Methods of using il-1 antagonists to treat alzheimer's disease

Patent metadata

Field	Value
Publication number	US-2016120941-A1
Application number	US-201414893932-A
Country	US
Kind code	A1
Filing date	May 30, 2014
Priority date	May 31, 2013
Publication date	May 5, 2016
Grant date	—

Abstract

The invention provides methods of treating, inhibiting, or ameliorating a disease characterized by aberrant deposition of beta amyloid in a subject in need thereof, comprising administering to a subject a therapeutic amount of an interleukin 1 (IL-1) antagonist, wherein the disease, or condition is treated, inhibited, or ameliorated, or wherein the onset or progression of the disease, or at least one symptom of the disease, is delayed. The IL-1 antagonist is an IL-1 trap, preferably comprising a sequence selected from the group consisting of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, and 28 and capable of binding and inhibiting IL-1. The therapeutic methods are useful for treating a human adult suffering from Alzheimer's Disease or cerebral amyloid angiopathy.

First claim

1 . A method for treating, or delaying the onset, or the progression of a disease characterized in part by beta amyloid expression, activity, or deposition in a subject in need thereof, or for ameliorating at least one symptom associated with the disease, the method comprising administering to the subject a therapeutically effective amount of an IL-1 antagonist as a first therapeutic agent, wherein the IL-1 antagonist is selected from the group consisting of an antibody specific for IL-1 alpha or IL-1 beta, or an antigen-binding fragment thereof, a soluble IL-1 receptor, and an IL-1 trap, wherein the IL-1 trap is a fusion protein comprising an IL-1 binding portion of the extracellular domain of IL-1RAcP, an IL-1 binding portion of the extracellular domain of IL-1R1, and a multimerizing component.

2 . A method for treating, or delaying the onset, or the progression of a disease characterized in part by beta amyloid expression, activity, or deposition in a subject in need thereof, or for ameliorating at least one symptom associated with the disease, the method comprising administering to the subject a therapeutically effective amount of an IL-1 antagonist as a first therapeutic agent, wherein the IL-1 antagonist is an IL-1 trap, wherein the IL-1 trap is a fusion protein comprising an IL-1 binding portion of the extracellular domain of IL-1RAcP, an IL-1 binding portion of the extracellular domain of IL-1R1, and a multimerizing component.

3 . The method of either claim 1 or 2 , wherein the subject is a human.

4 . The method of claim 1 , wherein the disease is selected from the group consisting of Alzheimer's disease (AD), Down's syndrome, multi-infarct dementia, cognitive impairment and cerebral amyloid angiopathy (CAA).

5 . The method of claim 4 , wherein the Alzheimer's disease is clinical, pre-clinical or prodromal Alzheimer's disease.

6 . The method of claim 4 , wherein the cerebral amyloid angiopathy is clinical or pre-clinical cerebral amyloid angiopathy.

7 . The method of claim 1 , wherein the IL-1 antagonist is an IL-1 trap comprising a fusion protein having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, and 28, or a substantially identical sequence having at least 95% identity to the sequence selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, and 28 and capable of binding and inhibiting IL-1.

8 . The method of claim 7 , wherein the IL-1 trap is a fusion protein comprising the amino acid sequence of SEQ ID NO:10 or SEQ ID NO: 28.

9 . The method of claim 1 , wherein administration is subcutaneous, intramuscular, intranasal, intraarterial, intravenous, intrathecal, intraventricular, intracerebral, topical, transdermal administration or oral.

10 . The method of claim 1 , wherein a therapeutically effective amount is between about 1 mg/kg to about 750 mg/kg.

11 . The method of claim 10 , wherein a therapeutically effective amount is between about 10 mg/kg to about 500 mg/kg.

12 . The method of claim 11 , wherein a therapeutically effective amount is between about 50 mg/kg to about 150 mg/kg.

13 . The method of claim 1 , further comprising administering to a subject in need thereof a therapeutically effective amount of one or more other therapeutic agents, wherein the disease or at least one symptom associated with the disease is lessened in severity or duration, or wherein the onset or progression of the disease or at least one symptom associated with the disease is delayed.

14 . The method of claim 1 , wherein the at least one symptom associated with the disease is selected from the group consisting of memory loss, depression, anxiety, inattention, dementia, irritability, confusion, mood swings, and aggressive and/or apathetic behavior.

15 . The method of claim 13 , wherein administration of the other therapeutic agent is subcutaneous, intramuscular, intranasal, intraarterial, intravenous, intrathecal, intraventricular, intracerebral, topical, transdermal administration or oral.

16 . The method of claim 13 , wherein the other therapeutic agent is an acetylcholinesterase inhibitor or a glutamate pathway modifier.

17 . The method of claim 16 , wherein the acetylcholinesterase inhibitor is selected from the group consisting of ARICEPT® (donepezil HCl), EXELON® (rivastigmine tartrate), and RAZADYNE® (galantamine HBr).

18 . The method of claim 16 , wherein the glutamate pathway modifier is Namenda (memantine).

19 . The method of claim 13 , wherein the other therapeutic agent is selected from the group consisting of a different IL-1 antagonist, an anti-inflammatory agent, an antibody specific for tau, an antibody specific for beta amyloid and a microtubule stabilizer.

20 . The method of claim 19 , wherein the different IL-1 antagonist is selected from the group consisting of an IL-1 alpha or IL-1 beta antibody, a soluble IL-1 receptor, a different IL-1 trap, anakinra and canakinumab.

21 . The method of claim 19 , wherein the anti-inflammatory agent is aspirin or a different NSAID.

22 . The method of claim 19 , wherein the antibody specific for beta amyloid is selected from the group consisting of solanezumab, gantenerumab, and bapineuzumab.

23 . The method of claim 19 , wherein the microtubule stabilizer is epothilone.

24 . A method of improving cognitive impairment in a mammal having beta amyloid deposits in brain tissue, the method comprising administering to the subject a therapeutically effective amount of an IL-1 antagonist as a first therapeutic agent, wherein the IL-1 antagonist is selected from the group consisting of an antibody specific for IL-1 alpha or IL-1 beta, or an antigen binding fragment thereof, a soluble IL-1 receptor, and an IL-1 fusion protein (IL-1 trap) comprising an IL-1 binding portion of the extracellular domain of IL-1RAcP, an IL-1 binding portion of the extracellular domain of IL-1R1, and a multimerizing component, wherein the mammal demonstrates an improvement in cognitive function(s) without necessarily exhibiting a concurrent change in the beta amyloid plaque burden in the brain.

25 . A method of improving cognitive impairment in a mammal having beta amyloid deposits in brain tissue, the method comprising administering to the subject a therapeutically effective amount of an IL-1 antagonist as a first therapeutic agent, wherein the IL-1 antagonist is an IL-1 fusion protein (IL-1 trap) comprising an IL-1 binding portion of the extracellular domain of IL-1RAcP, an IL-1 binding portion of the extracellular domain of IL-1R1, and a multimerizing component, wherein the mammal demonstrates an improvement in cognitive function(s) without necessarily exhibiting a concurrent change in the beta amyloid plaque burden in the brain.

26 . The method of claim 24 , wherein the IL-1 antagonist is an IL-1 trap comprising a fusion protein having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, and 28, or a substantially identical sequence having at least 95% identity to the sequence selected from the group consisting of SEQ ID NOs: 2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22, 24, 26, and 28 and capable of binding and inhibiting IL-1.

27 . The method of claim 25 , wherein the IL-1 trap is a fusion protein comprising the amino acid sequence of SEQ ID NO:10 or SEQ ID NO: 28.

Assignees

• Regeneron Pharma

Inventors

• Croll Susan D
• Wiegand Stanley

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title