# US 11,439,629 B2 · Methods for the administration of certain VMAT2 inhibitors

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- Number: US 11,439,629 B2
- Document ID: US11439629B2
- Status: Granted
- Kind: B2
- Application number: 17/080,343
- Filed: 2020-10-26
- Published: 2021-02-18
- Granted: 2022-09-13
- Earliest claimed: 2017-01-27
- Assignees: Neurocrine Biosciences, Inc.
- Applicants: Neurocrine Biosciences, Inc.
- Inventors: Christopher F. O'Brien; Haig P. Bozigian
- Web page: https://patentgrep.com/patent/US11439629B2

## CPC

- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 31/4525: containing a five-membered ring with oxygen as a ring hetero atom
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- C07D 455/06: containing benzo [a] quinolizine ring systems
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided are methods of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1, 3,4, 6,7,11 b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof wherein the patient is a CYP2D6 poor metabolizer.

## Claims

### Claim 1

A method of treating a patient with a hyperkinetic movement disorder, wherein the patient is a cytochrome P450 2D6 (CYP2D6) poor metabolizer, comprising:
orally administering once daily to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor chosen from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof, wherein the therapeutically effective amount is an amount equivalent to about 40 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester once daily wherein the hyperkinetic movement disorder is chorea.

### Claim 2 (depends on 1)

The method of claim 1, wherein the patient has a CYP2D6 poor metabolizer genotype.

### Claim 3 (depends on 2)

The method of claim 2, wherein the CYP2D6 poor metabolizer genotype is CYP2D6G1846A genotype or CYP2D6C100T genotype.

### Claim 4 (depends on 2)

The method of claim 2, wherein the CYP2D6 poor metabolizer genotype is CYP2D6G1846A (AA) genotype.

### Claim 5 (depends on 2)

The method of claim 2, wherein the CYP2D6 poor metabolizer genotype is CYP2D6C100T (TT) genotype or CYP2D6C100T (CT) genotype.

### Claim 6 (depends on 1)

The method of claim 1, further comprising monitoring the patient for one or more exposure-related adverse reactions.

### Claim 7 (depends on 6)

The method of claim 6, wherein the one or more exposure-related adverse reactions is chosen from somnolence, anticholinergic effects, balance disorders or falls, headache, akathisia, vomiting, nausea, arthralgia, QT prolongation, increase in blood glucose, increase in weight, respiratory infections, drooling, dyskinesia, extrapyramidal symptoms (non-akathisia), anxiety, insomnia, increase in prolactin, increase in alkaline phosphatase, and increase in bilirubin.

### Claim 8 (depends on 6)

The method of claim 6, wherein the one or more exposure-related adverse reactions is chosen from somnolence and QT prolongation.

### Claim 9 (depends on 6)

The method of claim 6, wherein the one or more exposure-related adverse reactions is QT prolongation.

### Claim 10 (depends on 1)

The method of claim 1, wherein the VMAT2 inhibitor is administered in the form of a capsule.

### Claim 11 (depends on 1)

The method of claim 1, wherein the VMAT2 inhibitor is a pharmaceutically acceptable salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

### Claim 12 (depends on 11)

The method of claim 11, wherein the VMAT2 inhibitor is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

### Claim 13 (depends on 12)

The method of claim 12, wherein the ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester is in polymorphic Form I.

### Claim 14 (depends on 1)

The method of claim 1, wherein the patient who is a CYP2D6 poor metabolizer has an increased exposure to the active metabolite of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester compared with the patient who is not a poor CYP2D6 metabolizer when both patients are administered the same amount of the VMAT2 inhibitor.

### Claim 15 (depends on 14)

The method of claim 14, wherein the exposure is measured by Cmax or AUC0-∞.

### Claim 16 (depends on 11)

The method of claim 11, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

### Claim 17 (depends on 1)

The method of claim 1, wherein the method further comprises increasing the therapeutically effective amount to an amount equivalent to about 80 mg as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester once daily after one week.

### Claim 18

A method of treating a patient with a hyperkinetic movement disorder, comprising:
(a) orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor chosen from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof;
(b) subsequently determining that the patient is a cytochrome P450 2D6 (CYP2D6) poor metabolizer; and
(c) reducing dosage of the VMAT2 inhibitor administered to the patient to an amount equivalent to about 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester wherein the hyperkinetic movement disorder is chorea.

### Claim 19 (depends on 18)

The method of claim 18, wherein the therapeutically effective amount is an amount equivalent to about 60 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

### Claim 20 (depends on 18)

The method of claim 18, wherein the therapeutically effective amount is an amount equivalent to about 80 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

### Claim 21 (depends on 18)

The method of claim 18, wherein the patient has CYP2D6G1846A (AA) genotype.

### Claim 22 (depends on 18)

The method of claim 18, wherein the patient has CYP2D6C100T (TT) genotype or CYP2D6C100T (CT) genotype.

### Claim 23 (depends on 18)

The method of claim 18, further comprising monitoring the patient for one or more exposure-related adverse reactions.

### Claim 24 (depends on 23)

The method of claim 23, wherein the one or more exposure-related adverse reactions is QT prolongation.

### Claim 25 (depends on 18)

The method of claim 18, wherein the VMAT2 inhibitor is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

### Claim 26 (depends on 18)

The method of claim 18, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

### Claim 27

A method of treating a patient with a hyperkinetic movement disorder, comprising:
determining if the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6); and
if the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6), then orally administering to the patient a first therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor chosen from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof, wherein the first therapeutically effective amount is an amount equivalent to about 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester; or
if the patient is not a poor metabolizer of cytochrome P450 2D6 (CYP2D6), then orally administering to the patient a second therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor chosen from (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester and pharmaceutically acceptable salts thereof, wherein the second therapeutically effective amount is an amount equivalent to about 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester for one week, and subsequently administering an increased amount of the VMAT2 inhibitor after one week wherein the hyperkinetic movement disorder is chorea.

### Claim 28 (depends on 27)

The method of claim 27, wherein the VMAT2 inhibitor is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

### Claim 29 (depends on 27)

The method of claim 27, wherein the increased amount is an amount equivalent to about 80 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester.

### Claim 30 (depends on 27)

The method of claim 27, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

### Claim 31

A method of treating a patient with a hyperkinetic movement disorder, comprising:
(a) orally administering to the patient a therapeutically effective amount of a vesicular monoamine transporter 2 (VMAT2) inhibitor which is a ditosylate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester, wherein the therapeutically effective amount is an amount equivalent to about 40 mg once daily as measured by (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester;
(b) subsequently determining that the patient is a poor metabolizer of cytochrome P450 2D6 (CYP2D6); and
(c) administering the same therapeutically effective amount of the VMAT2 inhibitor to the patient wherein the hyperkinetic movement disorder is chorea.

### Claim 32 (depends on 31)

The method of claim 31, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.