US 12,221,610 B2
RNAi agents for inhibiting expression of HIF-2 alpha (EPAS1), compositions thereof, and methods of use
Zhen Li, San Diego, CA (US); Dongxu Shu, Madison, WI (US); Anthony Nicholas, Oregon, WI (US); Rui Zhu, San Diego, CA (US); Jeffrey Carlson, Madison, WI (US); So Wong, Oregon, WI (US); Xiaokai Li, Middleton, WI (US); Erich Altenhofer, Madison, WI (US); Matthew Fowler-Watters, Madison, WI (US); and Bo Chen, Scarsdale, NY (US)
Assigned to Arrowhead Pharmaceuticals, Inc., Pasadena, CA (US)
Appl. No. 17/420,460
Filed by Arrowhead Pharmaceuticals, Inc., Pasadena, CA (US)
PCT Filed Jan. 8, 2020, PCT No. PCT/US2020/012775
§ 371(c)(1), (2) Date Jul. 2, 2021,
PCT Pub. No. WO2020/146521, PCT Pub. Date Jul. 16, 2020.
Claims priority of provisional application 62/839,381, filed on Apr. 26, 2019.
Claims priority of provisional application 62/827,564, filed on Apr. 1, 2019.
Claims priority of provisional application 62/790,360, filed on Jan. 9, 2019.
Prior Publication US 2022/0204976 A1, Jun. 30, 2022
Int. Cl. C12N 15/11 (2006.01); A61P 35/00 (2006.01); C12N 15/113 (2010.01)
CPC C12N 15/1138 (2013.01) [A61P 35/00 (2018.01); C12N 2310/14 (2013.01); C12N 2310/351 (2013.01); C12N 2320/30 (2013.01)] 20 Claims
 
1. An RNAi agent comprising an antisense strand comprising the sequence usUfsusCfaUfgAfaAfuCfgUfuAfcGfuUfsg (SEQ ID NO: 30), and a sense strand comprising the sequence Y-(NH-C6) scsaacguaaCfGfAfuuuZcaZugZaaZsa (invAb) (6-S)-X (SEQ ID NO: 761), wherein a, c, g, and u represent 2′-O-methyl adenosine, cytidine, guanosine, and uridine, respectively; Af, Cf, Gf, and Uf represent 2′-fluoro adenosine, cytidine, guanosine, and uridine, respectively; s represents a phosphorothioate linkage; uZ, aZ, gZ, and cZ represent uridine, adenosine, guanosine and cytidine, respectively, with a pharmacological moiety comprising Z linked at the 2′ position of the nucleotide; Y-(NH-C6) s represents:

OG Complex Work Unit Chemistry
(invAb) represents:
linkage towards 5′ end

OG Complex Work Unit Chemistry
linkage towards 3′ end; (6-S) represents:

OG Complex Work Unit Chemistry
and each X, Y and Z independently represents:
(i) a targeting group comprising one or more targeting ligands, wherein the targeting ligand is selected from the group consisting of: Structure 2a, Structure 2.11a, Structure 29a, and Structure 32a;
(ii) a targeting ligand having a structure selected from the group consisting of: Structure 2a, Structure 2.11a, Structure 29a, and Structure 32a; or
(iii) a PK enhancer having a structure selected from the group consisting of C-18 diacid, C-18 triacid, Mal-C17-vinyl-PO3, and C20 acid.