Dosage and administration of anti-C5 antibodies for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS)

1. A method of treating a human patient with Paroxysmal Nocturnal Hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS), the method comprising administering to the patient 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, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered:

(a) once on Day 1 of the administration cycle at a dose of: 2400 mg to a patient weighing ≥40 to <60 kg, 2700 mg to a patient weighing ≥60 to <100 kg, or 3000 mg to a patient weighing ≥100 kg; and

(b) on Day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg to a patient weighing ≥40 to <60 kg, 3300 mg to a patient weighing ≥60 to <100 kg, or 3600 mg to a patient weighing ≥100 kg.

2. A method of treating a human patient with Paroxysmal Nocturnal Hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS), the method comprising administering to the patient 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, CDR1, CDR2, and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5, and 6, respectively, and 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, wherein the anti-C5 antibody, or antigen binding fragment thereof, is administered:

(a) once on Day 1 of the administration cycle at a dose of: 2400 mg to a patient weighing ≥40 to <60 kg, 2700 mg to a patient weighing ≥60 to <100 kg, or 3000 mg to a patient weighing ≥100 kg; and

(b) on Day 15 of the administration cycle and every eight weeks thereafter at a dose of 3000 mg to a patient weighing ≥40 to <60 kg, 3300 mg to a patient weighing ≥60 to <100 kg, or 3600 mg to a patient weighing ≥100 kg.

3. The method of claim 1 , wherein the patient has previously been treated with eculizumab.

4. The method of claim 1 , wherein the administration cycle starts at least two weeks after the patient's last dose of eculizumab.

5. The method of claim 1 , wherein the patient has been treated with eculizumab:

(a) for at least 6 months prior to Day 1 of the administration cycle; and/or

(b) at a dose of 900 mg every 2 weeks.

6. The method of claim 1 , wherein the anti-C5 antibody, or antigen-binding fragment thereof, comprises:

(a) a heavy chain variable region depicted in SEQ ID NO:12 and a light chain variable region depicted in SEQ ID NO:8;

(b) a heavy chain constant region depicted in SEQ ID NO:13; and/or

(c) a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:14 and a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO:11.

7. The method of claim 1 , wherein the anti-C5 antibody, or antigen-binding fragment thereof, binds to human C5:

(a) at pH 7.4 and 25° C. with an affinity dissociation constant (K D ) that is in the range 0.1 nM ≤K D ≤1 nM; or

(b) at pH 6.0 and 25° C. with a K D ≥10 nM.

8. The method of claim 1 , wherein the treatment:

(a) maintains a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of 100 μg/ml or greater during the administration cycle;

(b) maintains a serum trough concentration of the anti-C5 antibody, or antigen binding fragment thereof, of 200 μg/ml or greater during the administration cycle;

(c) maintains a free C5 concentration of 0.309 to 0.5 μg/mL or below;

(d) reduces free C5 concentration by greater than 99% throughout the treatment period; and/or

(e) reduces free C5 concentration by greater than 99.5% throughout the treatment period.

9. The method of claim 1 , wherein the anti-05 antibody, or antigen binding fragment thereof, is administered at a dose of 3000 mg, 3300 mg, or 3600 mg every eight weeks after the administration cycle for up to two years.

10. The method of claim 1 , wherein the anti-C5 antibody, or antigen binding fragment thereof, is formulated for intravenous administration.

11. The method of claim 1 , wherein the administration cycle is a total of 26 weeks of treatment.

12. The method of claim 1 , wherein the treatment results in:

(a) terminal complement inhibition;

(b) a reduction of hemolysis as assessed by lactate dehydrogenase (LDH) levels;

(c) normalization of LDH levels;

(d) normalization of LDH levels by at least day 24 of treatment;

(e) a percent change in LDH levels (LDH-PCHG) of less than 15% as compared to treatment with eculizumab;

(f) a reduction in breakthrough hemolysis relative to treatment with eculizumab;

(g) an elimination of breakthrough hemolysis during the treatment period;

(h) a reduction of breakthrough hemolysis compared to pretreatment baseline amount of breakthrough hemolysis;

(i) at least one therapeutic effect selected from the group consisting of a reduction or cessation in abdominal pain, dyspnea, dysphagia, chest pain, erectile dysfunction;

(j) a shift toward normal levels of a hemolysis-related hematologic biomarker selected from the group consisting free hemoglobin, haptoglobin, reticulocyte count, PNH red blood cell (RBC) clone and D-dimer;

(k) at least one therapeutic effect selected from the group consisting of a reduction or cessation in severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia, and renal function impairment;

(l) a shift toward normal levels of Factor Ba, soluble tumor necrosis factor receptor 1 (sTNFR1), soluble vascular adhesion molecule 1 (sVCAM1), thrombomodulin, D-dimer, and cystatin C;

(m) an increase in hemoglobin stabilization from the pretreatment baseline;

(n) a reduction in the need for blood transfusions;

(o) a greater than 70% increase in transfusion avoidance;

(p) a reduction in major adverse vascular events (MAVEs);

(q) a shift toward normal levels of a chronic disease associated biomarker selected from the group consisting estimated glomerular filtration rate (eGFR) and spot urine:albumin:creatinine and plasma brain natriuretic peptide (BNP);

(r) a change from baseline in quality of life, assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, version 4 and the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 Scale; and/or

(s) a change from baseline in quality of life, assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, version 4 and the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 Scale by at least 7 points from the patient's untreated baseline score.