B9
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`3 July 2008 (03.07.2008)
`
`PCT
`
`(10) International Publication Number
`WO 2008/079398 Al
`(81) Designated States (unless otheiwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
`CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG,
`ES, Fl, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL,
`IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK,
`LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
`MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
`PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY,
`Tl, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`
`(84) Designated States (unless otheiwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`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, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL,
`PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(51) International Patent Classification:
`A61K 311397 (2006.01)
`A61K 3114468 (2006.01)
`A61K 311437 (2006.01)
`A61P 3104 (2006.01)
`
`(21) International Application Number:
`PCT/US2007 /026300
`
`(22) International Filing Date:
`21December2007 (21.12.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/876,280
`
`21 December2006 (21.12.2006) US
`
`(71) Applicant (for all designated States except US): AEGE(cid:173)
`RION PHARMACEUTICALS, INC. [US/US]; 1140
`Route 22 East, Suite 304, Bridgewater, NJ 08807 (US).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): WISLER, Gerald, L.
`[US/US]; 5 Forest View Drive, Gladstone, NJ 07934 (US).
`
`(74) Agents: KAVANAUGH, Theresa, C. et al.; Goodwin
`Procter LLP, Exchange Place, Boston, MA 02109 (US).
`
`---iiiiiiiiiiiiiii
`iiiiiiiiiiiiiii -----
`----iiiiiiiiiiiiiii
`iiiiiiiiiiiiiii ----
`
`QIO
`O"..
`~
`O".. r-
`--. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`0
`~ (54) Title: METHODS FOR TREATING OBESITY WITH A COMBINATION COMPRISING A MTP INHIBITOR AND A
`0 CHOLESTEROL ABSORPTION INHIBITOR
`M O (57) Abstract: The invention is directed to methods for treating and/or controlling obesity in a patient. The methods involve com(cid:173)
`> bination therapies using a microsomal triglyceride transfer protein (MTP) inhibitor (for example, AEGR-733 and implitapide) and
`
`~ a cholesterol absorption inhibitor (CAI) (for example, ezetimibe).
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`METHODS FOR TREATING OBESITY WITH A COMBINATION COMPRISING
`A MTP INHIBITOR AND A CHOLESTEROL ABSORPTION INHIBITOR
`
`RELATED APPLICATIONS
`
`[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No.
`
`60/876,280 filed December 21, 2006, the entire disclosure of which is incorporated by
`
`reference herein
`
`FIELD OF THE INVENTION
`
`5
`
`[0002] This invention relates generally to methods of treating and/or controlling obesity in a
`
`patient. More particularly, the invention relates to therapies using a microsomal triglyceride.
`
`transfer protein (MTP) inhibitor in combination with a cholesterol absorption inhibitor (CAI).
`
`BACKGROUND
`
`[0003] Obesity is a major public health concern and is now recognized as a chronic disease that
`
`Io
`
`requires treatment to reduce its associated health risks. It is understood that more than 100
`
`million adults in the United States are overweight or obese. The medical problems caused by
`
`overweight and obesity can be serious and often life-threatening, and include diabetes,
`
`shortness of breath, gallbladder disease, hypertension, elevated blood cholesterol levels, cancer,
`
`arthritis, other orthopedic problems, reflux esophagitis (heartburn), snoring, sleep apnea,
`
`15 menstrual irregularities, infertility and heart trouble. Moreover, obesity and overweight
`
`substantially increase the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes,
`
`coronary heart disease, stroke, gallbladder disease, osteoarthritis and endometrial, breast,
`
`prostate, and colon cancers. Higher body weights are also associated with increases in all(cid:173)
`
`cause mortality. Most or all of these problems are alleviated or improved by permanent
`
`20
`
`significant weight loss. Longevity is likewise significantly increased by permanent significant
`
`weight loss. Hence, it is believed that a 2-10% intentional reduction in body weight may
`
`reduce morbidity and mortality. There is a clear on-going need for methods for treating obesity
`
`that effectively reduce body mass in a patient in need thereof.
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`(0004] Microsomal triglyceride transfer protein (MTP) inhibitors have been developed as
`
`potent inhibitors of MTP-mediated neutral lipid transfer activity. MTP catalyzes the transport
`
`of triglyceride, cholesteryl ester, and phosphatidylcholine between small unilamellar vesicles.
`
`[0005] Cholesterol absorption inhibitors such as ezetimbe impair the intestinal reabsorption of
`
`5
`
`both dietary and hepatically-excreted biliary cholesterol. Ezetimbe, for example, is used for
`
`reducing low density lipoprotein cholesterol in patients. Cholesterol absorption inhibitors are
`
`not known to be effective, when used in monotherapy, for use in treating obesity or for use as a
`
`weight loss agent.
`
`SUMMARY OF THE INVENTION
`
`10
`
`(0006] The invention provides methods for treating and/or controlling obesity. The method
`
`includes administering an MTP inhibitor, such as AEGR-733 or implitapide, in combination
`
`with a cholesterol absorption inhibitor (CAI), such as ezetimibe. The MTP inhibitors can be
`
`administered at certain lower dosages that are still therapeutically effective when combined
`
`with a CAI but yet create fewer or reduced adverse effects when compared to therapies using
`
`15
`
`therapeutically effective dosages of the MTP inhibitors during monotherapy. The
`
`administration of one or more MTP inhibitors, when administered in combination with one: or
`
`more CAis, may provide an additive or synergistic therapeutic effect, e.g. may result in patient
`
`weight loss that is greater than the sum of the expected weight loss due to administration of a
`
`MTP inhibitor and CAI when administered alone. In some embodiments, disclosed methods
`
`20
`
`can result in fewer incidences of gastrointestinal adverse events in a patient as compared to
`
`administration of a MTP inhibitor alone.
`
`(0007] An exemplary method includes a method of treating obesity comprising administering
`
`to a patient in need thereof a MTP inhibitor in combination with a cholesterol absorption
`
`inhibitor, wherein the administration of the combination results in a greater reduction in body
`
`25 mass of the patient after 12 weeks of daily administration as compared to 12 weeks of daily
`
`administration of a cholesterol absorption inhibitor or a MTP inhibitor alone.
`
`(0008] For example, a method of treating obesity is disclosed that comprises administering to a
`
`patient in need thereof a MTP inhibitor in combination with a cholesterol absorption inhibitor,
`
`wherein the administration of the combination results in a greater reduction in body mass of the
`
`30
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`patient after 12 weeks of daily administration as compared to 12 weeks of daily administration
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`of a cholesterol absorption inhibitor or a MTP inhibitor alone, and wherein the method results
`
`in fewer incidences of gastrointestinal adverse events in the patient as compared to
`
`administration of a MTP inhibitor alone.
`
`[0009] Another exemplary method contemplated by this disclosure includes a method of
`
`5
`
`inducing weight loss in a patient comprising administering to the patient an MTP inhibitor in
`
`combination with a cholesterol absorption inhibitor so as to induce weight loss in the patient.
`
`In some embodiments, the weight loss achieved, after e.g. 4 weeks, 8 weeks, 12 weeks, or even
`
`6 months, is greater than that achieved by administering the cholesterol inhibitor alone or the
`
`MTP inhibitor alone. In an embodiment, weight loss achieved by the disclosed methods is
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`Io
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`greater than the additive effect of administering the MTP inhibitor alone and the cholesterol
`
`absorption inhibitor alone.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0010] Throughout this entire disclosure, including the figures and claims, the terms "AEGR-
`
`733" and "BMS-.201038" have the same meaning and are used interchangeably.
`
`15
`
`[0011] Figure 1 depicts body mass reduction at 4 weeks, 8 weeks, and 12 weeks of daily
`
`administration of AEGR-733 and ezetimibe in the patient study described in Example 1.
`
`[0012] Figure 2 depicts the occurrence rate of gastrointestinal adverse events and the GSRS
`
`results of patients assessed at 12 weeks in the patient study described in Example 1.
`
`[0013] Figure 3 depicts body mass reduction at 4 weeks, 8 weeks, and 12 weeks of daily
`
`20
`
`administration of AEGR-733 and ezetimibe for those patients with an initial BMI greater than
`30 kg/m2 in the patient study as described in Example 1.
`
`[0014] Figure 4 depicts body mass reduction at 4 weeks, 8 weeks, and 12 weeks of daily
`
`administration of AEGR-733 and ezetimibe for those patients with an initial BMI less than or
`equal to 30 kg/m2 in the patient study as described in Example 1.
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`DETAILED DESCRIPTION
`
`[0015] The invention relates, in part, to methods of treating and/or controlling obesity
`
`comprising administering to a patient in need thereof a MTP inhibitor in combination with a
`
`5
`
`cholesterol absorption inhibitor. Such a patient may have, for example, a body mass index
`, e.g. between about 30 kg/m2 and about 60 kg/m2 before
`greater than or equal to about 30 kg/m2
`treatment. Alternatively, a patient may have a body mass index between about 25 kg/m2 and
`about 30 kg/m2 before treatment.
`
`[0016] The methods described herein result in a greater reduction in body mass of a patient
`
`after, for example, four, eight and/or twelve weeks of daily administration, or 4, 5, and/or 6
`
`Io months or 1 year of substantially daily administration, as compared to daily administration of a
`
`cholesterol absorption inhibitor or a MTP inhibitor alone for the same time interval.
`
`[0017] Administering combinations of a MTP inhibitor and a cholesterol absorption inhibitor,
`
`under certain circumstances, provide an additive and/or synergistic therapeutic effect, e.g.
`
`provide a total reduction in body mass that is greater than the sum of the reduction in body
`
`15 mass resulting from administering a MTP inhibitor or a cholesterol absorption inhibitor alone.
`
`1. Definitions
`
`[0018] For convenience, certain terms used in the specification, examples, and appended
`
`claims are collected in this section.
`
`[0019] The phrase "combination therapy," as used herein, refers to co-administering an MTP
`
`20
`
`inhibitor, for example, AEGR-733 and implitapide, or a combination thereof, and CAI, for
`
`example, ezetimibe, as part of a specific treatment regimen intended to provide the beneficial
`
`effect from the co-action of these therapeutic agents. The beneficial effect of the combination
`
`includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from
`
`the combination of therapeutic agents. Administration of these therapeutic agents in
`
`25
`
`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 manner, that is, wherein each
`
`therapeutic agent is administered at a different time, as well as administration of these
`
`therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous
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`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 or tablets for each of the therapeutic agents. Sequential or
`
`substantially simultaneous administration of each therapeutic agent can be effected by any
`
`5
`
`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
`
`the combination selected may be administered by intravenous injection while the other
`
`therapeutic agents of the combination may be administered orally. Alternatively, for example,
`
`1 O
`
`all therapeutic agents may be administered orally or all therapeutic agents may be administered
`
`by intravenous injection.
`
`[0020] Combination therapy can also embrace the administration of the therapeutic agents as
`
`described above in further combination with other biologically active ingredients and non-drug
`
`therapies. Where the combination therapy further comprises a non-drug treatment, the non-
`
`15
`
`drug treatment may be conducted at any suitable time so long as a beneficial effect from the co(cid:173)
`
`action of the combination of the therapeutic agents and non-drug treatment is achieved. For
`
`example, in appropriate cases, the beneficial effect is still achieved when the non-drug
`
`treatment is temporally removed from the administration of the therapeutic agents, perhaps by
`
`days or even weeks.
`
`20
`
`[0021] The components of the combination may be administered to a patient simultaneously
`
`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
`
`25
`
`sequentially.
`
`[0022] The terms, "individual," "patient," or "subject" are used interchangeably herein and
`
`include any mammal, including animals, for example, primates, for example, humans, 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,
`
`30
`
`for example, an animal in need of veterinary treatment, for example, domestic animals (for
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`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).
`
`[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
`
`5
`
`side effects associated with the use of MTP inhibitors of the present invention. Side effects of
`
`traditional use of the MTP inhibitors include, without limitation, diarrhea, nausea,
`
`gastrointestional disorders, steatorrhea, abdominal cramping, distention, elevated liver function
`
`tests, fatty liver (hepatic steatosis); hepatic fat build up, polyneuropathy, peripheral neuropathy,
`
`rhabdomyolysis, arthralgia, myalgia, chest pain, rhinitis, dizziness, arthritis, peripheral edema,
`
`IO
`
`gastroenteritis, liver function tests abnormal, colitis, rectal hemorrhage, esophagitis, eructation,
`
`stomatitis, biliary pain, cheilitis, duodenal ulcer, dysphagia, enteritis, melena, gum hemorrhage,
`
`stomach ulcer, tenesmus, ulcerative stomatitis, hepatitis, pancreatitis, cholestatic jaundice,
`
`paresthesia, amnesia, libido decreased, emotional !ability, incoordination, torticollis, facial
`
`paralysis, hyperkinesia, depression, hypesthesia, hypertonia, leg cramps, bursitis, tenosynovitis,
`
`15 myasthenia, tendinous contracture, myositis, hyperglycemia, creatine phosphokinase increased,
`
`gout, weight gain, hypoglycemia, anaphylaxis, angioneurotic edema, and bullous rashes
`
`(including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis).
`
`Accordingly, the methods described herein provide an effective therapy while at the same time
`
`may cause fewer or less significant adverse events as compared to larger monotherapies alone.
`
`20
`
`[0024] In certain embodiments, side effects are partially eliminated. As used herein, the phrase
`
`"partially eliminated" refers to a reduction in the severity, extent, or duration of the particular
`
`side effect by at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 99% relative to that
`
`found by administering 25 mg/day of AEGR-733 during monotherapy or either 80 mg/day or
`
`160 mg/day of implitapide during monotherapy. In certain embodiments, side effects are
`
`25
`
`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
`
`effect. Assessment of side effects can be conducted using assessments and/or tests as known to
`
`those skilled in the art. For example, gastrointestinal side effects can be assessed, for example,
`
`using the Gastrointestinal Symptom Rating Scale. In some embodiments, two or more side
`
`30
`
`effects are ameliorated.
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`[0025] The Gastrointestinal Symptom Rating Scale ("GSRS") is an assessment tool for patients
`
`with general gastrointestinal complaints, and has been extensively validated in previous studies.
`
`The GSRS includes up to 15 items that addresses different gastrointestinal symptoms and
`
`typically uses a 7-point Likert response scale with verbal descriptors. The response scale is
`
`5
`
`designed to measure the amount of discomfort a patient has experienced (none at all, minor,
`
`mild, moderate, moderately severe, severe, and very severe). A higher score in a GSRS cluster
`
`indicates more discomfort, with the scale from 1 (no discomfort) to 7. The recall period can
`
`refer, for example, to the past week. The 15 exemplary items can combine into five symptom
`
`clusters labeled reflux, abdominal pain, indigestion, diarrhea, and constipation. From
`
`10
`
`individual items within a cluster, a mean score is calculated.
`
`[0026] The term "synergistic" refers to two or more agents, e.g. a MTP inhibitor and a CAI,
`
`when taken together, produce a total joint effect that is greater than the sum of the effects of
`
`each drug when taken alone.
`
`[0027] The term, "therapeutically effective" refers to the ability of an active ingredient, alone
`
`15
`
`or in combination with another active agent, to elicit the biological or medical response that is
`
`being sought by a researcher, veterinarian, medical doctor or other clinician.
`
`(0028] The term, "therapeutically effective amount" includes the amount of an active
`
`ingredient, or combination of active ingredients, that will elicit the biological or medical
`
`response that is being sought by the researcher, veterinarian, medical doctor or other clinician.
`
`20
`
`The compounds of the invention are administered in amounts effective for treating and/or
`
`reducing obesity. Alternatively, a therapeutically effective amount of an active ingredient 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
`
`in the symptoms associated with the condition (for example, to meet an end-point).
`
`25
`
`[0029] The terms, "pharmaceutically acceptable" or "pharmacologically acceptable" refer to
`
`molecular entities and compositions that do not produce an adverse, allergic or other untoward
`
`reaction when administered to an animal, or to a human, as appropriate. The term,
`
`"pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings,
`
`antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The
`
`30
`
`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,
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`its use in the therapeutic compositions is contemplated. Supplementary active ingredients can
`
`also be incorporated into the compositions.
`
`[0030] Pharmaceutically acceptable salts of the disclosed compounds can be synthesized, for
`
`example, from the parent compound, which contains a basic or acidic moiety, by conventional
`
`5
`
`chemical methods. Generally, such salts can be prepared by reacting the free acid or base
`
`forms of these compounds with a stochiometric amount of the appropriate base or acid in water
`
`or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether,
`
`ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found
`
`in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore,
`
`IO MD, 2000, p. 704.
`
`[0031] As used herein, the term "stereoisomers" refers to compounds made up of the same
`
`atoms bonded by the same bonds but having different spatial structures which are not
`
`interchangeable. The three-dimensional structures are called configurations. As used herein,
`
`the term "enantiomers" refers to two stereoisomers whose molecules are nonsuperimposable
`
`15 mirror images of one another. The terms "racemate," "racemic mixture" or "racemic
`
`modification" refer to a mixture of equal parts of enantiomers.
`
`2. Methods of the Invention
`
`[0032] In general the invention provides methods for treating and/or controlling obesity using
`
`one or more MTP inhibitors, for example, AEGR-733 or implitapide, in combination with a
`
`20
`
`cholesterol absorption inhibitor, for example ezetemibe. The MTP inhibitors can be used at
`
`dosages lower than those already found to result in one or more adverse events, for example,
`
`gastrointestinal disorders, abnormalities in liver functional and/or hepatic steatosis (for
`
`example, 25 mg/day of AEGR-733, 80 mg/day ofimplitapide and 160 mg/day ofimplitapide
`
`have been found to cause gastrointestinal disorders, abnormalities in liver function and/or
`
`25
`
`hepatic steatosis) but at doses which are therapeutically effective when combined with a
`
`cholesterol absorption inhibitor, for example, ezetimibe. The dosages need not be smaller but
`
`may additionally and/or optionally be administered less frequently. It is contemplated that such
`
`a combination may be effective at treating and/or controlling obesity, e.g. effective in
`
`promoting weight reduction, in a patient even when larger dosages of AEGR-733 are
`
`30
`
`administered together with a dose of a cholesterol absorption inhibitor.
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`[0033] Also contemplated herein are methods of treating obesity-related disorders such as
`
`those associated with, caused by, or result from obesity. Examples of obesity-related disorders
`
`include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations
`
`and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon
`
`5
`
`cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal
`
`heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart
`
`disease, sudden death, stroke, polycystic ovary disease or syndrome, craniopharyngioma, the
`
`Prader-Willi Syndrome, Frohlich's syndrome, OH-deficient subjects, normal variant short
`
`stature, Turner's syndrome, and other pathological conditions showing reduced metabolic
`
`IO
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`activity or a decrease in resting energy expenditure, e.g, children with acute lymphoblastic
`
`leukemia. Further examples of obesity-related disorders are Metabolic Syndrome, also known
`
`as Syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as
`
`infertility, hypogonadism in males and hirsutism in females, acanthosis nigricans,
`
`gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory
`
`15
`
`disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular
`
`disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis,
`
`hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney
`
`cancer. The compositions of the present invention also are useful for reducing the risk of
`
`secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
`
`20 Methods for treating patients at risk of obesity, such as those patients who are overweight, e.g.
`with a BMI of between about 25 and 30 kg/m2
`
`, are also contemplated. Therefore, the present
`
`invention includes a method of treating each of the foregoing diseases or conditions in a patient
`
`with one or more of the diseases or conditions comprising administering to the patient in need
`
`of such treatment dosage combinations of a MTP inhibitor compound and cholesterol
`
`25
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`absorption inhibitor.
`
`[0034] Also provided herein is a method of inducing weight loss in a patient comprising
`
`administering to the patient an MTP inhibitor in combination with a cholesterol absorption
`
`inhibitor so as to induce weight loss in the patient. Such weight loss may be greater than that
`
`achieved by administering the cholesterol inhibitor alone or the MTP inhibitor alone, for
`
`30
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`example, the weight loss may be greater than the additive effect of administering the MTP
`
`inhibitor alone and the cholesterol absorption inhibitor alone.
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`PCT /US2007 /026300
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`- 10 -
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`[0035] "Obesity" is a condition in which there is an excess of body fat. Typically, the
`
`definition of obesity is based on the Body Mass Index (BMI), which is calculated as body
`weight per height in meters squared (kg/m2
`). Obesity refers to a condition whereby an
`otherwise healthy patient has a Body Mass Index (BMI) greater than or equal to 30 kg/m2 or a
`
`5
`
`condition whereby a patient with at least one co-morbidity has a BMI greater than or equal to
`27 kg/m2
`
`• Obesity can also refer to those patients with a waist-to-hip ratio of 0.85 or more for
`
`women and 1.0 or more for men. Obesity can also refer to patients with a waist circumference
`
`of about 102 cm for males and about 88 cm for females.
`
`IO
`
`[0036] A patient at risk of obesity is an otherwise healthy subject with a BMI of25 kg/m2 to
`less than 30 kg/m2 or a subject with at least one co-morbidity with a BMI of25 kg/m2 to less
`than 27 kg/m2
`• Alternatively or additionally, a patient at risk of obesity can refer to those
`
`patients with a waist-to-hip ratio of, e.g. 0.8 to 0.9 (women) and 0.9 to 1.0 (men). Such a
`
`patient may be in need of controlling obesity.
`
`[0037] The increased risks associated with obesity occur at a lower Body Mass Index (BMI) in
`
`15
`
`Asian patients or patients with Asian ancestry. In Asian countries, including Japan, obesity
`
`may refer to a condition whereby a patient with at least one obesity-induced or obesity-related
`
`co-morbidity, that requires weight reduction or that would be improved by weight reduction,
`has a BMI greater than or equal to 25 kg/m2
`• For Asian patients a subject at risk of obesity is a
`subject with a BMI of greater than 23 kg/m2 and less than 25 kg/m2
`
`•
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`20
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`(a) Combination Therapies Using MTP inhibitors and Cholesterol Absorption
`
`Inhibitors
`
`[0038] The method comprises a combination therapy, which can be achieved by co(cid:173)
`
`administering to the mammal a MTP inhibitor and a cholesterol absorption inhibitor. The MTP
`
`inhibitor and the cholesterol absorption inhibitor can be administered as a (i) single dosage
`
`25
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`form or composition, (ii) simultaneously as separate dosage forms or pharmaceutical
`
`compositions, (iii) sequentially, as separate dosage forms starting with the MTP inhibitor and
`
`then administering the cholesterol absorption inhibitor, or starting with the cholesterol
`
`absorption inhibitor and then administering the MTP inhibitor, (iv) successively, separated by
`
`for example 1-4 hours, 1-8 hours or 1-12 hours, a day, or 2 or more days, e.g. 2 to 3 days, or (v)
`
`30
`
`individually followed by the combination. The methods disclosed herein may occur before,
`
`during, or after other dosing regimens that may include, for example MTP inhibitors,
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`- 11 -
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`cholesterol absorption inhibitors, other agents for treating obesity, and/or agents for reducing
`
`cholesterol such as for example a HMG-CoA reductase inhibitor, a bile acid sequestrant, a
`
`fibric acid derivative, niacin, squalene synthetase inhibitors, ACA T inhibitors, and/or CETP
`
`inhibitors.
`
`5
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`[0039] In some embodiments, the MTP inhibitor is administered in escalating doses. Such
`
`escalating doses may comprise a first dose level and a second dose level. In other
`
`embodiments, escalating doses may comprise at least a first dosage level, a second dosage
`
`level, and a third dosage level, and optionally a fourth, fifth, or sixth dosage level. The
`
`cholesterol absorption inhibitor may be provided in one dosage level when in administered in
`
`IO
`
`combination with a MTP inhibitor, or may be administered in escalating doses.
`
`[0040] A first, second, third or more dosage levels can be administered to a patient for about 2
`
`days to about 6 months or more in duration. For example, first, second and/or third dose levels
`
`are each administered to a subject for about 1 week to about 26 weeks, or about 1 week to
`
`about 12 weeks, or about I week to about four weeks. Alternatively, the first, second and/or
`
`15
`
`third dosage levels are administered to a subject for about 2 days to about 40 days or to about 6
`
`months.
`
`[0041] The methods disclosed herein may reduce the body mass of a patient due to a decrease
`
`in caloric fat absorption. For example, after twelve weeks of a disclosed therapy, a patient may
`
`20
`
`have a 2%, 3% or more reduction in body mass. For a patient with a BMI of greater than 30
`kg/m2
`body mass after, for example, one, two, four, eight, twelve, twenty-four, or more weeks of a
`
`, such a patient may have 3%, 3.5%, 5%, 6%, 7%, 8%, 9%, 10% or more reduction in
`
`disclosed therapy.
`
`[0042] The MTP inhibitor and/or the cholesterol absorption inhibitor each may be administered
`
`in a therapeutically effective amount and/or each in a synergistically effective amount. Such
`
`25
`
`dosages of a MTP inhibitor and/or a cholesterol absorption inhibitor may, while not effective
`
`when used in monotherapy, may be effective when used in the combinations disclosed herein.
`
`[0043] Administration of the MTP inhibitor and the cholesterol absorption inhibitor may result
`
`in fewer gastrointestinal adverse events, such as GI disorders, as compared to administration of
`
`a MTP inhibitor alone. In some embodiments, administration of the MTP inhibitor and the
`
`30
`
`cholesterol absorption inhibitor may result in greater weight loss and fewer gastrointestinal
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`adverse events as compared to administration of a MTP inhibitor or cholesterol absorption
`
`- 12 -
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`inhibitor alone.
`
`MTP Inhibitors
`
`[0044] In one embodiment, the MTP