US 2002O155091A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0155091A1 Huval et al. (43) Pub. Date: Oct. 24, 2002 (54) COMBINATION THERAPY FOR TREATING Publication Classification HYPERCHOLESTEROLEMIA (51) Int. Cl." ..................................................... A61K 31/74 (75) Inventors: Chad Cori Huval, Somerville, MA (US); Stephen Randall Holmes-Farley, (52) U.S. Cl. .......................................................... 424/78.29 Arlington, MA (US); John S. Petersen, Acton, MA (US); Pradeep K. Dhal, Westford, MA (US) (57) ABSTRACT Correspondence Address: HAMILTON, BROOK, SMITH & REYNOLDS, The invention relates to methods for treating hypercholes P.C. terolemia and atherosclerosis, and reducing Serum choles 530 VIRGINA ROAD terol in a mammal. The methods of the invention comprise P.O. BOX 91.33 administering to a mammal a first amount of a bile acid CONCORD, MA 01742-9133 (US) Sequestrant compound which is an unsubstituted polydial lylamine polymer and a Second amount of a cholesterol (73) Assignee: GelTex Pharmaceuticals, Inc., lowering agent. The first and Second amounts together Waltham, MA comprise a therapeutically effective amount. (21) Appl. No.: 10/025, 184 The invention further relates to pharmaceutical composi tions useful for the treatment of hypercholesterolemia and (22) Filed: Dec. 19, 2001 atherOSclerosis, and for reducing Serum cholesterol. The pharmaceutical compositions comprise a combination of a Related U.S. Application Data first amount of an unsubstituted polydiallylamine polymer compound and a Second amount of a cholesterol-lowering (63) Continuation of application No. 09/311,103, filed on agent. The first and Second amounts comprise a therapeuti May 13, 1999, now Pat. No. 6,365,186, which is a cally effective amount. The pharmaceutical compositions of continuation-in-part of application No. 08/964,536, the present invention may optionally contain a pharmaceu filed on Nov. 5, 1997, now Pat. No. 6,083,497. tically acceptable carrier. US 2002/O155091A1 Oct. 24, 2002 COMBINATION THERAPY FOR TREATING 0008. In addition, there are many known cholesterol HYPERCHOLESTEROLEMIA lowering agents which are not members of a particular class of agents. These other cholesterol-lowering agents include, RELATED APPLICATIONS Acifran, AZacosterol, Benfluorex, B-Benzalbutyramide, Car 0001. This application is a Continuation of U.S. Ser. No. nitine, Chondroitin Sulfate, Clomestrone, DetaXtran, Dext 09/311,103, filed on May 13, 1999, which is a Continuation ran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, in-Part of U.S. Ser. No. 08/964,536, filed on Nov. 5, 1997, Eritadenine, Furazabol, Meglutol, Melinamide, Mytatriene now U.S. Pat. No. 6,083,497. The entire teachings of the diol, Ornithine, Y-Oryzanol, Pantethine, Pentaerythritol Tet above documents are incorporated herein by reference. raacetate, C-phenybutyramide, Priozadil, Probucol, B-Sito sterol, Sultosilic Acid, Piperazine Salt, Tiadenol, Triparanol BACKGROUND OF THE INVENTION and Xenbucin. 0002 Reabsorption of bile acids from the intestine con 0009. The present invention furthers efforts for treating Serves lipoprotein cholesterol in the bloodstream. Con hypercholesterolemia and atherosclerosis, as well reducing versely, blood cholesterol levels can be diminished by Serum cholesterol, by providing a combination therapy reducing reabsorption of bile acids. approach and a novel pharmaceutical composition useful 0003. One method of reducing the amount of bile acids therefor. that are reabsorbed and, thus, reducing Serum cholesterol is the oral administration of compounds that Sequester the bile SUMMARY OF THE INVENTION acids and cannot themselves be absorbed. The Sequestered 0010. The invention relates to methods for treating hyper bile acids are excreted. cholesterolemia and atherosclerosis, and reducing Serum 0004 Compounds which have been suggested for bile cholesterol in a mammal. The methods of the invention acid Sequestration include various ion exchange polymers. comprise administering to a mammal a first amount of a bile One Such polymer is cholestyramine, a copolymer of divi acid Sequestrant compound which is an unsubstituted poly nylbenzene and trimethylammoniummethyl Styrene. It has diallylamine polymer and a Second amount of a cholesterol been long recognized that this polymer is unpalatable, gritty, lowering agent Selected from the group consisting of and constipating. More recently, various polymers have been fibrates, nicotinic acid and derivatives thereof, and other Suggested which are characterized by hydrophobic Substitu cholesterol-lowering agents Such as Acifran, AZacosterol, ents and quaternary ammonium radicals Substituted upon an Benfluorex, B-Benzalbutyramide, Carnitine, Chondroitin amine polymer backbone (Ahlers, et al. U.S. Pat. Nos. Sulfate, Clomestrone, DetaXtran, Dextran Sulfate Sodium, 5,428,112 and 5,430,110 and McTaggart, et al., U.S. Pat. No. 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, 5,462,730, which are incorporated herein by reference). In Furazabol, Meglutol, Melinamide, Mytatrienediol, Orni Some cases, these polymerS have had disappointing efficacy thine, Y-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, and require complex processes for their manufacture. C-phenybutyramide, Priozadil, Probucol, B-Sitosterol, Sul 0005 Fibrates are also a known class of compounds tosilic Acid, Piperazine Salt, Tiadenol, Triparanol and Xen which has been used as cholesterol-lowering agents. bucin, and combinations thereof. The first and Second Fibrates are peroxisome proliferator-activated receptor amounts together comprise a therapeutically effective antagonist that effectively lower plasma triglycerides by amount. Further, the combination therapy can also include increasing VLDL lipolysis and clearance, and by decreasing HMG CoA reductase inhibitors Such as those described in hepatic VLDL triglyceride output. Fibrate treatment also U.S. patent application Ser. No. 09/311,402 filed on May 13, raises HDL levels by increasing hepatic HDL synthesis. 1999 entitled, Combination Therapy for Treating Hyperc Examples of fibrates include, Clofibrate (ATROMID-SCR), holesterolemia, by C. Huval, S. Holmes-Farley, J. Petersen Gemfibrozil (LOPID(R), Fenofibrate, Benzafibrate and the and P. Dhal, the entire content of which is incorporated compounds listed in Table 1. herein by reference. 0006 Another class of compounds which have been used 0011. The invention further relates to pharmaceutical as cholesterol-lowering agents are nicotinic acid, commonly compositions useful for the treatment of hypercholester referred to as niacin, and derivatives thereof. Niacin is a olemia and atherosclerosis, and for reducing Serum choles potent triglyceride reducing agent with an HDL-elevating terol. The pharmaceutical compositions comprise a combi effect. Niacin therapy is prescribed to treat patients with nation of a first amount of an unsubstituted polydiallylamine moderate to Severe hypertriglyceridemia and does not usu polymer compound and a Second amount of a cholesterol ally produce a significant LDL cholesterol-lowering effect. lowering agent Selected from the group consisting of fibrates, nicotinic acid and derivatives thereof, and other Niacin acts within the liver to decrease VLDL triglyceride cholesterol-lowering agents Such as Acifran, AZacosterol, output and in the periphery to increase its clearance. The side Benfluorex, B-Benzalbutyramide, Camitine, Chondroitin effects of niacin are well-known and usually limit usage. For Sulfate, Clomestrone, DetaXtran, Dextran Sulfate Sodium, example, high doses cause pruritis and flushing. In addition, 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, an elevation in liver enzymes, abdominal cramps, diarrhea, Furazabol, Meglutol, Melinamide, Mytatrienediol, Omith nausea and vomiting have been observed. Niacin is avail ine, Y-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, able, for example, as NICOLAR(R) tablets. Nicotinic acid C-phenybutyramide, Priozadil, Probucol, B-Sitosterol, Sul derivatives include, Acipimox, Aluminum Nicotinate, Nic tosilic Acid, Piperazine Salt, Tiadenol, Triparanol and Xen eritrol, Nicoclonate, Nicomol and OXiniacic Acid. bucin, and combinations thereof. The first and Second 0007 Another class of compounds which are useful in amounts together comprise a therapeutically effective cholesterol-lowering therapy are thyroid hormones and ana amount. Further, the pharmaceutical compositions can also logs Such as EtiroXate, Thyropropic Acid and ThyroXine. include HMG CoA reductase inhibitors such as those US 2002/O155091A1 Oct. 24, 2002 described in U.S. patent application Ser. No. 09/311,402 Sulfate, Clomestrone, DetaXtran, Dextran Sulfate Sodium, filed on May 13, 1999 entitled, Combination Therapy for 5,8,11,14,17-Eicosapentaenoic Acid, Eritadenine, Treating Hypercholesterolemia, by C. Huval, S. Holmes Furazabol, Meglutol, Melinamide, Mytatrienediol, Omith Farley, J. Petersen and P. Dhal, the entire content of which ine, Y-Oryzanol, Pantethine, Pentaerythritol Tetraacetate, is incorporated herein by reference. The pharmaceutical C-phenybutyramide, Priozadil, Probucol, B-Sitosterol, Sul compositions of the present invention may optionally con tosilic Acid, Piperazine Salt, Tiadenol, Triparanol and Xen tain a pharmaceutically acceptable carrier. bucin, and combinations thereof. The first and Second 0012. The unsubstituted polydiallylamine polymers are amounts together comprise a therapeutically effective characterized by one or more monomeric