# US 9,433,617 B1 · Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,433,617 B1
- Document ID: US9433617B1
- Status: Granted
- Kind: B1
- Application number: 15/155,647
- Filed: 2016-05-16
- Published: 2016-09-08
- Granted: 2016-09-06
- Earliest claimed: 2004-03-05
- Assignees: The Trustees of the University of Pennsylvania
- Applicants: The Trustees of the University of Pennsylvania
- Inventors: Daniel J. Rader
- Web page: https://patentgrep.com/patent/US9433617B1

## CPC

- A61K 31/4468: having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/21: Esters, e.g. nitroglycerine, selenocyanates
- A61K 31/405: Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61P 3/06: Antihyperlipidemics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 31/52: Purines, e.g. adenine
- 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

## 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

### Claim 1

A method of treating a subject suffering from hyperlipidemia or hypercholesterolemia, the method comprising orally administering to the subject an effective amount of an MTP inhibitor, wherein said administration comprises three step-wise, increasing dose levels of the MTP inhibitor, wherein each dose level is 50% of the immediately following dose level, wherein the third dose level is about 0.2 to about 0.59 mg/kg/day, and 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 each dose level is administered about 1 to about 12 weeks.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The method of claim 1, where each dose level is administered about 7 to about 35 days.

### Claim 4 (depends on 1)

The method of claim 1, wherein the first dose level is administered for about 2 weeks and the second and third dose levels are each administered for about 4 weeks.

### Claim 5 (depends on 1)

The method of claim 1, wherein administration further comprises a fourth dose level, wherein the third dose level is 50% of the fourth dose level.

### Claim 6 (depends on 5)

The method of claim 5, upon administration, the LDL-cholesterol of the subject is reduced by at least 25% compared to pre-treatment levels.

### Claim 7 (depends on 1)

The method of claim 1, wherein upon administration the subject has reduced symptoms of steatorrhea and/or hepatic fat as compared to a subject administered a starting dose of 25 mg/day of the MTP inhibitor.

### Claim 8

A method of treating a subject suffering from hyperlipidemia or hypercholesterolemia the method comprising administering to the subject an effective amount of an MTP inhibitor, wherein said administration comprises at least three step-wise, increasing dose levels of the MTP inhibitor, wherein each dose level is 50% of the immediately following dose level, wherein the second dose level is about 0.06 mg/kg/day to about 0.19 mg/kg/day, wherein the MTP inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′-(trifluoromethyl)[l,r-biphenyl]-2-yl] carbonyl] amino]-l-piperidinyl]butyl]-9H-fluorene-9-carboxamide, methanesulfonate, and wherein each dose level is administered about 1 to about 12 weeks.

### Claim 9 (depends on 8)

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

### Claim 10 (depends on 8)

The method of claim 8, where each dose level is administered about 7 to about 35 days.

### Claim 11 (depends on 8)

The method of claim 8, wherein the first dose level is administered for about 2 weeks and the second and third dose levels are each administered for about 4 weeks.

### Claim 12 (depends on 8)

The method of claim 8, wherein said increasing dose levels further comprise a fourth dose level, wherein the third dose level is 50% of the fourth dose level.

### Claim 13 (depends on 12)

The method of claim 12, upon administration, the LDL-cholesterol of the subject is reduced by at least 25% compared to pre-treatment levels.

### Claim 14 (depends on 8)

The method of claim 8, wherein upon administration the subject has reduced symptoms of steatorrhea and/or hepatic fat as compared to a subject administered a starting dose of 25 mg/day of the MTP inhibitor.

### Claim 15

A method of treating a subject suffering from hyperlipidemia or hypercholesterolemia, the method comprising administering to the subject an effective amount of an MTP inhibitor, wherein said administration comprises three step-wise, increasing dose levels of the MTP inhibitor, wherein each dose level is no more than 50% of the immediately following dose level, and wherein the first dose level is about 0.02 to about 0.059 mg/kg/day, the second dose level is about 0.06 mg/kg/day to about 0.19 mg/kg/day, and the third dose level is about 0.2 to about 0.59 mg/kg/day; wherein the MTP inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′-(trifluoromethyl)[l,r-biphenyl]-2-yl] carbonyl] amino]-l-piperidinyl]butyl]-9H-fluorene-9-carboxamide, methanesulfonate; and wherein each dose level is administered about 1 to about 12 weeks.

### Claim 16 (depends on 15)

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

### Claim 17 (depends on 15)

The method of claim 15, where each dose level is administered about 7 to about 35 days.

### Claim 18 (depends on 15)

The method of claim 15, wherein said increasing dose levels further comprise a fourth dose level, wherein the fourth dose level is about 0.6 to about 2.0 mg/kg/day.

### Claim 19 (depends on 18)

The method of claim 18, upon administration, the LDL-cholesterol of the subject is reduced by at least 25% compared to pre-treatment levels.

### Claim 20 (depends on 15)

The method of claim 15, wherein upon administration the subject has reduced symptoms of steatorrhea and/or hepatic fat as compared to a subject administered a starting dose of 25 mg/day of the MTP inhibitor.