AU769897B2

AU769897B2 - Use of cholesterol-lowering agent

Info

Publication number: AU769897B2
Application number: AU23051/00A
Authority: AU
Inventors: Ali Raza
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 1999-02-06
Filing date: 2000-02-01
Publication date: 2004-02-05
Anticipated expiration: 2020-02-01
Also published as: NZ512681A; NO20013810D0; IS5996A; WO2000045819A1; CA2358641A1; TR200102236T2; MY136382A; IL144662A0; HK1040924A1; NO20013810L; BR0007991A; CZ20012631A3; AR022462A1; NO319827B1; CN1347320A; EE200100404A; HUP0105019A2; SK11112001A3; HUP0105019A3; KR20010089631A

Description

WO 00/45819 PCT/GBOO/00285 -1- USE OF CHOLESTEROL-LOWERING AGENT The present invention relates to the use of a cholesterol-lowering agent, and more particularly to the administration of a particular dose or dosage range of the HMG CoA reductase inhibitor, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid and pharmaceutically acceptable salts thereof, hereinafter referred to as "the Agent" and illustrated (as the calcium salt) in formula I hereinafter. The invention further relates to the dosage range, start dose and dosage forms of the Agent.

The Agent is disclosed in European Patent Application, Publication No. 0521471, and in Bioorganic and Medicinal Chemistry, (1997), 437-444 as an inhibitor of 3-hydroxy-3methylglutaryl CoA reductase (HMG-CoA reductase) which is a major rate-limiting enzyme in cholesterol biosynthesis. The Agent is taught as useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. HMG-CoA reductase inhibitors are the most widely used prescription medication for the treatment of hypercholesterolaemia. A number of HMG-CoA reductase inhibitors are marketed, namely lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and cerivastatin, and are collectively referred to as 'statins'. Despite the benefits of statin therapy, less than optimal results may be achieved in patients, due to the level of efficacy and safety achieved at the recommended dosages of the currently marketed statins. Accordingly it is important to find dosages of alternative statins which beneficially alter lipid levels to a significantly greater extent than similar dosages of currently used statins and which have a similar or improved safety profile.

Surprisingly it has now been found that when dosed orally to patients with hypercholesterolemia at particular dosages or in a particular dosage range the Agent lowers total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) by an unexpected degree, and without any significant adverse side effects. When dosed at the same dosages or in the same dosage range, the Agent also modifies other lipoprotein levels (such as raising high density lipid cholesterol (HDL-C) levels, lowering triglyceride (TG) levels and lowering apolipoprotein B-100 (Apo-B) levels) to an unexpected and beneficial extent, without any significant adverse side effects. Elevations of alanine aminotransferase (ALT) liver enzyme levels are reported for other HMG-CoA reductase inhibitors. Surprisingly it has now been WO 00/45819 PCT/GBOO/00285 -2found that when the Agent is dosed at the dosages or in the dosage ranges discussed herein, clinically significant rises in these levels are less frequently observed.

Accordingly, one aspect of the present invention comprises a method of lowering LDL-C levels by 40% or more, and/or lowering total cholesterol levels by 30% or more, and/or lowering triglyceride levels by 10% or more, and/or lowering apolipoprotein B-100 levels by 30% or more, and/or raising HDL-C levels by 5% or more, in a patient in need thereof, by administration of 5 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of treatment of hypercholesterolemia in a patient in need thereof by administration of 5 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of lowering LDL-C levels by 40% or more in a patient in need thereof by administration of 5 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of lowering LDL-C levels by 45% or more in a patient in need thereof by administration of 10 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of lowering LDL-C levels by 50% or more in a patient in need thereof by administration of 10 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of lowering LDL-C levels by 55% or more in a patient in need thereof by administration of 20 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of lowering LDL-C levels by 60% or more in a patient in need thereof by administration of 40 to 80 mg per day of the Agent.

A preferred feature of the present invention comprises a method of treatment as described above wherein the LDL-C level of the patient prior to treatment with the Agent, when measured after 12 hours of fasting (water permitted) is 4.1 mmol/litre or more.

A further aspect of the present invention comprises a method of lowering total cholesterol levels by 30% or more in a patient in need thereof by administration of 10 to mg per day of the Agent.

WO 00/45819 PCT/GBOO/00285 -3- A further aspect of the present invention comprises a method of lowering total cholesterol levels by 35% or more in a patient in need thereof by administration of 10 to mg per day of the Agent.

A further aspect of the present invention comprises a method of lowering total cholesterol levels by 40% or more in a patient in need thereof by administration of 40 to mg per day of the Agent.

A further aspect of the present invention comprises a method of treating a hypercholesterolemic patient to bring said patient within recommended NCEP guidelines (or other recognised guidelines) by administration of 5 to 80 mg per day of the Agent.

Recommended NCEP guidelines refer to the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) II target LDL-C levels, which are incorporated herein by reference. A summary of these guidelines is given in JAMA, June 16, 1993-Vol 629, No. 23, pages 3015-3023, particularly Figue 1 ,page 3018-3019. NCEP guidelines recommend that patients with clinically evident coronary heart disease (CHD), such as documented atherosclerosis, are titrated to LDL-C concentrations less than or equal to 100 mg/dl. Other recognised guidelines includes the European Atherosclerosis Society (EAS) guidelines, which recommend aggressive management of lipids in such patients with a target LDL-C of 115 mg/dl. Where a patient has no clinically evident CHD, but has 2 or more risk factors for such a disease, NCEP guidelines recommend patients are titrated to LDL-C concentrations less than 130 mg/ml. Where a patient has no clinically evident CHD and one or no risk factors, the NCEP guideline target is less than 160 mg/dl.

A further aspect of the present invention comprises a method of treating hypertriglyceridemia by administration of 5 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of raising high density lipid (HDL) levels in a patient in need thereof by administration of 5 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of raising or maintaining HDL levels whilst lowering LDL-C levels in a patient in need thereof by administration of to 80 mg per day of the Agent. Preferred levels of lowering LDL-C levels, whilst maintaining or raising HDL levels, include the percentage levels of reduction in LDL-C given in the above methods.

WO 00/45819 PCT/GB00/00285 -4- A further aspect of the present invention comprises a method of lowering Apolipoprotein B levels in a patient in need thereof by administration of 5 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of treatment of mixed hyperlipidemia in a patient in need thereof by administration of 5 to 80 mg per day of the Agent.

A further aspect of the present invention comprises a method of treatment of atherosclerosis in a patient in need thereof by administration of 5 to 80 mg per day of the Agent.

When a dose range of 5 to 80 mg per day, 10 to 80 mg per day, 20 to 80 mg per day or to 80 mg per day is referred to herein, other particular dosage ranges which are further independent aspects of the invention include (as appropriate) 10 to 80 mg per day, 10 to mg per day, 10 to 40 mg per day, 5 to 40 mg per day, 5 to 20 mg per day, 10 to 20 mg per day, 20 to 60 mg per day, 20 to 40 mg per day and 40 to 60 mg per day.

Accordingly, for the avoidance of doubt, particular independent aspects of the present invention comprise the following:a method of lowering LDL-C levels in a patient in need thereof by 40% or more by administration of 5 to 20 mg per day of the Agent; (ii) 45% or more by administration of 10-20 (preferably 10) mg per day of the Agent; (iii) 50% or more by administration of 10-20 (preferably 10) mg per day of the Agent; (iv) 55% or more by administration of 20-40 mg per day of the Agent; or 60% or more by administration of 40-80 mg per day of the Agent; a method of lowering total cholesterol levels in a patient in need thereof by 30% or more by administration of 5 to 10 mg per day of the Agent; (ii) 35% or more by administration of 10 to 20 mg per day of the Agent; (iii) 40% or more by administration of 20-40 mg per day of the Agent; or (iv) 45% or more by administration of 40-80 mg per day of the Agent; a method of raising HDL-C levels in a patient in need thereof by 5% or more by administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; WO 00/45819 PCT/GB00/00285 (ii) 8% or more by administration of 5 to 20 mg per day of the Agent; or (iii) 10% or more by administration of 5 to 10 mg per day (especially 10 mg per day) of the Agent; a method of lowering apolipoprotein B-100 levels in a patient in need thereof by 30% or more by administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; (ii) 35% or more by administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; (iii) 40% or more by administration of 10 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; (iv) 45% or more by administration of 20 to 80 mg per day of the Agent; or 50% or more by administration of 40 to 80 mg per day of the Agent; a method of lowering triglyceride levels levels in a patient in need thereof by 10% or more by administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; or (ii) 20% or more by administration of 20 to 40 mg per day of the Agent; Further independent aspects of the present invention comprise the following:a method of lowering LDL-C levels in a patient in need thereof by 30% or more by administration of 1 to 5 mg per day, more particularly 2.5 to 5 mg per day, of the Agent; a method of lowering total cholesterol levels in a patient in need thereof by 30% or more by administration of 2.5 to 5 mg per day of the Agent; a method of raising HDL-C levels in a patient in need thereof by 5 or more by administration of 2.5 to 5 mg per day of the Agent; a method of lowering apolipoprotein B- 100 levels in a patient in need thereof by 30% or more by administration of 2.5 to 5 mg per day of the Agent; or a method of lowering triglyceride levels in a patient in need thereof by 10% or more by administration of 2.5 to 5 mg per day of the Agent.

WO 00/45819 PCT/GBOO/00285 -6- Further aspects of the present invention comprise the following:a method of lowering LDL-C levels by 30% or more and raising HDL-C levels by 5% (more particularly or more in a patient in need thereof by administration of 1 to 5 mg per day of the Agent; a method of lowering LDL-C levels by 40% or more and raising HDL-C levels by (more particularly or more in a patient in need thereof by administration of to 10 mg per day of the Agent; a method of lowering LDL-C levels by 45% or more and raising HDL-C levels by (more particularly or more in a patient in need thereof by administration of to 20 mg per day of the Agent; a method of lowering LDL-C levels by 50% or more and raising HDL-C levels by (more particularly or more in a patient in need thereof by administration of to 20 mg per day of the Agent; a method of lowering LDL-C levels by 55% or more and raising HDL-C levels by (more particularly or more in a patient in need thereof by administration of to 40 mg per day of the Agent; or a method of lowering LDL-C levels by 60% or more and raising HDL-C levels by 5% (more particularly or more in a patient in need thereof by administration of to 80 mg per day of the Agent.

Further aspects of the present invention comprise the following:a method of lowering LDL-C levels by 30% or more and lowering apolipoprotein B-100 levels by 25% or more by administration of 1 to 5 mg per day of the Agent; a method of lowering LDL-C levels by 45% or more and lowering apolipoprotein B-100 levels by 35% or more by administration of 5 to 20 mg per day (particularly to 10 mg per day) of the Agent; a method of lowering LDL-C levels by 50% or more and lowering apolipoprotein B-100 levels by 40% or more by administration of 10 to 20 mg per day of the Agent; WO 00/45819 PCT/GBO/00285 -7a method of lowering LDL-C levels by 55% or more and lowering apolipoprotein B-100 levels by 45% or more by administration of 20 to 40 mg per day of the Agent; or a method of lowering LDL-C levels by 60% or more and lowering apolipoprotein B-100 levels by 50% or more by administration of 40 to 80 mg per day of the Agent.

Further aspects of the present invention comprise the following:a method of lowering LDL-C levels by 30% or more and lowering triglyceride levels by 10% or more by administration of 1 to 5 mg per day of the Agent; a method of lowering LDL-C levels by 45% or more and lowering triglyceride levels by 10% or more by administration of 5 to 20 mg per day (particularly 5 to mg per day) of the Agent; a method of lowering LDL-C levels by 50% or more and lowering triglyceride levels by 10% or more by administration of 10 to 20 mg per day of the Agent; a method of lowering LDL-C levels by 55% or more and lowering triglyceride levels by 10% (more especially 20%) or more by administration of 20 to 40 mg per day of the Agent; or a method of lowering LDL-C levels by 60% or more and lowering triglyceride levels by 10% (more especially 20%) or more by administration of 40 to 80 mg per day of the Agent.

Further aspects of the present invention comprise the following:- A method of raising HDL-C levels by 5 (particularly 8% and more particularly or more and lowering apolipoprotein B-100 levels by 25 or more in a patient in need thereof by administration of 1 to 5 mg per day of the Agent; or A method of raising HDL-C levels by 5 (particularly 8% and more particularly 10%) or more and lowering triglyceride levels by 10 or more in a patient in need thereof by administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent.

WO 00/45819 PCT/GBOO/00285 -8- Further aspects of the present invention comprise the following:a method of lowering LDL-C levels by 30% or more, raising HDL-C levels by (more particularly or more and lowering triglyceride levels by 10% or more in a patient in need thereof by administration of 1 to 5 mg per day of the Agent; a method of lowering LDL-C levels by 40% or more, raising HDL-C levels by (more particularly or more and lowering triglyceride levels by 10% or more in a patient in need thereof by administration of 2.5 to 10 mg per day of the Agent; a method of lowering LDL-C levels by 45% or more, raising HDL-C levels by (more particularly or more and lowering triglyceride levels by 10% or more in a patient in need thereof by administration of 5 to 20 mg per day of the Agent; a method of lowering LDL-C levels by 50% or more, raising HDL-C levels by (more particularly or more and lowering triglyceride levels by 10% or more in a patient in need thereof by administration of 10 to 20 mg per day of the Agent; a method of lowering LDL-C levels by 55% or more, raising HDL-C levels by (more particularly or more and lowering triglyceride levels by 10% or more in a patient in need thereof by administration of 20 to 40 mg per day of the Agent; or a method of lowering LDL-C levels by 60% or more, raising HDL-C levels by (more particularly or more and lowering triglyceride levels by 10% or more in a patient in need thereof by administration of 40 to 80 mg per day of the Agent.

Further aspects of the present invention comprise the following:- A method of raising HDL-C levels by 5 (particularly 8% and more particularly or more, lowering apolipoprotein B-100 levels by 25 or more and lowering triglyceride levels by 10% or more in a patient in need thereof by administration of 1 to 5 mg per day of the Agent; or A method of raising HDL-C levels by 5 (particularly 8% and more particularly 10%) or more, lowering apolipoprotein B-100 levels by 25 or more and lowering triglyceride levels by 10 or more in a patient in need thereof by administration of WO 00/45819 PCT/GBOO/00285 -9to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent.

Further aspects of the present invention comprise the following:a method of reducing the LDL-C/HDL-C lipid ratio to below 2.2 in a patient in need thereof by administration of 1 to 5 mg per day of the Agent; a method of reducing the LDL-C/HDL-C lipid ratio to below 2.0 in a patient in need thereof by administration of 5 to 10 mg per day of the Agent; a method of reducing the LDL-C/HDL-C lipid ratio to below 1.5 in a patient in need thereof by administration of 20 to 40 mg per day of the Agent; a method of reducing the LDL-C/HDL-C lipid ratio to below 1.2 in a patient in need thereof by administration of 80 mg per day of the Agent; a method of reducing the non-HDL-C/HDL-C lipid ratio to below 2.6 in a patient in need thereof by administration of 1 to 5 mg per day of the Agent; a method of reducing the non-HDL-C/HDL-C lipid ratio to below 2.2 in a patient in need thereof by administration of 5 to 10 mg per day of the Agent; a method of reducing the non-HDL-C/HDL-C lipid ratio to below 2.0 in a patient in need thereof by administration of 20 to 40 mg per day of the Agent; a method of reducing the non-HDL-C/HDL-C lipid ratio to below 1.5 in a patient in need thereof by administration of 1 to 5 mg per day of the Agent; a method of reducing the TC/HDL-C lipid ratio to below 3.6 in a patient in need thereof by administration of 1 to 5 mg per day of the Agent; a method of reducing the TC/HDL-C lipid ratio to below 3.3 in a patient in need thereof by administration of 5 to 10 mg per day of the Agent; (11) a method of reducing the TC/HDL-C lipid ratio to below 3.0 in a patient in need thereof by administration of 20 to 40 mg per day of the Agent; or (12) a method of reducing the TC/HDL-C lipid ratio to below 2.5 in a patient in need thereof by administration of 80 mg per day of the Agent.

A particularly suitable starting dose of the Agent in the methods referred herein is 5 to mg per day, especially 10 mg per day. After initiation and/or upon titration of the Agent, WO 00/45819 PCT/GB00/00285 lipid levels may be analysed and the dosage adjusted accordingly. A further aspect of the invention is therefore a method as defined above when the Agent is administered at a starting dose of 5 or 10 mg per day, for example a method of lowering LDL-C levels in a patient in need thereof by 40% or more by administration of 5 or 10 mg per day of the Agent. A further aspect of the present invention comprises a dosing regime comprising administration of a starting dose of 5 or 10 mg per day of the Agent to a patient in need thereof, such as a patient with an LDL-C level of 160 mg/dl or greater with no chronic heart disease (CHD) or peripheral vascular disease (PVD) and 1 or no risk factors, a patient with an LDL-C level of greater than 130 mg/dl with no CHD or PVD and with 2 or more risk factors, or a patient with an LDL-C level of greater than 100 mg/dl with clinically evident CHD or PVD. Another particular group of patients who are beneficially treated by administration of a start dose of or 10 mg per day of the Agent includes, for example, those patients whose LDL-C level is >4 mmol/liter and/or whose TC level is >5 mmol/litre and/or whose HDL-C level is 1 mmol/litre and/or whose TG level is 2mmol/litre. A starting dose of 5 or 10 mg per day of the Agent unexpectedly has a superior efficacy and a comparable or better safety profile compared to the starting doses of other statins, and is therefore particularly advantageous.

In carrying out the methods of the invention, the Agent will be administered to a patient in the form of a pharmaceutical composition. A further aspect of the invention is therefore a pharmaceutical composition which comprises 5 to 80 mg of the Agent together with a pharmaceutically acceptable excipient or diluent. Particular pharmaceutical compositions which themselves are further independent aspects of the invention comprise, for example, 5 mg, 10 mg, 20 mg, 40 mg and 80 mg of the Agent together with a pharmaceutically acceptable excipient or diluent. The pharmaceutical compositions will be in the form of a conventional dosage unit form, for example, tablets or capsules. Accordingly, a further aspect of the invention comprises, a tablet or capsule containing the Agent in the amounts given above. The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Preferably the Agent is administered as a single dose once daily.

It will be appreciated that for each method of treatment referred to above, a further aspect of the invention comprises the use of the Agent in the amount specified for the manufacture of a medicament for use in said methods of treatment.

-11- Preferably the Agent is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt. Where herein a dose of (or a pharmaceutical composition comprising) 5 mg, mg, 20 mg, 40 mg or 80 mg of the Agent is referred to, this includes a dose (or pharmaceutical composition comprising) of 5.2 mg, 10.4 mg, 20.8 mg, 4 1.6 mg and 83.2 mg respectively of the calcium salt of formula 1. Such doses (or compositions) are calculated to provide the equivalent of 5 mg, 10 mg, 20 mg, 40 mg and 80 mg respectively of the free acid form when dosed.

e P:\OPERUgc\23051-00 spc.doc-18/02/03 11A- In a further aspect of the invention there is provided a pharmaceutical composition adapted for oral administration as a single, once daily dose which comprises 5 mg to 10 mg of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid, in the form of the free acid or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

In a further aspect of the invention there is provided a pharmaceutical composition adapted for oral administration as a single, once daily dose which comprises 5.2 mg to 10.4 mg of the calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid, together with a pharmaceutically acceptable diluent or carrier.

In a further aspect of the invention there is provided a method of preparing the above pharmaceutical compositions which comprises admixing (E)-7-[4-(4-fluorophenyl)- 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept- 6-enoic acid or pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier.

In a further aspect of the invention there is provided a method of treating a patient suffering from hypercholesterolemia which comprises administration of a single, once daily, oral dose of 5 to 10 mg of the compound (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- S. 20 [methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical composition, in the form of a pharmaceutical composition.

In a further aspect of the invention there is provided a method of treating a patient suffering from hypercholesterolemia which comprises administration of a single, once daily, oral dose of 5.2 to 10.4 mg of the calcium salt of the compound fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5dihydroxyhept-6-enoic acid in the form of a pharmaceutical composition.

In a further aspect of the invention there is provided in a method of treatment as described in the above two paragraphs wherein the patient has an LDL-C level of 30 160mg/dl or greater with no chronic heart disease or peripheral vascular disease and one or no risk factors for such a disease; P:OPERU\g\23051-00 spc.doc- I/0203 -11Ban LCL-C level of greater than 130 mg/dl with no chronic heart disease or peripheral vascular disease and two or more risk factors for such a disease; or an LDL-C level of greater than 100 mg/dl with clinically evident chronic heart disease or peripheral vascular disease.

Pharmaceutical compositions The following Example illustrates, but is not intended to limit, pharmaceutical dosage forms which are suitable for use in the invention as defined herein: Capsule mg The Agent Lactose 42.5 Corn Starch 20.0 Microcrystalline cellulose 32.0 Pregelatinised starch 3.3 20 Synthetic Hydrotalcite 1.1 Magnesium stearate 1.1 Capsules containing 1, 2.5 or 10 mg of the Agent may be obtained similarly using more or less lactose as appropriate to maintain a total fill weight of 105 mg.

Preferred such formulations are those in which the Agent is fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5dihydroxyhept-6-enoic acid] calcium salt.

To illustrate the invention, a randomised, dose response parallel-group study with .i 30 bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl] 3 R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt (hereinafter referred to as ZD4522) and atorvastatin (ATORV) in subjects with primary hypercholesterolaemia was carried out.

WO 00/45819 PCT/GBOO/00285 -12- Primary objectives The primary objective of this trial was to estimate the dose-response relationship between the dose of ZD4522 and the percentage reduction of LDL-C from the baseline value with respect to placebo.

Secondary objectives Secondary objectives of this trial included: to estimate the effect of 10 and 80 mg doses of atorvastatin on LDL-C levels; to estimate the effects of ZD4522 and atorvastatin on HDL-C, TG, TC, apolipoprotein A-1,apolipoprotein Lp(a), apolipoprotein B-100 levels and LDL- C (by indirect method); to assess the pharmacokinetics of oral doses of 1, 2.5, 5, 10, 20, and 40 mg ZD4522 (capsule formulations) over a 6 week treatment period; and to assess the tolerability and safety of ZD4522 in comparison with placebo.

Trial Design After a 6-week dietary run-in, subjects were randomised to either atorvastatin doses or 80 mg supplied open labelled, or to placebo or 1 of 6 ZD4522 doses supplied blinded). Analysis of the blinded portion of the trial addressed the primary objective. The open atorvastatin groups were included to obtain additional data on the starting and high doses, of a proven cholesterol-lowering agent in this patient population.

Trial Plan A total of 10 visits were made to each clinic. Three of these took place during the placebo controlled dietary run-in period (Weeks -2 and five during the treatment phase (Week 0 randomisation visit, Weeks +4 and and two follow up visits (Weeks +8 and Number of Subjects The primary endpoint on which the sample size is based is on percentage reduction from baseline in LDL-C (LDL cholesterol) values. A sample size of 9 in each group will have power to detect a difference in means of 25% between 2 groups, assuming that the common standard deviation is 15%, using a 2 group t-test with a 0.05 two-sided significance WO 00/45819 PCT/GBOO/00285 -13level. This has been increased to 12 subjects per group to adjust for multiple comparisons of groups against placebo while preserving a power of at least 90% (based on simulations). This sample size also leads to an estimate of the dose-response curve for percentage decline in LDL-C with a width of the confidence band less than 10% for most of the dose range.

Inclusion Criteria For inclusion in the dietary run-in period, subjects had to fulfil all of the following criteria: fasting LDL cholesterol (>4.14 but <6.21 mmol/L); fasting levels of triglycerides (<3.39 mmol/L); male subjects, age 18 to 70 years. Female subjects age 50 to 70 years; absence of menstruation for more than two years and follicle stimulating hormone (FSH), luteinising hormone (LH) and oestradiol within the post-menopausal range (using local laboratory ranges); body mass index 5 30 kg/m 2 For inclusion in the randomised treatment phase of the trial, subjects had to fulfil all of the following criteria: fasting LDL cholesterol >4.14 mmol/L but 5.69 mmol/L from measurements taken at weeks -2 and -1 before randomisation, with the lower value within 15% of the higher value; fasting TG 3.39mmol/L at Weeks and before randomisation; a Food Record Rating Score (FRR) 5 15 at Weeks -2 and before randomisation, to demonstrate compliance with the American Heart Association Step -1 diet.

Exclusion Criteria Any of the following was regarded as a criterion for exclusion from the trial: Subjects using cholesterol lowering drugs (this therapy must have been discontinued at least 4 weeks before the start of the dietary run-in period. Subjects taking probucol should have discontinued 12 months before inclusion in this study).

History of serious or hypersensitivity reactions to other HMG-CoA reductase inhibitors.

WO 00/45819 PCT/GBOO/00285 -14- Subjects with active arterial disease such as unstable angina, myocardial infarction, transient ischaemic attack (TIA), cerebro vascular accident (CVA) or coronary artery bypass graft (CABG) within 6 months or angioplasty within 3 months of study entry.

History of malignancy except subjects whose only malignancy has been basal or squamous cell skin carcinoma. Female subjects who have a history of cervical dysplasia unless 3 consecutive normal cervical smears have been recorded prior to entry.

Uncontrolled hypertension (diastolic blood pressure 2 95 mm Hg). Subjects who are taking thiazide diuretics and beta blockers will not be excluded provided they are maintained at a stable dose from 3 months before starting the study and throughout the study.

Diabetes mellitus and/or other metabolic endocrine disease known to be associated with alterations in plasma lipid levels (uncontrolled hypothyroidism defined as a times the ULN at week subjects with nephrotic syndrome).

Known homozygous familial hypercholesterolaemia or known type III hyperlipoproteinaemia (familial dysbetalipoproteinaemia).

Use of concomitant medications detailed as follows: WO 00/45819 PCT/GB00/00285 DISALLOWED MEDICATIONS CLASS OF DRUG GENERIC NAME Erythromycin Base Antibiotics/ antifungals Erythromycin Ethyl Succinate, Acetyl Sulfisoxazole Rifampicin Fluconazole Ketaconazole Itraconzole Anti-epileptics/ antidepressants Phenytoin Phenobarbitone Fluoxetine Carbemazepine Acne treatment Isotretinoin Cimetidine Antiulcer drugs Cisapride Triamcinolone Acetonide Systemic Steroids Triamcinolone Diacetate Betamethasone Sodium Phosphate Betamethasone Acetate Hydrocortisone Hydrocortisone Acetate Hydrocortisone Sodium Phosphate Hydrocortisone Sodium Succinate Cortisone Acetate Dexamethasone Dexamethasone Acetate Dexamethasone Sodium Anti arrhythmic Digoxin Anticoagulant Warfarin Antihistamine Astemizole Terfenadine Phosphate Prednisolone Systemic Steroids Methylprednisolone Methylprenisolone Acetate Methylprednisolone Sodium Succinate Systemic Steroids continued Prednisolone Tebutate Prednisolone Sodium Phosphate Methyltestosterone Fluoxymesterone any hormone replacement therapies (HRT) WO 00/45819 PCT/GB00/00285 -16- Tolbutamide Oral hypoglycaemic agents Niacin/Nicotinic Acid Lipid Regulation Probucol Psyllium Preparations Clofibrate Cholestyramine Colestipol Hydrochloride Gemfibrozil Lovastatin Pravastatin Sodium Simvastatin Fluvastatin Lymphocyte Immune Globulin Immunosuppresents Rho(D) Immune Globulin Azathiopane Sodium Muromonab-CD3 Cyclosporin History of alcohol and/or drug abuse.

Subjects with active liver disease or hepatic dysfunction as defined by elevations in liver enzymes (ALT, AST, yGT, ALP) or bilirubin 1.5 times ULN at any time before randomisation at Visit 4.

(11) Subjects with a serum creatinine 180 jimol/L prior to randomisation.

(12) Participation in another study less than 3 months before enrolment in the Dietary Runin period.

(13) Serum CK 3 times ULN at Weeks -6 and -1 (Visit 1 and 3).

(14) Clinically significant ophthalmic abnormalities, simple refractive errors will be allowed.

Subjects who have received randomised medication cannot be re-entered in this study.

(16) Subjects who have serious or unstable medical or psychological conditions which in the opinion of the investigator, would compromise the subject's safety or successful participation in the study.

(17) Subjects who are receiving hormone replacement therapy (HRT).

(18) Subjects who are receiving digoxin and/or coumarin anti-coagulants.

WO 00/45819 PCT/GBOO/00285 -17- Trial Methods Summary The subjects were requested to take the study drug once daily, not less than 3 hours after the evening meal. At Visits 1, 2, 3, 4, 6, 7, 8, 9 and 10 the trial subjects reported to the clinic after fasting for twelve hours (water permitted) and blood was drawn to determine fasting lipids. Subjects provided a urine sample, and blood samples for haematology and clinical biochemistry evaluation. Where lipid and clinical biochemistry measurements fell at the same visit, only one sample was taken. At Visits 4, 6, 7 and 8 pharmacokinetic samples were collected. Weight, blood pressure and heart rate were measured and recorded at all visits. At Visits 1 and 10 an ECG was performed.

The analytical laboratory used is certified for standardisation of lipid analysis as specified by the Standardisation programme of the Centres for Disease Control and Prevention and the National Heart, Lung and Blood Institute.

Analysis Lipid Concentrations of the following lipids were determined LDL-C, HDL-C, TG, TC, apo A-I, apo A-II, Lp(a), apo B, LDL-C (by Friedewald equation and P-quantification method).

Biochemistry Concentrations of the following were determined, AST, ALT, CKi, yGT, ALP and total bilirubin, sodium, potassium, calcium, chloride, phosphate, bicarbonate creatinine, fasting blood glucose and serum thyroxine (T 4 and thyroid stimulating hormone (TSH).

Unless surgically sterilised female subjects had post menopausal status confirmed by measurement ofFSH, LH and oestradiol at Visit 1.

Haematology Full blood count was performed and included the following; erythrocyte count, haemoglobin, haematocrit, leucocyte cell count, platelets, red cell distribution width, percentage differential leukocyte count (including percentage large unstained cells), mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration. A clotting screen was performed at Visits 1 and 10 only.

WO 00/45819 PCT/GBOO/00285 -18- Urinalysis At Visits 1, 3, 4, 5, 6, 7, 8, 9 and 10 urinalysis was performed on 10 ml mid-stream urine samples and tested in the clinic for the following using labstix /dipstix: pH, glucose, blood, ketones, protein, and bilirubin.

Results 1 Study Arm Placebo ZD4522 1 mg ZD4522 2.5 mg ZD4522 5 mg ZD4522 10 mg ZD4522 20 mg ZD4522 40 mg Atorvastatin 10 mg Atorvastatin 80 mg 2 Study Arm Placebo ZD4522 1 mg ZD4522 2.5 mg ZD4522 5 mg ZD4522 10 mg ZD4522 20 mg ZD4522 40 mg Atorvastatin 10 mg Atorvastatin 80 mg Mean Lowering of LDL-C at week 6(Friedewald method) Lipid parameter (mean change from baseline at week 6) TC TG HDL-C Apo-B -5.3 -1.7 +2.8 -2.8 -25.3 -16.9 +8.8 -28.8 -30.8 -12.3 +8.8 -34.6 -32.9 -34.8 +13.2 -37.6 -36.7 -12.0 +13.7 -42.3 -41.9 -26.2 +9.2 -48.9 -46.1 -25.5 +9.4 -54.6 -32.0 -13.6 +6.8 -36.4 -46.1 -30.7 -3.2 -50.2 Note: In 2, a positive value indicates a mean increase of the lipid parameter level and a negative value indicates a mean reduction of the lipid parameter level WO 00/45819 PCT/GB00/00285 -19- 3 Study Arm Placebo ZD4522 1 mg ZD4522 2.5 mg ZD4522 5 mg ZD4522 10 mg ZD4522 20 mg ZD4522 40 mg Atorvastatin 10 mg Atorvastatin 80 mg Lipid Ratios (mean value at week 6) non HDL-C/HDL-C TC/HDL-C LDL-C/HDL-C 4.3 5.3 3.8 2.5 3.5 2.2 2.5 3.5 2.1 2.2 3.2 1.9 2.2 3.2 1.8 1.8 2.8 1.4 1.5 2.5 1.3 2.5 3.5 2.1 2.1 3.1 1.7 4 Effects in each study arm on percentage change of total cholesterol from baseline are given in Fig. 1. Dosing began at BASELINE after an initial dietary run in period of 6 weeks, as per the clinical protocol above. Dosing stopped at 6 weeks after BASELINE.

Effects in each study arm on percentage LDL cholesterol (Friedewald equation calculation) percentage change from baseline are given in Fig 2. Dosing began at BASELINE after an initial dietary run in period of 6 weeks, as per the clinical protocol above. Dosing stopped at 6 weeks after BASELINE.

6 Effects on each study arm on HDL cholesterol percentage change from baseline are given in Fig. 3. Dosing began at BASELINE after an initial dietary run in period of 6 weeks, as per the clinical protocol above. Dosing stopped at 6 weeks after BASELINE.

7 Effects on each study arm on Apolipoprotein B-100 percentage change from baseline are given in Fig. 4. Dosing began at BASELINE after an initial dietary run in period of 6 weeks, as per the clinical protocol above. Dosing stopped at 6 weeks after BASELINE.

WO 00/45819 PCT/GBOO/00285 8. Effects on each study arm on triglyceride percentage change from baseline are given in Fig. 5. Dosing began at BASELINE after an initial dietary run in period of 6 weeks, as per the clinical protocol above. Dosing stopped at 6 weeks after BASELINE It will be appreciated that alternative or additional trials, of shorter or longer duration, may be carried out with the Agent to demonstrate the present invention, such as other randomized double blind, optionally placebo controlled, trials with selected doses of the Agent and selected doses of commercially available statins atorvastatin, pravastatin, simvastatin) as comparators in subjects with hypercholesterolaemia with or without a history of CHD or PVD or with risk factors therefor, measuring changes in LDL-C and other lipid or lipoprotein fractions and the safety of the Agent in respect of, for example, serum transaminase levels.

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SO2CH3 2 Formula I P:\OPERgc\2305 -00 spcc.doc-] 8/02/03 -21 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Claims

12-12-03:10:14AM:DAVIES COLLISON CAVE 5/ 7 r:0PEygs30$14^4e.IU\Il) -22- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A method of treating a patient suffering from hypercholesterolemia which comprises administration as a starting dose of a single, once daily, oral dose of 5 to 10 mg of the compound (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid, or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical composition. 2. A method of treating a patient suffering from hypercholesterolemia which 10 comprises administration of a single, once daily, oral dose of 5.2 to 10.4 mg of the calcium o salt of the compound (E)-7-[4-(4-flurophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino)pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid in the form of a pharmaceutical composition. 15 3. A methods as claimed in claim 1 or 2 wherein the patient has an LDL-C level of 160mg/dl or greater with no chronic heart disease or peripheral vascular disease and one or 5 no risk factors for such a disease; *1 an LCL-C level of greater than 130 mg/dl with no chronic heart disease or peripheral vascular disease and two or more risk factors for such a disease; or 20 an LDL-C level of greater than 100 mg/dl with clinically evident chronic heart disease or peripheral vascular disease. DATED: 12 December, 2003 AstraZeneca AB by DAVIES COLLISON CAVE Patent Attorneys for the Applicant(s): COMS ID No: SMBI-00533097 Received by IP Australia: Time 10:17 Date 2003-12-12