Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side effects

• US 10,016,404 B2
• Filed: 05/25/2017
• Issued: 07/10/2018
• Est. Priority Date: 03/05/2004
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Rader, Daniel J.
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US15/605,548
• Publication Number:
  US 20170258776A1
• Time in Patent Office: 411 Days
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention provides methods and compositions for treating hyperlipidemia and/or hypercholesterolemia comprising administering to the subject an effective amount of an MTP inhibitor to inhibit hyperlipidemia and/or hypercholesterolemia in said subject, wherein said administration comprises an escalating series of doses of the MTP inhibitor. In some embodiments the method comprises administering at least three step-wise, increasing dosages of the MTP inhibitor to the subject. In some embodiments, the method further comprises the administration of one or more other lipid modifying compounds.

Claims

1. A method of treating a human subject suffering from hyperlipidemia or hypercholesterolemia, the method comprising administering to the human subject an effective amount of an MTP inhibitor, the administration of the MTP inhibitor comprising three step-wise, increasing dose levels of the MTP inhibitor, wherein each of the dose levels is no more than 50% of the immediately following dose level;

wherein each of the dose levels is administered for about 1 to about 12 weeks;

wherein the MTP inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′

(trifluoromethyl)[1,1′

-biphenyl]-2-yl] carbonyl] amino]-1-piperidinyl]butyl]-9H-fluorene-9 carboxamide, methanesulfonate; and

wherein the administration of the MTP inhibitor reduces total cholesterol of the human subject by at least 30% as compared to control blood levels.

2. The method of claim 1, wherein the human subject suffering from hyperlipidemia or hypercholesterolemia has homozygous familial hypercholesterolemia.

3. The method of claim 1, wherein the administration of the MTP inhibitor further comprises a fourth dose level, and wherein the third dose level is no more than 50% of the fourth dose level.

4. The method of claim 1, wherein the administration of the MTP inhibitor reduces non-high- density lipoprotein cholesterol of the human subject by at least 30% as compared to control blood levels.

5. The method of claim 1, wherein the administration of the MTP inhibitor minimizes side effects as compared to administration of the MTP inhibitor to a human subject at a starting dose of 25 mg/day.

6. The method of claim 5, wherein the side effects minimized by the administration of the MTP inhibitor comprise an increase in liver transaminases, an increase in hepatic fat, or a combination thereof.

7. A method of treating a human subject suffering from hyperlipidemia or hypercholesterolemia, the method comprising administering to the human subject an effective amount of an MTP inhibitor, the administration of the MTP inhibitor comprising three step-wise, increasing dose levels of the MTP inhibitor, wherein each of the dose levels is no more than 50% of the immediately following dose level;

wherein each of the dose levels is administered for about 1 to about 12 weeks;

wherein the MTP inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′

(trifluoromethyl)[1,1′

-biphenyl]-2-yl] carbonyl] amino]-1-piperidinyl]butyl]-9H-fluorene-9 carboxamide, methanesulfonate; and

wherein the administration of the MTP inhibitor minimizes side effects as compared to administration of the MTP inhibitor to a human subject at a starting dose of 25 mg/day.

8. The method of claim 7, wherein the human subject suffering from hyperlipidemia or hypercholesterolemia has homozygous familial hypercholesterolemia.

9. The method of claim 7, wherein the administration of the MTP inhibitor further comprises a fourth dose level, and wherein the third dose level is no more than 50% of the fourth dose level.

10. The method of claim 7, wherein the administration of the MTP inhibitor reduces non-high- density lipoprotein cholesterol of the human subject by at least 30% as compared to control blood levels.

11. The method of claim 7, wherein the side effects minimized by the administration of the MTP inhibitor comprise an increase in liver transaminases, an increase in hepatic fat, or a combination thereof.

12. The method of claim 11, wherein the side effects minimized by the administration of the MTP inhibitor comprise an increase in hepatic fat.

13. The method of claim 12, wherein the increase in hepatic fat is not greater than 37% from baseline.

14. A method of treating a human subject suffering from hyperlipidemia or hypercholesterolemia, the method comprising administering to the human subject an effective amount of an MTP inhibitor, the administration of the MTP inhibitor comprising three step-wise, increasing dose levels of the MTP inhibitor, wherein each of the dose levels is no more than 50% of the immediately following dose level;

wherein each of the dose levels is administered for about 1 to about 12 weeks;

wherein the first dose level is sub-therapeutic;

wherein the MTP inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′

(trifluoromethyl)[1,1′

-biphenyl]-2-yl] carbonyl] amino]-1-piperidinyl]butyl]-9H-fluorene-9 carboxamide, methanesulfonate; and

wherein the administration of the MTP inhibitor reduces total cholesterol of the human subject by at least 30% as compared to control blood levels.

15. The method of claim 14, wherein the human subject suffering from hyperlipidemia or hypercholesterolemia has homozygous familial hypercholesterolemia.

16. The method of claim 14, wherein the administration of the MTP inhibitor further comprises a fourth dose level, and wherein the third dose level is no more than 50% of the fourth dose level.

17. The method of claim 14, wherein the administration of the MTP inhibitor reduces non-high- density lipoprotein cholesterol of the human subject by at least 30% as compared to control blood levels.

18. The method of claim 14, wherein the administration of the MTP inhibitor minimizes side effects as compared to administration of the MTP inhibitor to a human subject at a starting dose of 25 mg/day.

19. The method of claim 18, wherein the side effects minimized by the administration of the MTP inhibitor comprise an increase in liver transaminases, an increase in hepatic fat, or a combination thereof.

20. A method of treating a human subject suffering from hyperlipidemia or hypercholesterolemia, the method comprising administering to the human subject an effective amount of an MTP inhibitor, the administration of the MTP inhibitor comprising three step-wise, increasing dose levels of the MTP inhibitor, wherein each of the dose levels is no more than 50% of the immediately following dose level;

wherein each of the dose levels is administered for about 1 to about 12 weeks;

wherein the first dose level is sub-therapeutic;

wherein the MTP inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′

(trifluoromethyl)[1,1′

-biphenyl]-2-yl] carbonyl] amino]-1-piperidinyl]butyl]-9H-fluorene-9 carboxamide, methanesulfonate; and

wherein the administration of the MTP inhibitor minimizes side effects as compared to administration of the MTP inhibitor to a human subject at a starting dose of 25 mg/day.

21. The method of claim 20, wherein the human subject suffering from hyperlipidemia or hypercholesterolemia has homozygous familial hypercholesterolemia.

22. The method of claim 20, wherein the administration of the MTP inhibitor further comprises a fourth dose level, and wherein the third dose level is no more than 50% of the fourth dose level.

23. The method of claim 20, wherein the administration of the MTP inhibitor reduces non-high- density lipoprotein cholesterol of the human subject by at least 30% as compared to control blood levels.

24. The method of claim 20, wherein the side effects minimized by the administration of the MTP inhibitor comprise an increase in liver transaminases, an increase in hepatic fat, or a combination thereof.

25. The method of claim 24, wherein the side effects minimized by the administration of the MTP inhibitor comprise an increase in hepatic fat.

26. The method of claim 25, wherein the increase in hepatic fat is not greater than 37% from baseline.