Dosage and administration of anti-C5 antibodies for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS)
Inventors
PAYTON, Lori • ROTTINGHAUS, Scott T. • Pradhan, Rajendra • Damokosh, Andrew • Gao, Xiang
Assignees
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Publication Number
US-12128101-B2
Publication Date
2024-10-29
Expiration Date
Abstract
Provided are methods for clinical treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH) and Atypical Hemolytic Uremic Syndrome (aHUS) using an anti-C5 antibody, or antigen binding fragment thereof.
Core Innovation
The disclosed invention relates to a method of treating a human patient with Paroxysmal Nocturnal Hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS) by administering an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, during an administration cycle. The anti-C5 antibody is characterized by specific heavy chain and light chain CDR1, CDR2, and CDR3 sequences as set forth in SEQ ID NOs.
In certain embodiments, the anti-C5 antibody additionally includes a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), with the Fc CH3 constant region comprising Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region.
The administration schedule includes dosing on Day 1 and then on Day 15 with dosing every eight weeks thereafter. The disclosed approach is presented in the context of clinical-trial eligibility criteria and study conduct for complement inhibition in PNH/aHUS.
Claims Coverage
The partial content provides two independent claims. The inventive coverage centers on treatment of PNH or aHUS with a sequence-defined anti-C5 antibody, administered on Day 1 and Day 15 followed by dosing every eight weeks, with one claim further requiring an FcRn-binding Fc variant.
Treating PNH or aHUS with a specified anti-C5 antibody sequence
Administering during an administration cycle an effective amount of an anti-C5 antibody, or antigen binding fragment thereof, comprising CDR1, CDR2, and CDR3 heavy chain sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively.
Day 1 and Day 15 anti-C5 dosing with then-every-eight-weeks schedule
Administering the anti-C5 antibody, or antigen binding fragment, once on Day 1 of the administration cycle and on Day 15 of the administration cycle and every eight weeks thereafter.
FcRn-binding Fc variant in the anti-C5 antibody
Administering the anti-C5 antibody, or antigen binding fragment thereof, comprising a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering.
Across the independent claims, the inventive coverage centers on treatment of PNH or aHUS using a sequence-defined anti-C5 antibody with specific heavy- and light-chain CDR sequences and a Day 1/Day 15 then every eight weeks dosing cycle, with one claim also requiring an Fc variant that binds FcRn.
Stated Advantages
Terminal complement inhibition and improvement of hemolysis outcomes are stated for complement-mediated disease treatment.
Improvement is stated for clinical, hematologic, biomarker, transfusion, vascular event, renal, and quality-of-life outcomes as measured by specified markers and scoring scales.
Serum trough concentration maintenance and reduction of free C5 concentration are stated as pharmacodynamic goals.
LDH normalization and achievement of thresholds or reduction criteria for LDH and quality-of-life change are stated.
Noninferiority on coprimary endpoints including TA and LDH normalization versus the active control.
No meningococcal infections during the primary period.
Documented Applications
Treating Paroxysmal Nocturnal Hemoglobinuria (PNH) in a human patient with a method comprising administering an anti-C5 antibody or antigen binding fragment.
Treating atypical hemolytic uremic syndrome (aHUS) in a human patient with a method comprising administering an anti-C5 antibody or antigen binding fragment.
Complement inhibition clinical trial in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS), including eligibility confirmation using high-sensitivity flow cytometry clone-size thresholds and comparative assessment of ALXN1210 (ravulizumab) versus eculizumab.
Assessment of efficacy, safety, PK/PD, and quality of life outcomes during the trial, including LDH normalization and quality-of-life measures.
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