# US 11,079,379 B2 · Methods of treating transthyretin (TTR) mediated amyloidosis

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- Number: US 11,079,379 B2
- Document ID: US11079379B2
- Status: Granted
- Kind: B2
- Application number: 16/054,854
- Filed: 2018-08-03
- Published: 2019-05-30
- Granted: 2021-08-03
- Earliest claimed: 2014-08-29
- Assignees: Alnylam Pharmaceuticals, Inc.
- Applicants: Alnylam Pharmaceuticals, Inc.
- Inventors: Brian Bettencourt
- Web page: https://patentgrep.com/patent/US11079379B2

## CPC

- A61P 9/00: Drugs for disorders of the cardiovascular system
- G01N 33/566: using specific carrier or receptor proteins as ligand binding reagents {where possible specific carrier or receptor proteins are classified with their target compounds}
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/603: having further aromatic rings, e.g. diflunisal
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/02: for peripheral neuropathies
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 263/57: Aryl or substituted aryl radicals
- 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)}
- G01N 33/50: Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing (measuring or testing processes involving enzymes or microorganisms, compositions or test papers therefor; processes for forming such compositions, condition responsive control in microbiological or enzymological processes C12Q)
- G01N 33/53: Immunoassay; Biospecific binding assay; Materials therefor
- G01N 33/567: utilising isolate of tissue or organ as binding agent
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- C07K 1/00: General methods for the preparation of peptides {, i.e. processes for the organic chemical preparation of peptides or proteins of any length}
- C12N 2310/14: interfering nucleic acids [NA]
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Disclosed herein are methods for reducing or arresting an increase in a Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) in a human subject by administering an effective amount of a transthyretin (TTR)-inhibiting composition.

## Claims

### Claim 1

A method of treating polyneuropathy in a patient with hereditary transthyretin-mediated amyloidosis (hATTR), the method comprising administering a dose of a TTR siRNA with lipid excipients to the patient,
wherein the TTR siRNA consists of a sense strand consisting of SEQ ID NO:1 and an antisense strand consisting of SEQ ID NO:2; and
the lipid excipients consist of DLin-MC3-DMA ((6Z, 9Z, 28Z, 31Z)-heptatriaconta-6, 9, 28, 31-tetraen-19-yl-4-(dimethylamino) butanoate), DSPC ((1,2-Distearoyl-sn-Glycero-3-Phosphocholine), cholesterol, and PEG2000-C-DMG (((R)-methoxy-PEG2000-carbamoyl-di-O-myristyl-sn-glyceride) in isotonic phosphate buffered saline;
wherein the dose is 0.3 mg siRNA per kg body weight, and the TTR siRNA with lipid excipients is administered via IV infusion once every three weeks, and the patient receives a premedication before infusion to reduce the risk of infusion-related reactions.

### Claim 2 (depends on 1)

The method of claim 1, wherein the patient receives the premedication on the evening before and the day of infusion.

### Claim 3 (depends on 1)

The method of claim 1, wherein the premedication comprises dexamethasone, acetaminophen, diphenhydramine, and ranitidine.

### Claim 4 (depends on 1)

The method of claim 1, wherein the premedication comprises dexamethasone, acetaminophen, cetirizine, and ranitidine.

### Claim 5 (depends on 1)

The method of claim 1, wherein the premedication comprises dexamethasone, paracetamol (acetaminophen), an H2 blocker and an H1 blocker.

### Claim 6 (depends on 5)

The method of claim 5, wherein the H2 blocker is ranitidine or famotidine.

### Claim 7 (depends on 5)

The method of claim 5, wherein the H1 blocker is cetirizine, hydroxyzine or fexofenadine.

### Claim 8 (depends on 1)

The method of claim 1, wherein the TTR siRNA with lipid excipients is administered via a 70 minute infusion of 1 mL/min for 15 minutes followed by 3 mL/min for 55 minutes.

### Claim 9 (depends on 1)

The method of claim 1, wherein the TTR siRNA with lipid excipients is administered via a 70 minute infusion of 1 mL/min for 15 minutes followed by 3 mL/min for 55 minutes and the premedication comprises dexamethasone, paracetamol (acetaminophen), an H2 blocker and an H1 blocker.

### Claim 10 (depends on 1)

The method of claim 1, wherein the patient has cardiomyopathy.

### Claim 11 (depends on 1)

The method of claim 1, wherein the patient has does not have cardiomyopathy.