Treatment with dapiglutide

Abstract

The present invention relates to use of a GLP-1R / GLP-2R dual agonist, namely dapiglutide, for reducing cholesterol, in particular total cholesterol (TC) and low-density lipoprotein cholesterol (LDL cholesterol). The invention also relates to dapiglutide for treatment of hyperlipidaemia, in particular hypercholesterolaemia.

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, for reducing cholesterol, in particular total cholesterol (TO) and low-density lipoprotein cholesterol (LDL cholesterol). The invention also relates to dapiglutide for treatment of hyperlipidaemia, in particular hypercholesterolaemia.

[0004] BACKGROUND TO THE INVENTION

[0005] Hyperlipidaemia is the elevation of plasma lipids including cholesterol (hypercholesterolaemia) and triglycerides (hypertriglyceridemia) that contributes to the development of atherosclerosis. That is, abnormal levels of lipids, particularly elevated levels of LDL cholesterol, in the blood can lead to the formation of fatty deposits in arterial blood vessel walls, ultimately forming an atherosclerotic plaque that may end up in symptomatic atherosclerotic cardiovascular disease. Atherosclerotic cardiovascular disease may result in serious cardiovascular events like heart attack, stroke and death.

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

[0008] 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.

[0009] SUMMARY OF THE INVENTION

[0010] The present inventors have found out that dapiglutide is capable of reducing cholesterol in a subject, in particular total cholesterol and LDL cholesterol. Hence, the invention relates to reduction of cholesterol using dapiglutide.

[0011] Accordingly, the invention provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating hyperlipidaemia, in particular hypercholesterolaemia, in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0012] The invention also provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of reducing total cholesterol and / or LDL cholesterol in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject. Preferably, said subject is a patient in need of treatment of hyperlipidaemia, in particular hypercholesterolaemia.

[0013] The invention also provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of preventing atherosclerosis and / or an atherosclerotic cardiovascular disease in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject. The invention also provides a non-therapeutic method of reducing total cholesterol and / or LDL cholesterol in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0014] DESCRIPTION OF THE FIGURES

[0015] Figure 1 :

[0016] 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).

[0017] 1b: Trial design for the Phase 1 Multiple Ascending Dose (MAD) trial, part 2 (28 weeks duration with titration every 4thweek).

[0018] Figure 2:

[0019] 2a: Mean total Cholesterol Data with Standard Error Bars - Per-Protocol Analysis Set.2b: Mean total Cholesterol Data with Standard Error Bars - Change from Baseline (Day -1) - Per-Protocol Analysis Set.

[0020] ♦ Dapiglutide 7.5 mg; ■ Dapiglutide 10.0 mg; A Dapiglutide 13.0 mg; • Placebo

[0021] Figure 3:

[0022] 3a: Mean LDL Cholesterol Data with Standard Error Bars - Per-Protocol Analysis Set.

[0023] 3b: Mean LDL Cholesterol Data with Standard Error Bars - Change from Baseline (Day -1) - Per-Protocol Analysis Set.

[0024] ♦ Dapiglutide 7.5 mg; ■ Dapiglutide 10.0 mg; A Dapiglutide 13.0 mg; • Placebo

[0025] DESCRIPTION OF THE INVENTION

[0026] Dapiglutide

[0027] Dapiglutide is an acylated peptide molecule that agonises both GLP-1 R and GLP-2R.

[0028] 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.

[0029] The amino acid sequence of dapiglutide is as follows: Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD- OH (SEQ ID NO 1). 218

[0030] 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.:

[0031] 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.

[0032] “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.

[0033] “[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.

[0034] 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.

[0035] Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts. Similarly, salts can be formed using organic or inorganic acids. Amino acid addition salts can also be formed with amino acids.

[0036] Examples of pharmaceutically acceptable salts are described in Remington’s

[0037] Pharmaceutical Sciences, 17th edition. Ed. Alfonso R. Gennaro (Ed.), Mack Publishing 218

[0038] Company, Easton, PA, U.S.A., 1985 and more recent editions, and in the Encyclopaedia of Pharmaceutical Technology.

[0039] 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.

[0040] Medical use

[0041] In some embodiments, the invention provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of reducing total cholesterol and / or LDL cholesterol in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0042] The invention further provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating hyperlipidaemia, in particular hypercholesterolaemia in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject. Preferably, said subject is a patient in need of treatment of hypercholesterolaemia.

[0043] The invention also provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating hypercholesterolaemia in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0044] In some embodiments, the method reduces total cholesterol and / or LDL cholesterol in the subject. In some embodiments, the method reduces total cholesterol in the subject. In some embodiments, the method reduces LDL cholesterol in the subject. Hence, the invention provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of treating hyperlipidaemia, in particular hypercholesterolaemia, in a subject in need thereof, by reducing total cholesterol and / or LDL cholesterol in said subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0045] In some embodiments, said subject is unable to take statins or does not tolerate statins. 218

[0046] In some embodiments, said subject has previously been treated with one or more statins, wherein said treatment may have been ceased due to lack of sufficient reduction of total cholesterol and / or LDL cholesterol; or wherein said treatment has ceased due to side effects.

[0047] Preventing atherosclerosis and atherosclerotic cardiovascular disease

[0048] The invention provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of preventing atherosclerosis and / or an atherosclerotic cardiovascular disease in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0049] In some embodiments, the invention provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of preventing atherosclerosis in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0050] In some embodiments, the invention provides dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of preventing an atherosclerotic cardiovascular disease in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0051] In some embodiments, the atherosclerotic cardiovascular disease is coronary artery disease, heart attack, heart failure, transient ischaemic attack, stroke, peripheral artery disease, lower extremity arterial disease, carotid artery disease and / or retinal vascular disease.

[0052] In some embodiments, the atherosclerotic cardiovascular disease is coronary artery disease. In some embodiments, the atherosclerotic cardiovascular disease is heart attack.

[0053] In some embodiments, the atherosclerotic cardiovascular disease is heart failure.

[0054] In some embodiments, the atherosclerotic cardiovascular disease is transient ischaemic attack.

[0055] In some embodiments, the atherosclerotic cardiovascular disease is stroke.

[0056] In some embodiments, the atherosclerotic cardiovascular disease is peripheral artery disease.

[0057] In some embodiments, the atherosclerotic cardiovascular disease is lower extremity arterial disease.

[0058] In some embodiments, the atherosclerotic cardiovascular disease is carotid artery disease. In some embodiments, the atherosclerotic cardiovascular disease is retinal vascular disease. 218

[0059] Methods of treatment and use in manufacture of a medicament

[0060] The present invention is expressed herein as dapiglutide or a pharmaceutically acceptable salt thereof for use in the methods described herein.

[0061] The invention may be alternatively expressed as methods of treatment comprising administering to the subject dapiglutide or a pharmaceutically acceptable salt thereof.

[0062] Thus, the invention further provides a method for reducing total cholesterol and / or LDL cholesterol comprising administering to a subject in need thereof a therapeutically effective amount of dapiglutide or a pharmaceutically acceptable salt thereof.

[0063] The invention further provides a method for treating hyperlipidaemia, in particular hypercholesterolaemia, comprising administering to a subject in need thereof a therapeutically effective amount of dapiglutide or a pharmaceutically acceptable salt thereof.

[0064] The invention also provides a method for preventing atherosclerosis and / or an atherosclerotic cardiovascular disease in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0065] 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.

[0066] Thus, the invention provides use of dapiglutide in the manufacture of a medicament for treating hyperlipidaemia, in particular hypercholesterolaemia in a subject in need thereof.

[0067] The invention also provides use of dapiglutide in the manufacture of a medicament for treating hypercholesterolaemia in a subject in need thereof.

[0068] The invention also provides use of dapiglutide in the manufacture of a medicament for reducing total cholesterol and / or LDL cholesterol in a subject in need thereof.

[0069] The invention also provides use of dapiglutide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing atherosclerosis and / or an atherosclerotic cardiovascular disease in a subject in need thereof. Treating and treatment

[0070] 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 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.

[0071] The methods of treatment include administering a therapeutically effective amount dapiglutide that reduces at least one symptom of a disorder to a subject who is in need of such treatment.

[0072] 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.

[0073] The methods of treatment further include administering dapiglutide or a pharmaceutically acceptable salt thereof to a subject being at risk of or predisposed of developing one or more disease or disorder associated with elevated cholesterol, in particular elevated LDL cholesterol. Said disease or disorder may be an atherosclerotic cardiovascular disease. Hyperlipidaemia and cholesterol

[0074] Hyperlipidaemia is the elevation of plasma lipids including cholesterol (hypercholesterolaemia) and triglycerides (hypertriglyceridemia) that contributes to the development of atherosclerosis. That is, abnormal levels of lipids, particularly elevated levels of LDL cholesterol, in the blood can lead to the formation of fatty deposits in arterial blood vessel walls, ultimately forming an atherosclerotic plaque that may end up in symptomatic atherosclerotic cardiovascular disease.

[0075] Atherosclerotic cardiovascular disease is subdivided based on different anatomical regions of the body including the blood vessels of the heart, of the brain and of the rest of the body. Thus, hyperlipidaemia and ensuing atherosclerosis may affect:

[0076] • The coronary arteries of the heart and leading to coronary artery disease. This can ultimately lead to heart attack or heart failure and may result in death.

[0077] • The arteries supplying the brain and leading to transient ischemic attack or stroke and may result in death.

[0078] • The arteries supplying the rest of the body, leading to peripheral artery disease (including lower extremity arterial disease, carotid artery disease, and retinal vascular disease) and potential acute obstruction of these and may result in death.

[0079] Hyperlipidaemia, in particular elevated LDL cholesterol, is therefore an unwanted condition and to diagnose this, one must assess plasma levels of lipids (including cholesterol and triglycerides) and lipoproteins (proteins that bind lipids in the blood, including LDL, VLDL and HDL). The most important ones include:

[0080] • Total cholesterol which is the total amount of cholesterol in the blood.

[0081] • Low-density lipoprotein (LDL) cholesterol that is elevated is the main contributor of atherosclerosis.

[0082] • Very low-density lipoprotein (VLDL) cholesterol is also involved in atherosclerosis.

[0083] • High-density lipoprotein (HDL) cholesterol inhibits atherosclerosis, i.e. elevated levels are preferred, and low levels contribute to atherosclerosis.

[0084] • Triglycerides that are elevated are associated with an increased risk of heart disease.

[0085] As LDL cholesterol is the main driver of atherosclerosis, it is of interest to diagnose hypercholesterolaemia specifically. This may be done based on plasma levels of total cholesterol or LDL cholesterol above a certain threshold, measured as either milligrams per decilitre) or as millimoles per litre (mmol / l). 218

[0086] Treatment targets and goals for cholesterol reduction may be individually determined for the subject e.g. based on cardiovascular risk estimation for the individual subject as described in European Heart Journal (2020) 41 , 111-188 “ESC / EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk".

[0087] Another more simplified guideline for threshold levels have been disclosed in: lnformedHealth.org [Internet], Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Overview: High cholesterol. [Updated 2022 Feb 7], Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK279318 / Web page visited on 8 September 2024.

[0088] • Total cholesterol: 200 mg / dL (5.2 mmol / L)

[0089] • LDL cholesterol: 130 mg / dL (3.4 mmol / L)

[0090] Hence, “hyperlipidaemia” or “hypercholesterolaemia” may refer to a level of cholesterol in the blood of a subject of 200 mg / dL or more, or 5.2 mmol / L or more. “Hyperlipidaemia” or “hypercholesterolaemia” may refer to a level of LDL cholesterol in the blood of a subject of 130 mg / dL or more, or 3.4 mmol / L or more.

[0091] In some embodiments, hyperlipidaemia is defined as the subject having 200 mg / dL or more total cholesterol in their blood.

[0092] In some embodiments, hyperlipidaemia is defined as the subject having 5.2 mmol / L or more total cholesterol in their blood.

[0093] In some embodiments, hyperlipidaemia is defined as the subject having 130 mg / dL or more LDL cholesterol in their blood.

[0094] In some embodiments, hyperlipidaemia is defined as the subject having 3.4 mmol / L or more LDL cholesterol in their blood.

[0095] In some embodiments, hypercholesterolaemia is defined as the subject having 200 mg / dL or more total cholesterol in their blood.

[0096] In some embodiments, hypercholesterolaemia is defined as the subject having 5.2 mmol / L or more total cholesterol in their blood.

[0097] In some embodiments, hypercholesterolaemia is defined as the subject having 130 mg / dL or more LDL cholesterol in their blood.

[0098] In some embodiments, hypercholesterolaemia is defined as the subject having 3.4 mmol / L or more LDL cholesterol in their blood. 218

[0099] Known pharmaceutical agents frequently used for reducing cholesterol and treating hypercholesterolaemia are statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

[0100] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the total cholesterol of the subject by at least about 2%, 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%.

[0101] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the total cholesterol of the subject by from about 1% to about 10%, such as from about 1% to about 9%, from about 1 % to about 8%, from about 1% to about 7%, from about 1 % to about 6%, from about 1% to about 5%, from about 1 % to about 4%, from about 2% to about 10%, from about 3% to about 10%, from about 4% to about 10%, from about 5% to about 10%, from about 6% to about 10%, from about 7% to about 10%, or from about 8% to about 10%.

[0102] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the total cholesterol of the subject by from about 4% to about 9%, such as from about 5% to about 9%, from about 6% to about 9%, from about 7% to about 9%, from about 4% to about 8%, from about 4% to about 7%, or from about 5% to about 7%.

[0103] Preferably, the total cholesterol of the subject is reduced to a level below 5.2 mmol / L, such as below 5.0 mmol / L, 4.8 mmol / L, 4.6 mmol / L or 4.4 mmol / L.

[0104] In some embodiments, the method results in a decrease in the subject’s total cholesterol, preferably to a level below 200 mg / dL (5.2 mmol / L) over a period of 13 weeks.

[0105] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the LDL cholesterol of the subject by at least about 2%, 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%.

[0106] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the LDL cholesterol of the subject by from about 1 % to about 10%, such as 218 from about 1% to about 9%, from about 1% to about 8%, from about 1% to about 7%, from about 1 % to about 6%, from about 1 % to about 5%, from about 1% to about 4%, from about 2% to about 10%, from about 3% to about 10%, from about 4% to about 10%, from about 5% to about 10%, from about 6% to about 10%, from about 7% to about 10%, or from about 8% to about 10%.

[0107] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the total cholesterol of the subject by from about 2% to about 9%, such as from about 3% to about 9%, from about 4% to about 9%, from about 2% to about 8%, from about 3% to about 8%, or from about 4% to about 8%.

[0108] Preferably, the LDL cholesterol of the subject is reduced to a level below 3.4 mmol / L, such as below 3.2 mmol / L, 3.0 mmol / L, 2.8 mmol / L, 2.6 mmol / L, 2.4 mmol / L, 2.2 mmol / L or 2.0 mmol / L.

[0109] In some embodiments, the method results in a decrease in the subject’s LDL cholesterol, preferably to a level below 130 mg / dL (3.4 mmol / L) over a period of 13 weeks.

[0110] In some embodiments, the total cholesterol and / or LDL cholesterol 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 over a period of at least 3 months, such as at least 4 months or at least 13 weeks.

[0111] In some embodiments, the method results in a decrease in the subject’s total cholesterol and / or LDL cholesterol when dapiglutide or a pharmaceutically acceptable salt thereof has been administered to the subject for at least 13 weeks. In other words, after being administered dapiglutide or a pharmaceutically acceptable salt thereof for at least 13 weeks, the total cholesterol and / or LDL cholesterol of the subject has decreased.

[0112] In some embodiments, the method results in a decrease in the subject’s total cholesterol to a level below 200 mg / dL (5.2 mmol / L) and / or LDL cholesterol to a level below 130 mg / dL (3.4 mmol / L) when dapiglutide or a pharmaceutically acceptable salt thereof has been administered to the subject for at least 13 weeks.

[0113] In some embodiments, the method results in a decrease in the subject’s total cholesterol to a level below 200 mg / dL (5.2 mmol / L) when dapiglutide or a pharmaceutically acceptable salt thereof has been administered to the subject for at least 13 weeks. 218

[0114] In some embodiments, the method results in a decrease in the subject’s LDL cholesterol to a level below 130 mg / dL (3.4 mmol / L) when dapiglutide or a pharmaceutically acceptable salt thereof has been administered to the subject for at least 13 weeks.

[0115] In some embodiments, the method results in a decrease in the subject’s total cholesterol to a level below 200 mg / dL (5.2 mmol / L) and / or LDL cholesterol to a level below 130 mg / dL (3.4 mmol / L) when dapiglutide or a pharmaceutically acceptable salt thereof has been administered to the subject for at least 28 weeks.

[0116] In some embodiments, the method results in a decrease in the subject’s total cholesterol to a level below 200 mg / dL (5.2 mmol / L) when dapiglutide or a pharmaceutically acceptable salt thereof has been administered to the subject for at least 28 weeks.

[0117] In some embodiments, the method results in a decrease in the subject’s LDL cholesterol to a level below 130 mg / dL (3.4 mmol / L) when dapiglutide or a pharmaceutically acceptable salt thereof has been administered to the subject for at least 28 weeks.

[0118] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the total cholesterol of the subject by from about 4% to about 8%, such a about 5% to about 7%, over a period of about 13 weeks.

[0119] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the total cholesterol of the subject by about 7%, over a period of about 28 weeks.

[0120] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the total cholesterol of the subject by from about 3% to about 4%, such as about 3%, or about 4%, over a period of about 13 weeks.

[0121] In some embodiments, administration of dapiglutide or a pharmaceutically acceptable salt thereof reduces the LDL cholesterol of the subject by about 8%, over a period of about 28 weeks.

[0122] Further medical conditions

[0123] In one embodiment, said subject additionally suffers from a disease or disorder selected from overweight, overweight in the presence of at least one weight- related comorbid 218 condition, obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, diabetes (e.g. type 2 diabetes), prediabetes or metabolic syndrome.

[0124] In one embodiment, said treatment of hyperlipidaemia further includes 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, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain, reducing food intake, reducing appetite or promoting weight loss.

[0125] In one embodiment, said treatment of hyperlipidaemia further includes treating one or more disease or disorder selected from obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain, reducing food intake, reducing appetite or promoting weight loss.

[0126] In one embodiment, said treatment of hyperlipidaemia further includes 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, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome.

[0127] In one embodiment, said treatment of hyperlipidaemia further includes treating one or more disease or disorder selected from obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome.

[0128] In the context of the invention the term “diabetes” refers to “diabetes mellitus”.

[0129] Non-therapeutic use

[0130] The invention provides a non-therapeutic method for reducing total cholesterol and / or LDL cholesterol in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject. 218

[0131] In some embodiments, the invention provides the use of dapiglutide or a pharmaceutically acceptable salt thereof in a non-therapeutic method for reducing total cholesterol and / or LDL cholesterol in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0132] The non-therapeutic method of the invention comprises administration of dapiglutide or a pharmaceutically acceptable salt thereof to a subject. Accordingly, the non-therapeutic method of the invention may comprise any of the features relating to administration of dapiglutide or a pharmaceutically acceptable salt thereof (such as dose, timing of administration or mode of administration) described herein in the context of therapeutic methods and medical uses of the invention.

[0133] Other effects of administering dapiglutide

[0134] Reduced body weight

[0135] 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%.

[0136] 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%.

[0137] 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%.

[0138] 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%.

[0139] 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. 218

[0140] Reduced appetite

[0141] In some embodiments, the subject has decreased appetite following administration of dapiglutide.

[0142] The term “appetite” refers to a subject’s desire to consume food. The appetite of the subject may be determined by measuring how much food the subject consumes using techniques known in the art, such as the mixed meal test or standard meal test described in Example 6 of WO 2023 / 031380. Thus, in some embodiments, appetite is measured using the mixed meal test. In some embodiments, appetite is measured using the standard meal test. In some embodiments, following administration of dapiglutide the appetite of the subject is reduced by at least 5%. In some embodiments, following administration of dapiglutide the appetite of the subject is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% or at least 60%.

[0143] In some embodiments, the subject has reduced food consumption following administration of dapiglutide. “Food consumption” is synonymous with “food intake”. Thus, in a preferred embodiment, the subject has reduced food intake following administration of dapiglutide. The term “food consumption” refers to the amount of food the subject consumes in a given setting or period, such as a single meal, over multiple meals or over a particular period. Food consumption of the subject may be measured by techniques known in the art, such as the mixed meal test or standard meal test described in Example 6 of WO 2023 / 031380. Thus, in some embodiments, food consumption is measured using the mixed meal test. In some embodiments, food consumption is measured using the standard meal test.

[0144] In some embodiments, following administration of dapiglutide the food consumption of the subject is reduced by at least 5%. In some embodiments, following administration of dapiglutide the food consumption of the subject is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.

[0145] In some embodiments, following administration of dapiglutide the amount of food consumed by the subject is reduced to 95% or less of the amount of food consumed by the subject prior to administration of dapiglutide. In some embodiments, following administration of dapiglutide the amount of food consumed by the subject is reduced to 90% or less, 85% or 218 less, 80% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, or 50% or less of the amount of food consumed by the subject prior to administration of dapiglutide.

[0146] Subject

[0147] As described herein, the invention relates to administering dapiglutide or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0148] 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. In a preferred embodiment, the subject is a patient in need of treatment of hyperlipidaemia, in particular hypercholesterolemia.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] Dosage regime

[0155] 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. 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.

[0156] 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.

[0157] The dosage regime typically involves 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, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 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, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more or 28 or more times.

[0158] Treatment with dapiglutide may continue for as long as is necessary to reduce total cholesterol and / or LDL cholesterol to a level below a certain threshold, preferably to a level below 200 mg / dL (5.2 mmol / L) for total cholesterol and below 130 mg / dL (3.4 mmol / L) for LDL cholesterol.

[0159] 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.

[0160] 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.

[0161] In some embodiments, dapiglutide is administered in conjunction with one or more further therapeutic agents which may for example be selected from statins, such as atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

[0162] Dose

[0163] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject in a therapeutically effective amount.

[0164] As will be apparent to one skilled in the medical art, a “therapeutically effective amount” may 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 subject (patient) under consideration, the subject’s (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 treating and / or the desired reduction of cholesterol including LDL cholesterol, will be within the ambit of the skilled person.

[0165] As used herein, the term “therapeutically effective amount” refers to an amount which reduces total cholesterol and / or LDL cholesterol and thereby may be used in treatment of prevention of one or more disease or disorder associated with elevated cholesterol, in particular elevated LDL cholesterol.

[0166] In some embodiments of the invention, administration of dapiglutide commences 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. 218

[0167] Dapiglutide may be administered to the subject at any dose suitable to achieve treatment of hyperlipidaemia, preferably hypercholesterolaemia.

[0168] Dapiglutide may be administered to the subject at any dose suitable to achieve reduction of total cholesterol and / or LDL cholesterol to a level below a certain threshold which may depend on the risk factors for the patient to be treated. Preferably cholesterol is reduced to a level below 200 mg / dL (5.2 mmol / L) for total cholesterol and below 130 mg / dL (3.4 mmol / L) for LDL cholesterol.

[0169] 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).

[0170] 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.

[0171] 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.

[0172] 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. 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] Titration

[0179] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject following a titration protocol. 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to a subject following an up-titration protocol wherein up-titration occurs every second week or every fourth week.

[0185] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to a subject following an up-titration protocol wherein up-titration occurs every second week. 218

[0186] In some embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to a subject following an up-titration protocol wherein up-titration occurs every fourth week.

[0187] Timing of administration

[0188] Dapiglutide may be administered to the subject at any interval suitable to achieve treatment of hyperlipidaemia, in particular hypercholesterolemia. In particular, dapiglutide may be administered to the subject at any interval suitable to reduce the level of cholesterol to below a certain threshold, preferably to a level below 200 mg / dL (5.2 mmol / L) for total cholesterol and / or to a level below 130 mg / dL (3.4 mmol / L) for LDL cholesterol.

[0189] In preferred embodiments, dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject about once weekly.

[0190] 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.

[0191] Mode of administration

[0192] Dapiglutide or a pharmaceutically acceptable salt thereof may be administered to the subject by any mode of administration common or standard in the art.

[0193] The term “mode of administration” refers to the means or route by which dapiglutide is administered to the subject.

[0194] 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.

[0195] In preferred embodiments, dapiglutide or the pharmaceutically acceptable salt is administered to the subject by subcutaneous injection. 218

[0196] Composition

[0197] Dapiglutide or the pharmaceutically acceptable salt thereof may be formulated as a composition, in particular a pharmaceutical composition for storage or administration.

[0198] 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, preferably a pharmaceutically acceptable carrier.

[0199] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient or vehicle.

[0200] 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.

[0201] In some embodiments, the pharmaceutical composition is formulated for parenteral injection. Preferably, the pharmaceutical composition is formulated for subcutaneous injection.

[0202] An exemplary pharmaceutical composition with dapiglutide for subcutaneous injection is shown in Example 1, Table 3.

[0203] Definitions

[0204] 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.

[0205] 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.

[0206] The singular forms “a”, “an”, and “the” as used herein include the plurals unless the context clearly dictates otherwise.

[0207] 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. 218

[0208] 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.

[0209] Each embodiment of the invention described herein may be taken alone or in combination with one or more other embodiments of the invention.

[0210] 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.

[0211] EXAMPLES

[0212] The following examples are provided to illustrate preferred aspects of the invention and are not intended to limit the scope of the invention.

[0213] Example 1 :

[0214] Phase 1 Multiple Ascending Dose (MAD) trial

[0215] 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.

[0216] 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.

[0217] 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).

[0218] 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 1 b).

[0219] Objectives of the study: 218

[0220] 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.

[0221] 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.

[0222] Explorative and other objectives included cholesterol measurements.

[0223] Trial design:

[0224] The trial was a 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.

[0225] 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.

[0226] In Part 2, subjects were randomized to dapiglutide or placebo with the randomization ratio 2:1 and an observation period of 33 weeks.

[0227] Trial population:

[0228] 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.

[0229] Interventions:

[0230] 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.

[0231] 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. 218

[0232] Table 1: Interventions

[0233] Inclusion criteria:

[0234] 1. Signed and dated informed consent obtained before any trial-related activities. Trial related activities are any procedures that would not have been done during normal management of the subject

[0235] 2. Male subject or female subject of non-child-bearing potential.

[0236] 3. Age between 18 and 64 years, both inclusive.

[0237] 4. Body Mass Index (BMI) between 27.0 and 39.9 kg / m2, both inclusive.

[0238] 5. Body weight of at least 60 kg at screening

[0239] 6. Stable body weight + / - 5% for at least 3 months prior to screening as reported by subject

[0240] 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

[0241] 8. HbA1c <6.5%

[0242] 9. Heart rate after at least 5 minutes rest in supine position inside the range of 45-90 beats / min.

[0243] 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.

[0244] 11. Have venous access sufficient to allow cannulation for blood sampling as required by the protocol.

[0245] 12. Able and willing to comply with all trial procedures.

[0246] 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.

[0247] Pharmaceutical formulation: Table 2: Dapiglutide pharmaceutical formulation for s.c. dosing.

[0248] MAD trial Part 1 (Cohort 1-3) Table 3: Demography - Randomised and exposed.

[0249] Results:

[0250] Safety: 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. 218

[0251] 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. Weight loss:

[0252] Body weight was measured at day -1 (baseline), day 1 (the first day of dosing), 29, 43, 57, 71 , 85, 92 and 127 (follow-up). 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.

[0253] Tables 4a and 4b shows the observed mean change in body weight, wherein the Full Analysis Set (FAS) is based on the intention-to-treat principle and includes all randomized subjects, while the Per-Protocol Analysis Set (PPAS) includes all subjects of the FAS who completed the trial without any important protocol deviations and who followed the planned dose scheme.

[0254] Table 4a: Observed mean change in body weight from baseline to week 13, full analysis set

[0255] Table 4b: Observed mean change in body weight from baseline to week 13, per protocol analysis set (PPAS) 218

[0256] Cholesterol:

[0257] Blood sampling for lipid measure measurements was performed in all cohorts at day 1 (pre dose), day 43 and day 92 under fasting conditions.

[0258] Table 5: Total cholesterol (mMol / L), per-protocol analysis set (PPAS)

[0259] (*)Planned maintenance dose level, subjects of cohort 1-3 receiving placebo are pooled.

[0260] Table 5 and Figures 2a and 2b shows that total cholesterol is reduced by administration of dapiglutide for a period of 6-13 weeks.

[0261] Table 6: LDL cholesterol (mMol / L), per-protocol analysis set (PPAS)

[0262] (*)Planned maintenance dose level, subjects of cohort 1-3 receiving placebo are pooled.

[0263] Table 6 and Figures 3a and 3b shows that LDL cholesterol is reduced by administration of dapiglutide for a period of 6-13 weeks. MAD trial Part 2 (Cohort 4)

[0264] Table 7: Demography - Randomised and exposed

[0265] Safety:

[0266] 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.

[0267] 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. 218

[0268] 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. Weight loss:

[0269] Data presented here 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.

[0270] Table 8: Observed mean change in body weight from baseline to week 28, full analysis set (FAS)

[0271] Cholesterol:

[0272] Blood sampling for lipid measure measurements was performed in all cohorts at day -1, day 85, day 141 and day 197 under fasting conditions.

[0273] Despite the variation in doses, the weight loss and cholesterol data from Part 2 confirms the data from Part 1.

[0274] Table 9: Total cholesterol (mMol / L), full analysis set (FAS) 218

[0275] Table 10: LDL cholesterol (mMol / L), full analysis set (FAS) Tables 9 and 10 confirm that dapiglutide reduces total cholesterol and LDL cholesterol. 218

[0276] CLAUSES

[0277] The invention is defined in the following numbered clauses:

[0278] 1. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of treating hyperlipidaemia in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0279] 2. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of treating hypercholesterolaemia in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0280] 3. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of treating hyperlipidaemia in a subject in need thereof, by reducing total cholesterol and / or LDL cholesterol in said subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0281] 4. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of treating hypercholesterolaemia in a subject in need thereof, by reducing total cholesterol and / or LDL cholesterol in said subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0282] 5. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of reducing total cholesterol and / or LDL cholesterol in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0283] 6. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of reducing total cholesterol in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0284] 7. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of reducing LDL cholesterol in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject. 218

[0285] 8. Dapiglutide according to any of the previous clauses wherein said subject is a patient in need of treatment of hyperlipidaemia, in particular hypercholesterolaemia.

[0286] 9. Dapiglutide according to any of the previous clauses, wherein said subject is at risk of developing an atherosclerotic cardiovascular disease.

[0287] 10. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of preventing atherosclerosis and / or an atherosclerotic cardiovascular disease in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0288] 11. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of preventing an atherosclerotic cardiovascular disease in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0289] 12. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of clauses 9 to 11, wherein the atherosclerotic cardiovascular disease is coronary artery disease, heart attack, heart failure, transient ischaemic attack, stroke, peripheral artery disease, lower extremity arterial disease, carotid artery disease and / or retinal vascular disease.

[0290] 13. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of preventing atherosclerosis in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

[0291] 14. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses wherein total cholesterol is reduced to a level below 200 mg / dL (5.2 mmol / L) and / or LDL cholesterol is reduced to a level below 130 mg / dL (3.4 mmol / L).

[0292] 15. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein said subject has hyperlipidaemia, in particular hypercholesterolaemia.

[0293] 16. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein said subject has previously been treated with one or more statins. 218

[0294] 17. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein said subject is unable to take or tolerate statins.

[0295] 18. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein said subject said subject has previously been treated with one or more statins, wherein said treatment has been ceased due to lack of sufficient reduction of total cholesterol and / or LDL cholesterol; or wherein said treatment has been ceased due to side effects.

[0296] 19. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein said subject additionally suffers from 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, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome.

[0297] 20. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein the method further comprises treating one or more disease or disorder selected from obesity, overweight, overweight in the presence of at least one weight-related comorbid condition, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnoea, inadequate glucose control, glucose tolerance, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or the method comprises reducing body weight, inhibiting weight gain, reducing food intake, reducing appetite or promoting weight loss.

[0298] 21. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any one of the previous clauses, 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.

[0299] 22. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein the subject has a body mass index (BMI) of 18.5 to 24.9 kg / m2corresponding to healthy weight. 218

[0300] 23. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein the subject has a level of total cholesterol above 200 mg / dL (5.2 mmol / L) and / or a level of LDL cholesterol above 130 mg / dL (3.4 mmol / L).

[0301] 24. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein said method results in a decrease in the subject’s total cholesterol and / or LDL cholesterol, preferably to a level below 200 mg / dL (5.2 mmol / L) for total cholesterol and to a level below 130 mg / dL (3.4 mmol / L) for LDL cholesterol.

[0302] 25. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein said method results in a decrease in the subject’s total cholesterol and / or LDL cholesterol, preferably to a level below 200 mg / dL (5.2 mmol / L) for total cholesterol and to a level below 130 mg / dL (3.4 mmol / L) for LDL cholesterol, when dapiglutide or a pharmaceutically acceptable salt thereof has been administered to the subject for at least 13 weeks .

[0303] 26. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject following a titration protocol.

[0304] 27. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject about once weekly.

[0305] 28. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, 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 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. 218

[0306] 29. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, 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 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.

[0307] 30. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein dapiglutide or the pharmaceutically acceptable salt is administered to the subject by parenteral injection, such as subcutaneous injection, intravenous injection or intramuscular injection; preferably wherein dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject by subcutaneous injection.

[0308] 31. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, 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.

[0309] 32. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein the pharmaceutical composition is formulated for parenteral injection, preferably subcutaneous injection.

[0310] 33. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein the total cholesterol of the subject is reduced by at least about 2%, 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%.

[0311] 34. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein the total cholesterol of the subject is reduced to a level below 5.2 mmol / L, such as below 5.0 mmol / L, 4.8 mmol / L, 4.6 mmol / L or 4.4 mmol / L. 218

[0312] 35. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein the LDL cholesterol of the subject is reduced to a level below 3.4 mmol / L, such as below 3.2 mmol / L, 3.0 mmol / L, 2.8 mmol / L, 2.6 mmol / L, 2.4 mmol / L, 2.2 mmol / L or 2.0 mmol / L.

[0313] 36. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein the LDL cholesterol of the subject is reduced by at least about such as 2%, 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% or at least about 30%, at least about 40%, or at least about 50%.

[0314] 37. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous clauses, wherein the total cholesterol and / or LDL cholesterol 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 28 weeks, 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.

[0315] 38. Dapiglutide or a pharmaceutically acceptable salt thereof for use in the treatment of hyperlipidaemia, in particular hypercholesterolemia in a patient in need thereof, 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 7.5 mg to about 30.0 mg, 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.

[0316] 39. A method for treating hyperlipidaemia, in particular hypercholesterolaemia comprising administering to a subject in need thereof a therapeutically effective amount of dapiglutide or a pharmaceutically acceptable salt thereof to said subject.

[0317] 40. A method for reducing total cholesterol and / or LDL cholesterol comprising administering to a subject in need thereof a therapeutically effective amount of dapiglutide or a pharmaceutically acceptable salt thereof to said subject. 218

[0318] 41. Use of dapiglutide in the manufacture of a medicament for treating hyperlipidaemia, in particular hypercholesterolaemia, in a subject in need thereof.

[0319] 42. Use of dapiglutide in the manufacture of a medicament for reducing total cholesterol and / or LDL cholesterol in a subject in need thereof.

[0320] 43. A non-therapeutic method of reducing total cholesterol and / or LDL cholesterol in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

Claims

CLAIMS1. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of treating hyperlipidaemia in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

2. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the method is a method of treating hypercholesterolaemia.

3. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to claim 1 or claim 2, wherein the method reduces total cholesterol and / or low density lipoprotein (LDL) cholesterol in the subject.

4. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a therapeutic method of reducing total cholesterol and / or LDL cholesterol in a subject in need thereof, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

5. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of preventing atherosclerosis and / or an atherosclerotic cardiovascular disease in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

6. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to claim 5, wherein the atherosclerotic cardiovascular disease is coronary artery disease, heart attack, heart failure, transient ischaemic attack, stroke, peripheral artery disease, lower extremity arterial disease, carotid artery disease and / or retinal vascular disease.

7. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous claims, wherein the subject’s total cholesterol and / or the subject’s LDL cholesterol is reduced, preferably wherein the subject’s total cholesterol is reduced to a level below 200 mg / dL (5.2 mmol / L) and / or the subject’s LDL cholesterol is reduced to a level below 130 mg / dL (3.4 mmol / L).

8. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous claims, wherein the subject has hyperlipidaemia, in particular hypercholesterolaemia.

9. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous claims, wherein the subject has previously been treated with one or more statins, optionally wherein said treatment has been ceased due to lack of sufficient reduction of total cholesterol and / or LDL cholesterol; or wherein said treatment has been ceased due to side effects.

10. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous claims, wherein the subject additionally suffers from 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, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, preferably wherein the method further comprises 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, diabetes (e.g. type 2 diabetes), pre-diabetes or metabolic syndrome, or of reducing body weight, inhibiting weight gain, reducing food intake, reducing appetite or promoting weight loss.

11. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous claims, wherein said method results in a decrease in the subject’s total cholesterol and / or LDL cholesterol, preferably to a level below 200 mg / dL (5.2 mmol / L) for total cholesterol and to a level below 130 mg / dL (3.4 mmol / L) for LDL cholesterol, when dapiglutide or a pharmaceutically acceptable salt thereof has been administered to the subject for at least 13 weeks .

12. Dapiglutide or a pharmaceutically acceptable salt thereof for use according to any of the previous claims, wherein dapiglutide or the pharmaceutically acceptable salt thereof is administered to the subject(a) following a titration protocol; and / or(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, about15.0 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; and / or(d) by parenteral injection, such as subcutaneous injection, intravenous injection, intramuscular injection or intradermal 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 the previous claims, 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, preferably wherein the pharmaceutical composition is formulated for parenteral injection, preferably subcutaneous injection.

14. Dapiglutide or a pharmaceutically acceptable salt thereof for use in a method of treating hypercholesterolaemia in a subject in need thereof, wherein dapiglutide is administered to the subject by subcutaneous injection about once weekly at a dosage of about 5.0 mg to about 30.0 mg.

15. A non-therapeutic method of reducing total cholesterol and / or LDL cholesterol in a subject, the method comprising administering dapiglutide or a pharmaceutically acceptable salt thereof to the subject.

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