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1. WO2020114616 - TOPICAL TREATMENT OF IMMUNE CHECKPOINT INHIBITOR INDUCED DIARRHOEA, COLITIS OR ENTEROCOLITIS USING ANTIBODIES AND FRAGMENTS THEREOF

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Claims

1. A pharmaceutical composition comprising an active agent selected from the group consisting of antibodies specific to tumour necrosis factor alpha (TNFa) and functional fragments and derivatives thereof, for use in the treatment or prevention of at least one adverse event of the gastro-intestinal tract induced by a cancer therapy in a patient, preferably induced by one or more immune checkpoint (ICP) inhibitors, wherein said treatment or prevention comprises the topical administration of said composition to the affected part of the gastrointestinal tract of said patient, e.g. to the ileum and/or the large intestine of said patient.

2. The pharmaceutical composition for use according to claim 1 , wherein the patient is also undergoing systemic treatment with one or more ICP inhibitors.

3. The pharmaceutical composition for use according to claim 2, wherein treatment with one or more ICP inhibitors is interrupted for less than four weeks, preferably less than two weeks, more preferably one week, even more preferably less than five, four, three, two days or one day, and most preferably wherein treatment is not interrupted.

4. The pharmaceutical composition for use according to any of the preceding claims, wherein said adverse event is selected from the group consisting of ICP inhibitor- induced diarrhoea, ICP inhibitor-induced colitis, ICP inhibitor-induced enterocolitis and combinations thereof.

5. The pharmaceutical composition for use according to claim 4, wherein said ICP inhibitor-induced diarrhoea, colitis and/or enterocolitis is characterized by grade 1 toxicity or grade 2 toxicity.

6. The pharmaceutical composition for use according to claim 4, wherein said treatment prevents progression of said ICP inhibitor-induced diarrhoea, colitis and/or enterocolitis to a higher grade toxicity.

7. The pharmaceutical composition for use according to any one of the preceding claims, wherein said use comprises a prophylactic therapy for ICP inhibitor-induced diarrhoea, colitis and/or enterocolitis.

8. The pharmaceutical composition for use according to claim 7, wherein the patient is at the same time undergoing systemic treatment with one or more ICP inhibitors.

9. The pharmaceutical composition for use according to any one of the preceding claims, wherein said patient is suffering from ICP inhibitor-induced diarrhoea, but not of ICP inhibitor-induced colitis or ICP inhibitor-induced enterocolitis, and wherein said composition is for use in preventing the development or onset of ICP inhibitor-induced colitis and/or ICP inhibitor-induced enterocolitis in said patient.

10. The pharmaceutical composition for use according to claim 9, wherein said patient is suffering from ICP inhibitor-induced diarrhoea of grade 2 toxicity.

1 1. The pharmaceutical composition for use according to claim 9, wherein said patient is suffering from ICP inhibitor-induced diarrhoea of grade 1 toxicity.

12. The pharmaceutical composition for use according to any of the preceding claims, wherein the one or more ICP inhibitors are selected from the group consisting of antibodies specific to cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), antibodies specific to programmed cell death protein-1 (PD-1 ) and antibodies specific to programmed death-ligand 1 (PD-L1 ).

13. The pharmaceutical composition for use according to claim 12, wherein the antibodies specific to PD-1 are selected from the group consisting of pembrolizumab and nivolumab; the antibodies specific to PD-L1 are selected from the group consisting of atezolizumab, avelumab and durvalumab; or the antibodies specific to CTLA-4 are selected from the group consisting of ipilimumab and tremelimumab.

14. The pharmaceutical composition for use according to any of the preceding claims, wherein the antibodies specific to TNFa and functional fragments thereof are selected from the group consisting of infliximab, adalimumab, etanercept, certolizumab pegol, golimumab, and functional fragments and derivatives thereof.

15. The pharmaceutical composition for use according to any of the preceding claims, wherein the amino acid sequence of the antibodies specific to TNFa and functional fragments thereof comprise

i) the amino acids 233P, 234V, 235A, and a deletion at amino acid position 236; and the amino acid 434A or the amino acids 252Y, 254T and 256E; and optionally the amino acids 239D, 330L and 332E or the amino acids 326A, 332E and 333A; and/or

ii) the amino acids 380A and 434A, and optionally the amino acid 307T; and/or iii) the amino acid 434W, and optionally the amino acid 428E and/or the amino acid 311 R,

wherein the amino acid numbering refers to EU numbering.

16. The pharmaceutical composition for use according to any one of the preceding claims, wherein said topical administration comprises or consists of oral administration of the pharmaceutical composition.

17. The pharmaceutical composition for use according to claim 16, wherein the pharmaceutical composition is a delayed release formulation.

18. The pharmaceutical composition for use according to claim 16 or 17, wherein the pharmaceutical composition is a solid dosage form in the form of a pellet, granule, micro particle, nano particle, mini tablet, sphere, capsule, tablet or multiparticulate drug delivery system coated with a delayed release coating, which prevents release of the active agent before entering the ileum, the ileocolonic region or the large intestine of the gastrointestinal (Gl) tract.

19. The pharmaceutical composition for use according to claim 18, wherein the delayed release coating comprises at least one component selected from the group consisting of poly vinyl acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate HP-50, HP-55 or HP-55S, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(methacrylic acid, ethyl acrylate) 1 :1 , poly(methacrylic acid, methyl methacrylate) 1 :1 , poly(methacrylic acid, methyl methacrylate) 1 :2, chondroitin sulfate, pectin, guar gum, chitosan, inulin, lactulose, raffinose, stachyose, alginate, dextran, xanthan gum, locust bean gum, arabinogalactan, amylose, cyclodextrin, pullulan, carrageenan, scleroglucan, chitin, curdulan, levan, amylopectin, starch, resistant starch, azo compounds being degraded by azo bonds splitting bacteria, and combinations thereof.

20. The pharmaceutical composition for use according to any one of claims 16 to 19, which comprises a sustained release coating or a sustained release matrix.

21. The pharmaceutical composition for use according to claim 20, wherein said sustained release coating or a sustained release matrix comprises a material that disintegrates time-dependently.

22. The pharmaceutical composition for use according to claim 21 , wherein said material that disintegrates time-dependently is selected from the group consisting of poly(ethyl acrylate, methyl methacrylate) 2 : 1 (e.g. Eudragit® NM 30D, or Eudragit NE 30D); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.1 (e.g. Eudragit® RS 30D); ethylcellulose (e.g.

Surelease® or Aquacoat ECD); poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2 : 0.2 (e.g. Eudragit® RL 30D); polyvinyl acetate (eg. Kollicoat® SR 30D); and combinations thereof.

23. The pharmaceutical composition for use according to any one of claims 16 to 22, wherein said composition comprises a sustained release core coated with a delayed release coating.

24. The pharmaceutical composition for use according to any one of claims 16 to 22, wherein said composition comprises a core, a sustained release coating and a delayed release coating.

25. The pharmaceutical composition for use according to any one of claims 1 to 15, wherein said treatment comprises the rectal administration of the composition, and wherein the composition preferably is an enema, a gel, a foam or a suppository.