate levels in the urine and formation of small crystals (example 1) and b) the time course and dose dependence of urate level changes in single volunteers (example 2) a new therapeutic treatment scheme was invented. In this example a treatment scheme was applied to a three week clinical phase I trial consisting of two different doses “dose 1” of 25 mg daily dose and “dose 2” of 50 mg daily dose. 8 subjects received a lower dose 1 for 7 days followed by the higher (double) dose 2 for further 14 days, whereas another 8 subjects received placebo for 7 days then followed by treatment with the 50 mg high dose (dose 2). 4 subjects received placebo during the foll three week period. During this study urine was collected at four different timepoints (pre-dose, day 1, day 7, day 14) and analyzed for urate/uric acid levels.

[0082] The mean increase in 24 hours urinary urate levels of all 20 patients was 15% from 684.1 mg to 789.5 mg after 1 day of treatment (4-28 hours) including the patients receiving placebo.

[0083] Surprinsingly, the mean urate levels in the collected urine at the first day of application of dose 2 (day 7 of the full trial) did not increase (789.5 to 789.7 mg), even if 8 of the volunteers were treated with the high dose of 50 mg immediately without receiving dose 1 before. After the full period of three weeks (day 21) the overall increased slightly by 4% from 789.7 mg to 815.9 mg.

Conclusion:

[0084] Using a stepwise dosing of IMU-838 with a lower first dose of 25 mg IMU-838 followed by a higher second dose of 50 mg IMU-838 leads to a reduced increase of mean amounts of urate in the urine, in this case to a reduction of the mean urate levels in the timeframe of 4 to 28 hours after intake of 50 mg. Even if the data is diluted with individuals receiving placebo, the effect was clearly seen.

[0085] We conclude that starting with a low-dose treatment and then switching to a higher dose can avoid an unwanted fast and or strong immediate excretion of high amounts of uric acid/urate while reaching higher therapeutic levels of IMU-838 when increasing the dose in the second phase. The experiment resulted in an updosing scheme with a lower urate gradient compared with immediate dosing.

Example 4

Clinical Study Comparing Treatment With and Without Pre-treatment Phase

[0086] A double-blind clinical study, Placebo controlled, Ascending Dose has been conducted. This study has been reported (Study Number P1-IMU-838-MAD).

[0087] The urinary excretion of uric acid increased in all but the 30 mg group after treatment initiation with IMU-838 (vidofludimus-calcium). No dose-dependency was apparent.

[0088] Uric acid excretion in urine could be however modified with a pre-treatment period. Pre-treatment with 25 mg IMU-838 for 6 days in subjects receiving 50 mg IMU-838 resulted in a smaller increase in uric acid excreted in urine on Day 0 (the first day of receiving the 50 mg dose) as compared to pre-treatment with placebo (49.5 mg/24 hours vs 86.5 mg/24 hours, respectively, median levels).

TABLE-US-00003 Placebo group/ Pre-dosing group Group 50 mg 25 mg/50 mg n 8 8 Change in Median 86.5 49.5 (mg/24 h)

[0089] Thus, the superiority of a treatment regimen including a pre-treatment phase in comparison to a treatment without such a pre-treatment phase has been proven.