Methods for the treatment of abnormal involuntary movement disorders

• US 10,959,996 B2
• Filed: 07/19/2018
• Issued: 03/30/2021
• 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
• Primary Examiner(s): Rao, Savitha M
• Assistant Examiner(s): Lee, Andrew P
• Application Number:
  US16/040,012
• Publication Number:
  US 20180318281A1
• Time in Patent Office: 985 Days
• Field of Search: None
• 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 human from tetrabenazine to deutetrabenazine for the treatment of chorea associated with Huntington'"'"'s disease, comprising:

a) discontinuing a daily amount of tetrabenazine; and

b) administering an initial daily amount of deutetrabenazine the next day to the human,

wherein the daily amount of tetrabenazine is 12.5 mg and the initial total daily amount of deutetrabenazine is 6 mg;

or

wherein the daily amount of tetrabenazine is 25 mg and the initial total daily amount of deutetrabenazine is 12 mg;

or

wherein the daily amount of tetrabenazine is 37.5 mg and the initial total daily amount of deutetrabenazine is 18 mg;

or

wherein the daily amount of tetrabenazine is 50 mg and the initial total daily amount of deutetrabenazine is 24 mg;

or

wherein the daily amount of tetrabenazine is 62.5 mg and the initial total daily amount of deutetrabenazine is 30 mg;

or

wherein the daily amount of tetrabenazine is 75 mg and the initial total daily amount of deutetrabenazine is 36 mg;

or

wherein the daily amount of tetrabenazine is 87.5 mg and the initial total daily amount of deutetrabenazine is 42 mg;

or

wherein the daily amount of tetrabenazine is 100 mg and the initial total daily amount of deutetrabenazine is 48 mg.

2. The method of claim 1, wherein the transitioning results in the chorea control is improved by a reduction of at least 0.5 points on the Total Maximal Chorea (TMC) score.

3. The method of claim 2, wherein the improvement is measured from a pre-treatment, baseline to maintenance therapy.

4. The method of claim 1, wherein the transitioning results in a reduction of chorea by at least 15%.

5. The method of claim 1, wherein:

(i) the transitioning results in a reduction of chorea by at least 10% and said method also provides at least one of the following;

motor function is improved by at least 10%;

the human'"'"'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 human'"'"'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.

6. The method of claim 1, wherein the initial daily amount is 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg and the initial daily amount is administered in two doses.

7. The method of claim 6, wherein:

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

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

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

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

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

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

or

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

8. The method of claim 7, further comprising:

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

d) increasing the daily amount of the deutetrabenazine upward by 6 mg/day to a subsequent daily amount of the deutetrabenazine if the transitioning does not result in at least a maintenance of chorea control and the initial daily amount is tolerable.

9. The method of claim 8, further comprising:

e) after about one week, repeating steps c) and d) in those humans wherein abnormal involuntary movement is reduced and the daily amount of deutetrabenazine is tolerated.

10. The method of claim 9,

decreasing the amount of deutetrabenazine by 6 mg/day to a subsequent daily amount in those humans wherein any subsequent daily amount is not tolerated.

11. The method of claim 9, further comprising repeating step e) until the degree of control of abnormal involuntary movement is adequate and the daily amount of deutetrabenazine is tolerable.

12. The method of claim 1, wherein the initial daily amount is 6 mg and is administered in one dose.

13. The method of claim 1, wherein the initial daily amount of deutetrabenazine is 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, or 42 mg, further comprising:

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

d) increasing the daily amount of the deutetrabenazine by 6 mg/day to a subsequent daily amount in those humans wherein the transitioning does not result in at least a maintenance of chorea control and the initial daily amount is tolerable.

14. The method of claim 13, wherein the subsequent daily amount is 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, or 42 mg, further comprising:

e) after about one week, repeating steps c) and d) in those patients wherein abnormal involuntary movement is reduced and the daily amount of deutetrabenazine is tolerated.

15. The method of claim 14, wherein the daily amount is 18 mg, 24 mg, 30 mg, 36 mg, or 42 mg, further comprising repeating step e) until the degree of control of abnormal involuntary movement is adequate and the daily amount of deutetrabenazine is tolerable.

16. The method of claim 15, wherein the total maximum daily dose is 48 mg.

17. The method of claim 15, where in the total maximum daily dose is 36 mg.

18. The method of claim 17, wherein the human is concurrently receiving a strong CYP2D6 inhibitor.

19. The method of claim 18, wherein the strong CYP2D6 inhibitor is fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, or ritonavir.

20. The method of claim 19, wherein the strong CYP2D6 inhibitor is paroxetine, fluoxetine, or bupropion.

21. The method of claim 1, wherein the daily amount of tetrabenazine is 12.5 mg and the initial total daily amount of deutetrabenazine is 6 mg.

22. The method of claim 1, wherein the daily amount of tetrabenazine is 25 mg and the initial total daily amount of deutetrabenazine is 12 mg.

23. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, wherein the first dose is 6 mg and the second dose is 6 mg.

24. The method of claim 1, wherein the daily amount of tetrabenazine is 37.5 mg and the initial total daily amount of deutetrabenazine is 18 mg.

25. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, wherein the first dose is 9 mg and the second dose is 9 mg.

26. The method of claim 1, wherein the daily amount of tetrabenazine is 50 mg and the initial total daily amount of deutetrabenazine is 24 mg.

27. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, wherein the first dose is 12 mg and the second dose is 12 mg.

28. The method of claim 1, wherein the daily amount of tetrabenazine is 62.5 mg and the initial total daily amount of deutetrabenazine is 30 mg.

29. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, wherein the first dose is 15 mg and the second dose is 15 mg.

30. The method of claim 1, wherein the daily amount of tetrabenazine is 75 mg and the initial total daily amount of deutetrabenazine is 36 mg.

31. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, wherein the first dose is 18 mg and the second dose is 18 mg.

32. The method of claim 1, wherein the daily amount of tetrabenazine is 87.5 mg and the initial total daily amount of deutetrabenazine is 42 mg.

33. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, wherein the first dose is 21 mg and the second dose is 21 mg.

34. The method of claim 1, wherein the daily amount of tetrabenazine is 100 mg and the initial total daily amount of deutetrabenazine is 48 mg.

35. The method of claim 22, wherein the initial total daily amount of deutetrabenazine is administered in two doses, wherein the first dose is 24 mg and the second dose is 24 mg.

36. The method of claim 1, wherein the transitioning results in at least a maintenance of chorea control in the human.

37. The method of claim 1, wherein the initial total daily amount of deutetrabenazine is 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, or 36 mg.

38. The method of claim 37, wherein the human is concurrently receiving a strong CYP2D6 inhibitor.

39. The method of claim 38, wherein the strong CYP2D6 inhibitor is fluoxetine, paroxetine, bupropion, quinidine, cinacalcet, or ritonavir.

40. The method of claim 38, wherein the strong CYP2D6 inhibitor is paroxetine, fluoxetine, or bupropion.