Claims for Patent: 10,849,919

Summary for Patent: 10,849,919

Title:	Cladribine regimen for treating progressive forms of multiple sclerosis
Abstract:	Specific oral dosings, specific oral dosage forms, and/or specific oral dose regimens including Cladribine can be effective for the treatment of progressive forms of Multiple Sclerosis, especially Primary Progressive Multiple Sclerosis and/or Secondary Progressive Multiple Sclerosis. Methods of treatment can be based on specific oral dosings, specific oral dosage forms, and/or specific oral dose regimens including Cladribine.
Inventor(s):	Dangond; Fernando (Weston, MA), Dotzauer; Matthias (Erzhausen, DE)
Assignee:	Merck Patent GmbH (Darmstadt, DE)
Application Number:	16/199,119
Patent Claims:	1. A method of treating a progressive form of Multiple Sclerosis, said method comprising: orally administering Cladribine to a patient in need thereof at fixed dose per patient, per body weight and per treatment year, wherein said fixed dose is in a range of 1.5 mg/kg to 4.0 mg/kg, wherein the progressive form of Multiple Sclerosis is selected from the group consisting of Secondary Progressive Multiple Sclerosis (SPMS), Primary Progressive Multiple Sclerosis (PPMS), and Progressive Relapsing Multiple Sclerosis (PRMS), and wherein the progressive form of Multiple Sclerosis does not include Early Secondary Progressive Multiple Sclerosis (ESPMS). 2. The method according to claim 1, wherein said fixed dose per patient is 1.75 mg/kg per treatment year with a maximum deviation of +/-0.2 mg/kg. 3. The method according to claim 1, wherein said progressive form of multiple sclerosis comprises Primary Progressive Multiple Sclerosis and/or Secondary Progressive Multiple Sclerosis. 4. The method according to claim 1, wherein said fixed dose is orally administered to said patient within two adjacent months within said treatment year. 5. The method according to claim 4, wherein said fixed dose is orally administered to said patient within one week or two adjacent weeks at the beginning of each one of said two adjacent months. 6. The method according to claim 4, wherein said fixed dose is orally administered to said patient within 4 to 5 days during said week, or within 4 to 5 days of each of said weeks. 7. The method according to claim 1, wherein said Cladribine is orally administered for at least three treatment years. 8. The method according to claim 1, wherein each treatment year comprises: (i) a treatment period of 2 months at the beginning of said treatment year, wherein said fixed dose of Cladribine is orally administered on 3 to 5 days each month at the beginning of each month, said fixed dose being divided into daily doses of 10 or 20 mg of Cladribine, and (ii) a Cladribine-free period lasting 10 months, during which no Cladribine is administered. 9. The method according to claim 1, wherein said patient suffers from Primary Progressive Multiple Sclerosis and/or from Secondary Progressive Multiple Sclerosis, wherein said fixed dose per patient is 1.75 mg/kg per treatment year with a maximum deviation of +/-0.2 mg/kg, and wherein orally administering Cladribine comprises at least two treatment years. 10. The method according to claim 1, wherein orally administering Cladribine comprises at least three treatment years, a) wherein said fixed dose per treatment year is from 0.75 mg/kg to 2.0 mg/kg, b) wherein the third treatment year comprises: (i) a treatment period of 1 month or 2 months at the beginning of said treatment year, wherein said fixed dose of Cladribine is orally administered on 3 to 5 days each month at the beginning of each month, said fixed dose being divided into daily doses of 10 or 20 mg of Cladribine, and (ii) a Cladribine-free period lasting 11 or 10 months respectively, during which no Cladribine is administered. 11. The method according to claim 1, wherein orally administering Cladribine is in one or two treatment years, optionally plus an additional subsequent treatment year, followed by at least one year in which no Cladribine is administered to said patient. 12. The method according to claim 1, wherein said Cladribine is orally administered as a liquid, a tablet, or a capsule. 13. The method according to claim 1, wherein said Cladribine is orally administered as a tablet comprising 10 mg of Cladribine in the form of a mixture of Cladribine, 2-hydroxypropyl-.beta.-cyclodextrin and Cladribine-2-hydroxypropyl-.beta.-cyclodextrin-complexes, wherein the weight ratio of Cladribine to 2-hydroxypropyl-.beta.-cyclodextrin is between about 1:10 to about 1:16. 14. A method of treating a patient diagnosed as suffering from a progressive form of Multiple Sclerosis, said method comprising: orally administering to said patient a cumulative dose of Cladribine of about 3.5 mg/kg body weight, with a maximum deviation of +/-0.4 mg/kg, over 2 years, administered in each year as 1 treatment course of about 1.75 mg/kg+/-0.2 mg/kg per year, wherein each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year, wherein the progressive form of Multiple Sclerosis is selected from the group consisting of Secondary Progressive Multiple Sclerosis (SPMS), Primary Progressive Multiple Sclerosis (PPMS), and Progressive Relapsing Multiple Sclerosis (PRMS), and wherein the progressive form of Multiple Sclerosis does not include Early Secondary Progressive Multiple Sclerosis (ESPMS). 15. The method according to claim 14, wherein each treatment week consists of 4 or 5 days on which said patient receives 10 mg or 20 mg of Cladribine for oral administration, depending on the body weight of the patient. 16. The method according to claim 15, wherein said patient receives the 10 mg or 20 mg of Cladribine for oral administration as a tablet or capsule. 17. The method according to claim 16, wherein said patient receives the 10 mg or 20 mg of Cladribine for oral administration as a tablet or capsule comprising 10 mg of Cladribine in the form of a mixture of Cladribine, 2-hydroxypropyl-.beta.-cyclodextrin and Cladribine-2-hydroxypropyl-.beta.-cyclodextrin-complexes, wherein the weight ratio of Cladribine to 2-hydroxypropyl-.beta.-cyclodextrin is between about 1:10 to about 1:16. 18. The method according to claim 14, where the progressive form of Multiple Sclerosis is selected from the group consisting of Primary Progressive Multiple Sclerosis and Secondary Progressive Multiple Sclerosis. 19. The method according to claim 18, wherein each treatment week consists of 4 or 5 days on which said patient receives 10 mg or 20 mg of Cladribine for oral administration. 20. The method according to claim 14, wherein said patient is between 18 and 65 years old. 21. The method according to claim 14, wherein the patient additionally receives at least one disease modifying drug other than Cladribine. 22. The method according to claim 21, wherein said at least one disease modifying drug other than Cladribine is an interferon selected from the group consisting of: Interferon beta-1a, Beta interferon-1a, Interferon beta-1b, Beta interferon-1b, and Peginterferon beta 1a. 23. The method according to claim 14, wherein after the completion of said 2 years with said 2 treatment courses, no Cladribine is administered to the patients in the subsequent 1 or 2 years following the completion of said 2 years with said 2 treatment courses. 24. A method of treating a patient suffering from a progressive form of Multiple Sclerosis, comprising orally administering to said patient tablets or capsules containing about 10 mg of Cladribine each, wherein said tablets or capsules are administered during a treatment year comprising the following regimen: (i) a treatment course lasting 2 months, wherein Cladribine tablets or capsules are orally administered daily at a daily dose of 10 or 20 mg of Cladribine on a treatment week of from 3 to up to 6 days each month; (ii) followed by a Cladribine-free period lasting 10 months wherein no Cladribine is administered to said patient; wherein patients having a bodyweight in the range of 40 to less than 50 kg are administered 1) 4 tablets or capsules (40 mg of Cladribine) in the 1st treatment week of said treatment course, 2) 4 tablets or capsules (40 mg of Cladribine) in the 2nd treatment week of said treatment course; in the range of 50 to less than 60 kg are administered 1) 5 tablets or capsules (50 mg of Cladribine) in the 1st treatment week of said treatment course, respectively, 2) 5 tablets or capsules (50 mg of Cladribine) in the 2nd treatment week of said treatment course; in the range of 60 to less than 70 kg are administered 1) 6 tablets or capsules (60 mg of Cladribine) in the 1st treatment week of said treatment course, 2) 6 tablets or capsules (60 mg of Cladribine) in the 2nd treatment week of said treatment course; in the range of 70 to less than 80 kg are administered 1) 7 tablets or capsules (70 mg of Cladribine) in the 1st treatment week of said treatment course, 2) 7 tablets or capsules (70 mg of Cladribine) in the 2nd treatment week of said treatment course; in the range of 80 to less than 90 kg are administered 1) 8 tablets or capsules (80 mg of Cladribine) in the 1st treatment week of said treatment course, 2) 7 tablets or capsules (70 mg of Cladribine) in the 2nd treatment week of said treatment course; in the range of 90 to less than 100 kg are administered 1) 9 tablets or capsules (90 mg of Cladribine) in the 1st treatment week of said treatment course, 2) 8 tablets or capsules (80 mg of Cladribine) in the 2nd treatment week of said treatment course; in the range of 100 to less than 110 kg are administered 1) 10 tablets or capsules (100 mg of Cladribine) in the 1st treatment week of said treatment course, 2) 9 tablets or capsules (90 mg of Cladribine) in the 2nd treatment week of said treatment course; or in the range of 110 kg and above are administered 1) 10 tablets or capsules (100 mg of Cladribine) in the 1st treatment week of said treatment course, 2) 10 tablets or capsules (100 mg of Cladribine) in the 2nd treatment week of said treatment course. 25. The method according to claim 24, wherein the method further comprises at least one subsequent additional treatment year, wherein said additional treatment year is substantially identical to said treatment year. 26. The method according to claim 25, wherein said additional treatment year is directly adjacent to said treatment year, or wherein the method comprises a gap of 1 to 10 months in between the two treatment years. 27. A method of treating a patient suffering from a progressive form of Multiple Sclerosis, wherein the progressive form of Multiple Sclerosis is selected from the group consisting of Secondary Progressive Multiple Sclerosis (SPMS), Primary Progressive Multiple Sclerosis (PPMS), and Progressive Relapsing Multiple Sclerosis (PRMS), and wherein the progressive form of Multiple Sclerosis does not include Early Secondary Progressive Multiple Sclerosis (ESPMS), said method comprising orally administering to said patient tablets or capsules containing about 10 mg of Cladribine each, wherein said tablets or capsules are administered during two treatment years comprising the following regimen: (i) a first treatment course lasting 2 months, wherein Cladribine tablets or capsules are orally administered daily at a daily dose of 10 or 20 mg of Cladribine on 3 to up to 6 days each month; (ii) followed by a first Cladribine-free period lasting 10 months, wherein no Cladribine is administered to said patient; (iii) followed by a second treatment course lasting 2 months, wherein Cladribine tablets or capsules are orally administered daily at a daily dose of 10 or 20 mg of Cladribine on 3 to up to 6 days each month; and (iv) followed by a second Cladribine-free period lasting 10 months, wherein no Cladribine is administered to said patient, and wherein patients having a bodyweight in the range of 40 to less than 50 kg are administered 1) 4 tablets or capsules (40 mg of Cladribine) in the 1st treatment week of both the 1st and the 2nd treatment course, respectively, 2) 4 tablets or capsules (40 mg of Cladribine) in the 2nd treatment week of both the 1st and the 2nd treatment course, respectively: in the range of 50 to less than 60 kg are administered 1) 5 tablets or capsules (50 mg of Cladribine) in the 1st treatment week of both the 1st and the 2nd treatment course, respectively, 2) 5 tablets or capsules (50 mg of Cladribine) in the 2nd treatment week of both the 1st and the 2nd treatment course, respectively: in the range of 60 to less than 70 kg are administered 1) 6 tablets or capsules (60 mg of Cladribine) in the 1st treatment week of both the 1st and the 2nd treatment course, respectively, 2) 6 tablets or capsules (60 mg of Cladribine) in the 2nd treatment week of both the 1st and the 2nd treatment course, respectively; in the range of 70 to less than 80 kg are administered 1) 7 tablets or capsules (70 mg of Cladribine) in the 1st treatment week of both the 1st and the 2nd treatment course, respectively, 2) 7 tablets or capsules (70 mg of Cladribine) in the 2nd treatment week of both the 1st and the 2nd treatment course, respectively; in the range of 80 to less than 90 kg are administered 1) 8 tablets or capsules (80 mg of Cladribine) in the 1st treatment week of both the 1st and the 2nd treatment course, respectively, 2) 7 tablets or capsules (70 mg of Cladribine) in the 2nd treatment week of both the 1st and the 2nd treatment course, respectively; in the range of 90 to less than 100 kg are administered 1) 9 tablets or capsules (90 mg of Cladribine) in the 1st treatment week of both the 1st and the 2nd treatment course, respectively, 2) 8 tablets or capsules (80 mg of Cladribine) in the 2nd treatment week of both the 1st and the 2nd treatment course, respectively; in the range of 100 to less than 110 kg are administered 1) 10 tablets or capsules (100 mg of Cladribine) in the 1st treatment week of both the 1st and the 2nd treatment course, respectively, 2) 9 tablets or capsules (90 mg of Cladribine) in the 2nd treatment week of both the 1st and the 2nd treatment course, respectively; or in the range of 110 kg and above are administered 1) 10 tablets or capsules (100 mg of Cladribine) in the 1st treatment week of both the 1st and the 2nd treatment course, respectively, 2) 10 tablets or capsules (100 mg of Cladribine) in the 2nd treatment week of both the 1st and the 2nd treatment course, respectively. 28. The method according to claim 27, wherein said 10 mg or 20 mg of Cladribine for oral administration are administered to the patient as a tablet or capsule comprising 10 mg of Cladribine in the form of a mixture of Cladribine, 2-hydroxypropyl-.beta.-cyclodextrin and Cladribine-2-hydroxypropyl-.beta.-cyclodextrin-complexes, wherein the weight ratio of Cladribine to 2-hydroxypropyl-.beta.-cyclodextrin is between about 1:10 to about 1:16. 29. The method according to claim 27, wherein the progressive form of Multiple Sclerosis is Primary Progressive Multiple Sclerosis. 30. The method according to claim 27, wherein the progressive form of Multiple Sclerosis is Secondary Progressive Multiple Sclerosis. 31. The method according to claim 27, wherein the patient additionally receives at least one disease modifying drug other than Cladribine. 32. The method according to claim 31, wherein said at least one disease modifying drug other than Cladribine is an interferon selected from the group consisting of: Interferon beta-1a, Beta interferon-1a, Interferon beta-1b, Beta interferon-1b, and Peginterferon beta 1a. 33. The method according to claim 27, wherein to the patients having completed said 2 treatment courses of one year each, no further Cladribine treatment is administered to said patients in the subsequent years 3 and 4. 34. The method according to claim 27, wherein the progressive form of Multiple Sclerosis is selected from the group consisting of Primary Progressive Multiple Sclerosis and Secondary Progressive Multiple Sclerosis.