Analogues with improved properties

Abstract

The present invention relates to therapeutic and non-therapeutic methods using peptide hormone analogues. In particular, the invention relates to use of amylin analogues with improved properties, specifically amylin analogues that do not delay gastric emptying.

Description

[0001] ANALOGUES WITH IMPROVED PROPERTIES

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to therapeutic and non-therapeutic methods using peptide hormone analogues. In particular, the invention relates to use of amylin analogues with improved properties, specifically amylin analogues that do not delay gastric emptying.

[0004] BACKGROUND TO THE INVENTION

[0005] Obesity is a 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. As such, more efficacious pharmacological treatment options are needed.

[0006] Amylin is a family of peptide hormones that includes amylin, calcitonin, calcitonin gene- related peptide, adrenomedullin and intermedin (intermedin also being known as AFP-6), and has been implicated in various metabolic diseases and disorders.

[0007] Human amylin was first isolated, purified and characterized as the major component of amyloid deposits in the islets of pancreases from type 2 diabetes patients.

[0008] Native human amylin is a 37-amino acid peptide having the formula:

[0009] H-KC()NTATC()ATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2(SEQ ID NO: 1) wherein H- at the N-terminus designates a hydrogen atom, corresponding to the presence of a free amino group on the N-terminal amino acid residue [i.e. the lysine (K) residue at sequence position number 1 in the sequence shown above]; wherein -NH2at the C-terminus indicates that the C-terminal carboxyl group is in the amide form; and wherein the parentheses “()” associated with the two cysteine (C, Cys) residues at sequence positions 2 and 7 indicate the presence of an intramolecular disulfide bridge between the two Cys residues in question.

[0010] Amylin may be beneficial in treating metabolic disorders such as diabetes and / or obesity. Amylin is believed to slow gastric emptying, suppress glucagon secretion and reduce food intake, thereby regulating the rate of glucose release to the circulation. Amylin appears to complement the actions of insulin. Compared to healthy adults, type 1 diabetes patients have no circulating amylin, and type 2 diabetes patients exhibit reduced postprandial amylin concentrations. WO 93 / 10146 describes an amylin analogue known as pramlintide, which has the sequence:

[0011] Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-GIn-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser- Ser-Asn-Asn-Phe-Gly-Pro-lle-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO: 2)

[0012] Pramlintide also possesses a disulphide bridge between the cysteine residues at positions 2 and 7, and, in human trials, has been shown to reduce body weight or reduce weight gain.

[0013] An alternative amylin analogue incorporating N-methylated residues and having a reduced tendency to fibrillation, designated IAPP-GI, has been described by Yan et al. (PNAS, 103(7), 2046-2051, 2006; Angew. Chem. Int. Ed. 2013, 52, 10378-10383; W02006 / 042745). IAPP-GI appears to have lower activity than native amylin, however.

[0014] WO 2018 / 046719 describes amylin analogues having, inter alia, a lactam bridge instead of a disulfide bridge, N-methylated residues, and a deletion corresponding to the residues Asn21 and Asn22 of native human amylin. Such analogues have considerably lower tendency towards fibrillation than native amylin, while also having higher potency than the analogues described by Yan et al. (supra).

[0015] Whilst the delayed gastric emptying associated with amylin and amylin analogues may result in a beneficial reduction in food intake, delayed gastric emptying can be undesirable in certain circumstances.

[0016] For example, delayed gastric emptying can cause unwanted changes to the exposure of, or need for, concomitant medications. Such drug-drug interactions are undesirable. SUMMARY OF THE INVENTION

[0017] The present invention relates to the surprising finding that an amylin analogue, whilst inducing weight loss, decreasing glucagon release and increasing satiety in subjects, surprisingly does not affect gastric emptying.

[0018] As such, the invention relates to a functional analogue of amylin that does not give rise to delayed gastric emptying.

[0019] In a broad aspect, the present invention relates to a dosage regimen for a subject, wherein the dosage regimen comprises:

[0020] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0021] (b) administering a concomitant agent to the subject.

[0022] According to the invention, the amylin analogue that does not affect the rate of gastric emptying comprises or consists of a peptide of formula:

[0023] R1-Z-R2wherein:

[0024] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0025] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and

[0026] Z is an amino acid sequence of formula I:

[0027] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17- Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37 (SEQ ID NO: 4) wherein:

[0028] X1 is selected from the group consisting of Arg, Lys and Glu;

[0029] X3 is selected from the group consisting of Gly, Gin and Pro;

[0030] X4 is selected from the group consisting of Thr and Glu;

[0031] X5 is selected from the group consisting of Ala and Leu;

[0032] X6 is selected from the group consisting of Thr and Ser;

[0033] X10 is selected from the group consisting of Glu and Gin;

[0034] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0035] X17 is selected from the group consisting of Gin, His and Thr;

[0036] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent; X27 is selected from the group consisting of Leu and Pro;

[0037] X32 is selected from the group consisting of Vai and Thr;

[0038] X35 is selected from the group consisting of Asn and Ser;

[0039] X37 is selected from the group consisting of Hyp and Pro; and

[0040] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0041] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0042] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0043] Preferably, the amylin analogue comprises or consists of a peptide of formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)- LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 3), or a pharmaceutically acceptable salt and / or derivative thereof.

[0044] In preferred embodiments, the amylin analogue is petrelintide, which is a compound having the formula:

[0045] [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)-LSSTEVGSNT- Hyp-NH2(SEQ ID NO: 3) wherein an intramolecular lactam bridge is formed between the side chains of residues indicated by parentheses “()”; and wherein [19CD]-isoGlu is a 19-carboxynonadecanoyl group covalently attached to the alpha amino group of an iso-glutamic acid linker; or a pharmaceutically acceptable salt thereof.

[0046] In one aspect, the invention provides a dosage regimen for a subject, wherein the dosage regimen comprises:

[0047] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0048] (b) administering a concomitant agent to the subject; wherein the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another.

[0049] In one aspect, the invention provides a method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, and / or reducing body weight in a subject, wherein the method comprises: (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0050] (b) administering a concomitant agent to the subject; wherein the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another.

[0051] In one aspect, the method of inhibiting or reducing weight gain, promoting weight loss, reducing food intake, and / or reducing excess body weight in a subject is a non-therapeutic method.

[0052] In one aspect, the invention provides a method of treating or preventing a disease in a subject, wherein the method comprises:

[0053] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0054] (b) administering a concomitant agent to the subject; wherein the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another.

[0055] In one aspect, the invention provides an amylin analogue that does not affect the rate of gastric emptying for use in a method of treating or preventing a disease in a subject, wherein the method comprises:

[0056] (a) administering the amylin analogue to the subject; and

[0057] (b) administering a concomitant agent to the subject; wherein the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another.

[0058] In one aspect, the invention provides a use of an amylin analogue that does not affect the rate of gastric emptying for manufacture of a medicament for use in a method of treating or preventing a disease in a subject, wherein the method comprises:

[0059] (a) administering the amylin analogue to the subject; and

[0060] (b) administering a concomitant agent to the subject; wherein the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another.

[0061] BRIEF DESCRIPTION OF THE FIGURES Figure 1 : single ascending dose trial design

[0062] The single ascending dose (SAD) trial of Example 1 comprised 7 cohorts each consisting of

[0063] 6 participants receiving the amylin analogue of SEQ ID NO: 3, and 2 participants receiving a placebo. Doses were administered subcutaneously. An additional cohort of identical composition (not shown) received an intravenous dose at 0.35mg.

[0064] Figure 2: pharmacokinetic profiles are consistent between cohorts

[0065] Pharmacokinetic profiles for each cohort are displayed. Individual measured amylin analogue concentration in the blood following single dose subcutaneous administration is shown (A) as well as the geometric mean for each cohort for up to 35 days (B) and for up to

[0066] 7 days (C). Each cohort exhibits a consistent pharmacokinetic profile. Further, there is little within cohort variability in exposure.

[0067] Figure 3: dose-dependent reduction in bodyweight

[0068] A dose-dependent and sustained reduction in body weight is observed in human subjects receiving a single dose of the amylin analogue. (A) Shows the change in body weight of the individual subjects in each cohort. (B) Shows mean change in body weight and 95% confidence level.

[0069] Figure 4: dose-dependent reduction of glucagon secretion

[0070] A dose-dependent reduction in glucagon secretion following a Mixed test meal (MTM) is observed in participants receiving a single dose of the amylin analogue.

[0071] Figure 5: acetaminophen absorption is unaffected by the amylin analogue

[0072] No dose relationship is observed between the amylin analogue and acetaminophen absorption. Measured blood acetaminophen concentration following mixed test meal (MTM) and acetaminophen consumption is essentially unaltered by the amylin analogue. Acetaminophen concentration in the blood is displayed as a function of time post MTM in (A); the corresponding area under the curve for the first hour from the start of the MTM (B) is also shown. (C) Shows gastric emptying (acetaminophen concentration AUG) as percentage of placebo, further evidencing the lack of appreciable effect on acetaminophen concentration and therefore gastric emptying.

[0073] Figure 6: Multiple Ascending Dose trial design

[0074] The Multiple Ascending Dose (MAD) trial of Example 2 comprised 2 cohorts each consisting of 7 participants receiving the amylin analogue of SEQ ID NO: 3, and 3 participants receiving a placebo. Doses were administered subcutaneously. Figure 7: weight loss

[0075] A reduction in body weight is observed in human subjects receiving multiple doses of the amylin analogue. Panels are (l-r) Placebo, Amylin 0.6 mg and Amylin 1.2 mg. Graphs show the individual subjects (thin lines) and the mean (thick line) for each cohort.

[0076] Figure 8: acetaminophen absorption is unaffected by the amylin analogue

[0077] No dose relationship is observed between the amylin analogue and acetaminophen absorption. Measured blood acetaminophen concentration following mixed test meal (MTM) and acetaminophen consumption is essentially unaltered from day -1 by the amylin analogue at day 5 and day 40.

[0078] Figure 9: reduction of glucagon secretion

[0079] A reduction in glucagon secretion following a mixed test meal (MTM) is observed on day 5 in participants receiving a dose of the amylin analogue.

[0080] Figure 10: Multiple Ascending Dose trial design - part 2

[0081] The Multiple Ascending Dose (MAD) trial of Example 3 comprised 3 cohorts each consisting of 12 participants receiving the amylin analogue of SEQ ID NO: 3, and 4 participants receiving a placebo. Doses were administered subcutaneously.

[0082] DETAILED DESCRIPTION OF THE INVENTION

[0083] 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.

[0084] Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[0085] 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.

[0086] Each embodiment of the invention described herein may be taken alone or in combination with one or more other embodiments of the invention. Various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention.

[0087] Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in biochemistry, molecular biology or related fields are intended to be within the scope of the following aspects.

[0088] Definitions

[0089] Unless specified otherwise, the following definitions are provided for specific terms, which are used in the present written description. All other terms will be understood as having a meaning that is common in the art as would be attributed to them by the person skilled in the art.

[0090] Throughout this specification, the word “comprise”, and grammatical variants thereof, such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or component, or group of integers or components, but not the exclusion of any other integer or component, or group of integers or components.

[0091] The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictates otherwise.

[0092] The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” may be used interchangeably.

[0093] 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).

[0094] The term “solvate” in the context of the present invention refers to a complex of defined stoichiometry formed between a solute in casu, a peptide or pharmaceutically acceptable salt thereof according to the invention) and a solvent. The solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable, typically small- molecular organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is normally referred to as a hydrate.

[0095] Sequence alignment can be carried out by the skilled person using techniques well known in the art, for example using publicly available software such as BLAST, BLAST2 or Align software. For examples, see Altschul et al., Methods in Enzymology 266: 460-480 (1996) or Pearson et al., Genomics 46: 24-36, 1997.

[0096] Percentage sequence identities used herein in the context of the present invention may be determined using these programs with their default settings. More generally, the skilled worker can readily determine appropriate parameters for determining alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0097] Amylin analogues

[0098] An amylin analogue is a molecule that is an amylin receptor agonist, i.e. the molecule is capable of binding to, and inducing signaling by, one or more receptors or receptor complexes regarded as physiological receptors for human amylin. The terms “amylin analogue” and “amylin receptor agonist” are used interchangeably herein. Amylin analogues may also be referred to as compounds, molecules or peptides herein.

[0099] Amylin analogues (which may also be referred herein to as compounds, molecules or peptides) may suitably be manufactured by standard synthetic methods. Thus, the peptides may be synthesized by, e.g., methods comprising synthesizing the peptide by standard solid-phase or liquid-phase methodology, either stepwise or by fragment assembly, and optionally isolating and purifying the final peptide product. The method typically further comprises the step of forming an amide bond between the side chains at positions 2 and 7, e.g. as described below. In the case of solid phase synthesis, cyclisation may be performed in situ on the solid phase (e.g. resin), i.e. before removal of the peptide from the solid phase.

[0100] Amylin analogues described herein may have the formula:

[0101] R1-Z-R2wherein:

[0102] R1is hydrogen, CM acyl, benzoyl or CM alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0103] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and

[0104] Z is an amino acid sequence of formula I: X1 -X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-Arg-X19-X20- Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) and wherein:

[0105] • X1 is selected from the group consisting of Arg, Lys and Glu;

[0106] • X3 is selected from the group consisting of Gly, Gin and Pro;

[0107] • X4 is selected from the group consisting of Thr and Glu;

[0108] • X5 is selected from the group consisting of Ala and Leu;

[0109] • X6 is selected from the group consisting of Thr and Ser;

[0110] • X10 is selected from the group consisting of Glu and Gin;

[0111] • X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0112] • X17 is selected from the group consisting of Gin, His and Thr;

[0113] • X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and

[0114] Ala-Asn or is absent;

[0115] • X27 is selected from the group consisting of Leu and Pro;

[0116] • X32 is selected from the group consisting of Vai and Thr;

[0117] • X35 is selected from the group consisting of Asn and Ser;

[0118] • X37 is selected from the group consisting of Hyp and Pro; and

[0119] • X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0120] • Gly(Me) is N-methylglycine [also known as sarcosine (Sar)]

[0121] • lle(Me) is N-methylisoleucine

[0122] • Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid] , also known as homo-glutamic acid; or a pharmaceutically acceptable salt or solvate thereof.

[0123] Preferably, the amylin analogue is petrelintide, which has the formula:

[0124] [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)-

[0125] LSSTEVGSNT-Hyp-NH2(SEQ ID NO: 3). wherein:

[0126] • Gly(Me): N-methylglycine [also known as sarcosine (Sar)]

[0127] • lle(Me): N-methylisoleucine

[0128] • Aad: 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2-aminohexanedioic acid], also known as homo-glutamic acid

[0129] • Hyp: 4-hydroxyproline, e.g. (2S,4R)-4-hydroxyproline [also denoted (4R)-4-hydroxy- L-proline] • [19CD]-isoGlu: the backbone nitrogen of an Arg residue (present at position X1 of the amylin analogue’s peptide sequence Z) is covalently attached to the side chain carboxyl group of a Glu moiety via an amide linkage. A 19-carboxy-nonadecanoyl group is covalently attached to the alpha amino group of the Glu linker via an amide linkage (as described below).

[0130] Parentheses “()” shown after the symbols for particular amino acid residues indicate residues whose side chains participate in an intramolecular lactam bridge. Thus, the amylin analogue compound of the invention has an intramolecular lactam bridge formed between the side chains of the residues (aspartic acid and lysine respectively) indicated by parentheses.

[0131] In preferred embodiments, the amylin analogue is petrelintide, which is a compound having the formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)-LSSTEVGSNT- Hyp-NH2(SEQ ID NO: 3) wherein an intramolecular lactam bridge is formed between the side chains of residues indicated by parentheses “()”; and wherein [19CD]-isoGlu is a 19-carboxynonadecanoyl group covalently attached to the alpha amino group of an iso-glutamic acid linker; or a pharmaceutically acceptable salt thereof.

[0132] Throughout the present description and claims the conventional three-letter and one-letter codes for naturally occurring amino acids are used, i.e.: 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); as well as generally accepted three-letter codes for other a-amino acids, such as sarcosine (Sar), norleucine (Nle), a-aminoisobutyric acid (Aib), 2,3-diaminopropanoic acid (Dap), 2,4-diaminobutanoic acid (Dab) and 2,5- diaminopentanoic acid (ornithine; Orn). Such other a-amino acids may be shown in square brackets “[ ]” (e.g. “[Aib]”) when used in a general formula or sequence in the present specification, especially when the rest of the formula or sequence is shown using the single letter code. Unless otherwise specified, amino acid residues in peptides of the invention are of the L-configuration. However, D-configuration amino acids may be incorporated. In the present context, an amino acid code written with a small letter represents the D-configuration of said amino acid, e.g. “k” represents the D-configuration of lysine (K).

[0133] The amylin analogue of SEQ ID NO: 3 is petrelintide, and may also be referred to as ZP8396. ZP8396 (petrelintide) is also described in detail in WO 2018 / 046719, which is incorporated herein by reference in its entirety. In WO 2018 / 046719, the amylin analogue of

[0134] SEQ ID NO: 3 (ZP8396, petrelintide) is also referred to as ‘compound 35’.

[0135] The amylin analogue may be in the form of a pharmaceutically acceptable salt or solvate, such as a pharmaceutically acceptable acid addition salt.

[0136] Half-life extending moieties M

[0137] As described herein, the N-terminal moiety R1in a compound of the invention may be a halflife extending moiety M (sometimes referred to in the literature as, inter alia, a duration enhancing moiety or albumin binding moiety), optionally linked (covalently attached) to the peptide moiety Z via a linker moiety L. Among suitable half-life extending moieties are certain types of lipophilic substituents. Without wishing to be bound by any particular theory, it is thought that such lipophilic substituents (and other classes of half-life extending moieties) bind albumin in the blood stream, thereby shielding the compound of the invention from renal filtration as well as enzymatic degradation and thus possibly enhancing the halflife of the compound in vivo. The lipophilic substituent may also modulate the potency of the compound as an agonist to the amylin (calcitonin) receptor.

[0138] The lipophilic substituent may be attached to the N-terminal amino acid residue or to the linker L via an ester, a sulfonyl ester, a thioester, an amide, an amine or a sulfonamide. Accordingly, it will be understood that preferably the lipophilic substituent includes an acyl group, a sulfonyl group, an N atom, an O atom or an S atom which forms part of the ester, sulfonyl ester, thioester, amide, amine or sulfonamide. Preferably, an acyl group in the lipophilic substituent forms part of an amide or ester with the amino acid residue or the linker.

[0139] The lipophilic substituent may comprise a hydrocarbon chain having from 10 to 24 C atoms, e.g. from 14 to 22 C atoms, e.g. from 16 to 20 C atoms. Preferably it has at least 14 C atoms, and preferably has 20 C atoms or fewer. For example, the hydrocarbon chain may contain 14, 15, 16, 17, 18, 19 or 20 carbon atoms. The hydrocarbon chain may be linear or branched, and may be saturated or unsaturated. Furthermore, it can include a functional group at the end of the hydrocarbon chain, e.g. a carboxylic acid group which may or may not be protected during synthesis. From the discussion above it will also be understood that the hydrocarbon chain is preferably substituted with a moiety which forms part of the attachment to the N-terminal amino acid residue of the peptide moiety Z or to the linker L, for example an acyl group, a sulfonyl group, an N atom, an O atom or an S atom. Most preferably, the hydrocarbon chain is substituted with an acyl group, and accordingly the hydrocarbon chain may be part of an alkanoyl group, for example a dodecanoyl, 2- butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl or eicosanoyl group. Examples of functionalized hydrocarbon chains are 15-carboxy- pentadecanoyl, 17-carboxy-heptadecanoyl and 19-carboxy-nonadecanoyl.

[0140] As mentioned above, a lipophilic substituent M may be linked to the N-terminal amino acid residue of Z via a linker L. In embodiments, the linker moiety L may itself comprise one, two, three or more linked sub-moieties L1, L2, L3, etc. When the linker L comprises only one such moiety, it is attached to the lipophilic substituent and to the N-terminal amino acid residue of Z. The linker may then be attached to the lipophilic substituent and to the N-terminal amino acid residue of Z independently by means of an ester, a sulfonyl ester, a thioester, an amide, an amine or a sulfonamide bond. Accordingly, it may include two moieties independently selected from acyl, sulfonyl, an N atom, an O atom and an S atom. The linker may consist of a linear or branched C1-10 hydrocarbon chain or more preferably a linear C1-5 hydrocarbon chain. Furthermore, the linker can be substituted with one or more substituents selected from C1-6 alkyl, amino C1-6 alkyl, hydroxy C1-6 alkyl and carboxy C1-6 alkyl.

[0141] In some embodiments the linker may comprise one or more (e.g. one, two or three) linked amino acid residues, which may each independently be a residue of any naturally occurring or non-naturally occurring amino acid. For example, the linker may comprise one, two or three linked amino acid residues, each of which may independently be a residue of Gly, Pro, Ala, Vai, Leu, lie, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gin, Asn, a-Glu, y-Glu, e-Lys, Asp, p-Asp, Ser, Thr, Gaba, Aib, p-Ala (i.e. 3-aminopropanoyl), 4-aminobutanoyl, 5- aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9- aminononanoyl, 10-aminodecanoyl or 8Ado (i.e. 8-amino-3,6-dioxaoctanoyl).

[0142] References to y-Glu, e-Lys, and p-Asp indicate residues of amino acids which participate in bonds via their side chain carboxyl or amine functional groups. Thus y-Glu, and p-Asp participate in bonds via their alpha amino and side chain carboxyl groups, while e-Lys participates via its carboxyl and side chain amino groups. In the context of the present invention, y-Glu and isoGlu are used interchangeably.

[0143] In certain embodiments, the linker comprises or consists of one, two or three independently selected residues of Glu, y-Glu, e -Lys, p-Ala, 4-aminobutanoyl, 8-aminooctanoyl or 8Ado. Linkers consisting of isoGlu and isoGlu-isoGlu may be particularly preferred.

[0144] An example of a lipophilic substituent comprising a lipophilic moiety M and linker L is shown in the formula below:

[0145] Here, the backbone nitrogen of an Arg residue (present at position X1 of the amylin analogue’s peptide sequence Z) is covalently attached to the side chain carboxyl group of a Glu moiety via an amide linkage. A 19-carboxy-nonadecanoyl group is covalently attached to the alpha amino group of the Glu linker via an amide linkage. Thus the Glu linker is in an iso-Glu (or y-Glu) configuration. This combination of lipophilic moiety and linker, attached to an Arg residue, may be referred to by the shorthand notation [19CD]-isoGlu-R, e.g. when shown in formulae of specific compounds.

[0146] The skilled person will be well aware of suitable techniques for preparing the compounds employed in the context of the invention. For examples of suitable chemistry, see, e.g., WO98 / 08871, WOOO / 55184, WOOO / 55119, Madsen et al (J. Med. Chem. 2007, 50, 6126- 32), and Knudsen et al. 2000 (J. Med Chem. 43, 1664-1669).

[0147] The hydrocarbon chain in a lipophilic substituent may be further substituted. For example, it may be further substituted with up to three substituents selected from NH2, OH and COOH. If the hydrocarbon chain is further substituted, it is preferably further substituted with only one substituent. Alternatively or additionally, the hydrocarbon chain may include a cycloalkane or heterocycloalkane moiety, for example as shown below: In some embodiments, the cycloalkane or heterocycloalkane moiety is a six-membered ring, e.g. a piperidine ring.

[0148] In alternative embodiments of the present invention, the N-terminal amino acid of Z in a compound of the invention may be linked (covalently attached) to a biotinylic substituent, optionally via a linker moiety L. Without wishing to be bound by any particular theory, it is likewise believed that such biotinylic substituents bind to albumin in the blood stream, thereby shielding the compound of the invention from enzymatic degradation and thus possibly enhancing the half-life of the compound in vivo. A linker, when present, may provide spacing between the peptide moiety Z and the biotinylic substituent.

[0149] The biotinylic substituent may be attached to the N-terminal amino acid residue or to the linker via an maleimide ester bond, a sulfonyl ester bond, a thioester bond, an amide bond, an amine bond or a sulfonamide bond. Accordingly, it will be understood that the biotinylic substituent preferably comprises an maleimido group, an acyl group, a sulfonyl group, an N atom, an O atom or an S atom which forms part of the ester, sulfonyl ester, thioester, amide, amine or sulfonamide bond in question.

[0150] Examples of biotinylic substituents may include

[0151] Biotin is known as Vitamin H or Coenzyme R, and is a water-soluble B-complex vitamin (vitamin B7). It has been shown to increase oral uptake of certain drugs.

[0152] Efficacy of compounds

[0153] The compounds (i.e. amylin analogues) of the invention are amylin receptor agonists, i.e. they are capable of binding to, and inducing signaling by one or more receptors or receptor complexes regarded as physiological receptors for human amylin. These include the human calcitonin receptor hCT-R, as well as complexes comprising the human calcitonin receptor hCT-R and at least one of the human receptor activity modifying proteins designated hRAMPI, hRAMP2 and hRAMP3. Complexes between hCT-R and hRAMPI, hRAMP2 and hRAMP3 are designated hAMYRI, hAMYR2 and hAMYR3 (i.e. human amylin receptors 1, 2 and 3) respectively.

[0154] A compound may be considered an amylin receptor agonist if it has agonist activity at one or more of hAMYRI, hAMYR2 and hAMYR3, e.g. against hAMYRI and / or hAMYR3, e.g. at hAMYR3.

[0155] Typically, an amylin receptor agonist will also have agonist activity at hCT-R when expressed in the absence of hRAMPI, hRAMP2 and hRAMP3. Typically, the agonist will have activity at hCT-R (when expressed in the absence of hRAMPI , hRAMP2 and hRAMP3) which is less than 10-fold higher than its activity at any one of hAMYRI, hAMYR2 and hAMYR3 (i.e. its activity at all of these receptors) in a comparable assay. Agonist activity at hCT-R may be less than 5-fold higher than agonist activity at hAMYRI , hAMYR2 and hAMYR3, substantially equal to (e.g. + / - 10%) agonist activity at hAMYRI, hAMYR2 and hAMYR3, or less than agonist activity at hAMYRI , hAMYR2 and hAMYR3. In this regard, it may be sufficient just to compare activity between hCT-R and hAMYR3.

[0156] The ability to induce cAMP formation (i.e. to induce adenylate cyclase activity) as a result of binding to the relevant receptor or receptor complex is typically regarded as indicative of agonist activity. Other intracellular signaling pathways or events may also be used as readouts for amylin receptor agonist activity. These may include calcium release, p-arrestin recruitment, receptor internalization, kinase activation or inactivation, lipase activation, inositol phosphate release, diacylglycerol release or nuclear transcription factor translocation.

[0157] A suitable comparable assay format would utilize cells which express hCT-R and which differ only in their expression of hRAMPI, 2 and 3. For example, a “base” cell line which does not express any of hCT-R, hRAMPI, hRAMP2 and hRAMP3 may be engineered to generate cells which express (i) hCT-R, and (ii) one of hAMYRI, hAMYR2 and hAMYR3 (i.e. hCT-R plus one of hRAMPI, hRAMP2 and hRAMP3), e.g. hAMYR3. The base cells will typically be mammalian cells and may be primate cells. They may be non-human primate cells. Preferably the base cell does not express any of CT-R, RAMP1, RAMP2 or RAMP3 (whether human, or native to the base cell if the base cell is non-human). The base cells may be fibroblast cells. Suitable non-human fibroblast base cells include COS7 cells, from African green monkey, which do not express native CT-R or RAMPs.

[0158] Comparative activity may be measured by any suitable means, such as via determination of EC50 values as described below. It will be apparent that the same biological read-out must be for both receptor types.

[0159] Compounds of the present invention may exhibit a number of advantageous properties in relation to human amylin and existing analogues thereof, such as pramlintide, IAPP-GI, and analogues described in WO2012 / 168430, WO2012 / 168431 and WO2012 / 168432. As compared to human amylin or any of those analogues, compounds of the invention may, for example, exhibit improved efficacy (e.g., in the form of improved in vitro activity or potency at one or more of the receptors hCT-R, hAMYRI, hAMYR2 or hAMYR3. Additionally, or alternatively, compounds of the invention may exhibit improved solubility in aqueous media, especially at pH values in the range from 4 to 7.5, or at a range of pH values across that range. Moreover, compounds of the present invention may additionally or alternatively exhibit reduced tendency to undergo fibrillation in pharmaceutically relevant aqueous media, especially at pH values in the range from 4 to 7, or at a range of pH values across that range. Furthermore, compounds of the present invention may additionally or alternatively exhibit improved chemical stability (i.e. reduced tendency to undergo chemical degradation) in aqueous media, especially at pH values in the range from 4 to 9, or at a range of pH values across that range.

[0160] Compounds of the invention may thus be well suited for formulation in acidic media (e.g. pH 4) and in neutral or near-neutral media (e.g. pH 7 or 7.4). In contrast to pramlintide, for example, which generally exhibits poor chemical stability and rapid fibrillation in pharmaceutically relevant aqueous media at neutral pH, compounds of the invention may be thus well suited for co-formulation with, for example, insulin, various insulin analogues and / or other therapeutic (e.g. anti-diabetic or anti-obesity) agents that require a neutral or nearneutral formulation pH.

[0161] Surprisingly, it has been found that the compounds (amylin analogues) of the present invention do not induce a delay in gastric emptying. As such, when administered to a subject, these compounds (amylin analogues) do not alter, such as do not slow down, gastric emptying. In general, it is preferred to use a biological assay which measures intracellular signalling caused by binding of the compound to the relevant receptor, as discussed above. Activation of the calcitonin / amylin receptor by compounds of the invention (which behave as agonists of the receptor) induces cAMP formation and activation of other intracellular signaling pathways and events. Thus, production of cAMP or any other suitable parameter in suitable cells expressing the receptor can be used to monitor agonist activity towards the receptor.

[0162] The skilled person will be aware of suitable assay formats, and examples are provided below. For example, the assays may make use of the human calcitonin receptor (hCT-R, e.g. isoform 2 of the hCT-R) or the hAMYR3 receptor (see the examples below). Where sequences of precursor proteins are referred to, it should be understood that assays may make use of the mature protein, lacking the signal sequence.

[0163] EC50 values may be used as a numerical measure of agonist potency at a given receptor. An EC50 value is a measure of the concentration of a compound required to achieve half of that compound’s maximal activity in a particular assay. Thus, for example, a compound having EC50 [hCT-R] lower than the EC50 [hCT-R] of native human amylin, or lower than that of pramlintide, in a particular assay may be considered to have higher potency or activity at the receptor than native human amylin, or higher than that of pramlintide, respectively.

[0164] In some embodiments of compounds of the present invention, the EC50 towards hCT-R is below about 1.5 nM (e.g. about 0.001 to about 1.5 nM).

[0165] In some embodiments of compounds of the present invention, the EC50 towards hCT-R is below about 0.9 nM (e.g. about 0.001 to about 0.9 nM).

[0166] In some embodiments of compounds of the present invention, the EC50 towards hCT-R is below about 0.5 nM (e.g. about 0.001 to about 0.5 nM).

[0167] In some embodiments of compounds of the present invention, the EC50 towards hCT-R is below about 0.3 nM (e.g. about 0.001 to about 0.3 nM).

[0168] In some embodiments of compounds of the present invention, the EC50 towards hCT-R is below about 0.2 nM (e.g. about 0.001 to about 0.2 nM). The ECso at hCT-R may be an indication of the effect of a compound on food intake, weight gain and / or weight loss. Compounds with lower ECso values at hCT-R may have a greater effect on these parameters.

[0169] In some embodiments of compounds of the present invention, the ECso towards hAMYR3 is below about 1.0 nM (e.g. about 0.001 to about 1.0 nM).

[0170] In some embodiments of compounds of the present invention, the ECso towards hAMYR3 is below about 0.5 nM (e.g. about 0.001 to about 0.5 nM).

[0171] In some embodiments of compounds of the present invention, the ECso towards hAMYR3 is below about 0.4 nM (e.g. about 0.001 to about 0.4 nM).

[0172] In some embodiments of compounds of the present invention, the ECso towards hAMYR3 is below about 0.3 nM (e.g. about 0.001 to about 0.3 nM).

[0173] In some embodiments of compounds of the present invention, the ECso towards hAMYR3 is below about 0.2 nM (e.g. about 0.001 to about 0.2 nM).

[0174] The ECso at hCT-R (when expressed in the absence of hRAMPI , hRAMP2 and hRAMP3) may be less than the ECso at any or all of hAMYRI , hAMYR2 and hAMYR3, e.g. at hAMYR3.

[0175] For example, the ECso at hCT-R (when expressed in the absence of hRAMPI , hRAMP2 and hRAMP3) may be less than 10-fold lower than the ECso at any or all of hAMYRI , hAMYR2 and hAMYR3, e.g. at hAMYR3.

[0176] The ECso at hCT-R (when expressed in the absence of hRAMPI , hRAMP2 and hRAMP3) may be less than 5-fold lower than the ECso at any or all of hAMYRI , hAMYR2 and hAMYR3, e.g. at hAMYR3.

[0177] The ECso at hCT-R (when expressed in the absence of hRAMPI , hRAMP2 and hRAMP3) may be substantially equal to (e.g. + / - 50%) the ECso at any or all of hAMYRI , hAMYR2 and hAMYR3, e.g. at hAMYR3. The ECso at hCT-R (when expressed in the absence of hRAMPI , hRAMP2 and hRAMP3) may be higher than the EC50 at any or all of hAMYRI , hAMYR2 and hAMYR3, e.g. at hAMYR3.

[0178] Gastric emptying

[0179] Gastric emptying refers to the process by which stomach contents are emptied into the duodenum.

[0180] Alterations to gastric emptying may affect the residence time of a given molecule within the stomach and may therefore alter the time taken for said molecule to reach a given downstream compartment, e.g., the duodenum, small intestine, and large intestine. As such, gastric emptying can delay the absorption of concomitantly administered oral medicaments.

[0181] Furthermore, a delay in gastric emptying can affect blood glucose levels and thus impact any concomitant agents (such as non-oral medicaments) used in the control thereof, e.g., insulin.

[0182] Peptide hormones in the prior art (particularly peptide hormones for reducing body weight or treatment of obesity and diabetes) are known to cause a delay in gastric emptying.

[0183] For example, tirzepatide (sold under the brand names Mounjaro and Zepbound) delays gastric emptying (llrva et al. Diabetes Obes Metab 202022 1886-1891), and thereby has the potential to impact the absorption of concomitantly administered oral medications. Subjects are advised to exercise caution when oral medications are concomitantly administered with Mounjaro. Physicians are advised to monitor subjects on oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with Mounjaro. Subjects using oral hormonal contraceptives are advised to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with Mounjaro.

[0184] In particular, prior art amylin analogues are known to cause a delay in gastric emptying. This delay impinges upon concomitant agents. For example, subjects receiving the amylin analogue Pramlintide (SYMLIN®) are advised to administer certain concomitant oral medicaments at least 1 hour before SYMLIN® administration or 2 hours after SYMLIN® administration. By way of further example, subjects receiving the amylin analogue Pramlintide (SYMLIN®) are also warned of the risks of severe hypoglycemia and are advised to reduce mealtime insulin doses, including that of premixed insulins, by 50% to reduce the risk of hypoglycemia and thereafter closely monitor blood glucose.

[0185] Thus, as well as facilitating dosage regimens wherein the timing of a concomitant agent is unaffected by administration of the amylin analogue of the invention, the invention also provides for regimens wherein the dose of a concomitant agent is unaffected by administration of the amylin analogue of the invention.

[0186] Furthermore, subjects are also advised not to administer SYMLIN® if they are already taking medications that alter gastrointestinal motility (https: / / www.rxlist.com / symlin- drug.htm#warnings).

[0187] Amylin analogues of the present invention do not affect gastric emptying. In other words, amylin analogues of the present invention do not slow gastric emptying.

[0188] It is envisaged that, due to an absence of delayed gastric emptying, such considerations will not be applicable to the amylin analogues of the present invention.

[0189] Gastric emptying is measured by the acetaminophen absorption test. In this test, a fasted subject is given an oral dose of acetaminophen at the same time as a standardized meal. The concentration of acetaminophen in the blood is followed after the meal. When comparing the concentration of acetaminophen in the blood of those treated with an amylin analogue with the acetaminophen concentration in subjects treated with placebo, this can be used as an indication of the relative speed of gastric emptying. It can be readily determined whether a given amylin analogue affects (i.e. slows) gastric emptying using the acetaminophen test.

[0190] Concomitant agent

[0191] In the dosage regimens, methods and medical uses of the invention, the amylin analogue of the invention is administered to a subject within about 120 minutes of (such as at the same time as) a concomitant agent.

[0192] A concomitant agent is an agent (such as a medicament, compound, molecule or supplement) that is used (e.g. administered to the subject) at the same time or a similar time (e.g. within two hours) to the amylin analogue. A “concomitant agent” may also be referred to as an “additional agent”. The term “concomitant agent” does not impose or imply any relationship between the amylin analogue and concomitant agent other than a temporal one (i.e., them being administered at a similar time).

[0193] The concomitant agent is different to the amylin analogue that does not affect the rate of gastric emptying to the subject.

[0194] The concomitant agent may be a medicament (i.e. an agent which treats a disease or disorder). The concomitant agent may be a non-medicament, such as a nutritional supplement. The concomitant agent may be any agent which is not an amylin analogue. The term “concomitant agent” may refer to any number of concomitant agents that are not an amylin analogue.

[0195] The concomitant agent may be any agent for which the administration of said agent is affected by the rate of gastric emptying. Preferably, the concomitant agent is an agent for which effectiveness is affected by the rate of gastric emptying. For example, where rapid onset of a medicament or a threshold concentration is required for therapeutic efficacy, a concomitant agent - in particular orally administered medicaments - may be dependent upon the rate of gastric emptying. Such medicaments include analgesics, antibiotics, and contraceptives.

[0196] In some embodiments the concomitant agent is a medicament for which rapid onset is required. In some embodiments the concomitant agent is an oral medicament for which rapid onset is required.

[0197] In some embodiments the concomitant agent is an oral medicament.

[0198] In some embodiments the concomitant agent is an analgesic.

[0199] In some embodiments the concomitant agent is an antibiotic.

[0200] In some embodiments the concomitant agent is an oral contraceptive.

[0201] In some embodiments the concomitant agent is a nutritional supplement.

[0202] In some embodiments the concomitant agent is a non-oral medicament. In some embodiment the concomitant agent is administered intravenously, intramuscularly, or subcutaneously.

[0203] In some embodiments the concomitant agent is selected from the group consisting of: analgesics, antibiotics, anti-coagulants, contraceptives, anti-hypotensive medicine, statins, antifungals, hypoglycemic agents, contraceptives, oral medicines with narrow therapeutic index and nutritional supplements.

[0204] In some embodiments the concomitant agent is selected from the group consisting of: insulin, acetaminophen, digoxin, warfarin, metformin, hydrocortisone, griseofulvin, glibenclamide, gliclazide, and glipizide.

[0205] In some embodiments the concomitant agent is a Sulfonylurea, such as glibenclamide, gliclazide, glipizide.

[0206] In some embodiments the concomitant agent is insulin.

[0207] A subject may be independently administered one or more concomitant agents, as defined herein. For example, in the case of a subject being administered, for example, three medicaments at the same time as the amylin analogue of the invention, each of the three medicaments would independently be considered a “concomitant agent” in accordance with the present invention.

[0208] Thus, in some embodiments, the amylin analogue is administered to the subject at the same time as (within about 120 minutes of) at least one concomitant agent, such as at least two concomitant agents, at least three concomitant agents, at least four concomitant agents, at least five concomitant agents, at least six concomitant agents, at least seven concomitant agents, at least eight concomitant agents, at least nine concomitant agents, or at least ten concomitant agents.

[0209] In some embodiments, the amylin analogue is administered to the subject at the same time as (within about 120 minutes of) one or more concomitant agent, such as two or more concomitant agents, three or more concomitant agents, four or more concomitant agents, five or more concomitant agents, six or more concomitant agents, seven or more concomitant agents, eight or more concomitant agents, nine or more concomitant agents, or ten or more concomitant agents. In some embodiments, the amylin analogue is administered to the subject at the same time as (within about 120 minutes of) one concomitant agent, two concomitant agents, three concomitant agents, four concomitant agents, five concomitant agents, six concomitant agents, seven concomitant agents, eight concomitant agents, nine concomitant agents, or ten concomitant agents.

[0210] Timing of administration

[0211] Surprisingly, the amylin analogues of the invention do not result in any appreciable delay in gastric emptying. As such, these compounds are suitable for administration at the same time as, or close in time to, other compounds or medicaments, i.e. , concomitant agents.

[0212] In particular, where a medicament is dosed orally its administration can be sensitive to gastric emptying, and its administration will be dependent upon the administration of any other medicament that delays gastric emptying, such as prior art amylin analogues.

[0213] For example, it may be necessary to delay administration of a medicament until 2 hours or more have passed since administration of an amylin analogue that delays gastric emptying. Alternatively, it may be necessary to bring forward administration of the medicament (or delay administration of the amylin analogue) such that at least one hour has passed following administration of the medicament, before administering the amylin analogue.

[0214] In both cases, administration of the medicaments is temporally interdependent. As such, the subject may have to alter existing dosage regimens, devise onerous new administration regimes, and / or risk drug-drug interactions that reduce the efficacy of the non-amylin analogue medicament.

[0215] Advantageously, the amylin analogues of the present invention having no effect on gastric emptying - i.e., not delaying it as amylin and other hormone peptide therapeutics and amylin analogues do - means that timing of the administration of one or more other (non-amylin analogue) agents to the subject does not need to be adjusted to account for administration of the amylin analogues of the invention. For example, the amylin analogues of the present invention advantageously do not delay gastric emptying, unlike tirzepatide or pramlintide.

[0216] Hence, the timing of administration of the amylin analogue does not affect the timing of administration of the concomitant agent. Thus, administration of the amylin analogue and administration of the concomitant agent are essentially temporally independent. Put another way, the amylin analogues of the invention allow for temporally independent administration of the amylin analogue of the invention and one or more concomitant agents.

[0217] Thus, in the dosage regimens, methods and medical uses of the invention, the amylin analogue of the invention is administered to a subject within about 120 minutes of (such as at the same time as) administration of the concomitant agent to the subject.

[0218] It will be understood that the concomitant agent, when not administered concomitantly with an amylin analogue of the invention, may be administered at any time, such as a time dictated by any dosage regimen for said concomitant agent. Thus, the administration of the concomitant agent is not limited by the administration of the amylin analogue.

[0219] The amylin analogue and concomitant agent may be administered independently of one another. It will be understood that the order in which the amylin analogue and concomitant agent are presented herein does not limit the order of their administration. Thus, the amylin analogue may be administered before, at the same time, or after the concomitant agent, and vice versa.

[0220] The present invention allows the amylin analogue to be administered to the subject at the same time as one or more concomitant agents are also administered to the subject. Practically, the amylin analogue and concomitant agent may be administered to the subject close in time (i.e. at a similar time) to one another, though not necessarily at precisely the same moment. The key factor is that the invention allows administration of the concomitant agent at a point in time relative to administration of the amylin analogue which would not otherwise be possible were it not for the amylin analogue of the invention not delaying gastric emptying.

[0221] Thus, in some embodiments, the amylin analogue is administered to the subject within about 120 minutes of administration to the subject of the concomitant agent, such as within about 110 minutes, such as within about 100 minutes, such as within about 90 minutes, such as within about 80 minutes, such as within about 70 minutes, such as within about 60 minutes, such as within about 50 minutes, such as within about 45 minutes, such as within about 40 minutes, such as within about 30 minutes, such as within about 20 minutes, such as within about 15 minutes, such as within about 10 minutes, such as within about 9 minutes, such as within about 8 minutes, such as within about 7 minutes, such as within about 6 minutes, such as within about 5 minutes, such as within about 4 minutes, such as within about 3 minutes, such as within about 2 minutes, or such as within about 1 minute, of administration to the subject of the concomitant agent.

[0222] In some embodiments, the amylin analogue is administered to the subject before the concomitant agent is administered to the subject. In some embodiments, the amylin analogue is administered to the subject about 120 minutes before administration to the subject of the concomitant agent, such as about 110 minutes before, such as about 100 minutes before, such as about 90 minutes before, such as about 80 minutes before, such as about 70 minutes before, such as about 60 minutes before, such as about 50 minutes before, such as about 45 minutes before, such as about 40 minutes before, such as about 30 minutes before, such as about 20 minutes before, such as about 15 minutes before, such as about 10 minutes before, such as about 9 minutes before, such as about 8 minutes before, such as about 7 minutes before, such as about 6 minutes before, such as about 5 minutes before, such as about 4 minutes before, such as about 3 minutes before, such as about 2 minutes before, or such as about 1 minute before, administration to the subject of the concomitant agent.

[0223] In one embodiment, the amylin analogue is administered to the subject after the concomitant agent is administered to the subject. In some embodiments, the amylin analogue is administered to the subject about 120 minutes after administration to the subject of the concomitant agent, such as about 110 minutes after, such as about 100 minutes after, such as about 90 minutes after, such as about 80 minutes after, such as about 70 minutes after, such as about 60 minutes after, such as about 50 minutes after, such as about 45 minutes after, such as about 40 minutes after, such as about 30 minutes after, such as about 20 minutes after, such as about 15 minutes after, such as about 10 minutes after, such as about 9 minutes after, such as about 8 minutes after, such as about 7 minutes after, such as about

[0224] 6 minutes after, such as about 5 minutes after, such as about 4 minutes after, such as about

[0225] 3 minutes after, such as about 2 minutes after, or such as about 1 minute after, administration to the subject of the concomitant agent.

[0226] In some embodiments, the amylin analogue is administered to the subject at the same time as the concomitant agent is administered to the subject. By at the same time it will be understood that administration occurs at substantially the same time, such as within 5 minutes of one another. Dose and dosage

[0227] Herein, the term “dose” refers to the quantity of a given compound (amylin analogue or concomitant agent) administered to a subject at each administration event. The term “dosage” refers to both the quantity and frequency at which a given compound is administered to a subject.

[0228] The dosage of the amylin analogue may be independently selected from the dosage of the concomitant agent.

[0229] A typical dosage of an amylin analogue as employed in the present invention may be in the range from about 0.0001 to about 100 mg / kg body weight per day or every other day, such as from about 0.0005 to about 50 mg / kg body weight per day or every other day, such as from about 0.001 to about 10 mg / kg body weight per day or every other day, e.g. from about 0.01 to about 1 mg / kg body weight per day or every other day, administered in one or more doses, such as from one to three doses. The exact dosage employed will depend, inter alia, on: the nature and severity of the disease or disorder to be treated, on the sex, age, body weight and general condition of the subject to be treated, on possible other, concomitant, disease or disorder that is undergoing or is to undergo treatment, as well as on other factors that will be known to a medical practitioner of skill in the art.

[0230] A typical dosage of an amylin analogue as employed in the present invention may be in the range from about 0.5 mg to about 10.0 mg per day or every other day, about 0.6 mg to about 7.5 mg per day or every other day, preferably about 1.2 mg to about 7.5 mg per day or every other day, preferably about 1.2 to about 6.0 mg per day or every other day, preferably about 2.4 to about 6.0 mg per day or every other day, preferably about 2.4 to about 4.0 mg per day or every other day, preferably about 2.4 to about 3.5 mg per day or every other day.

[0231] In some embodiments, the amylin analogue is administered to the subject at a dose of from about 0.04 mg to about 10 mg, such as about 0.04 mg to about 7 mg, about 0.04 mg to about 6 mg, about 0.04 mg to about 4.4 mg, about 0.04 mg to about 2.4 mg, about 0.6 mg to about 6 mg, about 0.6 mg to about 4.4 mg, about 0.6 mg to about 2.4 mg, about 0.7 mg to about 6 mg, about 0.7 mg to about 4.4 mg, or about 0.7 mg to about 2.4 mg.

[0232] In some embodiments, the amylin analogue is administered to the subject at a dose of from about 0.6 mg to about 4.8 mg, about 0.6 mg to about 3.6 mg, about 0.6 mg to about 2.4 mg, or about 0.6 mg to about 1.2 mg. In some embodiments, the amylin analogue is administered to the subject at a dose of from about 1.2 mg to about 4.8 mg, about 1.2 mg to about 3.6 mg, or about 1.2 mg to about 2.4 mg. In some embodiments, the amylin analogue is administered to the subject at a dose of from about 2.4 mg to about 4.8 mg, or about 2.4 mg to about 3.6 mg. In some embodiments, the amylin analogue is administered to the subject at a dose of from about 3.6 mg to about 4.8 mg.

[0233] In some embodiments, the amylin analogue is administered to the subject at a dose of up to about 10 mg, such as up to about 9.5 mg, up to about 9 mg, up to about 8.5 mg, up to about 8 mg, up to about 7.5 mg, up to about 7 mg, up to about 6.5 mg, up to about 6 mg, up to about 5.5 mg, up to about 5 mg, up to about 4.8 mg, up to about 4.5 mg, up to about 4 mg, up to about 3.6 mg, up to about 3.5 mg, up to about 3 mg, up to about 2.5 mg, up to about 2.4 mg, up to about 2 mg, up to about 1.5 mg, up to about 1.2 mg, up to about 1 mg, up to about 0.6 mg, up to about 0.5 mg, or up to about 0.25 mg.

[0234] In some embodiments, the amylin analogue is administered to the subject at a dose of about 10 mg, such as about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.8 mg, about 4.5 mg, about 4.4 mg, about 4 mg, about 3.6 mg, about 3.5 mg, about 3.4 mg, about 3 mg, about 2.5 mg, about 2.4 mg, about 2 mg, about 1.5 mg, about 1.4 mg, about 1.2 mg, about 1 mg, about 0.6 mg, about 0.5 mg, about 0.35 mg, about 0.25 mg, about 0.16 mg, about 0.08 mg, or about 0.04mg.

[0235] In some embodiments, the amylin analogue according to the invention is administered at regular intervals. In some embodiments, the amylin analogue is administered to the subject once a day, once every two days, once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the amylin analogue is administered to the subject once a month.

[0236] In some embodiments, the dose of amylin analogue is not the same during each administration. In some embodiments, the dose of amylin analogue is increased for each successive administration. In some embodiments, the dose of amylin analogue is increased for each successive administration until a desired maximum dose is reached. Optionally, the desired maximum dose may be maintained over a given time period (i.e. the dosage plateaus). In some embodiments, the dose of amylin analogue is the same during each administration. Advantageously, the amylin analogues of the present invention having no effect on gastric emptying - i.e., not delaying it as amylin and other amylin analogues do - means that the dose or dosage of the one or more other (non-amylin analogue) agents administered to the subject does not need to be adjusted to account for administration of the amylin analogues of the invention.

[0237] Hence, the administration of the amylin analogue does not affect the dose or dosage of the administered concomitant agent. Thus, the dose or dosage of amylin analogue and concomitant agent are essentially independent. Put another way, the amylin analogues of the invention allow for independent dose selection for the administration of the amylin analogue of the invention and one or more concomitant agents. Thus, the administration of the concomitant agent is not limited by the administration of the amylin analogue.

[0238] Thus, in the dosage regimens, methods and medical uses of the invention, the amylin analogue of the invention and a concomitant agent is administered to a subject, wherein the dose of the administered concomitant agent is unaltered relative to the dose of the concomitant agent administered in the absence of the amylin analogue.

[0239] Further, in the dosage regimens, methods and medical uses of the invention, the amylin analogue of the invention is administered to a subject within about 120 minutes of (such as at the same time as) administration of the concomitant agent to the subject and the dose of the administered concomitant agent is unaltered relative to the dose administered in the absence of the amylin analogue.

[0240] The concomitant agent may be an agent for which the administered dose is dependent upon the rate of gastric emptying, optionally wherein said dependence is due to blood glucose levels or the rate of change thereof.

[0241] According to the foregoing, the concomitant agent may be an oral hypoglycemic agent such as a Sulfonylurea. In further embodiments, the oral hypoglycemic agent is glibenclamide, gliclazide, and / or glipizide.

[0242] Further, according to the foregoing, the concomitant agent is insulin.

[0243] It will be understood that the dose or dosage of the concomitant agent may be adjusted independently of the timing and / or dose of amylin analogue administration. Dosage regimen

[0244] The invention provides a dosage regimen for a subject, wherein the dosage regimen comprises:

[0245] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0246] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0247] R1-Z-R2wherein:

[0248] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0249] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I:

[0250] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0251] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37 (SEQ ID NO: 4) wherein:

[0252] X1 is selected from the group consisting of Arg, Lys and Glu;

[0253] X3 is selected from the group consisting of Gly, Gin and Pro;

[0254] X4 is selected from the group consisting of Thr and Glu;

[0255] X5 is selected from the group consisting of Ala and Leu;

[0256] X6 is selected from the group consisting of Thr and Ser;

[0257] X10 is selected from the group consisting of Glu and Gin;

[0258] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0259] X17 is selected from the group consisting of Gin, His and Thr;

[0260] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0261] X27 is selected from the group consisting of Leu and Pro;

[0262] X32 is selected from the group consisting of Vai and Thr;

[0263] X35 is selected from the group consisting of Asn and Ser;

[0264] X37 is selected from the group consisting of Hyp and Pro; and

[0265] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0266] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0267] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0268] In some embodiments, the invention provides a dosage regimen for a subject, wherein the dosage regimen comprises:

[0269] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0270] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)- LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 3), wherein:

[0271] Gly(Me): N-methylglycine [also known as sarcosine (Sar)] lle(Me): N-methylisoleucine

[0272] Aad: 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2-aminohexanedioic acid], also known as homo-glutamic acid

[0273] Hyp: 4-hydroxyproline, e.g. (2S,4R)-4-hydroxyproline [also denoted (4R)-4-hydroxy- L-proline]

[0274] [19CD]-isoGlu: the backbone nitrogen of an Arg residue (present at position X1 of the amylin analogue’s peptide sequence Z) is covalently attached to the side chain carboxyl group of a Glu moiety via an amide linkage; 19-carboxy-nonadecanoyl group is covalently attached to the alpha amino group of the Glu linker via an amide linkage (as described herein); or a pharmaceutically acceptable salt and / or derivative thereof.

[0275] In one embodiment, the invention provides a dosage regimen for a subject, wherein the dosage regimen comprises:

[0276] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0277] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; the amylin analogue comprises or consists of a peptide of formula:

[0278] R1-Z-R2wherein:

[0279] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0280] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I:

[0281] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0282] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37 (SEQ ID NO: 4) wherein:

[0283] X1 is selected from the group consisting of Arg, Lys and Glu;

[0284] X3 is selected from the group consisting of Gly, Gin and Pro;

[0285] X4 is selected from the group consisting of Thr and Glu;

[0286] X5 is selected from the group consisting of Ala and Leu;

[0287] X6 is selected from the group consisting of Thr and Ser;

[0288] X10 is selected from the group consisting of Glu and Gin;

[0289] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0290] X17 is selected from the group consisting of Gin, His and Thr;

[0291] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0292] X27 is selected from the group consisting of Leu and Pro;

[0293] X32 is selected from the group consisting of Vai and Thr;

[0294] X35 is selected from the group consisting of Asn and Ser;

[0295] X37 is selected from the group consisting of Hyp and Pro; and

[0296] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0297] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0298] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof; and the dose of the administered concomitant agent is unaltered relative to the dose of concomitant agent administered in the absence of the amylin analogue. Methods of inhibiting weight gain or reducing body weight

[0299] The invention provides a method of inhibiting weight gain and / or reducing body weight in a subject, wherein the method comprises:

[0300] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0301] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0302] R1-Z-R2wherein:

[0303] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0304] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I:

[0305] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0306] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37(SEQ ID NO: 4) wherein:

[0307] X1 is selected from the group consisting of Arg, Lys and Glu;

[0308] X3 is selected from the group consisting of Gly, Gin and Pro;

[0309] X4 is selected from the group consisting of Thr and Glu;

[0310] X5 is selected from the group consisting of Ala and Leu;

[0311] X6 is selected from the group consisting of Thr and Ser;

[0312] X10 is selected from the group consisting of Glu and Gin;

[0313] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0314] X17 is selected from the group consisting of Gin, His and Thr;

[0315] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0316] X27 is selected from the group consisting of Leu and Pro;

[0317] X32 is selected from the group consisting of Vai and Thr;

[0318] X35 is selected from the group consisting of Asn and Ser;

[0319] X37 is selected from the group consisting of Hyp and Pro; and

[0320] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0321] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0322] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0323] In some embodiments, the invention provides a method of inhibiting weight gain and / or reducing body weight in a subject, wherein the method comprises:

[0324] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0325] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)- LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 3), wherein:

[0326] Gly(Me): N-methylglycine [also known as sarcosine (Sar)] lle(Me): N-methylisoleucine

[0327] Aad: 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2-aminohexanedioic acid], also known as homo-glutamic acid

[0328] Hyp: 4-hydroxyproline, e.g. (2S,4R)-4-hydroxyproline [also denoted (4R)-4-hydroxy- L-proline]

[0329] [19CD]-isoGlu: the backbone nitrogen of an Arg residue (present at position X1 of the amylin analogue’s peptide sequence Z) is covalently attached to the side chain carboxyl group of a Glu moiety via an amide linkage; 19-carboxy-nonadecanoyl group is covalently attached to the alpha amino group of the Glu linker via an amide linkage (as described herein); or a pharmaceutically acceptable salt and / or derivative thereof.

[0330] Suppression of glucagon secretion and food intake associated with amylin and amylin analogues may promote weight loss, or at least slow (i.e. reduce or inhibit) weight gain. Thus, the method of the invention may be expressed as a method of inhibiting or reducing weight gain, a method of promoting weight loss, a method of reducing food intake, and / or a method of reducing body weight in a subject. Non-therapeutic uses

[0331] The amylin analogue of the invention may be used for non-therapeutic purposes. In this respect, it may be desirable for a subject to reduce food intake so as to lose weight (or inhibit weight gain) despite the subject not being overweight, obese, diabetic or suffering from any other weight-related disease, such as for cosmetic reasons. Administration of an amylin analogue may achieve these desired effects (reduced food intake, weight loss and / or inhibited weight gain). In such embodiments, administration of the amylin analogue would not be therapeutic as no disease or disorder is being treated by the amylin analogue.

[0332] Likewise, the concomitant agent is not required to be a medicament, and does not necessarily have a therapeutic effect. For example, a concomitant agent that is a nutritional supplement would not have a therapeutic effect.

[0333] Thus, in some embodiments the dosing regimen of the invention is a non-therapeutic dosing regimen. The invention therefore provides a non-therapeutic dosage regimen for a subject, wherein the dosage regimen comprises:

[0334] (a) administering the amylin analogue that does not affect the rate of gastric emptying of the invention to the subject; and

[0335] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another.

[0336] In some embodiments, the method of inhibiting weight gain and / or reducing body weight in a subject is a non-therapeutic method. The invention therefore provides a non-therapeutic method of inhibiting weight gain and / or reducing body weight in a subject, wherein the method comprises:

[0337] (a) administering an amylin analogue that does not affect the rate of gastric emptying of the invention to the subject; and

[0338] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another.

[0339] In some embodiments, the method of inhibiting weight gain and / or reducing body weight in a subject is a cosmetic method. Considerations regarding gastric emptying and concomitant agents (i.e., the second medicaments) as outlined herein apply equally when the amylin analogue is used for therapeutic and non-therapeutic purposes.

[0340] Such non-therapeutic methods aim to reduce body weight of subjects that are not obese or morbidly obese.

[0341] In some embodiments of the non-therapeutic methods 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. In some embodiments, the subject has a BMI of 18.5 to 24.9 kg / m2corresponding to healthy weight.

[0342] In some embodiments of the non-therapeutic methods of the invention, 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.

[0343] Therapeutic uses

[0344] In accordance with the surprising finding that the amylin analogues described herein do not stimulate delayed gastric emptying, they have utility in a number of therapeutic settings. The amylin analogues of the invention are useful in the treatment or prevention of disease.

[0345] More specifically, the amylin analogues of the invention are useful, inter alia, in the reduction of food intake, promotion of weight loss, and inhibition or reduction of weight gain. They may therefore provide an attractive treatment option for, inter alia, obesity and metabolic diseases caused, characterised by, or associated with, excess body weight. Treatment may be achieved, for example, by control of appetite, feeding, food intake, calorie intake and / or energy expenditure.

[0346] 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. Accordingly, "treatment" refers both to therapeutic treatment and to prophylactic or preventative measures. As used in the context of prophylactic or preventative measures, the amylin analogue or concomitant agent need not completely prevent the development of the disease or 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, and is not necessarily meant to imply complete cessation or cure of the relevant condition. The term “prevention” (as well as “preventing” and other grammatical variants thereof) refers to prophylaxis of disease, such as by reducing symptoms of disease.

[0347] A subject may be taking any number of other medicaments (i.e. not the amylin analogues described herein) in order to prevent or treat any number of the diseases or disorders described herein, or indeed, any other diseases or disorders. As such, the amylin analogues described herein are particularly advantageous as they do not interfere with the administration of such other medicaments, as described elsewhere herein.

[0348] Methods of treatment

[0349] Accordingly, the invention provides a method of treating or preventing a disease in a subject, wherein the method comprises:

[0350] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0351] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0352] R1-Z-R2wherein:

[0353] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0354] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I: X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0355] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-

[0356] Ser-X35-Thr-X37(SEQ ID NO: 4) wherein:

[0357] X1 is selected from the group consisting of Arg, Lys and Glu;

[0358] X3 is selected from the group consisting of Gly, Gin and Pro;

[0359] X4 is selected from the group consisting of Thr and Glu;

[0360] X5 is selected from the group consisting of Ala and Leu;

[0361] X6 is selected from the group consisting of Thr and Ser;

[0362] X10 is selected from the group consisting of Glu and Gin;

[0363] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0364] X17 is selected from the group consisting of Gin, His and Thr;

[0365] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0366] X27 is selected from the group consisting of Leu and Pro;

[0367] X32 is selected from the group consisting of Vai and Thr;

[0368] X35 is selected from the group consisting of Asn and Ser;

[0369] X37 is selected from the group consisting of Hyp and Pro; and

[0370] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0371] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0372] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0373] In some embodiments, the invention provides a method of treating or preventing a disease in a subject, wherein the method comprises:

[0374] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0375] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about

[0376] 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0377] [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)-

[0378] LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 3), wherein:

[0379] Gly(Me): N-methylglycine [also known as sarcosine (Sar)] lle(Me): N-methylisoleucine

[0380] Aad: 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2-aminohexanedioic acid], also known as homo-glutamic acid

[0381] Hyp: 4-hydroxyproline, e.g. (2S,4R)-4-hydroxyproline [also denoted (4R)-4-hydroxy- L-proline]

[0382] [19CD]-isoGlu: the backbone nitrogen of an Arg residue (present at position X1 of the amylin analogue’s peptide sequence Z) is covalently attached to the side chain carboxyl group of a Glu moiety via an amide linkage; 19-carboxy-nonadecanoyl group is covalently attached to the alpha amino group of the Glu linker via an amide linkage (as described herein); or a pharmaceutically acceptable salt and / or derivative thereof.

[0383] In some embodiments, the invention provides a method for treating a subject without altering (such as delaying) gastric emptying, said method comprising administering an amylin analogue according to the present invention to a subject in need thereof.

[0384] In some embodiments, the invention provides a method for maintaining a normal administration regimen of one or more concomitantly administered medicaments in a subject in need of treatment with an amylin analogue, wherein the method comprises administering to the subject an amylin analogue according to the present invention.

[0385] Medical uses

[0386] The invention also provides an amylin analogue that does not affect the rate of gastric emptying for use in a method of treating or preventing a disease in a subject, wherein the method comprises:

[0387] (a) administering the amylin analogue to the subject; and

[0388] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0389] R1-Z-R2wherein:

[0390] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L; R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I:

[0391] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0392] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37 (SEQ ID NO: 4) wherein:

[0393] X1 is selected from the group consisting of Arg, Lys and Glu;

[0394] X3 is selected from the group consisting of Gly, Gin and Pro;

[0395] X4 is selected from the group consisting of Thr and Glu;

[0396] X5 is selected from the group consisting of Ala and Leu;

[0397] X6 is selected from the group consisting of Thr and Ser;

[0398] X10 is selected from the group consisting of Glu and Gin;

[0399] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0400] X17 is selected from the group consisting of Gin, His and Thr;

[0401] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0402] X27 is selected from the group consisting of Leu and Pro;

[0403] X32 is selected from the group consisting of Vai and Thr;

[0404] X35 is selected from the group consisting of Asn and Ser;

[0405] X37 is selected from the group consisting of Hyp and Pro; and

[0406] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0407] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0408] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0409] The invention also provides use of an amylin analogue that does not affect the rate of gastric emptying for manufacture of a medicament for use in a method of treating or preventing a disease in a subject, wherein the method comprises:

[0410] (a) administering the amylin analogue to the subject; and

[0411] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula: R1-Z-R2wherein:

[0412] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0413] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and

[0414] Z is an amino acid sequence of formula I:

[0415] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0416] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37(SEQ ID NO: 4) wherein:

[0417] X1 is selected from the group consisting of Arg, Lys and Glu;

[0418] X3 is selected from the group consisting of Gly, Gin and Pro;

[0419] X4 is selected from the group consisting of Thr and Glu;

[0420] X5 is selected from the group consisting of Ala and Leu;

[0421] X6 is selected from the group consisting of Thr and Ser;

[0422] X10 is selected from the group consisting of Glu and Gin;

[0423] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0424] X17 is selected from the group consisting of Gin, His and Thr;

[0425] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0426] X27 is selected from the group consisting of Leu and Pro;

[0427] X32 is selected from the group consisting of Vai and Thr;

[0428] X35 is selected from the group consisting of Asn and Ser;

[0429] X37 is selected from the group consisting of Hyp and Pro; and

[0430] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0431] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0432] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0433] In some embodiments, the invention provides an amylin analogue according to the present invention for use in therapy, wherein the amylin analogue does not alter gastric emptying.

[0434] In some embodiments, the invention provides an amylin analogue according to the present invention for use in therapy, wherein the amylin analogue does not slow gastric emptying. In some embodiments, the invention provides an amylin analogue according to the present invention for use in a method of treating or preventing obesity, overweight and / or diabetes whilst maintaining normal gastric emptying.

[0435] In some embodiments, the invention provides an amylin analogue according to the present invention for use in a method of treating or preventing obesity, overweight and / or diabetes whilst not delaying gastric emptying.

[0436] 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.

[0437] 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.

[0438] 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.

[0439] In some embodiments, the invention provides an amylin analogue according to the present invention for use in a method of treating a subject in need thereof wherein said subject is receiving one or more concomitantly administered medicaments.

[0440] Diseases

[0441] The terms “disease”, “disorder” and “condition” are synonymous and are used interchangeably herein to refer to a state of malfunction of the body.

[0442] The amylin analogue of the invention may be used to treat obesity as well as associated diseases, disorders and health conditions, including, but not limited to, morbid obesity, obesity prior to surgery, obesity-linked inflammation, obesity-linked gallbladder disease and obesity-induced sleep apnea and respiratory problems, degeneration of cartilage, osteoarthritis, and reproductive health complications of obesity or overweight such as infertility.

[0443] Thus, in some embodiments of the dosage regimens, methods and medical uses of the invention, the disease is overweight, obesity, morbid obesity, diabetes, or a disease linked to obesity or to diabetes. In other words, in some embodiments of the dosage regimens, methods and medical uses of the invention, the subject is overweight, has obesity, has morbid obesity, has diabetes, or has a disease linked to obesity or to diabetes. Diabetes may be type 1 diabetes or type 2 diabetes.

[0444] In some embodiments of the dosage regimens, methods and medical uses of the invention, the disease linked to obesity or to diabetes is selected from the group consisting of: obesity- linked inflammation, obesity-linked gallbladder disease, obesity-induced sleep apnea, obesity-linked respiratory problems, degeneration of cartilage, osteoarthritis, infertility, Alzheimer’s disease, pre-diabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, metabolic disease, metabolic syndrome, hyperglycemia, hypertension, atherogenic dyslipidemia, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), kidney failure, arteriosclerosis, macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a diabetic complication, coronary heart disease, peripheral artery disease and stroke.

[0445] The compounds may also be useful in lowering circulating LDL levels and / or increasing HDL / LDL ratio.

[0446] The effects of the compounds described above may be mediated in whole or in part via an effect on body weight, or may be independent thereof.

[0447] Metabolic syndrome is characterized by a group of metabolic risk factors in one person. They include abdominal obesity (excessive fat tissue around the abdominal internal organs), atherogenic dyslipidemia (blood fat disorders including high triglycerides, low HDL cholesterol and / or high LDL cholesterol, which foster plaque buildup in artery walls), elevated blood pressure (hypertension), insulin resistance and glucose intolerance, prothrombotic state (e.g. high fibrinogen or plasminogen activator inhibitor-1 in the blood), and proinflammatory state (e.g., elevated C-reactive protein in the blood).

[0448] Individuals with metabolic syndrome are at increased risk of coronary heart disease and other diseases related to other manifestations of arteriosclerosis (e.g. stroke and peripheral vascular disease). The dominant underlying risk factor for this syndrome appears to be abdominal obesity. Pharmaceutical compositions

[0449] Described herein are pharmaceutical compositions, comprising the amylin analogues. As with all aspects of the invention, it is to be understood that reference to an amylin analogue encompasses reference to pharmaceutically acceptable salts and solvates.

[0450] The amylin analogues of the present invention may be formulated as pharmaceutical compositions which are suited for administration with or without storage, and which typically comprise a therapeutically effective amount of at least one peptide of the invention, together with a pharmaceutically acceptable carrier, excipient or vehicle.

[0451] The term “pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art and are described, for example, in “Remington's Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985. For example, sterile saline and phosphate-buffered saline at slightly acidic or physiological pH may be used. Suitable pH-buffering agents may, e.g., be phosphate, citrate, acetate, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3- aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine or acetate (e.g. as sodium acetate), or mixtures thereof. The term further encompasses any carrier agents listed in the US Pharmacopeia for use in animals, including humans.

[0452] A pharmaceutical composition of the invention may be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component or components. The unit dosage form may be presented as a packaged preparation, the package containing discrete quantities of the preparation, for example, packaged tablets, capsules or powders in vials or ampoules. The unit dosage form may also be, e.g., a capsule, cachet or tablet in itself, or it may be an appropriate number of any of these packaged forms. A unit dosage form may also be provided in single-dose injectable form, for example in the form of a pen device containing a liquid-phase (typically aqueous) composition. Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for e.g. oral, intravitreal, rectal, vaginal, nasal, topical, enteral or parenteral (including subcutaneous (sc), intramuscular (im), intravenous (iv), intradermal and transdermal) administration or administration by inhalation. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmaceutical formulation. Subcutaneous or transdermal modes of administration may in some cases be suitable for peptides of the invention.

[0453] Further embodiments relate to devices, dosage forms and packages used to deliver the pharmaceutical formulations of the present invention. Thus, at least one peptide in a stable or preserved formulation or solution described herein can be administered to a patient in accordance with the present invention via a variety of delivery methods, including by sc or im injection, or by transdermal, pulmonary or transmucosal administration, or by implant, or by use of an osmotic pump, cartridge, micro-pump or other means recognized by a person of skill in the art.

[0454] Still further embodiments relate to oral formulations and oral administration. Formulations for oral administration may rely on the co-administration of adjuvants (e.g. resorcinols and / or nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to artificially increase the permeability of the intestinal walls, and / or the coadministration of enzymatic inhibitors (e.g. pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) or trasylol) to inhibit enzymatic degradation. The active constituent compound of a solid-type dosage form for oral administration can be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, or glyceride. These dosage forms can also contain other type(s) of additives, e.g. an inactive diluting agent, a lubricant (such as magnesium stearate), a paraben, a preserving agent (such as sorbic acid, ascorbic acid or alpha-tocopherol), an antioxidant (such as cysteine), a disintegrant, binder, thickener, buffering agent, pH-adjusting agent, sweetening agent, flavoring agent or perfuming agent.

[0455] Devices and kits

[0456] In some embodiments, the invention relates to a device comprising an amylin analogue or pharmaceutical composition of the invention, for delivery of the analogue to a subject. Via such devices, the amylin analogues can be administered to a subject via a variety of delivery methods, including: intravenous, subcutaneous, intramuscular or intraperitoneal injection; oral administration; transdermal administration; pulmonary or transmucosal administration; administration by implant, osmotic pump, cartridge or micro pump; or by other means recognized by a person of skill in the art. In some embodiments, the invention relates to a kit comprising the amylin analogue of the invention or a pharmaceutical composition thereof and one or more second medicaments. In certain embodiments, the kit further comprises packaging and / or instructions for use.

[0457] ASPECTS OF THE INVENTION

[0458] The invention is described by way of the following numbered aspects.

[0459] Aspect 1. A dosage regimen for a subject, wherein the dosage regimen comprises:

[0460] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0461] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0462] R1-Z-R2wherein:

[0463] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0464] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and

[0465] Z is an amino acid sequence of formula I:

[0466] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0467] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37 (SEQ ID NO: 4) wherein:

[0468] X1 is selected from the group consisting of Arg, Lys and Glu;

[0469] X3 is selected from the group consisting of Gly, Gin and Pro;

[0470] X4 is selected from the group consisting of Thr and Glu;

[0471] X5 is selected from the group consisting of Ala and Leu;

[0472] X6 is selected from the group consisting of Thr and Ser;

[0473] X10 is selected from the group consisting of Glu and Gin;

[0474] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0475] X17 is selected from the group consisting of Gin, His and Thr;

[0476] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0477] X27 is selected from the group consisting of Leu and Pro; X32 is selected from the group consisting of Vai and Thr;

[0478] X35 is selected from the group consisting of Asn and Ser;

[0479] X37 is selected from the group consisting of Hyp and Pro; and

[0480] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0481] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0482] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0483] Aspect 2. The dosing regimen of aspect 1 , wherein the dosing regimen is a non-therapeutic dosing regimen.

[0484] Aspect 3. The dosage regimen of aspect 1 or aspect 2, wherein the subject:

[0485] (i) is overweight;

[0486] (ii) has obesity;

[0487] (iii) has morbid obesity;

[0488] (iv) has diabetes; and / or

[0489] (v) has a disease linked to obesity or to diabetes.

[0490] Aspect 4. A method of inhibiting weight gain and / or reducing body weight in a subject, wherein the method comprises:

[0491] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0492] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0493] R1-Z-R2wherein:

[0494] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0495] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and

[0496] Z is an amino acid sequence of formula I: X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0497] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-

[0498] Ser-X35-Thr-X37(SEQ ID NO: 4) wherein:

[0499] X1 is selected from the group consisting of Arg, Lys and Glu;

[0500] X3 is selected from the group consisting of Gly, Gin and Pro;

[0501] X4 is selected from the group consisting of Thr and Glu;

[0502] X5 is selected from the group consisting of Ala and Leu;

[0503] X6 is selected from the group consisting of Thr and Ser;

[0504] X10 is selected from the group consisting of Glu and Gin;

[0505] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0506] X17 is selected from the group consisting of Gin, His and Thr;

[0507] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0508] X27 is selected from the group consisting of Leu and Pro;

[0509] X32 is selected from the group consisting of Vai and Thr;

[0510] X35 is selected from the group consisting of Asn and Ser;

[0511] X37 is selected from the group consisting of Hyp and Pro; and

[0512] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0513] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0514] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0515] Aspect 5. The method of aspect 4, wherein the method is a non-therapeutic method.

[0516] Aspect 6. The method of aspect 4 or aspect 5, wherein the subject:

[0517] (i) is overweight;

[0518] (ii) has obesity;

[0519] (iii) has morbid obesity;

[0520] (iv) has diabetes; and / or

[0521] (v) has a disease linked to obesity or to diabetes.

[0522] Aspect 7. A method of treating or preventing a disease in a subject, wherein the method comprises: (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0523] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0524] R1-Z-R2wherein:

[0525] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0526] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and

[0527] Z is an amino acid sequence of formula I:

[0528] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0529] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37(SEQ ID NO: 4) wherein:

[0530] X1 is selected from the group consisting of Arg, Lys and Glu;

[0531] X3 is selected from the group consisting of Gly, Gin and Pro;

[0532] X4 is selected from the group consisting of Thr and Glu;

[0533] X5 is selected from the group consisting of Ala and Leu;

[0534] X6 is selected from the group consisting of Thr and Ser;

[0535] X10 is selected from the group consisting of Glu and Gin;

[0536] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0537] X17 is selected from the group consisting of Gin, His and Thr;

[0538] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0539] X27 is selected from the group consisting of Leu and Pro;

[0540] X32 is selected from the group consisting of Vai and Thr;

[0541] X35 is selected from the group consisting of Asn and Ser;

[0542] X37 is selected from the group consisting of Hyp and Pro; and

[0543] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0544] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0545] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0546] Aspect 8. An amylin analogue that does not affect the rate of gastric emptying for use in a method of treating or preventing a disease in a subject, wherein the method comprises:

[0547] (a) administering the amylin analogue to the subject; and

[0548] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0549] R1-Z-R2wherein:

[0550] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0551] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I:

[0552] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-

[0553] Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37 (SEQ ID NO: 4) wherein:

[0554] X1 is selected from the group consisting of Arg, Lys and Glu;

[0555] X3 is selected from the group consisting of Gly, Gin and Pro;

[0556] X4 is selected from the group consisting of Thr and Glu;

[0557] X5 is selected from the group consisting of Ala and Leu;

[0558] X6 is selected from the group consisting of Thr and Ser;

[0559] X10 is selected from the group consisting of Glu and Gin;

[0560] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0561] X17 is selected from the group consisting of Gin, His and Thr;

[0562] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0563] X27 is selected from the group consisting of Leu and Pro;

[0564] X32 is selected from the group consisting of Vai and Thr;

[0565] X35 is selected from the group consisting of Asn and Ser;

[0566] X37 is selected from the group consisting of Hyp and Pro; and

[0567] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0568] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0569] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0570] Aspect 9. Use of an amylin analogue that does not affect the rate of gastric emptying for manufacture of a medicament for use in a method of treating or preventing a disease in a subject, wherein the method comprises:

[0571] (a) administering the amylin analogue to the subject; and

[0572] (b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:

[0573] R1-Z-R2wherein:

[0574] R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;

[0575] R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and

[0576] Z is an amino acid sequence of formula I:

[0577] X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17- Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37(SEQ ID NO: 4) wherein:

[0578] X1 is selected from the group consisting of Arg, Lys and Glu;

[0579] X3 is selected from the group consisting of Gly, Gin and Pro;

[0580] X4 is selected from the group consisting of Thr and Glu;

[0581] X5 is selected from the group consisting of Ala and Leu;

[0582] X6 is selected from the group consisting of Thr and Ser;

[0583] X10 is selected from the group consisting of Glu and Gin;

[0584] X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;

[0585] X17 is selected from the group consisting of Gin, His and Thr;

[0586] X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;

[0587] X27 is selected from the group consisting of Leu and Pro;

[0588] X32 is selected from the group consisting of Vai and Thr;

[0589] X35 is selected from the group consisting of Asn and Ser; X37 is selected from the group consisting of Hyp and Pro; and

[0590] X2 and X7 are amino acid residues whose side chains together form a lactam bridge;

[0591] Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucine

[0592] Aad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

[0593] Aspect 10. The method of aspect 7, the amylin analogue for use of aspect 8 or the use of aspect 9, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease linked to obesity or to diabetes.

[0594] Aspect 11 . The dosage regimen of aspect 3, the method of aspect 6, or the method, amylin analogue for use or the use of aspect 10, wherein the diabetes is type 1 diabetes or type 2 diabetes.

[0595] Aspect 12. The dosage regimen of aspect 3, the method of aspect 6 or the method, the amylin analogue for use or the use of aspect 10, wherein the disease linked to obesity or to diabetes is selected from the group consisting of: obesity-linked inflammation, obesity-linked gallbladder disease, obesity-induced sleep apnea, obesity-linked respiratory problems, degeneration of cartilage, osteoarthritis, infertility, Alzheimer’s disease, pre-diabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, metabolic disease, metabolic syndrome, hyperglycemia, hypertension, atherogenic dyslipidemia, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), kidney failure, arteriosclerosis, macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a diabetic complication, coronary heart disease, peripheral artery disease and stroke.

[0596] Aspect 13. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 12, wherein the amylin analogue comprises or consists of a peptide of formula:

[0597] [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)-

[0598] LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 3), or a pharmaceutically acceptable salt and / or derivative thereof; and wherein the parentheses () indicate an intramolecular lactam bridge formed between the side chains of the residues at sequence positions X2 and X7.

[0599] Aspect 14. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 13, wherein the amylin analogue and the concomitant agent are administered to the subject within 90 minutes of one another, within 60 minutes of one another, within 45 minutes of one another, within 30 minutes of one another, within 15 of one another and / or at substantially the same time as one another.

[0600] Aspect 15. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 14, wherein the amylin analogue is administered to the subject at a dose of between about 0.04 mg to about 10 mg, such as about 0.04 mg to 7 mg, about 0.04 mg to about 6 mg, about 0.04 mg to about 4.4 mg, about 0.04 mg to about 2.4 mg, about 0.6 mg to about 6 mg, about 0.6 mg to about 4.4 mg, about 0.6 mg to about 2.4 mg, about 0.7 mg to about 6 mg, about 0.7 mg to about 4.4 mg, about 0.7 mg to about 2.4 mg,

[0601] Aspect 16. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 15, wherein the amylin analogue is administered to the subject at a dose of about 10 mg, about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 4.4 mg, about 3.4 mg, about 2.4 mg, about 1.4 mg, about 0.7 mg, about 0.35 mg, about 0.16 mg, about 0.08 mg, and / or about 0.04 mg.

[0602] Aspect 17. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 16, wherein the amylin analogue is administered to the subject at regular intervals.

[0603] Aspect 18. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 17, wherein the amylin analogue is administered to the subject once a day, once every two days, once a week, once every two weeks, once every three weeks, or once every four weeks.

[0604] Aspect 19. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 18, wherein the dosage of amylin analogue is the same at each administration. Aspect 20. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 18, wherein the dosage of amylin analogue is different at each administration.

[0605] Aspect 21. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 20, wherein the amylin analogue is administered intravenously.

[0606] Aspect 22. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 20, wherein the amylin analogue is administered subcutaneously.

[0607] Aspect 23. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 22, wherein the activity of the concomitant agent is affected by the rate of gastric emptying.

[0608] Aspect 24. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 23, wherein the administration of the concomitant agent is affected by or dependent upon the rate of gastric emptying.

[0609] Aspect 25. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 24, wherein the dose of the administered concomitant agent is affected by or dependent upon the rate of gastric emptying.

[0610] Aspect 26. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 25, wherein the concomitant agent is an oral medicament.

[0611] Aspect 27. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 26, wherein the concomitant agent is a non-oral medicament.

[0612] Aspect 28. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 29, wherein the concomitant agent is selected from the group consisting of: analgesics, antibiotics, anti-coagulants, contraceptives, anti-hypotensive medicine, statins, antifungals, hypoglycemic agents, contraceptives, oral medicines with narrow therapeutic index and nutritional supplements.

[0613] Aspect 29. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 28, wherein the concomitant agent is selected from the group consisting of: insulin, acetaminophen, digoxin, warfarin, metformin, hydrocortisone, griseofulvin, glibenclamide, gliclazide, and glipizide.

[0614] Aspect 30. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 29, wherein the concomitant agent is insulin.

[0615] Aspect 31. The dosage regimen, the method, the amylin analogue for use or the use of any one of aspects 1 to 30, wherein the subject is a human subject.

[0616] Aspect 32. A dosage regimen for a subject, wherein the dosage regimen comprises:

[0617] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0618] (b) administering a concomitant agent to the subject.

[0619] Aspect 33. A method of treating or preventing a disease in a subject, wherein the method comprises:

[0620] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0621] (b) administering a concomitant agent to the subject.

[0622] Aspect 34. An amylin analogue that does not affect the rate of gastric emptying for use in a method of treating or preventing a disease in a subject, wherein the method comprises:

[0623] (a) administering the amylin analogue to the subject; and

[0624] (b) administering a concomitant agent to the subject.

[0625] Aspect 35. Use of an amylin analogue that does not affect the rate of gastric emptying for manufacture of a medicament for use in a method of treating or preventing a disease in a subject, wherein the method comprises:

[0626] (a) administering the amylin analogue to the subject; and

[0627] (b) administering a concomitant agent to the subject.

[0628] Aspect 36. A method of inhibiting weight gain and / or reducing body weight in a subject, wherein the method comprises:

[0629] (a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and

[0630] (b) administering a concomitant agent to the subject. Aspect 37. The aspect of any one of aspects 32 to 36 comprising one or more of the features of any one or more of aspects 1 to 31.

[0631] EXAMPLES

[0632] The following examples are provided to illustrate preferred aspects of the invention and are not intended to limit the scope of the invention.

[0633] Materials & Methods

[0634] Mixed Test Meal (MTM)

[0635] In dose cohorts with single doses of > 0.7 mg identical mixed test meal (MTM) was performed on Day -1 and Day 5 (Example 1). In dose cohorts with multiple doses of >0.6 mg, identical mixed test meal (MTM) was performed on Day -1 and Day 5, and Day 40 (Example 2).

[0636] A population-predefined MTM (see below) was served for breakfast, which was standardised according to the average subject characteristics (two BMI classes were used). The meal consisted of a fixed nutrient content.

[0637] Start of intake of the acetaminophen tablets together with the liquid component of the meal was defined as time point 0 (t=0).

[0638] Subjects were required to be in a fasting state prior to the test. A fixed composition meal was served as MTM and consumed by the subject in a predefined order, within 15 minutes of time point 0 (zero).

[0639] During the intake of the mixed meal, the subjects were allowed to sit.

[0640] Subjects were advised to refrain from eating until after the meal test period (240 minutes).

[0641] Apart from water served with the test meal, water consumption was not allowed during the first 2 hours after start of the meal intake, thereafter subjects could drink water at will. Subjects were asked to lie in a semi-supine position for at least 4 hours after the MTM I acetaminophen administration and in a supine or semi-supine position thereafter until the last blood sample has been taken according to the blood sampling schedule (see Table 1 below) for the determination of post-prandial glucose (PPG), insulin, glucagon, and acetaminophen concentrations.

[0642] Acetaminophen concentrations were used as a post prandial marker for gastric emptying.

[0643] After the end of the meal test procedure, the subject were be served a meal. In case of early termination of each meal test, the reason for termination was recorded in a case report form.

[0644] Table 1: Blood sampling scheme

[0645] 1 Samples for acetaminophen, plasma glucose, insulin and glucagon, were taken within the following time windows:

[0646] -30 minutes for t=0 (Pre-ingestion) and time windows: ±2 minutes from t= 15 to t= 120 minutes; ±5 minutes from t=180 and 240 minutes. 2 Nominal timepoint t=0 min is defined as start of acetaminophen intake (2x500 mg) together with the liquid component of the MTM. Test meal should be consumed within 15 minutes.

[0647] Table 2: Composition of the Standardised Test Meal for subjects having BMI: > 21.0 to <

[0648] 25.0 kg / m2

[0649] 30 % of Total Energy Expenditure Amount Ingredients kcal Protein Fat CarbsFibre g g g g

[0650] 100 Gram Apple juice 43 0.1 0.1 10.3 0.2

[0651] 76 Gram Whole-grain oats bread roll 169 6.8 2.1 29.9 4.0

[0652] 56 Gram Sunflower seed bread 128 3.6 3.9 16.8 5.9

[0653] 12 Gram Diet margarine 64 0.0 7.2 0.0 0.0

[0654] 32 Gram Cheese 30% fat 87 9.6 5.4 0.0 0.0

[0655] 30 Gram Herb curd cheese, 20% fat 29 3.1 1.3 1.2 0.0

[0656] 34 Gram Curd cheese, low fat 26 4.6 0,1 1.4 0.0

[0657] 25 Gram Strawberry jam 61 0.1 0.1 15.0 0.0

[0658] 155 Gram Yoghurt, sugar reduced 90 6.4 2.5 10.7 -

[0659] 5 Gram Dietary fibre concentrate (Inulin) 10 0.0 0.0 0.4 4.4

[0660] To rinse: 0.0 0.0 0.0 0.0 0.0

[0661] 50 millilitre Salinger mineral water

[0662] Total 707 34.3 22.7 85.7 14.5

[0663] Nutrient relation

[0664] Energy 707 kcal

[0665] Amount rel.

[0666] Fibre 14.5 g 4 %

[0667] Protein 34.3 g 19 %

[0668] Fat 22.7 g 29 %

[0669] Carbs 85.7 g 48 % The ingredients of the mixed meal are examples and may vary with regard to flavour, aversion or allergy by the subjects but the relation of nutrients was identical.

[0670] Table 3: Composition of the Standardised Test Meal for subjects having BMI: >25.0 to 29.9 kg / m2

[0671] 30 % of Total Energy Expenditure

[0672] Amount Ingredients kcal Protein Fat Carbs Fibre g g g g

[0673] 100 Gram Apple juice 43 0.1 0.1 10.3 0.2

[0674] 80 Gram Whole-grain oats bread roll 177 7.2 2.2 31.5 4.3

[0675] 60 Gram Sunflower seed bread 137 3.9 4.1 18.0 6.3

[0676] 14 Gram Diet margarine 74 0.0 8.4 0.0 0.0

[0677] 32 Gram Cheese 30% fat 87 9.6 5.4 0.0 0.0

[0678] 30 Gram Hurb curd cheese, 20% fat 29 3.1 1.3 1.2 0.0

[0679] 40 Gram Curd cheese, low fat 30 5.4 0.1 1.6 0.0

[0680] 28 Gram Strawberry jam 68 0.1 0.1 16.8 0.0

[0681] 170 Gram Yoghurt, sugar reduced 99 7.0 2.7 11.7 -

[0682] 5 Gram Dietary fibre concentrate (Inulin) 10 0.0 0.0 0.4 4.4

[0683] To rinse:

[0684] 50 millilitre Salinger mineral water 0.0 0.0 0.0 0.0 0.0

[0685] Total 754 36.4 24.4 91.5 15.2

[0686] Nutrient relation

[0687] Energy 754 kcal

[0688] Amount rel.

[0689] Fibre 15.2 g 4 %

[0690] Protein 36.4 g 19 %

[0691] Fat 24.4 g 29 %

[0692] Carbs 91.5 g 48 %

[0693] The ingredients of the mixed meal are examples and may vary with regard to flavour, aversion or allergy by the subjects, but the relation of nutrients was identical. Acetaminophen absorption test

[0694] Two 500 mg tablets (1000 mg in total) of acetaminophen were administered together with a predefined solid MTM. Subjects were instructed to take the tablets at the start of the meal test together with the liquid component of the meal. Frequent blood sampling for acetaminophen concentrations was performed as described above.

[0695] Example 1 : Phase 1a clinical trial assessing single ascending doses

[0696] A first-in-human, randomized, single ascending dose (SAD) trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of the amylin analogue of SEQ ID NO: 3 administered to healthy subjects was performed.

[0697] Subjects were healthy male subjects that were of normal weight and overweight (BMI: 21.0- 29.9 kg / m2).

[0698] Trial design

[0699] The trial was a single-centre, randomised, double-blind, placebo-controlled, single ascending dose trial in normal weight and overweight but otherwise healthy male subjects randomised to the amylin analogue of SEQ ID NO: 3 or placebo (randomisation ratio 3:1 ; n= 6 and n= 2) within each cohort. I. 56 subjects were allocated to the following seven ascending dose levels: 0.04, 0.08, 0.16, 0.35, 0.7, 1.4, 2.4 mg with subcutaneous (s.c.) dose administration as shown in Figure 1. An i.v. cohort of eight subjects was allocated to one dose level of 0.35 mg.

[0700] A sentinel dosing approach (sequential dosing) was applied within cohorts. The entire observation period comprised 50 days starting with an in-house stay (from Day -1 to Day 8), where discharge was performed on Day 8, followed by six ambulatory visits and an End of Trial (EOT) Visit on Day 50.

[0701] A blinded evaluation of each cohort was performed by a Trial Safety Group (TSG) to determine whether the trial would progress to the next dose level based on the stopping rules applied for the trial.

[0702] The formulation of the amylin analogue of SEQ ID NO: 3 (4mg / mL) and placebo is shown in Table 4 below. Table 4: Formulation parameters

[0703] Manufacturing of the of the above Drug Product and matching placebo was performed by Rechon Life Science AB.Limhamn, Sweden on behalf of Zealand Pharma A / S. Klifo A / S, Glostrup, Denmark is responsible for secondary packaging and labelling of Drug Product and matching placebo.

[0704] Subjects received a single dose which consisted of either 0.04 mg, 0.08 mg, 0.16 mg, 0.35 mg, 0.7 mg, 1.4 mg, or 2.4 mg of the amylin analogue or placebo administered subcutaneously, or 0.35 mg administered intravenously as shown in the below table.

[0705] Table 5: Dose and cohort parameters

[0706] All demographics were balanced across cohorts of healthy subjects. The baseline characteristics of the subjects are shown below.

[0707] Table 6: Subject parameters

[0708] Subjects were tested according to the mixed meal test and the Acetaminophen absorption test described under Methods.

[0709] Results

[0710] Subjects receiving the amylin analogue exhibited a dose-dependent and sustained reduction in bodyweight (Figure 3). The results from the mixed meal test shows that subjects administered the amylin analogue herein exhibited a dose-dependent inhibition of glucagon secretion (Figure 4). Amylin is known to affect glucagon secretion, inhibit its secretion stimulated by amino acids, and reduce endogenous glucose production during the postprandial period.

[0711] Surprisingly, no dose relationship was observed between the administered amylin analogue and acetaminophen (Figure 5 and Table 7).

[0712] Both the maximal concentration (Cmax) and time taken to achieve said maximal concentration (Tmax) of acetaminophen in the acetaminophen absorption test is effectively unaltered by the amylin analogue as compared with the placebo.

[0713] Table 7: Pharmacokinetic parameters of acetaminophen in the acetaminophen absorption test

[0714] As such, these data indicate that the amylin analogue, at all doses, does not alter the rate of gastric emptying relative to placebo.

[0715] The amylin analogue was well tolerated, with no serious or severe adverse events (AEs) and no withdrawals.

[0716] The most frequent AEs were decreased appetite, nausea and vomiting; most AEs were mild and transient.

[0717] Furthermore, no anti-drug antibodies were detected. Table 8: Adverse events (AEs)

[0718] All events meeting the definition of an AE were collected and reported from the first trial-related activity after the subject has signed the informed consent until the end of the post-treatment follow-up period. At each contact with the site (visit or telephone, excluding safety visits, where the subject were not seeing the Investigator or sites staff (e.g. visits to the laboratory)) the subject were asked about AEs. All AEs, either observed by the Investigator or reported by the subject, were recorded by the Investigator and evaluated.

[0719] The Investigator recorded the diagnosis, if possible. If no diagnosis could be made the Investigator recorded each sign and symptom as individual AEs. The maximum intensity (severity) of all AEs were assessed by the investigator and documented.

[0720] Severity was graded when the AE outcome was known, in accordance with the following:

[0721] • Mild: A type of adverse event that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living.

[0722] • Moderate: A type of adverse event that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant.

[0723] • Severe: A type of adverse event that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. A ‘severe’ reaction does not necessarily deem the AE as ‘serious’ and a SAE may not be ‘severe’ in nature.

[0724] The consistent dose-dependent reduction in bodyweight observed is indicative of the suitability of the amylin analogue for the treatment of obesity or to aid weight loss.

[0725] Furthermore, the surprising lack of effect on gastric emptying may facilitate dosage regimens and concomitant dosing that would not be recommended or effective for other amylin analogues.

[0726] Summary of Example 1

[0727] The amylin analogue of the invention is a long-acting amylin analog that was originally designed for once-weekly dosing that has demonstrated the potential to reduce body weight and improve glycemia in animal models of obesity and diabetes.

[0728] The objectives of the examples was to provide a first-in-human trial to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the amylin analogue of SEQ ID NO: 3, with the primary endpoint being adverse events (AEs) and secondary endpoints being the PL parameters of the amylin analogue and PD parameters in relation to a mixed test meal (MTM).

[0729] The amylin analogue of SEQ ID NO: 3 may be referred to as ZP8396. The aforementioned trial was a randomized, double-blind, placebo-controlled trial to assess safety, PK, and PD of a single subcutaneous injection of the amylin analogue of SEQ ID NO: 3 in healthy, lean and overweight male subjects. A total of 56 subjects (mean age 38.1 years; mean BMI 25.6 kg / m2) were randomized to the amylin analogue or placebo (6:2) within seven dose cohorts ranging from 0.04 to 2.4 mg.

[0730] After 1 week of observation, mean body weight decreased by -0.6%, 2.6%, 3.6%, and 4.2% from baseline following a single dose of placebo, 0.7, 1.4 and 2.4 mg, respectively. The amylin analogue was well tolerated, with no serious or severe AEs and no withdrawals. The number and severity of gastrointestinal AEs increased with dose; the mean half-life of the amylin analogue was approximately 10 days (Figure 2) and a dose-dependent reduction in glucagon release was observed (Figure 4). Further, no anti-drug antibodies were detected.

[0731] The data reveal that the amylin analogue was well-tolerated in single doses of up to 2.4 mg. The most common related AEs were decreased appetite, nausea and vomiting, however most events were mild and transient (Table 8). A half-life of approximately 10 days is suitable for once weekly dosing. Further, a single dose of the amylin analogue resulted in dose-dependent and consistent reductions in body weight (Figure 2), supporting the potential as a treatment for obesity.

[0732] Importantly, the data in this example indicate that the amylin analogue, ZP8396, at all doses tested, does not alter the rate of gastric emptying relative to placebo.

[0733] Example 2: Phase 1 clinical trial assessing multiple ascending doses (Part 1)

[0734] A first-in-human, randomized, multiple ascending dose (MAD) trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of the amylin analogue of SEQ ID NO: 3 administered to healthy subjects was performed.

[0735] Subjects were healthy male subjects that were of normal weight and overweight (BMI: 21.0- 29.9 kg / m2).

[0736] Trial design

[0737] The trial was a single-centre, randomised and double-blind within cohorts, placebo- controlled, sequential multiple ascending dose trial in normal weight and overweight but otherwise healthy subjects randomised to the amylin analogue of SEQ ID NO: 3 or placebo (randomisation ratio 7:3) within each cohort. Subjects were allocated to the following two ascending dose levels of 6 once weekly administration of the amylin analogue or placebo: 0.6 or 1.2 mg with subcutaneous (s.c.) dose administration, as shown in Figure 6.

[0738] A sentinel dosing approach (sequential dosing) was applied within cohorts. The entire observation period comprised 92 days starting with a first in-house stay (from Day -1 to Day 2), where discharge was planned for Day 2, followed by one ambulatory visit (Day 5), a second in-house stay (from Day 8 to Day 12), where discharge was planned for Day 12, a third in-house stay (from Day 15 to Day 19), where discharge was planned for Day 19, a fourth in-house stay (from Day 22 to Day 24), where discharge was planned for Day 24, followed by one ambulatory visit (Day 26), a fifth in-house stay (from Day 29 to Day 31), where discharge was planned for Day 31, a sixth in-house stay (from Day 36 to Day 38), where discharge was planned for Day 38, followed by five ambulatory visit (Day 40, Day 43, Day 50, Day 64 and Day 75), and an End of Trial (EOT) Visit on Day 92.

[0739] A blinded evaluation of each cohort was performed by a Trial Safety Group (TSG) to determine whether the trial would progress to the next dose level based on the stopping rules specified applied for the trial.

[0740] The formulation of the amylin analogue of SEQ ID NO: 3 (4mg / mL) and placebo is shown in Table 9 below.

[0741] Table 9: Formulation parameters

[0742] Manufacture of the of the above drug product and matching placebo was performed by Rechon Life Science AB, Limhamn, Sweden on behalf of Zealand Pharma A / S. Klifo A / S, Glostrup, Denmark was responsible for secondary packaging and labelling of drug product and matching placebo.

[0743] Subjects received a single dose once weekly, which consisted of either 0.6 mg or 1.2 mg of the amylin analogue or placebo, administered subcutaneously, as shown in the below table.

[0744] Table 10: Dose and cohort parameters

[0745] All demographics were balanced across cohorts of healthy subjects. The baseline characteristics of the subjects are shown in Table 11 below.

[0746] Table 11: Subject parameters

[0747] 20 subjects having a mean body weight of 82 kg and BMI of 25.4 kg / m2participated in the trial. Two subjects did not receive the 6thdose. All 20 randomized subjects completed the trial.

[0748] Subjects were tested according to the mixed meal test and the acetaminophen absorption test described in the “Materials & Methods” section herein. Results

[0749] In accordance with the trial design, as detailed above, data pertaining to successive dose cohorts (i.e. cohorts receiving an ascending dose relative to the preceding cohort) became available sequentially.

[0750] Initial data indicate favourable results that are in line with the SAD trial.

[0751] Subjects receiving the amylin analogue exhibited a body weight decrease of 0.4%, 5.3% and 5.1% from baseline following six weekly doses of placebo, 0.6 mg and 1.2 mg, respectively. Figure 7 shows individual and mean (bold line) weight loss during the trial.

[0752] Table 12: Mean weiqht chanqe one week after the sixth dose of placebo or the amvlin analogue of SEQ ID NO: 3

[0753] The results from the mixed meal test further show that subjects administered the amylin analogue herein had no significant difference in acetaminophen concentration following either a single dose, (day 5) or six doses (day 40), compared to predose or placebo (Table x and Figure 8).

[0754] Table 13: Pharmacokinetic parameters of acetaminophen in the acetaminophen absorption test

[0755] The results from the mixed test meal show that subjects administered the amylin analogue herein had a significant difference to placebo for change in glucagon concentration from baseline on day 5, a high variation of glucagon concentrations within individuals caused no effect to be shown versus placebo at day 40 (Figure 9). Amylin is known to affect glucagon secretion, inhibit its secretion stimulated by amino acids, and reduce endogenous glucose production during the postprandial period.

[0756] The amylin analogue was well tolerated, with no serious or severe adverse events (AEs) and no withdrawals.

[0757] Table 14: Adverse events (AEs)

[0758] Summary of Example 2

[0759] The amylin analogue of SEQ ID NO: 3 designed for once weekly dosing that has demonstrated the potential to reduce body weight and improve glycemia in animal models of obesity and diabetes. Dose-dependent and consistent reductions in body weight were shown in healthy subjects after a single dose of the amylin analogue, supporting the potential of the amylin analogue as a treatment for obesity.

[0760] The first part of a randomized, double-blind, placebo-controlled trial to assess safety, pharmacokinetics, and pharmacodynamics of six weekly subcutaneous injections of the amylin analogue of SEQ ID NO: 3 in healthy lean and overweight subjects has been concluded. A total of 20 subjects (mean body weight of 82 kg and BMI of 25.4 kg / m2) were randomized to the amylin analogue of SEQ ID NO: 3 or placebo (7:3) within two dose cohorts.

[0761] The mean body weight decreased by 0.4%, 5.3% and 5.1% from baseline following six weekly doses of placebo, 0.6 mg and 1.2 mg, respectively.

[0762] The amylin analogue of SEQ ID NO: 3 was well tolerated, with no serious or severe adverse events (AEs) and no withdrawals. The most frequent related AEs were decreased appetite, early satiety, food aversion and nausea, all were mild and transient. Nausea was experienced by only three subjects treated with the amylin analogue, with one also reporting vomiting. No injection site reactions were reported, and no anti-drug antibodies detected.

[0763] Treatment with six doses of the amylin analogue of SEQ ID NO: 3 was safe and well tolerated and resulted in meaningful reductions in body weight. The most common related AEs were related to the Gl system, were all mild and most had onset within 2 days of the first dose. These data confirm the observations of weight loss after single doses of the amylin analogue and are similar to weight loss observed after 6 weeks with other weight loss treatments. Cohorts with longer treatment duration and dose up-titration exploring amylin analogue doses above 1.2 mg are ongoing to further assess the clinical potential of the amylin analogue of SEQ ID NO: 3.

[0764] Importantly, the data in this example indicate that the amylin analogue, ZP8396, at all doses tested, does not alter the rate of gastric emptying relative to placebo.

[0765] Example 3: Phase 1 clinical trial assessing multiple ascending doses (Part 2)

[0766] A randomized, multiple ascending dose trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of the amylin analogue of SEQ ID NO: 3 administered to healthy subjects.

[0767] Subjects were healthy male subjects or female subject of non-childbearing potential that were overweight and obese but otherwise healthy subjects with a Body Mass Index (BMI) between 27.0 and 39.9 kg / m2.

[0768] Trial design

[0769] Part 2 of the MAD trial is a single-centre, randomised and double-blind within cohorts, placebo-controlled, sequential multiple ascending dose trial in overweight and obese, but otherwise healthy subjects, randomised to the amylin analogue of SEQ ID NO: 3 or placebo (randomisation ratio 3:1) within each cohort. Use of dose up-titration will be explored in order to reach higher exposure of the amylin analogue of SEQ ID NO: 3.

[0770] After six weekly doses of the amylin analogue of SEQ ID NO: 3 of the maintenance dose for a given cohort, steady state is achieved. Subjects will be allocated to the following three cohorts targeting three different maintenance doses with 16 once-weekly subcutaneous (s.c.) dose administrations of the amylin analogue of SEQ ID NO: 3 or placebo (as shown in Figure 10): 1. Cohort 1 : 0.6, 0.6, 1.2, 1.2 mg followed by a maintenance dose of 2.4 mg for 12 weeks.

[0771] 2. Cohort 2: 0.6, 0.6, 1 .2, 1 .2, 2.4, 2.4, 3.6, 3.6 mg followed by a maintenance dose of 4.8 mg for 8 weeks.

[0772] 3. Cohort 3: 0.6, 0.6, 1 .2, 1 .2, 2.4, 2.4, 3.6, 3.6, 4.8, 4.8 mg followed by a maintenance dose of 6.0 mg for 6 weeks.

[0773] 48 subjects were randomised to the three cohorts of 16 subjects, where subjects in a 3:1 ratio with 12 subjects received the amylin analogue of SEQ ID NO: 3 and 4 subjects received placebo in each cohort.

[0774] The total observation period is 25 weeks started with an initial in-house stay (from Day -1 to Day 2), with scheduled discharge on Day 2, followed by 3 ambulatory visits for once-weekly dosing, and subsequent 13 in-house visits of 1-4 overnight stays depending on the dose level. The 16 once-weekly dosings (Day 1 , 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 , 78, 85, 92, 99 and 106) were followed by six ambulatory visits (Day 108, 110, 113±1 , 120±1 , 134±1 , 148±1) for the 1stcohort and five ambulatory visits (Day 110, 113±1 , 120±1 , 134±1 , 148±1) for the 2ndand 3rdcohort and an End of Trial (EOT) Visit on Day 169±2. A blinded evaluation of each cohort were performed by a Trial Safety Group (TSG) with data up to the predose assessments of the 5thmaintenance dose (Cohort 1 : Day 57 and Cohort 2: Day 85 and Cohort 3: Day 99) to determine if the current dose level is considered safe and if dose escalation could continue in the next cohort based on the stopping rules.

[0775] The formulation of the amylin analogue of SEQ ID NO: 3 (4mg / mL) and placebo is shown in Table 15 below.

[0776] Table 15: Formulation parameters

[0777] Manufacture of the of the above drug product and matching placebo was performed by Rechon Life Science AB, Limhamn, Sweden on behalf of Zealand Pharma A / S. Klifo A / S, Glostrup, Denmark was responsible for secondary packaging and labelling of drug product and matching placebo.

[0778] Subjects were tested according to the mixed meal test and the Acetaminophen absorption test described in the “Materials & Methods” section herein on day -1 and day 110.

[0779] Results

[0780] In accordance with the trial design, as detailed above, data pertaining to successive dose cohorts (i.e. , cohorts receiving an ascending dose relative to the preceding cohort) became available sequentially.

[0781] Initial data indicate favourable results that are broadly consistent with the SAD trial in Example 1 herein and the MAD trial part 1 in Example 2 herein.

[0782] All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in biochemistry, molecular biology or related fields are intended to be within the scope of the following aspects.

Claims

CLAIMS1 . An amylin analogue that does not affect the rate of gastric emptying for use in a method of treating or preventing a disease in a subject, wherein the method comprises:(a) administering the amylin analogue to the subject; and(b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:R1-Z-R2wherein:R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I:X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37 (SEQ ID NO: 4) wherein:X1 is selected from the group consisting of Arg, Lys and Glu;X3 is selected from the group consisting of Gly, Gin and Pro;X4 is selected from the group consisting of Thr and Glu;X5 is selected from the group consisting of Ala and Leu;X6 is selected from the group consisting of Thr and Ser;X10 is selected from the group consisting of Glu and Gin;X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;X17 is selected from the group consisting of Gin, His and Thr;X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;X27 is selected from the group consisting of Leu and Pro;X32 is selected from the group consisting of Vai and Thr;X35 is selected from the group consisting of Asn and Ser;X37 is selected from the group consisting of Hyp and Pro; andX2 and X7 are amino acid residues whose side chains together form a lactam bridge;Gly(Me) is N-methylglycine [also known as sarcosine (Sar)]lle(Me) is N-methylisoleucineAad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

2. A non-therapeutic dosage regimen for a subject, wherein the dosage regimen comprises:(a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and(b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:R1-Z-R2wherein:R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; andZ is an amino acid sequence of formula I:X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17- Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37 (SEQ ID NO: 4) wherein:X1 is selected from the group consisting of Arg, Lys and Glu;X3 is selected from the group consisting of Gly, Gin and Pro;X4 is selected from the group consisting of Thr and Glu;X5 is selected from the group consisting of Ala and Leu;X6 is selected from the group consisting of Thr and Ser;X10 is selected from the group consisting of Glu and Gin;X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;X17 is selected from the group consisting of Gin, His and Thr;X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;X27 is selected from the group consisting of Leu and Pro;X32 is selected from the group consisting of Vai and Thr;X35 is selected from the group consisting of Asn and Ser;X37 is selected from the group consisting of Hyp and Pro; andX2 and X7 are amino acid residues whose side chains together form a lactam bridge;Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucineAad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

3. A non-therapeutic method of inhibiting weight gain and / or reducing body weight in a subject, wherein the method comprises:(a) administering an amylin analogue that does not affect the rate of gastric emptying to the subject; and(b) administering a concomitant agent to the subject; wherein: the amylin analogue and the concomitant agent are administered to the subject within about 120 minutes of one another; and the amylin analogue comprises or consists of a peptide of formula:R1-Z-R2wherein:R1is hydrogen, C1-4 acyl, benzoyl or C1-4 alkyl, or a half-life extending moiety M, wherein M is optionally linked to Z via a linker moiety L;R2is OH or NHR3, wherein R3is hydrogen or Ci-3-alkyl; and Z is an amino acid sequence of formula I:X1-X2-X3-X4-X5-X6-X7-Ala-Thr-X10-Arg-Leu-Ala-X14-Phe-Leu-X17-Arg-X19-X20-Phe-Gly(Me)-Ala-lle(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly- Ser-X35-Thr-X37(SEQ ID NO: 4) wherein:X1 is selected from the group consisting of Arg, Lys and Glu;X3 is selected from the group consisting of Gly, Gin and Pro;X4 is selected from the group consisting of Thr and Glu;X5 is selected from the group consisting of Ala and Leu;X6 is selected from the group consisting of Thr and Ser;X10 is selected from the group consisting of Glu and Gin;X14 is selected from the group consisting of Aad, His, Asp, Asn and Arg;X17 is selected from the group consisting of Gin, His and Thr;X19-X20 is selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly and Ala-Asn or is absent;X27 is selected from the group consisting of Leu and Pro; X32 is selected from the group consisting of Vai and Thr; X35 is selected from the group consisting of Asn and Ser; X37 is selected from the group consisting of Hyp and Pro; and X2 and X7 are amino acid residues whose side chains together form a lactam bridge;Gly(Me) is N-methylglycine [also known as sarcosine (Sar)] lle(Me) is N-methylisoleucineAad is 2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid [also (2S)-2- aminohexanedioic acid], also known as homo-glutamic acid; or a pharmaceutically acceptable salt and / or derivative thereof.

4. The dosage regimen of claim 2 or the method of claim 3, wherein the subject is overweight, obese or morbidly obese.

5. The amylin analogue for use of claim 1, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease linked to obesity or to diabetes.

6. The amylin analogue for use of claim 5, wherein the disease linked to obesity or to diabetes is selected from the group consisting of: obesity-linked inflammation, obesity-linked gallbladder disease, obesity-induced sleep apnea, obesity-linked respiratory problems, degeneration of cartilage, osteoarthritis, infertility, Alzheimer’s disease, pre-diabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, metabolic disease, metabolic syndrome, hyperglycemia, hypertension, atherogenic dyslipidemia, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), kidney failure, arteriosclerosis, macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a diabetic complication, coronary heart disease, peripheral artery disease and stroke.

7. The amylin analogue for use of any one of claims 1 , 5 and 6, the dosage regimen of claim 2 or claim 4, or the method of claim 3 or claim 4 wherein the amylin analogue comprises or consists of a peptide of formula:[19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)- LSSTEVGSNT-Hyp-NH2 (SEQ ID NO: 3), or a pharmaceutically acceptable salt and / or derivative thereof.

8. The amylin analogue for use, the dosage regimen, or the method of claim 7, wherein the amylin analogue is petrelintide, which is a compound having the formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-lle(Me)-LSSTEVGSNT- Hyp-NH2(SEQ ID NO: 3) wherein an intramolecular lactam bridge is formed between the side chains of residues indicated by parenthesesand wherein [19CD]-isoGlu is a 19-carboxynonadecanoyl group covalently attached to the alpha amino group of an iso-glutamic acid linker; or a pharmaceutically acceptable salt thereof.

9. The amylin analogue for use, the dosage regimen, or the method of any one of claims 1 to 8, wherein the amylin analogue and the concomitant agent are administered to the subject within about 90 minutes of one another, within about 60 minutes of one another, within about 45 minutes of one another, within about 30 minutes of one another, within about 15 of one another and / or at substantially the same time as one another.

10. The amylin analogue for use, the dosage regimen, or the method of any one of claims 1 to 9, wherein the amylin analogue is administered to the subject at a dose of between about 0.04 mg to about 10 mg, such as about 0.04 mg to 7 mg, about 0.04 mg to about 6 mg, about 0.04 mg to about 4.4 mg, about 0.04 mg to about 2.4 mg, about 0.6 mg to about 6 mg, about 0.6 mg to about 4.4 mg, about 0.6 mg to about 2.4 mg, about 0.7 mg to about 6 mg, about 0.7 mg to about 4.4 mg, about 0.7 mg to about 2.4 mg,11. The amylin analogue for use, the dosage regimen, or the method of any one of claims 1 to 10, wherein the amylin analogue is administered to the subject at a dose of about 10 mg, about 9.5 mg, about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about 6.5 mg, about 6 mg, about 4.4 mg, about 3.4 mg, about 2.4 mg, about 1.4 mg, about 0.7 mg, about 0.35 mg, about 0.16 mg, about 0.08 mg, and / or about 0.04 mg.

12. The amylin analogue for use, the dosage regimen, or the method of any one of claims 1 to 11, wherein the amylin analogue is administered to the subject once a day, once every two days, once a week, once every two weeks, once every three weeks, or once every four weeks.

13. The amylin analogue for use, the dosage regimen, or the method of any one of claims 1 to 12, wherein:(i) the activity of the concomitant agent is affected by the rate of gastric emptying;(ii) the timing of administration of the concomitant agent is affected by or dependent upon the rate of gastric emptying; and / or(iii) the dose of the administered concomitant agent is affected by or dependent upon the rate of gastric emptying.

14. The amylin analogue for use, the dosage regimen, or the method of any one of claims 1 to 13, wherein the concomitant agent is an oral medicament or a non-oral medicament.

15. The amylin analogue for use, the dosage regimen, or the method of any one of claims 1 to 14, wherein the concomitant agent is a medicament selected from the group consisting of: analgesics, antibiotics, anti-coagulants, contraceptives, anti-hypotensive medicine, statins, antifungals, hypoglycemic agents, oral medicines with narrow therapeutic index, and nutritional supplements.

16. The amylin analogue for use, the dosage regimen, or the method of any one of claims 1 to 15, wherein the concomitant agent is selected from the group consisting of: insulin, acetaminophen, digoxin, warfarin, metformin, hydrocortisone, griseofulvin, glibenclamide, gliclazide, and glipizide.

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