REBAMIPIDE FOR USE IN PREVENTION AND TREATMENT OF CROHN'S DISEASE

Abstract

The present invention provides rebamipide for use in a method of prevention and/or treatment of Crohn's disease. In particular, rebamipide is used in prevention and/or treatment of Crohn's disease in a person suffering from increased intestinal permeability or in a person who is at risk of increased intestinal permeability.

Claims

1. A method of prevention and/or treatment of Crohn's disease comprising administration of rebamipide.

2. The method according to claim 1, wherein rebamipide is combined with at least one other drug effective against Crohn's disease.

3. The method according to claim 2, wherein it comprises the steps of administering rebamipide to a person being treated with a dose of at least one other drug effective against Crohn's disease; and decreasing the dose of said other drug.

4. The method according to claim 3, wherein the dose of said other drug is decreased at the beginning of rebamipide administration.

5. The method according to claim 3, wherein the dose of said other drug is decreased after symptom improvement.

6. The method according to claim 2, wherein said other drug is discontinued after the person reaches remission.

7. The method according to claim 2, wherein rebamipide is used for treatment of Crohn's disease.

8. The method according to claim 7, wherein rebamipide is adminstered to a person with active Crohn's disease to induce remission.

9. The method according to claim 1, wherein the method is a monotherapy.

10. The method according to claim 9, wherein rebamipide is used for prevention of Crohn's disease.

11. The method according to claim 9, wherein rebamipide is adminstered to a person in remission of the disease to prevent disease relapse and/or recurrence.

12. (canceled)

13. The method according to claim 2, wherein said other drug is selected from 5-aminosalicylates, preferably selected from sulfasalazine and mesalazine; corticosteroids, preferably selected from prednisone, prednisolone, methylprednisolone, hydrocortisone and budesonide; immunosuppressants, preferably selected from thiopurines, methotrexate, cyclosporine and tacrolimus; antibiotics, preferably selected from metronidazole and ciprofloxacin; and antibodies, preferably selected from infliximab, adalimumab, vedolizumab and biosimilars thereof.

14. The method according to claim 13, wherein said other drug is selected from corticosteroids, immunosuppressants, and antibodies.

15. The method according to claim 13, wherein said other drug is a corticosteroid, preferably 20 to 60 mg of prednisone or equivalent dose of another corticosteroid.

16. The method according to claim 1, wherein rebamipide is used in prevention and/or treatment of Crohn's disease in a person suffering from increased intestinal permeability or in a person who is at risk of increased intestinal permeability.

17. The method according to claim 16, wherein the person suffering from increased intestinal permeability is a person suffering from at least one condition selected from low grade inflammation of the gut wall, chronic constipation or gastroparesis.

18. The method according to claim 16, wherein the person at risk of increased intestinal permeability is a person suffering from stress, imbalanced diet, bacterial, viral or parasitic infection.

19. The method according to claim 16, wherein the person at risk of increased intestinal permeability is a person exposed to at least one substance selected from non-steroidal anti-inflammatory drugs, alcohol, nicotine, food additives, chemotherapeutics and antibiotics.

20. The method according to claim 16, wherein the person at risk of increased intestinal permeability is a person suffering from or exposed to at least one condition selected from stress-induced gastritis, alimentary intoxication, disbalance of cholic acids, gastric HCl and pepsin secretion, non-infectious diarrhea, radiation therapy, chemotherapy, infectious or post-infectious impairment of the GIT mucosa, dysmicrobia.

21. The method according to claim 1, wherein rebamipide is administered in an oral pharmaceutical form, preferably selected from tablets, capsules, dragees, granules, microgranules (sachets), orodispersible tablets or films, sublingual tablets, crushed tablets, oral solutions, oral suspensions, syrups, mouthwashes or rinses.

22. (canceled)

23. (canceled)

24. (canceled)

25. (canceled)

26. The method according to claim 1, wherein rebamipide is administered in a daily dose of 1 to 5000 mg, more preferably from 50 to 2500 mg, even more preferably from 100 to 1000 mg, and most preferably from 300 to 600 mg.

Description

EXAMPLES

[0058] Several patients suffering from Crohn's disease for at least 5 years without sufficient response to standard treatment were given rebamipide tablets three times a day. These patients had long history of treatment with various medicaments but were not able to reach remission after relapse of the disease using standard options. The severity of the disease was quantified by the CDAI, and the level of inflammation by fecal calprotectin.

[0059] Crohn's Disease Activity Index (CDAI) is a research tool used to quantify the symptoms of patients with Crohn's disease. It consists of eight factors, each summed after adjustment with a weighting factor. Remission of Crohn's disease is defined as CDAI below 150, whereas severe disease is defined as a value of greater than 450.

[0060] Calprotectin (FC) is a small calcium-binding protein that is used as a biomarker for inflammatory bowel diseases since its fecal concentration correlates well with the disease severity. Calprotectin values lower than 200 μg/g feces are considered the normal level. It was measured in stool samples using commercially available enzyme-linked immunosorbent assay (ELISA) kit (EK-CAL, Bühlmann).

Example 1

[0061] A female patient, age 39, suffering from Crohn's ileocolitis, was diagnosed 16 years ago. Over the course of the disease she was given various medications including peroral, parenteral and topical corticosteroids, azathioprine, and TNFα inhibitors infliximab and adalimumab. After immunological response had developed against these antibodies, affecting skin and joints, the patient switched to vedolizumab (Entyvio), that was able to stabilize her for the next 22 months. During the relapse of the disease, the patient suffered with abdominal pain, increased stool frequency, joint and muscle pain, subfebrile fever, fatigue, and dry dermatitis with fecal calprotectin levels up to 1939 μg/g and CDAI of 358 points. Her treatment continued with methylprednisolon 24 mg/day without success. Concomitantly with the corticosteroid treatment she started being given rebamipide 100 mg three times daily resulting in fast remission of the disease as evidenced by alleviation of the disease symptoms (CDAI of 181 points) and decrease of calprotectin level to 228 μg/g after 6 weeks of the treatment. The corticosteroid dose was then reduced to half without any adverse effect. Corticosteroids were completely withdrawn after another 6 weeks when the calprotectin level lowered to 63 μg/g and CDAI to 73 points and the patient continued only rebamipide. No worsening in disease activity has been observed so far.

Example 2

[0062] A male patient, age 27, was diagnosed with Crohn's ileocolitis 5 years ago and treated with mesalazine (Pentasa), budesonid, and metronidazole. He developed pancreatitis after three months on mesalazine. The medication was subsequently switched to azathioprine combined with prednisone and later to methotrexate. However, the medication was not well tolerated and the patient was indicated for biological therapy. He was treated with infliximab (Remicade) and later with adalimumab (Humira). After the last relapse (calprotectin 2215 μg/g; CDAI of 479 points) he was given prednisone 40 mg/day but was not able to reach remission. He started taking rebamipide 200 mg t.i.d. as an add-on to prednisone. After 6 weeks (calprotectin 356 μg/g; CDAI of 225 points) the rebamipide dose was adjusted to 100 mg t.i.d. and prednisone dose to 30 mg/day. Prednisone dose was then lowered by 10 mg every 2 weeks and completely discontinued after another 6 weeks (calprotectin 110 μg/g; CDAI of 84 points). The patient continued only rebamipide 100 mg t.i.d. No worsening in disease activity has been observed so far.

Example 3

[0063] A female patient, age 32, was diagnosed with Crohn's ileitis 12 years ago. Therapy with budesonide and mesalazine was able to maintain remission for about 10 years. She was thereafter hospitalized with abdominal pain and loose stool 3-4 times a day, with calprotectin level up to 1051 μg/g and CDAI of 377 points. She was prescribed azathioprine but it had to be discontinued after two weeks due to acute pancreatitis. Her treatment continued with prednisone 50 mg/day concomitantly with rebamipide 100 mg three times daily. The prednisone dose was adjusted to 25 mg after 14 days due to alleviation of the clinical symptoms and completely withdrawn after another 6 weeks with calprotectin level lowered to 122 μg/g and CDAI of 98 points and she continued only rebamipide. No worsening in disease activity has been observed so far.

[0064] The results obtained with the patient sample show that rebamipide is able to manage the disease symptoms, normalize calprotectin levels and induce remission even in those patients, who exhausted standard treatment options. The treatment started as an add-on to corticosteroid treatment due to ethical reasons but it is believed that it would be efficient even if prescribed as the only treatment. It is important to note that the corticosteroid treatment alone was not able to completely suppress the disease symptoms and neither patient had calprotectin lower than 200 μg/g feces, and CDAI lower than 150 points using only corticosteroids. Moreover, long-term therapy with rebamipide alone seems to be well tolerated and able to maintain remission.