Methods and compositions for treating excessive sleepiness

Patent metadata

Field	Value
Publication number	US-10959976-B2
Application number	US-201816618735-A
Country	US
Kind code	B2
Filing date	Jun 1, 2018
Priority date	Jun 2, 2017
Publication date	Mar 30, 2021
Grant date	Mar 30, 2021

Abstract

The present invention relates to carbamoyl phenylalaninol compounds and methods of using the same to treat disorders. The invention further relates to the development of methods for treating excessive sleepiness in a subject, e.g., due to narcolepsy or obstructive sleep apnea, with the surprising outcome that “normal” levels of wakefulness are achieved based on standard objective and subjective sleepiness tests.

First claim

What is claimed is:

1. A method of improving excessive sleepiness in a human patient in need thereof, said method comprising administering [R]-2-amino-3-phenylpropylcarbamate (APC) or a pharmaceutically acceptable salt thereof to the human patient in accordance with a dosing regimen, said dosing regimen comprising a once-daily dose of 75 mg for at least 3 days followed by a once-daily dose of 150 mg, wherein the once-daily dose of 150 mg is the maximum dose in the dosing regimen, and wherein the APC or pharmaceutically acceptable salt thereof effects an improvement in excessive sleepiness in the human patient by at least 25% as measured by a change in Epworth Sleepiness Scale (ESS) score from baseline at the 12th week of the dosing regimen.

2. The method of claim 1 , wherein the dosing regimen comprises a starting dose of 75 mg once daily for 3 days followed by a dose of 150 mg once daily.

3. The method of claim 1 , wherein the patient has a baseline ESS score greater than 10.

4. The method of claim 1 , wherein the excessive sleepiness is excessive daytime sleepiness.

5. The method of claim 1 , wherein the APC is provided as a pharmaceutically acceptable salt of APC.

6. The method of claim 5 , wherein the APC is in the form of a hydrochloride salt.

7. The method of claim 1 , wherein the patient has narcolepsy.

8. The method of claim 1 , wherein the patient has obstructive sleep apnea (OSA).

9. A method of treating excessive sleepiness in a human patient with narcolepsy in need thereof, said method comprising orally administering [R]-2-amino-3-phenylpropylcarbamate (APC) or a pharmaceutically acceptable salt thereof to the human patient in accordance with a dosing regimen comprising a starting dose of 75 mg once daily for at least 3 days followed by a dose of 150 mg once daily, wherein the once-daily dose of 150 mg is the maximum dose in the dosing regimen.

10. The method of claim 9 , wherein the dosing regimen comprises a starting dose of 75 mg once daily for 3 days followed by a dose of 150 mg once daily.

11. The method of claim 9 , wherein the APC or pharmaceutically acceptable salt thereof effects an improvement in excessive sleepiness in the human patient by at least 25% as measured by a change in Epworth Sleepiness Scale (ESS) score from baseline at the 12th week of the dosing regimen.

12. The method of claim 9 , wherein the excessive sleepiness is excessive daytime sleepiness.

13. The method of claim 9 , wherein the APC is provided as a pharmaceutically acceptable salt of APC.

14. The method of claim 13 , wherein the APC is provided in the form of a hydrochloride salt.

15. A method of improving excessive sleepiness in a human patient in need thereof, said method comprising administering [R]-2-amino-3-phenylpropylcarbamate (APC) or a pharmaceutically acceptable salt thereof to the human patient in accordance with a dosing regimen, said dosing regimen comprising a once-daily dose of 75 mg for at least 3 days followed by a once-daily dose of 150 mg, wherein the once-daily dose of 150 mg is the maximum dose in the dosing regimen, and wherein the APC or pharmaceutically acceptable salt thereof effects an improvement in excessive sleepiness in the human patient by at least 25% as measured by a change in Maintenance of Wakefulness Test (MWT) score from baseline at the 12th week of the dosing regimen.

16. The method of claim 15 , wherein the dosing regimen comprises a starting dose of 75 mg once daily for 3 days followed by a dose of 150 mg once daily.

17. The method of claim 15 , wherein the patient has a baseline ESS score greater than 10.

18. The method of claim 15 , wherein the excessive sleepiness is excessive daytime sleepiness.

19. The method of claim 15 , wherein the APC is provided as a pharmaceutically acceptable salt of APC.

20. The method of claim 19 , wherein the APC is in the form of a hydrochloride salt.

21. The method of claim 15 , wherein the patient has narcolepsy.

22. The method of claim 15 , wherein the patient has OSA.

23. A method of providing [R]-2-amino-3-phenylpropylcarbamate (APC) or a pharmaceutically acceptable salt thereof to a subject in need thereof according to a dose escalation regimen, said method comprising
administering to the subject a daily dose of 75 mg APC for at least 3 days; and
increasing the daily dose not more than once every 3 days until a maximum tolerated dose is achieved in the subject, wherein a once-daily dose of 150 mg is the maximum dose in the dosing regimen.

24. The method of claim 23 , wherein the daily dose is increased not more than once every 4, 5, 6, or 7 days.

25. The method of claim 23 , wherein a first increase in the daily dose is an increase to a daily dose of 150 mg APC.

26. The method of claim 23 , further comprising decreasing the daily dose not more than once every 3 days if the subject exhibits signs that the previously provided daily dose exceeds the maximum tolerated dose.

27. The method of claim 26 , wherein the daily dose is decreased not more than once every 4, 5, 6, or 7 days.

28. The method of claim 26 , wherein the decrease in the daily dose is a decrease to a daily dose of 75 mg APC.

29. The method of claim 26 , wherein the decrease in the daily dose is a decrease to a daily dose of 37.5 mg APC.

30. The method of claim 23 , wherein the APC is provided as a pharmaceutically acceptable salt of APC.

31. The method of claim 30 , wherein the APC is provided as the hydrochloride salt.

32. The method of claim 23 , wherein the subject is provided APC or a pharmaceutically acceptable salt thereof for the treatment of excessive daytime sleepiness.

33. The method of claim 32 , wherein the excessive daytime sleepiness is associated with narcolepsy.

34. The method of claim 32 , wherein the excessive daytime sleepiness is associated with obstructive sleep apnea.

Assignees

• Jazz Pharmaceuticals Ireland Ltd

Inventors

• Carter Lawrence Patrick
• Lu Yuan
• Zomorodi Katayoun

Classifications

• A61K9/2013

  Organic compounds, e.g. phospholipids, fats · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61P25/00 Primary

  Drugs for disorders of the nervous system · CPC title

• A61K31/27 Primary

  of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine · CPC title

• A61K9/20

  Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)} · CPC title