Merck Sharp + Dohme Corp.

Merck + Co., Inc.

Sirna Therapeutics, Inc.

Ra Pharmaceuticals, Inc.

William H. Rorer, Inc.

Thomas Joseph Tucker

William C Lumma, Jr

Steven L Colletti

Weimin Wang

David M Tellers

Anthony W Shaw

Elisabetta Bianchi

Rubina G Parmar

Yusheng Xiong

Joseph P Vacca

Hubert B Josien

Fa-Xiang Ding

Stephen F Brady

George D Hartman

Jian Liu

Alonso Ricardo

Harold B Wood

Matthew G Stanton

Rob Burke

Philip E Sanderson

Neville J Anthony

Roger M Freidinger

Ling Tong

Michael Man-Chu Lo

Christopher S Burgey

Liangqin Guo

Eric J Gilbert

Jeffrey M Bergman

Zhong Ma

Henry F Campbell

William L Studt

Ravi P Nargund

Ian M Bell

Anandan Palani

Theresa M Williams

Mark T Bilodeau

Craig Alan Coburn

Samuel L Graham

Christopher J Dinsmore

Vasant R Jadhav

Craig A Stump

Gerald E Stokker

S Jane deSolms

Francis Gosselin

John T Sisko

Chengwei Wu

Kathleen B Calati

Angela Dawn Kerekes

Danila Branca

Sookhee Nicole Ha

Yu Yuan

Raffaele Ingenito

Abbas M Walji

Anthony M Smith

Hyewon Youm

Lu Tian

Marina Busuek

Robert A Kowtoniuk

Jeffrey Aaronson

Aaron Momose

Rachel Anne Storr

Vadim Y Dudkin

Nicolas Cedric Boyer

Aurash Shahripour

Willy Costantini

Terry A Lyle

Alessia Santoprete

Boyoung Kim

Jeffrey G Aaronson

Mark W Embrey

Dong-Mei Feng

Ketki Ashok Dhamnaskar

Anilkumar G Nair

Robert M Tynebor

Immacolata Conte

Stefania Colarusso

Kenneth J Stauffer

Joseph R Stringer

Derek M LaPlaca

Roberto Costante

Daniel Vincent Paone

Antonello Pessi

Peter J Manley

Dai-Shi Su

Bruce F Molino

Robert P Gomez

Qiaolin Deng

Jules A Shafer

Jacob M Hoffman

Diem N Nguyen

Federica Orvieto

Sobhana Babu Boga

Paul E Carrington

William C Lumma

Stanley F Barnett

Daniel Zewge

Samson M Jolly

Leonard Rodman

Keith M Witherup

Disclosed herein is a modular composition comprising 1) an oligonucleotide; 2) one or more tetraGalNAc ligands of Formula (I), which may be the same or different; optionally, 3) one or more linkers, which may be the same or different; 4) one or more peptides independently selected from Table 3, which may be the same or different; and optionally, 5) one or more targeting ligands, solubilizing agents, pharmacokinetics enhancing agents, lipids, and/or masking agents.

Tetragalnac and peptide containing conjugates and methods for delivery of oligonucleotides

Disclosed are compounds of Formula I, or a salt thereof:

PCSK9 antagonist compounds

Disclosed are compounds of Formula A, or a pharmaceutically acceptable salt thereof: where A, X, R, and Rare as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula I or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions.

Provided herein are cyclic polypeptide compounds that can, e.g., bind specifically to human proprotein convertase subtilisin/kexin type 9 (PCSK9) and optionally also inhibit interaction between human PCSK9 and human low density lipoprotein receptor (LDLR), and pharmaceutical compositions comprising one or more of these compounds. Also provided are methods of reducing LDL cholesterol level in a subject in need thereof that include administering to the subject one or more of the cyclic polypeptide compounds or a pharmaceutical composition provided herein.

Cyclic polypeptides for PCSK9 inhibition

Disclosed are compounds of Formula I, or a salt thereof: where A, B, D, X, R, Rand Rare as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula I or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions.

Disclosed are compounds of Formula I, or a salt thereof cyclic polypeptide of Formula I: Formula I where A, B, E, R, and Rare as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula I or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions 

PCSK9 antagonists bicyclo-compounds

Disclosed herein is a method for inhibiting expression of a gene of a subject comprising administering (1) a composition comprising R-(L)-(G); wherein R is an oligonucleotide selected from the group consisting of DNA, RNA, siRNA, and microRNA; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; each of a and b is independently 0, 1, 2, 3 or 4; and (2) a composition comprising (P)-(L)-(G); wherein P is a peptide and each occurrence of P is independently selected from Table 2; L is a linker and each occurrence of L is independently selected from Table 3; G is a targeting ligand and each occurrence of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. Compositions in (1) and (2) can be co-administered or sequentially administered.

Dual molecular delivery of oligonucleotides and peptide containing conjugates

Described are peptide analogs of glucagon, which have been modified to be resistant to cleavage and inactivation by dipeptidyl peptidase IV (DPP-IV) and to increase in vivo half-life of the peptide analog while enabling the peptide analog to have relatively balanced agonist activity at the glucagon-like peptide 1 (GLP-1) receptor and the glucagon (GCG) receptor, and the use of such GLP-1 receptor/GCG receptor co-agonists for treatment of metabolic disorders such as diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and obesity.

Co-agonists of the glucagon and GLP-1 receptors

Disclosed herein is a peptide containing conjugate comprising (P)-(L)-(G), wherein P is a peptide and each occurance of P is independently selected from Table 2; L is an optional linker and each occurance of L, if present, is independently selected from Table 3; G is a targeting ligand and each occurance of G is independently selected from Table 4; d is 0, 1, 2, 3, 4, 5 or 6; and each of c and e is independently 1, 2, 3, 4, 5 or 6. The conjugate can be administered to a subject either alone or in combination with a composition comprising R-(L)-(G), wherein R is an oligonucleotide as defined herein, to inhibit expression of a gene of the subject.

Peptide containing conjugates for dual molecular delivery of oligonucleotides

Growing community of inventors

North Wales, PA, United States of America

Thomas Joseph Tucker