# US 10,766,952 B2 · Methods for reducing migraine frequency in a subject in need thereof

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- Number: US 10,766,952 B2
- Document ID: US10766952B2
- Status: Granted
- Kind: B2
- Application number: 15/909,895
- Filed: 2018-03-01
- Published: 2019-03-21
- Granted: 2020-09-08
- Earliest claimed: 2017-03-02
- Assignees: Beth Israel Deaconess Medical Center, Inc.
- Applicants: Beth Israel Deaconess Medical Center, Inc.
- Inventors: Rami Burstein
- Web page: https://patentgrep.com/patent/US10766952B2

## CPC

- C07K 16/18: against material from animals or humans
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61P 25/06: Antimigraine agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/51: Complete heavy chain or Fd fragment, i.e. VH + CH1
- C07K 2317/515: Complete light chain, i.e. VL + CL
- C07K 2317/55: Fab or Fab'
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to methods for selecting a headache patient responsive to treatment with an anti-CGRP antibody and to methods for reducing headache frequency in the selected patient comprising administering an anti-CGRP antibody.

## Claims

### Claim 1

A method for reducing migraine frequency in a subject suffering from chronic or episodic migraine comprising administering to the subject an antibody or antigen-binding fragment thereof that blocks, inhibits, suppresses, or reduces the calcitonin gene related peptide (CGRP) pathway, wherein the antibody or antigen-binding fragment thereof is an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody, thereby reducing migraine frequency in the subject, wherein, prior to administration of the antibody or antigen-binding fragment thereof, the subject is known to exhibit allodynia and/or hyperalgesia during an acute phase of a migraine but not during an interictal phase of the migraine.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject suffers from episodic migraine.

### Claim 3 (depends on 1)

The method of claim 1, wherein the subject suffers from chronic migraine.

### Claim 4 (depends on 1)

The method of claim 1, wherein the subject is known to exhibit allodynia and or hyperalgesia during an acute phase of a migraine but not during an interictal phase of the migraine.

### Claim 5 (depends on 1)

The method of claim 1, wherein the absence of allodynia and/or hyperalgesia during the interictal phase of migraine was determined by quantitative sensory testing (QST).

### Claim 6 (depends on 1)

The method of claim 1, further comprising determining whether the subject exhibits allodynia and/or hyperalgesia during an acute phase of a migraine but not during an interictal phase of the migraine prior to administration of the antibody or antigen-binding fragment thereof.

### Claim 7 (depends on 6)

The method of claim 6, wherein absence of allodynia and/or hyperalgesia during the interictal phase of migraine is determined by quantitative sensory testing (QST).

### Claim 8 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody, a humanized antibody, or an antigen-binding fragment selected from a Fab, a Fab′, a F(ab′)2, an Fv, or an ScFv.

### Claim 9 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a CDR H1 amino acid sequence as set forth in SEQ ID NO: 3; a CDR H2 amino acid sequence as set forth in SEQ ID NO: 4; a CDR H3 amino acid sequence as set forth in SEQ ID NO: 5; a CDR L1 amino acid sequence as set forth in SEQ ID NO: 6; a CDR L2 amino acid sequence as set forth in SEQ ID NO: 7; and a CDR L3 amino acid sequence as set forth in SEQ ID NO: 8.

### Claim 10 (depends on 9)

The method of claim 9, wherein:
the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:2; or
the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 11, and a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 12.

### Claim 11 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a CDR H1 amino acid sequence as set forth in SEQ ID NO: 87; a CDR H2 amino acid sequence as set forth in SEQ ID NO: 88; a CDR H3 amino acid sequence as set forth in SEQ ID NO:89; a CDR L1 amino acid sequence as set forth in SEQ ID NO:84; a CDR L2 amino acid sequence as set forth in SEQ ID NO:85; and a CDR L3 amino acid sequence as set forth in SEQ ID NO:86.

### Claim 12 (depends on 11)

The method of claim 11, wherein:
the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 82, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 80; or
the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 83, and a light chain comprising the amino acid sequence as set forth in SEQ ID NO:81.

### Claim 13 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a CDR H1 amino acid sequence as set forth in SEQ ID NO:93; a CDR H2 amino acid sequence as set forth in SEQ ID NO:94; a CDR H3 amino acid sequence as set forth in SEQ ID NO:95; a CDR L1 amino acid sequence as set forth in SEQ ID NO:91; a CDR L2 amino acid sequence as set forth in SEQ ID NO:92; and a CDR L3 amino acid sequence as set forth in SEQ ID NO:90.

### Claim 14 (depends on 13)

The method of claim 13, wherein:
the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 97, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 96; or
the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO:99, and a light chain comprising the amino acid sequence as set forth in SEQ ID NO:98.

### Claim 15 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a CDR H1 amino acid sequence as set forth in SEQ ID NO: 103; a CDR H2 amino acid sequence as set forth in SEQ ID NO: 104; a CDR H3 amino acid sequence as set forth in SEQ ID NO: 105; a CDR L1 amino acid sequence as set forth in SEQ ID NO: 100; a CDR L2 amino acid sequence as set forth in SEQ ID NO: 101; and a CDR L3 amino acid sequence as set forth in SEQ ID NO: 102.

### Claim 16 (depends on 15)

The method of claim 15, wherein:
the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 107, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 106; or
the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 109, and a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 108.

### Claim 17 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered while the patient is migraine-free.

### Claim 18

A method for reducing migraine frequency in a subject suffering from chronic or episodic migraine comprising:
a) determining whether the subject exhibits allodynia and/or hyperalgesia during the interictal phase of a migraine, and
b) administering an antibody or antigen-binding fragment thereof that blocks, inhibits, suppresses, or reduces the calcitonin gene related peptide (CGRP) pathway to the subject that does not exhibit signs of allodynia and/or hyperalgesia during the interictal phase of the migraine; wherein the antibody or antigen-binding fragment thereof is an anti-CGRP antagonist antibody or an anti-CGRP receptor antibody.