Novo Nordisk A/s

Novo Nordick A/s

Janos Tibor Kodra

Jesper F Lau

Peter Madsen

Patrick William Garibay

Paw Bloch

Thomas Hoeg-Jensen

Jacob Kofoed

Thomas Boerglum Kjeldsen

Lone Jeppesen

Robert Carl Andrews

Dharma Rao Polisetti

Mustafa Guzel

Anthony Murray

Michael Ankersen

Govindan Subramanian

Carsten Behrens

Per Vedso

Tina Moeller Tagmose

Adnan M M Mjalli

Palle Jakobsen

Ib Jonassen

Anker S Jorgensen

Kalpathy Chidambareswaran Santhosh

Lars Linderoth

Inge Thoger Christensen

Christian Klarner Sams

Thomas Kruse

Henning Thoegersen

Frantisek Hubalek

Jane Spetzler

Birgit Wieczorek

Larry Kenneth Truesdale

Maria Carmen Valcarce Lopez

Niels Blume

Per Sauerberg

Min Teng

Yuanyuan Zhang

Preben H Olesen

Svend Havelund

Ingrid Pettersson

Kjeld Madsen

Michael Bruno Plewe

Lauge Schaeffer

Flemming Seier Nielsen

Steffen Reedtz-Runge

Thomas Børglum Kjeldsen

Dilip Ramakant Bhumralkar

Tina Møller Tagmose

Anthony Lai Ling

Shenghua Shi

Liselotte Bjerre Knudsen

Jianhe Chen

Michael David Johnson

Henning Thøgersen

Christine Thomas

Ulla Grove Sidelmann

Martin Werner Borchsenius Muenzel

Kirsten Raun

Ingrid Petterson

Tine Glendorf

Jacob Sten Petersen

Dan Kiel

Adnan Mm Mjalli

Lennart Lykke

Johannes Cornelis De Jong

Alice Ravn Madsen

Behrend Frederik Lundt

Dorte Xenia Gram

Rikke Bjerring Andersen

Anette Sams Nielsen

Charlotte Harkjaer Fynbo

Poul Enrico Nielsen

Inge Thøger Christensen

Anker Steen Jøgensen

Lone Pridal

Leonardo De Maria

Zhaosheng Lin

Zhe Wan

Santhosh Chidambareswaran Kalpathy

Carsten Engaard Stidsen

Johannes Fels

Cecilia Nilsson

Salka Elboel Rasmussen

Charlotte Harkjær Fynbo

Thomas Berglum Kjeldsen

This invention is in the field of protein conjugates. More specifically the invention relates to oligomer extended insulins with covalently attached Fc monomer polypeptides, for use in the treatment of a metabolic disorder or condition, and to methods of producing such oligomer extended insulin-Fc conjugates. The invention also relates to novel Fc fragments, to intermediate products, and to the use of such intermediate products in processes for the synthesis of the oligomer extended insulin-Fc conjugates of the invention. Finally the invention provides pharmaceutical compositions comprising the oligomer extended insulin-Fc conjugates of the invention, and relates to the use of such compositions for the treatment or prevention of medical conditions relating to metabolic disorders or conditions.

Oligomer extended insulin-Fc conjugates

The invention relates to GLP-1 analogues and derivatives having a Trp at a position corresponding to position 8 of GLP-1(7-37), and their pharmaceutical use e.g. in the treatment of type 2 diabetes. These Trp8 compounds are very stable against degradation by DPP-IV, while maintaining the capability to bind to and activate the GLP-1 receptor. The derivatives have one or two substituents (P-L) attached to a Lys residue of the GLP-1 analogue via an optional Branching group (B), wherein P is a Protracting moiety such as a fatty diacid, and L is a linker consisting of one or more linker elements such as, for example, 8-amino-3,6-dioxaoctanoic acid. Examples of compounds of the invention include the 8W variants of liraglutide and dulaglutide. The invention also relates to a method for the fully recombinant preparation of 8W GLP-1 analogues and derivatives which is more simple and thereby cheaper as compared to the preparation of known GLP-1 analogues that have been DPP-IV stabilised by inclusion of one or more non-coded amino acids.

GLP-1 derivatives and uses thereof

The invention relates to compounds derived from the EGF(A) domain of LDL-R, in particular compounds comprising a peptide analogue of the wild-type EGF(A) (LDL-R(293-332)) sequence and at least one substituent comprising at least one fatty acid group. The invention also relates to a pharmaceutical composition thereof and use a medicament. The novel EGF(A) compounds of the invention are useful as treatment e.g. in the field of cholesterol lowering, dyslipidaemia and cardiovascular disease.

EGF(A) analogues with fatty acid substituents

The invention relates to a derivative of a GLP-1 peptide, which peptide comprises a first Lys residue at a position corresponding to position 36 of GLP-1(7-37) (SEQ ID NO: 1), a second Lys residue at a position corresponding to position 37 of GLP-1(7-37) (SEQ ID NO: 1), and a maximum of seven amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 1); which derivative comprises two protractors attached to said first and second Lys residue, respectively, each via a linker; wherein the protractor is selected from:HOOC&#x2014;CH&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;*, and&#x2003;&#x2003;Chem. 1:HOOC&#x2014;(CH)&#x2014;CO&#x2014;*,&#x2003;&#x2003;Chem. 2:wherein y is an integer in the range of 8-11, and x is 12; and the linker comprises at least one of:*&#x2014;NH&#x2014;CH(COOH)&#x2014;(CH)&#x2014;CO&#x2014;*,&#x2003;&#x2003;Chem. 3:*&#x2014;NH&#x2014;CH((CH)&#x2014;COOH)&#x2014;CO&#x2014;*, and/or&#x2003;&#x2003;Chem. 4:*&#x2014;NH&#x2014;(CH)&#x2014;[O&#x2014;(CH)]&#x2014;O&#x2014;[CH]&#x2014;CO&#x2014;*,&#x2003;&#x2003;Chem. 5:wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical uses thereof, such as for the treatment of diabetes and obesity, as well as to the GLP-1 peptides forming part of these derivatives which have Lys residues at positions 36 and 37 and no other Lys residues, and the GLP-1(9-37) fragments thereof. The invention furthermore relates to an intermediate product comprising 3-carboxyphenoxy-nonanoic acid with a protection group at the carboxy group of the nonanoic acid, optionally via a linker. The derivatives have a very good potency and a long half-life which makes them potentially useful for, e.g., oral administration.

Double-acylated GLP-1 compounds

Novel acylated insulin analogues exhibiting resistance towards proteases can, effectively, be administered pulmonary or orally. The insulin analogues contain B25H and A14E or A14H.

Protease stabilized acylated insulin analogues

The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1, Chem. 2, and Chem. 3:HOOC&#x2014;(CH)&#x2014;CO&#x2014;*&#x2003;&#x2003;Chem. 1:HOOC&#x2014;CH&#x2014;O&#x2014;(CH)&#x2014;CO&#x2014;*&#x2003;&#x2003;Chem. 2:R&#x2014;CH&#x2014;(CH)&#x2014;CO&#x2014;*,&#x2003;&#x2003;Chem. 3: The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are suitable for oral administration.

Double-acylated GLP-1 derivatives

Novel acylated insulin analoges exhibiting resistance towards proteases can, effectively, be administered pulmonary or orally. The insulin analoges contain B25H and A14E or A14H.

The invention relates to truncated GLP-1 analogs, in particular a GLP-1 analog which is a modified GLP-1(7-35) (SEQ ID No 1) having: i) a total of 2, 3, 4, 5 6, 7, 8, or 9 amino acid substitutions as compared to GLP-1(7-35), including a) a Glu residue at a position equivalent to position 22 of GLP-1(7-35), and b) an Arg residue at a position equivalent to position 26 of GLP-1(7-35); as well as derivatives thereof, and therapeutic uses and compositions. These analogs and derivatives are highly potent, have a good binding affinity to the GLP-1 receptor, also to the extracellular domain of the GLP-1 receptor, which is of potential relevance achieving long-acting, stable GLP-1 compounds with a potential for once weekly administration.

Truncated GLP-1 derivatives and their therapeutical use

The present invention relates to insulin derivatives having a side chain attached either to the &#x3b1;-amino group of the N-terminal amino acid residue of the B chain or to the &#x3b5;-amino group of a Lys residue present in the B chain of the parent insulin via an amide bond which side chain comprises at least one aromatic group; at least one free carboxylic acid group or a group which is negatively charged at neutral pH, a fatty acid moiety with 4 to 22 carbon atoms in the carbon chain; and possible linkers which link the individual components in the side chain together via amide bonds.

Insulin derivatives

This invention relates to aryl carbonyl derivatives which are activators of glucokinase which may be useful for the management, treatment, control, or adjunct treatment of diseases, where increasing glucokinase activity is beneficial.

Aryl carbonyl derivatives as therapeutic agents

The present invention relates to gastrin derivatives comprising gastrin or an analogue or fragment thereof and a derivatisation group and therapeutic use thereof.

Long-acting gastrin derivatives

Acylated insulins wherein an acyl moiety is attached to the parent insulin and wherein the acyl moiety comprises repeating units of alkylene glycol containing amino acids and wherein there is only one lysine residue (K & Lys) in the parent insulin, having satisfactory properties when administered pulmonary.

Insulins with an acyl moiety comprising repeating units of alkylene glycol containing amino acids

Acylated insulins wherein an acyl moiety is attached to the parent insulin and wherein said acyl moiety comprises repeating units of alkylene glycol containing amino acids and wherein there is only one lysine residue (K & Lys) in the parent insulin have satisfactory properties when administered pulmonary.

The present invention relates to novel human insulin derivatives which are soluble at physiological pH values and have a prolonged profile of action. The invention also relates to methods of providing such derivatives, to pharmaceutical compositions containing them, to methods of treating diabetes and hyperglycaemia using the insulin derivatives of the invention and to the use of such insulin derivatives in the treatment of diabetes and hyperglycaemia.

Insulin derivative

Acylated CGRP compounds with a linker have prolonged action and are valuable as medicaments.

Derivatives of CGRP

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Copenhagen, Denmark

Janos Tibor Kodra