Arrowhead Pharmaceuticals, Inc.

The present disclosure relates to delivery platforms that specifically and efficiently direct multimeric RNAi agent payloads to hepatocytes in a subject, in vivo. The delivery platforms disclosed herein include metabolically stabilized N-Acetylgalactosamine (NAG or GalNAc) targeting ligands conjugated to two or more RNAi agents, to facilitate the delivery of the oligonucleotide-based payloads to cells, including to hepatocytes. Pharmaceutical compositions that include the metabolically stabilized multimeric RNAi agent conjugate delivery platform are also described, as well as methods of use for the treatment of various diseases and disorders where delivery of a therapeutic payload to a hepatocyte is desirable.

The present disclosure relates to delivery platforms that specifically and efficiently direct stabilized RNAi agent payloads to hepatocytes in a subject, in vivo. The delivery platforms disclosed herein include metabolically stabilized N-Acetylgalactosamine (NAG or GalNAc) targeting ligands conjugated to one or more oligonucleotides through a metabolically stabilized linkage that is more stable than a phosphodiester linkage, to facilitate the delivery of the oligonucleotide-based payloads to cells, including to hepatocytes. Pharmaceutical compositions that include the metabolically stabilized RNAi agent conjugate delivery platform are also described, as well as methods of use for the treatment of various diseases and disorders where delivery of a therapeutic payload to a hepatocyte is desirable.

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a beta-ENaC (SCNN1B) gene. The beta-ENaC RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of a beta-ENaC gene. Pharmaceutical compositions that include one or more beta-ENaC RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described beta-ENaC RNAi agents to epithelial cells, such as pulmonary epithelial cells, in vivo, provides for inhibition of beta-ENaC gene expression and a reduction in ENaC activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including chronic obstructive pulmonary disease (COPD).

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a Mucin 5AC (MUC5AC) gene. The MUC5AC RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of an MUC5AC gene. Pharmaceutical compositions that include one or more MUC5AC RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described MUC5AC RNAi agents to pulmonary epithelial cells, in vivo, provides for inhibition of MUC5AC gene expression and a reduction in MUC5AC production, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including mucoobstructive lung disease such as severe asthma and various cancers.

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, able to inhibit xanthine dehydrogenase (XDH) gene expression. Also disclosed are pharmaceutical compositions that include XDH RNAi agents and methods of use thereof. The XDH RNAi agents disclosed herein may be conjugated to targeting ligands to facilitate the delivery to cells, including to hepatocytes. Delivery of the XDH RNAi agents in vivo provides for inhibition of XDH gene expression. The RNAi agents can be used in methods of treatment of diseases, disorders, or symptoms mediated in part by XDH gene expression, such as gout and hyperuricemia.

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of an Activin Receptor-Like Kinase 7 (ALK7) gene. The ALK7 RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of an ALK7 gene. Pharmaceutical compositions that include one or more ALK7 RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described ALK7 RNAi agents to adipose tissue, in vivo, provides for inhibition of ALK7 gene expression and a reduction in ALK7 activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including obesity, diabetes, or insulin resistance.

Compounds having affinity for integrins, the synthesis of these compounds, and the use of these compounds as ligands to facilitate the delivery of cargo molecules to cells expressing integrins are described. The described integrin targeting ligands have serum stability and affinity for αvβ3 integrin and/or αvβ5 integrin, and are suitable for conjugation to cargo molecules, such as such as oligonucleotide-based therapeutic agents (e.g., RNAi agents), to facilitate delivery of the cargo molecules to cells and tissues, such as tumor cells, that express integrin αvβ3, integrin αvβ5, or both integrin αvβ3 and integrin αvβ5. Compositions that include integrin targeting ligands and methods of use are also described.

Described are methods for treating alpha-1 antitrypsin deficiency (AATD) in a human patient in need of treatment, using pharmaceutical compositions that include AAT RNAi agents. The pharmaceutical compositions disclosed herein that include AAT RNAi agents, when administered to a human patient in need thereof, treat liver diseases associated with AAT deficiency such as chronic hepatitis, cirrhosis, increased risk of hepatocellular carcinoma, transaminitis, cholestasis, fibrosis, fulminant hepatic failure, and other liver-related diseases.

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of an influenza A viral genome. The influenza A viral (IAV) RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of an influenza A viral genome at targeted portions of the genome that are conserved across a variety of known influenza A viral genome variants, and are therefore capable of inhibiting expression of various influenza A virus strains. Pharmaceutical compositions that include one or more IAV RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described IAV RNAi agents to pulmonary cells, in vivo, provides for inhibition of influenza A viral genome expression, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases, disorders, and/or symptoms caused by influenza A viral infection.

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a microtubule associated protein tau (MAPT) gene. The MAPT RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of a MAPT gene. The MAPT RNAi agents are conjugated to an antigen binding protein that may enable subcutaneous delivery of the RNAi agents by facilitating crossing of the blood brain barrier (BBB). Pharmaceutical compositions that include one or more MAPT RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described MAPT RNAi agents to central nervous system (CNS) tissue, in vivo, provides for inhibition of MAPT gene expression and a reduction in MAPT activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including Alzheimer's disease, Frontotemporal lobar degeneration dementia (FTLD), Progressive supranuclear palsy, and other tauopathies.