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.

What is claimed: 
     
         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 2 , wherein the antibody is an isolated human antibody, or an antigen-binding portion thereof, that dissociates from human TNFα with a K d  of 1×10 −8  M or less and a K off  rate constant of 1×10 −3  s −1  or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC 50  of 1×10 −7  M or less. 
     
     
         4 . The method of  claim 2 , wherein the antibody has the following characteristics:
 a) dissociates from human TNFα with a K off  rate constant of 1×10 −3  s −1  or less, as determined by surface plasmon resonance;   b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;   c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.   
     
     
         5 . The method of  claim 2 , wherein the antibody either
 a) has a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:1 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:2; or   b) is the antibody D2E7.   
     
     
         6 . The method of  claim 1 , wherein the TNFα inhibitor is etanercept or infliximab. 
     
     
         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 . The method of  claim 1 , wherein the induction dose ranges from about 80 to about 160 mg. 
     
     
         12 . The method of  claim 1 , wherein the treatment dose ranges from about 20 to about 120 mg. 
     
     
         13 . The method of  claim 1 , wherein the treatment does ranges from about 40 to about 80 mg. 
     
     
         14 . The method of  claim 1 , wherein the induction dose comprises about 160 mg. 
     
     
         15 . The method of  claim 14 , wherein the treatment dose comprises about 80 mg. 
     
     
         16 . The method of  claim 1 , wherein the induction dose comprises about 80 mg. 
     
     
         17 . The method of  16 , wherein the treatment dose comprises about 40 mg. 
     
     
         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 . The method of  claim 1 , wherein the treatment dose is administered 2 weeks following the induction dose. 
     
     
         22 . A multiple-variable dose method for treating Crohn's disease or psoriasis, 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.   
     
     
         23 . A multiple-variable dose method of inducing remission of Crohn's disease or reducing psoriatic plaques, comprising:
 administering to a subject in need thereof at least one induction dose of D2E7 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 D2E7 within a treatment phase, such that treatment occurs.   
     
     
         24 . 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 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.