IP Library › Granted Patent US 12,221,610
Granted Patent B2
US 12,221,610 · App. 17/420,460 · Granted Feb 11, 2025

RNAi agents for inhibiting expression of HIF-2 alpha (

Inventors: Zhen Li (San Diego, CA); Dongxu Shu (Madison, WI); Anthony Nicholas (Oregon, WI); Rui Zhu (San Diego, CA); Jeffrey Carlson (Madison, WI); So Wong (Oregon, WI); Xiaokai Li (Middleton, WI); Erich Altenhofer (Madison, WI); Matthew Fowler-Watters (Madison, WI); Bo Chen (Scarsdale, NY)
Assignee: Arrowhead Pharmaceuticals, Inc.
C12N15/1138A61P35/00C12N2310/14C12N2310/351C12N2320/30
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Quick Facts
Patent No.
US 12,221,610
App. No.
17/420,460
Granted
Feb 11, 2025
Kind
B2
Abstract

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.

Claims (35)

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) scsaacguaaCfGfAfuuu Z ca Z ug Z aa Z sa (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; u Z , a Z , g Z , and c Z 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:

(invAb) represents:

linkage towards 5′ end

linkage towards 3′ end; (6-S) represents:

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-C 17 -vinyl-PO 3 , and C20 acid.

2. The RNAi agent of claim 1 , wherein each Z is a targeting ligand having a structure of Structure 2a:

wherein indicates the point of attachment.

3. The RNAi agent of claim 1 , wherein each Z is a targeting ligand having a structure of Structure 2.11a:

wherein indicates the point of attachment.

4. The RNAi agent of claim 1 , wherein each Z is a targeting ligand having a structure of Structure 29a:

wherein indicates the point of attachment.

5. The RNAi agent of claim 1 , wherein each Z is a targeting ligand having a structure of Structure 32a:

wherein indicates the point of attachment.

6. The RNAi agent of claim 1 , wherein X is a PK enhancer having a structure of C-18 diacid:

wherein indicates the point of attachment.

7. The RNAi agent of claim 1 , wherein the RNAi agent includes 2, 3, 4, 5, 6, 7, 8, 9, or 10 targeting ligands.

8. The RNAi agent of claim 7 , wherein the RNAi agent includes 7 targeting ligands.

9. The RNAi agent of claim 8 , wherein Y is a targeting group having the structure of TriAlk 14:

or TriAlk 14s:

wherein TL comprises a targeting ligand selected from the group consisting of: Structure 2a, Structure 2.11a, Structure 29a, and Structure 32a.

10. The RNAi agent of claim 9 , wherein each TL comprises Structure 2a:

wherein indicates the point of attachment.

11. The RNAi agent of claim 1 , wherein the nucleotides of the antisense strand consist of the nucleotides of SEQ ID NO: 30.

12. The RNAi agent of claim 1 , wherein the nucleotides of the sense strand consist of the nucleotides of SEQ ID NO: 761.

13. A composition comprising the RNAi agent of claim 1 , wherein the composition comprises a pharmaceutically acceptable excipient.

14. The composition of claim 13 , further comprising a second RNAi agent for inhibiting the expression of HIF-2 alpha.

15. The composition of claim 13 , further comprising one or more additional therapeutics.

16. A method for inhibiting expression of a HIF-2 alpha (EPAS1) gene in a cell, the method comprising introducing into a cell an effective amount of an RNAi agent of claim 1 .

17. The method of claim 16 , wherein the HIF2-alpha gene expression is inhibited by at least about 30% in vivo.

18. A method of treating a HIF2-alpha-related disease or disorder, the method comprising administering to a human subject in need thereof a therapeutically effective amount of the composition of claim 13 .

19. The method of claim 18 , wherein the disease or disorder is cancer, renal cancer, clear cell renal cell carcinoma, non-small cell lung cancer, astrocytoma (brain cancer), bladder cancer, breast cancer, chondrosarcoma, colorectal carcinoma, gastric carcinoma, glioblastoma, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, neuroblastoma, melanoma, multiple myeloma, ovarian cancer, rectal cancer, metastases, gingivitis, psoriasis, Kaposi's sarcoma-associated herpesvirus, preeclampsia, inflammation, chronic inflammation, neovascular diseases, or rheumatoid arthritis.

20. The method of claim 18 , wherein the disease is clear cell renal cell carcinoma (ccRCC).

Assignments (4)
SECURITY INTEREST Recorded Aug 7, 2024
From: ARROWHEAD PHARMACEUTICALS, INC.
To: SIXTH STREETLENDING PARTNERS, AS THE ADMINISTRATIVE AGENT
Reel/Frame 068510/0363 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 17, 2022
From: LI, ZHEN
To: ARROWHEAD PHARMACEUTICALS, INC.
Reel/Frame 059034/0092 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 17, 2022
From: ZHU, RUI
To: ARROWHEAD PHARMACEUTICALS, INC.
Reel/Frame 059034/0192 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 17, 2022
From: SHU, DONGXU; NICHOLAS, ANTHONY; CARLSON, JEFFREY; LI, XIAOKAI; ALTENHOFER, ERICH; FOWLER-WATTERS, MATTHEW; CHEN, BO; WONG, SO
To: ARROWHEAD PHARMACEUTICALS, INC.
Reel/Frame 059034/0319 →
Continuity (4)
Provisional Application 62839381 · Apr 26, 2019
Provisional Application 62827564 · Apr 1, 2019
Provisional Application 62790360 · Jan 9, 2019
Related Publication 20220204976A1 · Jun 30, 2022
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