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WO1998001100A2 - Method for treating homozygous familial hypercholesterolemia - Google Patents

Method for treating homozygous familial hypercholesterolemia Download PDF

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Publication number
WO1998001100A2
WO1998001100A2 PCT/US1997/011792 US9711792W WO9801100A2 WO 1998001100 A2 WO1998001100 A2 WO 1998001100A2 US 9711792 W US9711792 W US 9711792W WO 9801100 A2 WO9801100 A2 WO 9801100A2
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WO
WIPO (PCT)
Prior art keywords
simvastatin
day
ldl
familial hypercholesterolemia
homozygous familial
Prior art date
Application number
PCT/US1997/011792
Other languages
French (fr)
Other versions
WO1998001100A3 (en
Inventor
Yale B. Mitchel
Jonathan A. Tobert
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9617898.3A external-priority patent/GB9617898D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU42289/97A priority Critical patent/AU4228997A/en
Publication of WO1998001100A2 publication Critical patent/WO1998001100A2/en
Publication of WO1998001100A3 publication Critical patent/WO1998001100A3/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • A61K31/366Lactones having six-membered rings, e.g. delta-lactones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring

Definitions

  • Homozygous familial hypercholesterolemia is a rare disorder characterized by the presence of two abnormal low density lipoprotein (LDL) receptor genes which results in the patient having dysfunctional LDL receptors. This results in severe hypercholesterolemia, particularly extreme elevations in LDL levels, and rapid development of coronary atherosclerosis and coronary heart disease in those who suffer with HFH. Most patients develop coronary disease in adolescence and usually do not survive beyond their teen-age years.
  • LDL low density lipoprotein
  • HMG-CoA reductase inhibitors such as compactin, lovastatin, simvastatin, pravastatin, etc., are believed to work by upregulating LDL receptor activity and increasing LDL removal from the blood. Since FH homozygotes do not have functional LDL receptors, this class of drugs was generally believed to be ineffective in these patients. Previous experience with HMG-CoA reductase inhibitors in FH homozygote children bore this out. For example, in J.
  • LDL aphaeresis is a technique where plasma is removed from patients and run over columns either with an antibody to apo B or reagents to precipitate LDL. It is usually performed once every two weeks in this population with about a 70% reduction in LDL cholesterol immediately after the procedure, with levels returning to baseline at one week post- treatment. Both treatment options are associated with considerable morbidity and are in limited supply.
  • atorvastatin a second-generation HMG-CoA reductase inhibitor, atorvastatin, has been shown to be useful for treating HFH.
  • simvastatin (marketed in the U.S. under the trademark ZOCOR®) in doses above 40 mg per day can be used to treat patients suffering with HFH.
  • the main object of the instant invention is to provide a method for treating homozygous familial hypercholesterolemia comprising administering a therapeutically effective amount of simvastatin to a person in need of such treatment.
  • a person in need of such treatment is one who has homozygous familial hypercholesterolemia. Additional objects will be evident from the following detailed description.
  • simvastatin in daily dosages above 40 mg are useful for the treatment of HFH.
  • the daily dosage is at least 80 mg, and more preferably, at least 160 mg.
  • the compound may be administered in a single daily dose, or divided doses, for example two, three or four times daily.
  • Simvastatin may also be administered in a sustained release formulation, for example employing the formulation described in U.S. Patent No. 5,366,738. Sustained release and daily divided dose administration is preferred.
  • the following study results demonstrate the usefulness of simvastatin in the treatment of HFH.
  • T-C total cholesterol
  • LDL-C low density lipoprotein cholesterol
  • TRIG triglyceride level
  • HDL-C high density lipoprotein cholesterol
  • simvastatin at therapeutically effective doses of 80 mg/day and higher is effective in lowering LDL-C in patients suffering with homozygous familial hypercholesterolemia.
  • simvastatin may be administered as monotherapy to a patient suffering with HFH, or it may be administered in combination with other therapies which are suitable for the treatment of HFH.
  • simvastatin may be co-adminstered with one or more additional drugs which are effective in lowering LDL cholesterol such as HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol; cholesterol abso ⁇ tion inhibitors; and bile acid sequestrants.
  • Agents such as aspirin and beta-blockers may also be co- administered with simvastatin.
  • Simvastatin may also be administered in conjunction with therapies such as

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Homozygous familial hypercholesterolemia can be treated in patients suffering with this condition by administering a therapeutically effective amount of simvastatin. Dosages above 40 mg/day, and more particularly at or above 80 mg/day, were found to effectively reduce the LDL cholesterol levels in these patients.

Description

TITLE OF THE INVENTION
METHOD FOR TREATING HOMOZYGOUS FAMILIAL
HYPERCHOLESTEROLEMIA
RELATED APPLICATIONS
This application is a continuing application and claims priority to U.S. provisional application number 60/021 ,420, filed July 9, 1996, and to U.S. provisional application number 60/029,351, filed October 31 ,1996.
BACKGROUND OF THE INVENTION
Homozygous familial hypercholesterolemia (HFH) is a rare disorder characterized by the presence of two abnormal low density lipoprotein (LDL) receptor genes which results in the patient having dysfunctional LDL receptors. This results in severe hypercholesterolemia, particularly extreme elevations in LDL levels, and rapid development of coronary atherosclerosis and coronary heart disease in those who suffer with HFH. Most patients develop coronary disease in adolescence and usually do not survive beyond their teen-age years.
HMG-CoA reductase inhibitors such as compactin, lovastatin, simvastatin, pravastatin, etc., are believed to work by upregulating LDL receptor activity and increasing LDL removal from the blood. Since FH homozygotes do not have functional LDL receptors, this class of drugs was generally believed to be ineffective in these patients. Previous experience with HMG-CoA reductase inhibitors in FH homozygote children bore this out. For example, in J. Thiery, et al., European Journal of Pediatrics, (1990) 149: 716-721 , it is noted that compactin, at dosages as high as 200 mg per day, and lovastatin caused only marginal lowering of LDL cholesterol levels in HFΗ patients and therefore were not considered to be useful therapies for this condition.
The treatment options available to those suffering with HFH have been limited to liver transplantation or LDL aphaeresis therapy. LDL aphaeresis is a technique where plasma is removed from patients and run over columns either with an antibody to apo B or reagents to precipitate LDL. It is usually performed once every two weeks in this population with about a 70% reduction in LDL cholesterol immediately after the procedure, with levels returning to baseline at one week post- treatment. Both treatment options are associated with considerable morbidity and are in limited supply.
More recently, a second-generation HMG-CoA reductase inhibitor, atorvastatin, has been shown to be useful for treating HFH.
Contrary to what was previously believed due to the nature of HFH and the mechanism of action understood to be associated with HMG-CoA reductase inhibitors as well as the available published studies in this field, it has been discovered that simvastatin (marketed in the U.S. under the trademark ZOCOR®) in doses above 40 mg per day can be used to treat patients suffering with HFH.
SUMMARY OF THE INVENTION
The main object of the instant invention is to provide a method for treating homozygous familial hypercholesterolemia comprising administering a therapeutically effective amount of simvastatin to a person in need of such treatment. A person in need of such treatment is one who has homozygous familial hypercholesterolemia. Additional objects will be evident from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that simvastatin in daily dosages above 40 mg are useful for the treatment of HFH. Preferably, the daily dosage is at least 80 mg, and more preferably, at least 160 mg. The compound may be administered in a single daily dose, or divided doses, for example two, three or four times daily. Simvastatin may also be administered in a sustained release formulation, for example employing the formulation described in U.S. Patent No. 5,366,738. Sustained release and daily divided dose administration is preferred. The following study results demonstrate the usefulness of simvastatin in the treatment of HFH.
I. Study Design
Design: double blinded, randomized, parallel, dose-escalation, controlled, 1 week study
Patients: 12 patients with well-characterized HFH Treatment: After a 4 week placebo diet run in period, the 12 patients were randomized to simvastatin (S) 80 mg/day (group 1 , n=8) or 40 mg/day (group 2, n=4). After 9 weeks, the dose in group 1 was increased to 160 mg/day while the dose in group 2 was kept at 40 mg/day and treatment continued for an additional 9 weeks. Simvastatin was administered orally. The simvastatin treatment information is summarized in the table, below.
Period 1 (9 weeks) Period 2 (9 weeks)
Group 1 (n=8): 80 mg/day in 3 divided 160 mg/day in 3 divided doses doses Group 2 (n=4): 40 mg/day once a day 40 mg/day in 3 divided doses
Endpoint: Change in low density lipoprotein cholesterol
II. Study Results
The results of the study are as follows. For T-C, LDL-C and HDL-C, mean baseline and mean % change from baseline are shown; for TRIG, median baseline and median % change from baseline are shown: GROUP 1 GROUP 2
(n=8) (n=4)
BL 80 160 BL 40 40
(mg/dl) mg/day mg/day (mg/dl) mg/day mg/day tid dosing tid dosing hs tid dosing
% change % change % change % change
T-C 627 -23 -29 562 -12 -13
LDL-C 570 -25 -31 519 -14 - 15
TRIG 136 -9 -15 72 7 - 1 1
HDL-C 32 12 6 28 1 1 17
BL = baseline
T-C = total cholesterol
LDL-C = low density lipoprotein cholesterol
TRIG = triglyceride level
HDL-C = high density lipoprotein cholesterol
All 12 patients completed the trial and there were no serious or unexpected adverse events. No patients sustained significant hepatic transaminase or creatine kinase elevations.
As can be seen from the above study results, simvastatin at therapeutically effective doses of 80 mg/day and higher is effective in lowering LDL-C in patients suffering with homozygous familial hypercholesterolemia.
As such, simvastatin may be administered as monotherapy to a patient suffering with HFH, or it may be administered in combination with other therapies which are suitable for the treatment of HFH. For example, simvastatin may be co-adminstered with one or more additional drugs which are effective in lowering LDL cholesterol such as HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol; cholesterol absoφtion inhibitors; and bile acid sequestrants. Agents such as aspirin and beta-blockers may also be co- administered with simvastatin. Simvastatin may also be administered in conjunction with therapies such as LDL aphaeresis.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated. Likewise, the specific pharmacological responses observed may vary depending upon the particular pharmaceutical carriers employed, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A method of treating homozygous familial hypercholesterolemia comprising administering a therapeutically effective amount of simvastatin to a person in need of such treatment.
2. The method of claim 1 wherein the daily dosage of simvastatin is more than 40 mg.
3. The method of claim 2 wherein the daily dosage of simvastatin is at least 80 mg.
4. The method of claim 3 wherein the daily dosage of simvastatin is 80 mg.
5. The method of claim 2 wherein the daily dosage of simvastatin is at least 160 mg.
6. The method of claim 5 wherein the daily dosage of simvastatin is 160 mg.
7. The method of claim 1 wherein the simvastatin is administered in a single daily dose.
8. The method of claim 1 wherein the simvastatin is administered in divided daily doses.
9. The method of claim 1 wherein the simvastatin is administered in a controlled time-release formulation.
PCT/US1997/011792 1996-07-09 1997-07-03 Method for treating homozygous familial hypercholesterolemia WO1998001100A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU42289/97A AU4228997A (en) 1996-07-09 1997-07-03 Method for treating homozygous familial hypercholesterolemia

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US2142096P 1996-07-09 1996-07-09
US60/021,420 1996-07-09
GB9617898.3 1996-08-28
GBGB9617898.3A GB9617898D0 (en) 1996-08-28 1996-08-28 Method for treating homozygous familial hypercholesterolemia
US2935196P 1996-10-31 1996-10-31
US60/029,351 1996-10-31

Publications (2)

Publication Number Publication Date
WO1998001100A2 true WO1998001100A2 (en) 1998-01-15
WO1998001100A3 WO1998001100A3 (en) 1998-02-12

Family

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Family Applications (3)

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PCT/US1997/012426 WO1998001116A1 (en) 1996-07-09 1997-07-03 Therapy for combined hyperlipidemia
PCT/US1997/011792 WO1998001100A2 (en) 1996-07-09 1997-07-03 Method for treating homozygous familial hypercholesterolemia
PCT/US1997/010867 WO1998001119A2 (en) 1996-07-09 1997-07-03 Pharmaceutical compositions comprising simvastatin

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PCT/US1997/012426 WO1998001116A1 (en) 1996-07-09 1997-07-03 Therapy for combined hyperlipidemia

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US1997/010867 WO1998001119A2 (en) 1996-07-09 1997-07-03 Pharmaceutical compositions comprising simvastatin

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WO (3) WO1998001116A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
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WO2000018395A1 (en) * 1998-09-30 2000-04-06 Warner-Lambert Company Method for preventing or delaying catheter-based revascularization
WO2003055991A1 (en) * 2001-12-21 2003-07-10 Rigshospitalet Igamete recruitment and developmental competence in mammals by inhibiting the de novo sterol biosynthesis and/or promoting sterol efflux
US6627757B2 (en) 2001-03-28 2003-09-30 Schering Corporation Enantioselective synthesis of azetidinone intermediate compounds
US9056915B2 (en) 2007-08-23 2015-06-16 Amgen Inc. Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9)

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US20030212996A1 (en) * 1996-02-08 2003-11-13 Wolzien Thomas R. System for interconnection of audio program data transmitted by radio to remote vehicle or individual with GPS location
US6982251B2 (en) 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
US7071181B2 (en) 2001-01-26 2006-07-04 Schering Corporation Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors
IL156422A0 (en) 2001-01-26 2004-01-04 Schering Corp The use of substituted azetidinone compounds for the treatment of sitosterolemia
CA2563051A1 (en) 2001-01-26 2002-08-01 Schering Corporation Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications
US7053080B2 (en) 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
ATE345793T1 (en) 2001-09-21 2006-12-15 Schering Corp TREATMENT OF XANTHOMA USING AZETIDINONE DERIVATIVES AS STEROL ABSORPTION INHIBITORS
US7056906B2 (en) 2001-09-21 2006-06-06 Schering Corporation Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women
AR040588A1 (en) 2002-07-26 2005-04-13 Schering Corp PHARMACEUTICAL FORMULATION INCLUDING AN INHIBITOR OF CHOLESTEROL ABSORPTION AND AN INHIBITOR OF A HMGCO TO REDUCTASE
WO2004043456A1 (en) 2002-11-06 2004-05-27 Schering Corporation Cholesterol absorption inhibitors for the treatment of demyelination
US7459442B2 (en) 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
ES2318274T3 (en) 2003-03-07 2009-05-01 Schering Corporation AZETIDINONA SUBSTITUTED COMPOUNDS, FORMULATIONS AND USE OF THE SAME FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA.
JP2006519869A (en) 2003-03-07 2006-08-31 シェーリング コーポレイション Substituted azetidinone compounds, processes for preparing substituted azetidinone compounds, their formulations and uses
ATE406364T1 (en) 2003-03-07 2008-09-15 Schering Corp SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE IN THE TREATMENT OF HYPERCHOLESTEROLEMIA

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806564A (en) * 1987-05-26 1989-02-21 Merck & Co., Inc. Antihypercholesterolemic beta-lactones
US4997849A (en) * 1989-06-23 1991-03-05 Merck & Co., Inc. Microbial transformation of simvastatin
US5393893A (en) * 1993-11-08 1995-02-28 Apotex, Inc. Process for producing simvastatin and analogs thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018395A1 (en) * 1998-09-30 2000-04-06 Warner-Lambert Company Method for preventing or delaying catheter-based revascularization
EA007427B1 (en) * 1998-09-30 2006-10-27 Варнер Ламберт Компани Method for preventing or delaying catheter-based revascularization
AP1708A (en) * 1998-09-30 2007-01-10 Warner Lambert Co Method for preventing or delaying catheter-based revascularization.
US6627757B2 (en) 2001-03-28 2003-09-30 Schering Corporation Enantioselective synthesis of azetidinone intermediate compounds
WO2003055991A1 (en) * 2001-12-21 2003-07-10 Rigshospitalet Igamete recruitment and developmental competence in mammals by inhibiting the de novo sterol biosynthesis and/or promoting sterol efflux
US9056915B2 (en) 2007-08-23 2015-06-16 Amgen Inc. Antigen binding proteins to proprotein convertase subtilisin kexin type 9 (PCSK9)
US9920134B2 (en) 2007-08-23 2018-03-20 Amgen Inc. Monoclonal antibodies to proprotein convertase subtilisin kexin type 9 (PCSK9)

Also Published As

Publication number Publication date
AU4228997A (en) 1998-02-02
AU4326197A (en) 1998-02-02
WO1998001100A3 (en) 1998-02-12
AU3667297A (en) 1998-02-02
WO1998001116A1 (en) 1998-01-15
WO1998001119A2 (en) 1998-01-15

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