Claims for Patent: 12,365,899

Summary for Patent: 12,365,899

Title:	RNAi agents and compositions for inhibiting expression of apolipoprotein C-III (APOC3)
Abstract:	The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, capable of inhibiting Apolipoprotein C-III (also called APOC3, apoC-III, APOC-III, and APO C-III) gene expression, and compositions that include APOC3 RNAi agents. The APOC3 RNAi agents disclosed herein may be conjugated to targeting ligands, including ligands that include N-acetyl-galactosamine, to facilitate the delivery to cells, including to hepatocytes. Pharmaceutical compositions that include one or more APOC3 RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the APOC3 RNAi agents in vivo provides for inhibition of APOC3 gene expression, and can result in lower triglycerides and/or cholesterol levels in the subject. The APOC3 RNAi agents can be used in methods of treatment of APOC3-related diseases and disorders, including hypertriglyceridemia, cardiovascular disease, and other metabolic-related disorders and diseases.
Inventor(s):	Zhen Li, Rui Zhu, Tao Pei, Steven Kanner, So Wong
Assignee:	Arrowhead Pharmaceuticals Inc
Application Number:	US18/145,218
Patent Claims:	1. An RNAi agent for inhibiting expression of an APOC3 gene comprising: an antisense strand comprising nucleotides 1-21 of SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 710, or SEQ ID NO. 711; a sense strand comprising a nucleotide sequence that is at least partially complementary to the antisense strand; wherein the RNAi agent is in a salt form suitable for in vivo delivery to a human subject. 2. The RNAi agent of claim 1, wherein the salt is a sodium salt. 3. The RNAi agent of claim 1, wherein the sense strand comprises one or two inverted abasic residues. 4. The RNAi agent of claim 3, wherein the RNAi agent is conjugated to a targeting ligand that comprises an N-acetyl-galactosamine moiety. 5. The RNAi agent of claim 4, wherein the targeting ligand comprises (NAG37) s. 6. The RNAi agent of claim 5, wherein the sense strand of the RNAi agent is conjugated at the 5′ terminal end to (NAG37) s. 7. The RNAi agent of claim 1, wherein the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5. 8. The RNAi agent of claim 7, wherein the sense strand comprises the nucleotide sequence of SEQ ID NO: 18. 9. The RNAi agent of claim 1, wherein the antisense strand comprises the modified nucleotide sequence of usCfsasCfuGfagaauAfcUfgUfcCfcGfsu (SEQ ID NO: 4) (5′→3′), wherein a represents 2′-O-methyl adenosine, c represents 2′-O-methyl cytidine, g represents 2′-O-methyl guanosine, and u represents 2′-O-methyl uridine; Af, represents 2′-fluoro adenosine, Cf represents 2′-fluoro cytidine, Gf represents 2′-fluoro guanosine, and Uf represents 2′-fluoro uridine; s represents a phosphorothioate linkage; and wherein all or substantially all of the nucleotides on the sense strand are modified nucleotides. 10. The RNAi agent of claim 9, wherein the sense strand comprises the modified nucleotide sequence of acgggacaGfUfAfuucucaguia (SEQ ID NO:572) (5′→3′), wherein a represents 2′-O-methyl adenosine, c represents 2′-O-methyl cytidine, g represents 2′-O-methyl guanosine, u represents 2′-O-methyl uridine, and i represents 2′-O-methyl inosine; Af, represents 2′-fluoro adenosine, Cf represents 2′-fluoro cytidine, Gf represents 2′-fluoro guanosine, and Uf represents 2′-fluoro uridine; s represents a phosphorothioate linkage. 11. A composition comprising the RNAi agent of claim 10, wherein the composition comprises a pharmaceutically acceptable excipient. 12. A composition comprising the RNAi agent of claim 9, wherein the composition comprises a pharmaceutically acceptable excipient. 13. The RNAi agent of claim 1, wherein the RNAi agent has the duplex structure of AD05876 (SEQ ID Nos: 4 and 572). 14. A composition comprising the RNAi agent of claim 1, wherein the composition comprises a pharmaceutically acceptable excipient. 15. A method for inhibiting expression of an APOC3 gene in a cell, the method comprising introducing into a cell an effective amount of the RNAi agent of claim 1. 16. The method of claim 15, wherein the cell is within a subject. 17. The method of claim 16, wherein the subject is a human subject. 18. A method of lowering triglyceride levels in a subject, the method comprising administering to the subject an effective amount of a composition of claim 14. 19. A method of lowering low density lipoprotein (LDL) levels in a subject, the method comprising administering to the subject an effective amount of the composition of claim 14. 20. A method of treating an APOC3-related disease or disorder, the method comprising administering to a human subject in need thereof a therapeutically effective amount of the composition of claim 14. 21. The method of claim 20, wherein the disease is a cardiometabolic disease. 22. The method of claim 21, wherein the cardiometabolic disease is hypertriglyceridemia, obesity, hyperlipidemia, abnormal lipid and/or abnormal cholesterol metabolism, atherosclerosis, cardiovascular disease, coronary artery disease, hypertriglyceridemia induced pancreatitis, metabolic syndrome, type II diabetes mellitus, familial chylomicronemia syndrome, or familial partial lipodystrophy.