Methods of lowering serum cholesterol

• US 10,293,043 B2
• Filed: 05/06/2015
• Issued: 05/21/2019
• Est. Priority Date: 06/02/2014
• Status: Active Grant

• Current Assignee: Armo BioSciences Inc. (Eli Lilly and Company)
• Original Assignee: Armo BioSciences Inc. (Eli Lilly and Company)
• Inventors: Mumm, John Brian, Chan, Ivan Ho
• Primary Examiner(s): Stoica, Elly-Gerald
• Application Number:
  US15/313,465
• Publication Number:
  US 20170296653A1
• Time in Patent Office: 1,476 Days
• Field of Search: None
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1796 for hormones for neuromediators A61K38/1787
• CPC Class Codes: A61K 38/2066 IL-10
• CPC Class Codes: A61K 39/385 Haptens or antigens, bound to carriers
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/4705 stimulating, promoting or activating activity
• CPC Class Codes: C07K 14/4718 Cytokine-induced proteins
• CPC Class Codes: C07K 14/715 for cytokines; for lymphokines; for interferons
• CPC Class Codes: C07K 17/02 Peptides being immobilised on, or in, an organic carrier
• CPC Class Codes: C12Q 1/60 involving cholesterol
• CPC Class Codes: G01N 33/5055 involving macrophages
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743

Abstract

Methods of treating subjects having diseases, disorders, or conditions, including disorders associated with cholesterol homeostasis, responsive to agents modulating Kupffer cell function, including methods of administration and dosing regimens associated therewith, are provided. Methods of treating subjects having liver diseases, disorders, or conditions, including non-alcoholic steatohepatitis and non-alcoholic fatty liver disease, with an IL-10 agent are also provided.

Claims

1. A method of treating non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD) in a subject, the method comprising:

administering parenterally to a subject having NASH or NAFLD a therapeutically effective amount of a composition comprising a PEGylated interleukin-10 (PEG-IL-10) agent, wherein the amount is sufficient to maintain an IL-10 serum trough concentration from 1.0 pg/mL to 10.0 ng/mL, over a period of time of at least 24 hours.

2. The method of claim 1, wherein the PEG-IL-10 agent comprises mature human IL-10.

3. The method of claim 1, wherein the PEG-IL-10 agent comprises a variant of mature human IL-10, and wherein the variant exhibits activity comparable to the activity of mature human IL-10.

4. The method of claim 1, wherein said administering is effective to decrease cholesterol in the subject.

5. The method of claim 1, wherein said administering is effective to decrease triglycerides in the subject.

6. The method of claim 1, wherein said administering is effective to decrease peri-portal collagen deposition in the subject.

7. The method of claim 1, wherein said administering is effective to increase hepatocyte proliferation in the subject.

8. The method of claim 1, wherein said administering is subcutaneous.

9. The method of claim 1, wherein the method comprises administering at least one additional prophylactic or therapeutic agent.

10. The method of claim 1, wherein the PEG-IL-10 agent comprises at least one PEG molecule covalently attached to at least one amino acid residue of at least one subunit of IL-10.

11. The method of claim 1, wherein the PEG-IL-10 agent comprises a mixture of mono-pegylated and di-pegylated IL-10.

12. The method of claim 1, wherein the PEG component of the PEG-IL-10 agent has a molecular mass from about 5 kDa to about 20 kDa.

13. The method of claim 1, wherein the PEG component of the PEG-IL-10 agent has a molecular mass greater than about 20 kDa.

14. The method of claim 1, wherein the PEG component of the PEG-IL-10 agent has a molecular mass of at least about 30 kD.

15. The method of claim 1, wherein the subject is a human.

16. A method of treating hypercholesterolemia or a hypercholesterolemia-associated disease, disorder or condition in a subject having non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD), the method comprising:

administering parenterally to the subject a composition comprising PEGylated interleukin-10 (PEG-IL-10) agent and a composition comprising ezetimibe,

wherein said administering is effective to reduce cholesterol in the subject and wherein the amount is sufficient to maintain an IL-10 serum trough concentration from 1.0 pg/mL to 10.0 ng/mL, over a period of time of at least 24 hours.

17. The method of claim 16, wherein the composition comprising PEG-IL-10 and the composition comprising a ezetimibe are administered sequentially.

18. The method of claim 16, wherein the PEG-IL-10 agent comprises mature human IL-10.

19. The method of claim 16, wherein the PEG-IL-10 agent comprises a variant of mature human IL-10, and wherein the variant exhibits activity comparable to the activity of mature human IL-10.

20. The method of claim 16, wherein said administering of the composition comprising the PEG-IL-10 agent is subcutaneous.

21. The method of claim 16, wherein the PEG-IL-10 agent comprises at least one PEG molecule covalently attached to at least one amino acid residue of at least one subunit of IL-10.

22. The method of claim 16, wherein the PEG-IL-10 agent comprises a mixture of mono-pegylated and di-pegylated IL-10.

23. The method of claim 16, wherein the PEG component of the PEG-IL-10 agent has a molecular mass from about 5 kDa to about 20 kDa.

24. The method of claim 16, wherein the PEG component of the PEG-IL-10 agent has a molecular mass greater than about 20 kDa.

25. The method of claim 16, wherein the PEG component of the PEG-IL-10 agent has a molecular mass of at least about 30 kD.

26. The method of claim 16, wherein the subject is a human.