Treatment with dapiglutide

Abstract

The present invention relates to use of a GLP-1R / GLP-2R dual agonist, namely dapiglutide, to reduce body fat or inhibit gain of body fat whilst preserving lean mass.

Description

[0001] TREATMENT WITH DAPIGLUTIDE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to use of a GLP-1R / GLP-2R dual agonist, namely dapiglutide, to reduce body fat or inhibit gain of body fat whilst preserving lean mass.

[0004] BACKGROUND OF THE INVENTION

[0005] Obesity is currently a significant public health issue across much of the developed world and is correlated with the development of several serious conditions, such as cardiovascular disease, type 2 diabetes, sleep apnoea, and certain cancers. The standard treatment for obesity is lifestyle intervention, including the reduction of energy intake and the increase of exercise. However, while such interventions can achieve temporary success, it is often challenging for patients to sustain such lifestyle changes over a long period such that the weight loss achieved is permanent. It is known that besides the total weight, the body composition, i.e. the balance between fat and lean mass (including muscle mass) is an important parameter for a person’s health. Thus, although weight loss is important for obese persons, the loss of fat vs. the loss of lean mass makes a difference to the health condition. For example, the preservation of lean mass is associated with better insulin sensitivity and a lower risk of metabolic syndrome. Because skeletal muscle is the major site of postprandial glucose uptake a decrease in lean mass may be associated with impaired glucose metabolism in individuals with type 2 diabetes (DeFronzo and Tripathy; Diabetes Care; Vol. 32, S157; 2009).

[0006] Glucagon-like peptide (GLP)-1 is a hormone with a broad range of effects spanning from metabolic to neurological; including induction of glucose-dependent insulin secretion and suppression of glucagon secretion, improvement of cardiovascular performance, stimulation of neuroprotective effects, reduction of inflammation, reduction of gastric emptying and suppression of food intake. GLP-1 reduces appetite and induces satiety, translating to reduced energy intake. GLP-1 receptors are expressed in human brain, pancreas, kidney, stomach, heart and adipose tissue, underscoring the potential of the hormone. Presently, two GLP-1 receptor (GLP-1 R) agonists, liraglutide and semaglutide, are approved for the treatment of obesity.

[0007] GLP-2 is a specific intestinal growth factor that plays a role in enhancing small intestinal mucosal morphology, function, and integrity both under normal and pathophysiological conditions. GLP-2 binds to and acts via a single G-protein-coupled receptor, which has been localized in the small intestine, colon, stomach, and brain (though to a lesser extent). Exogenous GLP-2 induces significant growth of the small intestinal mucosal epithelium via the stimulation of stem cell proliferation in the crypts and inhibition of apoptosis on the villi. This trophic effect of GLP-2 has been observed in numerous species, including humans. Additional reported effects of GLP-2 in animals include inhibition of gastric emptying and gastric acid secretion, stimulation of nutrient absorption, enhancement of intestinal barrier function, increase in intestinal blood flow, and reduction of intestinal inflammation.

[0008] Dapiglutide is a 33-amino acid acylated peptide molecule that agonises both GLP-1R and GLP-2R. The peptide was disclosed for the first time by Zealand Pharma in WO 2018 / 104561 A1 (Compound 18 and SEQ ID NO 18 therein) and has the following peptide sequence:

[0009] Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]isoGlu)]QAARDFIAWLIQHKITD- OH (SEQ ID NO 1).

[0010] Dapiglutide reduces blood glucose and increases small intestine weight in mice. Human subjects administered four once-weekly doses of dapiglutide exhibited a dose-dependent reduction in appetite and body weight in a Multiple Ascending Dose Trial Assessing Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of dapiglutide (clinical trial No. NCT04612517) as described in Example 6 of WO 2023 / 031380 A9.

[0011] SUMMARY OF THE INVENTION

[0012] Broadly, the present invention relates to methods for reducing body fat whilst preserving lean mass in a subject. More specifically, the invention is based on the surprising finding that administration to a subject of dapiglutide results in loss of body fat without loss of lean mass.

[0013] The methods and uses of the invention therefore advantageously promote healthy weight loss because when losing weight, it is preferable that body fat is lost rather than lean mass such as e.g. muscle.

[0014] The methods and uses of the invention may thus be useful for therapy, allowing treatment or prevention of conditions characterised by, or associated with, excess body fat, such as overweight, obesity and morbid obesity whilst avoiding side-effects associated with concomitant loss of lean mass.

[0015] In particular, the methods and uses of the invention may be useful for treating a disease or disorder selected from overweight, overweight in the presence of at least one weight- related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity- induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome; whilst avoiding sideeffects associated with concomitant loss of lean mass.

[0016] In the context of the invention the term “diabetes” refers to “diabetes mellitus”.

[0017] Dapiglutide is of use particularly in treatment of diseases associated with excess body fat and loss of lean mass (e.g. muscle wasting) as excess body fat may be reduced without exacerbating loss of lean mass.

[0018] Additionally, reduction of body fat whilst retaining lean mass is often desired for cosmetic reasons, even in subjects that do not suffer from a medical condition or disease such as obesity. Thus, the invention also provides use of dapiglutide in non-therapeutic methods of reducing body fat whilst preserving lean mass. Examples of non-therapeutic uses include reducing body weight, inhibiting weight gain and promoting weight loss.

[0019] Thus, the invention provides a method of reducing body fat whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0020] The invention also provides a method for reducing body weight, inhibiting weight gain or promoting weight loss in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0021] The invention also provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain or promoting weight loss, in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0022] The invention also provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes, pre-diabetes or metabolic syndrome in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0023] DESCRIPTION OF THE FIGURES

[0024] Figure 1 :

[0025] 1a: Trial design for the Phase 1 Multiple Ascending Dose (MAD) trial, part 1 , on which Example 1 is based. (13 weeks duration with titration every 2ndweek).

[0026] 1b: Trial design for the Phase 1 Multiple Ascending Dose (MAD) trial, part 2 (28 weeks duration with titration every 4thweek).

[0027] DESCRIPTION OF THE INVENTION

[0028] Dapiglutide

[0029] Dapiglutide is an acylated peptide molecule that agonises both GLP-1 R and GLP-2R. Dapiglutide is thus a GLP-1 R / GLP-2R dual agonist (sometimes denoted GLP-1 / GLP-2 receptor dual agonist or GLP-1 / GLP-2 dual agonist). Dapiglutide is Compound 18 (Cpd. 18) in the patent application published as WO 2018 / 104561 A1, which is incorporated herein by reference.

[0030] The amino acid sequence of dapiglutide is as follows: Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD- OH (SEQ ID NO 1).

[0031] The amino acids of the peptide part of dapiglutide are represented in the above sequence (and in other sequences herein) using the conventional one-letter code for naturally occurring amino acids, i.e.:

[0032] A (Ala), G (Gly), L (Leu), I (lie), V (Vai), F (Phe), W (Trp), S (Ser), T (Thr), Y (Tyr), N (Asn), Q (Gin), D (Asp), E (Glu), K (Lys), R (Arg), H (His), M (Met), C (Cys) and P (Pro). “[Aib]” refers to a-aminoisobutyric acid. The amino acid residues are of the L-configuration. The amino acid sequence is written left to right in amino (N-) to carboxy (C-) orientation, respectively.

[0033] “Hy-” at the N-terminus of the dapiglutide peptide sequence indicates a free primary amine group (-NH2) at the N-terminus. “-OH” at the C-terminus of the dapiglutide peptide sequence indicates a carboxyl group (-COOH) at the C-terminus. 219

[0034] “[K([17-carboxy-heptadecanoyl]-isoGlu)]” indicates a 17-carboxy-heptadecanoyl group linked via an iso-glutamate (isoGlu) residue to the side-chain of a lysine residue in the dapiglutide peptide sequence. [17-carboxy-heptadecanoyl]-isoGlu (i.e. , a 17-carboxy-heptadecanoyl group linked to an isoGlu residue) has the following structure: wherein the dotted line indicates the covalent bind linking to the nitrogen atom in the sidechain of the lysine in the dapiglutide peptide.

[0035] Dapiglutide as used in the invention may be in the form of a pharmaceutically acceptable salt. Thus, any reference herein to dapiglutide encompasses pharmaceutically acceptable salts thereof. As used herein, the term “pharmaceutically acceptable salt” is intended to indicate a salt which is not harmful to a subject to which the salt in question is administered.

[0036] Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts.

[0037] Similarly, salts can be formed using organic or inorganic acids. Amino acid addition salts can also be formed with amino acids. Examples of pharmaceutically acceptable salts are described in Remington’s Pharmaceutical Sciences, 17th edition. Ed. Alfonso R. Gennaro (Ed.), Mack Publishing Company, Easton, PA, U.S.A., 1985 and more recent editions, and in the Encyclopaedia of Pharmaceutical Technology.

[0038] Dapiglutide may be synthesised using techniques known in the art, such as by solid-phase or liquid-phase peptide synthesis methodology. In this context, reference may also be made to WO 98 / 11125 and, among many others, Fields, G.B. et al., 2002, “Principles and practice of solid-phase peptide synthesis”. In: Synthetic Peptides (2nd Edition). Synthesis of dapiglutide is described in Example 1 of WO 2018 / 104561 A1.

[0039] Reducing body fat whilst preserving lean mass

[0040] The invention provides a method of reducing body fat whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject. The method of the invention may also be expressed as a method of inhibiting or reducing weight gain, a method of promoting weight loss, and / or a method of reducing body weight in a subject, wherein lean mass is preserved in the subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0041] The invention also provides a method of inhibiting weight gain whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0042] The invention also provides a method of inhibiting gain of body fat whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0043] The invention also provides a method of promoting weight loss whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0044] The invention also relates to dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain or promoting weight loss, in a subject; wherein the method reduces body fat whilst preserving lean mass in the subject; the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0045] The term “body fat” refers to adipose tissue, which is the type of tissue which stores fat in the body. Body fat includes so-called “brown fat”, “beige fat” “white fat” and “pink fat”. Body fat includes particularly subcutaneous adipose tissue that stores excess fat, such as in the belly, thighs and hips of human subjects.

[0046] The term “lean mass” refers to all mass of a subject which is not body fat. Lean mass may also be referred to as “fat-free mass”. “Lean mass” primarily includes the combined mass of 219 muscle, bone, viscera (i.e. organs such as heart, lungs, gastrointestinal tract etc.) and other tissues such as arteries, veins, lymph nodes etc.

[0047] It is well-understood that excess fat can be undesirable for medical reasons (such as in overweight, obese or morbidly obese subjects) or for cosmetic reasons (such as in subjects of a healthy weight). The central concept of the present invention is that use of dapiglutide and pharmaceutically acceptable salts thereof can reduce unwanted body fat without reducing desirable lean mass, in particular muscle. The terms “body fat” and “lean mass” are used in that context herein, to indicate the types of mass which it is typically desirable to lose (body fat) or retain (lean mass, particularly muscle) when losing weight.

[0048] Thus, the term “preserving lean mass” means to prevent or avoid loss of lean mass. In quantitative terms, preserving lean mass means that lean mass of the subject increases or does not change or, if lean mass of the subject decreases, then it does so only to an insignificant degree. Accordingly, a method of the invention may also be expressed as a method of reducing body fat whilst preventing loss of lean mass in a subject or a method of reducing body fat whilst avoiding loss of lean mass in a subject.

[0049] The most important constituent of lean mass in the context of the present invention is muscle (i.e. muscle mass). The mass of both subcutaneous adipose tissue and muscle tissue may be reduced upon weight loss (particularly weight loss through calorific restriction without associated exercise). It is desirable to avoid loss of muscle during weight loss due to the functional and perceived cosmetic benefits therefrom. Accordingly, a method of the invention may also be expressed as a method of reducing body fat whilst preserving muscle in a subject.

[0050] The amount of body fat (and accordingly lean mass) in a given subject may be determined by methods known in the art. Such methods include BOD POD analysis which has been described in Dempster P, Aitkens S: A new air displacement method for the determination of human body composition. Med Sci Sports Exerc 1995, 27:1692-1697.

[0051] Reducing body fat

[0052] The amount of body fat of a subject may be expressed in terms of weight, i.e., weight of body fat in grams (g) or kilograms (kg) or as a proportion of the total body weight of the subject. The proportion of the total body weight of the subject that is body fat is referred to herein as “% body fat” or “proportion of body fat”, and is abbreviated “%BF”. In other words, the amount of body fat of a subject may be expressed as the actual weight of the subject’s body fat (using the unit “kg”) or as the proportion of the total body weight of the subject (using the unit “%BF”).

[0053] According to the invention herein, the term “%BF” means a unit corresponding to the proportion of body fat per total body weight of the subject.

[0054] The %BF of a subject can be calculated by dividing the weight of body fat of the subject by the total body weight of the subject, and multiplying by 100. Practically, the weight of body fat (in kg) and the %BF of a subject can be measured using techniques known in the art, such as the BOD POD® measurement system described in Example 1 herein.

[0055] Absolute change in body fat

[0056] A change in body fat, such as a reduction in body fat, can be expressed herein both as an absolute change in weight of body fat (kg) or an absolute change in proportion of the total body weight that is body fat (%BF) over time.

[0057] Thus, a change in body fat can be expressed as an absolute change in kg. For example, the weight of body fat of the subject may be reduced from a certain weight (in kg) to a lower weight (in kg) (i.e., the body fat of the subject weighs less).

[0058] A change in body fat can also be expressed as an absolute change in %BF. For example, the proportion of the total body weight of the subject that is body fat (%BF) may be reduced from a certain %BF to a lower %BF (i.e., the body fat of the subject becomes a lower proportion of the total body weight of the subject).

[0059] The term “absolute change” is used herein to refer to the actual, numerical change in a value (either weight or proportion), in contrast to a percentage change, which is necessarily a relative change (i.e., relative to a starting value, such as starting weight or proportion).

[0060] In some embodiments, as a result of the method of the invention, the proportion of body fat of the subject is reduced by an absolute change of at least about 1 %BF. In other words, the proportion of the total body weight of the subject which is body fat decreases from a higher proportion (i.e., %BF) to a lower proportion (i.e., %BF) by an increment of 1 .

[0061] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 1.5 %BF, such as at least about 2 %BF, such as at least about 2.5 %BF, such as at least about 3 %BF, at least about 4 %BF, at least about 5 %BF, at least about 6 %BF, at least about 7 %BF, at least about 8 %BF, at least about 9 %BF, at least about 10 %BF, at least about 15 %BF, at least about 20 %BF, at least about 25 %BF, at least about 30 %BF, at least about 40 %BF, or at least about 50 %BF.

[0062] In some embodiments, as a result of the method of the invention, the proportion of body fat of the subject is reduced by an absolute change of about 1 %BF. In some embodiments, the body fat of the subject is reduced by an absolute change of about 1.5 %BF, about 2 %BF, about 2.5 %BF, about 3 %BF, about 3.5 %BF, about 4 %BF, about 5 %BF, about 6 %BF, about 7% BF, about 8 %BF, about 9 %BF, about 10 %BF, about 15 %BF, about 20 %BF, about 25 %BF, about 30 %BF, about 40 %BF, or about 50 %BF.

[0063] In some embodiments, as a result of the method of the invention, the proportion of body fat of the subject is reduced by an absolute change of from about 1 %BF to about 20 %BF, such as from about 2 %BF to about 20 %BF, from about 2 %BF to about 10 %BF, from about 2 %BF to about 10 %BF, from about 5 %BF to about 20 %BF, from about 5%BF to about 10 %BF, from about 2 %BF to about 13 %BF, from about 5%BF to about 13 %BF, or from about 13 %BF to about 20 %BF.

[0064] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of from about 1 %BF to about 6 %BF, such as 1.5 %BF to about 6 %BF, from about 1 %BF to about 5 %BF, from about 1.5 %BF to about 5 %BF, or from about 1.5 %BF to about 4 %BF.

[0065] Percentage change in body fat

[0066] A change in body fat, such as a reduction in body fat, may also be expressed as a percentage change (% change), instead of, or in addition to, being expressed as an absolute change. In other words, the change in body fat can be expressed as a percentage of the original amount of body fat of the subject.

[0067] A change in body fat can be expressed as a % change in weight of body fat (kg). The % change in weight of body fat can be calculated by dividing the absolute change in weight of body fat (in kg) by the starting weight of body fat (in kg), and then multiplying this value by 100. For example, the weight of body fat of the subject may be reduced from a certain weight (in kg) to a lower weight (in kg) (i.e., the body fat of the subject weighs less). The difference in these two weights can be expressed as a percentage of the starting weight - this is the % change in body fat weight. In some embodiments, the weight of body fat of the subject is reduced by a % change of at least about 1%, such as at least about 1.5%, such as at least about 2%, such as at least about 2.5%, such as at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or at least about 50%.

[0068] In some embodiments, the weight of body fat of the subject is reduced by a % change of about 1%. In some embodiments, the weight of body fat of the subject is reduced by a % change of 1.5%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 20%, about 25%, about 30%, about 40%, or about 50%.

[0069] In some embodiments, the weight of body fat of the subject is reduced by a % change of from about 1% to about 30%, such as from about 5% to about 30%, from about 10% to about 30%, from about 15% to about 30%, from about 10% to about 25%, from about 10% to about 26%, from about 11 % to about 26%, from about 11 % to about 16%, or from about 10% to about 15%.

[0070] A change in body fat can also be expressed as a percentage change (% change) in proportion of the total body weight that is body fat (%BF). The % change in %BF can be calculated by dividing the absolute change in %BF by the starting %BF, and then multiplying this value by 100. For example, the proportion of the total body weight of the subject that is body fat (%BF) may be reduced from a certain %BF to a lower %BF (i.e. , the body fat of the subject becomes a lower proportion of the total body weight of the subject). The difference in these two %BF values can be expressed as a percentage of the starting %BF - this is the % change in %BF.

[0071] In some embodiments, as a result of the method of the invention, the proportion of body fat (%BF) of the subject is reduced by a % change of at least about 1%. That is, in some embodiments, the proportion of the body weight of the subject which is body fat is reduced by a % change of at least about 1%. In some embodiments, the proportion of body fat (%BF) of the subject is reduced by a % change of at least about 1.5%, such as at least about 2%, such as at least about 2.5%, such as at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or at least about 50%. 219

[0072] In some embodiments, as a result of the method of the invention, the proportion of body fat (%BF) of the subject is reduced by a % change of about 1%. In some embodiments, the proportion of body fat (%BF) of the subject is reduced by a % change of 1.5%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, or about 50%.

[0073] In some embodiments, as a result of the method of the invention, the proportion of body fat (%BF) of the subject is reduced by a % change of from about 1% to about 20%, such as from about 2% to about 20%, from about 1% to about 10%, from about 2% to about 10%, from about 5% to about 20%, from about 5% to about 10%, from about 2% to about 13%, from about 5% to about 13%, or from about 13% to about 20%.

[0074] In some embodiments, the proportion of body fat (%BF) of the subject is reduced by a % change of from about 5% to about 20%, such as from about 6% to about 20%, from about 6% to about 18%, from about 5% to about 10%, or from about 6% to about 9%.

[0075] Body fat change over time

[0076] To determine whether and by how much body fat of the subject has been reduced, body fat of the subject is measured over time. In other words, in some embodiments, as a result of the method of the invention, the body fat of the subject is reduced by a given amount over a given period (i.e. the body fat of the subject at the end of the period differs from the body fat of the subject at the start of the period by a given amount).

[0077] In some embodiments, the body fat of the subject is reduced over a period of about 1 week.

[0078] In some embodiments, the body fat of the subject is reduced over a period of about 30 days.

[0079] In some embodiments, the body fat of the subject is reduced over a period of about 1 month.

[0080] In some embodiments, the body fat of the subject is reduced over a period of about 6 months. In some embodiments, the body fat of the subject is reduced over a period of about 1 year. In some embodiments, the body fat of the subject is reduced over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0081] In one embodiment, the body fat of the subject is reduced over a period of at least 3 months, such as at least 4 months or at least 13 weeks. In some embodiments, the proportion of body fat (%BF) of the subject is reduced by an absolute change of at least about 1 %BF over a period of about 1 week, or by a % change of at least about 1% over a period of about 1 week. In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 1 %BF over a period of about 30 days, or by a % change of at least about 1% over a period of about 30 days. In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 1 %BF over a period of about 1 month, or by a % change of at least about 1% over a period of about 1 month. In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 1 %BF over a period of about 6 months, or by a % change of at least about 1% over a period of about 6 months In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 1 %BF over a period of about 1 year, or by a % change of at least about 1% over a period of about 1 year.

[0082] In some embodiments, the proportion of body fat (%BF) of the subject is reduced by an absolute change of at least about 2 %BF over a period of about 1 week, or by a % change of at least about 2% over a period of about 1 week. In some embodiments, the body fat of the subject is reduced by an absolute change of at least about 2 %BF over a period of about 30 days, or by a % change of at least about 2% over a period of about 30 days. In some embodiments, the body fat of the subject is reduced by an absolute change of at least about 2 %BF over a period of about 1 month, or by a % change of at least about 2% over a period of about 1 month. In some embodiments, the body fat of the subject is reduced by an absolute change of at least about 2 %BF over a period of about 6 months, or by a % change of at least about 2% over a period of about 6 months. In some embodiments, the body fat of the subject is reduced by an absolute change of at least about 2 %BF over a period of about 1 year, or by a % change of at least about 2% over a period of about 1 year.

[0083] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 5 %BF over a period of about 6 months, or by a % change of at least about 5% over a period of about 6 months. In some embodiments, the body fat of the subject is reduced by an absolute change of at least about 5 %BF over a period of about 1 year, or by a % change of at least about 5% over a period of about 1 year.

[0084] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 10 %BF over a period of about 1 year, or by a % change of at least about 10% over a period of about 1 year. 219

[0085] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 1 %BF or by a % change of at least about 1%, over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0086] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 2 %BF or by a % change of at least about 2%, over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0087] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 3 %BF or by a % change of at least about 3%, over a period of about 1 year over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0088] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 4 %BF or by a % change of at least about 4%. over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0089] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 5 %BF or by a % change of at least about 5%, over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0090] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 6 %BF or by a % change of at least about 6%, over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years. In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 7 %BF or by a % change of at least about 7%, over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0091] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 8 %BF or by a % change of at least about 8%, over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0092] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 9 %BF or by a % change of at least about 9%, over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0093] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of at least about 10 %BF or by a % change of at least about 10%, over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0094] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of from about 1 %BF to about 5 %BF, such as from about 2 BF% to about 4 %BF; or by a % change of from about 5% to about 10%; over a period of about 10 to 20 weeks.

[0095] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of from about 1 %BF to about 5 %BF, such as from about 2 BF% to about 4 %BF; or by a % change of from about 5% to about 10%; over a period of about 13 weeks.

[0096] In some embodiments, the proportion of body fat of the subject is reduced by a % change of from about 5 %BF to about 10 %BF, such as from about 6 BF% to about 9 %BF, or by a % change of about 5%, about 6%, about 9%, or about 10%, over a period of about 13 weeks. 219

[0097] In some embodiments, the proportion of body fat of the subject is reduced by an absolute change of from about 5% to about 10%; or by a % change of from about 10% to about 20% over a period of about 18 weeks.

[0098] In some embodiments, the proportion of body fat of the subject (%BF) is reduced by an absolute change of from about 5 %BF to about 6 %BF, or about 6 %BF, or about 5 %BF, over a period of about 28 weeks.

[0099] In some embodiments, the proportion of body fat of the subject (%BF) is reduced by a % change of about 20%, or about 18%, over a period of about 28 weeks.

[0100] Preserving lean mass

[0101] As body fat decreases whilst lean mass is preserved, the ratio of lean mass to body fat of the subject increases. Therefore, a method of the invention may be expressed as a method of increasing the ratio of lean mass to body fat in the subject. In some embodiments, the method is a method of increasing the ratio of muscle to body fat in the subject.

[0102] The amount of lean mass of a subject may be expressed in terms of weight, i.e., weight of lean mass in grams (g) or kilograms (kg) or as a proportion of the total body weight of the subject. The proportion of the total body weight of the subject that is lean mass is referred to herein as “%lean mass” or “proportion of lean mass”, and is abbreviated “%LM”. In other words, the amount of lean mass of a subject may be expressed as the actual weight of the subject’s lean mass (using the unit “kg”) or as the proportion of the total body weight of the subject (using the unit “%LM”).

[0103] According to the invention herein, the term “%LM” means a unit corresponding to the proportion of lean mass per total body weight of the subject.

[0104] The %LM of a subject can be calculated by dividing the weight of lean mass of the subject by the total body weight of the subject, and multiplying by 100. Practically, the weight of lean mass (in kg) and the %LM of a subject can be measured using techniques known in the art, such as the BOD POD® measurement system described in Example 1 herein.

[0105] Change in lean mass

[0106] A change in lean mass, such as an increase in lean mass, can be expressed herein both as an absolute change in weight of lean mass (kg) or an absolute change in proportion of the total body weight that is lean mass (%LM). Thus, a change in lean mass can be expressed as an absolute change in kg. For example, the weight of lean mass of the subject may remain at a certain weight (in kg), meaning the change in lean mass weight is 0 kg.

[0107] A change in lean mass can also be expressed as an absolute change in %LM. For example, the proportion of the total body weight of the subject that is lean mass (i.e., proportion lean mass, %LM) may increase from a certain %LM to a higher %LM (i.e., the lean mass of the subject becomes a higher proportion of the total body weight of the subject).

[0108] It will be appreciated that when a subject loses body fat but not lean mass, the overall body weight decreases, the weight of body fat decreases, and the weight of lean mass remains the same. In such cases, the proportion of the subject’s total body weight that is body fat (%BF) decreases and the proportion of the subject’s total body weight that is lean mass (%LM) increases. Thus, %LM may increase, even though the weight of lean mass (in kg) does not increase.

[0109] A change in lean mass may also be expressed as a percentage change (% change), instead of, or in addition to, being expressed as an absolute change. In other words, the change in lean mass can be expressed as a percentage of the original amount of lean mass of the subject.

[0110] A change in lean mass can be expressed as a % change in weight of lean mass (kg). The % change in weight of lean mass can be calculated by dividing the absolute change in weight of lean mass (in kg) by the starting weight of lean mass (in kg), and then multiplying this value by 100. For example, the weight of lean mass of the subject may increase from a certain weight (in kg) to a higher weight (in kg) (i.e., the lean mass of the subject weighs more). The difference in these two weights can be expressed as a percentage of the starting weight - this is the % change in lean mass weight.

[0111] A change in lean mass can also be expressed as a percentage change (% change) in proportion of the total body weight that is lean mass (%LM). The % change in %LM can be calculated by dividing the absolute change in %LM by the starting %LM, and then multiplying this value by 100. For example, the proportion of the total body weight of the subject that is lean mass (%LM) may increase from a certain %LM to a higher %LM (i.e., the lean mass of the subject becomes a higher proportion of the total body weight of the subject). The 219 difference in these two %LM values can be expressed as a percentage of the starting %LM - this is the % change in %LM.

[0112] In some embodiments, as a result of the method of the invention, the weight of lean mass of the subject (in kg) is reduced insignificantly, or does not change, or increases.

[0113] In some embodiments, the lean mass expressed in absolute terms (i.e. , the weight of lean mass in grams or kilograms) remains stable.

[0114] In some embodiments, the lean mass of the subject expressed in absolute terms (i.e., weight of lean mass) is reduced insignificantly.

[0115] In some embodiments, the weight of lean mass of the subject does not change. The weight of lean mass of the subject not changing means a % change of from -0.5% to +0.5% weight of lean mass.

[0116] In some embodiments, as a result of the method of the invention the weight of lean mass of the subject is reduced by less than about 3%, such as less than about 2%, preferably less than about 1 %, such as by about 0%.

[0117] In some embodiments, as a result of the method of the invention, the weight of lean mass of the subject is not reduced. In other words, the absolute weight of lean mass is not reduced, or is not significantly reduced.

[0118] In some embodiments the weight of lean mass of the subject is reduced by no more than 1 %, by no more than 2%, by no more than 3%, by no more than 4%, by no more than 5% or by no more than 6%.

[0119] In one embodiment, the weight of lean mass of the subject is reduced by no more than 1 %.

[0120] In one embodiment, the weight of lean mass of the subject is reduced by no more than 2%.

[0121] In one embodiment, the weight of lean mass of the subject is reduced by no more than 3%.

[0122] In one embodiment, the weight lean mass of the subject is reduced by no more than 4%. In some embodiments, the weight of lean mass of the subject is reduced by no more than from about 0.1% to about 6%, such as no more than from about 0.1% to about 4%, or no more than from about 0.1% to about 3%.

[0123] In some embodiments, the absolute change in the proportion of lean mass (%LM) of the subject increases. It will be understood that if a subject loses body fat at a greater rate than lean mass, the %LM may increase, even if the absolute amount of lean mass remains constant, because the remaining lean mass makes up a larger proportion of the total body mass than before the loss of body fat.

[0124] In some embodiments, as a result of the method of the invention the proportion of the lean mass (%LM) of the subject increases by an absolute change of at least about 1.0 %LM, at least about 1.5 %LM, at least about 2.0 %LM, at least about 2.5 %LM, at least about 3.0 %LM, at least about 3.5 %LM, at least about 4.0 %LM, at least about 4.5 %LM, at least about 5.0 %LM, at least about 5.5 %LM, at least about 6.0 %LM, at least about 6.5 %LM, at least about 7.0 %LM, at least about 7.5 %LM, at least about 8.0 %LM, at least about 8.5 %LM, at least about 9.0 %LM, at least about 9.5 %LM, at least about 10.0 %LM, at least about 11.0 %LM, at least about 12 %LM, at least about 13 %LM, at least about 14 %LM, at least about 15 %LM, at least about 16 %LM, at least about 17 %LM, at least about 18 %LM, at least about 19 %LM, or at least about 20.0 %LM, at least about 25 %LM, at least about 30 %LM, at least about 40 %LM, or at least about 50 %LM.

[0125] In some embodiments, as a result of the method of the invention the proportion of the lean mass (%LM) of the subject increases by an absolute change of from about 1 %LM to about 20 %LM, such as from about 2 %LM to about 20 %LM, from about 1 %LM to about 10 %LM, such as from about 1 %LM to about 9 %LM, from about 1 %LM to about 6 %LM, from about 2 %LM to about 13 %LM, from about 2 %LM to about 10 %LM, from about 3 %LM to about 6 %LM, from about 5 %LM to about 13 %LM, from about 5 %LM to about 9 %LM, or from about 13 %LM to about 20 %LM.

[0126] In some embodiments, as a result of the method of the invention the proportion of the lean mass (%LM) of the subject increases by a % change of at least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 3.0%, at least about 3.5%, at least about 4.0%, at least about 4.5%, at least about 5.0%, at least about 5.5%, at least about 6.0%, at least about 6.5%, at least about 7.0%, at least about 7.5%, at least about 8.0%, at least about 8.5%, at least about 9.0%, at least about 9.5%LM, at least about 10.0%, at least about 11.0%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20.0%, at least about 25%, at least about 30%, at least about 40%, or at least about 50%.

[0127] In some embodiments, as a result of the method of the invention the proportion of the lean mass (%LM) of the subject increases by a % change of from about 1% to 20%, such as from about 2% to 20%, from about 1% to about 10%, such as from about 1% to about 9%, from about 1% to about 6%, from about 2% to about 13%, from about 2% to about 10%, from about 3% to about 6%, from about 5% to about 13%, from about 5% to about 9%, or from about 13% to about 20%.

[0128] Lean mass change over time

[0129] To determine whether and by how much lean mass of the subject has changed, lean mass of the subject is measured over time. In other words, in some embodiments, as a result of the method of the invention, the lean mass of the subject changes by a given amount (or does not change) over a given period (i.e. the lean mass of the subject at the end of the period differs from the lean mass of the subject at the start of the period by a given amount).

[0130] In some embodiments, as a result of the method of the invention, the proportion of the lean mass (%LM) increases over a period of about 1 week. In some embodiments, the %LM increases over a period of about 30 days. In some embodiments, the %LM increases over a period of about 1 month. In some embodiments, the lean mass of the subject increases over a period of about 6 months. In some embodiments, the lean mass of the subject increases over a period of about 1 year. In some embodiments, the %LM increases over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0131] In one embodiment, the %LM increases over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

[0132] In some embodiments, as a result of the method of the invention, the weight of lean mass of the subject (expressed in g or kg) does not change over a period of about 1 week. In some embodiments, the weight of lean mass of the subject does not change over a period of about 30 days. In some embodiments, the weight of lean mass of the subject does not change over a period of about 1 month. In some embodiments, the lean mass of the subject does not change over a period of about 6 months. In some embodiments, the weight of lean mass of the subject does not change over a period of about 1 year. In some embodiments, the weight of lean mass of the subject does not change over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years.

[0133] In one embodiment, the weight of lean mass of the subject does not change over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

[0134] To determine whether a given use of the dapiglutide according to the invention has reduced body fat whilst preserving lean mass, the change in body fat and change in lean mass in the subject should be measured over the same time period. In this way, it is possible to determine that body fat has indeed reduced whilst no change or an increase of lean mass has occurred.

[0135] Thus, in some embodiments, as a result of the method of the invention, the change in body fat and lean mass are measured over a period of about 1 week. In some embodiments, the change in body fat and lean mass are measured over a period of about 30 days. In some embodiments, the change in body fat and lean mass are measured over a period of about 1 month. In some embodiments, the change in body fat and lean mass are measured over a period of about 3 months. In some embodiments, the change in body fat and lean mass are measured over a period of about 4 months. In some embodiments, the change in body fat and lean mass are measured over a period of about 6 months. In some embodiments, the change in body fat and lean mass are measured over a period of about 1 year. In some embodiments, the change in body fat and lean mass are measured over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years. Preferably, the change in body fat and lean mass are measured over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

[0136] In some embodiments, the proportion of lean mass of the subject (%LM) is increased by an absolute change of from about 1 %LM to about 5 %LM, such as from about 2 %LM% to about 4 %LM; or by a % change from about 2% to about 10%, such as in from about 2% to 7%; over a period of about 10 to 20 weeks. In some embodiments, the proportion of lean mass of the subject is reduced by an absolute change of from about 1 %LM to about 5 %LM, such as from about 2 %LM to about 4 %LM; or by a % change of from about 2% to about 10%, such as from about 2% to about 7%; over a period of about 13 weeks.

[0137] In some embodiments, the proportion of lean mass of the subject is reduced by an absolute change of from about 5 %LM to about 10 %LM, such as about 6 %LM; or by a % change of from about 5% to about 10%, such as about 8% or about 9%; over a period of about 28 weeks.

[0138] Reducing body weight

[0139] In some embodiments, the invention provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of inhibiting weight gain and / or reducing body weight in a subject, wherein dapiglutide reduces body fat whilst preserving lean mass in the subject.

[0140] In other words, the invention provides a method of inhibiting weight gain and / or reducing body weight in a subject, wherein dapiglutide reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0141] “Inhibiting weight gain” may also be referred to as “reducing weight gain”. “Reducing body weight” may also be referred to as “promoting weight loss”.

[0142] Dapiglutide as described herein may be used for therapeutic or cosmetic purposes. Thus, the inhibition of weight gain or reduction of body weight of the subject may be cosmetic (i.e. non-therapeutic). The effects of dapiglutide on body composition may be therapeutic or cosmetic.

[0143] In some embodiments, the invention relates to dapiglutide or a pharmaceutically acceptable salt thereof for use in methods that are not directed towards treating a disease perse. Such uses and methods may be considered preventative of disease in so far as they may be utilised prior to the onset of disease (e.g. pre diagnosis) e.g. to ameliorate unwanted physiological characteristics or alter certain physiological parameters. Furthermore, such uses or methods may be considered cosmetic. The effects of dapiglutide as described herein may be mediated in whole or in part via an effect on body weight or may be independent thereof. Independently of their effect on body weight, dapiglutide may have a beneficial effect on glucose tolerance and / or glucose control.

[0144] In some embodiments, the subject exhibits a reduction in body weight upon treatment with the dapiglutide. In some embodiments, the subject exhibits a reduction in body weight, expressed as a % change, of at least 1%, such as at least 5%, at least 10%, at least 15%, at least 20%, at least 22.5% or at least 25%, compared to their body weight before treatment. In some embodiments, the subject exhibits a reduction in body weight of at least 0.5% per month (i.e. 0.5% reduction in body weight at the end of each month compared to body weight at the start of the month), such as at least 0.75% per month, at least 1% per month, at least 1.25% per month or at least 1.3% per month. In some embodiments, the subject exhibits a reduction in body weight of 0.5% per month, 0.75% per month, 1% per month, 1.25% per month or 1.3% per month.

[0145] In some embodiments, the subject exhibits a reduction in body weight of from about 1% to about 20%, such as from about 1% to about 15%, from about 1% to about 11%, from about 3% to about 11%, from about 3% to about 7%, from about 3% to about 5%, from about 5% to about 11%, such as from about 5% to about 7%.

[0146] Therapeutic uses

[0147] In accordance with the surprising finding that dapiglutide reduces body fat whilst preserving lean mass, dapiglutide has utility in a number of therapeutic settings.

[0148] More specifically, dapiglutide is useful, inter alia, in the promotion of weight loss, and inhibition or reduction of weight gain; wherein dapiglutide reduces body fat whilst preserving lean mass. Dapiglutide may therefore provide an attractive treatment option for, inter alia, obesity and metabolic diseases caused, characterized by, or associated with, excess body weight.

[0149] The term “treatment” (as well as “treating” and other grammatical variants thereof) as employed in the context of the invention refers to an approach for obtaining beneficial or desired clinical results. For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization of (i.e. not worsening of) state of disease, delay or slowing of disease progression, amelioration or palliation of disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" may also refer to 219 prolongation of survival compared to expected survival in the absence of treatment. "Treatment" is an intervention performed with the intention of preventing the development of, or altering the pathology of, a disorder. Those in need of treatment include those already suffering from the disorder, as well as those in which development of the disorder is to be prevented. “Treatment” also means inhibition or reduction of an increase in pathology or symptoms (e.g. weight gain or hypoglycaemia) compared to the absence of treatment. As is common in the art, “treatment” is not necessarily meant to imply complete cessation or cure of the relevant condition.

[0150] The terms "prevention" and grammatical variants thereof (e.g., “prevented”, “preventing”, “prevent”) as employed in the present context refer to an approach for hindering or preventing the development of, or altering the pathology of, a condition, disease or disorder. Accordingly, "prevention" may refer to prophylactic or preventive measures. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, prevention or slowing of symptoms, progression or development of a disease, whether detectable or undetectable. A subject (e.g. a human) in need of “prevention” may thus be a subject not yet afflicted with the disease or disorder in question. The term “prevention” thus includes inhibiting or slowing the onset of disease relative to the absence of intervention (e.g., with dapiglutide), and is not necessarily meant to imply permanent prevention of the relevant disease, disorder or condition. In some embodiments, “prevention” or “prophylaxis” in the context of the present invention may mean prevention of weight gain (i.e. inhibiting weight gain). In some embodiments, “prevention” or “prophylaxis” may mean prevention of gain of body fat.

[0151] The invention provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain or promoting weight loss, in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0152] Weight is defined in the medical field by body mass index (BMI), which is calculated for human subjects by dividing the weight of the subject in kilograms by the square of the height of the subject in metres. A BMI of 18.5 kg / m2to 24.9 kg / m2corresponds to healthy weight.

[0153] The term “overweight” refers to an overall body weight which is more than a healthy weight. In other words, “overweight” means a body weight which is not considered normal or desirable. A BMI of 25.0 kg / m2to 29.9 kg / m2corresponds to overweight.

[0154] The term “obesity” refers to a medical condition characterized by excessive body fat accumulation, presenting a risk to health, according to the World Health Organization (WHO). A BMI of 30.0 kg / m2to 39.9 kg / m2corresponds to obese.

[0155] The term “morbid obesity” refers to a severe form of obesity. In other words, a morbidly obese subject has extremely excessive body weight. A BMI of 40.0 or higher corresponds to morbidly obese.

[0156] The term “obesity” may be used herein to refer to obesity and morbid obesity together. In other words, the term “obesity” may be used herein to refer to any state in which a subject has a medical condition characterized by excess body weight, regardless of the severity of the condition. In this context, a BMI of 30.0 kg / m2or higher / greater is “obese”.

[0157] The severity of obesity may also be referred to using three obesity “classes”. Thus, obesity (class I) corresponds to a BMI of 30.0 kg / m2to 34.9 kg / m2, obesity (class II) (also referred to as “severe obesity”) corresponds to a BMI of 35.0 kg / m2to 39.9 kg / m2, and obesity (class III) (also referred to as “morbid obesity”) corresponds to a BMI of 40.0 kg / m2or higher.

[0158] The invention also provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain or promoting weight loss, in a subject; wherein the method reduces body fat whilst preserving lean mass in the subject; the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0159] In one embodiment, there is provided dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating one or more disease or disorder selected from overweight, overweight in the presence of at least one weight related comorbid condition, 219 obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain or promoting weight loss, in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0160] In one embodiment, there is provided dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain or promoting weight loss, in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0161] The invention also provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes and metabolic syndrome, in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0162] The invention also provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes and metabolic syndrome, in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0163] In some embodiments, the method is for treating one or more disease or disorder selected from overweight, obesity, morbid obesity, obesity-linked gallbladder disease and obesity- induced sleep apnoea. In some embodiments, said method is for treating overweight in the presence of at least one weight-related comorbid condition, disease, or disorder.

[0164] In one embodiment, there is provided dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder, wherein the disease or disorder is a comorbid condition associated with or caused by overweight or obesity.

[0165] In some embodiments, said method is for treating one or more disease or disorder selected from obesity, morbid obesity, obesity-linked gallbladder disease and obesity-induced sleep apnoea.

[0166] In some embodiments, said method is for treating one or more disease or disorder selected from, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome.

[0167] In some embodiments, the invention provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of reducing body weight, inhibiting weight gain promoting weight loss, in a subject; wherein the method reduces body fat whilst preserving lean mass in the subject; the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0168] In some embodiments, dapiglutide is not co-administered to the subject together with an apelin receptor agonist.

[0169] In some embodiments, dapiglutide is the only active compound administered to the subject for reducing body fat whilst preserving lean mass in said subject.

[0170] Methods of treatment and use in manufacture of a medicament

[0171] The present invention is expressed herein as dapiglutide or a pharmaceutically acceptable salt thereof for use in the methods described herein.

[0172] The invention may be alternatively expressed as a method of treatment comprising administering to the subject dapiglutide or a pharmaceutically acceptable salt thereof; wherein the method reduces body fat whilst preserving lean mass in the subject. 219

[0173] Thus, invention further provides method of treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity- induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, in a subject; wherein the method reduces body fat whilst preserving lean mass in the subject; the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0174] In one embodiment, there is provided a method of treating one or more disease or disorder selected from overweight, overweight in the presence of at least one weight- related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity- induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, in a subject; wherein the method reduces body fat whilst preserving lean mass in the subject; the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0175] In one embodiment, there is provided a method of preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity- induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, in a subject; wherein the method reduces body fat whilst preserving lean mass in the subject; the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0176] In one embodiment, said method is for treating one or more disease or disorder selected from overweight, overweight in the presence of at least one weight- related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, and obesity-induced sleep apnoea.

[0177] In one embodiment, said method is for treating one or more disease or disorder selected from obesity, morbid obesity, obesity-linked gallbladder disease, and obesity-induced sleep apnoea. In one embodiment, said method is for treating one or more disease or disorder selected from, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome.

[0178] In one embodiment, the invention provides a therapeutic method for reducing body weight, inhibiting weight gain or promoting weight loss, in a subject; wherein the method reduces body fat whilst preserving lean mass in the subject; the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject; wherein the method reduces body fat whilst preserving lean mass in the subject.

[0179] The present invention may alternatively be expressed as use of dapiglutide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the purposes and methods described herein; wherein the medicament reduces body fat whilst preserving lean mass in the subject.

[0180] Thus, the invention further provides the use of dapiglutide in the manufacture of a medicament for a method of reducing body fat whilst preserving lean mass in a subject in need thereof.

[0181] In one embodiment, said method is a therapeutic method.

[0182] In one embodiment, said method is a non-therapeutic method, e.g. a cosmetic method.

[0183] In one embodiment, said method is for reducing body weight, inhibiting weight gain or promoting weight loss, in the subject.

[0184] In one embodiment, said method is for treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight- related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity- induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, in the subject.

[0185] Subject body weight

[0186] In some embodiments of the methods of treatment and medical uses of the invention, the subject is of a healthy weight. In other words, in some embodiments, the subject is not overweight, not obese and not morbidly obese.

[0187] In some embodiments, the subject has a Body Mass Index (BMI) of 18.5 to 24.9 corresponding to healthy weight. 219

[0188] BMI is calculated for human subjects by dividing the weight of the subject in kilograms by the square of the height of the subject in metres.

[0189] In some embodiments of the methods of treatment and medical uses of the invention, wherein the subject is overweight, obese or morbidly obese.

[0190] In some embodiments, the subject is overweight.

[0191] In some embodiments, the subject is obese.

[0192] In some embodiments, the subject is morbidly obese.

[0193] In some embodiments of the methods of treatment and medical uses of the invention, the subject has a BMI of 25.0 to 29.9 corresponding to overweight, a BMI of 30.0 to 39.9 corresponding to obese, or a BMI of 40.0 or higher corresponding to morbidly obese.

[0194] In some embodiments, the subject has a BMI of 25.0 to 29.9 corresponding to overweight.

[0195] In some embodiments, the subject has a BMI of 30.0 to 39.9 corresponding to obese.

[0196] In some embodiments, the subject has a BMI of 40.0 or higher corresponding to morbidly obese.

[0197] Obesity and diseases associated with obesity

[0198] The terms “disease”, “disorder” and “condition” are synonymous and are used interchangeably herein to refer to a state of malfunction of the body. The term “disease” thus encompasses “disorder” and “condition”.

[0199] The term “obesity” may be used herein to refer to obesity and morbid obesity together.

[0200] Dapiglutide for use in the methods and medical uses of the present invention reduce body fat or prevent increase in body fat or inhibit gain of body fat whilst preserving lean mass. Dapiglutide may therefore provide an attractive treatment option for, inter alia, obesity and metabolic diseases caused by, or associated with, excess body weight.

[0201] Accordingly, the invention provides methods and medical uses of treating or preventing overweight, obesity, morbid obesity or a disease associated with overweight, obesity or morbid obesity in a subject.

[0202] In some embodiments, the disease is selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome.

[0203] The invention also provides methods and medical uses of reducing body fat whilst preserving lean mass in a subject, wherein the subject suffers from a disease. In such embodiments of the invention, the reduction of body fat whilst preserving lean mass treats or prevents the disease.

[0204] The invention also provides methods and medical uses of inhibiting weight gain whilst preserving lean mass in a subject, wherein the subject suffers from a disease. In such embodiments of the invention, the inhibition of weight gain whilst preserving lean mass treats or prevents the disease.

[0205] In some embodiments, the subject suffers from a disease or disorder selected from the group consisting of overweight, overweight in the presence of at least one weight- related comorbid condition obesity, morbid obesity, obesity-linked gallbladder disease, obesity- induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome.

[0206] The reduction of body fat, inhibition of weight gain or inhibition of gain of body fat whilst preserving lean mass treats or prevents the disease(s).

[0207] Dapiglutide is useful, inter alia in reducing body weight, inhibiting weight gain or promoting weight loss, in a subject. Thus, dapiglutide for use in the invention may be used in methods of treating, inhibiting or reducing weight gain, promoting weight loss and / or reducing excess body weight.

[0208] Weight-related comorbid conditions

[0209] The term “overweight in the presence of at least one weight-related comorbid condition” refers to the state where a subject is overweight and also suffers from a condition associated with being overweight. To put it another way, it is well-known that being overweight or obese leads to further health complications (i.e., disease). Such a disease is referred to as a “weight-related comorbid condition”. A weight-related comorbid condition may be described as being linked, to, associated with or caused by overweight. By reducing body fat whilst preserving lean mass, dapiglutide can treat overweight and thereby alleviate symptoms of the weight- related comorbid condition. 219

[0210] In some embodiments, the disease is overweight in the presence of at least one weight- related comorbid condition.

[0211] In some embodiments, the disease is a comorbid condition or comorbidity associated with or caused by overweight.

[0212] In some embodiments, the weight-related comorbid condition is selected from gallbladder disease, sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes, pre-diabetes and metabolic syndrome.

[0213] Diseases associated with gain of body fat and loss of lean mass

[0214] In some embodiments of the methods and medical uses of the invention, the subject suffers from a disease associated with weight gain. A disease associated with weight gain is a disease wherein the body weight of the subject increases or is at risk of increasing due to the disease. Typically, the increase in body weight is due to an increase in body fat. In some embodiments, the subject suffers from a disease associated with gain of body fat or increase in body fat.

[0215] In some embodiments of the methods and medical uses of the invention, the subject suffers from a disease associated with loss of lean mass. A disease associated with loss of lean mass is a disease wherein the lean mass of the subject decreases or is at risk of decreasing due to the disease. Typically, loss of lean mass is specifically loss of muscle (i.e. loss of muscle mass, also referred to as muscle wasting). In some embodiments, the subject suffers from a disease associated with loss of muscle mass. In some embodiments, the subject suffers from a disease associated with muscle wasting or atrophy (i.e. a disease wherein the muscle mass of the subject decreases or is at risk of decreasing due to the disease).

[0216] In some embodiments, the subject suffers from a disease associated with both gain of body fat and loss of lean mass.

[0217] Diseases associated with both gain of body fat and loss of lean mass are often diseases associated with exercise intolerance. A disease associated with exercise intolerance is a disease wherein the subject suffering from the disease finds it difficult to exercise.

[0218] Consequently, the subject is at risk gain of body fat and loss of lean mass (i.e. loss of muscle mass, muscle wasting). Diseases associated with both gain of body fat and loss of lean mass include sarcopenic obesity, Duchenne muscular dystrophy (DMD), Charcot-Marie-Tooth disease (CMT), chronic obstructive pulmonary disease (COPD), McArdle disease, hypothyroidism, testosterone deficiency syndrome (TD), heart failure and anaemia.

[0219] Thus, in some embodiments, the subject suffers from a disease selected from sarcopenic obesity, Duchenne muscular dystrophy (DMD), Charcot-Marie-Tooth disease (CMT), chronic obstructive pulmonary disease (COPD), McArdle disease, hypothyroidism, testosterone deficiency syndrome (TD), heart failure and anaemia.

[0220] Furthermore, the invention provides a method of treating or preventing sarcopenic obesity, Duchenne muscular dystrophy (DMD), Charcot-Marie-Tooth disease (CMT), chronic obstructive pulmonary disease (COPD), McArdle disease, hypothyroidism, testosterone deficiency syndrome (TD), heart failure and anaemia in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof.

[0221] Non-therapeutic uses

[0222] The methods of reducing body fat whilst preserving lean mass of the invention may be non- therapeutic methods. In other words, dapiglutide or a pharmaceutically acceptable salt thereof may be used for non-therapeutic purposes. In this respect, it may be desirable for a subject to inhibit weight gain, and thereby reduce body fat, despite the subject not being overweight, obese, diabetic or suffering from any other weight-related disease, such as for cosmetic reasons. Administration of dapiglutide may achieve these desired effects (weight loss and / or inhibited weight gain). In such embodiments, administration of dapiglutide would not be therapeutic as no disease or disorder is being treated by dapiglutide.

[0223] Thus, in some embodiments, the method of the invention is a non-therapeutic method.

[0224] In some embodiments, the invention provides a non-therapeutic method of reducing body fat whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0225] In some embodiments, the invention provides a non-therapeutic method of inhibiting weight gain whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject. 219

[0226] In some embodiments, the invention provides a non-therapeutic method for reducing body weight, inhibiting weight gain or promoting weight loss, in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0227] The non-therapeutic nature of certain methods of the invention is particularly pertinent when the subject is of healthy weight (i.e. a subject that is not overweight, obese or morbidly obese). Administration of dapiglutide to a subject of healthy weight, for which there are no therapeutic reasons to reduce body fat, may be a cosmetic (non-therapeutic) method.

[0228] In some embodiments, the invention provides a non-therapeutic method of reducing body fat whilst preserving lean mass in a subject of healthy weight, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0229] In some embodiments, the invention provides a non-therapeutic method of inhibiting weight gain whilst preserving lean mass in a subject of healthy weight, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0230] Healthy weight is defined in the medical field by body mass index (BMI). A BMI of 18.5 to 24.9 corresponds to healthy weight. Thus, in some embodiments of the non-therapeutic methods of the invention, the subject has a Body Mass Index (BMI) of 18.5 to 24.9 corresponding to healthy weight.

[0231] In other words, the subject of a non-therapeutic method of the invention of reducing body or inhibiting weight gain whilst preserving lean mass need not be overweight, obese or morbidly obese.

[0232] Administration of dapiglutide to a subject that is overweight may also be considered a non- therapeutic method, if being overweight is not considered a disease. Hence, in some embodiments, the invention provides a non-therapeutic method of reducing body fat whilst preserving lean mass in an overweight subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0233] In some embodiments, the invention provides a non-therapeutic method of inhibiting weight gain whilst preserving lean mass in an overweight subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject. A BMI of 25.0 to 29.9 corresponds to overweight. Thus, in some embodiments of the non- therapeutic methods of the invention, the subject has a Body Mass Index (BMI) of 25.0 to 29.9 corresponding to overweight.

[0234] In other words, the subject of a non-therapeutic method of the invention of reducing body or inhibiting weight gain whilst preserving lean mass need not be obese or morbidly obese.

[0235] Considerations regarding dapiglutide as outlined herein apply equally when the dapiglutide is used for therapeutic and non-therapeutic purposes.

[0236] Reduced body weight

[0237] In some embodiments, the subject has reduced body weight following administration of dapiglutide. In some embodiments, following administration of dapiglutide the body weight of the subject is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40%.

[0238] In some embodiments, following administration of dapiglutide the body weight of the subject is reduced by about 1% to about 15%, such as by about 1% to about 4%, about 1% to about 3%, about 3% to about 7%, about 5% to about 7%, about 5% to about 10%, about 5% to about 11 %, or about 5% to about 15%.

[0239] In some embodiments, following administration of dapiglutide the body weight of the subject is reduced by at least about 1% to about 15%, such as by at least about 1% to about 4%, at least about 1% to about 3%, at least about 3% to about 7%, at least about 5% to about 7%, at least about 5% to about 10%, at least about 5% to about 11%, or at least about 5% to about 15%.

[0240] In some embodiments, the subject has reduced body mass index (BMI) following administration of dapiglutide. In some embodiments, following administration of dapiglutide the BMI of the subject is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40%. BMI is calculated for human subjects by dividing the weight of the subject in kilograms by the square of the height of the subject in metres. 219

[0241] Subject

[0242] As described herein, the invention relates to a method of reducing body fat whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0243] The terms “patient”, “subject” and “individual” may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., bovines and porcines), companion animals (e.g., canines and felines) and rodents (e.g., mice and rats). In a preferred embodiment, the subject is a human subject.

[0244] The body weight of a subject may be referred to using Body Mass Index (BMI), which is calculated for human subjects by dividing the weight of the subject in kilograms by the square of the height of the subject in metres.

[0245] In some embodiments, the subject is obese. In some embodiments, the subject has a BMI of 30.0 to 39.9 kg / m2corresponding to obese.

[0246] In some embodiments, the subject is morbidly obese. In some embodiments, the subject has a BMI of 40.0 kg / m2or higher corresponding to morbidly obese.

[0247] In some embodiments, the subject is of a healthy weight. In other words, in some embodiments, the subject is not overweight, not obese and not morbidly obese. In some embodiments, the subject has a BMI of 18.5 to 24.9 kg / m2corresponding to healthy weight.

[0248] In some embodiments, the subject is overweight. In other words, in some embodiments, the subject is not of a healthy weight, but is not obese and not morbidly obese. In some embodiments, the subject has a BMI of 25.0 to 29.9 kg / m2corresponding to overweight.

[0249] Dosage regime

[0250] According to the invention, dapiglutide or a pharmaceutically acceptable salt thereof is administered to the subject following any appropriate dosage regime, such as any dosage regime described herein.

[0251] The term “dosage regime” (or “dosage regimen”, “dosage protocol” or “treatment protocol”, all of which are used interchangeably herein) refers to the manner in which dapiglutide is administered to the subject, encompassing the dose of dapiglutide administered to the subject at each administration event, the timing of individual administration events (i.e., the interval between administration events) and the mode of administration of dapiglutide to the subject (i.e., the means by which dapiglutide is introduced into the body of the subject). The term “administration event” refers to the introduction of dapiglutide into the body of the subject at a given point in time. For example, an injection of a composition of dapiglutide would be an administration event.

[0252] An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject. Such considerations are known to the skilled person.

[0253] The dosage regime may involve administering more than one dose of dapiglutide. Thus, in some embodiments, dapiglutide is administered to the subject one or more times. In some embodiments, dapiglutide is administered to the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 times. In some embodiments, dapiglutide is administered to the subject 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more times.

[0254] Treatment with dapiglutide may continue for as long as is necessary to obtain the desired reduction of body fat whilst preserving lean mass in the subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0255] In some embodiments, dapiglutide is administered to the subject over a period of weeks or months, or for 1 year or more than 1 year. Dapiglutide may be administered to the subject for a period of, for example, one month to twenty years, for example for a period of one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, eleven years, twelve years, thirteen years, fourteen years, fifteen years, sixteen years, seventeen years, eighteen years, nineteen years or twenty years. In some embodiments, dapiglutide is administered to the subject for the remaining lifetime of the subject.

[0256] In some embodiments, dapiglutide is the only therapeutic agent / active that is administered to the subject. In some embodiments, dapiglutide is the only therapeutic agent / active that is administered to the subject within a 24 hour period. 219

[0257] In some embodiments, dapiglutide is the only peptide therapeutic agent / active that is administered to the subject. In some embodiments, dapiglutide is the only peptide therapeutic agent / active that is administered to the subject within a 24 hour period.

[0258] In some embodiments, the methods of the present invention do not involve co-administration of another non-dapiglutide peptide therapeutic or active. In some embodiments, the methods of the present invention do not involve co-administration of another non-dapiglutide peptide therapeutic or active within a 24 hour period.

[0259] Dose

[0260] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject in a therapeutically effective amount.

[0261] As will be apparent to one skilled in the medical art, a “therapeutically effective amount” will vary depending upon, inter alia, the age, weight and / or gender of the subject (patient) to be treated. Other factors that may be of relevance include the physical characteristics of the specific patient under consideration, the patient’s diet, the nature of any concurrent medication, the particular compound(s) employed, the particular mode of administration, the desired pharmacological effect(s) and the particular therapeutic indication. Because these factors and their relationship in determining this amount are well known in the medical arts, the determination of therapeutically effective dosage levels, the amount necessary to achieve the desired result of reducing body fat whilst preserving lean mass, will be within the ambit of the skilled person.

[0262] As used herein, the term “therapeutically effective amount” refers to an amount which reduces symptoms of a given condition or pathology, or is anticipated to provide prophylactic treatment, reduce the rate of progression or reduce the risk of developing a disorder. Reduction of symptoms or normalization of physiological responses can be determined using methods routine in the art and may vary with a given condition or pathology.

[0263] In some embodiments of the invention, administration of dapiglutide commenced at lower dosage levels, with dosage levels being increased until the desired effect of preventing / treating the relevant medical indication is achieved. This would define a therapeutically effective amount. Dapiglutide may be administered to the subject at any dose suitable to obtain the desired reduction of body fat whilst preserving lean mass in the subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0264] The term “dose” refers to the amount of dapiglutide or pharmaceutically acceptable salt thereof administered to a subject at a given administration event (e.g., a “dose” of 1.0 mg dapiglutide). Depending on the context, the term “dose” may also refer to the administration event perse (i.e. , a single dose formulation) (e.g., the subject being given a “dose” of dapiglutide).

[0265] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 1.0 mg to about 30.0 mg. In other words, in some embodiments, each single dosage formulation administered to the subject comprises about 1.0 mg to about 30.0 mg of dapiglutide or the pharmaceutically acceptable salt thereof.

[0266] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 1.0 mg to about 30.0 mg, about 5.0 mg to about 30.0 mg, about 7.5 mg to about 30.0 mg, about 10.0 mg to about 30.0 mg, about 13.0 mg to about 30.0 mg, about 15.0 mg to about 30.0 mg, about 20.0 mg to about 30.0 mg, about 25.0 mg to about 30.0 mg, about 1.0 mg to about 25.0 mg, about 5.0 mg to about 25.0 mg, about 7.5 mg to about 25.0 mg, about 10.0 mg to about 25.0 mg, about 13.0 mg to about 25.0 mg, about 15.0 mg to about 25.0 mg, about 20.0 mg to about 25.0 mg, about 1.0 mg to about 20.0 mg, about 5.0 mg to about 20.0 mg, about 7.5 mg to about 20.0 mg, about 10.0 mg to about 20.0 mg, about 13.0 mg to about 20.0 mg, about 15.0 mg to about 20.0 mg, about 1.0 mg to about 15.0 mg, about 5.0 mg to about 15.0 mg, about 10.0 mg to about 15.0 mg, about 1.0 mg to about 10.0 mg, or about 5.0 mg to about 10.0 mg.

[0267] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 7.5 mg to about 26.0 mg, about 10.0 mg to about 26.0 mg, or about 13.0 mg to about 26.0 mg.

[0268] Preferably, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 5.0 mg to about 30.0 mg, such as about 10.0 mg to about 30.0 mg, or about 5.0 mg to about 25 mg, such as about 5.0 mg to about 20.0 mg, or about 10.0 mg to about 25.0 mg, such as about 10.0 mg to about 20.0 mg. 219

[0269] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, about 16.0 mg, about 17.0 mg, about 18.0 mg, about 19.0 mg, about 20.0 mg, about 21.0 mg, about 22.0 mg, about 23.0 mg, about 24.0 mg, about 25.0 mg, about 26.0 mg, about 27.0 mg, about 28.0 mg, about 29.0 mg, or about 30.0 mg.

[0270] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 7.5 mg, about 10.0 mg, about 13.0 mg, about 20.0 mg, or about 26.0 mg.

[0271] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of at least about 1.0 mg, at least about 2.0 mg, at least about 2.25 mg, at least about 3.0 mg, at least about 4.0 mg, at least about 5.0 mg, at least about 6.0 mg, at least about 7.0 mg, at least about 8.0 mg, at least about 9.0 mg, or at least about 10.0 mg.

[0272] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of up to about 10.0 mg, up to about 15.0 mg, up to about 20.0 mg, up to about 25.0 mg, up to about 26.0 mg, or up to about 30.0 mg.

[0273] In some embodiments, the dose of dapiglutide is the same, or substantially the same, at each administration. In other words, in some embodiments, dapiglutide is administered at the same dose each time. In other embodiments, the dose of dapiglutide may differ at each administration. Typically, dapiglutide is administered at the same dose at each administration but this is not a requirement.

[0274] Titration

[0275] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject following a titration protocol.

[0276] The term “titration protocol” means that dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject in a series of ascending doses (i.e., starting from a low dose and increasing to progressively higher doses) until a final treatment dose is reached, after which the subject continues with treatment at the treatment dose. A first purpose of following a titration protocol may be to determine an appropriate dose of dapiglutide for the subject. The increasing dose of dapiglutide allows a physician to observe side effects at different doses and thereby determine an appropriate dose for treatment.

[0277] A second purpose of following a titration protocol may be to acclimatise the subject to any side effects of dapiglutide. Initial administration of dapiglutide may produce side effects which decrease in severity after further administrations as the subject adapts. Administering dapiglutide at a lower dose according to the titration protocol may curtail the initial severity of these side effects.

[0278] Thus, in some embodiments, dapiglutide is administered to the subject in ascending doses. In some embodiments, dapiglutide is administered to the subject following an ascending dose protocol. In some embodiments, dapiglutide is administered to the subject following an up-titration protocol. An “up-titration protocol” refers to administering dapiglutide in progressively increasing doses, as described herein, and contrasts with “down-titration”, wherein the dose is progressively decreased.

[0279] The dose of dapiglutide or the pharmaceutically acceptable salt thereof administered to the subject according to the titration protocol may be any dose described herein. Likewise, the treatment dose of dapiglutide or the pharmaceutically acceptable salt thereof (i.e., the dose administered to the subject for a prolonged period following up-titration, to achieve reduced body weight) may be any dose described herein.

[0280] Timing of administration

[0281] Dapiglutide may be administered to the subject at any interval suitable to achieve the desired reduction of body fat whilst lean mass is preserved.

[0282] Dapiglutide may furthermore be administered to the subject at any interval suitable to achieve treatment of a disease or disorder selected from inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes, metabolic syndrome, obesity, morbid obesity, obesity-linked gallbladder disease or obesity-induced sleep apnoea, or to achieve reduction of body weight, inhibition of weight gain or promotion of weight loss, wherein body fat is reduced whilst lean mass is preserved in the subject.

[0283] In preferred embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject about once weekly. 219

[0284] The term “week” means approximately 7 days, such as approximately 5, 5.5, 6. 6.5, 7, 7.5, 8, 8.5 or 9 days with each “day” being counted as approximately a 24 hour period. In some embodiments, “week” means 7 days ±2 days. That is to say, the administration may take place either up to and including two days before, or up to and including two days after the stated day. As such, the administration may take place 2 or 1 days before, or 1 or 2 days after, the stated day. In preferred embodiments, administration takes place once every 7thday.

[0285] Mode of administration

[0286] Dapiglutide or a pharmaceutically acceptable salt thereof may be administered to the subject by any mode of administration common or standard in the art.

[0287] The term “mode of administration” refers to the means or route by which dapiglutide is administered to the subject.

[0288] Thus, in some embodiments, dapiglutide or the pharmaceutically acceptable salt is administered to the subject by parenteral injection such as subcutaneous injection, intravenous injection or intramuscular injection. In some embodiments, dapiglutide or the pharmaceutically acceptable salt may be administered to the subject by other routes of administration such as by the, oral, sublingual, transdermal, intranasal or rectal route.

[0289] In preferred embodiments, dapiglutide or the pharmaceutically acceptable salt is administered to the subject by subcutaneous injection.

[0290] Composition

[0291] Dapiglutide or the pharmaceutically acceptable salt thereof may be formulated as a composition or pharmaceutical composition for storage or administration.

[0292] Thus, in some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is in the form of a composition comprising dapiglutide or the pharmaceutically acceptable salt thereof in admixture with a carrier.

[0293] In some embodiments, the composition is a pharmaceutical composition, and the carrier is a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient or vehicle.

[0294] In some embodiments, the pharmaceutical composition is a solution for injection. In some embodiments, the pharmaceutical composition is a liquid for injection. In some embodiments, the pharmaceutical composition is a liquid for infusion.

[0295] In some embodiments, the pharmaceutical composition is formulated for parenteral injection. Preferably, the pharmaceutical composition is formulated for subcutaneous injection.

[0296] Definitions

[0297] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0298] All patents, published patent applications and non-patent publications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0299] The singular forms “a”, “an”, and “the” as used herein include the plurals unless the context clearly dictates otherwise.

[0300] The terms “comprising”, “comprises” and “comprised of” as used herein are synonymous with “including”, “includes” or “containing”, “contains”, and are inclusive or open-ended and do not exclude additional, non-recited features. The terms “comprising”, “comprises” and “comprised of” also include the term “consisting of”. The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” may be used interchangeably.

[0301] When referring to an increase or decrease that includes a range of values, e.g., “increases by about 1 % to about 10%”, it will be understood from the context that the increase / decrease achieved is a single value selected from a range of possible values that fall within the defined range. That is - in this example - the increase is not from about 1 % to about 10%; the range does not represent the temporal change of a measured value.

[0302] Each embodiment of the invention described herein may be taken alone or in combination with one or more other embodiments of the invention. 219

[0303] The invention will now be further described by way of Examples, which are meant to serve to assist one of ordinary skill in the art in carrying out the invention and are not intended in any way to limit the scope of the invention.

[0304] EXAMPLES

[0305] The following examples are provided to illustrate preferred aspects of the invention and are not intended to limit the scope of the invention.

[0306] Example 1 :

[0307] Phase 1 Multiple Ascending Dose (MAD) trial

[0308] The data presented here originate from a randomised, multiple ascending dose trial assessing safety, tolerability, pharmacokinetics and pharmacodynamics of dapiglutide administered in subjects with overweight or obesity (Clinical trial No. NCT06000891). Dapiglutide was referred to in the trial as “ZP7570”. The trial was divided into Part 1 and Part 2.

[0309] The overall purpose of this trial was to evaluate the safety and tolerability when applying dose titration of ascending doses of dapiglutide and at steady state.

[0310] In Part 1 a dose range of 2.5 to 13 mg dapiglutide was tested with once-weekly dosing over a 13-week period with dose up-titration regime every 2ndweek until the maintenance dose was reached (Figure 1a).

[0311] Part 2 was conducted with a titration scheme up to 26 mg once-weekly dosing over a 28- week period with up-titration every 4thweek (Figure 1b).

[0312] Objectives of the study:

[0313] The study had the main objective to evaluate the safety and tolerability of dapiglutide administered as multiple subcutaneous (s.c.) injections in overweight and obese but otherwise healthy subjects in order to identify the maximum tolerated dose with the applied dose up-titration regimen.

[0314] Secondary objectives were to investigate the PK properties of dapiglutide after multiple s.c. doses in overweight and obese subjects and to assess the PD response to dapiglutide on body weight after multiple s.c. doses in overweight and obese subjects.

[0315] Explorative and other objectives included assessment of body weight and body composition. Trial design:

[0316] The trial was Phase 1, single-center, randomised and double-blind within cohorts, placebo controlled, sequential multiple ascending dose trial in a semi-parallel design in overweight and obese but otherwise healthy subjects.

[0317] The Part 1 trial included three cohorts. Subjects were randomised to dapiglutide or placebo (randomisation ratio 14:4) within each cohort where the observational period was 18 weeks for all cohorts.

[0318] In Part 2, subjects were randomized to dapiglutide or placebo with the randomization ratio 2:1 and an observation period of 33 weeks.

[0319] Trial population:

[0320] Overweight and obese, but otherwise healthy subjects aged 18-64 years, with normal kidney and liver function and without history for gastrointestinal diseases including functional complaints.

[0321] Interventions:

[0322] All subjects in Part 1 were dosed for 13 weeks with ascending weekly doses of dapiglutide at dose levels ranging from 2.5 mg to 13 mg, or with corresponding volume of placebo. Doses were up titrated every second week.

[0323] All subjects in Part 2 were dosed for 28 weeks with ascending weekly doses of dapiglutide at dose levels ranging from 3 mg to 26 mg, or with corresponding volume of placebo. Doses were up titrated every fourth week.

[0324] Table 1: Interventions

[0325] Inclusion criteria:

[0326] 1. Signed and dated informed consent obtained before any trial-related activities. Trial- related 219 activities are any procedures that would not have been done during normal management of the subject

[0327] 2. Male subject or female subject of non-child-bearing potential.

[0328] 3. Age between 18 and 64 years, both inclusive.

[0329] 4. Body Mass Index (BMI) between 27.0 and 39.9 kg / m2, both inclusive.

[0330] 5. Body weight of at least 60 kg at screening

[0331] 6. Stable body weight + / - 5% for at least 3 months prior to screening as reported by subject

[0332] 7. No major changes in exercise or diet habits within 3 months prior to the trial and willing to maintain the usual diet and exercise pattern at baseline throughout the trial

[0333] 8. HbA1c <6.5%

[0334] 9. Heart rate after at least 5 minutes rest in supine position inside the range of 45-90 beats / min.

[0335] 10. In overall good health according to age (medical history, physical and neurological examination, vital signs, and laboratory assessments), as judged by the investigator at screening.

[0336] 11. Have venous access sufficient to allow cannulation for blood sampling as required by the protocol.

[0337] 12. Able and willing to comply with all trial procedures.

[0338] 13. Willing to limit the regular average intake of alcohol to 24 g daily for men and 12 g daily for women throughout the trial and no intake within 24 hours before visits.

[0339] Pharmaceutical formulation:

[0340] Table 2: Dapiqlutide pharmaceutical formulation for s.c. dosing

[0341] Body composition measurements

[0342] Subjects underwent body composition assessment by way of non-invasive air displacement plethysmography (BOD POD® measurement system, COSMED, Rome, Italy). The device utilizes whole body densitometry to estimate the amount of fat mass and fat free mass in the body. Whole body densitometry is based on the calculation of body density by measuring body mass and volume. Body mass is measured using an electronic scale, and body density is measured in a fiberglass test chamber. The following parameters were measured: body volume (I), body density (kg / l), fat mass (kg), fat free mass (kg), % fat and % fat free mass. The subjects were undergoing the measurement of body composition wearing tight underwear or bathing gear with a swim cap, if necessary.

[0343] MAD trial Part 1 (Cohort 1-3)

[0344] Table 3: Demography - Randomised and exposed

[0345] Safety:

[0346] Thirteen weeks of treatment with dapiglutide maintenance doses up to 13.0 mg was safe and well tolerated with GIAEs (Gastro Intestinal Adverse Events) as expected for GLP-1 and GLP-2 therapy with by-weekly up titration.

[0347] Most frequently reported TEAEs (Treatment Emergent Adverse Events) by dapiglutide treated participants (>10 subject overall) were nausea, decreased appetite, headache, vomiting, eructation, diarrhoea, dyspepsia and nasopharyngitis.

[0348] Weight loss and body composition: 219

[0349] Body composition measurements were performed at day -1, 92 and 127 (follow-up visit). If scheduled on the same day, measurements were performed prior to MTM assessments.

[0350] Table 4 shows the observed mean change in overall body weight, based on the Per-Protocol Analysis Set (PPAS) which includes all subjects of the Full Analysis Set (FAS) who completed the trial without any important protocol deviations and who followed the planned dose scheme. (FAS is based on the intention-to-treat principle and includes all randomized subjects).

[0351] Body composition is divided into the body mass categories of fat mass and lean mass (also called fat-free mass). The loss of fat mass is shown in Table 5a and 5b, while the loss of lean mass is shown in Table 6a and 6b.

[0352] The % change (in body weight, body fat or lean mass) shown in Tables 4, 5a, 5b, 6a, 6b, 8, 9a, 9b, 10 and 10b is the mean of the % changes of individual participants. In other words, the % change shown in Tables 4, 5a, 5b, 6a, 6b, 8, 9a, 9b, 10 and 10b was determined by first determining the % change of each individual participant over the relevant period, and then calculating the mean of those % changes.

[0353] Data for cohorts 1-3 are based on the Per-Protocol Analysis Set (PPAS) which includes all subjects of the Full Analysis Set (FAS) who completed the trial without any important protocol deviations and who followed the planned dose scheme. (FAS is based on the intention-to-treat principle and includes all randomized subjects).

[0354] Table 4: Body weight measurement (kg), per-protocol analysis set (PPAS), derived from Bod pod.

[0355] (*)Planned maintenance dose level, subjects of cohort 1-3 receiving placebo are pooled.

[0356] Table 4 shows that for all maintenance doses of dapiglutide (7.5 mg, 10.0 mg and 13.0 mg) a greater decrease in body weight was observed compared to placebo.

[0357] Table 5a: Body fat, weight (kg), per-protocol analysis set (PPAS)

[0358] (*)Planned maintenance dose level, subjects of cohort 1-3 receiving placebo are pooled.

[0359] Table 5a shows that the weight of body fat decreased by up to about 15% from baseline to week 13 in subjects treated with dapiglutide. The weight of body fat was still reduced at the 18 weeks follow-up visit.

[0360] Table 5b: Body fat, change in proportion of total body weight (%BF), per- protocol analysis set (PPAS) 219

[0361] (*)Planned maintenance dose level, subjects of cohort 1-3 receiving placebo are pooled.

[0362] Table 5b shows that the proportion of body fat (%BF) decreased from baseline to week 13 in subjects treated with dapiglutide and was still reduced at the 18 weeks follow-up visit.

[0363] Table 6a: Lean body mass, weight (kg), per-protocol analysis set (PPAS)

[0364] (*)Planned maintenance dose level, subjects of cohort 1-3 receiving placebo are pooled.

[0365] Table 6a shows that the weight of lean (fat-free) body mass remained stable throughout the study period. Table 6b: Lean body mass, change in proportion of total body weight (%LM), per-protocol analysis set (PPAS)

[0366] (*)Planned maintenance dose level, subjects of cohort 1-3 receiving placebo are pooled. Table 6b shows that the proportion of lean (fat-free) body mass (%LM) was increasing from baseline to week 13 in subjects treated with dapiglutide. The proportion of lean body mass (%LM) was still increased at 18 weeks follow-up visit.

[0367] MAD trial Part 2 (Cohort 4) Table 7: Demography - Randomised and exposed 219

[0368] Safety:

[0369] Dapiglutide treatment with doses up to 20 mg was assessed to be safe and well-tolerated with gastrointestinal adverse events consistent with the profile reported with other incretinbased therapies. Limited data is available for doses above 20 mg due to early termination of the trial.

[0370] Most frequently reported TEAEs (by dapiglutide treated participants (>5 subjects overall) were injection site reaction, dyspepsia, nausea, nasopharyngitis, vomiting, headache, decreased appetite, diarrhoea, constipation and eructation.

[0371] Weight loss and body composition:

[0372] Body composition measurements were performed at day -1 (base line) day 197 and day 232 (follow-up visit). If scheduled on the same day, measurements were performed prior to MTM assessments.

[0373] Body composition is divided into the body mass categories of fat mass and lean mass (also called fat-free mass). The loss of fat mass is shown in Table 9a and 9b, while the loss of lean mass is shown in Table 10a and 10b. The mean change in overall body weight is shown in Table 8.

[0374] Data for Cohort 4 are based on the Full Analysis Set (FAS) which is based on the intention- to-treat principle and includes all randomized subjects).

[0375] Because of technical issues, the study was terminated early for some of the subjects, who were thus not up titrated to the 26 mg dose. Furthermore, some subjects chose to stay on a lower dose throughout the study.

[0376] Despite the variation in doses, the weight loss and body composition data from Part 2 confirms the data from Part 1.

[0377] Table 8: Body weight measurement (kg), full analysis set (FAS), derived from Bod Pod.

[0378] Table 8 shows that for patients treated with dapiglutide, a greater decrease in body weight was observed compared to patients treated with placebo. Table 9a: Body fat, weight (kg), full analysis set (FAS)

[0379] Table 9a shows that the weight of body fat decreased by about 28% from baseline to week 28 in subjects treated with dapiglutide. The weight of body fat was still reduced at the 33 weeks follow-up visit.

[0380] Table 9b: Body fat, change in proportion of total body weight (%BF), full analysis set (FAS) 219

[0381] Table 9b shows that the proportion of body fat (%BF) decreased from baseline to week 28 in subjects treated with dapiglutide and was still reduced at the 33 weeks follow-up visit. Table 10a: Lean body mass, weight (kg), full analysis set (FAS)

[0382] Table 10a shows that the weight of lean (fat-free) body mass remained stable throughout the study period. Table 10b: Lean body mass, change in lean mass composition (%LM), full analysis set

[0383]

[0384] Table 10b shows that the proportion of lean mass (%LM) increased from baseline to week 28 in subjects treated with dapiglutide. The proportion of lean body mass (%LM) was still increased at the 33 weeks follow-up visit.

[0385] 219

[0386] CLAUSES

[0387] 1. A method of reducing body fat whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0388] 2. The method according to clause 1 , wherein the method is a non-therapeutic method.

[0389] 3. The method according to clause 1 or clause 2, wherein the method is for reducing body weight, inhibiting weight gain or promoting weight loss, in a subject.

[0390] 4. The method according to clause 1, wherein the method is for treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome.

[0391] 5. The method according to clause 1, wherein the method is for treating or preventing one or more disease or disorder and wherein the disease or disorder is a comorbid condition associated with or caused by overweight or obesity.

[0392] 6. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain or promoting weight loss, in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0393] 7. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes, pre-diabetes or metabolic syndrome, in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0394] 8. Dapiglutide or a pharmaceutically acceptable salt thereof for the use according to clause 6 or clause 7, wherein the method is for treating one or more disease or disorder selected from overweight, overweight in the presence of at least one weight related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity- induced sleep apnoea.

[0395] 9. Dapiglutide or a pharmaceutically acceptable salt thereof for the use according to clause 6, wherein the method is for treating one or more disease or disorder selected from, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome.

[0396] 10. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of reducing body weight, inhibiting weight gain, or promoting weight loss in a subject, wherein the method reduces body fat whilst preserving lean mass in the subject, and wherein the method comprises administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0397] 11. The method according to any of clauses 1-5, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-10, wherein the proportion of the total body weight of the subject that is body fat (%BF) is reduced by an absolute change of at least about 1 %BF, such as by an absolute change of at least about 1.5 %BF, such as at least about 2 %BF, such as at least about 2.5 %BF, such as at least about 3 %BF, at least about 4 %BF, at least about 5 %BF, at least about 6 %BF, at least about 7 %BF, at least about 8 %BF, at least about 9 %BF, at least about 10 %BF, at least about 15 %BF, at least about 20 %BF, at least about 25 %BF, at least about 30 %BF, at least about 40 %BF, or at least about 50 %BF.

[0398] 12. The method according to any of clauses 1-5, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-10, wherein the proportion of the total body weight of the subject that is body fat (%BF) is reduced by a % change of at least about 1 %, such as by a % change of at least about 1.5%, such as at least about 2%, such as at least about 2.5%, such as at least about 3%, at least about 4%, at least about 219

[0399] 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or at least about 50%.

[0400] 13. The method according to any of clauses 1-5 and 11-12, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-12, wherein the body fat of the subject is reduced over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years; preferably the body fat of the subject is reduced over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

[0401] 14. The method according to any of clauses 1-5 and 11-13, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-13, wherein the method is a method of reducing body fat whilst preserving muscle in the subject.

[0402] 15. The method according to any of clauses 1-5 and 11-14, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-14, wherein the method is a method of inhibiting gain of body fat whilst preserving muscle in the subject.

[0403] 16. The method according to any of clauses 1-5 and 11-15, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-15, wherein the method increases the ratio of lean mass to body fat in the subject.

[0404] 17. The method according to any of clauses 1-5 and 11-16, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-16, wherein the method increases the ratio of muscle to body fat in the subject.

[0405] 18. The method according to any of clauses 1-5 and 11-17, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-17, wherein the lean mass of the subject is reduced insignificantly, or does not change, or increases.

[0406] 19. The method according to any of clauses 1-5 and 11-18, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-18, wherein the weight of lean mass of the subject is reduced insignificantly, or does not change, or increases over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years; preferably, the weight of lean mass of the subject is reduced insignificantly, or does not change, or increases over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

[0407] 20. The method according to any of clauses 1-5 and 11-19, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-19, wherein the weight of lean mass of the subject is reduced by less than about 3%, such as less than about 2%, such as less than about 1%, such as by about 0%.

[0408] 21. The method according to any of clauses 1-5 and 11-20, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-20, wherein the weight of lean mass of the subject is reduced by less than about 3%, such as less than about 2%, such as less than about 1% over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years; preferably over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

[0409] 22. The method according to any of clauses 1-5 and 11-17, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-17; wherein the proportion of the total body weight of the subject that is lean mass (%LM) is increased by an absolute change of at least about 1.0 %LM, at least about 1.5 %LM, at least about 2.0 %LM, at least about 2.5 %LM, at least about 3.0 %LM, at least about 3.5 %LM, at least about 4.0 %LM, at least about 4.5 %LM, at least about 5.0 %LM, at least about 5.5 %LM, at least about 6.0 %LM, at least about 6.5 %LM, at least about 7.0 %LM, at least about 7.5 %LM, at least about 8.0 %LM, at least about 8.5 %LM, at least about 9.0 %LM, at least about 9.5 %LM, at least about 10.0 %LM, at least about 11.0 %LM, at least about 12 %LM, at least about 13 %LM, at least about 14 %LM, at least about 15 %LM, at least about 16 %LM, at least about 17 %LM, at least about 18 %LM, at least about 19 %LM, or at least about 20.0 %LM, at least about 25 %LM, at least about 30 %LM, at least about 40 %LM, or at least about 50 %LM. 219

[0410] 23. The method according to any of clauses 1-5 and 11-17, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-17; wherein the proportion of the total body weight of the subject that is lean mass (%LM) increases by a % change of at least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 3.0%, at least about 3.5%, at least about 4.0%, at least about 4.5%, at least about 5.0%, at least about 5.5%, at least about 6.0%, at least about 6.5%, at least about 7.0%, at least about 7.5%, at least about 8.0%, at least about 8.5%, at least about 9.0%, at least about 9.5%LM, at least about 10.0%, at least about 11.0%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20.0%, at least about 25%, at least about 30%, at least about 40%, or at least about 50%.

[0411] 24. The method according to any of clauses 1-5 and 11-16 and 22-23, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-16 and 22-23; wherein the lean mass of the subject increases over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years, preferably the lean mass of the subject increases over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

[0412] 25. The method according to any of clauses 1-5 and 11-24, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-24, wherein the subject has a body mass index (BMI) of 25.0 to 29.9 kg / m2corresponding to overweight, a BMI of 30.0 to 39.9 kg / m2corresponding to obese, or a BMI of 40.0 kg / m2or higher corresponding to morbidly obese.

[0413] 26. The method according to any of clauses 1-5 and 11-25, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-25, wherein the subject has a body mass index (BMI) of 18.5 to 24.9 kg / m2corresponding to healthy weight.

[0414] 27. The method according to any of clauses 1-5 and 11-26, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-26, wherein dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject following a titration protocol. 28. The method according to any of clauses 1-5 and 11-27, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-27, wherein dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject about once weekly.

[0415] 29. The method according to any of clauses 1-5 and 11-28, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-28, wherein dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 1.0 mg to about 30.0 mg, about 5.0 mg to about 30.0 mg, about

[0416] 7.5 mg to about 30.0 mg, about 10.0 mg to about 30.0 mg, about 13.0 mg to about 30.0 mg, about 15.0 mg to about 30.0 mg, about 20.0 mg to about 30.0 mg, about 25.0 mg to about 30.0 mg, about 1.0 mg to about 25.0 mg, about 5.0 mg to about 25.0 mg, about 7.5 mg to about 25.0 mg, about 10.0 mg to about 25.0 mg, about 13.0 mg to about 25.0 mg, about 15.0 mg to about 25.0 mg, about 20.0 mg to about 25.0 mg, about 1.0 mg to about 20.0 mg, about 5.0 mg to about 20.0 mg, about 7.5 mg to about 20.0 mg, about 10.0 mg to about 20.0 mg, about 13.0 mg to about 20.0 mg, about 15.0 mg to about 20.0 mg, about 1.0 mg to about 15.0 mg, about 5.0 mg to about 15.0 mg, about 10.0 mg to about 15.0 mg, about 1.0 mg to about 10.0 mg, or about 5.0 mg to about 10.0 mg.

[0417] 30. The method according to any of clauses 1-5 and 11-29, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-29, wherein dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about

[0418] 6.5 mg, about 7.0 mg, about 7.5 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, about 16.0 mg, about 17.0 mg, about 18.0 mg, about 19.0 mg, about 20.0 mg, about 21.0 mg, about 22.0 mg, about 23.0 mg, about 24.0 mg, about 25.0 mg, about 26.0 mg, about 27.0 mg, about 28.0 mg, about 29.0 mg, or about 30.0 mg.

[0419] 31. The method according to any of clauses 1-5 and 11-30, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-30, wherein dapiglutide or the pharmaceutically acceptable salt is administered to the subject by parenteral injection, such as subcutaneous injection, intravenous injection or intramuscular injection, or by oral, sublingual, intranasal or rectal route, preferably wherein dapiglutide or the pharmaceutically acceptable salt is administered to the subject by subcutaneous injection. 219

[0420] 32. The method according to any of clauses 1-5 and 11-31 , or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-29, wherein dapiglutide or the pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition comprising dapiglutide or the pharmaceutically acceptable salt thereof in admixture with a carrier, preferably wherein the composition is a pharmaceutical composition, and the carrier is a pharmaceutically acceptable carrier.

[0421] 33. The method according to clause 32, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to clause 32, wherein the pharmaceutical composition is formulated for parenteral injection, preferably subcutaneous injection.

[0422] 34. The method according to any of clauses 1-5 and 11-33, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-33, wherein dapiglutide is administered by parenteral injection, preferably subcutaneous injection, and wherein dapiglutide is administered to the subject once weekly in a dosage of about 5.0 mg to about 30.0 mg, such as about 10.0 mg to about 30.0 mg, or about 5.0 mg to about 25 mg, such as about 5.0 mg to about 20.0 mg, or about 10.0 mg to about 25.0 mg.

[0423] 35. Use of dapiglutide in the manufacture of a medicament for a method of reducing body fat whilst preserving lean mass in a subject in need thereof.

[0424] 36. The use according to clause 35, wherein the method is a non-therapeutic method.

[0425] 37. The use according to any of clauses 35-36, wherein the method is for reducing body weight, inhibiting weight gain or promoting weight loss, in the subject.

[0426] 38. The use according to clause 35, wherein the method is for treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, in the subject.

[0427] 39. The use according to any of clauses 35 to 38, wherein the method is as defined in any one of clauses 1 to 34. 40. The method according to any of clauses 1-5 and 11-34, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-34, with the proviso that dapiglutide is not co-administered together with an apelin receptor agonist.

[0428] 41. The method according to any of clauses 1-5 and 11-34, or dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of clauses 6-34, with the proviso that dapiglutide is the only active compound administered to the subject for reducing body fat whilst preserving lean mass in said subject.

Claims

CLAIMS1. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing one or more disease or disorder selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes, pre-diabetes and / or metabolic syndrome, or of reducing body weight, inhibiting weight gain or promoting weight loss, in a subject; wherein the method reduces body fat whilst preserving lean mass in the subject; the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

2. Dapiglutide or a pharmaceutically acceptable salt thereof for the use according to claim 1, wherein the method is for treating one or more disease or disorder selected from overweight, overweight in the presence of at least one weight-related comorbid condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, dyslipidaemia, diabetes, pre-diabetes and / or metabolic syndrome, optionally wherein the diabetes is type 2 diabetes.

3. A method of reducing body fat whilst preserving lean mass in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

4. The method according to claim 3, wherein the method is for reducing body weight, inhibiting weight gain or promoting weight loss, in a subject.

5. The method according to claim 3 or claim 4, wherein the method is a non-therapeutic method.

6. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to claim 1 or claim 2, or the method according to any of claims 3-5, wherein the proportion of the total body weight of the subject that is body fat (%BF) is reduced by an absolute change of at least about 1 %BF such as at least about 1.5 %BF, such as at least about 2 %BF, such as at least about 2.5 %BF, such as at least about 3 %BF, at least about 4 %BF, at least about 5 %BF, at least about 6 %BF, at least about 7 %BF, at least about 8 %BF, at least about 9 %BF, at least about 10 %BF, at least about 15 %BF, at least about 20 %BF, at least about25 %BF, at least about 30 %BF, at least about 40 %BF, or at least about 50 %BF; over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years, preferably the body fat of the subject is reduced over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

7. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of claims 1 , 2 and 6, or the method according to any of claims 3-6, wherein the proportion of the total body weight of the subject that is body fat (%BF) is reduced by a % change of at least about 1%, such as by a % change of at least about 1.5%, such as at least about 2%, such as at least about 2.5%, such as at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or at least about 50%; over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years, preferably a period of at least 3 months, such as at least 4 months or at least 13 weeks.

8. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of claims 1 , 2, 6 and 7, or the method according to any of claims 3-7, wherein the weight of lean mass of the subject is reduced by a percentage change of less than about 3%, such as less than about 2%, such as less than about 1%; over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years, preferably over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

9. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of claims 1 , 2, and 6-8, or the method according to any of claims 3-8; wherein the proportion of the total body weight of the subject that is lean mass (%LM) is increased by an absolute change of at least about 1.0 %LM, at least about 1.5 %LM, at least about 2.0 %LM, at least about 2.5 %LM, at least about 3.0 %LM, at least about 3.5 %LM, at least about 4.0 %LM, at least about 4.5 %LM, at least about 5.0 %LM, at least about 5.5 %LM, at least about 6.0 %LM, at least about 6.5 %LM, at least about 7.0 %LM, at least about 7.5 %LM, at least about 8.0 %LM, at least about 8.5 %LM, at least about 9.0 %LM, at least about 9.5 %LM, atleast about 10.0 %LM, at least about 11.0 %LM, at least about 12 %LM, at least about 13 %LM, at least about 14 %LM, at least about 15 %LM, at least about 16 %LM, at least about 17 %LM, at least about 18 %LM, at least about 19 %LM, or at least about 20.0 %LM, at least about 25 %LM, at least about 30 %LM, at least about 40 %LM, or at least about 50 %LM; over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years, preferably over a period of at least 3 months, such as at least 4 months or at least 13 weeks..

10. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of claims 1 , 2, and 6-9, or the method according to any of claims 3-9, wherein the proportion of the total body weight of the subject that is lean mass (%LM) increases by a % change of at least about 1.0%, at least about 1.5%, at least about 2.0%, at least about 2.5%, at least about 3.0%, at least about 3.5%, at least about 4.0%, at least about 4.5%, at least about 5.0%, at least about 5.5%, at least about 6.0%, at least about 6.5%, at least about 7.0%, at least about 7.5%, at least about 8.0%, at least about 8.5%, at least about 9.0%, at least about 9.5%LM, at least about 10.0%, at least about 11.0%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20.0%, at least about 25%, at least about 30%, at least about 40%, or at least about 50%; over a period selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 30 days, about 1 month, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, about 2 years, about 5 years or about 10 years, preferably over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

11. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of claims 1, 2, and 6-10, or the method according to any of claims 3-10, wherein dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject(a) following a titration protocol;(b) about once weekly; and / or(c) at a dose of about 1.0 mg to about 30.0 mg, about 5.0 mg to about 30.0 mg, about 7.5 mg to about 30.0 mg, about 10.0 mg to about 30.0 mg, about 13.0 mg to about 30.0 mg, about 15.0 mg to about 30.0 mg, about 20.0 mg to about 30.0 mg, about 25.0 mg to about 30.0 mg, about 1.0 mg to about 25.0 mg, about 5.0 mg to about 25.0 mg, about 7.5 mg to about 25.0 mg, about 10.0 mg to about 25.0 mg, about 13.0 mg to about 25.0 mg, about 15.0 mg to about 25.0 mg, about 20.0 mg to about 25.0 mg, about 1.0 mg to about 20.0 mg, about 5.0 mg to about 20.0 mg, about 7.5 mg to about 20.0 mg, about 10.0 mg to about 20.0mg, about 13.0 mg to about 20.0 mg, about 15.0 mg to about 20.0 mg, about 1.0 mg to about 15.0 mg, about 5.0 mg to about 15.0 mg, about 10.0 mg to about 15.0 mg, about 1.0 mg to about 10.0 mg, or about 5.0 mg to about 10.0 mg.

12. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of claims 1, 2, and 6-11, or the method according to any of claims 3-11 , wherein dapiglutide or the pharmaceutically acceptable salt is administered to the subject by parenteral injection, such as subcutaneous injection, intravenous injection or intramuscular injection, or by oral, sublingual, intranasal or rectal route, preferably wherein dapiglutide or the pharmaceutically acceptable salt is administered to the subject by subcutaneous injection.

13. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of claims 1, 2, and 6-12, or the method according to any of claims 3-12, wherein dapiglutide or the pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition comprising dapiglutide or the pharmaceutically acceptable salt thereof in admixture with a carrier, preferably wherein the composition is a pharmaceutical composition, and the carrier is a pharmaceutically acceptable carrier.

14. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to claim 13, or the method according to claim 13, wherein the pharmaceutical composition is formulated for parenteral injection, preferably subcutaneous injection.

15. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of claims 1, 2, and 6-14, or the method according to any of claims 3-14, wherein dapiglutide is administered by parenteral injection, preferably subcutaneous injection, and wherein dapiglutide is administered to the subject once weekly in a dosage of about 5.0 mg to about 30.0 mg, such as about 10.0 mg to about 30.0 mg, or about 5.0 mg to about 25 mg, such as about 5.0 mg to about 20.0 mg, or about 10.0 mg to about 25.0 mg.

16. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of claims 1 , 2, and 6-15, or the method according to any of claims 3-15, with the proviso that dapiglutide is not co-administered together with an apelin receptor agonist.

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