(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I aUI Hlllll ~ EHll UHllHllll 1111mm11m lllllllllllllHlllll 1111Bllll11111111 Rll
`
`(43) International Publication Date
`26 April 2007 (26.04.2007)
`
`PCT
`
`[US/USJ; S Forest View Drive, Gladstone, NJ 07934 (US).
`
`(74) Agents: KAVANAUGH. Theresa, C. et al.; GOODWIN
`PROCTER LLP, Exchange Place, Boston, MA 02109 (US).
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing al tlie begin(cid:173)
`ning of each regular Lrs~ of the PCT Gazette.
`
`--
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`-
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`- =
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`N <
`= 00
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`I""--~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`~ (54) Title: METI-IODS AND COMPOSITTONS FOR TREATING DISORDERS ASSOCIATED WITH HYPERLIPIDEMTA IN
`r::: A MAMMAL
`= Q
`
`(57) Abstract: The invention provides methods and compositions for treating hyperlipidemia and disorders associated with hyper-
`N
`lipidemia in a mammal. Compositions useful in the practice of the invention include a microsomal triglyceride transport protein
`O inhibitor ("MTPI") and at least two other cholesterol lowering drugs selected from the group consisting of a ·cholesterol absorption
`:> inhibitor ("CAI"), 11 HMG-CoA reductase inhibitor, 11 bile acid sequestnmt, a fibric acid derivative, niacin, and squalene sythetase
`;iii'- inhibitor.
`
`(SI) Jntematlonal Patent Classlllcatlon:
`A61K 311397 (2006.01)
`A61K 311437 (2006.01)
`A61K 31140 (2006.01)
`A61K 3114468 (2006.01)
`
`(21) Ioternatlonal Appllcatlon Number:
`PCT/US2006/040953
`
`(22) International Filing Date: 18 October 2006 (18.10.2006)
`
`(25) Filing Language:
`
`(26) Publlc:Btloo Language:
`
`English
`
`English
`
`-
`
`(72) Inventor; and
`
`(30) Priority Data:
`60fl27,664
`18 October 2005 (18.10.2005) US
`60fl88,616
`3 April 2006 (03.04.2006) US
`:= (71) Applicant (for all designated Suites except US): AEGE-
`=
`RION PHARMACEUTIC~ [US/US]; 1140 ROUTE
`-
`22 EAST, Suite 304, Bridgewater, NJ 08807 (US).
`= (7S) Ioventor/Appllcaot (for US only): WISLER, Gerald, L.
`
`(10) International Publication Number
`WO 2007/047880 A2 ·
`(81) Designated Slates (unless otherwise indicased, jor every
`kind of national protection available): AE, AG, AL, AM;
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ. CA, CH, CN;
`CO, CR, CU, CZ. DE, DK, DM, DZ. EC, EE, EG, ES, Fl.
`GB, OD, GE, GH, GM, ·OT, HN, HR, HU, ID, II,., IN, IS;
`JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
`LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY,
`MZ. NA, NG, NI, NO, NZ, OM, PQ, PH, PL, PT, RO, RS,
`RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN,
`TR, TT, Tz. UA, UO, US, UZ, VC, VN, ZA, ZM, 'ZW.
`
`(84) Designated Slates (unless othenvise indicated, for every
`kind of regional protection available): ARIPO (BW, OH,
`GM, KE, LS, MW, MZ. NA, SD, SL, SZ. Tz. UG, ZM,
`'ZW), Eurasian (AM, AZ, BY, KG, Kz, MD, RU, TJ, TM).
`European (AT, BE, BO, CH, CY, CZ. DE, DK, EE, ES, FI.
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CP, CO, Cl, CM, GA,
`ON, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Publlsbed:
`-
`without inlernational search report .and to be· republished
`·
`.
`·
`·upon receipt of that report
`~
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`METHODS AND COMPOSITIONS FOR TREATING DISORDERS
`ASSOCIATED WITH BYPERLIPIDEMIA IN A MAMMAL
`
`RELATED APPLICATIONS
`
`(0001] This application claims the benefit of U.S. Provisional Patent Application SerialNo~
`
`60n88,616, filed April 3, 2006, and U.S. Provisional Patent Application Serial No. 60/727,664,
`
`filed October 18, 2005, the entire disclosures of which are incorporated by reference herein.
`
`FIELD OF THE INVENTION
`
`s ·
`
`[0002) The present invention relates generally to the field.ofphannaceutical compositions and
`their use in the treatment of hyperlipidemia, and more particularly relates to therapeutic
`combinations comprising a microsomal triglyceride transfer protein inhibitor and at least two
`
`other cholesterol lowering agents, and their use in the treatment of hyperlipidemia.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`(0003] There are several known risk factors for atherosclerotic cardiovascular disease (ASCVD),
`
`the major cause of mortality in the Western world. One key risk factor is hyperlipidemia, which
`
`is the presence of elevated levels of lipids in blood plasma. YarioW! epidemiological studies
`
`have demonstrated that drug mediated lowering of total cholesterol (TC) and low density
`
`lipoprotein {LDL) cholesterol (LDL-C) is associated with a significant reduction in
`
`15
`
`cardiovascular events. The National Cholesterol Education Prognu:ll's (NCEP's) updated
`
`guidelines recommends that the overall goal for high-risk patients is to achieve less than 100
`mg/dL of LDL, with a therapeutic option to set the goal for such patients to achieve a LDL level ·
`less than 70 mg/dL.
`
`[0004] One fonn of hyperlipidemia is known as hypertriglyceridemia and results in the presence
`
`20
`
`of elevated amounts of triglycerides in the blood. Although triglycerides are necessary for good
`
`health, higher-than-normal triglyceride levels, often are associated with known risk factors for
`
`heart disease.
`
`[0005] Another form of hyperlipidemia, known as hypercholesterolemia, which is the presence
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`of elevated amolJ.Ilts of cholesterol in the blood, is a polygenic disorder. Modificatiom in
`lifestyle and conventional drug treabnent are usually successful in reducing cholesrei:ol levelS.
`However, in some cases, as in familial hypercholesterolemia (FH), the cause is a monogenic
`
`defect Treatment of a patient with FH can be more challenging because the levels of LDL-C
`
`s
`
`remain elevated despite aggressive use of conventional therapy.
`
`[0006] For example, one type ofFH~ homozygous familial hypercholesterolemia (hoFH), is a
`
`serious life-threatening genetic disease caused by homozygosity or compound heterozygosity for
`
`mutations in the low density lipoprotein (LDL) receptor. Patients with hoFH typicaliy:have total
`
`plasma cholesterol levels over 400 mg/dL resulting in premature atherosclerotic vascular disease ..
`
`10 When left untreated, most patients develop atherosclerosis before age 20 and generally do not
`
`survive past age 30. However, patients diagnosed with hoFH are largely unresponsive to
`
`conventional drug therapy 81\d have limited treatment options. Specifically, treatment with'
`
`statins, which reduce LDL-C by inhibiting cholesterol synthesis and upregulating the hepatic
`
`LDL receptor, have negligiole effect in patients whose LDL receptors are non-existent or
`
`IS
`
`defective. A mean LDL-C reduction of only less than about 20% has been recently reported in
`
`patients with genotype-confirmed hoFH treated with the maximal dose of statins (atorvastatin or
`
`simvastatin administered at 80 mg/day). The addition of ezetimloe 10 mg/day to this regimen
`
`resulted in a total reduction ofLDL-C levels of 27%, which is still far from optimal. Non-.
`
`pharmacological options have also been tested, including surgical interventions, such as
`
`20
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`portacaval shunt and ilea! bypass, and orthotopic liver transplantatiQn, but with clear
`
`disadvantages and risks. Therefore, there is a tremendous unmet medical need for n~w medical
`
`therapies for hoFH.
`
`[0007] Microsomal triglyceride transfer protein (MTP) inhibitors have been developed as potent
`
`inhloitors ofMTP-mediated neutral lipid transfer activity. MI'P catalyzes the transport of
`
`2s
`
`triglyceride, cholesteryl ester, and phosphatidylcholine between small unilamellar vesicles; One
`exemplary MTP inhibitor is BMS-201038, developed by Bristol-Myers Sqwob. See, U.S. Patent
`
`Nos. 5,739,135; and 5,712,279. Studies using an animal model for homozygous FH indicated
`
`that BMS-201038 effectively reduced plasma cholesterol levels in a dose dependent manner, for
`example, at 25 mg/day, suggesting that this compound might be effective for treating patients
`
`30 with hoFH. It was noticed, however, that certain patients treated with 25 mg/day of BMS-·
`
`201038 experienced certain adverse events, for example, gastrointestinal disturbances,
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`abnormalities in liver function, and hepatic steatosis. Although a promising therapeutic agent, ·
`large scale clinical trials ofBMS-201038 have been discontinued. Another potent MI'P inhibitOr
`known as implitapide has been developed. See, U.S. Patent Nos. 6,265,431, 6,479,503,
`
`5,952,498. During clinical studies, dosages of implitapide of 80 mg/day or greater, although
`
`S
`
`.therapeutically effective, were found to result in certain adverse .events, for example:
`gastrointestinal disturbances, abnonna1ities in liver function, and hepatic steatosis. Large -scale·
`
`clinical studies using implitapide have also been discontinued.
`
`[0008] Accordingly, there is still a need for methoclS for aggressively treating hyperlipidemias .
`
`· that effectively lower, for example, circulating cholesterol and triglycerides levels so as to
`
`10
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`improve the rates of achieving goals of therapy based on published guidelines, for example,
`
`NCEP guidelines, but with fewer or reduced adverse effects that typically result when higher
`dosages of the MTP inhi'bitor are used alone in mono therapy.
`
`BRIEF SUMMARY OF THE INVENTION
`
`[0009J The invention is based, in part, upon the development of compositions comprising an
`15 MI'P inhibitor in combination with at lea5t two other cholesterol lowering agents. It.is
`contemplated that the combination of active ingredients will not only provide a .grea~r degree of.
`
`goal attainment, but it will also permit the goa1s to be achieved at lower dosage~ of the individual
`
`active ingredients thereby reducing the incidence and/or severity of dose-related adverse events
`associated with the individual active ingredients. It is contemplated that, for example, lowering
`
`20
`
`blood LDL levels below those already achieved in earlier clinical trials by using, for example, an
`
`MTP inhibitor in combination with a HMG-CoA reductase inhi'bitor plus a cholesterol
`absorption inln'bitor (CAI) w;ill provide further improvements in cardiovascular event rate
`
`reduction and/or plaque regression.
`
`{0010] For example, the oompositions can be used to reduce the fasting levels of cho.lesterol
`
`25
`
`and/or triglycerides in the blood of a mammal to meet a clinical endpoint but with fewer Qr
`reduced adverse events than (i) when the MfP inhibitor is administered a1one in a monotherapy
`at a dosage sufficient to meet the clinical endpoint or (ii) when the MTP inhibitor is administered
`
`together with another cholesterol lowering agent, where the MTP inhibitor and the other
`
`cholesterol lowering agent are administered at dosages sufficient to meet the clinical end point
`
`30
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`{0011] Furthermore, the compositions can be used to reduce by at least 55%, 60%, or 65%, the
`blood LDL concentration in a population of patients who, prior to therapy have circulating LDL
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`concentrations of at least 130 mg/dL, so as to meet the goal of having an IDL concentration of
`
`70 mgldL or less, where {i) less than 2% of the patients in the population have Liver Function
`Test results three times greater than the uj,per limit of normal 'of a standard clinical ~boratozy
`range or {ii) the patients have statistically significant lower rates of skeletal mu8cle side effects:
`{e.g., myalgia and/or myopathy) relative to patients receiving the maximum permitted dose of a
`HMG-CoA reductase inhibitor. In this context, the term "permitted" refers to a maximum
`dosage permitted by a regulatory agency, for example, the U.S. Food and Drug Agency.
`
`s
`
`[0012) Furthermore, it is contemplated that the eompositions, when administered to the
`
`recipient, will not only permit the recipient to meet a cholesterol goal but will also slow down or
`
`10
`
`stop the build up of plaques, for example, atherosclerotic plaques, on the walls of blood vessels.
`
`Under certain circumstances, it is contemplated that the compositions, when administered, will
`
`also induce regression of existing plaques.
`
`[0013] In one aspect, the invention provides a pharmaceutical composition comprising (i) a MI'P
`inhibitor, {ii) a CAI, and (iii) at least one cholesterol lowering drug selected from the group
`consisting of a HMG-CoA reductase inhibitor, a bile acid sequestrant, a fl.bric acid derivative,
`niacin, and a squalene sythetase inhibitor. In another aspect, the Invention provides :a ·
`
`15
`
`pharmaceutical composition comprising (i) an MI'PI, {ii) a HMG-CoA reductase in:bibitor, and·
`
`(iii) at least one cholesterol lowering drug selected from the group consisting of a 'bile aeid'
`
`sequestrant, a fibric acid derivative, niacin, and a squalene sythetase inhibitor.·
`
`20
`
`(0014) It is possible that the pharmaceutical composition can comprise an MfPI, {ii) a ~AI, {iii)
`a HMG-CoA reductase inlnbitor, and {iv) a cholesterol lowering drug selected from the group
`
`consisting of a bile acid sequestrant, a fibric acid derivative, and niacin.
`
`[0015) The MTPI can be selected from known compounds selected from the group consisting of
`
`BMS-201038, implitapide, ITf-130 and CP-346086, and SLx-4090. The HMG-CoAreductase
`
`25
`
`inln'bitor can be selected from the group consisting of mevastatin, lovastatin, pravastatin,
`
`simvastatin, fluvastatin, cerivastatin, atorvastatin, tenivastatin, rosuvastatin, pitavastatin. The
`
`CAI can be selected from the group_ consisting of ezetimibe or a derivative thereof, MD-0727,
`
`FM-VP4, LPD-179, LPD84, and LPD145. The bile acid sequestrant can be selected from :the·
`group consisting of cholestyramine, colesevelam and colestipol nie fibric acid derivative can
`be selected from the group consisting offenofibrate, bezafibrate, ciprofibrate, clofibrate, and
`
`30
`
`gemfibrozil.
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`DETAILED DESCRIPTION OF THE INVENTION
`
`(1)
`
`Definitions
`
`[0016] For convenience, certain terms used in the specification, examples, and appe1:1ded claims
`
`5
`
`are collected here.
`
`[0017] The phrase "combination therapy," as used herein, refers to co-administering: an MTP
`inlnoitor and at least two other cholesterol lowering agents, for example, where one is a HMO :
`
`Co-A reductase and tJ:ie other is a CAI, as part of a specific treatment regimen intended to
`
`provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect
`
`IO
`
`of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co(cid:173)
`
`action resulting from the combination of therapeutic agents. Administration of these therapeutic
`
`agents in combination typically is carried out over a defined time period (usually weeks, months
`
`or years depending upon the combination selected). Combination therapy is intended to embrace
`administration of multiple therapeutic agents in a sequential manne~, that is, wherein each
`therapeutic agent is administered at a different time, as well as administration of these
`
`15
`
`· therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous
`
`manner. Substantially simultaneous administration can be accomplished, for example, by
`
`administering to the subject a single tablet or capsule having a fixed ratio of each therapeutic
`
`agent or in multiple, single ·capsules for each of the therapeutic agents. Sequential or
`
`· 20
`
`substantially simultaneous administration of each therapeutic agent can be effected by any
`
`appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular
`
`routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be
`
`administered by the same route or by different routes. For example, a first therapeutic agent of
`
`25
`
`the combination selected may be administered by intravenous injection while the oth~
`therapeutic agents of the combination may be administered orally. Alternatively, foF example,
`all therapeutic agents may be administered orally or all therapelitic' agents-may be administered
`
`by intravenous injection.
`
`(0018] _Combination therapy also can embrace the administration of the therapeutic agents'as
`described above in further combination with other biologically active ingredients ·and non-drug
`
`30
`
`therapies. Where the combination therapy further comprises a non-drug treatment, the non-drug
`
`. treabnent may be conducted at any suitable time so long as a beneficial effect from the co-action
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`of the combination of the.therapeutic agents and non-drug ln'.8tment is achieved. For example,:
`in appropriate cases, the beneficial effect is still achieved when the non-drug treatm~nt is
`· temporally removed from the administration of the therapeutic agents, perhaps by days or even•
`weeks.
`
`s
`
`[0019) The components of the· combination may be administered to a patient simultaneo1lsly
`or sequentially. It will be appreciated that the components may be •present in the same
`
`pharmaceutically acceptable carrier and, therefore, are administered simultaneously.
`
`Alternatively, the active ingredients may be present in separate pharmaceutical carriers, such'
`
`as, conventional oral dosage forms, that can be administered either simultaneously or
`
`10
`
`sequentially.
`
`{0020) The terms, "individual," "patient," or "subject" are used interchangeably herein and
`.
`.
`include any mammal, including animals, for example, pnmates, for example, hlimans, and other
`
`:
`
`animals, for example, dogs, cats, swine, cattle, sheep, and horses. The compounds of the
`
`invention can be administered to a mammal, such as a human, but can also be other mammals,
`
`15
`
`for example, an animal in need of veterinary treatment, for example, domestic animals (for
`
`example, dogs, cats, and the like), farm animals (for example, cows, sheep, pigs, horses, and the
`
`like) and laboratory animals (for example, rats, mice, guinea pigs, and the like).
`
`(0021) The term. ''patient resistant to statin monotherapy," as used herein includes those patients
`
`for whom conventional statin monotherapy has been found ineffective or less effective than
`desired. A physician designing lipid reduction therapy for a patient will be able to determine via
`
`20
`
`diagnosis and observation of periodic blood cholesterol and/or triglyceride levels whether such a
`
`patient is or has been resistant to statin monotherapy.
`
`(0022) The term, "statin-intolerant patient," as used herein includes those patients for whom
`
`conventional statin therapy, for example, for serum lipid reduction, has been found to be
`
`25
`
`ineffective and/or fo~ whom an effective lipid-reducing dose of statins is too high to be tolerated
`
`or that there is an unacceptable adverse event associated with a particular dose: For 'example,
`
`statin therapy may be discontinued by the physician/patient due to concern over an adverse event
`such as Liver Function Test abnormality, muscle aches and pains or inflammation - myalgia or
`
`30
`
`myostitis, elevation in enzymes (CK) showing muscle adverse event A physiCian desigmrig
`lipid reduction therapy for a patient will be able to determine via diagnosis and observation of
`periodic blood cholesterol and/or triglyceride levels whether such a patient is statin-intolerant
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`[0023] The phrase "minimizing adverse effects," "reducing adverse events," or "reduced adverse .
`
`events," as used herein refer to an amelioration or elimination of one or more undesired ~ide
`
`effects associated with the use of MTP inhibitors of the present invention. Side effects ·of
`
`s
`
`traditional use of the MTP inln'bitors include, without limitation, nausea, gastrointestinal
`disorders, steatorrhea, abdominal cramping, distention, elevated liver function tests, fatty liver
`(hepatic steatosis); hepatic fat build up, polyneuropathy, peripheral neuropathy, rhapdomyo~ysis,
`
`arthralgia, myalgia, chest pain, rhinitis, dizziness, arthritis, peripheral edema, gastroenteritis,
`
`liver function tests abnormal, colitis, rectal hemorrhage, esophagi.tis, eructation, stonµititis, ·
`
`biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gum hemorrhage, stomach
`ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice, paresthesia,
`
`10
`
`amnesia, libido decreased, emotional lability, ·incoordination, torticollis, facial paralysis,
`
`hyperkinesia, depression, bypesthesia, hypertonia, leg cramps, bursitis, tenosynovitis,
`
`myasthenia, tendinous contracture, myositis, hyperglycemia:, creatine phosphokinase increased,
`
`gout, weight gain. hypoglycemia, anaphylaxis, angioneurotic edema, and bullous rashes
`
`15
`
`(including erytbema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis).
`
`Accordingly, the methods described herein provide an effective theJBPy while at the s~e time ,
`
`causing few~r or less significant adverse events.
`
`[0024] In certain embodiments, side effects are partiaUy eliminated.- As used herein; the phrase
`
`"partially eliminated" refers to a reduction in the severity, extent, or duration of the particular
`
`20
`
`side effect by at least 30%, 40%, 50%, 60%, 70%, 80o/o, 90%, 95% and 99% relative to .that
`
`found by administering 25 mg/day ofBMS-201038 during monotherapy or either 80 mg/day or
`
`160 mg/day of implitapide during monotherapy. In certain embodiments, side effects are
`completely eliminated. Those skilled in the art are credited with the ability to detect and grade
`
`the severity, extent, or duration of side effects as well as the degree of amelioration of a side
`
`25
`
`effect. In some embodiments, two or more side effects are ameliorated.
`
`(0025] The term, "therapeutically effective" refers to the ability of an active ingredient, for
`
`example, BMS-201038 and implitapide, to elicit the biological or medical response ihat is being
`
`sought by a researcher, veterinarian, medical doctor or other clinician. Non-limitiilg examples
`include reduction of cholesterol (for example, LDL-C) and/or triglyceride levels in a patient,
`
`30
`
`reduction of the amount of plaques, for example, arterial plaques, on the wall of a bfood vessel,
`
`and the like.
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`(0026} The term, "therapeutically effective amount'' include~ the amount of an active ingredient,
`
`for example, BMS-201038 and implitapide, that will elicit the biological or medical respoD:!e
`that is being sought by the researcher, veterinarian, medical doctor or other clinician.: The . ·
`compounds of the invention are administered in amounts effective at lowering the cholesterol
`concentration in the blood, and/or the triglyceride concentration in the blood and/or l'.t:ducing the
`amount of plaques, for example, arterial plaques disposed upon the blood contacting w8ll of one
`
`s
`
`or more blood vessels. Alternatively, a therapeutically effective amount of an active in~dien!: .
`is the quantity of the compound required to achieve a desired therapeutic and/or prophylactic
`effect, such as the amount of the active ingredient that results in the prevention of or a decrease·
`
`10
`
`in the symptoms associated with the condition (for example, to meet an end-point).
`
`[0027) The terms, "phannaceutically acceptable" or ''pharmacologically acceptable" refer to
`
`molecular entities and compositions that do not produce an adverse, allergic or other untowBrd
`reaction when administered to an animal, or to a human, as appropriate. The tenn.
`"pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings,
`
`15
`
`antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use
`
`of such media and agents for pharmaceutical active substances is well known in the art. Except
`
`insofar as any conventional media or agent is incompatible with the active ingredient; its use in
`the therapeutic compositions is contemplated. Supplementary active ingredients can al8o be
`
`incorporated into the compositfons.
`
`20
`
`[0028) The terms "treating" or ''treatment", refers to any effect, for example, lessening,
`
`inhibiting, reducing, modulating, or eliminating, that results in the improvement of the condition,
`·disease, or disorder.
`
`(2)
`
`Formulations for Combination Therapy
`
`(0029) The compositions provided herem are useful for treating a number of disorders associated
`
`25 with elevated levels of cholesterol and/or triglycerides in the. blood. The compositions comprise
`
`an MTP inhibitor in combination with at least two other cholesterol lowering drugs.
`
`f 0030] In one aspect, the composition comprises (i) an MrP inhibitor, (ii) a CAI, and (iii) at
`least one cholesterol lowering drug selected from the group consisting of a HMG-CoA reductase
`
`inhibitor, a bile acid sequestrant, a fibric acid derivative, niacin, and squalene sythetase inhibitor.
`30 When three active ingredients are used, this is referred to as a triple combination. However, .it is
`
`contemplated that more than three of the active ingredients can be used in the practic~ of the
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`[0031) In another aspect. the composition comprises (i) and MTP inln"bitor, {ii) a HMG-CoA
`
`reductase inlu'bitor, and (iii) at least one cholesterol lowering drug selected from the group
`
`s
`
`consisting of a bile acid sequestmnt. a fibric acid derivative, niacin, and squalene syi;hetase ·
`inhibitor. It is contemplated that more than three of the active ingredients can be Used :in the
`practice of the invention.
`
`[0032) It is contemplated that the combination of active ingredients will not oniy provide a.
`greater degree of goal attainment, but it will also permit the goals to be achieved at lower
`
`dosages of the individual active ingredients thereby reducing the incidence and/or· severity of
`
`10
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`dose-related adverse events associated with the individual active ingredients . .It is contemplated
`that. for ~le, lowering blood IDL levels below those already achieved in earlier clinical
`. trials by using, for example, an MTP inlu"bitor in combination with a HMG-CoA reductase
`inhibitor plus a CAI will provide further improvements in cardiovascular event rate reduction
`
`and/or plaque regression
`
`15
`
`[0033) For example, the compositions can be used to reduce the fasting levels of cholesterol
`
`and/or triglycerides in the blood of a mammal to meet a clinical end-point but with fewer or
`
`reduced adverse events than (i) when the MTP inhibitor is administered alone in a monotherapy
`
`at a dosage sufficient to achieve or substantially achieve (for example, within 10%) the clinical
`end-point or .(ii) when the MfP inhibitor is administered together with another cholesterol
`
`· 20
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`lowering agent, where the MTP inhibitor and the other cholesterol lowering agent are
`
`administered at dosages sufficient to achieve or substantially achieve the clinical end-point
`[0034) Furthermore, the compositions can be used to reduce by at least 55%, 60%, 6r 65%, the
`blood LDL concentration in a population o.f patients who, prior to therapy have ciiculatlng LDL
`
`25
`
`concentrations of at least 130 mgldL, so as to meet the goal of having an LDL concentration of
`.
`70 mg/dL or less, where (i) less than 2% of the patients in the population have Liver Function •
`Test results three times greater than the upper limit of nonnal of a standard cllilical laboratory
`
`.
`
`range or (ii) the patients have statistically ~ignificant lower rates of skeletal mtiscle side effects
`
`(e.g., myalgia and/or myopathy) relative to patients receiving the maximum permitted dose of a
`
`HMG-CoA reductase inhibitor.
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`30
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`(0035) Furthermore, it is contemplated that the composition$, when administered to the
`
`. recipient. will not only permit the recipient to meet a cholesterol goal but will also slow down or
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`stop the build up of plaques, for e~ple, atherosclerotic plaques, on the walls of blood vessels ..
`Under certain circumstances, it is contemplated that the compositions, when adminisieled, will
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`also induce regression of existing plaques.
`
`[0036) Preferred active agents that can be combined to meet the clinical end points describect
`
`s
`
`herein are set forth below.
`
`A.
`
`MTP Inhibitors
`
`[0037] In one embodiment, the MTP inhibitor may be BMS 201038 (denoted as Ml). As used
`
`herein, the phrase "BMS-201038" refers to a compound known as N-(2,2,2-Trifluorethyl)-9-[4-' ·
`
`[ 4-[[[ 4'-(tritluoromethyl)[l, 1 'biphenyl]-2-Yl]carbonyl]amino ]-l-piperidinyl]butyl]9H-fluorene-
`
`IO
`
`9-carboxamide, having the formula:
`
`and stereoisomers thereof, and pharmaceutically acceptable salts and esters thereof.
`
`(0038] In another embodiment, the MfP inhibitor may include benzimidazole-based analogues
`
`of BMS 201038 (denoted as M2). As used herein, the "M2" refers to a compound having the
`
`Is
`
`fomiula shown below:
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`_where n can be 0 to 10, and stereoisomers thereof, and phannaceutically acceptable salts and
`esters thereof.
`
`(0039] In another embodiment, the MTP inhibitor may be implitapide (denoted as Ml); As· used
`
`herein, the phrase "implitapide" refers to a compound (28)-2-cyclopentyl-2-[4-[(2,4-diJliethyl- '
`
`S
`
`9H-pyrido[2,3-b ]indol-9-yl)methyl]phenyl]-N-:[(1 S)-2-hydroxy-1-phenylethyl]etbanamide, and:·
`
`having the structure shown below:
`
`and stereoisomers thereof: and pharmaceutically acceptable salts 8;lld esters thereof.
`
`10·
`
`(0040) In another embodiment, the MTP inhibitor may be JTT-l 30m (denoted as M4) ·including
`pharmaceutically acceptable salts and esters thereof: described in AggarWal, et al., BMC
`CARDIOVASC. DISORD. 27;5(1):30 (2005). In another embodiment, the MTP inhibitOr may be
`
`CP-346086 (denoted MS) including pharmaceutically salts and esters thereof: descn"bed in
`Chandler, et al., J. LIPID. REs. 44(10):1887-901 (2003).
`
`· (4!041] Otb_er 'M'I!.i~bil!i~rs l!iclude those developed by Surface Logix_, Inc. e.g., SLx-4090
`(denoted as M6).
`
`15
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`Other Cholesterol Lowering Agents
`B.
`(0042] Cbolesterol loweiing agents that may be used in the compositions and methods described _
`
`herein include:
`
`Cholesterol Absorption Inhibitors (CAI)
`1.
`(0043] In one embodiment, the CAI may be ezetimibe (also k:Down as Zetia) (denoted as Cl), As
`
`20 ·
`
`used herein, the phrase "ezetimibe" refers to a compound having the structure shown below:
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`b F
`
`and stereoisomers thereo~ and pharmaceutically acceptable salts and esters thereof.
`
`(0044] In one embodiment, the CAI may be ?vm-0727 (denoted as C2) including
`pharmaceutically acceptable salts and esters thereof. In another embodiment, the CAI may be
`FM-VP4 (denoted as CJ). ~used herein, the phrase "FM-VP4" refers to a compound the ·
`
`s
`
`structure of which is set forth below:
`
`and stereo isomers thereof, and pharmaceutically acceptable salts and esters thereof
`
`(0045) In another embodiment, the CAI may be the structure below (denoted as C4), as
`
`10
`
`described in Ritter et al., Org. Biomo/. Chem., 3(19), 3514-3523, (2005):
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`F
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`and ~ereoisomers thereof, and pharmaceutically acceptable salts and esters thereof. ;
`
`[0046) In another embodiment, the CAI may be LPD179 (denoted as CS). AB used herein, the
`phrase ''LDPl 79" refers to a compound ha~g the structure set forth below:
`.
`\~o . .
`. o--S~OH .
`-....::::::::
`0
`·o~OH
`H
`
`..
`
`OH
`
`HO
`
`.
`
`OH
`
`~
`
`A
`U
`
`HO
`
`.
`
`.
`
`F
`
`"'Q
`
`5
`
`F
`and stereoisomers thereof, and pharmaceuticaJly acceptable salts and esters thereof . ·
`
`[0047] In another embodiment, the CAI may be LPD84 (denoted as C6). As used herein, the
`phrase "LPD84" refers to a compound having the structure set forth below:
`