Claims for Patent: 10,251,957

Summary for Patent: 10,251,957

Title:	Composition for treating diabetes comprising long-acting insulin conjugate and long-acting insulinotropic peptide conjugate
Abstract:	The present invention relates to a composition for the prevention or treatment of diabetes comprising a long-acting insulin conjugate and a long-acting insulinotropic peptide conjugate, and a therapeutic method for the treatment of diabetes, and more particularly, concurrent administration of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate inhibits weight gain caused by insulin treatment, and vomiting and nausea caused by insulinotropic peptide treatment, and reduces the required dose of insulin, thereby remarkably improving drug compliance. Moreover, each of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate of the present invention is prepared by linking insulin or insulinotropic peptide with an immunoglobulin Fc region via a non-peptidyl linker, thereby showing improved in-vivo duration of efficacy and stability.
Inventor(s):	Woo; Young Eun (Daejeon, KR), Jang; Myung Hyun (Seoul, KR), Park; Young Jin (Suwon-si, KR), Park; Young Kyung (Hwaseong-si, KR), Lim; Chang Ki (Hwaseong-si, KR), Kwon; Se Chang (Seoul, KR)
Assignee:	HANMI SCIENCE CO., LTD. (Hwaseong-si, KR)
Application Number:	14/123,355
Patent Claims:	1. A pharmaceutical composition comprising a long-acting insulin conjugate and a long-acting insulinotropic peptide conjugate, wherein each of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate is prepared by linking an insulin or an insulinotropic peptide with an immunoglobulin Fc region via a non-peptidyl linker selected from the group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, dextran, polyvinyl ethyl ether, a biodegradable polymer, a lipid polymer, chitin, hyaluronic acid, and a combination thereof; wherein the insulinotropic peptide is selected from the group consisting of glucagon like peptide-1, exendin-3, exendin-4, an exendin-4 derivative prepared by deleting N-terminal amine group, an exendin-4 derivative prepared by substituting N-terminal amine group with hydroxyl group, an exendin-4 derivative prepared by modifying N-terminal amine group with dimethyl group, and an exendin-4 derivative prepared by deleting .alpha.-carbon of the first amino acid of exendin-4; wherein said insulin of the long-acting insulin conjugate is selected from the group consisting of the following (i)-(v): (i) a native insulin comprising a first peptide of SEQ ID NO: 1 and a second peptide of SEQ ID NO: 2; (ii) a basal insulin; (iii) an insulin variant which comprises a first peptide of SEQ ID NO: 1 and a second peptide of SEQ ID NO: 2, in which one or more of the amino acid residues of SEQ ID NO: 1 and/or SEQ ID NO: 2 is different from the amino acid sequence of the native insulin (i) by way of substitution, deletion, modification, and/or addition, wherein the insulin variant retains a function of controlling blood glucose level in a body of subject to which said insulin variant is administered; (iv) an insulin derivative peptide which has at least 80% amino acid sequence identity to the native insulin (i), wherein a chemical group of one or more of the amino acid residues of SEQ ID NO: 1 and/or SEQ ID NO: 2 is chemically modified, and wherein the insulin derivative peptide retains a function of controlling blood glucose level in a body of subject to which said insulin derivative peptide is administered; or (v) a fragment of the native insulin (i), said fragment having one or more amino acids deleted at the N-terminus or the C-terminus of the native insulin (i) or having a non-naturally occurring amino acid, wherein the fragment retains a function of controlling blood glucose level in a body of subject to which said fragment is administered; and wherein the non-peptidyl linker has a molecular weight in a range from 1 kDa to 100 kDa. 2. The composition according to claim 1, wherein the insulin is modified with a non-peptidyl polymer. 3. The composition according to claim 2, wherein the non-peptidyl polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, a biodegradable polymer, a lipid polymer, chitin, hyaluronic acid, and a combination thereof. 4. The composition according to claim 1, wherein the immunoglobulin Fc region is aglycosylated. 5. The composition according to claim 1, wherein the immunoglobulin Fc region is composed of one to four domains selected from the group consisting of CH1, CH2, CH3 and CH4 domains. 6. The composition according to claim 1, wherein the immunoglobulin Fc region further includes a hinge region. 7. The composition according to claim 1, wherein the immunoglobulin Fc region is an Fc region derived from IgG, IgA, IgD, IgE, or IgM. 8. The composition according to claim 1, wherein the immunoglobulin Fc region is composed of domains having different origins, wherein the origin is selected from the group consisting of IgG, IgA, IgD, IgE, and IgM. 9. The composition according to claim 1, wherein the immunoglobulin Fc region is a dimer or a multimer composed of single-chain immunoglobulins of the same origin. 10. The composition according to claim 1, further comprising a pharmaceutically acceptable carrier. 11. The composition according to claim 1, wherein the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate are administered simultaneously, sequentially, or reversely. 12. The composition according to claim 1, wherein the basal insulin is insulin detemir, insulin glargine, or insulin deglude. 13. A method for treating diabetes, comprising the step of administering the composition of claim 1 to a subject having diabetes or at risk of having diabetes. 14. The method according to claim 13, wherein the administration step is performed by concurrent administration of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate. 15. The method according to claim 14, wherein the concurrent administration is performed by administrating the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate simultaneously, sequentially, or reversely.

Details for Patent 10,251,957

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Sanofi-aventis U.s. Llc	LANTUS	insulin glargine	Injection	021081	04/20/2000		2031-06-02
Sanofi-aventis U.s. Llc	LANTUS	insulin glargine	Injection	021081	04/25/2007		2031-06-02
Novo Nordisk Inc.	LEVEMIR	insulin detemir	Injection	021536	06/16/2005		2031-06-02
Novo Nordisk Inc.	LEVEMIR	insulin detemir	Injection	021536	10/31/2013		2031-06-02
Eli Lilly And Company	BASAGLAR	insulin glargine	Injection	205692	12/16/2015		2031-06-02
Eli Lilly And Company	BASAGLAR	insulin glargine	Injection	205692	11/15/2019		2031-06-02
Mylan Pharmaceuticals Inc.	SEMGLEE	insulin glargine	Injection	210605	06/11/2020		2031-06-02