B7
`
`(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
`19 June 2008 (19.06.2008)
`
`PCT
`
`(51) International Patent Classification:
`A61K 3114045 (2006.01)
`A61K 3114709 (2006.01)
`A61K 311437 (2006.01)
`A61K 311496 (2006.01)
`A61K 311451 (2006.01)
`A61P 3104 (2006.01)
`
`(21) International Application Number:
`PCT/IB2007/003855
`
`(22) International Filing Date:
`3 December 2007 (03.12.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`(30) Priority Data:
`60/870,018
`
`English
`
`English
`
`14December2006 (14.12.2006) US
`
`(71) Applicant (for all designated States except US): PFIZER
`PRODUCTS INC. [US/US]; Eastern Point Road, Groton,
`CT 06340 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): GOSSELLIN,
`Jacques [FR/GB]; Pfizer Global Research and Devel(cid:173)
`opment, Ramsgate Road, Sandwich, Kent CT13 9NJ
`(GB). HICKMAN, Mary, Anne [US/US]; Pfizer Global
`Research and Development, Eastern Point Road, Groton,
`CT 06340 (US). WREN, Jody, Ann [US/US]; Pfizer Inc.,
`7000 Portage Road, Kalamazoo, MI 49083 (US).
`
`(10) International Publication Number
`WO 2008/072061 Al
`(74) Agent: GROVER, F., Fuller, Jr.; Clo DROUIN,
`Stephane, Pfizer Global Research and Development,
`Ramsgate Road, Sandwich, Kent CT13 9NJ (GB).
`
`(81) Designated States (unless otherwise 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,
`TI, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`
`(84) Designated States (unless otherwise 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, TI, 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 repon
`
`[Continued on next page]
`
`(54) Title: METHOD OF TREATMENT OF OBESITY WITH AN MTP INHIBITOR IN CONJUNCTION WITH AN
`INCREASED-FAT DIET
`
`25
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`
`Mean (.±. SEM) daily food intake of rats on a high or low fat diet during the 3 day
`treatment period. Empty bar = low fat vehicle placebo, soHd black bar = low fat
`dirlotapide, small horizontal slashes = high fat vehicle, thick horizontal slashes = high
`fat dirlotapide. * Significantly different from appropriate diet vehicle.
`
`0
`0
`M
`0 (57) Abstract: A method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption,
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`:;;;...,. the method comprising administering to the subject a therapeutically effective amount of an MTP inhibitor in conjunction with an
`~ increased-fat diet.
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`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
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`1
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`METHOD OF TREATMENT OF OBESITY WITH AN MTP INHIBITOR IN CONJUNCTION WITH AN
`INCREASED-FAT DIET
`
`Field of the Invention
`The present invention generally relates to therapy for obesity or related eating
`
`disorders and/or redUGing food consumption using MTP inhibitors in conjunction with an
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`5
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`increased-fat diet.
`
`Background of the Invention
`
`10
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`15
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`Obesity is a major public health concern because o~ its increasing prevalence
`and associated health risks. Moreover, obesity may affect a person's or animal's quality
`of life through limited mobility and decreased physical endurance as well as through
`
`social, academic and job discrimination.
`Inhibitors of microsomal triglyceride transfer protein (MTP) and/or Apo B
`
`secretion are useful in reducing food intake in mammals (European patent application
`
`publication No. 1 099 438 A2), reducing intestinal fat absorption (European patent
`application publication No. 1 099 439 A2) and for treating obesity and associated
`aiseases. See, for example, PCT patent application publication Nos. WO 03/002533,
`WO 2005/046644 and WO 2005/080373, and US 6,066, 653.
`However, it has been reported in WO 2005/087234 that use of inhibitors of MTP
`
`can cause side effects such as hepatotoxicities.
`The instant inventors have also found that the MTP inhibitor dirlotapide
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`20
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`(disclosed in WO 03/002533) may cause emesis when admininstered according to
`
`conventional treatment regimens.
`Thus, there is a need to develop more effective methods for treating
`obesity or related eating disorders and/or reducing food consumption using MTP
`
`25
`
`inhibitors.
`
`Summary of the Invention
`
`The invention provides a method of treating a subject suffering from obesity or
`
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`related eating disorders and/or reducing food consumption, the method comprising
`administering to the subject a therapeutically effective amount of an MTP inhibitor in
`conjunction with an increased-fat diet.
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`The invention also provides the use of an MTP inhibitor in the manufacture of a
`medicament for treating a subject suffering from obesity or related eating disorders
`and/or reducing food consumption, wherein a therapeutically effective amount of an
`MTP inhibitor is administered in conjunction with an increased-fat diet.
`The invention also provides a method of treating a s1:.1bject suffering from obesity
`
`5
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`or related eating disorders and/or reducing food consumption, the method comprising
`
`administering to the subject a therapeutically effective amount of an MTP inhibitor in
`conjunction with an increased-fat diet optionally followed by administration of at least
`one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a
`10 weight maintenance/management or retraining phase.
`The invention also provides the use of an MTP inhibitor in the manufacture of a
`medicament for treating' a subject suffering from obesity or related eating disorders
`
`and/or reducing food consumption, wherein a therapeutically effective amount of an
`
`MTP inhibitor is administered in conjunction with an increased-fat diet optionally
`followed by administration of at least one step-wise, escalating dosage of the MTP
`inhibitor and, optionally, followed by a weight maintenance/management or retraining
`phase.
`
`The invention also provides a method of treating! a subject suffering from obesity
`or related eating disorders and/or reducing food consumption, the method comprising
`administering to the subject an MTP inhibitor in conjunction with an increased-fat diet
`such that the amount of said MTP inhibitor required to be therapeutically effective is
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`15
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`20
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`reduced compared with conventional treatment regimens.
`
`The invention also provides a method of increasing the rate of weight loss in a
`subject suffering from obesity or related eating disorders, the method comprising
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`25
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`administering to the subject a therapeutically effective amount of an MTP inhibitor in
`
`conjunction with an increased-fat diet.
`The invention also provides a method of treating a subject suffering from obesity
`or related eating disorders and/or reducing food consumption, the method comprising
`
`administering to the subject ar:i initial amount of an MTP inhibitor effective to ameliorate
`the obesity or disorder yet low enough to reduce the side effects associated with
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`followed by administration of at least one step-wise, escalating dosage of the MTP
`inhibitor and, optionally, followed by a weight maintenance/management or retraining
`
`phase.
`
`The inv~ntion also provides a method of treating a subject suffering from obesity
`or related eating disorders and/or reducing food consumption, the method comprising
`administering to the subject an initial amount of an MTP inhibitor in the range of 0.025 to
`0.30 mg/kg/day in conjunction with an increased-fat diet, optionally followed by
`administration of at least one step-wise, escalating dosage of the MTP inhibitor and,
`optionally, followed by a weight maintenance/management or retraining phase.
`
`The invention further provides a method for inhibiting MTP in a subject in need
`thereof, the method comprising administering to the subject a therapeutically effective
`amount of an MTP inhibitor in conjunction with an increased-fat diet.
`The invention further provides a method of treating a subject suffering from
`obesity or related eating disorders and/or reducing food consumption, or a method for
`inhibiting MTP in a subject in need thereof, the method comprising administering to the
`subject a therapeutically effective amount of an MTP inhibitor in conjunction with an
`increased-fat diet, and wherein said administration is in combination with at least one
`additional pharmaceutical agent, such as another anti-obesity agent.
`Also provided is a me~hod of weight control in a subject the method comprising
`administering to the subject an effective weight-controlling amount of an MTP inhibitor in
`conjunction with an increased-fat diet. The' MTP inhibitor may be used alone or in
`combination with at least one additi.onal pharmaceutical agent, preferably an anti-obesity
`agent.
`
`In some embodiments the MTP inhibitor is dirlotapide ((S)-N-{2-
`[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4'-trifluoromethyl)[1, 1 '(cid:173)
`biphenylJ-2-carboxamido J-1 H-indole-2-carboxamide ).
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`
`Definitions
`Obesity and overweight in humans are generally defined by body mass index (BMI),
`which is correlated with total body fat and serves as a measure of the risk of certain
`diseases. BMI is calculat.ed by weight in kilograms divided by height in meters squared
`(kg/m2
`). Overweight is typically defined as a BMI of 25-29.9 kg/m2
`, and obesity is
`typically defined as a BMI of 30 kg/m2 or higher. Obesity in dogs and cats is usually
`defined by Body Condition Score (BCS); obesity is>/= 8 and overweight is>/= 6 on a 9-
`point scale (Purina) or obesity is>/= 5 and overweight is >/= 4 on a 5-point scale (Hill's).
`The 9-point Purina scale is further discussed in
`Laflamme, DP. Body Condition Scoring and Weight Maintenance. Proc. N. Am. Vet.
`Cont. Jan 16-21, 1993. Orlando, FL pp 290-291; and Laflamme DP, Kealy RD.
`Schmidt, DA. Estimation of Body Fat by Body Composition Score. J. Vet. Int. Med.
`1994. vol 8, p 154.
`Reference to treating obesity included hereinbefore and hereinafter should also
`be taken to include treatment of overweight subjects.
`The phrase "pharmaceutically acceptable" indicates that the substance or
`composition must be compatible chemically and/or toxicologically; with the other
`ingredients comprising a formulation, and/or the mammal being treated therewith.
`The phrase "therapeutically effective amount" means an amount of a
`compound that (i) treats or prevents the particular disease, condition, or disorder, (ii)
`attenuates, ameliorates, or eliminates one or more symptoms of the particular disease,
`condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of
`the particular disease, condition, or disorder described herein (e.g., reduces food intake
`or the desire to consume food).
`The term "subject" or "animal" means humans as well as all other warm-blooded
`members of the animal kingdom possessed of a homeostatic mechanism, including
`mammals (e.g., companion animals, zoo animals and food-source animals) and birds.
`Some examples of companion animals are canines (e.g., dogs), felines (e.g., cats) and
`horses; some examples of food-source animals are pigs, cows, sheep, poultry and the
`like. Preferably, the animal is a mammal. Preferably, the mammal is a human, a
`companion animal or a food-source animal. More preferably, the animal is a human or
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`is a canine (e.g., a cat or a dog). For example the animal is a canine (e.g. a cat or,
`preferably, a dog).
`The terms "treating", "treat", or "treatment" embrace both preventative, i.e.
`prophylactic, and palliative treatment.
`
`In the practice of the present invention, the MTP inhibitors are preferably
`intestinal-acting MTP inhibitors and these are preferably intestinal selective. In this
`invention, the term "selectivity" refers to a greater effect of a compound in a first assay,
`compared to the effect of the same compound in a second assay.
`111 the above
`embodiment of the invention, the first assay is for the ability of the compound to inhibit
`intestinal fat absorption and the second assay is for the ability of the compound to lower
`serum triglycerides. In a preferred embodiment, the ability of the compound to inhibit
`intestinal fat absorption is measured by the dose that produces 25% fat absorption
`inhibition (ED25) of the compound in an intestinal fat absorption assay, such that a
`greater effect of the compound results in the observation of a lower absolute (numerical)
`value for the ED25 • In another preferred embodiment, the ability of the compound to
`lower serum triglycerides is measured by the ED25 of the compound in a serum
`triglyceride assay. Again, a greater effect of a compound in the serum triglyceride
`lowering assay results in the observation of a lower absolute (numerical) value for the
`ED25 • It is to be understood that any assay capable of measuring the effectiveness of a
`compound
`in
`inhibiting
`intestinal
`fat absorption, or capable of measuring
`the
`effectiveness of a compound in lowering serum triglycerides, is encompassed by the
`present invention. Examples of suitable assays are given in PCT Publication No. WO
`03/002533.
`Intestinal selectivity may be achieved by controlling the solubility of the inhibitor
`in the. intestinal tract and/or release of the inhibitor from the dosage form or by
`increasing lipid (fat) in the gut, i.e. administer with food and increase the dietary fat in
`the food.
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`Brief Description of the Drawings
`Figure 1 and Figure 2 relate to a study to show efficacy and safety of dirlotapide at a
`starting dose of 0.1 mg/kg in the treatment of excessive body weight in overweight
`Labrador dogs fed diets with varying fat contents for up to 52 weeks -
`Figure 1 provides a summary of the dose volumes administered throughout the study
`period;
`Figure 2 provides a summary of the mean cumulative body weight cliange (%)during
`the weight loss phase;
`Figure 3 provides a summary of the mean daily food intake in rats treated with
`( 4'-trifluoromethyl-biphenyl-2-'carboxylic acid I2-(2H-[1,2,4 ]triazol-3-ylmethyl)-1,2, 3,4-
`tetrahydro-isoquinolin-6-yl] amide) at 10, 30 or 1 OOmg/kg or vehicle with diets of 45°/o (A)
`or 10% (B) of total calories from fat;
`Figure 4 provides a summary of the mean daily food intake in rats treated with
`dirlotapide at 1 Omg/kg or vehicle with "high" or "low" fat diets.
`
`Detailed Description of the Invention
`Applicants have discovered that, although MTP inhibitors are effective
`anti-obesity agents when used with any diet, the efficacy of MTP inhibitors as anti(cid:173)
`obesity agents is significantly enhanced when the MTP inhibitor is administered in
`conjunction with an increased-fat diet. Thus, it has b~en found that weight loss can be
`achieved with lower doses of MTP inhibitor when the subject is fed with a higher-fat diet
`as opposed a lower-fat diet. Subjects also lost weight at a higher rate when the MTP
`inhibitor was administered in conjunction with an increased-fat diet. In addition,
`significant reductions in food intake can be achieved when the MTP inhibitor is
`administered in conjunction with an increased-fat diet.
`The term "increased-fat diet" or "high-fat diet" or similar when used in connection
`with the present invention means a diet having a fat content of approximately 10% or
`greater than 10%, i.e. at least approximately 10% (based on air dry matter as fed).
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`"Air dry matter as fed" relates to the air dry form of the feed as fed which typically
`includes around tO% moisture in dry dog food. Therefore, for example, 10% fat based
`on air dry matter as fed would be equivalent to approximately 11 % fat on a dry matter
`basis and 15% fat based on air dry matter as fed would be equivalent to approximately
`16. 7% fat on a dry matter basis.
`Thus, the term "increased-fat diet" includes those conventional pet (e.g. dog)
`foods marketed as typical fat or maintenance diets (having fat contents, for example, in
`the range of 10 to 17%) and those conventional pet (e.g. dog) foods marketed as high
`fat or active or performance diets (having fat contents, for example, greater than 18%)
`both based on air dry matter as fed.
`Alternatively, diets can be defined by the percentage of metabolizable energy
`(Kcal) they provide from fat (Kcal). Thus for example, the term "increased-fat diet" or
`similar when used in connection with the present invention means a diet providing
`approximately 24% or greater than 24% of total calories from fat, such as approximately
`34% or greater than 34% of total calories from fat, such as approximately 45% or
`greater than 45% of total calories from fat. Thus, the term "increased-fat diet" includes
`those conventional pet (e.g. dog) foods marketed as typical fat or maintenance diets
`(providing approximately, for example, 24 to 33% total calories from fat) and those ·
`conventional pet (e.g. dog) foods marketed as high fat or active or performance diets
`(providing approximately, for example, 34 to 50% t~tal calories from fat).
`As a particular example, the term "increased-fat diet" or similar when used in
`connection with the present invention means a diet having a fat content of approximately
`15% or greater than 15%, i.e. at least approximately 15% (based on air dry matter as
`fed). As a further particular example1 the term "increased-fat diet" or similar when used
`in connection with the present invention means a diet providing approximately 45% or
`greater than 45%, i.e. at least approximately 45% of total calories from fat.
`MTP inhibitors for use in the present invention are known in the art. Suitable
`MTP inhibitors include compounds disclosed in U.S. Patent Nos. 4,453,913; 4,473,425;
`'4,491,589; 4,540,458; 4,962,115; 5,057,525; 5,137,896; 5,286,647; 5,521,186;
`5,595,872; 5,646,162; 5,684,014; 5,693,650; 5,712,279; 5,714,494; 5,721,279;
`5,739,135; 5,747,505; 5,750,783; 5,760,246; 5,789,197; 5,811,429; 5,827,875;
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`5,837,733; 5,849,751; 5,883,099; 5,883, 109; 5,885,983; 5,892,114; 5,919,795;
`5,922,718; 5,925,646; 5,929,075; 5,929,091; 5,935,984; 5,952,498; 5,962,440;
`5,965,577; 5,968,950; 5,998,623; 6,025,378; 6,034,098; 6,034,115; ·6,051,229;
`6,051,387; 6,051,693; 6,057,339; 6,066,650; 6,066,653; 6,114,341; 6,121,283;
`6,191,157; 6,194,424; 6,197,798; 6,197,972; 6,200,9?:1; 6,235,730; 6,235,770;
`6,245,775; 6,255,330; 6,265,431; 6,281,228; 6,288,234; 6,329,360; 6,342,245;
`6,369,075; 6,417,362; 6,451,802; 6,479,503; 6,492,365; 6,583,144; 6,617,325;
`6,713,489; 6,720,351; 6,774,236; 6,777,414; and 6,878,724:
`
`US Patent Publication Nos. 2002/028940; 2002/032238; 2002/055635;
`2002/132806; 2002/147209; 2003/149073; 2003/073836; 2003/105093;
`2003/114442; 2003/0162788; 2003/166590; 2003/166637; 2003/181714;
`2004/009988; 2004/014971; 2004/024215; 2004/034028; 2004/044008;
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`2004/058903; 2004/102490; 2004/157866; and 2005/234099:
`PCT Patent Publication Nos. WO 96/262205; WO 98/016526; WO 98/031366;
`15 W099/55313; WO 00/005201; WO 01/000183; WO 01/000184; WO 01/000189; WO
`01/005767; WO 01/012601; WO 01/014355; WO 01/021604; WO 01/053260; WO
`01/074817; WO 01/077077; WO 02/014276; WO 02/014277; WO 02/081460; WO
`02/083658; WO 04/017969; and W005/080373: and
`Japanese Patent Publication Nos. JP2002-212179(14212179); and JP2002-
`
`20
`
`25
`
`220345(14220345).
`For a review of apo-B/MTP inhibitors, see, Williams, S.J. and J.D. Best, Expert
`Opin Ther Patents, 13(4), 479-488 (2003). For methods that may be used to identify
`active MTP inhibitors," see, Chang, G., et al., "Microsomal triglyceride transfer protein
`(MTP) inhibitors: Discovery of clinically active inhibitors using high-throughput screening
`and parallel synthesis paradigms," Current Opinion in Drug Discovery & Development,
`5(4), 562-570 (2002). All of the above patents, patent applications and references are
`
`incorporated herein by reference.
`Preferred intestinal-acting MTP inhibitors for use in the instant invention include
`dirlotapide
`( (S)-N-{2-[benzyl(methyl)amino ]-2-oxo-1-phenylethyl}-1-methyl-5-I4'-
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`trifluoromethyl)I1, 1 '-biphenyl]-2-carboxamido]-1 H-indole-2-carboxamide)
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`and 1-methyl-5-[( 4'-trifluo romethyl-biphenyl-2-carbonyl)-amino ]-1 H-indole-2-carboxylic
`acid (carbamoyl-phenyl-methyl)-amide which can both be prepared using methods
`described in U.S. Patent No. 6,720,351; (S)-2-[(4'-trifluoromethyl-biphenyl-2-carbonyl)(cid:173)
`amino]-quinoline-6-carboxylic a·cid (pentylcarbamoyl-phenyl-methyl)-amide, (S)-2-[(4'-
`tert-butyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid {[(4-fluoro-benzyl)(cid:173)
`methyl-carbamoyl]-phenyl-methyl}-amide, (S)-2-[(4'-tert-butyl-biphenyl-2-carbonyl)(cid:173)
`am ino ]-q uinoline-6-carboxylic acid [( 4-fluoro-benzylcarbamoyl)-phenyl-methyl]-am ide,
`and (S)-2-[(4'-isopropoxy-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid {[(4-
`fluoro-benzyl)-methyl-carbamoyl]-phenyl-methyl}-amide which can all be prepared as
`described in U.S. Publication No. 2005/0234099; (-)-4-[4-[4-[4-[[(2S,4R)-2-(4-
`chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]methyl·-1,3-dioxolan-4-
`yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-(1R)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-
`triazol-3-one (also known as Mitratapide or R103757) which can be prepared as
`described in U.S. Patent Nos. 5,521, 186 and 5,929,075; implitapide (BAY 13-9952)
`which can be prepared as described in U.S. Patent No. 6,265,431; R256918 which has
`the structure
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`and can be prepared as described in U.S. Patent No. p,878,724; and (4'-trifluoromethyl-
`biphenyl-2-carboxylic acid I2-(2H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-
`6-yl] amide). Most preferred iS dirlotapide, mitratapide, (S)-2-[(4'-trifluoromethyl(cid:173)
`biphenyl-2-carbonyl)-amino ]-quinoline-6-carboxylic acid (pentylcarbamoyl-phenyl(cid:173)
`methyl)-amide, (S)-2-[(4'-tert-butyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic
`acid {[( 4-fluoro-benzyl)-methyl-carbamoyl]-phenyl-methyl}-amide, (S )-2-[( 4 '-tert-butyl-
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`biphenyl-2-carbonyl)-amino ]-quinoline-6-carboxylic acid [ ( 4-f\uoro-benzylcarbamoyl)(cid:173)
`phenyl-methyl]-amide, (S)-2-[(4'-isopropoxy-biphenyl-2-carbonyl)-amino]-quinoline-6-
`carboxylic acid {[( 4-fluoro-benzyl}-methyl-carbamoyl]-phenyl-methyl}-amide, R256918,
`or (4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2H-[1,2,4]triazol-3-ylmethyl}-1,2,3,4-
`tetrahydro-isoquinolin-6-yl] amide}.
`In a preferred embodiment the MTP inhibitor for use in the methods of the
`present invention is (4'-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2H-[1,2,4]triazol-3-
`ylmethyl}-1,2,3,4-tetrahydro-isoquinolin-6-yl] amide, or more preferably, the compound
`dirlotapide.
`For human use, the conventional daily dose of the intestinal-acting MTPi is
`generally between about 0.05 mg to about 50 mg, preferably between about 0.5 mg to
`about 30 mg, more preferably between about 0.5 mg to about 20 mg, most preferably
`between about 1.0 mg to about 15 mg. For non-human use, those skilled in the art
`know how to adjust the dosage for the particular weight of the animal. In some
`circumstances, the MTPi may be administered in combination with an agent to reduce
`fatty liver (e.g., fibrate or PPAR-alpha agonist}. See, e.g., JP Publication No. 2002-
`220345 (Application No. 2001-015602} entitled "Remedial Agent for Fatty Liver"; and
`Kersten, S., "Peroxisome Proliferator Activated Receptors and Obesity," Eur J Pharm,
`440' 223-234 (2002}.
`In some embodiments, the MTP inhibitor is administered at escalating dosages.
`In some embodiments, the escalating dosages compris~ at least an initial first dose level
`and a second dose level. In some embodiments, the escalating dosages comprise at
`least a first dose level, a second dose level and a third dose level. In some
`embodiments, the escalating dosages further comprise a fourth dose level. In some
`embodiments, the escalating dosages comprise at least a first dose level, a second
`dose level, a third dose level, a fourth dose level and a fifth dose level. In some
`embodiments, six and further dose levels are contemplated.
`The original dose level may be increased by 10 %, 20%, 25%, 50%, 100% or
`300% to produce the next dose level. When the original dose level is increased by
`100%, the next dose level is double the original dose level. When the original dose
`level is increased by 300%, the next dose level is four times the original dose level. In
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`some embodiments the originat dose level is increased by 25%, 50% or 100%.
`Preferably, the original dose level is increased by 50% or 100%, for example 100%.
`Preferably, the first dose level is in the range of 0.025 to 0.30 mg/kg/day, for
`example in the range of 0.025 to 0.10 mg/kg/day, such as about 0.05 or 0.10 mg/kg/day,
`preferably about 0.05 mg/kg/day.
`Preferably, the second dose level is 100% greater than the first, for example is in
`the range of 0.05 to 0.6 mg/kg/day, or for example is in the range of 0.05 to 0.2
`mg/kg/day, such as about 0.10 or 0.2 mg/kg/day, preferably about 0.10 mg/kg/day.
`Preferably, the third dose level is 100% greater than the second dose level, for
`example is in the range of 0.10 to 1.2 mg/kg/day, or for example is in the range of 0.10
`to 0.4 mg/kg/day, for example about 0.2 or 0.4 mg/kg/day, preferably about 0.2
`mg/kg/day.
`Preferably, the fourth dose level is 50% greater than the third dose level, for
`example is in the range of 0.15 to 0.9 mg/kg/day, or for example is in the range of 0.15
`to 0.6 mg/kg/day, for example about 0.3 or 0.6 mg/kg/day, preferably about 0.3
`mg/kg/day.
`Preferably, the fourth dose level is increased by 50% thereafter to produce fifth,
`six and subsequent dose levels.
`When the MTP inhibitor is dirlotapide, preferably the first dose level is in the
`range of 0.025 to 0.10 mg/kg/day, for example about 0.05 or 0.10 mg/kg/day, prE?ferably
`about 0. 05 mg/kg/day. Preferably, the second dose level is 100% greater than the first,
`for example is in the range of 0.05 to 0.2 mg/kg/day, for example about 0.10 or 0.2
`mg/kg/day, preferably abol,Jt 0.10 mg/kg/day. Preferably, the third dose level is 100%
`greater than the second dose level, for example is in the range of 0.10 to 0.4 mg/kg/day,
`for example about 0.2 or 0.4 mg/kg/day, preferably about 0.2 mg/kg/day. Preferably, the
`fourth dose level is 50% greater than the third dose level, for example is in the range of
`0.15 to 0.6 mg/kg/day, for example about 0.3 or 0.6 mg/kg/day, preferably about 0.3
`mg/kg/day. Preferably, the fourth dose level is increased by 50% thereafter to produce
`fifth, six and subsequent dose levels.In some embodiments, each dose level is
`administered to the subject for from about 1 to 4 weeks, for example, the dose levels
`may be increased after 1 week, 2 weeks, or monthly. For example, the first dose level,
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`e.g. 0.05 mg/kg/day, may be administered for about 14 days, and then the second dose
`level, e.g. 0.01 mg/kg/day, may be administered for about 14 days, and then the third
`dose level, e.g. 0.2 mg/kg/day, may be administered for about a month, with subsequent
`dose increases being made at, for example, monthly intervals.
`For exal)1ple, when the MTP inhibitor is dirlotapide and the subject is a dog, the
`initial dose may be 0.05 mg/kg/day. After two weeks of therapy, the initial dose may be
`doubled to 0.10 mg/kg/day for two weeks. Following these initial 4 weeks of therapy,
`dogs may be weighed monthly and dose adjustments may be made monthly according
`to the following guidelines. At the end of each m.onth of therapy, the percentage of body
`weight loss is determined. If the body weight loss since previous monthly weighing has
`been greater than or equal to 3% body weight per month (equivalent to 0.1 % body
`weight per day); the dose may be kept the same. If the body weight loss since previous
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`monthly weighing has been less than 3% body weight per month; the dose may be
`increased without adjusting for the dog's current body weight. The first time a
`conditional increase is required, the dose may be increased by 100% (doubled). In
`subsequent required conditional increases, the dose may be increased by 50% up to a
`maximum dose of the product of 1 mg/kg current body weight. These adjustments may
`be continued until the weight targeted at the start of therapy is achieved.
`In cases where body weight loss since previous monthly weighing has been
`greater than or equal to 12% per month, the dose may be reduced by 25%.
`A mean weight loss of about 18 to 20% after six months of weight loss therapy
`can be anticipated.
`The initial "weight loss" phase may last a number of months, for example about 4
`months (i.e. about 16 weeks) to 6 months, or for example, about 112 to 196 days, or
`25 may last until the target weight loss is achieved, or may last until a particular Body
`Condition Score (BCS) is reached, for example a BCS of five.
`The weight maintenance/management or retraining phase may last for a period
`of months, for example about 3 months (i.e. about 12 weeks) or, for example, 84 days.
`During the retraining phase, the dose may be decreased, 'for example by 50%, or
`increased, for example by 100%, if the patient.was losing or gaining too much weight
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`(for example, more than 5%) from the start of the weight maintenance/management
`·retraining phase, respectively.
`As mentioned above, when the desired weight is reached, the weight
`maintenance/management or retraining phase can be commenced. During the weight
`5 maintenance/management or retraining phase the optimal level of food intake and
`physical activity .needed should be established. Administration of the MTP inhibitor
`should be continued during the weight maintenance/management or retraining phase
`until the food intake and physical activity needed to stabilize body weight at the desired
`weight is established.
`For example, when the MTP inhibitor is dirlotapide and the subj