Treatment of multiple sclerosis with combination of laquinimod and fingolimod

Abstract

This invention provides a method of treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising administering to the subject laquinimod as an add-on therapy to or in combination with fingolimod. This invention also provides a package and a pharmaceutical composition comprising laquinimod and fingolimod for treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome. This invention also provides laquinimod for use as an add-on therapy or in combination with fingolimod in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome. This invention further provides use of laquinimod and fingolimod in the preparation of a combination for treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome.

What is claimed is: 
     
         1 . A method of treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising periodically administering to the subject an amount of laquinimod and an amount of fingolimod, wherein the amounts when taken together are effective to treat the subject. 
     
     
         2 . The method of  claim 1 , wherein the amount of laquinimod or and the amount of fingolimod when administered together is more effective to treat the subject than when each agent at the same amount is administered alone. 
     
     
         3 . The method of  claim 1  or  2 , wherein the multiple sclerosis is relapsing multiple sclerosis. 
     
     
         4 . The method of  claim 3 , wherein the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the amount of laquinimod and the amount of fingolimod when taken together is effective to reduce a symptom of multiple sclerosis in the subject. 
     
     
         6 . The method of  claim 5 , wherein the symptom is a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, decreased time to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, deterioration of visual function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormalities observed in whole Brain MTR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work. 
     
     
         7 . The method of  claim 6 , wherein the amount of laquinimod and the amount of fingolimod when taken together is effective to decrease or inhibit reduction of brain volume. 
     
     
         8 . The method of  claim 7 , wherein brain volume is measured by percent brain volume change (PBVC). 
     
     
         9 . The method of  claim 6 , wherein the amount of laquinimod and the amount of fingolimod when taken together is effective to increase time to confirmed disease progression. 
     
     
         10 . The method of  claim 9 , wherein time to confirmed disease progression is increased by 20-60%. 
     
     
         11 . The method of  claim 9 , wherein time to confirmed disease progression is increased by at least 50%. 
     
     
         12 . The method of  claim 6 , wherein the amount of laquinimod and the amount of fingolimod when taken together is effective to decrease abnormalities observed in whole Brain MTR histogram. 
     
     
         13 . The method of  claim 6 , wherein the accumulation of physical disability is measured by Kurtzke Expanded Disability Status Scale (EDSS) score. 
     
     
         14 . The method of  claim 6 , wherein the accumulation of physical disability is assessed by the time to confirmed disease progression as measured by Kurtzke Expanded Disability Status Scale (EDSS) score. 
     
     
         15 . The method of  claim 13  or  14 , wherein the subject had an EDSS score of 0-5.5 at baseline. 
     
     
         16 . The method of  claim 13  or  14 , wherein the subject had an EDSS score of 1.5-4.5 at baseline. 
     
     
         17 . The method of  claim 13  or  14 , wherein the subject had an EDSS score of 5.5 or greater at baseline. 
     
     
         18 . The method of any one of  claims 13 - 17 , wherein confirmed disease progression is a 1 point increase of the EDSS score. 
     
     
         19 . The method of any one of  claims 13 - 17 , wherein confirmed disease progression is a 0.5 point increase of the EDSS score. 
     
     
         20 . The method of  claim 6 , wherein impaired mobility is assessed by the Timed-25 Foot Walk test. 
     
     
         21 . The method of  claim 6 , wherein impaired mobility is assessed by the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) self-report questionnaire. 
     
     
         22 . The method of  claim 6 , wherein impaired mobility is assessed by the Ambulation Index (AI). 
     
     
         23 . The method of  claim 6 , wherein impaired mobility is assessed by the Six-Minute Walk (6MW) Test. 
     
     
         24 . The method of  claim 6 , wherein impaired mobility is assessed by the Lower Extremity Manual Muscle Test (LEMMT) Test. 
     
     
         25 . The method of  claim 6 , wherein the amount of laquinimod and the amount of fingolimod when taken together is effective to reduce cognitive impairment. 
     
     
         26 . The method of  claim 25 , wherein cognitive impairment is assessed by the Symbol Digit Modalities Test (SDMT) score. 
     
     
         27 . The method of  claim 6 , wherein general health status is assessed by the EuroQoL (EQ5D) questionnaire, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC). 
     
     
         28 . The method of  claim 6 , wherein functional status is measured by the subject's Short-Form General Health survey (SF-36) Subject Reported Questionnaire score. 
     
     
         29 . The method of  claim 6 , wherein quality of life is assessed by SF-36, EQ5D, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC). 
     
     
         30 . The method of  claim 28  or  29 , wherein the subject's SF-36 mental component summary score (MSC) is improved. 
     
     
         31 . The method of any one of  claims 28 - 30 , wherein the subject's SF-36 physical component summary sore (PSC) is improved. 
     
     
         32 . The method of  claim 6 , wherein fatigue is assessed by the EQ5D, the subject's Modified Fatigue Impact Scale (MFIS) score or the French valid versions of the Fatigue Impact Scale (EMIF-SEP) score. 
     
     
         33 . The method of  claim 6 , wherein symptom severity on work is measured by the work productivity and activities impairment General Health (WPAI-GH) questionnaire. 
     
     
         34 . The method of any one of  claims 1 - 33 , wherein laquinimod is laquinimod sodium. 
     
     
         35 . The method of any one of  claims 1 - 34 , wherein fingolimod is fingolimod hydrochloride. 
     
     
         36 . The method of any one of  claims 1 - 35 , wherein the laquinimod and/or the fingolimod is administered via oral administration. 
     
     
         37 . The method of any one of  claims 1 - 36 , wherein the laquinimod and/or the fingolimod is administered daily. 
     
     
         38 . The method of any one of  claims 1 - 36 , wherein the laquinimod and/or the fingolimod is administered more often than once daily. 
     
     
         39 . The method of any one of  claims 1 - 36 , wherein the laquinimod and/or the fingolimod is administered less often than once daily. 
     
     
         40 . The method of any one of  claims 1 - 39 , wherein the amount laquinimod administered is less than 0.6 mg/day. 
     
     
         41 . The method of any one of  claims 1 - 40 , wherein the amount laquinimod administered is 0.1-40.0 mg/day. 
     
     
         42 . The method of  claim 41 , wherein the amount laquinimod administered is 0.1-2.5 mg/day. 
     
     
         43 . The method of  claim 42 , wherein the amount laquinimod administered is 0.25-2.0 mg/day. 
     
     
         44 . The method of  claim 43 , wherein the amount laquinimod administered is 0.5-1.2 mg/day. 
     
     
         45 . The method of  claim 41 , wherein the amount laquinimod administered is 0.25 mg/day. 
     
     
         46 . The method of  claim 41 , wherein the amount laquinimod administered is 0.3 mg/day. 
     
     
         47 . The method of  claim 41 , wherein the amount laquinimod administered is 0.5 mg/day. 
     
     
         48 . The method of  claim 41 , wherein the amount laquinimod administered is 0.6 mg/day. 
     
     
         49 . The method of  claim 41 , wherein the amount laquinimod administered is 1.0 mg/day. 
     
     
         50 . The method of  claim 41 , wherein the amount laquinimod administered is 1.2 mg/day. 
     
     
         51 . The method of  claim 41 , wherein the amount laquinimod administered is 1.5 mg/day. 
     
     
         52 . The method of  claim 41 , wherein the amount laquinimod administered is 2.0 mg/day. 
     
     
         53 . The method of any one of  claims 1 - 52 , wherein the amount fingolimod administered is less than 0.5 mg/day. 
     
     
         54 . The method of any one of  claims 1 - 53 , wherein the amount fingolimod administered is 0.01-2.5 mg/day. 
     
     
         55 . The method of  claim 54 , wherein the amount fingolimod administered is 2.5 mg/day. 
     
     
         56 . The method of  claim 54 , wherein the amount fingolimod administered is 0.01-1 mg/day. 
     
     
         57 . The method of  claim 56 , wherein the amount fingolimod administered is 0.1 mg/day. 
     
     
         58 . The method of  claim 56 , wherein the amount fingolimod administered is 0.25 mg/day. 
     
     
         59 . The method of  claim 56 , wherein the amount fingolimod administered is 0.5 mg/day. 
     
     
         60 . The method of any one of  claims 1 - 59 , wherein a loading dose of an amount different form the intended dose is administered for a period of time at the start of the periodic administration. 
     
     
         61 . The method of  claim 60 , wherein the loading dose is double the amount of the intended dose. 
     
     
         62 . The method of any one of  claims 1 - 61 , wherein the subject is receiving laquinimod therapy prior to initiating fingolimod therapy. 
     
     
         63 . The method  claim 62 , wherein the administration of laquinimod substantially precedes the administration of fingolimod. 
     
     
         64 . The method of any one of  claims 1 - 61 , wherein the subject is receiving fingolimod therapy prior to initiating laquinimod therapy. 
     
     
         65 . The method of  claim 64 , wherein the administration of fingolimod substantially precedes the administration of laquinimod. 
     
     
         66 . The method of  claim 64 , where in the subject is receiving fingolimod therapy for at least 24 weeks prior to initiating laquinimod therapy. 
     
     
         67 . The method of  claim 66 , where in the subject is receiving fingolimod therapy for at least 28 weeks prior to initiating laquinimod therapy. 
     
     
         68 . The method of  claim 67 , where in the subject is receiving fingolimod therapy for at least 48 weeks prior to initiating laquinimod therapy. 
     
     
         69 . The method of  claim 68 , where in the subject is receiving fingolimod therapy for at least 52 weeks prior to initiating laquinimod therapy. 
     
     
         70 . The method of any one of  claims 1 - 69 , further comprising administration of nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, slow-acting drugs, gold compounds, hydroxychloroquine, sulfasalazine, combinations of slow-acting drugs, corticosteroids, cytotoxic drugs, immunosuppressive drugs and/or antibodies. 
     
     
         71 . The method of any one of  claims 1 - 70 , wherein the periodic administration of laquinimod and fingolimod continues for at least 3 days. 
     
     
         72 . The method  claim 71 , wherein the periodic administration of laquinimod and fingolimod continues for more than 30 days. 
     
     
         73 . The method of  claim 72 , wherein the periodic administration of laquinimod and fingolimod continues for more than 42 days. 
     
     
         74 . The method of  claim 73 , wherein the periodic administration of laquinimod and fingolimod continues for 8 weeks or more. 
     
     
         75 . The method of  claim 74 , wherein the periodic administration of laquinimod and fingolimod continues for at least 12 weeks. 
     
     
         76 . The method of  claim 75 , wherein the periodic administration of laquinimod and fingolimod continues for at least 24 weeks. 
     
     
         77 . The method of  claim 76 , wherein the periodic administration of laquinimod and fingolimod continues for more than 24 weeks. 
     
     
         78 . The method of  claim 77 , wherein the periodic administration of laquinimod and fingolimod continues for 6 months or more. 
     
     
         79 . The method of any one of  claims 1 - 78 , wherein the administration of laquinimod and fingolimod inhibits a symptom of relapsing multiple sclerosis by at least 20%. 
     
     
         80 . The method  claim 79 , wherein the administration of laquinimod and fingolimod inhibits a symptom of relapsing multiple sclerosis by at least 30%. 
     
     
         81 . The method of  claim 80 , wherein the administration of laquinimod and fingolimod inhibits a symptom of relapsing multiple sclerosis by at least 50%. 
     
     
         82 . The method of  claim 81 , wherein the administration of laquinimod and fingolimod inhibits a symptom of relapsing multiple sclerosis by at least 70%. 
     
     
         83 . The method of  claim 82 , wherein the administration of laquinimod and fingolimod inhibits a symptom of relapsing multiple sclerosis by more than 100%. 
     
     
         84 . The method of  claim 83 , wherein the administration of laquinimod and fingolimod inhibits a symptom of relapsing multiple sclerosis by more than 300%. 
     
     
         85 . The method of  claim 84 , wherein the administration of laquinimod and fingolimod inhibits a symptom of relapsing multiple sclerosis by more than 1000%. 
     
     
         86 . The method of any one of  claims 1 - 85 , wherein each of the amount of laquinimod or pharmaceutically acceptable salt thereof when taken alone, and the amount of fingolimod when taken alone is effective to treat the subject. 
     
     
         87 . The method of any one of  claims 1 - 85 , wherein either the amount of laquinimod or pharmaceutically acceptable salt thereof when taken alone, the amount of fingolimod when taken alone, or each such amount when taken alone is not effective to treat the subject. 
     
     
         88 . The method of any one of  claims 1 - 87 , wherein the subject is a human patient. 
     
     
         89 . A package comprising:
 a first pharmaceutical composition comprising an amount of laquinimod and a pharmaceutically acceptable carrier;   b) a second pharmaceutical composition comprising an amount of fingolimod and a pharmaceutically acceptable carrier; and   c) instructions for use of the first and second pharmaceutical compositions together to treat a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome.   
     
     
         90 . The package of  claim 89 , wherein the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical composition are in an aerosol, an inhalable powder, an injectable, a liquid, a solid, a capsule or a tablet form. 
     
     
         91 . The package of  claim 89 , wherein the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical composition are in a liquid or a solid form. 
     
     
         92 . The package of  claim 91 , wherein the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical composition are in capsule form. 
     
     
         93 . The package of  claim 91 , the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical composition are in tablet form. 
     
     
         94 . The package of  claim 93 , wherein the tablets are coated with a coating which inhibits oxygen from contacting the core. 
     
     
         95 . The package of  claim 94 , wherein the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment. 
     
     
         96 . The package of anyone of  claims 89 - 95 , wherein the first pharmaceutical composition further comprises mannitol. 
     
     
         97 . The package of anyone of  claims 89 - 96 , wherein the first pharmaceutical composition further comprises an alkalinizing agent. 
     
     
         98 . The package of  claim 97 , wherein the alkalinizing agent is meglumine. 
     
     
         99 . The package of anyone of  claims 89 - 98 , wherein the first pharmaceutical composition further comprises an oxidation reducing agent. 
     
     
         100 . The package of anyone of  claims 89 - 96 , wherein the first pharmaceutical composition is stable and free of an alkalinizing agent or an oxidation reducing agent. 
     
     
         101 . The package of  claim 100 , wherein the first pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent. 
     
     
         102 . The package of anyone of  claims 89 - 101 , wherein the first pharmaceutical composition is stable and free of disintegrant. 
     
     
         103 . The package of anyone of  claims 89 - 102 , wherein the first pharmaceutical composition further comprises a lubricant. 
     
     
         104 . The package of  claim 103 , wherein the lubricant is present in the composition as solid particles. 
     
     
         105 . The package of  claim 103  or  104 , wherein the lubricant is sodium stearyl fumarate or magnesium stearate. 
     
     
         106 . The package of anyone of  claims 89 - 105 , wherein the first pharmaceutical composition further comprises a filler. 
     
     
         107 . The package of  claim 106 , wherein the filler is present in the composition as solid particles. 
     
     
         108 . The package of  claim 106  or  107 , wherein the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof. 
     
     
         109 . The package of  claim 108 , wherein the filler is mannitol or lactose monohydrate. 
     
     
         110 . The package of anyone of  claims 89 - 109 , further comprising a desiccant. 
     
     
         111 . The package of  claim 110 , wherein the desiccant is silica gel. 
     
     
         112 . The package of anyone of  claims 89 - 111 , wherein the first pharmaceutical composition is stable and has a moisture content of no more than 4%. 
     
     
         113 . The package of anyone of  claims 89 - 112 , wherein laquinimod is present in the composition as solid particles. 
     
     
         114 . The package of anyone of  claims 89 - 113 , wherein the package is a sealed packaging having a moisture permeability of not more than 15 mg/day per liter. 
     
     
         115 . The package of  claim 114 , wherein the scaled package is a blister pack in which the maximum moisture permeability is no more than 0.005 mg/day. 
     
     
         116 . The package of  claim 114 , wherein the sealed package is a bottle. 
     
     
         117 . The package of  claim 116 , wherein the bottle is closed with a heat induction liner. 
     
     
         118 . The package of anyone of  claims 114 - 117 , wherein the sealed package comprises an HDPE bottle. 
     
     
         119 . The package of anyone of  claims 114 - 118 , wherein the sealed package comprises an oxygen absorbing agent. 
     
     
         120 . The package of  claim 119 , wherein the oxygen absorbing agent is iron. 
     
     
         121 . The package of any one of  claims 89 - 120 , wherein the amount of laquinimod in the first composition is less than 0.6 mg. 
     
     
         122 . The package of any one of  claims 89 - 121 , wherein the amount of laquinimod in the first composition is 0.1-40.0 mg. 
     
     
         123 . The package of  claim 122 , wherein the amount of laquinimod in the first composition is 0.1-2.5 mg. 
     
     
         124 . The package of  claim 123 , wherein the amount of laquinimod in the first composition is 0.25-2.0 mg. 
     
     
         125 . The package of  claim 124 , wherein the amount of laquinimod in the first composition is 0.5-1.2 mg. 
     
     
         126 . The package of  claim 122 , wherein the amount of laquinimod in the first composition is 0.25 mg. 
     
     
         127 . The package of  claim 122 , wherein the amount of laquinimod in the first composition is 0.3 mg. 
     
     
         128 . The package of  claim 122 , wherein the amount of laquinimod in the first composition is 0.5 mg. 
     
     
         129 . The package of  claim 122 , wherein the amount of laquinimod in the first composition is 0.6 mg. 
     
     
         130 . The package of  claim 122 , wherein the amount of laquinimod in the first composition is 1.0 mg. 
     
     
         131 . The package of  claim 122 , wherein the amount of laquinimod in the first composition is 1.2 mg. 
     
     
         132 . The package of  claim 122 , wherein the amount of laquinimod in the first composition is 1.5 mg. 
     
     
         133 . The package of  claim 122 , wherein the amount of laquinimod in the first composition is 2.0 mg. 
     
     
         134 . The package of any one of  claim 89 - 133 , wherein the amount of fingolimod in the second composition is less than 0.5 mg. 
     
     
         135 . The package of any one of  claim 89 - 133 , wherein the amount of fingolimod in the second composition is 0.01-2.5 mg. 
     
     
         136 . The package of  claim 135 , wherein the amount of fingolimod in the second composition is 2.5 mg. 
     
     
         137 . The package of  claim 135 , wherein the amount of fingolimod in the second composition is 0.01-1 mg. 
     
     
         138 . The package of  claim 137 , wherein the amount of fingolimod in the second composition is 0.1 mg. 
     
     
         139 . The package of  claim 137 , wherein the amount of fingolimod in the second composition is 0.25 mg. 
     
     
         140 . The package of  claim 137 , wherein the amount of fingolimod in the second composition is 0.5 mg. 
     
     
         141 . Laquinimod for use as an add-on therapy or in combination with fingolimod in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome. 
     
     
         142 . A pharmaceutical composition comprising an amount of laquinimod and an amount of fingolimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the laquinimod and the fingolimod are administered simultaneously, contemporaneously or concomitantly. 
     
     
         143 . A pharmaceutical composition comprising an amount of laquinimod and an amount of fingolimod. 
     
     
         144 . The pharmaceutical composition of  claim 142  or  143 , wherein laquinimod is laquinimod sodium. 
     
     
         145 . The pharmaceutical composition of any one of  claims 142 - 144 , wherein fingolimod is fingolimod hydrochloride. 
     
     
         146 . The pharmaceutical composition of any one of  claims 142 - 145 , in an aerosol, an inhalable powder, an injectable, a liquid, a solid, a capsule or a tablet form. 
     
     
         147 . The pharmaceutical composition of any one of  claims 142 - 145 , in a liquid or a solid form. 
     
     
         148 . The pharmaceutical composition of  claim 147 , in capsule form. 
     
     
         149 . The pharmaceutical composition of  claim 147 , in tablet form. 
     
     
         150 . The pharmaceutical composition of  claim 149 , wherein the tablets are coated with a coating which inhibits oxygen from contacting the core. 
     
     
         151 . The pharmaceutical composition of  claim 150 , wherein the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment. 
     
     
         152 . The pharmaceutical composition of anyone of  claims 142 - 151 , further comprising mannitol. 
     
     
         153 . The pharmaceutical composition of anyone of  claims 142 - 152 , further comprising an alkalinizing agent. 
     
     
         154 . The pharmaceutical composition of  claim 153 , wherein the alkalinizing agent is meglumine. 
     
     
         155 . The pharmaceutical composition of anyone of  claims 142 - 154 , further comprising an oxidation reducing agent. 
     
     
         156 . The pharmaceutical composition of anyone of  claims 142 - 152 , which is free of an alkalinizing agent or an oxidation reducing agent. 
     
     
         157 . The pharmaceutical composition of  claim 156 , which is free of an alkalinizing agent and free of an oxidation reducing agent. 
     
     
         158 . The pharmaceutical composition of anyone of  claims 142 - 157 , which is stable and free of disintegrant. 
     
     
         159 . The pharmaceutical composition of anyone of  claims 142 - 159 , further comprising a lubricant. 
     
     
         160 . The pharmaceutical composition of  claim 159 , wherein the lubricant is present in the composition as solid particles. 
     
     
         161 . The pharmaceutical composition of  claim 159  or  160 , wherein the lubricant is sodium stearyl fumarate or magnesium stearate. 
     
     
         162 . The pharmaceutical composition of anyone of  claims 142 - 161 , further comprising a filler. 
     
     
         163 . The pharmaceutical composition of  claim 162 , wherein the filler is present in the composition as solid particles. 
     
     
         164 . The pharmaceutical composition of  claim 162  or  163 , wherein the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof. 
     
     
         165 . The pharmaceutical composition of  claim 164 , wherein the filler is mannitol or lactose monohydrate. 
     
     
         166 . The pharmaceutical composition of any one of  claims 142 - 165 , wherein the amount of laquinimod in the composition is less than 0.6 mg. 
     
     
         167 . The pharmaceutical composition of any one of  claims 142 - 166 , wherein the amount of laquinimod in the composition is 0.1-40.0 mg. 
     
     
         168 . The pharmaceutical composition of  claim 167 , wherein the amount of laquinimod in the composition is 0.1-2.5 mg. 
     
     
         169 . The pharmaceutical composition of  claim 168 , wherein the amount of laquinimod in the composition is 0.25-2.0 mg. 
     
     
         170 . The pharmaceutical composition of  claim 169 , wherein the amount of laquinimod in the composition is 0.5-1.2 mg. 
     
     
         171 . The pharmaceutical composition of  claim 167 , wherein the amount of laquinimod in the composition is 0.25 mg. 
     
     
         172 . The pharmaceutical composition of  claim 167 , wherein the amount of laquinimod in the composition is 0.3 mg. 
     
     
         173 . The pharmaceutical composition of  claim 167 , wherein the amount of laquinimod in the composition is 0.5 mg. 
     
     
         174 . The pharmaceutical composition of  claim 167 , wherein the amount of laquinimod in the composition is 0.6 mg. 
     
     
         175 . The pharmaceutical composition of  claim 167 , wherein the amount of laquinimod in the composition is 1.0 mg. 
     
     
         176 . The pharmaceutical composition of  claim 167 , wherein the amount of laquinimod in the composition is 1.2 mg. 
     
     
         177 . The pharmaceutical composition of  claim 167 , wherein the amount of laquinimod in the composition is 1.5 mg. 
     
     
         178 . The pharmaceutical composition of  claim 167 , wherein the amount of laquinimod in the composition is 2.0 mg. 
     
     
         179 . The pharmaceutical composition of any one of  claims 142 - 178 , wherein the amount of fingolimod in the composition is less than 0.5 mg. 
     
     
         180 . The pharmaceutical composition of any one of  claims 142 - 179 , wherein the amount of fingolimod in the composition is 0.01-2.5 mg. 
     
     
         181 . The pharmaceutical composition of  claim 180 , wherein the amount of fingolimod in the composition is 2.5 mg. 
     
     
         182 . The pharmaceutical composition of  claim 180 , wherein the amount of fingolimod in the composition is 0.01-1 mg. 
     
     
         183 . The pharmaceutical composition of  claim 182 , wherein the amount of fingolimod in the composition is 0.1 mg. 
     
     
         184 . The pharmaceutical composition of  claim 182 , wherein the amount of fingolimod in the composition is 0.25 mg. 
     
     
         185 . The pharmaceutical composition of  claim 182 , wherein the amount of fingolimod in the composition is 0.5 mg. 
     
     
         186 . Use of an amount of laquinimod and an amount of fingolimod in the preparation of a combination for treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome wherein the laquinimod and the fingolimod are administered simultaneously, contemporaneously or concomitantly. 
     
     
         187 . A pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome as an add-on therapy or in combination with fingolimod by periodically administering the pharmaceutical composition and the fingolimod to the subject. 
     
     
         188 . A pharmaceutical composition comprising an amount of fingolimod for use treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome as an add-on therapy or in combination with laquinimod by periodically administering the pharmaceutical composition and the laquinimod to the subject. 
     
     
         189 . A therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which comprises:
 a) one or more unit doses, each such unit dose comprising:
 i) an amount of laquinimod and 
 ii) an amount of fingolimod 
 wherein the respective amounts of said laquinimod and said fingolimod in said unit dose are effective, upon concomitant administration to said subject, to treat the subject, 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 subject.   
     
     
         190 . The therapeutic package of  claim 189 , wherein the respective amounts of said laquinimod and said fingolimod in said unit dose when taken together is more effective to treat the subject than when compared to the administration of said laquinimod in the absence of said fingolimod or the administration of said fingolimod in the absence of said laquinimod. 
     
     
         191 . A pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome, which comprises:
 a) an amount of laquinimod;   b) an amount of fingolimod,   wherein the respective amounts of said laquinimod and said fingolimod in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.   
     
     
         192 . The pharmaceutical composition of  claim 191 , wherein the respective amounts of said laquinimod and said fingolimod in said unit dose when taken together is more effective to treat the subject than when compared to the administration of said laquinimod in the absence of said fingolimod or the administration of said fingolimod in the absence of said laquinimod.