Claims for Patent: 8,410,115

Summary for Patent: 8,410,115

Title:	Methods of treating inflammatory and autoimmune diseases with alpha-4 inhibitory compounds
Abstract:	Alpha 4 inhibitors are used in treatment of inflammatory and autoimmune diseases, such as multiple sclerosis, Crohn\'s Disease, rheumatoid arthritis and asthma. Rare occurrences of progressive multifocal leucoencephalopathy during treatment with an alpha-4 agent suggest the possibility that it may be related to such treatment. Monitoring for the JC virus and educating caregivers and patients about the manifestations of progressive multifocal leucoencephalopathy can improve the safety of alpha 4 inhibitor therapy.
Inventor(s):	Lieberburg; Ivan (Berkeley, CA)
Assignee:	Elan Pharmaceuticals, Inc. (South San Francisco, CA)
Application Number:	11/711,874
Patent Claims:	1. A method of using an alpha-4 inhibitor compound to treat a patient with an inflammatory, or autoimmune disease comprising: (a) administering a pharmaceutically effective amount of the alpha-4 inhibitor compound; (b) monitoring the patient for at least one indicator of progressive multifocal leukoencephalopathy; and (c) discontinuing administration of the alpha-4 inhibitor compound when at least one indicator of progressive multifocal leukoencephalopathy is present; wherein the monitoring improves safety of treatment; wherein the alpha-4 inhibitor compound is a compound of Formula V, a pharmaceutically acceptable salt or ester of any of the foregoing: ##STR00025## wherein: R.sup.1 is selected from the group consisting of C.sub.1 to C.sub.4 alkyl and C.sub.1 to C.sub.4 haloalkyl; and R.sup.2 is selected from the group consisting of C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.2 to C.sub.4 alkynyl, C.sub.3-C.sub.6 cycloalkyl and benzyl. 2. The method of claim 1, wherein the disease comprises multiple sclerosis. 3. The method of claim 2, wherein the multiple sclerosis is selected from relapsing remitting, secondary progressive, primary progressive, and chronic progressive multiple sclerosis. 4. The method of claim 1, wherein the disease is chosen from inflammatory bowel disease and rheumatoid arthritis. 5. The method of claim 4, wherein the inflammatory bowel disease comprises Crohn's Disease. 6. The method of claim 1, wherein the monitoring detects JC virus in the patient's urine, blood, and/or cerebrospinal fluid. 7. The method of claim 6, wherein the monitoring comprises serially removing samples of the patient's blood, measuring an amount of IgG antibodies to JC virus in the samples, and comparing the amount of the antibodies in the samples to each other. 8. The method of claim 7, wherein the monitoring further comprises measuring an amount of IgM antibodies to JC virus in the samples, and comparing the amount of the IgM and IgG antibodies in the samples to each other. 9. The method of claim 7, wherein the monitoring detects seroconversion and/or an increasing titer of JC virus in the patient's blood, and further comprises (a) removing a sample of the patient's cerebrospinal fluid when comparison of the blood samples detects seroconversion and/or an increasing titer of JC virus; and (b) testing the cerebrospinal fluid for JC virus. 10. The method of claim 1, wherein the monitoring comprises testing for at least one symptom chosen from clinical and radiologic symptoms of progressive multifocal leukoencephalopathy. 11. The method of claim 10, wherein the testing for clinical symptoms comprises testing for new or progressing neurological symptoms. 12. The method of claim 11, wherein the neurological symptoms comprise one or more of central blindness, mental confusion, personality change, and dyskinesia. 13. The method of claim 10, wherein the testing for radiologic symptoms comprises performing a Gd-enhanced magnetic resonance imaging scan. 14. The method of claim 1, further comprising, when at least one indicator of progressive multifocal leukoencephalopathy is present, providing antiviral therapy. 15. The method of claim 14, wherein the antiviral therapy comprises administering at least one therapeutically effective dose of an antiviral agent selected from cytosine arabinoside (cytarabine), cidofovir, and a serotonin antagonist. 16. The method of claim 15, wherein the serotonin antagonist comprises a 5HT2a antagonist. 17. The method of claim 1, wherein the alpha-4 inhibitor compound is monotherapy without an immunosuppressive or antineoplastic agent. 18. The method of claim 17, wherein the immunosuppressive or antineoplastic agent is selected from one or more of chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide, hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan, mustargen, bleomycin, lomustine, semustine, mitomycin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate, raltitrexid, fluorodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel, amifostine, interferon alpha, tamoxefen, medroxyprogesterone, megestrol, raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoic acids, arsenic trioxide, rituximab, CAMPATH-1, mylotarg, mycophenolic acid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate, laquinimod, FTY-720, interferon tau, daclizumab, infliximab, IL10, anti-IL2 receptor antibody, anti-IL-12 antibody, anti-IL6 receptor antibody, CDP-571, adalimumab, entaneracept, leflunomide, anti-interferon gamma antibody, abatacept, fludarabine, cyclophosphamide, azathioprine, cyclosporine, intravenous immunoglobulin, 5-ASA (mesalamine), and a .beta.-interferon. 19. The method of claim 18, wherein the immunosuppressive agent comprises a .beta.-interferon. 20. A method of using an alpha-4 inhibitor compound to treat a patient with an inflammatory or autoimmune disease comprising: (a) removing a sample of blood from the patient; (b) testing serum or plasma of the sample for IgG antibodies to JC virus; (c) initiating treatment of the patient with the alpha-4 inhibitor compound, if the sample is negative for IgG antibodies to JC virus; (d) monitoring the patient for at least one indicator of progressive multifocal leukoencephalopathy; and (e) discontinuing administration of the alpha-4 inhibitor compound when at least one indicator of progressive multifocal leukoencephalopathy is present; wherein the testing and monitoring improve safety of the treatment; wherein the alpha-4 inhibitor compound is a compound of Formula V, a pharmaceutically acceptable salt or ester of any of the foregoing: ##STR00026## wherein: R.sup.1 is selected from the group consisting of C.sub.1 to C.sub.4 alkyl and C.sub.1 to C.sub.4 haloalkyl; and R.sup.2 is selected from the group consisting of C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.2 to C.sub.4 alkynyl, C.sub.3-C.sub.6 cycloalkyl and benzyl. 21. The method of claim 20, wherein the disease comprises multiple sclerosis. 22. The method of claim 21, wherein the multiple sclerosis is selected from relapsing remitting, secondary progressive, primary progressive, and chronic progressive multiple sclerosis. 23. The method of claim 20, wherein the disease is chosen from inflammatory bowel disease or rheumatoid arthritis. 24. The method of claim 23, wherein the inflammatory bowel disease comprises Crohn's Disease. 25. The method of claim 20, wherein the disease comprises asthma. 26. The method of claim 20, further comprising testing the serum or plasma of the sample for IgM antibodies to JC virus and initiating treatment if the serum or plasma is negative for both. IgG and IgM antibodies to JC virus. 27. The method of claim 20 wherein the monitoring detects JC virus in the patient's urine, blood, and/or cerebrospinal fluid. 28. The method of claim 27, wherein the monitoring comprises serially removing samples of the patient's blood, measuring an amount of IgG antibodies to JC virus in the samples, and comparing the amount of the antibodies in the samples to each other. 29. The method of claim 28, wherein the monitoring further comprises measuring an amount of IgM antibodies to JC virus in the samples, and comparing the amount of the IgM and IgG antibodies in the samples to each other. 30. The method of claim 28, wherein the monitoring detects seroconversion and/or an increasing titer of JC virus in the patients blood, and further comprises (a) removing a sample of the patient's cerebrospinal fluid when comparison of the blood samples detects seroconversion and/or an increasing titer of JC virus; and (b) testing the cerebrospinal fluid for JC virus. 31. The method of claim 20, wherein the monitoring comprises testing for at least one symptom chosen from clinical and radiologic symptoms of progressive multifocal leukoencephalopathy. 32. The method of claim 31, wherein the testing for clinical symptoms comprises testing for new or progressing neurological symptoms. 33. The method of claim 32, wherein the neurological symptoms comprise one or more of central blindness, mental confusion, personality change, and dyskinesia. 34. The method of claim 31, wherein the testing for radiologic symptoms comprises performing a Gd-enhanced magnetic resonance imaging scan. 35. The method of claim 20, further comprising, when at least one indicator of progressive multifocal leukoencephalopathy is present, providing antiviral therapy. 36. The method of claim 35, wherein the antiviral therapy comprises administering at least one therapeutically effective dose of an antiviral agent selected from cytosine arabinoside (cytarabine), cidofovir, and a serotonin antagonist. 37. The method of claim 36, wherein the serotonin antagonist comprises a 5HT2a antagonist. 38. The method of claim 20, wherein the alpha-4 inhibitor compound is a monotherapy without an immunosuppressive or antineoplastic agent. 39. The method of claim 38, wherein the immunosuppressive or antineoplastic agent is selected from one or more of chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide, hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan, mustargen, bleomycin, lomustine, semustine, mitomycin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate, raltitrexid, flurorodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel, amifostine, interferon alpha, tamoxefen, medroxyprogesterone, megestrol, raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoic acids, arsenic trioxide, rituximab, CAMPATH-1, mylotarg, mycophenolic acid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate, laquinimod, FTY-720, interferon tau, daclizumab, infliximab, IL10, anti-IL2 receptor antibody, anti-IL-12 antibody, anti-IL6 receptor antibody, CDP-571, adalimumab, entaneracept, leflunomide, anti-interferon gamma antibody, abatacept, fludarabine, cyclophosphamide, azathioprine, cyclosporine, intravenous immunoglobulin, 5-ASA (mesalamine), and a .beta.-interferon. 40. The method of claim 39, wherein the immunosuppressive agent comprises a .beta.-interferon. 41. A method of using an alpha-4 inhibitor compound to a patient with an inflammatory or autoimmune disease comprising: (a) removing a sample of blood from the patient; (b) testing serum or plasma of the sample for IgG antibodies to JC virus; (c) initiating treatment of the patient with the alpha-4 inhibitor compound, if the sample is positive for IgG antibodies to JC virus; (d) monitoring the patient for at least one indicator of progressive multifocal leukoencephalopathy; and (e) discontinuing administration of the alpha-4 inhibitor compound when at least one indicator of progressive multifocal leukoencephalopathy is present; wherein the testing and monitoring improves the safety of the treatment; wherein the alpha-4 inhibitor compound is a compound of Formula V, a pharmaceutically acceptable salt or ester of any of the foregoing: ##STR00027## wherein: R.sup.1 is selected from the group consisting of C.sub.1 to C.sub.4 alkyl and C.sub.1 to C.sub.4 haloalkyl; and R.sup.2 is selected from the group consisting of C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.2 to C.sub.4 alkynyl, C.sub.3-C.sub.6 cycloalkyl and benzyl. 42. The method of claim 41, wherein the disease comprises multiple sclerosis. 43. The method of claim 42, wherein the multiple sclerosis is selected from relapsing remitting, secondary progressive, primary progressive, and chronic progressive multiple sclerosis. 44. The method of claim 41, wherein the disease is chosen from inflammatory bowel disease and rheumatoid arthritis. 45. The method of claim 44, wherein the inflammatory bowel disease comprises Crohn's Disease. 46. The method of claim 41, wherein the disease comprises asthma. 47. The method of claim 41, wherein the monitoring detects JC virus in the patient's urine, blood, and/or cerebrospinal fluid. 48. The method of claim 47, wherein the monitoring comprises serially removing samples of the patient's blood, measuring an amount of IgG antibodies to JC virus in the samples, and comparing the amount of the antibodies in the samples to each other. 49. The method of claim 48, wherein the monitoring further comprises measuring an amount of IgM antibodies to JC virus in the samples, and comparing the amount of the IgM and IgG antibodies in the samples to each other. 50. The method of claim 48, wherein the monitoring detects seroconversion and/or an increasing titer of JC virus in the patient's blood, and further comprises (a) removing a sample of the patient's cerebrospinal fluid when comparison of the blood samples detect seroconversion and/or an increasing titer of JC virus; and (b) testing the cerebrospinal fluid for of JC virus. 51. The method of claim 41, wherein the monitoring comprises testing for at least one symptom chosen from clinical and radiologic symptoms of progressive multifocal leukoencephalopathy. 52. The method of claim 51, wherein the testing for clinical symptoms comprises testing for new or progressing neurological symptoms. 53. The method of claim 52, wherein the neurological symptoms comprise one or more of central blindness, mental confusion, personality change, and dyskinesia. 54. The method of claim 51, wherein the testing for radiologic symptoms comprises performing a Gd-enhanced magnetic resonance imaging scan. 55. The method of claim 41, further comprising, when at least one indicator of progressive multifocal leukoencephalopathy is present, providing antiviral therapy. 56. The method of claim 55, wherein the antiviral therapy comprises administering at least one therapeutically effective dose of an antiviral agent selected from cytosine arabinoside (cytarabine), cidofovir, and a serotonin antagonist. 57. The method of claim 56, wherein the serotonin antagonist comprises a 5HT2a antagonist. 58. The method of claim 41, wherein the alpha-4 inhibitor compound is a monotherapy without an immunosuppressive or antineoplastic agent. 59. The method of claim 58, wherein the immunosuppressive or antineoplastic agent is selected from one or more of chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide, hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan, mustargen, bleomycin, lomustine, semustine, mitomycin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate, raltitrexid, fluororodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel, amifostine, interferon alpha, tamoxefen, medroxyprogesterone, megestrol, raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoic acids, arsenic trioxide, rituximab, CAMPATH-I, mylotarg, mycophenolic acid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate, laquinimod, FTY-720, interferon tau, daclizumab, infliximab, IL10, anti-IL2 receptor antibody, anti-IL-12 antibody, anti-IL6 receptor antibody, CDP-571, adalimumab, entaneracept, leflunomide, anti-interferon gamma antibody, abatacept, fludarabine, cyclophosphamide, azathioprine, cyclosporine, intravenous immunoglobulin, 5-ASA (mesalamine), and a .beta.-interferon. 60. The method of claim 59, wherein the immunosuppressive agent comprises a .beta.-interferon. 61. A method of using an alpha-4 inhibitor compound to treat a patient with an inflammatory, or autoimmune disease comprising: (a) removing a sample of blood from the patient; (b) testing the sample for IgG antibodies to JC virus; (c) initiating treatment of the patient with the alpha-4 inhibitor compound, if the sample is positive for IgG antibodies to JC virus; (d) educating a prescribing physician about mental and physical symptoms of progressive multifocal leukoencephalopathy; (e) educating the patient about the mental and physical symptoms of progressive multifocal leukoencephalopathy and instructing the patient to report to the physician when at least one symptom is present; (f) monitoring the patient for at least one indicator of progressive multifocal leukoencephalopathy; and (g) discontinuing administration of alpha-4 inhibitor compound when at least one indicator of progressive multifocal leukoencephalopathy is present; wherein the testing, education, and monitoring improve safety of treatment; wherein the alpha-4 inhibitor compound is a compound of Formula V, a pharmaceutically acceptable salt or ester of any of the foregoing: ##STR00028## wherein: R.sup.1 is selected from the group consisting of C.sub.1 to C.sub.4 alkyl and C.sub.1 to C.sub.4 haloalkyl; and R.sup.2 is selected from the group consisting of C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.2 to C.sub.4 alkynyl, C.sub.3-C.sub.6 cycloalkyl and benzyl. 62. The method of claim 61, wherein the disease comprises multiple sclerosis. 63. The method of claim 62, wherein the multiple sclerosis is selected from relapsing remitting, secondary progressive, primary progressive, and chronic progressive multiple sclerosis. 64. The method of claim 61, wherein the disease is chosen from inflammatory bowel disease and rheumatoid arthritis. 65. The method of claim 64, wherein the inflammatory bowel disease comprises Crohn's Disease. 66. The method of claim 61, wherein the disease comprises asthma. 67. The method of claim 61, wherein the monitoring detects JC virus in the patient's urine, blood, and/or cerebrospinal fluid. 68. The method of claim 67, wherein the monitoring comprises serially removing samples of the patient's blood, measuring an amount of IgG antibodies to JC virus in the samples, and comparing the amount of the antibodies in the samples to each other. 69. The method of claim 68, wherein the monitoring further comprises measuring an amount of IgM antibodies to JC virus in the samples, and comparing the amount of the IgM and IgG antibodies in the samples to each other. 70. The method of claim 68, wherein the monitoring detects seroconversion and/or an increasing titer of JC virus in the patient's blood, and further comprises (a) removing a sample of the patient's cerebrospinal fluid when comparison of the blood samples detect seroconversion and/or an increasing titer of JC virus; and (b) testing the cerebrospinal fluid for JC virus. 71. The method of claim 61, wherein the monitoring comprises testing for at least one symptom chosen from clinical and radiologic symptoms of progressive multifocal leukoencephalopathy. 72. The method of claim 71, wherein the testing for clinical symptoms comprises testing for new or progressing neurological symptoms. 73. The method of claim 72, wherein the neurological symptoms comprise one or more of central blindness, mental confusion, personality change, and dyskinesia. 74. The method of claim 71, wherein the testing for radiologic symptoms comprises performing a Gd-enhanced magnetic resonance imaging scan. 75. The method of claim 61, further comprising, when at least one indicator of progressive multifocal leukoencephalopathy is present, providing antiviral therapy. 76. The method of claim 75, wherein the antiviral therapy comprises administering at least one therapeutically effective dose of an antiviral agent selected from cytosine arabinoside (cytarabine), cidofovir, and a serotonin antagonist. 77. The method of claim 76, wherein the serotonin antagonist comprises a 5HT2a antagonist. 78. The method of claim 61, wherein the alpha-4 inhibitor compound is a monotherapy without an immunosuppressive or antineoplastic agent. 79. The method of claim 78 wherein the immunosuppressive or antineoplastic agent is selected from one or more of chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide, hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan, mustargen, bleomycin, lomustine, semustine, mitomycin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate, raltitrexid, fluororodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel, amifostine, interferon alpha, tamoxefen, medroxyprogesterone, megestrol, raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoic acids, arsenic trioxide, rituximab, CAMPATH-1, mylotarg, mycophenolic acid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate, laquinimod, FTY-720, interferon tau, daclizumab, infliximab, IL10, anti-IL2 receptor antibody, anti-IL-12 antibody, anti-IL6 receptor antibody, CDP-571, adalimumab, entaneracept, leflunomide, anti-interferon gamma antibody, abatacept, fludarabine, cyclophosphamide, azathioprine, cyclosporine, intravenous immunoglobulin, 5-ASA (mesalamine), and a .beta.-interferon. 80. The method of claim 79, wherein the immunosuppressive agent comprises a .beta.-interferon.

Details for Patent 8,410,115

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
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