Methods for Treatment of Refractory Generalized Myasthenia Gravis

Abstract

The disclosure provides methods of treating myasthenia gravis (MG) in a subject in need thereof by administering to the subject a substance that specifically binds complement component 5 (C5). In certain embodiments, the substance that specifically binds C5 is a binding protein, such as an anti-C 5 antibody.

What is claimed is: 
     
         1 . A method of treating refractory generalized myasthenia gravis in a patient in need thereof comprising administering a therapeutically effective amount of eculizumab to the patient;
 wherein the patient is positive for auto-antibodies binding to nicotinic acetylcholine receptor (anti-AChR) and shows marked generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving therapy for myasthenia gravis including anticholinesterase inhibitor therapy and immunosuppressant therapy (IST) and requires chronic plasma exchange or chronic IVIg to maintain clinical stability; and   wherein the patient is administered eculizumab for at least 26 weeks.   
     
     
         2 . The method of  claim 1 , wherein eculizumab is administered using a phased dosing schedule with an induction phase comprising administering a 900 mg induction dose of eculizumab on day 1, administering 900 mg doses of eculizumab on days 7, 14, and 21, and administering 1200 mg of eculizumab as a fifth induction dose on day 28; and
 wherein the patient is administered eculizumab for at least 26 weeks.   
     
     
         3 . The method of  claim 2 , wherein the 28 day induction phase of eculizumab treatment is followed by a maintenance phase comprising administering 1200 mg of eculizumab 14 days after the fifth induction dose and administering 1200 mg of eculizumab every 14±2 days thereafter. 
     
     
         4 . The method of  claim 3 , further comprising performing plasmapheresis on the patient and administering eculizumab at a dose of between 300 mg and 1200 mg to the patient within 4 hours of completion of plasmapheresis. 
     
     
         5 . The method of  claim 3 , further comprising performing plasmapheresis on the patient and administering eculizumab at a dose of between 600 mg and 900 mg to the patient within 90 minutes of completion of plasmapheresis. 
     
     
         6 . The method of  claim 3 , further comprising performing plasmapheresis on the patient and administering eculizumab at a dose of 600 mg to the patient within 1 hour of completion of plasmapheresis. 
     
     
         7 . The method of  claim 1 , wherein the patient experiences a clinically meaningful improvement (reduction) in Myasthenia Gravis Activities of Daily Living (MG-ADL) score after 26 weeks of treatment. 
     
     
         8 . The method of  claim 7 , wherein the clinically meaningful improvement the patient experiences is at least a 3 point reduction in the patient's MG-ADL score after 26 weeks of treatment. 
     
     
         9 . The method of  claim 1 , wherein the patient experiences a clinically meaningful improvement (reduction) in quantitative Myasthenia Gravis score (QMG) after 26 weeks of treatment. 
     
     
         10 . The method of  claim 9 , wherein the clinically meaningful improvement the patient experiences is at least a 4 point reduction in the patient's QMG score after 26 weeks of treatment. 
     
     
         11 . The method of  claim 1 , wherein the patient experiences a clinically meaningful improvement (reduction) in Myasthenia Gravis Composite (MGC) score after 26 weeks of treatment. 
     
     
         12 . The method of  claim 11 , wherein the clinically meaningful improvement the patient experiences is at least a 6 point reduction in the patient's MGC score after 26 weeks of treatment. 
     
     
         13 . The method of  claim 1 , wherein the patient experiences a clinically meaningful improvement (reduction) in quality of life as measured by Myasthenia Gravis Quality of Life (MG-QOL-15) score after 26 weeks of treatment. 
     
     
         14 . The method of  claim 13 , wherein the clinically meaningful improvement the patient experiences is at least a 6 point reduction in the patient's MG-QOL-15 score after 26 weeks of treatment. 
     
     
         15 . The method of  claim 1 , wherein the patient experiences a clinically meaningful improvement (reduction) in neuro-fatigue as measured by Neuro-QOL Fatigue score after 26 weeks of treatment. 
     
     
         16 . The method of  claim 15 , wherein the clinically meaningful improvement the patient experiences is at least an 8 point reduction in the patient's Neuro-QOL score after 26 weeks of treatment. 
     
     
         17 . The method of  claim 1 , wherein the patient experiences a clinically meaningful improvement (increase) in health status as measured by EQ-5D health status score after 26 weeks of treatment. 
     
     
         18 . A method of treating refractory generalized myasthenia gravis in a patient in need thereof comprising administering eculizumab to the patient;
 wherein the patient is positive for auto-antibodies binding to nicotinic acetylcholine receptor (anti-AChR) and shows marked generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving therapy for myasthenia gravis including anticholinesterase inhibitor therapy and immunosuppressant therapy (IST) and requires chronic plasma exchange or chronic IVIg to maintain clinical stability;   wherein eculizumab is administered using a phased dosing schedule with an induction phase comprising administering a 900 mg induction dose of eculizumab on day 1, administering 900 mg doses of eculizumab on days 7, 14, and 21, and administering 1200 mg of eculizumab as a fifth induction dose on day 28;   wherein the patient is administered eculizumab for at least 26 weeks;   wherein the 28 day induction phase of eculizumab treatment is followed by a maintenance phase comprising administering 1200 mg of eculizumab 14 days after the fifth induction dose and administering 1200 mg of eculizumab every 14±2 days thereafter; and   wherein the patient has a clinically meaningful improvement (reduction) in at least two measurements of generalized myasthenia gravis severity selected from the group consisting of MG-ADL, QMG, MGC, MG-QOL, and Neuro-QOL.   
     
     
         19 . A method of treating refractory generalized myasthenia gravis in a patient in need thereof comprising administering eculizumab to the patient;
 wherein the patient is positive for auto-antibodies binding to nicotinic acetylcholine receptor (anti-AChR) and shows marked generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving therapy for myasthenia gravis including anticholinesterase inhibitor therapy and immunosuppressant therapy (IST) and requires chronic plasma exchange or chronic IVIg to maintain clinical stability;   wherein eculizumab is administered using a phased dosing schedule with an induction phase comprising administering a 900 mg induction dose of eculizumab on day 1, administering 900 mg doses of eculizumab on days 7, 14, and 21, and administering 1200 mg of eculizumab as a fifth induction dose on day 28;   wherein the patient is administered eculizumab for at least 26 weeks;   wherein the 28 day induction phase of eculizumab treatment is followed by a maintenance phase comprising administering 1200 mg of eculizumab 14 days after the fifth induction dose and administering 1200 mg of eculizumab every 14±2 days thereafter; and   wherein the patient has a clinically meaningful improvement (reduction) in five measurements of generalized myasthenia gravis severity, wherein the five measurements of generalized myasthenia gravis severity are a reduction in MG-ADL of at least 3 points, a reduction of QMG of at least 4 points, a reduction in MGC of at least 6 points, a reduction in MG-QOL of at least 6 points, and a reduction in Neuro-QOL of at least 8 points.   
     
     
         20 . The method of  claim 19 , wherein the patient has a clinically meaningful improvement (reduction) in five measurements of generalized myasthenia gravis, wherein the five measurements of generalized myasthenia gravis severity are a reduction in MG-ADL of at least 4 points, a reduction of QMG of at least 5 points, a reduction in MGC of at least 10 points, a reduction in MG-QOL of at least 11 points, and a reduction in Neuro-QOL of at least 16 points. 
     
     
         21 . The method of  claim 1 , wherein eculizumab is administered by intravenous infusion. 
     
     
         22 . The method of  claim 1 , wherein eculizumab is administered subcutaneously. 
     
     
         23 . The method of  claim 1 , wherein the eculizumab comprises a heavy chain amino acid sequence according to SEQ ID NO: 10 and a light chain amino acid sequence according to SEQ ID NO: 11. 
     
     
         24 . The method of  claim 1 , wherein the eculizumab is an eculizumab variant comprising a heavy chain amino acid sequence according to SEQ ID NO: 14 and a light chain amino acid sequence according to SEQ ID NO: 11. 
     
     
         25 . The method of  claim 1 , wherein the patient has failed treatment over one year or more with two or more ISTs in sequence or in combination. 
     
     
         26 . The method of  claim 1 , wherein the patient has failed at least one IST and requires chronic plasma exchange or IVIg to control symptoms. 
     
     
         27 . The method of  claim 1 , wherein the therapeutically effective amount of eculizumab is maintained at a concentration of between 50-100 μg/mL in the patient's serum. 
     
     
         28 . The method of  claim 1 , wherein the patient experiences a reduction in the administration of one or more IST following at least 26 weeks of treatment. 
     
     
         29 . The method of  claim 1 , wherein the patient experiences a reduction in IST dosing following at least 26 weeks of treatment. 
     
     
         30 . The method of  claim 1 , wherein the patient experiences a reduction in one or more IST dosing and a discontinuation in one or more IST following at least 26 of treatment.