MULTIPLE-VARIABLE DOSE REGIMEN FOR TREATING TNFalpha-RELATED DISORDERS

Abstract

Multiple-variable dose methods for treating TNFα-related disorders, including Crohn's disease and psoriasis, comprising administering TNFα inhibitors, including TNFα antibodies, are described. Multiple-variable dose methods include administration of a TNF-inhibitor in an induction or loading phase followed by administration of the agent in a maintenance or treatment phase, wherein the TNF-inhibitor is administered in a higher dosage during the induction phase.

1 . A multiple-variable dose method for treating a disorder in which TNFα activity is detrimental, comprising:
 administering to a subject in need thereof at least one induction dose of a TNFα inhibitor such that a threshold level of TNFα inhibitor is achieved within an induction phase; and 
 subsequently administering to the subject at least one treatment dose of the TNFα inhibitor within a treatment phase, such that treatment occurs. 
 
     
     
         2 . The method of  claim 1 , wherein the TNFα inhibitor is a human TNFα antibody, or antigen-binding fragment thereof. 
     
     
         3 . The method of  claim 1 , wherein the TNFα inhibitor is a recombinant human anti-TNFα antibody comprising:
 a heavy chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:8; a CDR2 comprising the amino acid sequence of SEQ ID NO:6; and a CDR3 comprising the amino acid sequence of SEQ ID NO:4; and 
 a light chain comprising a CDR1 comprising the amino acid sequence of SEQ ID NO:7; a CDR2 comprising the amino acid sequence of SEQ ID NO:5; and a CDR3 comprising the amino acid sequence of SEQ ID NO:3. 
 
     
     
         4 . The method of  claim 3 , wherein the heavy chain comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2, and the light chain comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:1. 
     
     
         5 . The method of  claim 4 , wherein the heavy chain comprises an IgG1 heavy chain constant region and the light chain comprises a kappa light chain constant region. 
     
     
         6 . The method of  claim 1 , wherein the TNFα inhibitor is adalimumab. 
     
     
         7 . The method of  claim 1 , wherein the disorder is selected from the group consisting of an autoimmune disease, an infectious disease, transplant rejection or graft-versus-host disease, malignancy, a pulmonary disorder, an intestinal disorder, a cardiac disorder, sepsis, a spondyloarthropathy, a metabolic disorder, anemia, pain, a hepatic disorder, a skin disorder, a nail disorder, and vasculitis. 
     
     
         8 . The method of  claim 1 , wherein the disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, psoriasis in combination with psoriatic arthritis, ulcerative colitis, and Crohn's disease. 
     
     
         9 . The method of  claim 1 , wherein the treatment dose is 40-60% of the induction dose. 
     
     
         10 . The method of  claim 1 , wherein the induction dose ranges from about 20 to about 200 mg. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the treatment dose ranges from about 20 to about 120 mg. 
     
     
         13 - 17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the TNFα inhibitor is administered subcutaneously. 
     
     
         19 . The method of  claim 1 , wherein the TNFα inhibitor is administered in combination with methotrexate. 
     
     
         20 . The method of  claim 19 , wherein the methotrexate is administered in a dose of between about 2.5 mg and about 30 mg. 
     
     
         21 - 40 . (canceled) 
     
     
         41 . The multiple-variable dose method of  claim 1 , wherein the method induces remission of Crohn's disease or reduces psoriatic plaques. 
     
     
         42 - 53 . (canceled) 
     
     
         54 . A kit for the treatment of a disorder in which TNFα activity is detrimental comprising:
 a) at least one container comprising an induction dose of a TNFα inhibitor; 
 b) at least one container comprising a treatment dose of a TNFα inhibitor; and 
 c) instructions for administration of the induction dose within an induction phase and the treatment dose of the TNFα inhibitor within a treatment phase. 
 
     
     
         55 . The kit of  claim 54 , wherein the disorder is selected from the group consisting of Crohn's disease, ulcerative colitis, psoriasis, and psoriasis in combination with psoriatic arthritis. 
     
     
         56 - 60 . (canceled) 
     
     
         61 . A method of treating Crohn's disease in a subject comprising administering to the subject a TNFα inhibitor such that a mean serum TNFα inhibitor trough level of about 12 μg/mL is achieved. 
     
     
         62 - 66 . (canceled) 
     
     
         67 . An article of manufacture comprising a TNFα inhibitor and a package insert, wherein the package insert indicates that in patients with Crohn's disease a loading dose at week 0 followed by a second dose which is about 40-60% of the loading dose on week 2 achieves a mean serum TNFα inhibitor trough level of approximately 12 μg/mL at week 2 and week 4. 
     
     
         68 - 75 . (canceled)