# US 12,110,492 B2 · RNAi agents for inhibiting expression of complement component C3 (C3), pharmaceutical compositions thereof, and methods of use

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- Number: US 12,110,492 B2
- Document ID: US12110492B2
- Status: Granted
- Kind: B2
- Application number: 18/495,278
- Filed: 2023-10-26
- Published: 2024-05-23
- Granted: 2024-10-08
- Earliest claimed: 2022-10-27
- Assignees: Arrowhead Pharmaceuticals, Inc.
- Applicants: Arrowhead Pharmaceuticals, Inc.
- Inventors: Jeffrey Carlson; Yichen Wang; Tao Pei; James C. Hamilton; Hamid Moradi
- Web page: https://patentgrep.com/patent/US12110492B2

## CPC

- A61K 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61K 47/02: Inorganic compounds
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C12N 2310/11: Antisense
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/317: with an inverted bond, e.g. a cap structure
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/351: Conjugate
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

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.

## Claims

### Claim 1

A method of treating IgA nephropathy (IgAN) or C3 glomerulopathy (C3G) in a human subject in need thereof, the method comprising administering to the human subject a pharmaceutical composition comprising a therapeutically effective amount of a RNAi agent for inhibiting expression of a C3 gene, wherein the RNAi agent comprises an antisense strand and a sense strand, wherein the antisense strand comprises the nucleotide sequence (5′→3′) usUfsusCfgAfacaacAfgAfgUfaGfGfgsu (SEQ ID NO:13), and the sense strand comprises the nucleotide sequence (5′→3′) (NAG37)s(invAb)sacccuacuCfUfGfuuguucgaaas(invAb) (SEQ ID NO:14), wherein a is 2′-O-methyl adenosine; c is 2′-O-methyl cytidine; g is 2′-O-methyl guanosine; u is 2′-O-methyl uridine, Af is 2′-fluoro adenosine, Cf is 2′-fluoro cytidine; Gf is 2′-fluoro guanosine; Uf is 2′-fluoro adenosine; s is a phosphorothioate linkage; (invAb) is an inverted abasic deoxyribose residue; and (NAG37)s comprises the following chemical structure:
and wherein the RNAi agent is administered by subcutaneous injection at a dose of between about 25 mg and about 400 mg of RNAi agent.

### Claim 2 (depends on 1)

The method of claim 1, wherein the RNAi agent is a pharmaceutically acceptable salt.

### Claim 3 (depends on 1)

The method of claim 1, wherein the RNAi agent is a sodium salt.

### Claim 4 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition comprises a sodium phosphate buffer.

### Claim 5 (depends on 1)

The method of claim 1, wherein the pharmaceutically composition comprises isotonic saline.

### Claim 6 (depends on 1)

The method of claim 1, wherein the pharmaceutically composition comprises water for injection.

### Claim 7 (depends on 1)

The method of claim 1, wherein the level of serum C3 protein is decreased in the subject.

### Claim 8 (depends on 1)

The method of claim 1, wherein the alternative complement pathway hemolytic activity (AH50) is reduced in the subject by at least about 50%.

### Claim 9 (depends on 8)

The method of claim 8, wherein the AH50 is reduced by approximately 90% or greater.

### Claim 10 (depends on 1)

The method of claim 1, wherein the RNAi agent is formulated at 200 mg/mL in an aqueous sodium phosphate buffer, wherein the aqueous sodium phosphate buffer has a concentration of about 0.5 mM of sodium phosphate monobasic, and a concentration of 0.5 mM of sodium phosphate dibasic.

### Claim 11 (depends on 1)

The method of claim 1, wherein the RNAi agent is administered to the human subject no more frequently than once every twelve weeks.

### Claim 12 (depends on 1)

The method of claim 1, wherein the RNAi agent is administered to the human subject no more frequently than four times in a year.

### Claim 13 (depends on 1)

The method of claim 1, wherein the method is for the treatment of IgA nephropathy (IgAN).

### Claim 14 (depends on 1)

The method of claim 1, wherein the method is for the treatment of C3 glomerulopathy (C3G).