Treatment Of Paroxysmal Nocturnal Hemoglobinuria Patients By An Inhibitor Of Complement

Abstract

Eculizumab, a humanized monoclonal antibody against C5 that inhibits terminal complement activation, showed activity in a preliminary 12-week open-label trial in a small cohort of patients with paroxysmal nocturnal hemoglobinuria (PNH). The present study examined whether chronic eculizumab therapy could reduce intravascular hemolysis, stabilize hemoglobin levels, reduce transfusion requirements, and improve quality of life in a double-blind, randomized, placebo-controlled, multi-center global Phase III trial. It has been found that eculizumab stabilized hemoglobin levels, decreased the need for transfusions, and improved quality of life in PNH patients via reduced intravascular hemolysis. Chronic eculizumab treatment appears to be a safe and effective therapy for PNH.

1 . A method to improve at least one aspect of the quality of life of a patient suffering from paroxysmal nocturnal hemoglobinuria, said method comprising administering to said patient in need thereof a compound which inhibits complement or inhibits formation of C5b-9. 
   
   
       2 . The method of  claim 1  wherein said quality of life is measured by a FACIT-Fatigue score. 
   
   
       3 . The method, of  claim 2  wherein the FACIT-Fatigue score increases by at least 3 points. 
   
   
       4 . The method of  claim 2  wherein the FACIT-Fatigue score increases by ≧4 points. 
   
   
       5 . The method of  claim 1  wherein said quality of life is measured by an EORTC QLQ-C30 score. 
   
   
       6 . The method of  claim 5  wherein said EORTC QLQ-C30 score improves by ≧10% of the pretreatment score. 
   
   
       7 . The method of  claim 5  wherein said aspect of the quality of life as measured by an EORTC QLQ-C30 score is selected from the group consisting of a) global health status, b) physical functioning, c) emotional functioning, d) cognitive functioning, e) role functioning, f) social functioning, g) fatigue, h) pain, i) dyspnea, j) appetite loss, and k) insomnia. 
   
   
       8 . The method of  claim 7  wherein said aspect of quality of life is fatigue. 
   
   
       9 . The method of  claim 1  wherein said compound is selected from the group consisting of CR1, LEX-CR1, MCP, DAF, CD59, Factor H, cobra venom factor, FUT-175, complestatin, and K76 COOH. 
   
   
       10 . The method of  claim 1  wherein said compound is a steroid that suppresses complement. 
   
   
       11 . The method of  claim 1  wherein said compound is selected from the group consisting of antibodies, active antibody fragments, soluble complement inhibitory compounds, proteins, soluble complement inhibitors with a lipid tail, protein fragments, peptides, small organic compounds, RNA aptamers, L-RNA aptamers, spiegelmers, antisense compounds, serine protease inhibitors, double stranded RNA, small interfering RNA, locked nucleic acid inhibitors, and peptide nucleic acid inhibitors. 
   
   
       12 . The method of  claim 11  wherein said compound is an antibody or an active antibody fragment. 
   
   
       13 . The method of  claim 12  wherein said antibody or active antibody fragment is selected from the group consisting of a) polyclonal antibodies, b) monoclonal antibodies, c) single chain antibodies, d) chimeric antibodies, e) humanized antibodies, f) Fabs, g) F(ab′)s, h) F(ab′) 2 S, i) Fvs, j) diabodies, and k) human antibodies. 
   
   
       14 . The method of  claim 12  wherein said antibody or active antibody fragment blocks C5 cleavage. 
   
   
       15 . The method of  claim 12  wherein said antibody or active antibody fragment inhibits the formation of C5b-9. 
   
   
       16 . The method of  claim 12  wherein said antibody is eculizumab. 
   
   
       17 . The method of  claim 12  wherein said antibody or active antibody fragment is administered for at least 6 months. 
   
   
       18 . The method of  claim 1  wherein said patient has aplastic anemia or myelodysplastic syndrome. 
   
   
       19 . The method of  claim 1  wherein said patient is anemic. 
   
   
       20 . The method of  claim 19  wherein said patient remains anemic following treatment. 
   
   
       21 . The method of  claim 19  wherein said patient has a hemoglobin level less than i) 14 g/dL if a man or ii) 12 g/dL if a woman. 
   
   
       22 . The method of  claim 19  wherein said patient has a hemoglobin level less than i) 13 g/dL if a man or ii) 11 g/dL if a woman. 
   
   
       23 . The method of  claim 19  wherein said patient has a hemoglobin level less than i) 12 g/dL if a man or ii) 10 g/dL if a woman. 
   
   
       24 . The method of  claim 1  wherein said compound inhibits intravascular hemolysis. 
   
   
       25 . The method of  claim 1  wherein said method results in a greater than 30% reduction in LDH in said patient. 
   
   
       26 - 43 . (canceled) 
   
   
       44 . The method of  claim 24  wherein said patient is anemic and said patient remains anemic after said administration. 
   
   
       45 - 67 . (canceled) 
   
   
       68 . A method of prolonging the health-adjusted life expectancy of a patient comprising administering to said patient in need thereof a compound which inhibits complement or inhibits formation of C5b-9. 
   
   
       69 . The method of  claim 68  wherein said patient is anemic. 
   
   
       70 . The method of  claim 69  wherein said patient remains anemic following treatment. 
   
   
       71 . The method of  claim 68  wherein said patient has a hemoglobin level less than i) 14 g/dL if a man or ii) 12 g/dL if a woman. 
   
   
       72 . The method of  claim 68  wherein said patient has a hemoglobin level less than i) 13 g/dL if a man or ii) 11 g/dL if a woman. 
   
   
       73 . The method of  claim 68  wherein said patient has a hemoglobin level less than i) 12 g/dL if a man or ii) 10 g/dL if a woman. 
   
   
       74 . The method of  claim 68  wherein said patient suffers from paroxysmal nocturnal hemoglobinuria. 
   
   
       75 . The method of  claim 68  wherein said health-adjusted life expectancy is measured according to a unit selected from the group consisting of Years of potential life lost, Disability-free life expectancy, Health-adjusted life year, Quality adjusted life year, Healthy years equivalents, Healthy days gained, Episode-free day, Q-TWiST, Health Utilities Index, or Years of healthy life. 
   
   
       76 . The method of  claim 75  wherein the health-adjusted life expectancy in a subject is prolonged by at least one day. 
   
   
       77 . The method of  claim 75  wherein the health-adjusted life expectancy in a subject is prolonged by at least week. 
   
   
       78 . The method of  claim 75  wherein the health-adjusted life expectancy in a subject is prolonged by at least one month. 
   
   
       79 . The method of  claim 75  wherein the health-adjusted life expectancy in a subject is prolonged by at least one year. 
   
   
       80 . The method of  claim 68  wherein said compound is selected from the group consisting of CR1, LEX-CR1, MCP, DAF, CD59, Factor H, cobra venom factor, FUT-175, complestatin, and K76 COOH. 
   
   
       81 . The method of  claim 68  wherein said compound is a steroid that suppresses complement. 
   
   
       82 . The method of  claim 68  wherein said compound is selected from the group consisting of antibodies, active antibody fragments, soluble complement inhibitory compounds, proteins, soluble complement inhibitors with a lipid tail, protein fragments, peptides, small organic compounds, RNA aptamers, L-RNA aptamers, spiegelmers, antisense compounds, serine protease inhibitors, double stranded RNA, small interfering RNA, locked nucleic acid inhibitors, and peptide nucleic acid inhibitors. 
   
   
       83 . The method of  claim 82  wherein said compound is an antibody or an active antibody fragment. 
   
   
       84 . The method of  claim 83  wherein said antibody or active antibody fragment is selected from the group consisting of a) polyclonal antibodies, b) monoclonal antibodies, c) single chain antibodies, d) chimeric antibodies, e) humanized antibodies, f) Fabs, g) F(ab′)s, h) F(ab′) 2 S, i) Fvs, j) diabodies, and k) human antibodies. 
   
   
       85 . The method of  claim 83  wherein said antibody or active antibody fragment blocks C5 cleavage. 
   
   
       86 . The method of  claim 83  wherein said antibody or active antibody fragment is administered for at least 6 months. 
   
   
       87 . The method of  claim 68  wherein said compound inhibits complement or inhibits the formation of C5b-9. 
   
   
       88 . The method of  claim 87  wherein said compound is an antibody or an active antibody fragment. 
   
   
       89 . The method of  claim 88  wherein said antibody is eculizumab. 
   
   
       90 . The method of  claim 68  wherein said patient has aplastic anemia or myelodysplastic syndrome. 
   
   
       91 . A method to improve at least one aspect of the quality of life of a patient suffering from paroxysmal nocturnal hemoglobinuria, said method comprising administering to said patient in need thereof a compound which inhibits intravascular hemolysis. 
   
   
       92 . A method to improve at least one aspect of the quality of life of an anemic patient whose anemia results at least in part from hemolysis, said method comprising administering to said patient in need thereof a compound which inhibits intravascular hemolysis, wherein said patient remains anemic.