Laquinimod for the treatment of relapsing-remitting multiple sclerosis (rrms) patients with a high disability status

Abstract

This invention provides a method for treating or for reducing ambulatory deterioration in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), comprising periodically administering to only the patient diagnosed with RRMS and having a high baseline disability score an amount of laquinimod effective to treat the patient or to reduce ambulatory deterioration. This invention further provides pharmaceutical compositions and packages comprising an effective amount of laquinimod for treating a human patient diagnosed to be afflicted with RRMS and having a high baseline disability score according to the EDSS.

What is claimed is: 
     
         1 . A method of treating a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), comprising periodically administering to only the patient diagnosed with RRMS and having a high baseline disability score an amount of laquinimod effective to treat the patient. 
     
     
         2 . A method of treating a human patient afflicted with relapsing-remitting multiple sclerosis (RRMS), comprising
 a) diagnosing the patient as having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), and   b) administering to the patient an amount of laquinimod effective to treat the patient only if the patient has been diagnosed as having a high baseline disability score.   
     
     
         3 . The method of  claim 1  or  2 , wherein the high baseline disability score is a baseline EDSS score of greater than 3. 
     
     
         4 . A method of treating a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, comprising periodically administering to only the patient diagnosed with RRMS and having a EDSS score of greater than 3.0 an amount of laquinimod effective to treat the patient. 
     
     
         5 . A method of treating a human patient afflicted with relapsing-remitting multiple sclerosis (RRMS), comprising
 a) diagnosing the patient as having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, and   b) administering to the patient an amount of laquinimod effective to treat the patient only if the patient has been diagnosed as having an EDSS score of greater than 3.0.   
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the amount of laquinimod is effective to reduce the patient's relapse rate. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the amount of laquinimod is effective to reduce the patient's accumulation of physical disability. 
     
     
         8 . The method of  claim 7 , wherein the accumulation of physical disability is assessed by the patient's Multiple Sclerosis Functional Composite (MSFC) score. 
     
     
         9 . The method of  claim 8 , wherein the amount of laquinimod is effective to reduce deterioration of the patient's ambulation. 
     
     
         10 . The method of  claim 9 , wherein ambulation is assessed by the patient's Timed-25 foot walk test score. 
     
     
         11 . The method of any one of  claims 7 - 10 , wherein after 24 months of periodic administration of laquinimod, the patient's accumulation of physical disability is reduced as compared to a patient not receiving periodic administration of laquinimod. 
     
     
         12 . The method of  claim 7 , wherein the accumulation of physical disability is assessed by the time to confirmed disease progression (CDP) as measured by EDSS score. 
     
     
         13 . The method of  claim 12 , wherein the patient has a baseline EDSS score of 3.5-5.0 and CDP is a 1 point increase of the baseline EDSS score. 
     
     
         14 . The method of  claim 12 , wherein the patient has a baseline EDSS score of greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, or greater than 5.5, and CDP is a 1 point increase of the baseline EDSS score. 
     
     
         15 . The method of  claim 12 , wherein the patient has a baseline EDSS score of 5.5 or greater and CDP is a 0.5 point increase of the baseline EDSS score. 
     
     
         16 . The method of any one of  claim 12 - 15 , wherein CDP is sustained for at least 3 months. 
     
     
         17 . The method of  claim 16 , wherein CDP is sustained for at least 6 months. 
     
     
         18 . A method of reducing ambulatory deterioration in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), comprising periodically administering to only the patient diagnosed with RRMS and having a high baseline disability score an amount of laquinimod effective to reduce ambulatory deterioration. 
     
     
         19 . The method of  claim 18 , wherein the high baseline disability score is a baseline EDSS score of greater than 3. 
     
     
         20 . A method of reducing ambulatory deterioration in a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, comprising periodically administering to only the patient diagnosed with RRMS and having a baseline EDSS of greater than 3.0 an amount of laquinimod effective to reduce ambulatory deterioration. 
     
     
         21 . The method of any one of  claims 18 - 20 , wherein ambulation is assessed by the patient's Timed-25 foot walk test score. 
     
     
         22 . The method of any one of  claims 18 - 21 , wherein after 24 months of periodic administration of laquinimod, deterioration of the patient's ambulation is reduced as compared to a patient not receiving periodic administration of laquinimod. 
     
     
         23 . The method of any one of  claims 1 - 22 , wherein the patient has been diagnosed with a baseline EDSS score of greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, or greater than 5.5. 
     
     
         24 . The method of any one of  claims 1 - 22 , wherein the patient has been diagnosed with a baseline EDSS score of 3.5-5.5. 
     
     
         25 . The method of any one of  claims 1 - 22 , wherein the patient is naïve to an RRMS treatment. 
     
     
         26 . The method of any one of  claims 1 - 22 , wherein the patient is naïve to laquinimod treatment. 
     
     
         27 . The method of any one of  claims 1 - 22 , wherein the patient is naïve to 0.3 mg/day laquinimod treatment. 
     
     
         28 . The method of any one of  claims 1 - 22 , wherein the patient is naïve to 0.6 mg/day laquinimod treatment. 
     
     
         29 . The method of any one of  claims 1 - 22 , wherein the patient is naïve to 1.2 mg/day laquinimod treatment. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein laquinimod is laquinimod sodium. 
     
     
         31 . The method of any one of  claims 1 - 30 , wherein laquinimod is administered orally. 
     
     
         32 . The method of any one of  claims 1 - 31 , wherein laquinimod is administered daily. 
     
     
         33 . The method of any one of  claims 1 - 32 , wherein laquinimod is administered at a daily dose of 0.1-2.5 mg laquinimod. 
     
     
         34 . The method of  claim 33 , wherein laquinimod is administered at a daily dose of 0.6 mg laquinimod. 
     
     
         35 . The method of  claim 33 , wherein laquinimod is administered at a daily dose of 1.2 mg laquinimod. 
     
     
         36 . The method of any one of  claims 1 - 35 , wherein the periodic administration is for a period of greater than 24 weeks. 
     
     
         37 . The method of any one of  claims 1 - 36 , wherein laquinimod is administered as monotherapy for RRMS. 
     
     
         38 . The method of any one of  claims 1 - 36 , wherein laquinimod is administered as adjunct therapy with an other RRMS treatment. 
     
     
         39 . The method of  claim 37 , wherein the other RRMS treatment is administration of interferon beta 1-a, interferon beta 1-b, glatiramer acetate, mitoxantrone or natalizumab. 
     
     
         40 . Laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS). 
     
     
         41 . The use of  claim 40 , wherein the high baseline disability score is a baseline EDSS score of greater than 3. 
     
     
         42 . A pharmaceutical composition comprising an effective amount of laquinimod for treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS). 
     
     
         43 . The pharmaceutical composition of  claim 42 , wherein the high baseline disability score is a baseline EDSS score of greater than 3. 
     
     
         44 . A package comprising:
 a) a pharmaceutical composition comprising an amount of laquinimod; and   b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS).   
     
     
         45 . The package of  claim 44 , wherein the high baseline disability score is a baseline EDSS score of greater than 3. 
     
     
         46 . A therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a high baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS), which comprises:
 a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, and   b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said patient.   
     
     
         47 . The therapeutic package of  claim 46 , wherein the high baseline disability score is a baseline EDSS score of greater than 3. 
     
     
         48 . Laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0. 
     
     
         49 . A pharmaceutical composition comprising an effective amount of laquinimod for treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0. 
     
     
         50 . A package comprising:
 a) a pharmaceutical composition comprising an amount of laquinimod; and   b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0.   
     
     
         51 . A therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0, which comprises:
 a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, and   b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said patient.   
     
     
         52 . A method of treating a human patient diagnosed to be afflicted with RRMS and having impaired mobility, comprising periodically administering to only the patient diagnosed with RRMS and having impaired mobility an amount of laquinimod effective to treat the patient. 
     
     
         53 . The method of  claim 52 , wherein mobility is assessed by the patient's Timed-25 foot walk test score, the MSWS-12 self-report questionnaire, the Ambulation Index, the Six-Minute Walk (6MW) Test or the LEMMT Test. 
     
     
         54 . The method of  claim 52  or  53 , wherein the mobility impairment is an ambulatory impairment. 
     
     
         55 . The method of any one of  claims 52 - 54 , wherein the patient is not ambulatory. 
     
     
         56 . A method of treating a human patient afflicted with RRMS, comprising
 a) diagnosing the patient as having a mobility impairment as assessed by the patient's Timed-25 foot walk test score, and   b) administering to the patient an amount of laquinimod effective to treat the patient only if the patient has been diagnosed as having a mobility impairment.   
     
     
         57 . The method of  claim 56 , wherein the mobility impairment is an ambulatory impairment. 
     
     
         58 . The method of  claim 56  or  57 , wherein the patient is not ambulatory. 
     
     
         59 . The method of any one of  claims 52 - 58 , wherein the amount of laquinimod is effective to reduce the patient's relapse rate. 
     
     
         60 . The method of any one of  claims 52 - 59 , wherein the amount of laquinimod is effective to reduce the patient's accumulation of physical disability. 
     
     
         61 . The method of  claim 60 , wherein the accumulation of physical disability is assessed by the patient's MSFC score. 
     
     
         62 . The method of  claim 61 , wherein the amount of laquinimod is effective to reduce deterioration of the patient's ambulation. 
     
     
         63 . The method of any one of  claims 60 - 62 , wherein after 24 months of periodic administration of laquinimod, the patient's accumulation of physical disability is reduced as compared to a patient not receiving periodic administration of laquinimod. 
     
     
         64 . The method of  claim 60 , wherein the accumulation of physical disability is assessed by the time to CDP as measured by EDSS score. 
     
     
         65 . The method of  claim 64 , wherein the patient has a baseline EDSS score of 3.5-5.0 and CDP is a 1 point increase of the baseline EDSS score. 
     
     
         66 . The method of  claim 64 , wherein the patient has a baseline EDSS score of greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, or greater than 5.5, and CDP is a 1 point increase of the baseline EDSS score. 
     
     
         67 . The method of  claim 64 , wherein the patient has a baseline EDSS score of 5.5 or greater and CDP is a 0.5 point increase of the baseline EDSS score. 
     
     
         68 . The method of any one of  claim 64 - 67 , wherein CDP is sustained for at least 3 months. 
     
     
         69 . The method of  claim 68 , wherein CDP is sustained for at least 6 months. 
     
     
         70 . A method of reducing mobility deterioration in a human patient diagnosed to be afflicted with RRMS and having impaired mobility, comprising periodically administering to only the patient diagnosed with RRMS and having impaired mobility an amount of laquinimod effective to reduce mobility deterioration. 
     
     
         71 . The method of  claim 70 , wherein the mobility impairment is an ambulatory impairment. 
     
     
         72 . The method of  claim 71 , wherein the patient is not ambulatory. 
     
     
         73 . The method of any one of  claims 70 - 72 , wherein mobility is assessed by the patient's Timed-25 foot walk test score. 
     
     
         74 . The method of any one of  claims 70 - 73 , wherein after 24 months of periodic administration of laquinimod, deterioration of the patient's mobility is reduced as compared to a patient not receiving periodic administration of laquinimod. 
     
     
         75 . The method of any one of  claims 52 - 74 , wherein the patient has been diagnosed with a baseline EDSS score of greater than 3.5, greater than 4.0, greater than 4.5, greater than 5.0, or greater than 5.5. 
     
     
         76 . The method of any one of  claims 52 - 74 , wherein the patient has been diagnosed with a baseline EDSS score of 3.5-5.5. 
     
     
         77 . The method of any one of  claims 52 - 74 , wherein the patient is naïve to an RRMS treatment. 
     
     
         78 . The method of any one of  claims 52 - 74 , wherein the patient is naïve to laquinimod treatment. 
     
     
         79 . The method of any one of  claims 52 - 74 , wherein the patient is naïve to 0.3 mg/day laquinimod treatment. 
     
     
         80 . The method of any one of  claims 52 - 74 , wherein the patient is naïve to 0.6 mg/day laquinimod treatment. 
     
     
         81 . The method of any one of  claims 52 - 74 , wherein the patient is naïve to 1.2 mg/day laquinimod treatment. 
     
     
         82 . The method of any one of  claims 52 - 81 , wherein laquinimod is laquinimod sodium. 
     
     
         83 . The method of any one of  claims 52 - 82 , wherein laquinimod is administered orally. 
     
     
         84 . The method of any one of  claims 52 - 83 , wherein laquinimod is administered daily. 
     
     
         85 . The method of any one of  claims 52 - 84 , wherein laquinimod is administered at a daily dose of 0.1-2.5 mg laquinimod. 
     
     
         86 . The method of  claim 85 , wherein laquinimod is administered at a daily dose of 0.6 mg laquinimod. 
     
     
         87 . The method of  claim 85 , wherein laquinimod is administered at a daily dose of 1.2 mg. 
     
     
         88 . The method of any one of  claims 52 - 87 , wherein the periodic administration is for a period of greater than 24 weeks. 
     
     
         89 . The method of any one of  claims 52 - 88 , wherein laquinimod is administered as monotherapy for RRMS. 
     
     
         90 . The method of any one of  claims 52 - 88 , wherein laquinimod is administered as adjunct therapy with an other RRMS treatment. 
     
     
         91 . The method of  claim 90 , wherein the other RRMS treatment is administration of interferon beta 1-a, interferon beta 1-b, glatiramer acetate, mitoxantrone or natalizumab. 
     
     
         92 . Laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with RRMS and having impaired mobility. 
     
     
         93 . The use of  claim 92 , wherein the mobility impairment is an ambulatory impairment. 
     
     
         94 . The use of  claim 93 , wherein the patient is not ambulatory. 
     
     
         95 . A pharmaceutical composition comprising an effective amount of laquinimod for use in treating only a human patient diagnosed to be afflicted with RRMS and having impaired mobility. 
     
     
         96 . The use of  claim 95 , wherein the mobility impairment is an ambulatory impairment. 
     
     
         97 . The use of  claim 95  or  96 , wherein the patient is not ambulatory. 
     
     
         98 . The use of any one of  claims 91 - 94 , wherein mobility is assessed by the patient's Timed-25 foot walk test score. 
     
     
         99 . A package comprising:
 a) a pharmaceutical composition comprising an amount of laquinimod; and   b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with RRMS and having impaired mobility.   
     
     
         100 . A therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with RRMS and having impaired mobility, which comprises:
 a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, and   b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said patient.   
     
     
         101 . The package of  claim 99 , or the therapeutic package of  claim 100 , wherein the mobility impairment is an ambulatory impairment. 
     
     
         102 . The package or therapeutic package of  claim 101 , wherein the patient is not ambulatory. 
     
     
         103 . The package of any one of  claims 99  and  101 - 102  or the therapeutic package of any one of  claims 100 - 102 , wherein the patient's mobility is assessed by the patient's Timed-25 foot walk test score. 
     
     
         104 . A method of treating a human patient diagnosed to be afflicted with RRMS and having worsening MS, comprising periodically administering to only the patient diagnosed with RRMS and having worsening MS an amount of laquinimod effective to treat the patient. 
     
     
         105 . The method of  claim 104 , wherein the patient has a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0. 
     
     
         106 . The method of  claim 104  or  105 , wherein laquinimod is laquinimod sodium. 
     
     
         107 . The method of any one of  claims 104 - 106 , wherein laquinimod is administered orally. 
     
     
         108 . The method of any one of  claims 104 - 107 , wherein laquinimod is administered daily. 
     
     
         109 . The method of any one of  claims 104 - 108 , wherein laquinimod is administered at a daily dose of 0.1-2.5 mg laquinimod. 
     
     
         110 . The method of  claim 109 , wherein laquinimod is administered at a daily dose of 0.6 mg laquinimod. 
     
     
         111 . The method of  claim 109 , wherein laquinimod is administered at a daily dose of 1.2 mg laquinimod. 
     
     
         112 . The method of any one of  claims 104 - 111 , wherein laquinimod is administered as monotherapy for RRMS. 
     
     
         113 . The method of any one of  claims 104 - 111 , wherein laquinimod is administered as adjunct therapy with another RRMS treatment. 
     
     
         114 . The method of  claim 113 , wherein the other RRMS treatment is administration of interferon beta 1-a, interferon beta 1-b, glatiramer acetate, mitoxantrone or natalizumab. 
     
     
         115 . Laquinimod for the manufacture of a medicament for use in treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having worsening MS. 
     
     
         116 . A pharmaceutical composition comprising an effective amount of laquinimod for treating only a human patient diagnosed to be afflicted with relapsing-remitting multiple sclerosis (RRMS) and having worsening MS. 
     
     
         117 . The laquinimod or pharmaceutical composition of  claims 115 - 116 , wherein the patient has a baseline disability score according to the Kurtzke Expanded Disability Status Scale (EDSS) of greater than 3.0. 
     
     
         118 . A package comprising:
 a) a pharmaceutical composition comprising an amount of laquinimod; and   b) instruction for use of the pharmaceutical composition to treat only a human patient diagnosed to be afflicted with RRMS and having worsening MS.   
     
     
         119 . A therapeutic package for dispensing to, or for use in dispensing to, only a human patient diagnosed to be afflicted with RRMS and having worsening MS, which comprises:
 a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said patient, to treat the patient, and   b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said patient.