# US 2021/0332147 A1 · DOSAGE AND ADMINISTRATION OF ANTI-C5 ANTIBODIES FOR TREATMENT OF ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS) IN PEDIATRIC PATIENTS

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- Number: US 2021/0332147 A1
- Document ID: US20210332147A1
- Status: Published application
- Kind: A1
- Application number: 17/057,898
- Filed: 2019-05-29
- Published: 2021-10-28
- Earliest claimed: 2018-06-04
- Assignees: Alexion Pharmaceuticals, Inc.
- Applicants: Alexion Pharmaceuticals, Inc.
- Inventors: Lori PAYTON; Andrew DENKER; Eugene Scott SWENSON; Rajendra PRADHAN; Stephan ORTIZ; Marc VALLEE; Christian MIX; Xiang GAO
- Web page: https://patentgrep.com/patent/US20210332147A1

## CPC

- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61K 2039/505: {comprising antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Provided are methods for clinical treatment of Atypical Hemolytic Uremic Syndrome (aHUS) using an anti-C5 antibody, or antigen binding fragment thereof, in pediatric patients.

## Claims

### Claim 1

A method of treating a human pediatric patient with Atypical Hemolytic Uremic Syndrome (aHUS), the method comprising administering to the patient 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 at a loading dose of:
i. 600 mg to a patient weighing ≥5 to <10 kg,
ii. 600 mg to a patient weighing ≥10 to <20 kg,
iii. 900 mg to a patient weighing ≥20 to <30 kg,
iv. 1200 mg to a patient weighing ≥30 to <40 kg,
v. 2400 mg to a patient weighing ≥40 to <60 kg,
vi. 2700 mg to a patient weighing ≥60 to <100 kg, or
vii. 3000 mg to a patient weighing ≥100 kg; and
(b) on Day 15 at a maintenance dose of:
i. 300 mg to a patient weighing ≥5 to <10 kg,
ii. 600 mg to a patient weighing ≥10 to <20 kg,
iii. 2100 mg to a patient weighing ≥20 to <30 kg,
iv. 2700 mg to a patient weighing ≥30 to <40 kg,
v. 3000 mg to a patient weighing ≥40 to <60 kg,
vi. 3300 mg to a patient weighing ≥60 to <100 kg, or
vii. 3600 mg to a patient weighing ≥100 kg; wherein patients weighing <20 kg receive additional maintenance doses every four weeks thereafter, and patients weighing ≥20 kg receive additional maintenance doses every eight weeks thereafter.

### Claim 2

A method of treating a human pediatric patient with Atypical Hemolytic Uremic Syndrome (aHUS), the method comprising administering to the patient 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 Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, each according to the EU numbering convention, wherein the anti-C5 antibody or antigen binding fragment thereof, is administered:
(a) once on Day 1 at a loading dose of:
i. 600 mg to a patient weighing ≥5 to <10 kg,
ii. 600 mg to a patient weighing ≥10 to <20 kg,
iii. 900 mg to a patient weighing ≥20 to <30 kg,
iv. 1200 mg to a patient weighing ≥30 to <40 kg,
v. 2400 mg to a patient weighing ≥40 to <60 kg,
vi. 2700 mg to a patient weighing ≥60 to <100 kg, or
vii. 3000 mg to a patient weighing ≥100 kg; and
(b) on Day 15 at a maintenance dose of:
i. 300 mg to a patient weighing ≥5 to <10 kg,
ii. 600 mg to a patient weighing ≥10 to <20 kg,
iii. 2100 mg to a patient weighing ≥20 to <30 kg,
iv. 2700 mg to a patient weighing ≥30 to <40 kg,
v. 3000 mg to a patient weighing ≥40 to <60 kg,
vi. 3300 mg to a patient weighing >60 to <100 kg, or
vii. 3600 mg to a patient weighing ≥100 kg;
wherein patients weighing <20 kg receive additional maintenance doses every four weeks thereafter, and patients weighing ≥20 kg receive additional maintenance doses every eight weeks thereafter.

### Claim 3 (depends on 1)

The method of claim 1, wherein the anti-C5 antibody comprises:
(a) a heavy chain variable region set forth in SEQ ID NO:12 and a light chain variable region set forth in SEQ ID NO:8;
(b) a heavy chain constant region set forth in SEQ ID NO:13; and/or
(c) a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO:14 and a light chain polypeptide comprising the amino acid sequence set forth in SEQ IDNO:11.

### Claim at position 4

4-5. (canceled)

### Claim 6 (depends on 1)

The method of claim 1, wherein the anti-C5 antibody binds to human C5 at pH 7.4 and 25° C. with an affinity dissociation constant (KD) that is in the range 0.1 nM to 1 nM.

### Claim 7 (depends on 1)

The method of claim 1, wherein the anti-C5 antibody binds to human C5 at pH 6.0 and 25° C. with a KD≥10 nM.

### Claim 8 (depends on 1)

The method of claim 1, wherein the anti-C5 antibody is administered to a patient weighing ≥5 to <10 kg:
(a) once on Day 1 at a loading dose of 600 mg; and
(b) once on Day 15 at a maintenance dose of 300 mg and every four weeks thereafter.

### Claim 9 (depends on 1)

The method of claim 1, wherein the anti-C5 antibody is administered to a patient weighing ≥10 to <20 kg:
(a) once on Day 1 at a loading dose of 600 mg; and
(b) once on Day 15 at a maintenance dose of 600 mg and every four weeks thereafter.

### Claim 10 (depends on 1)

The method of claim 1, wherein the anti-CS antibody is administered to a patient weighing ≥20 to <30 kg:
(a) once on Day 1 at a loading dose of 900 mg; and
(b) once on Day 15 at a maintenance dose of 2100 mg and every eight weeks thereafter.

### Claim 11 (depends on 1)

The method of claim 1, wherein the anti-C5 antibody is administered to a patient weighing ≥30 to <40 kg:
(a) once on Day 1 at a loading dose of 1200 mg; and
(b) once on Day 15 at a maintenance dose of 2700 mg and every eight weeks thereafter.

### Claim 12 (depends on 1)

The method of claim 1, wherein the anti-C5 antibody is administered to a patient weighing ≥40 to <60 kg:
(a) once on Day 1 at a loading dose of 2400 mg; and
(b) once on Day 15 at a maintenance dose of 3000 mg and every eight weeks thereafter.

### Claim 13 (depends on 1)

The method of claim 1, wherein the anti-CS antibody is administered to a patient weighing ≥60 to <100 kg:
(a) once on Day 1 at a loading dose of 2700 mg; and
(b) once on Day 15 at a maintenance dose of 3300 mg and every eight weeks thereafter.

### Claim 14 (depends on 1)

The method of claim 1, wherein the anti-CS antibody is administered to a patient weighing ≥100 kg:
(a) once on Day 1 at a loading dose of 3000 mg; and
(b) once on Day 15 at a maintenance dose of 3600 mg and every eight weeks thereafter.

### Claim 15 (depends on 1)

The method of claim 1, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 100 μg/mL or greater and/or a free C5 concentration of 0.309 to 0.5 μg/mL or lower.

### Claim at position 15

16-17. (canceled)

### Claim 18 (depends on 1)

The method of claim 1, wherein the anti-C5 antibody is administered at a dose of:
(a) 300 mg or 600 mg every four weeks after the treatment for up to two years; or
(b) 2100 mg, 2700 mg, 3000 mg, 3300 mg or 3600 mg every eight weeks after the treatment for up to two years.

### Claim 19

(canceled)

### Claim 20 (depends on 1)

The method of claim 1, wherein the anti-C5 antibody is formulated for intravenous administration.

### Claim 21 (depends on 1)

The method of claim 1, wherein the patient:
(a) has not previously been treated with a complement inhibitor; and/or
(b) is <18 years of age.

### Claim 22

(canceled)

### Claim 23 (depends on 1)

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

### Claim 24 (depends on 1)

The method of claim 1, wherein the treatment:
(a) results in terminal complement inhibition;
(b) results in a complete thrombotic microangiopathy (TMA) response;
(c) results in a ≥25% reduction in serum creatinine levels compared to baseline;
(d) results in an increase in platelet count compared to baseline;
(e) results in a reduction of hemolysis compared to baseline as assessed by lactate dehydrogenase (LDH) levels;
(f) produces a reduction or cessation of at least one therapeutic marker selected from the group consisting of: severe hypertension, proteinuria, uremia, lethargy, fatigue, irritability, thrombocytopenia, microangiopathic hemolytic anemia and renal function impairment, compared to baseline;
(g) produces a shift toward normal levels of a marker selected from the group consisting of: Factor Ba, soluble tumor necrosis factor receptor 1 (sTNFR1), soluble vascular adhesion molecule 1 (sVCAM1), thrombomodulin, D dimer and cystatin C, compared to baseline;
(h) produces a reduction in the need for blood transfusions compared to baseline;
(i) produces a reduction in major adverse vascular events (MAVEs) compared to baseline; and/or
(j) produces a change from baseline in quality of life, assessed via the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, version 4 or the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire Core 30 Scale compared to baseline.

### Claim at position 23

25-33. (canceled)

### Claim 34

A kit for treating Atypical Hemolytic Uremic Syndrome (aHUS) in a human pediatric patient, the kit comprising:
(a) a dose of an anti-C5 antibody or antigen binding fragment thereof, comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8; and
(b) instructions for using the anti-C5 antibody or antigen binding fragment thereof in the

### Claim at position 25

35-41. (canceled)

### Claim 42

An anti-C5 antibody or antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8, wherein the anti-C5 antibody or antigen binding fragment thereof is administered:
(a) once on Day 1 at a loading dose of:
i. 600 mg to a patient weighing ≥5 to <10 kg,
ii. 600 mg to a patient weighing ≥10 to <20 kg,
iii. 900 mg to a patient weighing ≥20 to <30 kg,
iv. 1200 mg to a patient weighing ≥30 to <40 kg,
v. 2400 mg to a patient weighing ≥40 to <60 kg,
vi. 2700 mg to a patient weighing ≥60 to <100 kg, or
vii. 3000 mg to a patient weighing ≥100 kg; and
(b) on Day 15 at a maintenance dose of:
i. 300 mg to a patient weighing ≥5 to <10 kg,
ii. 600 mg to a patient weighing ≥10 to <20 kg,
iii. 2100 mg to a patient weighing ≥20 to <30 kg,
iv. 2700 mg to a patient weighing ≥30 to <40 kg,
v. 3000 mg to a patient weighing ≥40 to <60 kg,
vi. 3300 mg to a patient weighing ≥60 to <100 kg, or
vii. 3600 mg to a patient weighing ≥100 kg;
wherein patients weighing <20 kg receive additional maintenance doses every four weeks thereafter, and patients weighing ≥20 kg receive additional maintenance doses every eight weeks thereafter.

### Claim 43

(canceled)