Methods, agents and compositions for treatment of inflammatory conditions

Abstract

The present invention relates to the screening, diagnosis, prognostic evaluation, and treatment or prevention of age associated inflammation, chronic inflammation, and inflammatory diseases. In particular, the present invention relates to treating or preventing inflammatory diseases (e.g. rheumatoid arthritis or spondyloarthritis) or patients with inflammatory peripheral GnRH with GnRH antagonists or drugs that lower the effects of GnRH.

1 . A method of treating or preventing an inflammatory condition in a subject, wherein said inflammatory condition is selected from an inflammatory disease, chronic inflammation, age-related inflammation or inflammatory peripheral GnRH, said method comprising:
 administering ASP1707 or a pharmaceutically acceptable salt thereof to said subject, wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered long-term to said subject for a period of at least 12 weeks.   
     
     
         2 . The method of  claim 1 , wherein said inflammatory condition is an autoimmune disease. 
     
     
         3 . The method of  claim 1 , wherein said inflammatory disease is rheumatoid arthritis, an inflammatory bowel disease, a spondyloarthritis, systemic sclerosis (scleroderma), psoriasis, nephritis, multiple sclerosis or osteoarthritis. 
     
     
         4 . The method of  claim 3 , wherein said disease is rheumatoid arthritis. 
     
     
         5 . The method of  claim 1 , wherein said inflammatory disease is ankylosing spondylitis. 
     
     
         6 . The method of  claim 3 , wherein said inflammatory bowel disease is colitis or Crohn's disease. 
     
     
         7 . The method of  claim 1 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is for use in treating or preventing osteoporosis or for increasing bone mineral density. 
     
     
         8 . The method of  claim 1 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is for use in treating a cardiovascular disease or metabolic syndrome, or for decreasing the risk of a cardiovascular event or of developing coronary heart disease or metabolic syndrome by treating one or more risk factors for cardiovascular disease in a subject. 
     
     
         9 . The method of  claim 8 , wherein ASP1707 or the pharmaceutically acceptable salt thereof decreases HBA1c, decreases blood pressure, or increases HDL levels in said subject. 
     
     
         10 . The method of  claim 8 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is for use in decreasing blood pressure. 
     
     
         11 . The method of  claim 1 , wherein the inflammatory condition is systemic chronic inflammation. 
     
     
         12 . The method of  claim 11 , wherein said systemic chronic inflammation is age-related systemic chronic inflammation. 
     
     
         13 . The method of  claim 11 , wherein the systemic chronic inflammation is low-level inflammation. 
     
     
         14 . The method of  claim 1 , wherein the inflammatory condition is cancer inflammation. 
     
     
         15 . The method of  claim 1 , wherein said method is for the treatment or prevention of low level systemic chronic inflammation in a subject who is without overt clinical symptoms of inflammatory disease. 
     
     
         16 . The method of  claim 1 , wherein said method is for the treatment or prevention of peripheral inflammatory GnRH in a subject who exhibits a level of peripheral GnRH which is 160 pg/ml or above. 
     
     
         17 . The method of  claim 16 , wherein the subject is healthy or is without overt clinical symptoms of inflammatory disease, 
     
     
         18 . The method of  claim 1 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is in the form of a conjugate with a polymer which serves to inhibit passage of ASP1707 or the salt thereof across the blood brain barrier. 
     
     
         19 . The method of  claim 18 , wherein the polymer is a polypeptide, a polyethylene glycol (PEG) or a polysaccharide. 
     
     
         20 . The method of  claim 1 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is used in combination with one or more additional active agents. 
     
     
         21 . The method of  claim 20 , wherein the additional active agent is an agent useful for the treatment of inflammation, particularly an agent useful in the treatment of an inflammatory disease or an autoimmune disease, including rheumatoid arthritis, an inflammatory bowel disease such as colitis or Crohn's disease, a spondyloarthritis, systemic sclerosis (scleroderma), psoriasis, nephritis, multiple sclerosis, osteoarthritis and ankylosing spondylitis. 
     
     
         22 . The method of  claim 20 , wherein ASP1707 or the pharmaceutically acceptable salt thereof and the additional active agent have a synergistic effect. 
     
     
         23 . The method of  claim 20 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is used in combination with an additional active agent which is a sex hormone, including oestrogen or testosterone, or an agent useful in sex hormone substitution therapy, including LH or FSH. 
     
     
         24 . The method of  claim 23 , wherein the sex hormone is titrated to a desired or selected level. 
     
     
         25 . The method of  claim 20 , wherein the additional active agent is selected from an anti-rheumatic agent, a non-steroidal anti-inflammatory drug (NSAID), a biologic agent, an analgesic, a steroid, a glucocorticoid, an agent used to treat osteoporosis and an agent used to treat multiple sclerosis. 
     
     
         26 . The method of  claim 20 , wherein said one or more additional active agents are selected from the group consisting of methotrexate, fampridine, daivobet, oestrogen and testosterone. 
     
     
         27 . The method of  claim 1 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject for at least five months. 
     
     
         28 . The method of  claim 27 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject for at least one year. 
     
     
         29 . The method of  claim 1 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject multiple times. 
     
     
         30 . The method of  claim 29 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject multiple times per day, daily, weekly, or monthly. 
     
     
         31 . The method of  claim 30 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject with a single loading dose followed by a lower maintenance dose administered multiple times per day, daily, weekly, or monthly. 
     
     
         32 . The method of  claim 31 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is in the form of a sustained release preparation and is for administration at an initial loading dose of 20 to 1000 mg, e.g. 240 mg, followed by a maintenance dose of either (i) 60 to 1000 mg, e.g. 80-160 mg, every 2 weeks, or (ii) 30 to 300 mg, e.g. 40-150 mg, every week. 
     
     
         33 . The method of  claim 1 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject at a dosage of 0.5 to 200 mg/day, administered 1 or more times a day. 
     
     
         34 . The method of  claim 33 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject at a dosage of 10 to 100 mg/day, administered 1 or more times a day, preferably twice a day. 
     
     
         35 . The method of  claim 34 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject at a dosage of 50 to 70 mg/day, preferably 60 mg/day, administered 1 or more times a day, preferably twice a day. 
     
     
         36 . The method of  claim 1 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject 2, 3, 4, 5 or 6 times a day. 
     
     
         37 . The method of  claim 34 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject twice a day, each dose being in the range from 5 to 50 mg, preferably 30 mg. 
     
     
         38 . The method of  claim 1 , wherein the level of peripheral GnRH in said subject is determined prior to administration of ASP1707 or the pharmaceutically acceptable salt thereof, or is monitored over a period of time, prior to and/or during administration of ASP1707 or the pharmaceutically acceptable salt thereof. 
     
     
         39 . The method of  claim 38 , wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject if the level of peripheral GnRH is 160 pg/ml or above. 
     
     
         40 . The method of  claim 1  wherein said subject is a post-menopausal female. 
     
     
         41 . The method of  claim 1  wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered orally to said subject. 
     
     
         42 . The method of  claim 1  wherein said subject is already being treated for the said inflammatory condition, preferably with methotrexate. 
     
     
         43 . The method of  claim 1 , wherein said inflammatory condition is rheumatoid arthritis, said subject is a post-menopausal female, and ASP1707 or the pharmaceutically acceptable salt thereof is administered orally to said subject twice daily, with a total daily dose in the range from 10 to 100 mg, preferably 60 mg, each of the two daily doses being of equal amounts in the range from 5 to 50 mg, preferably 30 mg. 
     
     
         44 . A method of treating or preventing an inflammatory condition in a subject, selected from an inflammatory disease, chronic inflammation, age-related inflammation or inflammatory peripheral GnRH, preferably an autoimmune disease, said method comprising:
 administering a combination of ASP1707 or a pharmaceutically acceptable salt thereof and an additional active agent for treatment of said condition to said subject, wherein ASP1707 or the pharmaceutically acceptable salt thereof and said additional active agent are administered long-term to said subject for a period of at least 12 weeks.   
     
     
         45 . The method of  claim 40 , wherein said additional active agent is an agent useful for the treatment of inflammation, particularly an agent useful in the treatment of an inflammatory disease or an autoimmune disease, including rheumatoid arthritis, an inflammatory bowel disease such as colitis or Crohn's disease, a spondyloarthritis, systemic sclerosis (scleroderma), psoriasis, nephritis, multiple sclerosis, osteoarthritis and ankylosing spondylitis, preferably wherein the additional active agent is selected from an anti-rheumatic agent, a non-steroidal anti-inflammatory drug (NSAID), a biologic agent, an analgesic, a steroid, a glucocorticoid, an agent used to treat osteoporosis and an agent used to treat multiple sclerosis, e.g. wherein said additional active agent is selected from the group consisting of methotrexate, fampridine, daivobet, oestrogen and testosterone. 
     
     
         46 . The method of  claim 40 , wherein the ASP1707 or the pharmaceutically acceptable salt thereof is in the form of a conjugate with a polymer which serves to inhibit passage of ASP1707 or the salt thereof across the blood brain barrier, and/or wherein ASP1707 or the pharmaceutically acceptable salt thereof is administered to said subject for at least five months, is administered to said subject multiple times, is administered to said subject at a dosage of 0.5 to 200 mg/day 1 or more times a day, or is administered to said subject 2, 3, 4, 5 or 6 times a day. 
     
     
         47 . A conjugate comprising ASP1707 or a pharmaceutically acceptable salt thereof linked to a polymer which serves to inhibit passage of ASP1707 or the pharmaceutically acceptable salt thereof across the blood brain barrier. 
     
     
         48 . A pharmaceutical composition comprising a conjugate as defined in  claim 43 , together with at least one pharmaceutically acceptable carrier or excipient.