Therapeutic regimens for treatment of paroxysmal nocturnal hemoglobinuria
Inventors
Huang, Mingjun • Patel, Dharaben • Podos, Steven D.
Assignees
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Publication Number
US-12076319-B2
Publication Date
2024-09-03
Expiration Date
Abstract
Provided herein are methods for treating a subject with PNH comprising administering to a subject a therapeutically effective amount of complement component C5 (C5) inhibitor, complement component C3 (C3) inhibitor, or complement factor B (CFB) inhibitor in combination with a therapeutically effective amount of small molecule complement factor D (CFD) inhibitor of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to treating paroxysmal nocturnal hemoglobinuria (PNH) in a human in need thereof by administering an anti-C5 monoclonal antibody in combination with orally administered Compound 1, or a pharmaceutically acceptable salt thereof. The human is experiencing extravascular hemolysis or residual intravascular hemolysis at the time of the first administration of Compound 1, and in some embodiments has previously been receiving a therapeutic regimen comprising administration of a C5 inhibitor.
The disclosure further relates to treating PNH by administering a factor D (CFD) inhibitor and complement inhibitors targeting C3, C5, or complement factor B (CFB). The complement-targeting component includes inhibitors of C3, including compstatin and compstatin analogs, inhibitors of C5, including anti-C5 monoclonal antibody, or inhibitors of CFB, including LNP023 and other inhibitors referenced in WO/PCT applications.
The invention further describes combining CFD inhibitors with complement inhibitors to achieve synergistic inhibition of hemolysis and CAP activity, with the synergy being directed to increased inhibition while reducing the required amounts of inhibitor. The described embodiments include combinations that pair CFD inhibition with C3 inhibition, with CFB inhibition, or with C3/C5/CFB complement-targeting strategies, and may include a pan-complement inhibitor embodiment for CFD.
Claims Coverage
The independent claims cover two related approaches, with nine inventive features in total: treating PNH using orally administered Compound 1 with anti-C5 monoclonal antibody, including patient-state and hemoglobin limitations, and broader combination treatment using CFD inhibitors with C3, C5, or CFB inhibitors.
Treating PNH with anti-C5 monoclonal antibody and orally administered Compound 1
A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a human in need thereof comprising administering to the subject a therapeutically effective amount of an anti-C5 monoclonal antibody in combination with a therapeutically effective amount of orally administered Compound 1, or a pharmaceutically acceptable salt thereof.
Extravascular hemolysis after prior C5-inhibitor regimen
The human at the time of the first administration of Compound 1 has previously been receiving a therapeutic regimen comprising administration of the C5 inhibitor, and is experiencing extravascular hemolysis.
Residual intravascular hemolysis after prior C5-inhibitor regimen
The human at the time of the first administration of Compound 1 has previously been receiving a therapeutic regimen comprising administration of the C5 inhibitor, and is experiencing residual intravascular hemolysis.
Low hemoglobin level with anti-C5 monoclonal antibody and Compound 1
The human at the time of the first administration of Compound 1 has previously been receiving a therapeutic regimen comprising administration of the C5 inhibitor, and has a hemoglobin level of less than about 10 g/dL.
Oral administration of Compound 1 with anti-C5 monoclonal antibody for extravascular hemolysis
A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a human in need thereof comprising administering an anti-C5 monoclonal antibody in combination with orally administered Compound 1 (or a pharmaceutically acceptable salt thereof), wherein the human at the time of the first administration of Compound 1 is experiencing extravascular hemolysis.
Oral Compound 1 plus anti-C5 monoclonal antibody in previously treated humans with extravascular hemolysis
A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a human in need thereof comprising orally administering Compound 1 (or a pharmaceutically acceptable salt thereof), and administering a C5 inhibitor wherein the C5 inhibitor is an anti-C5 monoclonal antibody, wherein the human at the time of the first administration of Compound 1 has previously been receiving a therapeutic regimen comprising administration of the C5 inhibitor, and wherein the human at the time of the first administration of Compound 1 is experiencing extravascular hemolysis.
Oral Compound 1 plus anti-C5 monoclonal antibody for residual intravascular hemolysis
A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a human in need thereof comprising orally administering Compound 1 (or a pharmaceutically acceptable salt thereof), and administering a complement C5 inhibitor wherein the C5 inhibitor is an anti-C5 monoclonal antibody, wherein the human at the time of the first administration of Compound 1 has previously been receiving a therapeutic regimen comprising administration of the C5 inhibitor, and wherein the human at the time of the first administration of Compound 1 is experiencing residual intravascular hemolysis.
Oral Compound 1 plus anti-C5 monoclonal antibody with hemoglobin level constraint
A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a human in need thereof comprising orally administering Compound 1 (or a pharmaceutically acceptable salt thereof), and administering a complement C5 inhibitor wherein the C5 inhibitor is an anti-C5 monoclonal antibody, wherein the human at the time of the first administration of Compound 1 has previously been receiving a therapeutic regimen comprising administration of the C5 inhibitor, and wherein the human at the time of the first administration of Compound 1 has a hemoglobin level of less than about 10 g/dL.
CFD inhibitors with complement inhibitors targeting C3, C5, or CFB
Combining a factor D (CFD) inhibitor with complement inhibitors targeting C3, C5, or complement factor B (CFB), including compstatin and compstatin analogs, anti-C5, and LNP023 and other CFB inhibitors.
The claims center on orally administered Compound 1 with an anti-C5 monoclonal antibody for PNH, with patient selection based on hemolysis status, prior C5-inhibitor treatment, and hemoglobin level. The additional claim content covers CFD inhibitor combinations with C3, C5, or CFB inhibitors for synergistic inhibition of hemolysis and CAP activity.
Stated Advantages
Reduces C3 fragment deposition on PNH erythrocytes by blocking upstream alternative-pathway C3 convertase assembly via CFD inhibition.
Synergistically improves inhibition of hemolysis and CAP activity while reducing the required amounts of inhibitor.
Improves inhibition of both intravascular and extravascular hemolysis versus C5 inhibition alone, including in suboptimal or partial responders.
Documented Applications
Therapeutic regimens for treating paroxysmal nocturnal hemoglobinuria (PNH) in a human in need thereof.
Use in patients experiencing extravascular hemolysis and/or residual intravascular hemolysis, including patients with prior C5-inhibitor treatment and hemoglobin or LDH criteria.
Combination embodiments with C3 inhibitors, complement factor B (CFB) inhibitors, or pan-complement inhibitors such as FUT-175.
Treating paroxysmal nocturnal hemoglobinuria (PNH) in a human in need thereof using Compound 1 in combination with an anti-C5 monoclonal antibody, with patient status specified at the time of first Compound 1 administration (extravascular hemolysis or residual intravascular hemolysis).
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