Methods for the Treatment of Abnormal Involuntary Movement Disorders

• US 20180318281A1
• Filed: 07/19/2018
• Published: 11/08/2018
• Est. Priority Date: 03/06/2015
• Status: Active Grant

• Current Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Stamler, David, Huang, Michael Fangching
• Granted Patent: US 10,959,996 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: 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
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents

Abstract

Disclosed herein are new dosage regimens for deuterium-substituted benzoquinoline compounds, and methods for the treatment of abnormal muscular activity, movement disorders, and related conditions.

Claims

1. A method of transitioning a subject having a movement disorder from tetrabenazine to deutetrabenazine for the treatment of abnormal involuntary movement, comprising:

a) discontinuing a daily amount of tetrabenazine; and

b) administering an initial daily amount of deutetrabenazine the next day to the subject, wherein said initial daily amount is about 30% to about 70% of the daily amount of the tetrabenazine and is about 6 mg/day to about 48 mg/day, administered in one or two doses;

wherein the daily amount of tetrabenazine was administered to the subject for the treatment of the abnormal involuntary movement; and

wherein the transitioning results in at least a maintenance of abnormal involuntary movement control in the subject.

2. The method of claim 1, wherein the abnormal involuntary movement is chorea associated with Huntington'"'"'s disease.

3. The method of claim 2, wherein the chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score.

4. The method of claim 3, wherein the improvement is measured from a pre-treatment, baseline to maintenance therapy.

5. The method of claim 2, wherein the chorea is reduced by at least 15%.

6. The method of claim 2, wherein:

(i) chorea is reduced by at least 10% and said method also provides at least one of the following;

motor function is improved by at least 10%;

the subject'"'"'s physical functioning is improved;

swallowing is improved;

balance is not worsened;

treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, fatigue, parkinsonism or dysphagia;

the maximal increases in QTcF is less than 5 ms;

or combinations thereof;

or

(ii) motor function is improved by at least 10%, and said method also provides at least one of the following;

chorea is reduced by at least 10%;

the subject'"'"'s physical functioning is improved;

swallowing is improved;

balance is not worsened;

treatment causes no significant increase in insomnia, depression, anxiety, agitation, suicidal ideation, akathisia, irritability, fatigue, parkinsonism or dysphagia;

the maximal increases in QTcF is less than 5 ms;

or combinations thereof.

7. The method of claim 1, wherein the subject has Huntington'"'"'s disease.

8. The method of claim 1, wherein the abnormal involuntary movement is chorea associated with Huntington'"'"'s disease.

9. The method of claim 1, wherein:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg;

or

the first dose about 24 mg and the second dose is about 24 mg.

18. The method of claim 1, further comprising:

c) determining the degree of control of abnormal involuntary movement achieved with the initial daily amount of deutetrabenazine and the tolerability of the initial daily amount after about one week; and

d) increasing the initial daily amount of deutetrabenazine by at least about 6 mg/day to a first subsequent daily amount if the degree of control of abnormal involuntary movement is not improved and the initial amount is tolerated.

19. The method of claim 18, further comprising:

e) repeating steps c) and d) after about one week until abnormal involuntary movement is reduced and the first subsequent daily amount is tolerated.

20. The method of claim 19, further comprising:

f) decreasing the first subsequent daily amount of deutetrabenazine by about 6 mg/day to a second subsequent daily amount if said first subsequent amount is not tolerated.

21. The method of claim 1, wherein the subject is human.

22. The method of claim 9, wherein the subject is human.

23. The method of claim 1, wherein the abnormal involuntary movement is measured by the AIMS.

24. The method of claim 1, wherein the subject is an adult.

25. The method of claim 24, wherein the reduction in abnormal involuntary movement is measured by the AIMS.

26. The method of claim 9, wherein the subject is an adult.

27. The method of claim 26, wherein the reduction in abnormal involuntary movement is measured by the AIMS.

10. A method of treating abnormal involuntary movement in a subject having a movement disorder, said method comprising administering an initial daily amount of deutetrabenazine of about 6 mg/day to about 48 mg/day, in one or two doses, to the subject, wherein:

a) the abnormal involuntary movement is reduced in said subject; and

b) one or more symptom of depression, insomnia, somnolence, fatigue, dizziness, restlessness, agitation, akathisia, parkinsonism, nausea, anxiety, impaired swallowing, body weight gain, irritability, or compulsive behavior is improved in said subject.

11. The method of claim 10, further comprising:

(i) determining after about one week of treatment the degree of control of abnormal involuntary movement achieved with the initial daily amount of deutetrabenazine and the tolerability of the initial daily amount; and

(ii) increasing the daily amount of the deutetrabenazine by at least about 6 mg/day to a first subsequent daily amount if abnormal involuntary movement is not reduced and the initial daily amount is tolerated;

(iii) optionally, repeating steps i) and ii) after one week until abnormal involuntary movement is reduced and the first subsequent daily amount is tolerated; and

(iv) decreasing the daily amount by at least about 6 mg/day to a second subsequent daily amount if any amount is not tolerated.

12. The method of claim 10, wherein the abnormal involuntary movement is chorea associated with Huntington'"'"'s disease.

13. The method of claim 12, wherein chorea control is improved by a reduction of at least 0.5 points as measured by the Total Maximal Chorea (TMC) score of the Unified Huntington'"'"'s Disease Rating Scale (UHDRS).

14. The method of claim 12, wherein the abnormal involuntary movement is improved by a reduction of at least 1 point as measured by the Total Motor Score (TMS) of the Unified Huntington'"'"'s Disease Rating Scale (UHDRS).

15. The method of claim 10, wherein:

the first dose about 6 mg and the second dose is about 6 mg;

the first dose about 9 mg and the second dose is about 9 mg;

the first dose about 12 mg and the second dose is about 12 mg;

the first dose about 15 mg and the second dose is about 15 mg;

the first dose about 18 mg and the second dose is about 18 mg;

the first dose about 21 mg and the second dose is about 21 mg;

or

the first dose about 24 mg and the second dose is about 24 mg.

16. The method of claim 15, wherein the daily amount of deutetrabenazine administered is about 6 mg to about 36 mg for a subject concurrently receiving a strong CYP2D6 inhibitor.

17. The method of claim 16, wherein the strong CYP2D6 inhibitor is fluoxetine, paroxetine, bupropion, quinidine, or cinacalcet.