# US 11,028,161 B2 · Treating refractory migraine

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- Number: US 11,028,161 B2
- Document ID: US11028161B2
- Status: Granted
- Kind: B2
- Application number: 17/076,772
- Filed: 2020-10-21
- Published: 2021-02-11
- Granted: 2021-06-08
- Earliest claimed: 2016-09-23
- Assignees: Teva Pharmaceuticals International GmbH
- Applicants: Teva Pharmaceuticals International GmbH
- Inventors: Marcelo Bigal; Ernesto Aycardi
- Web page: https://patentgrep.com/patent/US11028161B2

## 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}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/06: Antimigraine agents
- 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 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- 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 2317/55: 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 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)
- 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

Disclosed herein are methods of treating or reducing incidence of migraine and/or at least one secondary symptom associated with refractory migraine in a subject having refractory migraine comprising administering to the subject a monoclonal antibody that modulates the CGRP pathway. Compositions for use in the disclosed methods are also provided. Antagonist antibody G1 and antibodies derived from G1 directed to CGRP are also described.

## Claims

### Claim 1

A method of treating or preventing migraine in a subject having refractory migraine, the method comprising:
selecting a subject who has been treated with two or more different preventative migraine treatments wherein at least one of the preventative migraine treatments is selected from topiramate, carbamazepine, divalproex sodium, sodium valproate, valproic acid, divalproex, flunarizine, candesartan, pizotifen, amitriptyline, venlafaxine, nortriptyline, duloxetine, atenolol, nadolol, metoprolol, propranolol, bisopropol, timolol, onabotulinumtoxin A, lisinopril, and oxeterone; and
administering to the subject a therapeutically effective amount of a humanized monoclonal anti-calcitonin gene-related peptide (CGRP) antagonist antibody comprising the amino acid sequence of the heavy chain variable region set forth in SEQ ID NO: 63 and the amino acid sequence of the light chain variable region set forth in SEQ ID NO: 62.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject has been treated with two to four different preventative migraine treatments.

### Claim 3 (depends on 1)

The method of claim 1, wherein the at least one preventative migraine treatment is selected from propranolol, metoprolol, topiramate, divalproex sodium, sodium valproate, divalproex, valproic acid, amitriptyline, flunarizine, candesartan, and onabotulinumtoxin A.

### Claim 4 (depends on 1)

The method of claim 1, wherein the at least one preventative migraine treatment is selected from topiramate, carbamazepine, divalproex sodium, sodium valproate, flunarizine, pizotifen, amitriptyline, venlafaxine, nortriptyline, duloxetine, atenolol, nadolol, metoprolol, propranolol, timolol, and onabotulinumtoxinA.

### Claim 5 (depends on 1)

The method of claim 1, wherein the at least one preventative migraine treatment is selected from propranolol, metoprolol, topiramate, sodium valproate or divalproex, amitriptyline, flunarizine, candesartan, and onabotulinumtoxinA.

### Claim 6 (depends on 1)

The method of claim 1, wherein each of the two or more preventative migraine treatments are selected from different groups (a)-(g):
(a) propranolol or metoprolol,
(b) topiramate,
(c) sodium valproate or divalproex,
(d) amitriptyline,
(e) flunarizine,
(f) candesartan, and
(g) onabotulinumtoxinA.

### Claim 7 (depends on 1)

The method of claim 1, wherein each of the two or more preventative migraine treatments are selected from different groups (a)-(e):
(a) topiramate,
(b) divalproex sodium or sodium valproate,
(c) metoprolol, propranolol, timolol, atenolol, or nadolol,
(d) amitriptyline or nortriptyline, and
(e) venlafaxine or duloxetine.

### Claim 8 (depends on 1)

The method of claim 1, wherein the subject has been treated with the two or more different preventative migraine treatments within the 10 years prior to administering the monoclonal antibody.

### Claim 9 (depends on 1)

The method of claim 1, wherein the subject has been diagnosed with episodic migraine prior to administering the monoclonal antibody.

### Claim 10 (depends on 1)

The method of claim 1, wherein the subject has been diagnosed with chronic migraine prior to administering the monoclonal antibody.

### Claim 11 (depends on 1)

The method of claim 1, wherein the subject experiences migraines with aura.

### Claim 12 (depends on 1)

The method of claim 1, wherein the subject experiences migraines without aura.

### Claim 13 (depends on 1)

The method of claim 1, wherein the monoclonal antibody is administered at a dose of about 100 mg to about 500 mg.

### Claim 14 (depends on 13)

The method of claim 13, wherein the monoclonal antibody is administered at a dose of about 250 mg.

### Claim 15 (depends on 14)

The method of claim 14, wherein the dose of about 250 mg is administered as two separate injections of about 125 mg each.

### Claim 16 (depends on 13)

The method of claim 13, wherein the monoclonal antibody is administered at a dose of about 125 mg.

### Claim 17 (depends on 13)

The method of claim 13, wherein the monoclonal antibody is administered at a dose of about 250 mg followed by subsequent doses of about 125 mg at one month intervals.

### Claim 18 (depends on 17)

The method of claim 17, wherein the dose of about 250 mg is administered as two separate injections of about 125 mg each.

### Claim 19 (depends on 13)

The method of claim 13, wherein the monoclonal antibody is administered once per month.

### Claim 20 (depends on 1)

The method of claim 1, wherein the monoclonal antibody is administered as a liquid formulation comprising the monoclonal antibody at a concentration ranging from about 10 mg/mL to about 250 mg/mL.

### Claim 21 (depends on 1)

The method of claim 1, wherein the monoclonal antibody is administered as a liquid formulation comprising the monoclonal antibody at a concentration of about 120 mg/mL.

### Claim 22 (depends on 21)

The method of claim 21, wherein the liquid formulation is administered at a volume of about 0.5 mL to about 2.5 mL.

### Claim 23 (depends on 21)

The method of claim 21, wherein the liquid formulation is administered at a volume of about 1 mL.

### Claim 24 (depends on 21)

The method of claim 21, wherein the liquid formulation is administered at a volume of about 2 mL.

### Claim 25 (depends on 1)

The method of claim 1, wherein the administering comprises administering the antibody to the subject from a pre-filled syringe, pre-filled syringe with a needle safety device, injection pen, or auto-injector comprising a dose of the monoclonal antibody.

### Claim 26 (depends on 1)

The method of claim 1, wherein monthly headache days experienced by the subject after said administering is reduced by three or more days from a pre-administration level in the subject.

### Claim 27 (depends on 1)

The method of claim 1, comprising administering to the subject a second agent simultaneously or sequentially with the monoclonal antibody, wherein the second agent is an acute headache medication.

### Claim 28 (depends on 27)

The method of claim 27, wherein monthly use of the second agent by the subject is decreased by at least 15% after administering the monoclonal antibody.

### Claim 29 (depends on 1)

The method of claim 1, wherein the monoclonal antibody is administered subcutaneously.

### Claim 30 (depends on 1)

The method of claim 1, wherein the monoclonal antibody comprises the amino acid sequence of the heavy chain set forth in SEQ ID NO: 99, and the amino acid sequence of the light chain set forth in SEQ ID NO: 98.