Indiana University

Eli Lilly and Company

Ambrx, Inc.

Novo Nordisk A/s

Merck Sharp + Dohme Corp.

Marcadia Biotech, Inc.

Other

Hoffmann-La Roche Inc.

Msd Italia S.r.l.

Legacy Emanuel Hospital & Health Center

Istituto Di Recerche Di Biologia Molecolare P. Angeletti S.r.l.

Richard Dennis DiMarchi

David L Smiley

William F Heath, Jr

James E Shields

James A Hoffmann

David B Flora

Ho Sung Cho

Brigitte E Schoner

Margret B Basinski

Bin Yang

Troy Edward Wilson

Jonathan Wesley Day

David C Litzinger

Thomas O Daniel

Anna-Maria A Hays

Bee-Cheng Sim

Joseph Chabenne

Maria DiMarchi

Thea Norman

Feng Tian

Anna-Maria A Hays Putnam

Stephanie Chu

Joseph Sheffer

Denise Krawitz

Brian Finan

Brian P Ward

Tao Ma

Binbin Kou

James Harold Patterson

Yan Zhao

Todd Parody

Harlan B Long

Pengyun Li

Suad Efendic

John Philip Mayer

Patrick J Knerr

Fa Liu

Jonathan Meyers

Jesper F Lau

Konrad H Bleicher

Eric Argirios Kitas

Elisabetta Bianchi

Antonello Pessi

Henning Thoegersen

Bruce H Frank

Jie Han

Shujiang Cheng

Wolfgang Glaesner

Steffen Reedtz-Runge

Rohn Lee Millican, Jr

Lianshan Zhang

Michael Rosario DeFelippis

Ronald E Chance

Arnab De

Nicholas Cox

Kingman Ng

Wouter Frederik Johan Hogendorf

Gerald S Brooke

Yulia Azriel

Zachary Kaur

W Kenneth Ward

Russell Dean Stucky

Lawrence E Stramm

Mark Louis Heiman

Eike Hoffmann

Paul D Gesellchen

Alessia Santoprete

Joseph M Metzger

Paul E Carrington

Rama M Belagaje

Louis Vignati

Paolo Ingallinella

Donald J Marsh

Michael A Meehl

Ronald Norbert Hermeling

Michael Trautmann

Andrew Mark Vick

George J Eiermann

Anish A Konkar

Carl J Shaar

Ranabir Sinha Roy

Rebecca Anne Owens

James A Hoffman

Aidas V Kriauciunas

Victor J Chen

Sara Belli

Archita S Agrawal

Piotr Mroz

Alexei Kharitonenkov

Alessandro Pocai

Elena Capito

Li Fan

Carol Lynn Broderick

Fa Zhang

Chenguang Ouyang

Julia Azriel

Zach Kaur

Rohn Lee Junior Millican

Peptide co-agonists of the human GLP-1 and GIP receptors suitable for oral delivery, including long-acting derivatives, and their medical use in treatment and/or prevention of obesity, diabetes, and/or liver diseases are described.

Co-agonists at GLP-1 and GIP receptors suitable for oral delivery

The present invention relates to novel peptides that are derivatives of glucose-dependent insulinotropic polypeptide (GIP) analogues having improved physical stability in solution and a protracted profile of action. More particular the invention relates to such peptides that are agonists at the GIP receptor and to their use in weight management or for treatment of diseases such as obesity, diabetes or non-alcoholic steatohepatitis (NASH).

GIP derivatives and uses thereof

Disclosed herein are modified C-terminal fragments of FGF21 optimized for binding to Klotho &#x3b2; or antagonizing FGF21 activity. FGF21 peptides modified to comprise modifications to the C-terminal amino acid sequence are disclosed that have enhanced activity at the FGF21 receptor. Additionally, conjugates formed between the optimized FGF21 peptide fragments and insulin like peptides or nuclear hormone receptor ligands are provided.

FGF21 C-terminal peptide optimization

Provided herein are peptides and variant peptides that exhibit enhanced activity at the GLP-1 receptor, as compared to native glucagon.

Glucagon/GLP-1 receptor co-agonists

Disclosed herein are insulin agonist peptides conjugated to a glucagon analog wherein the insulin/glucagon conjugate is targeted to liver tissues upon administration to a patient.

Insulin-incretin conjugates

Modified glucagon peptides are disclosed having improved solubility and/or stability while retaining glucagon agonist activity. The glucagon peptides have been modified by the substitution of pyridyl-alanine for a native amino acid at one or more of positions 6, 10 or 13 and/or substitution with an amino acid in the D-conformation at position 20 or 21 compared to native glucagon.

Aqueously soluble and chemically stable glucagon peptides

The present invention relates to novel peptides that are derivatives of glucose-dependent insulinotropic polypeptide (GIP) analogues having improved physical stability in solution and a protracted profile of action. More particularly the invention relates to such peptides that are agonists at the GIP receptor and to their use in weight management or for treatment of diseases such as obesity, diabetes or non-alcoholic steatohepatitis (NASH). The peptides comprise a lysine residue at a position corresponding to position 24 of hGIP(1-31), and comprise a negatively charged modifying group attached to the epsilon amino group of the lysine residue.

Prodrug formulations of insulin and insulin analogs are provided wherein the insulin peptide has been modified by an amide bond linkage of a dipeptide prodrug element. The prodrugs disclosed herein have extended half-lives and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Lipidated amide-based insulin prodrugs

Disclosed herein are insulin agonist peptides conjugated to incretins wherein the incretin-insulin conjugate has agonist activity at the insulin receptor and the corresponding incretin receptor, and stimulates weight loss in an individual administered the compound.

Incretin-insulin conjugates

Single chain insulin analogs are provided having high potency and specificity for the insulin receptor. As disclosed herein optimally sized linking moieties can be used to link human insulin A and B chains, or analogs or derivatives thereof, wherein the carboxy terminus of the B25 amino acid of the B chain is linked to the amino terminus of the A1 amino acid of the A chain via the intervening linking moiety. In on embodiment the linking moiety comprises a polyethylene glycol of 6-16 monomer units and in an alternative embodiment the linking moiety comprises a non-native amino acid sequence derived form the IGF-1 C-peptide and comprising at least 8 amino acids and no more than 12 amino acid in length. Also disclosed are prodrug and conjugate derivatives of the single chain insulin analogs.

Single chain insulin agonists exhibiting high activity at the insulin receptor

Herein is reported a fusion polypeptide comprising i) one, two, three or four incretin receptor ligand polypeptides, and ii) one human immunoglobulin Fc-region, wherein at least one of the incretin receptor ligand polypeptides comprises an amino acid that is covalently conjugated to a lipid, and wherein each of the one, two, three or four incretin receptor ligand polypeptides is covalently conjugated by a peptide bond to a terminus of the human immunoglobulin Fc-region, whereby to each terminus of the human immunoglobulin Fc-region only a single incretin receptor ligand polypeptide is conjugated.

Lipidated incretin receptor ligand human immunoglobulin Fc-region fusion polypeptides

Provided herein are glucagon analogs which exhibit potent activity at the GIP receptor, and, as such are contemplated for use in treating diabetes and obesity. In exemplary embodiments, the glucagon analog of the present disclosures exhibit an EC50 at the GIP receptor which is within the nanomolar or picomolar range.

Analogs of glucagon exhibiting GIP receptor activity

Glucagon peptides with increased GIP activity are provided, optionally with GLP-1 and/or glucagon activity. In some embodiments, C-terminally extended glucagon peptides comprising an amino acid sequence substantially similar to native glucagon are provided herein.

GIP receptor-active glucagon compounds

Provided herein are glucagon superfamily peptides conjugated with NHR ligands that are capable of acting at a nuclear hormone receptor. Also provided herein are pharmaceutical compositions and kits of the conjugates of the invention. Further provided herein are methods of treating a disease, e.g., a metabolic disorder, such as diabetes and obesity, comprising administering the conjugates of the invention.

Glucagon superfamily peptides exhibiting nuclear hormone receptor activity

Growing community of inventors

Carmel, IN, United States of America

Richard Dennis DiMarchi