Arrowhead Pharmaceuticals, Inc.

Arrowhead Madison, Inc.

Jeffrey Carlson

Andrei V Blokhin

David B Rozema

Jonathan D Benson

Darren H Wakefield

David L Lewis

Anthony Nicholas

Aaron Almeida

So Wong

Jon Asher Wolff

Peter Mohr

Philipp Hadwiger

Torsten Hoffmann

Eric Argirios Kitas

Tao Pei

Zhen Li

Weijun Cheng

Hans Martin Mueller

Matthew Fowler-Watters

Steven B Kanner

Lauren Almeida

Ingo Roehl

Kerstin Jahn-Hofmann

Guenther Ott

Justin Woods

Agnieszka Glebocka

Erik W Bush

Xiaokai Li

Erich Altenhofer

Rui Zhu

Christine Esau

James C Hamilton

Yichen Wang

Ingo Röhl

Dongxu Shu

Günther Ott

Ji Young Suk

Hamid Moradi

Bo Chen

Kerstin Jahn-Hoffmann

Angieszka Glebocka

The present disclosure relates to RNAi agents, for example, double stranded RNAi agents, able to inhibit HIF-2 alpha (EPAS1) gene expression. Also disclosed are pharmaceutical compositions that include HIF-2 alpha RNAi agents and methods of use thereof. The HIF-2 alpha RNAi agents disclosed herein may be linked or conjugated to targeting ligands (such as compounds that have affinity for integrins, including alpha-v-beta-3 and alpha-v-beta-5 integrins) and pharmacokinetic (PK) enhancers, to facilitate the delivery to cells and tissues, including to clear cell renal cell carcinoma (ccRCC) cells and tumors. Delivery of compositions comprising the HIF-2 alpha RNAi agents in vivo provides for inhibition of HIF-2 alpha gene expression. The HIF-2 alpha RNAi agents can be used in methods of treatment of various diseases and disorders, including ccRCC.

RNAi agents for inhibiting expression of HIF-2 alpha (), compositions thereof, and methods of use

Integrin ligands having serum stability and affinity for αvβ6 integrins are described. Compositions comprising αvβ6 integrin ligands having serum stability and having affinity for αvβ6 integrins and methods of using them are also described.

Alpha-v beta-6 integrin ligands and uses thereof

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents or siRNAs, able to inhibit Complement Component C3 (C3) gene expression. Also disclosed are pharmaceutical compositions that include C3 RNAi agents and methods of use thereof. The C3 RNAi agents disclosed herein may be conjugated to targeting ligands, including ligands that comprise N-acetyl-galactosanine, to facilitate the delivery to hepatocyte cells. Delivery of the C3 RNAi agents in vivo provides for inhibition of C3 gene expression. The RNAi agents can be used in methods of treatment of diseases, disorders, or symptoms mediated in part by C3 gene expression, including IgA nephropathy, C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria, and/or other complement-mediated renal diseases.

RNAi agents for inhibiting expression of complement component C3 (C3), pharmaceutical compositions thereof, and methods of use

Described are improved linking agents that are useful for facilitating the attachment of targeting groups, pharmacokinetic (PK) enhancers or modifiers, or other delivery agents to oligonucleotides. The described linking agents may exhibit improved reaction yields, stability, and biological activity, particularly when used in connection with oligonucleotide-based compounds, such as RNA interference (RNAi) agents.

Trialkyne linking agents and methods of use

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a Superoxide Dismutase 1 (SOD1) gene. The SOD1 RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of an SOD1 gene. Pharmaceutical compositions that include one or more SOD1 RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described SOD1 RNAi agents to central nervous system (CNS) tissue, in vivo, provides for inhibition of SOD1 gene expression and a reduction in SOD1 activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including amyotrophic lateral sclerosis (ALS.).

RNAi agents for inhibiting expression of Superoxide Dismutase 1 (SOD1), compositions thereof, and methods of use

RNA interference (RNAi) triggers and RNAi trigger conjugates for inhibiting the expression of Hif2&#x3b1; (EPAS1) gene are described. Pharmaceutical compositions comprising one or more Hif2&#x3b1; RNAi triggers optionally with one or more additional therapeutics are also described. Delivery of the described Hif2&#x3b1; RNAi triggers to tumor cells in vivo provides for inhibition of Hif2&#x3b1; gene expression and treatment of cancer.

Compositions and methods for inhibiting gene expression of Hif2alpha

Integrin ligands having serum stability and affinity for &#x3b1;v&#x3b2;6 integrins are described. Compositions comprising &#x3b1;v&#x3b2;6 integrin ligands having serum stability and having affinity for &#x3b1;v&#x3b2;6 integrins and methods of using them are also described.

We describe anhydride compounds suitable for physiologically labile modification of amine-containing molecules. The described anhydrides form reversible linkages having desirable kinetics for in vivo delivery of biologically active molecules. Also described are endosomolytic polymers formed by modification of membrane active polyamines with the described anhydrides.

Disubstituted maleic anhydrides with altered kinetics of ring closure

Tetrapeptide linkers for reversibly linking a first compound to a amine-containing second compound are described. Compounds containing the tetrapeptide linkers and methods of using the tetrapeptide linkers are also described.

Biologically cleavable tetrapeptide linking agents

The present invention is directed compositions for delivery of RNA interference (RNAi) triggers to integrin positive tumor cells in vivo. The compositions comprise RGD ligand-targeted amphipathic membrane active polyamines reversibly modified with enzyme cleavable dipeptide-amidobenzyl-carbonate masking agents. Modification masks membrane activity of the polymer while reversibility provides physiological responsiveness. The reversibly modified polyamines (dynamic polyconjugate or conjugate) are further covalently linked to an RNAi trigger.

Polyconjugates for delivery of RNAi triggers to tumor cells in vivo

The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted melittin delivery peptides. Delivery peptides provide membrane penetration function for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness to the delivery peptides.

Peptide-based in vivo siRNA delivery system

The present invention is directed compositions for delivery of RNA interference (RNAi) polynucleotides to cells in vivo. The compositions comprise amphipathic membrane active polyamines reversibly modified with enzyme cleavable dipeptide-amidobenzyl-carbonate masking agents. Modification masks membrane activity of the polymer while reversibility provides physiological responsiveness. The reversibly modified polyamines (dynamic polyconjugate or DPC) are further covalently linked to an RNAi polynucleotide or co-administered with a targeted RNAi polynucleotide-targeting molecule conjugate.

In vivo polynucleotide delivery conjugates having enzyme sensitive linkages

Growing community of inventors

Madison, WI, United States of America

Jeffrey Carlson