WO2008072056A1

WO2008072056A1 - Use of mtp inhibitors for the treatment of obesity using low doses and dose-escalation

Info

Publication number: WO2008072056A1
Application number: PCT/IB2007/003842
Authority: WO
Inventors: Jacques Gossellin; Mary Anne Hickman; Simon Joseph Sunderland; Jody Ann Wren
Original assignee: Pfizer Ltd Great Britain
Current assignee: Pfizer Ltd Great Britain
Priority date: 2006-12-14
Filing date: 2007-12-03
Publication date: 2008-06-19
Anticipated expiration: 2009-06-14
Also published as: AR064344A1; JP2008150370A; TW200836718A

Abstract

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 effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, 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.

Description

USE OF MTP INHIBITORS FOR THE TREATMENT OF OBESITY USING LOW DOSES AND DOSE-ESCALATION

Field of the Invention The present invention generally relates to therapy for obesity or related eating disorders and/or reducing food consumption using low doses of MTP inhibitors optionally followed by dose escalation and optionally followed by a weight maintθnancθ/management or retraining phase.

Background of the Invention Obesity is a major public health concern because of 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 099439 A2) and for treating obesity and associated diseases. 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 (disclosed in WO 03/002533) may cause emesis when admininstered according to conventional treatment regimens.

It is reported in WO 2005/097131 that the administration of an apoB secretion/MTP inhibitor during a continuous period of eight weeks resulted in an initial reduction of body weight which however levelled off after three weeks. Sustained administration of the apoB secretion/MTP inhibitor did not result in a further reduction of body weight. WO 2005/097131 reports that an intermittent dosing regimen can overcome the problem of body weight reduction levelling off.

Thus, there is a need to develop methods for treating obesity or related eating disorders and/or reducing food consumption, that are efficacious yet without the side-effects associated with known treatments.

Summary of the Invention

The invention 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 effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor.

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 initial amount of an MTP inhibitor effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, 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 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 the initial amount of the MTP inhibitor is effective to ameliorate the obesity or related disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, 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 initial low dose of an MTP inhibitor followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor wherein said initial low dose is effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of conventional doses of the MTP inhibitor and wherein said initial low dose reduces the side effects associated with administration of said 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 increasing the rate of weight loss in a subject suffering from obesity or related eating disorders, the method comprising administering to the subject an initial amount of an MTP inhibitor effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, optionally followed by administration of at least one stepwise, 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 an amount of an MTP inhibitor effective to inhibit MTP, yet low enough to reduce the side effects associated with administration of the MTP inhibitor, 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 methods 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 at a dose at which the emesis associated with administration of the MTP inhibitor is reduced, 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 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 an amount of an MTP inhibitor effective to ameliorate the obesity or disorder, or effective to inhibit MTP, yet low enough to reduce the side effects associated with administration of the MTP inhibitor, and wherein said administration is in combination with at least one additional pharmaceutical agent, such as another anti-obesity agent, 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.

Also provided is a method of weight control in a subject the method comprising administering to the subject an effective weight-controlling amount of an MTP inhibitor which is low enough to reduce the side effects associated with administration of the MTP inhibitor, 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 MTP inhibitor may be used alone or in combination with at least one additional pharmaceutical agent, preferably an anti-obesity agent. 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 initial amount of an MTP inhibitor in the range of 0.025 to 0.30 mg/kg/day, 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. A further aspect of the present invention pertains to a pharmaceutical kit for use by a consumer in the treatment or prevention of obesity or related eating disorders and/or reducing food consumption, or for inhibiting MTP in a subject in need thereof. The kit comprises (a) at least two sets of pharmaceutical dosage units comprising an MTP inhibitor; and (b) instructions describing a method of using the dosage form to treat or prevent obesity or related eating disorders and/or reducing food consumption, or for inhibiting MTP in a subject in need thereof.

Another embodiment of the present invention relates to a pharmaceutical kit comprising: (a) a first pharmaceutical composition comprising at least two sets of pharmaceutical dosage units comprising an MTP inhibitor, (b) a second pharmaceutical composition comprising a second compound useful for the treatment or prevention of obesity or related eating disorders and/or reducing food consumption, or for inhibiting MTP in a subject in need thereof; and

(c) a container for containing the first and second compositions.

In some embodiments the MTP inhibitor is dirlotapide ((S)-N-{2-[benzyl(methyl)amino]-2-oxo-1- phenylethylJ-i-methyl-S-^'-trifluoromethyOII .I'-biphenylj^-carboxamidol-I H-indole^-carboxamide).

Definitions

Obesity and overweight are generally defined by body mass index (BMI) in humans, which is correlated with total body fat and serves as a measure of the risk of certain diseases. BMl is calculated 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 Conf. 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 all canine species (e.g., dogs), feline species (e.g., cats) and equine species (e.g., 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 is a canine or feline (e.g., a cat or a dog). For example the animal is a canine (e.g., 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. In 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 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. Another method for increasing intestinal selectivity may be rapid metabolism of the MTP inhibitor to an inactive form which in theory would decrease hepatic exposure. Brief Description of the Drawings

Figure 1 provides a summary of the incidence of the most frequent clinical signs identified as undesirable effects by dosing regimen and treatment over the weight loss phase of a study to assess the field efficacy and safety of three different dosing regimens of a commercial formulation of dirlotapide in the treatment of excessive body weight in adult overweight dogs (body condition score (BCS) greater than 5), in comparison with a placebo (Example 1).

Figure 2 provides a summary of the mean cumulative percentage body weight change, measured from day 0 to each scheduled visit for dogs treated with dirlotapide or placebo during studies A and B in Example 2.

Figure 3 provides a summary of the mean weekly percentage weight change since the previous visit measured at each scheduled visit for dogs treated with dirlotapide or placebo during studies A and B in Example 2.

Detailed Description of the Invention

Applicants have discovered that significant reductions in the side effects associated with the administration of MTP inhibitors according to conventional treatment regimens may be achieved by administering the MTP inhibitor at an initial low dose, optionally followed by administration of further escalating doses. Applicants have discovered, especially in the case of dirlotapide, that reduction of the initial dose has little or no effect on the overall efficacy of the MTP inhibitor as an anti-obesity agent and results in an enhanced tolerance profile. The use of an initial low dose, optionally but preferably followed by administration of further escalating doses, results in a lower and acceptable incidence and severity of vomiting, diarrhoea, lethargy and anorexia / inappetence and also results in fewer patients discontinuing the treatment, i.e. it improves patient compliance. Applicants have also discovered that use of an initial low dose followed by administration of further escalating doses results in optimal efficacy of the MTP inhibitor as an anti-obesity agent.

Similar to the outcome of many weight loss studies in humans, body weight has also been commonly observed to be regained by dogs following the removal of restrictions on dietary energy intake on completion of weight reduction programs. In weight reduction studies dependent on dietary restriction, the tendency to regain weight can be avoided or minimized through control of food volume and adjusting caloric intake to match the maintenance requirement of the individual dog and thus stabilize body weight. For owners to 'learn' how much to feed their dog following the weight loss phase according to the present invention, a period of treatment with a reduced dose of the MTP inhibitor has been designed to stabilize body weight before discontinuation of the drug to maintain the weight reductions achieved at the end of the weight loss phase. Applicants have found the incorporation of such a weight maintenance/mangement or retraining phase to be highly successful. The incorporation of a weight maintenance/mangement or retraining phase is therefore preferred.

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;

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; 6,200,971 ; 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;

2004/058903; 2004/102490; 2004/157866; and 2005/234099:

PCT Patent Publication Nos. WO 96/262205; WO 98/016526; WO 98/031366; WO99/55313; 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 WO05/080373: and

Japanese Patent Publication Nos. JP2002-212179(14212179); and JP2002-220345(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- [benzy^methyOaminol^-oxo-i-phenylethylJ-i-methyl-δ-^'-thfluoromethyOCI .I'-biphenylJ^-carboxamidol-I H- indole-2-carboxamide) and 1-methyl-5-[(4'-trifluoromethyl-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)-amino]-quinoline-6-carboxylic acid (pentylcarbamoyl-phenyl- 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-biphenyl-2-carbonyl)-amino]-quinoline-6- carboxylic acid [(4-fluoro-benzylcarbamoyl)-phenyl-methyl]-amide, 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; and R256918 which has the structure

and can be prepared as described in U.S. Patent No. 6,878,724. Most- preferred is dirlotapide, mitratapide, (S)-2-[(4^l-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (pentylcarbamoyl-phenyl- 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-biphenyI-2-carbonyl)-amino]-quinoline-6- carboxylic acid [(4-fluoro-benzylcarbamoyl)-phenyl-methy)]-amide, (S)-2-[(4'-isopropoxy-biphenyl-2-carbonyl)- amino]-quinoline-6-carboxylic acid {[(4-fluoro-benzyl)-methyl-carbamoyl]-phenyl-methyl}~amide or R256918. In a preferred embodiment the MTP inhibitor for use in the methods of the present invention is the compound dirlotapide.

In some embodiments the methods further comprise the administration of at least one additional pharmaceutical agent. Suitable additional pharmaceutical agents include other anti-obesity agents such as cannabinoid-1 (CB-1 ) antagonists (such as rimonabant), 11 β-hydroxy steroid dehydrogenase-1 (11 β-HSD type 1) inhibitors, peptide YY (PYY) and PYY agonists (such as PYY_3-36 or analogs or derivatives thereof), MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β₃ adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c receptor agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y receptor antagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like. Other suitable pharmaceutical agents include lipid modifying compounds which include HMG CoA reductase inhibitors, cholesterol absorption inhibitors, ezetimide, squalene synthetase inhibitors, fibrates, bile acid sequestrants, statins, probucol and derivatives, niacin, niacin derivatives, PPAR alpha agonists, PPAR gamma agonists, thiazolidinediones, and cholesterol ester transfer protein (CETP) inhibitors. Other suitable additional pharmaceutical agents include LDL-cholesterol lowering agents, triglyceride lowering agents, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an inhibitor of HMG-CoA reductase gene expression, a squalene synthetase inhibitor, a squaline epoxidase inhibitor, a squaline cyclase inhibitor, a combined squaline epoxidase/cydase inhibitor, a cholesterol synthesis inhibitor, a cholesterol absorption inhibitor such as Zetia™ (ezetimibe), a CETP inhibitor, a PPAR modulator or other cholesterol lowering agent such as a fibrate, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant. Other pharmaceutical agents useful in the practice of the combination aspect of the invention include bile acid reuptake inhibitors, ileal bile acid transporter inhibitors, ACC inhibitors, antihypertensive agents (such as Norvasc®), diuretics, garlic extract preparations, bile acid sequestrants, antibiotics, antidiabetics, and anti-inflammatory agents such as aspirin or, preferably, an anti-inflammatory agent that inhibits cyclooxygenase-2 (Cox-2) to a greater extent than it inhibits cyclooxygenase-1 (Cox-1) such as celecoxib (U.S. patent No. 5,466,823), valdecoxib (U.S. patent No. 5,633,272, parecoxib (U.S. patent No. 5,932,598), deracoxib (CAS RN 169590-41-4), rofecoxib ((CAS RN 162011-90-7), etoricoxib (CAS RN 202409-33-4), lumiracoxib (CAS RN 220991-20-8) or carprofen (CAS RN 53716-49-7).

Other suitable additional pharmaceutical agents include naturally occurring substances that act to lower plasma cholesterol levels. These naturally occurring materials are commonly called nutraceuticals and include, for example, garlic extract, Hoodia plant extracts and niacin.

The dosage of the additional pharmaceutical agent is generally dependent upon a number of factors including the health of the subject being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired. In general, the dosage range of the additional pharmaceutical agent is in the range of from about 0.001 mg to about 100 mg per kilogram body weight of the individual per day, preferably from about 0.1 mg to about 10 mg per kilogram body weight of the individual per day. However, some variability in the general dosage range may also be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered and the like. The determination of dosage ranges and optimal dosages for a particular patient is also well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.

In some embodiments, the MTP inhibitor is administered at escalating dosages. In some embodiments, the escalating dosages comprise 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 some embodiments the original 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, 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 0.2 mg/kg/day, for example 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 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, 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 example, 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 month 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 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 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 (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 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 subject is a dog, the dose adjustment during the weight maintenance/management or retraining phase may be as follows: First dose adjustment If the dog lost greater than or equal to 1% body weight per week in the last month of the weight loss phase, the dose should be decreased by 50%.

If the dog lost between 0 and 1 % the dose should remain the same.

If the dog gained weight, the dose should be increased by 50%. Subsequent dose adjustments In subsequent months the dose should be increased or decreased by 25% to maintain a constant weight.

If the dog is within -5% to +5% of the body weight at the end of the weight loss phase, the dose should remain unchanged.

If the dog lost greater than 5% body weight, then the dose should be decreased by 25%. If the dog gained greater than 5% body weight, then the dose should be increased by 25%. Based on the dog's current body weight a daily dose of 1 mg/kg should not be exceeded.

When the drug is discontinued, the daily amount of food offered and physical activity should be continued as established during the weight maintenance/management or retraining phase. In some embodiments, the additional pharmaceutically active agents are administered according to traditional treatment regimens. Jn some embodiments, the additional pharmaceutically active agents are administered at escalating dosages. As used herein the term "reduce the side effects associated with administration of the MTP inhibitor" or similar refers to an amelioration or elimination of one or more undesired side effects occurring as a result of administering MTP inhibitors according to traditional treatment regimens, for example at higher initial doses without dose escalation. Such side effects include emesis (vomiting), diarrhoea, lethargy, inappetence and anorexia, for example emesis (vomiting), diarrhea and lethargy and particularly include emesis. The present invention also pertains to a pharmaceutical kit for use by a consumer in the treatment or prevention of obesity or related eating disorders and/or reducing food consumption, or for inhibiting MTP in a subject in need thereof. In some embodiments the kit comprises (a) at least two sets of pharmaceutical dosage units comprising an MTP inhibitor wherein 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; and the second dose level 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; and (b) instructions for use.

According to the methods of treatment of the invention, the MTP inhibitor and any additional pharmaceutical agent (referred to herein as a "combination") is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition. In the combination aspect of the invention, the MTP inhibitor and the other pharmaceutical agent (e.g., another anti-obesity agent,) may be administered either separately or in a pharmaceutical composition comprising both. When a combination of MTP inhibitor and any other pharmaceutical agent are administered together, such administration may be sequential in time or simultaneous. Simultaneous administration of drug combinations is generally preferred. For sequential administration, the agents may be administered in any order. It is generally preferred that such administration be oral. It is especially preferred that such administration be oral and simultaneous. When the MTP inhibitor and the additional pharmaceutical agent are administered sequentially, the administration of each may be by the same or by different methods.

According to the methods of the invention, the MTP inhibitor or a combination is preferably administered in the form of a pharmaceutical composition. Administration of the agents can be separately or together in any conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular or subcutaneous), intracistemal, intravaginal, intraperitoneal, topical (e.g., powder, ointment, cream, spray or lotion), buccal or nasal dosage form (e.g., spray, drops or inhalant).

The MTP inhibitors or combinations can be administered alone but will generally be administered in an admixture with one or more suitable pharmaceutical excipients, adjuvants, diluents or carriers known in the art and selected with regard to the intended route of administration and standard pharmaceutical practice. The MTP inhibitors or combination may be formulated to provide immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release dosage forms depending on the desired route of administration and the specificity of release profile, commensurate with therapeutic needs. The pharmaceutical composition comprises an MTP inhibitor or a combination in an amount generally in the range of from about 1% to about 75%, 80%, 85%, 90% or even 95% (by weight) of the composition, usually in the range of about 1%, 2% or 3% to about 50%, 60% or 70%, more frequently in the range of about 1 %, 2% or 3% to less than 50% such as about 25%, 30% or 35%. Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known to those skilled in this art. For examples, see Remington: The Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore MD, 20^th ed. 2000.

Examples of suitable formulations are further described in, for example, WO 03/002533, WO 2005/046644 and WO2005/080373. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the MTP inhibitor or the combination, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil, sesame seed oil and the like), Miglyol^® (available from

CONDEA Vista Co., Cranford, NJ.) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition may also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Oral liquid forms of the MTP inhibitors or combinations include solutions, wherein the active compound is fully dissolved. Examples of solvents include all pharmaceutically precedented solvents suitable for oral administration, particularly those in which the compounds of the invention show good solubility, e.g., polyethylene glycol, polypropylene glycol, edible oils and glyceryl- and glyceride- based systems. Glyceryl- and glyceride- based systems may include, for example, the following branded products (and corresponding generic products): Captex™ 355 EP (glyceryl tricaprylate/caprate, from Abitec,

Columbus OH), Crodamol™ GTC/C (medium chain triglyceride, from Croda, Cowick Hall, UK) or Labrafac™ CC (medium chain triglyides, from Gattefosse), Captex™ 500P (glyceryl triacetate i.e. triacetin, from Abitec), Capmul™ MCM (medium chain mono- and diglycerides, fromAbitec), Migyol™ 812 (caprylic/capric triglyceride, from Condea, Cranford NJ), Migyol™ 829 (caprylic/capric/succinic triglyceride, from Condea), Migyol™ 840 (propylene glycol dicaprylate/dicaprate, from Condea), Labrafil™ M1944CS (oleoyl macrogol-6 glycerides, from Gattefosse), Peceol™ (glyceryl monooleate, from Gattefosse) and Maisine™ 35-1 (glyceryl monooleate, from Gattefosse). Of particular interest are the medium chain (about C₈ to C₁₀) triglyceride oils. These solvents frequently make up the predominant portion of the composition, i.e., greater than about 50%, usually greater than about 80%, for example about 95% or 99%. Adjuvants and additives may also be included with the solvents principally as taste-mask agents, palatability and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers and solubilizers.

Suspensions, in addition to the MTP inhibitor or the combination, may further comprise carriers such as suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

Conveniently, for administration to non-human animals, the MTP inhibitor (or combination) can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply. The compound can be directly metered into drinking water, preferably in the form of a liquid, water- soluble concentrate (such as an aqueous solution of a water-soluble salt).

Conveniently, the MTP inhibitor (or combination) can also be added directly to the feed, as such, or in the form of an animal feed supplement.

The present invention has several advantageous veterinary features. For the pet owner or veterinarian who wishes to increase leanness and/or trim unwanted fat from pet animals, the instant invention provides the means by which this may be accomplished. For poultry, beef and swine breeders, utilization of the method of the present invention yields leaner animals that command higher sale prices from the meat industry.

Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.

Examples

Example 1 Formulation: composition per mL - Dirlotapide: 5mg

Medium chain triglyceride oil up to 1mL

A multi-centre veterinary patient study was conducted with 36 Investigators from Germany, Spain, France and the United Kingdom to assess the field efficacy and safety of three different dosing regimens of a commercial formulation of dirlotapide in the treatment of excessive body weight in adult overweight dogs (body condition score (BCS) greater than 5), in comparison with a placebo (for more details see J. GOSSELLIN, J. MCKELVIE J. SHERINGTON, J. A. WREN, J. S. EAGLESON, T. G. ROWAN & S. J. SUNDERLAND (2007); An evaluation of dirlotapide to reduce body weight of client-owned dogs in two placebo-controlled clinical studies in Europe; Journal of Veterinary Pharmacology and Therapeutics, Volume 30 (s1), 73-80, incorporated herein by reference. Please note that this paper describes the finally selected dosing regimen whereas the study below looks at various dosing regimens). Patients were allocated at random to either the dirlotapide or the placebo treatment in a 2:1 ratio. They were also allocated to one of the three dosing regimens depending on their date of enrolment. At the enrolment visit and approximately ( every 28 days from the start until the end of the study (day 308 visit at the latest), each dog was physically examined, weighed and assessed for body condition. For each patient, the study period was divided into three consecutive phases: a "weight loss phase", extending from day 0 until the first scheduled visit where the patient reached a BCS of five or day 196 visit at the latest, followed by a 84-day "retraining phase" aimed at stabilizing body weight, then followed by a 28-day "post-treatment phase", during which the patient did not receive any treatment. Patients were treated, during the weight loss and retraining phases, with a once daily dose of dirlotapide or placebo, prescribed by the Investigator and administered by the owner at the time of a meal. The starting daily dose, to administer from study start until the first prescribed adjustment, was the only difference between the three sequentially tested dosing regimens: 0.2 mg/kg for regimen 1 , 0.1 mg/kg for regimen 2 and 0.05 mg/kg doubled to 0.1 mg/kg of initial body weight after two weeks for regimen 3. At each visit during the weight loss phase, the percentage of weight loss was assessed and the dose had to be increased (generally by 100%) in case of insufficient weight loss (less than 1% per week since previous adjustment). During the retraining phase, the dose was decreased by 50% or increased by 100% if the patient was losing or gaining too much weight (more than 5%) from the start of the retraining phase, respectively. The dose could also be decreased (generally by 50%) at any time during the study, in case of severe reduction in food intake or of Suspected Adverse Drug Events (SADE). The dose to be administered was limited to a maximum allowed of 1 mg/kg of current body weight.

A total of 255 animals (84 placebo and 171 dirlotapide) were enrolled in the study (71 , 98 and 86 in dosing regimens 1 , 2 and 3, respectively). Compared with the placebo, the dirlotapide treatment resulted in a significant (P ≤ 0.0002) mean weekly weight loss of 0.90%, 0.66% and 0.76% over the weight loss phase in regimens 1, 2 and 3, respectively, and in a comparable total mean weight loss between regimens after 7 months (28 weeks) of weight loss therapy (20.3%, 18.6% and 20.9 % in regimens 1, 2 and 3, respectively). In some animals, the dirlotapide treatment induced undesirable digestive clinical signs (vomiting and diarrhoea), and lethargy and anorexia/inappetence, with incidences over the 10-month study which were substantially decreased by reducing the starting dose from 0.2 mg/kg to 0.05 mg/kg. The number of animals withdrawn for undesirable clinical signs over the whole study period decreased from 31.9% in the first regimen to 10.5% in the third dosing regimen. The percentage of animals vomiting at least once during the study decreased from 72% to 42% from the first to the last regimen. The third dosing regimen (starting dose of 0.05 mg/kg) appears therefore to be the regimen of choice as it provides the same efficacy as the other regimens but results in an enhanced tolerance profile. In the three dosing regimens, the mean dose steadily and similarly increased over the weight loss phase with a high variability between individual animals. By day 168 of the weight loss phase in the third dosing regimen, the dosage of dirlotapide was 0.53 mg/kg of initial body weight on average (approximately a 10 fold increase from start) and ranged from 0.10 mg/kg to 0.93 mg/kg of initial body weight. Dirlotapide administered at a starting dose of 0.05 mg/kg doubled after two weeks of treatment was as efficacious as the other dosing regimens, resulting in a weight loss of 20.9% after 28 weeks of weight loss therapy and only 10.5 % of the population experiencing a weight loss lower than 5% after 12 weeks of therapy . The latter dosing regimen was also safe, like the other regimens, but better tolerated, resulting in a lower and acceptable incidence and severity of vomiting, diarrhoea, lethargy and anorexia / inappetence (monthly incidence of about 10% of treated patients or less for each sign beyond the first 28 days of therapy). It also resulted in fewer patients discontinuing the treatment (only 10.5 % of the treated population).

Table 1 provides a summary of the total percent weight change from study start at each scheduled visit of the weight loss phase; Table 2 provides a summary of the dose prescribed in mL/kg and in mg/kg at each scheduled visit of the weight loss phase; and Figure 1 provides a summary of the incidence of the most frequent clinical signs identified as undesirable effects by dosing regimen and treatment over the weight loss phase.

Example 2 Formulation: composition per mL - Dirlotapide: 5mg i

Medium chain triglyceride oil up to 1mL

Dirlotapide was evaluated in the management of obesity in dogs in two multicenter, clinical studies in North America (for more details see J. A. WREN, A. A. RAMUDO, S. L. CAMPBELL, V. L. KING, J. S. EAGLESON, J. GOSSELLIN, S. J. SUNDERLAND (2007); Efficacy and safety of dirlotapide in the management of obese dogs evaluated in two placebo-controlled, masked clinical studies in North America; Journal of Veterinary Pharmacology and Therapeutics 30 (s1), 81-89, incorporated herein by reference). A total of 335 obese dogs of various breeds were randomized to dirlotapide or placebo in a 2:1 ratio. Dirlotapide was administered orally once daily to dogs at an initial dose of 0.05 mg/kg, increased after 14 days to 0.1 (study B) or 0.2 mg/kg (study A) and then adjusted according to individual weight loss at 28-day intervals. Dogs were examined and weighed, and body condition scores (BCSs) were recorded every 28 days. Study A had three consecutive phases: weight loss (16 weeks, day 0-112); weight management (12 weeks); and post-treatment (8 weeks). Study B had a weight loss phase only.

Test materials

Dirlotapide (Slentrol™; Pfizer Animal Health, New York, NY, USA) was administered in the commercial formulation with an oil vehicle containing 5 mg dirlotapide/mL Control dogs received food-grade corn oil. Treatments were indistinguishable by appearance and packaging. Doses were calculated to provide equal volumes of each treatment based on initial body weight and at subsequent monthly intervals the dose volume was adjusted individually based on body weight loss response.

Animals Dogs enrolled in the studies were adult (12 months of age or older) males and females, both intact and neutered. Enrolled dogs had to be obese with a body condition score (BCS) of 8 or more.

Procedure

Within 7 days before the first treatment, each dog was examined and weighed, and blood and urine samples were collected to determine suitability for enrollment. Animal information and medical history, including concomitant medications, were recorded, and BCS was assessed. The study period for each dog commenced on day 0 - the day participating animals began treatment with either dirlotapide or placebo. Treatments were administered by the owner at home.

Study A comprised three consecutive phases: an initial weight loss phase from day 0 to day 112 (16 weeks), followed by weight management (12 weeks) and a post-treatment period (8 weeks); during this last period, body weight was monitored after cessation of treatment. During the management phase, the patient continued treatment with dirlotapide or placebo at a dose adjusted to maintain ±5% of the body weight achieved at the end of the weight loss phase. Dogs that had not lost sufficient body weight (minimum of 0.5% per week, equivalent to 8% over the whole phase) at the end of weight loss phase (day 112) completed the study and did not enter the management phase. Study B consisted of a 16-week (to day 112) weight loss phase only. Examination visits, at which dogs were weighed and BCS was assessed, were performed at 28- day intervals throughout each study. At the end of the weight loss phase, owners were asked to assess whether their dogs' level of physical activity had changed over the treatment period.

In additionio the pre-treatment samples, ^"blood samples were also collected at the end of eacHTstudy phase and at study completion (end of post-treatment phase in study A and end of weight loss phase in study B). Samples were analyzed for routine hematologic values and serum chemistry that included assessment of major organ function and lipid measurements (high-density lipoprotein, cholesterol, and triglyceride concentrations).

Dose adjustments All dogs received an initial dose of 0.05 mg/kg of dirlotapide or the equivalent of 0.01 mL/kg placebo. After the first 14 days, the dose was automatically increased to 0.1 mg/kg in study B - in accordance with label recommendations - or to 0.2 mg/kg in study A, based on initial body weight. Scales were calibrated accurate to 0.1 kg before and during the study and the calibration was verified before weighing each animal. Thereafter, adjustment of dose volume was determined by comparison of individual percentage weight changes at each assessment visit against percentage weight change targets.

Study A

At each monthly visit during the weight loss phase, the dose volume was increased by 50% at the first adjustment and by 25% thereafter if weight loss was <1 % per week since the previous visit. During the first scheduled weight management visit, the dose volume was increased by 50% if the dog had gained weight since the previous visit and the dose volume was reduced by 50% if the weekly weight loss was 1 % or more since the preceding visit. At subsequent visits, the dose volume was increased or decreased by 25% if weight gain or loss was >5% from the start of the management phase, respectively. The dose volume could only be increased 50% once during the weight management phase.

Study B At each monthly visit during the weight loss phase, the dose volume was increased by 100% at the first adjustment and by 50% at following adjustments if weight loss was ,<0.7% per week since the previous visit.

Results

A total of 335 dogs were enrolled in the two studies; 224 were allocated to dirlotapide treatment and 111 to placebo. Of the dogs enrolled and treated, 185 dirlotapide-treated dogs and 101 placebo-treated dogs completed the studies. In total, 16 dogs treated with dirlotapide and nine treated with placebo were withdrawn due to owner noncompliance with the protocol and incorrect dosing. A large variety of breeds were enrolled; the most common in both studies were Labrador retrievers (17.4-24.7% of enrolled dogs), followed by golden retrievers (8.9-9.1 %), beagles (7.8%), and dachshunds (5.4-7.8%). Other breeds representing at least 5% of dogs enrolled in either study were American cocker spaniels, German shepherds, rottweilers, Shetland sheepdogs, and pugs.

Diet

Overall, dogs were fed a wide_rj«2ge_o^corrjτnercially avaijab]e_dietsjι\terms of_type (e.g. various brands and flavors), percentage dry matter (dry, semi-moist, and moist), fat content, and protein content. In study A, 90.4% of dirlotapide-treated dogs and 95.7% of dogs receiving placebo were fed dry food only, and the remaining dogs all received a mixture of dry and canned food. Of the animals treated with dirlotapide and placebo in study A, 37% and 9%, respectively, were offered a combination of several commercial diets, while the other dogs were fed a single commercial diet throughout the study.

Adverse experiences during studies No treatment-related deaths occurred during the studies. One or more clinical signs associated with gastrointestinal dysfunction (emesis, diarrhea, anorexia, and lethargy) were frequently observed in both treated and controls dogs (for example, emesis on one or more occasions was observed in up to 48.1 % of dirlotapide-treated dogs and up to 20.6% of placebo-treated dogs) during 7 months of treatment. These occurrences resulted in some owners electing to discontinue participation in the studies (5.9% of dogs receiving dirlotapide and 1.1% of dogs receiving placebo in study B - label dosing regimen; and 14.8% of dirlotapide-treated dogs in study A). While the incidence of these clinical signs was generally higher in the dogs receiving dirlotapide than in those receiving placebo, the interpretation is confounded because most placebo-treated dogs in study A received treatment for three fewer months than the dirlotapide-treated dogs. Over the weight loss phase of study A (to day 112), emesis was recorded for 44% of dirlotapide-treated dogs and 26% of placebo-treated dogs, while diarrhea occurred in 13% of dirlotapide treatment compared with 17% of the placebo group. Owners were encouraged to report all observations during the studies, including those that were possibly unrelated to treatment. In general, these clinical signs, especially emesis, occurred more frequently during the first month for both treatments. After that time, the incidence decreased for the remainder of the treatment period except for a few days following a dose increase. All affected dogs, including those remaining on treatment in the study, recovered uneventfully in a day or two, and most without a change in dose or any medical intervention.

Weight loss phase

By day 112, mean cumulative percentage weight losses from day 0 for dirlotapide were significantly greater than for placebo: 14.0% vs. 3.0% (P = 0.0001) in study A and 11.8% vs. 3.9% (P = 0.0001 ) in study B (Table 3, Fig. 2). The percentage of dogs that successfully lost at least 13% body weight (an amount that has been associated with a health benefit in dogs with osteoarthritis) was also significantly greater for dirlotapide than for placebo: 50.0% vs. 5.6% (P = 0.0314) in study A and 39.1% vs. 5.3%, (P = 0.0002) in study B. In both studies, the rate of weight loss (Fig. 3) was generally highest for dirlotapide-treated animals over the first month of treatment and the rate was maintained in later months in parallel with the dose increases.

Management phase (study A only)

In study A, mean weight loss for dirlotapide-treated dogs slowed in the management phase but dogs were still losing weight (0.25-0.67% per week for day 112-196 compared with 0.7-1% per week up to day 112) and although the cumulative loss of 14% body weightatthe end-of the weight loss phase (day 112)^~had~ increased another 5.3% by the end of the management phase (day 196) (Figs. 2 and 3), the majority of the weight loss occurred during the first month of management (3.0%) after removal of the dogs that had not lost 0.5% body weight on a weekly basis and then stabilized with further dose decreases in the next 2 months of the management phase. By the final month, weight loss was relatively stable at 0.9% during the month (Fig.3). Most placebo-treated dogs were withdrawn after 112 days due to lack of efficacy (<0.5% weekly weight loss), and the four dogs remaining on placebo treatment through the management phase were those showing marked weight loss by the end of the weight loss phase. These four dogs showed a mean cumulative weight loss of 12.3% by the end of weight management.

Post-treatment phase (study A only)

During the post-treatment phase, there were slight weight increases, with mean weight gains of 0.48% and 0.24% per week during the first and second months, respectively, and by study completion the trend in the rate of weekly weight change was moving toward zero, indicating that weight management appeared to be ' relatively stable (Fig. 3). Over the post-treatment phase, dogs previously treated with dirlotapide had a mean weight gain of 1.8% during the first month post-treatment but maintained their weight during the second month post-treatment (0.8% increase). There was a mean weight loss from day 0 of 16.7% by the end of the post-treatment period (Fig. 2). The four placebo-treated dogs continued to lose body weight when treatment was discontinued, achieving a maximum weight loss of 14.0% by 1 month post-treatment.

Dosing

For study A, doses were administered directly into the mouth to 77% of dirlotapide-treated dogs and 64% of placebo-treated dogs. Remaining animals were dosed by placing a small amount on the animal's food. During the weight loss phase, the dose of dirlotapide was increased from 0.05 mg/kg for all dogs to a mean dose of 0.33 mg/kg (range, 0.14-0.52 mg/kg) in study A and 0.26 mg/kg (range, 0.11-0.53 mg/kg) in study B (Table 4). For both studies, the range of doses during 112 days of weight loss was 0.045-0.53 mg/kg. During the management phase in study A, dirlotapide doses decreased to a final mean of 0.26 mg/kg that varied widely (range, 0.07-0.54 mg/kg). Discussion

Dirlotapide was found to be consistently effective in generating weight loss in obese dogs in the absence of dietary restriction. At completion of the weight loss phase, dogs receiving dirlotapide lost significantly (P = 0.0001) more weight than those receiving placebo (14.0% and 11.8% by day 112 for studies A and B, respectively). Furthermore, in study A, mean weight loss from day 0 was 19.3% by day 196 and 16.7% at the end of the post-treatment phase. In addition, weight loss of at least 13% of body weight was achieved by significantly more dirlotapide-treated dogs over 112 days than by dogs receiving placebo (39.1-50.0% vs. 5.3-5.6%). In overweight dogs with hindlimb lameness secondary to hip osteoarthritis, weight reduction of at least 11-12% has substantially improved clinical signs. Over 50% of dogs on dirlotapide showed an improvement in BCS (of at least one category) during the 4-month weight loss phase. Similar to the outcome of many weight loss studies in humans, body weight has also been commonly observed to be regained by dogs following the removal of restrictions on dietary energy intake on completion of weight reduction programs. In weight reduction studies dependent on dietary restriction, the tendency to regain weight can be avoided or minimized through control of food volume and adjusting caloric intake to match the maintenance requirement of the individual dog and thus stabilize body weight. For owners to 'learn' how much to feed their dog in the current studies, a period of treatment with a reduced dose of dirlotapide was designed to stabilize body weight before discontinuation of the drug to maintain the weight reductions achieved at the end of the weight loss phase. Although mean weight loss during the management period continued, mean weight reductions recorded during the first month of management were artifactually affected by withdrawal of those dogs that did not show sufficient weight loss response to treatment (i.e. dirlotapide- treated dogs that lost <8% initial body weight by 16 weeks). By the third month of management, the mean dosage was decreased from 0.33 to 0.26 mg/kg and body weight was relatively stable, with a mean loss of approximately 1 %, well within the ±5% body weight change allowed. Thus, the management technique was highly successful, and only minimal weight regain was observed after 2 months post-treatment. Mean weight gains over the post-treatment phase for dirlotapide in study A were higher in the first month post-treatment than in the second month (gains of 1.8% and 0.8%, respectively). The body weight measurement at the end of the first month post-treatment enabled the owner to further adjust the food offered for those dogs that gained weight. This implies that although some weight gain occurred, the mean weight loss of 16.7% in dogs receiving dirlotapide from day 0 could probably be maintained for a much longer period with minimal further weight gains, provided that the new feeding and exercise regimens were continued. Since approximately 10% of fat calories may be excreted in the feces during dirlotapide treatment it is also possible that feeding the amount of food that stabilized body weight may slightly overestimate the dog's calorie needs when dirlotapide is discontinued, illustrating the importance of maintaining veterinary supervision after dirlotapide is discontinued. In the present studies, dirlotapide was found to be safe in clinical use. However, some emesis, diarrhea, lethargy, and anorexia were recorded for dogs in both treatments, and the frequency was higher in dirlotapide-treated dogs. These observations, especially emesis and anorexia, were usually most common during the first month and tended to decrease with continued treatment, although a low incidence of emesis and lethargy was observed in all treatment phases. Although most clinical signs resolved despite continued dirlotapide treatment, it has been found that the effects can be reduced by initiating treatment at a lower dose to enable the dog to acclimate to the drug. Thus, in these studies, the dose of dirlotapide was started at a low initial dose of 0.05 mg/kg and was subsequently increased incrementally to reach an optimal dose to produce weight loss for each dog and then adjusted to maintain weight loss. Moreover, in study B, the first incremental increase was to 0.1 mg/kg in accordance with label recommendations (and in contrast to the increase to 0.2 mg/kg in study A), and this was found to further minimize emesis. Over the treatment period, the mean doses recorded had wide standard deviations and large range in dose volumes, confirming the need for individual titration and correction for differences in individual diet, exercise level, or metabolism which might affect rate of body weight loss. Accordingly, during the present studies, the dose of dirlotapide was adjusted to maintain weight loss and this dosing strategy was found to be successful. Table 3 provides a summary of the mean percentage weight changes [and 95% confidence intervals (Cl)] for dogs treated with dirlotapide or placebo during 112 days of weight loss in both studies; Table 4 provides a summary of the mean doses of dirlotapide and placebo administered to dogs at the end of each phase in both studies; Figure 2 provides a summary of the mean cumulative percentage body weight change, measured from day 0 to each scheduled visit for dogs treated with dirlotapide or placebo during studies A and B; and Figure 3 provides a summary of the mean weekly percentage weight change since the previous visit measured at each scheduled visit for dogs treated with dirlotapide or placebo during studies A and B.

Table 1 : Total Percent Weight Change from Study Start at each Scheduled Visit of the Weight Loss Phase.

Table 2: Summary of Dose Prescribed in mL/kg and in mg/kg at each Scheduled visit of the Weight Loss Phase.

NB: For each scheduled visit, doses are those prescribed from the scheduled visit day onwards. At each scheduled visit, summaries include only animals kept in the study beyond that point.

κ>

Nominal Day of Scheduled Visit

112 140 168

Dose in Regimen TRT Mean SD Min Max Mean SD Min Max Mean SD Min Max ml 0.2 mg/kg T01 0.184 0.004 0.179 0.187 0.183 0.006 0.179 0.187 0.176 0.007 0.171 0.181 ml 0.1 mg/kg T01 0.173 0.011 0.164 0.187 0.181 0.005 0.175 0.187 0.179 0.009 0.170 0.187 ml 0.05 mg/kg T01 0.114 0.064 0.020 0.196 0.118 0.086 0.020 0.179 0.179 0.161 0.020 0.343 mg 0.2 mg/kg T02 18 0.58 0.30 0.18 0.91 15 0.56 0.31 0.18 0.87 14 0.60 0.28 0.18 0.85 mg 0.1 mg/kg T02 38 0.36 0.24 0.09 0.8: 28 0.46 0.28 0.09 0.88 24 0.51 0.26 0.10 0.87 mg 0.05 mg/kg T02 37 0.35 0.26 0.10 0.93 28 0.48 0.32 0.10 0.93 25 0.53 0.29 0.10 0.93

Table 3. Mean percentage weight changes [and 95% confidence intervals (Cl)] for dogs treated with dirlotapide or placebo during 112 days of weight loss in both studies

Table 4. Mean doses of dirlotapide and placebo administered to dogs at the end of each phase in both studies

Claims

1. 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 effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, optionally followed by administration of at least one step-wise, escalating dosage of the MTP

IO inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.

2. A method according to claim 1 wherein the initial administration is followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor.

3. A method according to claim 1 or 2 followed by a weight maintenance/management or retraining phase.

4. . A method according to any preceding claim wherein the initial amount of MTP inhibitor administered is in [5 the range of 0.025 to 0.30 mg/kg/day.

5. A method according to claim 4 wherein the initial amount of MTP inhibitor administered is about 0.05 mg/kg/day.

6. A method according to any preceding claim wherein said escalating doses comprise at least a first dose level and a second dose level.

IO 7. A method according to claim 6 wherein said second dose level is 100% greater than the first dose level.

8. A method according to claim 6 or 7 wherein said second dose level is about 0.10 mg/kg/day.

9. A method according to claim 5 wherein said escalating doses further comprise a third dose level.

10. A method according to claim 9 wherein said third dose level is 100% greater than the second dose level.

11. A method according to claim 9 wherein said escalating doses further comprise a fourth dose level.

15 12. A method according to claim 11 wherein said fourth dose level is 50% greater than the third dose level.

13. A method according to claim 10 wherein the first dose level is about 0.05 mg/kg/day, the second dose level is about 0.10 mg/kg/day, and the third dose level is about 0.20 mg/kg/day.

14. A method according to any preceding claim wherein the side effects associated with administration of the MTP inhibitor include emesis, diarrhoea, lethargy, inappetence and anorexia.

IO 15. A method according to any preceding claim wherein the MTP inhibitor is selected from the group consisting of: dirlotapide; mitratapide;

(S)-2-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (pentylcarbamoyl-phenyl- 5 methyl)-amide;

(S^-f^'-tert-butyl-biphenyl^-carbonylJ-aminoj-quinoline-^β-carboxylic acid {[(4-fluoro-benzyl)-methyl- carbamoyl]-phenyl-methyl}-amide; (S)-2-[(4'-tert-butyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid [(4-fluoro-benzylcarbamoyl)-phenyl- methyl]-amide;

(S)-2-[(4'-isopropoxy-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid {[(4-fluoro-benzyl)-methyl- carbamoyl]-phenyl-methyl}-amide; or

or a pharmaceutically acceptable salt, hydrate or solvate thereof.