Improved analog characteristics

Abstract

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

Description

[Technical Field]

[0001] The present invention relates to therapeutic and non-therapeutic methods using peptide hormone analogs. In particular, the present invention relates to the use of amylin analogues with improved properties, specifically amylin analogues that do not delay gastric emptying. [Background technology]

[0002] Obesity is now a major public health problem in most developed countries and is associated with the development of several serious conditions, such as cardiovascular disease, type 2 diabetes, sleep apnea, and certain cancers. Standard treatment for obesity involves lifestyle interventions, including reducing energy intake and increasing exercise. However, while such interventions can achieve initial success, in many cases, it is difficult for patients to maintain these lifestyle changes over the long term and make the achieved weight loss permanent. Therefore, more effective pharmacological treatment options are needed.

[0003] Amylin is a peptide hormone family that includes amylin, calcitonin, calcitonin gene-related peptide, adrenomedullin, and intermezin (also known as AFP-6), and is associated with a variety of metabolic diseases and disorders.

[0004] Human amylin was first isolated, purified, and characterized as a major component of amyloid deposition in pancreatic islets of patients with type 2 diabetes.

[0005] Native human amylin is, formula: H-KC()NTATC()ATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2(Sequence ID 1) It is a peptide composed of 37 amino acids, In the formula, the N-terminus H- indicates a hydrogen atom corresponding to the presence of a free amino group at the N-terminal amino acid residue [i.e., the lysine (K) residue at sequence position 1 in the sequence shown above], the C-terminus -NH2 indicates that the C-terminal carboxyl group is in amide form, and the parentheses "()" surrounding the two cysteine ​​(C,Cys) residues at positions 2 and 7 of the sequence indicate the presence of an intramolecular disulfide bridge between those two Cys residues.

[0006] Amylin may be beneficial in the treatment of metabolic disorders such as diabetes and / or obesity. Amylin is thought to regulate the ratio of glucose release into circulation by delaying gastric emptying, suppressing glucagon secretion, and reducing food intake. Amylin appears to complement the action of insulin. Compared to healthy adults, patients with type 1 diabetes have no circulating amylin, and patients with type 2 diabetes have low postprandial amylin concentrations. International Publication No. 93 / 10146 describes an amylin analog known as pramulintide, which has the following sequence: Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO: 2) It holds.

[0007] Plumlintide also has a disulfide bridge between the cysteine ​​residues at positions 2 and 7, and has been shown in human studies to reduce body weight or reduce weight gain.

[0008] Another amyrin analog called IAPP-GI, which incorporates N-methylated residues and reduces the tendency towards microfibrillation, has been described by Yan et al. (PNAS, 103(7), 2046-2051, 2006; Angew. Chem. Int. Ed. 2013, 52, 10378-10383; International Publication No. 2006 / 042745). However, IAPP-GI appears to be less active than native amyrin.

[0009] International Publication No. 2018 / 046719 describes amyrin analogs that have lactam crosslinks instead of disulfide crosslinks, N-methylated residues, and deletions corresponding to native human amyrin residues Asn21 and Asn22, in particular. Such analogs have a much lower tendency to cause microfibrillation than native amyrin, while also having higher potency than the analogs described by Yan et al. (above).

[0010] While the delayed gastric emptying associated with amylin and amylin analogs can lead to a favorable reduction in food intake, delayed gastric emptying may be undesirable in certain situations.

[0011] For example, delayed gastric emptying can lead to undesirable changes in exposure to or need for concomitant medications. Such drug interactions are undesirable. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] International Publication No. 93 / 10146 Pamphlet [Patent Document 2] International Publication No. 2006 / 042745 [Patent Document 3] International Publication No. 2018 / 046719 Brochure [Non-patent literature]

[0013] [Non-Patent Document 1] PNAS, 103(7), 2046-2051, 2006 [Non-Patent Document 2] Angew. Chem. Int. Ed. 2013, 52, 10378-10383 [Overview of the project]

[0014] This invention relates to the remarkable discovery that amylin analogs induce weight loss, reduce glucagon release, and increase satiety in subjects, while remarkably having no effect on gastric emptying.

[0015] Therefore, the present invention relates to a functional amylin analog that does not cause delay in gastric emptying.

[0016] In broad embodiments, the present invention relates to a dosage regimen for a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Regarding administration regimens that include this.

[0017] An amylin analog that does not affect gastric emptying rate according to the present invention is given by formula: R 1 -ZR 2 A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3 is hydrogen or C1-3 is alkyl and Z has the 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) is an amino acid sequence, wherein X1 is selected from the group consisting of Arg, Lys, and Glu, X3 is selected from the group consisting of Gly, Gln, 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 Gln, X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg, X17 is selected from the group consisting of Gln, 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 Val 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), Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid].

[0018] Preferably, the amilin analog is given by formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 3) It comprises or consists of the peptide or its pharmaceutically acceptable salts and / or derivatives.

[0019] In a preferred embodiment, the amilin analog is given by formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 3) Petrelintide or a pharmaceutically acceptable salt thereof is a compound having [19CD]-isoGlu, where the intramolecular lactam crosslink is formed between the side chains of the residues indicated by parentheses "()", and [19CD]-isoGlu is a 19-carboxynonadecanoyl group covalently bonded to the alpha-amino group of the isoglutamic acid linker.

[0020] In one aspect, the present invention is a dosage regimen for a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications A dosage regimen that includes, The present invention provides an administration regimen in which the amylin analog and the concomitant agent are administered to the subject within approximately 120 minutes of each other.

[0021] In one embodiment, the present invention relates to a method for inhibiting or reducing weight gain, promoting weight loss, reducing food intake, and / or reducing weight in a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, The present invention provides a method in which an amylin analog and a concomitant agent are administered to a subject within approximately 120 minutes of each other.

[0022] In one embodiment, a method that inhibits or reduces weight gain, promotes weight loss, reduces food intake, and / or reduces excess body weight in a subject is a non-therapeutic method.

[0023] In one aspect, the present invention relates to a method for treating or preventing a disease in a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, The present invention provides a method in which an amylin analog and a concomitant agent are administered to a subject within approximately 120 minutes of each other.

[0024] In one aspect, the present invention relates to an amylin analog for use in a method of treating or preventing a disease in a subject, wherein the method is: (a) A step of administering an amylin analog, and (b) Steps to administer concomitant medications The present invention provides an amylin analog comprising the amylin analog and a concomitant agent, wherein the amylin analog and the concomitant agent are administered to the subject within approximately 120 minutes of each other.

[0025] In one aspect, the present invention relates to the use of an amylin analog that does not affect gastric emptying rate for manufacturing a pharmaceutical for use in a method of treating or preventing a disease in a subject, and the method is (a) A step of administering an amylin analog, and (b) Steps to administer concomitant medications Includes, This invention provides a use in which the amylin analog and the concomitant agent are administered to the subject within approximately 120 minutes of each other. [Brief explanation of the drawing]

[0026] [Figure 1] This figure shows the design of a single ascending dose study. The single ascending dose (SAD) study in Example 1 consisted of seven cohorts, each consisting of six participants who received the amylin analog of SEQ ID NO: 3 and two participants who received a placebo. The dose was administered subcutaneously. Additional cohorts (not shown) with the same composition received an intravenous dose of 0.35 mg. [Figure 2A] ~ [Figure 2C] This figure shows that pharmacokinetic profiles are consistent across cohorts. The pharmacokinetic profile for each cohort is shown. Individual measured amylin analog concentrations in the blood after a single subcutaneous dose (A), as well as the geometric mean for each cohort up to 35 days (B) and up to 7 days (C), are shown. Each cohort shows a consistent pharmacokinetic profile. Furthermore, there is little variability in exposure within the cohorts. [Figure 3A] ~ [Figure 3B] This figure shows the dose-dependent reduction in body weight. A dose-dependent and sustained reduction in body weight is observed in human subjects who received a single dose of amylin analog. (A) Shows the change in body weight of individual subjects in each cohort. (B) Shows the mean and 95% confidence level of the change in body weight. [Figure 4] This figure shows the dose-dependent reduction in glucagon secretion. A dose-dependent reduction in glucagon secretion after a mixed test meal (MTM) is observed in participants who received a single dose of amylin analog. [Figure 5A] ~ [Figure 5C]This figure shows that acetaminophen absorption is not affected by amylin analogs. No dose-dependent relationship is observed between amylin analogs and acetaminophen absorption. Measured blood acetaminophen concentrations after consumption of mixed test meal (MTM) and acetaminophen are essentially unaffected by amylin analogs. In (A), blood acetaminophen concentration is shown as a function of time after MTM. The corresponding area under the curve (B) for the first hour from the start of MTM is also shown. In (C), gastric emptying (AUC of acetaminophen concentration) is shown as a percentage relative to placebo, further demonstrating that there is no apparent effect on acetaminophen concentration and therefore gastric emptying. [Figure 6] This figure shows the design of the repeated-dose escalation study. The repeated-dose escalation study (MAD) in Example 2 consisted of two cohorts, each consisting of seven participants who received the amylin analog of SEQ ID NO: 3 and three participants who received a placebo. The dose was administered subcutaneously. [Figure 7] This figure shows weight loss. Weight loss is observed in human subjects who received multiple doses of amylin analogs. The panel (from left to right) represents placebo, amylin 0.6 mg, and amylin 1.2 mg. The graph shows individual subjects (thin lines) and the mean (dark lines) for each cohort. [Figure 8] This figure shows that acetaminophen absorption is not affected by amylin analogs. No dose-dependent relationship was observed between amylin analogs and acetaminophen absorption. Blood acetaminophen concentrations measured after consumption of mixed test meal (MTM) and acetaminophen remained essentially unchanged from day -1 for each amylin analog on days 5 and 40. [Figure 9] This figure shows a reduction in glucagon secretion. A reduction in glucagon secretion after mixed test meal (MTM) is observed on day 5 in participants who received a single dose of amylin analog. [Figure 10]This figure shows the second part of the design for the repeated-dose escalation study. The repeated-dose escalation study (MAD) in Example 3 consisted of three cohorts, each consisting of 12 participants who received the amylin analog of SEQ ID NO: 3 and 4 participants who received a placebo. The dose was administered subcutaneously. [Modes for carrying out the invention]

[0027] Unless otherwise defined herein, scientific and technical terms used herein have the meanings generally understood by those skilled in the art. Overall, the terminology and techniques used herein in relation to chemistry, molecular biology, cell biology and cancer biology, immunology, microbiology, pharmacology, and protein chemistry and nucleic acid chemistry are well known and commonly used in the art.

[0028] All patents, published patent applications, and non-patent publications referenced herein are incorporated herein by reference. In case of any disagreement, this specification, including its specific definitions, shall prevail.

[0029] Each embodiment of the invention described herein may be carried out independently or in combination with one or more other embodiments of the invention.

[0030] Various modifications and variations of the methods and systems described in the present invention will be obvious to those skilled in the art without departing from the scope and spirit of the present invention.

[0031] Although the present invention is described in relation to specific preferred embodiments, it should be understood that the invention as described in the claims should not be unduly limited to such specific embodiments. In fact, various modifications of the described embodiments for carrying out the present invention that are obvious to those skilled in the art of biochemistry, molecular biology, or related fields are included within the scope of the following embodiments.

[0032] definition Unless otherwise specified, the following definitions are given to the specific terms used herein. All other terms will be understood to have the general meaning in the art to which they belong by those skilled in the art.

[0033] Throughout this specification, the word “comprise,” and its grammatical variations such as “comprises” or “comprising,” will be understood to mean that the integers or components, or groups of integers or components, described are included, but not that any other integers or components, or groups of integers or components, are excluded.

[0034] The singular forms "a," "an," and "the" include the plural form unless otherwise clearly indicated by the context.

[0035] The term "including" is used to mean "including but not limiting." "Including" and "including but not limiting" can be used interchangeably.

[0036] The terms “patient,” “subject,” and “individual” may be used interchangeably and refer to either human or non-human animals. These terms include mammals, e.g., humans, primates, domestic animals (e.g., cattle and pigs), companion animals (e.g., dogs and cats), and rodents (e.g., mice and rats).

[0037] In the context of this invention, the term "solvate" refers to a complex with a defined stoichiometry formed between a solute (in this case, a peptide according to this invention or a pharmaceutically acceptable salt thereof) and a solvent. The solvent, in this regard, may be, for example, water, ethanol, or another pharmaceutically acceptable, typically low-molecular-weight organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is usually called a hydrate.

[0038] Sequence alignment can be performed by those skilled in the art using techniques well known in the art, for example, using publicly available software such as BLAST, BLAST2, or Align software. See, for example, Altschul et al., Methods in Enzymology 266: 460-480 (1996), or Pearson et al., Genomics 46: 24-36, 1997.

[0039] The sequence identity percentage used herein in the context of the present invention can be determined by using these programs with their default settings. More generally, those skilled in the art can easily determine appropriate parameters for determining the alignment, including any algorithm necessary to obtain the maximum alignment over the full length of the sequences being compared.

[0040] Amilin Analog Amyrin analogs are molecules that are amyrin receptor agonists, meaning they can bind to one or more receptors or receptor complexes that are considered to be physiological receptors for human amyrin, and can induce signaling by such receptors or receptor complexes. The terms "amyrin analog" and "amyrin receptor agonist" are used herein without distinction. Amyrin analogs may also be referred to herein as compounds, molecules, or peptides.

[0041] Amylin analogs (which may also be referred to herein as compounds, molecules, or peptides) can be adequately prepared by standard synthetic methods. Thus, peptides can be synthesized, for example, by standard solid-phase or liquid-phase methodologies including stepwise or fragment assembly of peptide synthesis, and optional isolation and purification of the final peptide product. This method typically further includes, for example, the step of forming an amide bond between the 2- and 7-position side chains, as described below. In the case of solid-phase synthesis, cyclization may be performed in situ on a solid phase (e.g., a resin), i.e., before the peptide is removed from the solid phase.

[0042] The amilin analogs described herein are given by formula: R 1 -ZR 2 It may have, or may be a pharmaceutically acceptable salt or solvate thereof, in the formula: R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3 is hydrogen or C 1-3 It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows: - X1 is selected from the group consisting of Arg, Lys, and Glu. - X3 is selected from the group consisting of Gly, Gln, 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 Gln, - X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. - X17 is selected from the group consisting of Gln, His, and Thr. - X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. - X27 is selected from the group consisting of Leu and Pro. - X32 is selected from the group consisting of Val 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 crosslink. - Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], - Ile(Me) is N-methylisoleucine, - Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid].

[0043] Preferably, the amylin analog is petrelintide, and petrelintide is given by formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 3) It has, in the formula, Gly(Me): N-methylglycine [also known as sarcosine (Sar)] Ile(Me):N-methylisoleucine Aad: 2-aminoadipic acid, also known as homoglutamic acid, e.g., (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanedioic acid], Hyp: 4-hydroxyproline, e.g., (2S,4R)-4-hydroxyproline [also written as (4R)-4-hydroxy-L-proline] [19CD]-isoGlu: The nitrogen of the Arg residue backbone (located at position X1 in the Z of the amyrin analog peptide sequence) is covalently bonded to the carboxyl group of the Glu moiety side chain via an amide bond. The 19-carboxy-nonadecanoyl group is covalently bonded to the alpha-amino group of the Glu linker via an amide bond (as described below).

[0044] The parentheses "()" following the symbol of a specific amino acid residue indicate the residue whose side chain is involved in intramolecular lactam crosslinking. Therefore, the amylin analog compound of the present invention has intramolecular lactam crosslinks formed between the side chains of the residues indicated by the parentheses (aspartic acid and lysine, respectively).

[0045] In a preferred embodiment, the amilin analog is given by formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 3) Petrelintide, which is a compound having [a certain property], or a pharmaceutically acceptable salt thereof, Here, the intramolecular lactam crosslink is formed between the side chains of the residues indicated by parentheses "()", and [19CD]-isoGlu is a 19-carboxynonadecanoyl group covalently bonded to the alpha-amino group of the isoglutamic acid linker.

[0046] Throughout this specification and the claims, the conventional three-letter and one-letter codes for natural amino acids, namely, A(Ala), G(Gly), L(Leu), I(Ile), V(Val), F(Phe), W(Trp), S(Ser), T(Thr), Y(Tyr), N (Asn), Q(Gln), D(Asp), E(Glu), K(Lys), R(Arg), H(His), M(Met), C(Cys), and P(Pro), In addition, commonly recognized three-letter codes for other α-amino acids, such as sarcosine (Sar), norleucine (Nle), α-aminoisobutyric acid (Aib), 2,3-diaminopropanoic acid (Dap), 2,4-diaminobutanoic acid (Dab), and 2,5-diaminopentanoic acid (ornithine, Orn), are used. When such other α-amino acids are used herein in a general formula or sequence, they may be indicated in square brackets "[]" (e.g., "[Aib]"), especially when the remainder of the formula or sequence is indicated using a single-letter code. Unless otherwise specified, the amino acid residues in the peptides of the present invention are in L-conceptual structures. However, D-conceptual amino acids may also be incorporated. In this context, lowercase amino acid codes represent the D-conceptual structure of the amino acid; for example, "k" represents the D-conceptual structure of lysine (K).

[0047] The amyrin analog of Sequence ID No. 3 is petrelintide, which may also be referred to as ZP8396. ZP8396 (petrelintide) is also described in detail in International Publication No. 2018 / 046719, which is incorporated herein by reference in its entirety. In International Publication No. 2018 / 046719, the amyrin analog of Sequence ID No. 3 (ZP8396, petrelintide) is also referred to as "Compound 35".

[0048] Amylin analogs may be in the form of pharmaceutically acceptable salts or solvates, such as pharmaceutically acceptable acid addition salts.

[0049] Half-life extension portion M As described herein, the N-terminal portion R of the compound of the present invention 1 This may be a half-life extension moiety M (sometimes referred to in the literature as a period extension moiety or albumin-binding moiety), which may be linked (covalently) to the peptide moiety Z via a linker moiety L. Suitable half-life extension moieties include certain types of lipid-soluble substituents. While we do not wish to be bound by any particular theory, such lipid-soluble substituents (and other classes of half-life extension moieties) are thought to bind to albumin in the bloodstream, thereby protecting the compound of the present invention from renal filtration and enzymatic degradation, and thus possibly extending the half-life of the compound in vivo. Lipid-soluble substituents may also modulate the potency of the compound as an agonist to the amyrin (calcitonin) receptor.

[0050] Lipid-soluble substituents can be attached to an N-terminal amino acid residue or linker L via an ester, sulfonyl ester, thioester, amide, amine, or sulfonamide. Therefore, it is understood that the lipid-soluble substituents preferably include an acyl group, sulfonyl group, N atom, O atom, or S atom that forms part of an ester, sulfonyl ester, thioester, amide, amine, or sulfonamide. Preferably, the acyl group within the lipid-soluble substituent, together with the amino acid residue or linker, forms part of an amide or ester.

[0051] Lipid-soluble substituents may include hydrocarbon chains having 10 to 24 carbon atoms, for example, 14 to 22 carbon atoms, for example, 16 to 20 carbon atoms. Preferably, the hydrocarbon chain has at least 14 carbon atoms, and preferably 20 or fewer carbon atoms. For example, the hydrocarbon chain may have 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, the hydrocarbon chain may contain functional groups at its ends, such as carboxylic acid groups that may or may not be protected during synthesis. From the above discussion, it will also be understood that the hydrocarbon chain may be preferably substituted with a moiety that forms part of the bond of the peptide moiety Z to the N-terminal amino acid residue or to the linker L, for example, an acyl group, a sulfonyl group, an N atom, an O atom, or an S atom.

[0052] Most preferably, the hydrocarbon chain is substituted with an acyl group, and therefore the hydrocarbon chain may be part of an alkanoyl group, such as dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, or eicosaenoyl group. Examples of functionalized hydrocarbon chains are 15-carboxypentadecanoyl, 17-carboxyheptadecanoyl, and 19-carboxynonadecanoyl.

[0053] As described above, the lipophilic substituent M may be linked to the N-terminal amino acid residue of Z via a linker L. In the embodiment, the linker portion L is itself a small portion L linked to one, two, three or more other small portions L 1 , L 2 , L 3This may include, for example. If linker L contains only one such moiety, it is bonded to the lipophilic substituent and the N-terminal amino acid residue of Z. The linker may then be independently bonded to the lipophilic substituent and the N-terminal amino acid residue of Z by an ester bond, sulfonyl ester bond, thioester bond, amide bond, amine bond, or sulfonamide bond. Thus, it may contain two moieties independently selected from acyl, sulfonyl, N, O, and S atoms. The linker may be linear or branched C 1-10 hydrocarbon chains, or more preferably linear C 1-5 It can be composed of hydrocarbon chains. Furthermore, the linker is C 1-6 Alkyl, amino C 1-6 Alkyl, hydroxy C 1-6 Alkyl and carboxyl C 1-6 It may be substituted with one or more substituents selected from alkyl groups.

[0054] In some embodiments, the linker may comprise one or more linked amino acid residues (e.g., one, two, or three), each of which may independently be any natural or non-natural amino acid residue. For example, the linker may contain one, two, or three linked amino acid residues, each of which may independently be the residues Gly, Pro, Ala, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, α-Glu, γ-Glu, ε-Lys, Asp, β-Asp, Ser, Thr, Gaba, Aib, β-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).

[0055] References to γ-Glu, ε-Lys, and β-Asp refer to amino acid residues involved in the binding via the carboxyl or amine functional groups of their side chains. Therefore, γ-Glu and β-Asp are involved in the binding via their alpha-amino group and side-chain carboxyl group, while ε-Lys is involved via its carboxyl group and side-chain amino group. In the context of the present invention, γ-Glu and isoGlu are used without distinction.

[0056] In certain embodiments, the linker comprises or is composed of one, two, or three independently selected residues: Glu, γ-Glu, ε-Lys, β-Ala, 4-aminobutanoyl, 8-aminooctanoyl, or 8Ado.

[0057] Linkers composed of isoGlu and isoGlu-isoGlu may be particularly preferred.

[0058] An example of a lipophilic substituent including the lipophilic moiety M and linker L is shown by the following formula: [ka] In the formula, the skeletal nitrogen of the Arg residue (located at position X1 in the Z peptide sequence of the amyrin analog) is covalently bonded to the carboxyl group of the side chain of the Glu moiety via an amide bond. The 19-carboxy-nonadecanoyl group is covalently bonded to the alpha-amino group of the Glu linker via an amide bond. Thus, the Glu linker has an iso-Glu (or γ-Glu) stereostructure. This combination of the lipophilic moiety bonded to the Arg residue and the linker can be written in the simple notation [19CD]-isoGlu-R, for example, when shown in the formula of a particular compound.

[0059] Those skilled in the art will recognize appropriate techniques for preparing the compounds used in the context of the present invention. For examples of appropriate chemistry, see, for example, International Publication No. 98 / 08871, International Publication No. 00 / 55184, International Publication No. 00 / 55119, Madsen et al. (J. Med. Chem. 2007, 50, 6126-32), and Knudsen et al., 2000 (J. Med. Chem. 43, 1664-1669).

[0060] The hydrocarbon chain in the 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 substituted with only one substituent. Alternatively, the hydrocarbon chain may further include a cycloalkane or heterocycloalkane moiety, for example, as shown below. [ka]

[0061] In some embodiments, the cycloalkane or heterocycloalkane moiety is a six-membered ring, such as a piperidine ring.

[0062] In alternative embodiments of the present invention, the N-terminal amino acid Z in the compound of the present invention may be covalently linked to a biotinyl substituent, which may be via a linker moiety L. While we do not wish to be bound by any particular theory, it is similarly believed that such a biotinyl substituent binds to albumin in the bloodstream, thereby protecting the compound of the present invention from enzymatic degradation, and thus potentially extending the half-life of the compound in vivo. The linker, if present, may provide a space between the peptide moiety Z and the biotinyl substituent.

[0063] Biotinyl substituents can be attached to N-terminal amino acid residues or linkers via maleimide ester bonds, sulfonyl ester bonds, thioester bonds, amide bonds, amine bonds, or sulfonamide bonds. Therefore, it will be understood that biotinyl substituents preferably include maleimide groups, acyl groups, sulfonyl groups, N atoms, O atoms, or S atoms that form part of the ester bond, sulfonyl ester bond, thioester bond, amide bond, amine bond, or sulfonamide bond.

[0064] Examples of biotinyl substituents may include the following: [ka]

[0065] Biotin, also known as vitamin H or coenzyme R, is a water-soluble vitamin B (vitamin B7). It has been shown to increase the oral uptake rate of certain drugs.

[0066] Effectiveness of the compound The compounds of the present invention (i.e., amyrin analogs) are amyrin receptor agonists, meaning they can bind to one or more receptors or receptor complexes considered to be physiological receptors for human amyrin, and can induce signal transduction by said receptors or receptor complexes. These include the human calcitonin receptor hCT-R, and complexes comprising the human calcitonin receptor hCT-R and at least one of the human receptor activity regulatory proteins called hRAMP1, hRAMP2, and hRAMP3. The complexes between hCT-R and hRAMP1, hRAMP2, and hRAMP3 are called hAMYR1, hAMYR2, and hAMYR3 (i.e., human amyrin receptors 1, 2, and 3), respectively.

[0067] A compound can be considered an amyrin receptor agonist if it exhibits agonist activity with respect to one or more of hAMYR1, hAMYR2, and hAMYR3, for example, with respect to hAMYR1 and / or hAMYR3, for example, with respect to hAMYR3.

[0068] Typically, amyrin receptor agonists also exhibit agonist activity in hCT-R when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3. Typically, agonists exhibit activity in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) at a ratio less than 10 times that of their activity in any one of hAMYR1, hAMYR2, and hAMYR3 (i.e., their activity in all of these receptors) in comparable assays. The agonist activity at hCT-R may be less than five times that at hAMYR1, hAMYR2, and hAMYR3, substantially equal to (e.g., + / - 10%), or lower than that at hAMYR1, hAMYR2, and hAMYR3. In this regard, it may be sufficient to simply compare the activity between hCT-R and hAMYR3.

[0069] The ability to induce cAMP formation (i.e., induce adenylyl cyclase activity) as a result of binding to the relevant receptor or receptor complex is typically considered an indicator of agonist activity. Other intracellular signaling pathways or events may also be used as information read for amyrin receptor agonist activity. These may include calcium release, β-arrestin recruitment, receptor internalization, kinase activation or inactivation, lipase activation, inositol phosphate release, diacylglycerol release, or nuclear transcription factor transfer.

[0070] The cells utilized by a suitable equivalent assay format express hCT-R, differing only in their expression of hRAMP1, 2, and 3. For example, by manipulating a “base” cell line that does not express any of hCT-R, hRAMP1, hRAMP2, and hRAMP3, cells can be produced that express (i) hCT-R and (ii) one of hAMYR1, hAMYR2, and hAMYR3 (i.e., in addition to hCT-R, one of hRAMP1, hRAMP2, and hRAMP3), for example, hAMYR3. The base cells are typically mammalian cells and may be primate cells. These may be non-human primate cells. Preferably, the base cells do not express any of CT-R, RAMP1, RAMP2, or RAMP3 (human, or native to the base cells if the base cells are non-human). The base cells may be fibroblasts. Suitable non-human fibroblast-based cells include African green monkey COS7 cells, which do not express native CT-R or RAMP.

[0071] Equivalent activity is provided by the EC described below. 50 The value can be measured by any appropriate means, for example, through the determination of the value. It should be obvious that identical biological readout information must exist for both receptor types.

[0072] The compounds of the present invention may exhibit many advantageous properties of human amyrin and its existing analogs, such as plumrintide, IAPP-GI, and analogs, as described in International Publication No. 2012 / 168430, International Publication No. 2012 / 168431, and International Publication No. 2012 / 168432. Compared to human amyrin or any of these analogs, the compounds of the present invention may exhibit, for example, improved efficacy (e.g., in the form of improved in vitro activity or potency at one or more of the receptors hCT-R, hAMYR1, hAMYR2, or hAMYR3). Furthermore, or / or, the compounds of the present invention may exhibit improved solubility, particularly in aqueous media with pH values ​​in the range of 4 to 7.5, or a variety of pH values ​​within that range. Furthermore, the compounds of the present invention may further, or / or, exhibit reduced tendency to undergo microfibrillation, particularly in pharmaceutically relevant aqueous media with pH values ​​in the range of 4 to 7, or a variety of pH values ​​within that range. Furthermore, the compounds of the present invention may also exhibit improved chemical stability (i.e., reduced tendency to undergo chemical degradation) in aqueous media with pH values ​​in the range of 4 to 9, or a variety of pH values ​​within that range.

[0073] The compounds of the present invention are thus well suited for formulation in acidic media (e.g., pH 4) and neutral or near-neutral media (e.g., pH 7 or 7.4). In contrast to plumrintide, which typically exhibits low chemical stability and rapid fibrillation in pharmaceutically relevant aqueous media at a neutral pH, the compounds of the present invention are thus well suited for co-formulation with insulin, various insulin analogs, and / or other therapeutic agents (e.g., anti-diabetic or anti-obesity agents) that require a neutral or near-neutral formulation pH.

[0074] Surprisingly, the compounds of the present invention (amyrin analogs) were found not to induce a delay in gastric emptying. Therefore, when administered to a subject, these compounds (amyrin analogs) do not alter, for example, slow down, gastric emptying.

[0075] Generally, as described above, it is preferable to use biological assays that measure intracellular signaling resulting from the binding of compounds to the relevant receptors. Activation of the calcitonin / amyrin receptor by the compound of the present invention (which acts as an agonist of the receptor) induces cAMP formation, as well as activation of other intracellular signaling pathways and events. Therefore, cAMP production in appropriate cells expressing the receptor, or any other appropriate parameter, can be used to monitor agonist activity against the receptor.

[0076] Appropriate assay formats will be recognized by those skilled in the art, and examples are given below. For example, the assay can use the human calcitonin receptor (hCT-R, e.g., isoform 2 of hCT-R) or the hAMYR3 receptor (see Examples below). Where the sequence of the precursor protein is referenced, it should be understood that the assay may use mature proteins lacking the signal sequence.

[0077] EC 50 The value can be used as a numerical measure of agonist potency at a given receptor. 50 The value is a measure of the compound concentration required to achieve half of the compound's maximum activity in a particular assay. Therefore, for example, the EC of native human amylin... 50 [hCT-R] is lower than or the EC of plumlintide 50 Lower EC than [hCT-R] 50 Compounds containing [hCT-R] can be considered to have higher receptor potency or activity than native human amyrin or pramulintide, respectively, in certain assays.

[0078] In some embodiments of the compounds of the present invention, EC against hCT-R 50 This is less than approximately 1.5 nM (for example, between approximately 0.001 and approximately 1.5 nM).

[0079] In some embodiments of the compounds of the present invention, EC against hCT-R50 This is less than approximately 0.9 nM (for example, between approximately 0.001 and approximately 0.9 nM).

[0080] In some embodiments of the compounds of the present invention, EC against hCT-R 50 This is less than approximately 0.5 nM (for example, approximately 0.001 to approximately 0.5 nM).

[0081] In some embodiments of the compounds of the present invention, EC against hCT-R 50 This is less than approximately 0.3 nM (for example, approximately 0.001 to approximately 0.3 nM).

[0082] In some embodiments of the compounds of the present invention, EC against hCT-R 50 This is less than approximately 0.2 nM (for example, approximately 0.001 to approximately 0.2 nM).

[0083] EC in hCT-R 50 This can be an indicator of the compound's effect on food intake, weight gain, and / or weight loss. EC in hCT-R 50 Compounds with low values ​​may have superior effects on these parameters.

[0084] In some embodiments of the compounds of the present invention, EC against hAMYR3 50 This is less than approximately 1.0 nM (for example, between approximately 0.001 and approximately 1.0 nM).

[0085] In some embodiments of the compounds of the present invention, EC against hAMYR3 50 This is less than approximately 0.5 nM (for example, approximately 0.001 to approximately 0.5 nM).

[0086] In some embodiments of the compounds of the present invention, EC against hAMYR3 50 This is less than approximately 0.4 nM (for example, between approximately 0.001 and approximately 0.4 nM).

[0087] In some embodiments of the compounds of the present invention, EC against hAMYR3 50This is less than approximately 0.3 nM (for example, approximately 0.001 to approximately 0.3 nM).

[0088] In some embodiments of the compounds of the present invention, EC against hAMYR3 50 This is less than approximately 0.2 nM (for example, approximately 0.001 to approximately 0.2 nM).

[0089] EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 It may be lower than that.

[0090] For example, EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 It can sometimes exceed one-tenth of that.

[0091] EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 This can sometimes exceed one-fifth.

[0092] EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50 This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 It may be substantially equal to (for example, + / - 50%).

[0093] EC in hCT-R (when expressed in the absence of hRAMP1, hRAMP2, and hRAMP3) 50This refers to EC in any or all of hAMYR1, hAMYR2, and hAMYR3, for example, in hAMYR3. 50 It may be higher than that.

[0094] gastric emptying Gastric emptying refers to the process of emptying the stomach contents into the duodenum.

[0095] Changes in gastric emptying can affect the residence time of a given molecule in the stomach, and therefore can alter the time it takes for that molecule to reach a given downstream compartment, such as the duodenum, small intestine, and large intestine. Consequently, gastric emptying may delay the absorption of an adjunctly administered oral medication.

[0096] Furthermore, delayed gastric emptying can affect blood glucose levels, which in turn may affect any concomitant medications used to control glucose levels (e.g., parenteral drugs), such as insulin.

[0097] Prior-developed peptide hormones (particularly those used for weight loss or the treatment of obesity and diabetes) have been shown to cause delayed gastric emptying.

[0098] For example, tilzepatide (marketed under the brand names Manjaro and Zepbound) delays gastric emptying (Urva et al. Diabetes Obes Metab 2020 22 1886-1891), and therefore may affect the absorption of concurrently administered oral medications. Patients are advised to exercise caution when concurrently administering oral medications with Manjaro. Physicians are advised to monitor patients when concurrently administering oral medications whose efficacy depends on the threshold concentration or those with a narrow therapeutic index (e.g., warfarin) with Manjaro. Patients using oral hormonal contraceptives are advised to switch to parenteral contraception or to add barrier contraception for four weeks after starting Manjaro and for four weeks after each dose escalation of Manjaro.

[0099] In particular, prior art amylin analogs are known to cause a delay in gastric emptying. This delay affects concomitant medications. For example, patients receiving the amylin analog pramulintide (SYMLIN®) are advised to take certain concomitant oral medications at least one hour before or two hours after SYMLIN® administration.

[0100] As a further example, patients receiving the amylin analog pramulintide (SYMLIN®) are warned of the risk of severe hypoglycemia and are advised to reduce their pre-meal insulin dose, including biphasic insulin doses, by 50% to reduce the risk of hypoglycemia, followed by close monitoring of blood glucose levels.

[0101] Therefore, in addition to facilitating a dosage regimen in which the timing of concomitant agents is not affected by the administration of the amylin analog of the present invention, the present invention also provides a regimen in which the dose of concomitant agents is not affected by the administration of the amylin analog of the present invention.

[0102] Furthermore, patients are advised not to be administered SYMLIN® if they are already receiving medications that alter gastrointestinal motility (https: / / www.rxlist.com / symlin-drug.htm#warnings).

[0103] The amylin analog of the present invention does not affect gastric emptying. In other words, the amylin analog of the present invention does not delay gastric emptying.

[0104] Since there is no delay in gastric emptying, it is assumed that such considerations do not apply to the amylin analog of the present invention.

[0105] Gastric emptying is measured by the acetaminophen absorption test. In this test, fasted subjects are administered an oral dose of acetaminophen along with a standard meal. Blood acetaminophen concentrations are tracked after the meal. Comparing the blood acetaminophen concentration of subjects treated with an amylin analog to that of subjects treated with a placebo can be used as an indicator of the relative gastric emptying rate. Whether a given amylin analog affects (i.e., delays) gastric emptying can be easily determined using the acetaminophen test.

[0106] Concomitant drugs In the administration regimens, methods, and medical uses of the present invention, the amylin analog of the present invention is administered to the subject within approximately 120 minutes of the concomitant agent (for example, simultaneously with the concomitant agent).

[0107] A concomitant agent is an agent (e.g., a pharmaceutical, compound, molecule, or supplement) used simultaneously with or nearly simultaneously with (e.g., within two hours) an amylin analog. “Concomitant agent” may also be referred to as “additional agent.” The term “concomitant agent” does not impose, nor does it mean, any relationship between the amylin analog and the concomitant agent other than a temporal relationship (i.e., that they are administered nearly simultaneously).

[0108] The concomitant medication differs from amylin analogs, which do not affect the rate of gastric emptying.

[0109] Concomitant drugs may be pharmaceuticals (i.e., agents that treat a disease or disorder). Concomitant drugs may be non-pharmaceuticals, such as nutritional supplements. Concomitant drugs may be any agent other than an amylin analog. The term "concomitant drug" may refer to any number of concomitant drugs other than an amylin analog.

[0110] The concomitant agent may be any agent whose efficacy is affected by the gastric emptying rate. Preferably, the concomitant agent is an agent whose efficacy is affected by the gastric emptying rate. For example, when a rapid onset of a drug or threshold concentration is necessary for therapeutic efficacy, the concomitant agent, particularly an orally administered drug, may depend on the gastric emptying rate. Such drugs include analgesics, antibiotics, and contraceptives.

[0111] In some embodiments, the concomitant agent is a pharmaceutical drug that requires rapid onset of action. In some embodiments, the concomitant agent is an oral pharmaceutical drug that requires rapid onset of action.

[0112] In some embodiments, the concomitant agent is an oral medication.

[0113] In some embodiments, the concomitant agent is an analgesic.

[0114] In some embodiments, the concomitant agent is an antibiotic.

[0115] In some embodiments, the concomitant agent is an oral contraceptive.

[0116] In some embodiments, the concomitant agent is a nutritional supplement.

[0117] In some embodiments, the concomitant agent is a parenteral drug.

[0118] In some embodiments, the concomitant agent is administered intravenously, intramuscularly, or subcutaneously.

[0119] In some embodiments, the concomitant agent is selected from the group consisting of analgesics, antibiotics, anticoagulants, contraceptives, antihypertensives, statins, antifungals, hypoglycemic agents, contraceptives, oral medications with a narrow therapeutic index, and nutritional supplements.

[0120] In some embodiments, the concomitant agent is selected from the group consisting of insulin, acetaminophen, digoxin, warfarin, metformin, hydrocortisone, griseofulvin, glibenclamide, gliclazide, and glipizide.

[0121] In some embodiments, the concomitant agent is a sulfonylurea, such as glibenclamide, glyclazide, or glipizide.

[0122] In some embodiments, the concomitant agent is insulin.

[0123] The subject may be administered one or more combination agents as defined herein independently. For example, in a case where, for example, three pharmaceuticals are administered to the subject simultaneously with the amylin analog of the present invention, each of the three pharmaceuticals is considered independently a "combination agent" according to the present invention.

[0124] Therefore, in some embodiments, the amylin analog is administered to the subject simultaneously with (within approximately 120 minutes of) at least one combination agent, for example, at least two combination agents, at least three combination agents, at least four combination agents, at least five combination agents, at least six combination agents, at least seven combination agents, at least eight combination agents, at least nine combination agents, or at least ten combination agents.

[0125] In some embodiments, the amylin analog is administered to the subject simultaneously with one or more combination agents, for example, two or three or more combination agents, three or four or more combination agents, four or five or more combination agents, five or six or more combination agents, six or seven or more combination agents, seven or eight or more combination agents, eight or nine or more combination agents, nine or ten or more combination agents, or ten or eleven or more combination agents (within approximately 120 minutes of the administration of the combination agent).

[0126] In some embodiments, the amylin analog is administered to the subject simultaneously with one, two, three, four, five, six, seven, eight, nine, or ten combination agents (within approximately 120 minutes of the combination agent).

[0127] Timing of administration Remarkably, the amylin analogs of the present invention do not cause any apparent delay in gastric emptying. Therefore, these compounds are suitable for administration simultaneously with or in close proximity to other compounds or pharmaceuticals, i.e., concomitant agents.

[0128] In particular, when pharmaceuticals are administered orally, their administration can be susceptible to the effects of gastric emptying, and their administration may depend on the administration of any other pharmaceuticals that delay gastric emptying, such as amylin analogs of prior art.

[0129] For example, it may be necessary to delay the administration of a medication until at least two hours have passed since the administration of an amylin analog that delays gastric emptying. Alternatively, it may be necessary to advance the administration of the medication (or delay the administration of the amylin analog) so that at least one hour has passed between the administration of the medication and the administration of the amylin analog.

[0130] In both cases, the administration of medications is interdependent in time. Therefore, patients may need to change existing dosing regimens, develop complicated new dosing regimens, and / or take the risk of drug interactions that may reduce the effectiveness of non-amylin analog medications.

[0131] Advantageously, the amylin analog of the present invention does not affect gastric emptying, i.e., it does not delay gastric emptying like amylin and other hormonal peptide therapeutics and amylin analogs. This means that the timing of administration of one or more other (non-amylin analog) agents to a subject does not need to be adjusted to take into account the administration of the amylin analog of the present invention. For example, the amylin analog of the present invention advantageously does not delay gastric emptying, unlike tilzepatide or pramulintide.

[0132] Therefore, the timing of amylin analog administration does not affect the timing of concomitant drug administration. Thus, the administration of amylin analog and concomitant drug administration are essentially time-independent. In other words, the amylin analog of the present invention enables time-independent administration of the amylin analog and one or more concomitant drugs.

[0133] Therefore, in the administration regimens, methods, and medical uses of the present invention, the amylin analog of the present invention is administered to the subject within approximately 120 minutes of the administration of the concomitant agent to the subject (for example, simultaneously with the administration of the concomitant agent).

[0134] It will be understood that, if the concomitant agent is not administered simultaneously with the amylin analog of the present invention, it may be administered at any time, for example, at a time determined by any administration regimen for the concomitant agent. Therefore, the administration of the concomitant agent is not limited by the administration of the amylin analog.

[0135] Amylin analogs and concomitant agents may be administered independently of each other. It should be understood that the order in which amylin analogs and concomitant agents are described herein does not limit the order of their administration. Therefore, amylin analogs may be administered before, simultaneously with, or after concomitant agents, and vice versa.

[0136] The present invention makes it possible to administer an amylin analog to a subject simultaneously with one or more concomitant agents. In fact, the amylin analog and the concomitant agents can be administered to the subject in close proximity (i.e., almost simultaneously), but not necessarily at the exact same moment. The key element of the present invention is that it enables the administration of the concomitant agents at the time of administration of the amylin analog, which would not have been possible without the amylin analog of the present invention, which does not delay gastric emptying.

[0137] Therefore, in some embodiments, the amylin analog is administered to the subject within approximately 120 minutes of administration of the concomitant agent to the subject, for example within approximately 110 minutes, for example within approximately 100 minutes, for example within approximately 90 minutes, for example within approximately 80 minutes, for example within approximately 70 minutes, for example within approximately 60 minutes, for example within approximately 50 minutes, for example within approximately 45 minutes, for example within approximately 40 minutes, for example within approximately 30 minutes, for example within approximately 20 minutes, for example within approximately 15 minutes, for example within approximately 10 minutes, for example within approximately 9 minutes, for example within approximately 8 minutes, for example within approximately 7 minutes, for example within approximately 6 minutes, for example within approximately 5 minutes, for example within approximately 4 minutes, for example within approximately 3 minutes, for example within approximately 2 minutes, or for example within approximately 1 minute.

[0138] In some embodiments, the amylin analog is administered to the subject before the co-administered agent is administered to the subject. In some embodiments, the amylin analog is administered to the subject approximately 120 minutes before the administration of the co-administered agent to the subject, for example approximately 110 minutes, for example approximately 100 minutes, for example approximately 90 minutes, for example approximately 80 minutes, for example approximately 70 minutes, for example approximately 60 minutes, for example approximately 50 minutes, for example approximately 45 minutes, for example approximately 40 minutes, for example approximately 30 minutes, for example approximately 20 minutes, for example approximately 15 minutes, for example approximately 10 minutes, for example approximately 9 minutes, for example approximately 8 minutes, for example approximately 7 minutes, for example approximately 6 minutes, for example approximately 5 minutes, for example approximately 4 minutes, for example approximately 3 minutes, for example approximately 2 minutes, or for example approximately 1 minute before the administration of the co-administered agent to the subject.

[0139] In one embodiment, the amylin analog is administered to the subject after the co-administered agent has been administered to the subject. In some embodiments, the amylin analog is administered to the subject approximately 120 minutes after the administration of the co-administered agent, for example approximately 110 minutes, for example approximately 100 minutes, for example approximately 90 minutes, for example approximately 80 minutes, for example approximately 70 minutes, for example approximately 60 minutes, for example approximately 50 minutes, for example approximately 45 minutes, for example approximately 40 minutes, for example approximately 30 minutes, for example approximately 20 minutes, for example approximately 15 minutes, for example approximately 10 minutes, for example approximately 9 minutes, for example approximately 8 minutes, for example approximately 7 minutes, for example approximately 6 minutes, for example approximately 5 minutes, for example approximately 4 minutes, for example approximately 3 minutes, for example approximately 2 minutes, or for example approximately 1 minute after the administration of the co-administered agent.

[0140] In some embodiments, the amylin analog is administered to the subject at the same time as the co-administered agent. The term "at the same time" should be understood to mean that the administrations occur substantially simultaneously, for example, within 5 minutes of each other.

[0141] Dosage and administration In this specification, the term "dose" refers to the amount of a given compound (amyrin analog or combination agent) administered to a subject in each administration event. The term "administration" refers to both the amount and frequency of administration of a given compound to a subject.

[0142] The administration of amylin analogs can be selected independently of the administration of concomitant medications.

[0143] Typical administration of the amylin analog used in the present invention may be in one or more doses, for example, 1 to 3 doses, ranging from about 0.0001 to about 100 mg per kg of body weight per day or every other day, for example, from about 0.0005 to about 50 mg per kg of body weight per day or every other day, for example, from about 0.001 to about 10 mg per kg of body weight per day or every other day, for example, from about 0.01 to about 1 mg per kg of body weight per day or every other day. The exact dose to be used will depend, in particular, on the nature and severity of the disease or disorder being treated, the sex, age, weight, and overall condition of the patient, any other concomitant diseases or disorders that are being treated or are likely to be treated, and other factors known to physicians skilled in the art.

[0144] Typical doses of the amylin analog used in the present invention may range from about 0.5 mg to about 10.0 mg per day or every other day, from about 0.6 mg to about 7.5 mg per day or every other day, preferably from about 1.2 mg to about 7.5 mg per day or every other day, preferably from about 1.2 to about 6.0 mg per day or every other day, preferably from about 2.4 to about 6.0 mg per day or every other day, preferably from about 2.4 to about 4.0 mg per day or every other day, and preferably from about 2.4 to about 3.5 mg per day or every other day.

[0145] In some embodiments, the amylin analog is administered to the subject in doses of approximately 0.04 mg to approximately 10 mg, for example, approximately 0.04 mg to approximately 7 mg, approximately 0.04 mg to approximately 6 mg, approximately 0.04 mg to approximately 4.4 mg, approximately 0.04 mg to approximately 2.4 mg, approximately 0.6 mg to approximately 6 mg, approximately 0.6 mg to approximately 4.4 mg, approximately 0.6 mg to approximately 2.4 mg, approximately 0.7 mg to approximately 6 mg, approximately 0.7 mg to approximately 4.4 mg, or approximately 0.7 mg to approximately 2.4 mg.

[0146] In some embodiments, the amylin analog is administered to the subject in doses of approximately 0.6 mg to 4.8 mg, approximately 0.6 mg to 3.6 mg, approximately 0.6 mg to 2.4 mg, or approximately 0.6 mg to 1.2 mg.

[0147] In some embodiments, the amylin analog is administered to subjects in doses of approximately 1.2 mg to approximately 4.8 mg, approximately 1.2 mg to approximately 3.6 mg, or approximately 1.2 mg to approximately 2.4 mg. In some embodiments, the amylin analog is administered to subjects in doses of approximately 2.4 mg to approximately 4.8 mg, or approximately 2.4 mg to approximately 3.6 mg. In some embodiments, the amylin analog is administered to subjects in doses of approximately 3.6 mg to approximately 4.8 mg.

[0148] In some embodiments, the amylin analog is administered to the subject in doses up to approximately 10 mg, for example, up to approximately 9.5 mg, 9 mg, 8.5 mg, 8 mg, 7.5 mg, 7 mg, 6.5 mg, 6 mg, 5.5 mg, 5 mg, 4.8 mg, 4.5 mg, 4 mg, 3.6 mg, 3.5 mg, 3 mg, 2.5 mg, 2.4 mg, 2 mg, 1.5 mg, 1.2 mg, 1 mg, 0.6 mg, 0.5 mg, or 0.25 mg.

[0149] In some embodiments, the amylin analog is administered to the subject in doses of approximately 10 mg, for example, approximately 9.5 mg, 9 mg, 8.5 mg, 8 mg, 7.5 mg, 7 mg, 6.5 mg, 6 mg, 5.5 mg, 5 mg, 4.8 mg, 4.5 mg, 4.4 mg, 4 mg, 3.6 mg, 3.5 mg, 3.4 mg, 3 mg, 2.5 mg, 2.4 mg, 2 mg, 1.5 mg, 1.4 mg, 1.2 mg, 1 mg, 0.6 mg, 0.5 mg, 0.35 mg, 0.25 mg, 0.16 mg, 0.08 mg, or 0.04 mg.

[0150] In some embodiments, the amyrin analog according to the present invention is administered at regular intervals. In some embodiments, the amyrin analog is administered to the subject once daily, once every two days, once weekly, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the amyrin analog is administered to the subject once a month.

[0151] In some embodiments, the dose of the amylin analog is not the same with each administration. In some embodiments, the dose of the amylin analog increases with each sequential administration. In some embodiments, the dose of the amylin analog increases with each sequential administration until a desired maximum dose is reached. The desired maximum dose may be maintained over a given time (i.e., plateau administration). In some embodiments, the dose of the amylin analog is the same with each administration.

[0152] Advantageously, the amylin analog of the present invention does not affect gastric emptying, i.e., it does not delay gastric emptying like amylin and other amylin analogs, meaning that the dose or administration of one or more other (non-amylin analog) agents administered to a subject does not need to be adjusted in consideration of the administration of the amylin analog of the present invention.

[0153] Therefore, the administration of the amylin analog does not affect the dose or administration of the concomitant agent being administered. Thus, the dose or administration of the amylin analog and the concomitant agent are essentially independent. In other words, the amylin analog of the present invention enables independent dose selection for the administration of the amylin analog and one or more concomitant agents of the present invention. Therefore, the administration of the concomitant agent is not limited by the administration of the amylin analog.

[0154] Therefore, in the administration regimens, methods, and medical uses of the present invention, the amyrin analog and concomitant agents of the present invention are administered to the subject, and the dose of the concomitant agent administered is no different from the dose of the concomitant agent administered in the absence of the amyrin analog.

[0155] Furthermore, in the administration regimens, methods, and medical uses of the present invention, the amyrin analog of the present invention is administered to the subject within approximately 120 minutes of administration of the concomitant agent (for example, simultaneously with the administration of the concomitant agent), and the dose of the concomitant agent administered is no different compared to the dose administered in the absence of the amyrin analog.

[0156] The concomitant medication may be one in which the administered dose depends on the rate of gastric emptying, and this dependence may be due to blood glucose levels or the rate of change therein.

[0157] As described above, 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.

[0158] Furthermore, according to the previous description, the concomitant medication is insulin.

[0159] It should be understood that the dosage or administration of concomitant agents may be adjusted independently of the timing and / or dosage of amylin analog administration.

[0160] Administration regimen The present invention is a dosage regimen for a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: R 1 -ZR 2 A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3 However, hydrogen or C 1-3 It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. We provide a dosage regimen.

[0161] In some embodiments, the present invention is a dosage regimen for a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 3) The peptide comprises or consists of a pharmaceutically acceptable salt and / or derivative thereof, wherein, Gly(Me): N-methylglycine [also known as sarcosine (Sar)] Ile(Me):N-methylisoleucine Aad: 2-aminoadipic acid, also known as homoglutamic acid, e.g., (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid] Hyp: 4-hydroxyproline, e.g., (2S,4R)-4-hydroxyproline [also written as (4R)-4-hydroxy-L-proline] [19CD]-isoGlu: The nitrogen of the Arg residue backbone (located at position X1 of the Z peptide sequence of the amyrin analog) is covalently bonded to the carboxyl group of the side chain of the Glu moiety via an amide bond, and the 19-carboxy-nonadecanoyl group is covalently bonded to the alpha-amino group of the Glu linker via an amide bond (as described herein), That is, We provide a dosage regimen.

[0162] In one embodiment, the present invention is a dosage regimen for a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other. Amilin analog, formula: R 1 -ZR 2 A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3However, hydrogen or C 1-3 It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example (2S)-2-aminoadipic acid [(also known as (2S)-2-aminohexanedioic acid)], and the dosage of the co-administered agent is not changed as compared to the dosage of the co-administered agent administered in the absence of the amylin analog, providing an administration regimen.

[0163] A method of inhibiting weight gain or reducing body weight The present invention is a method of inhibiting weight gain and / or reducing body weight in a subject, (a) administering an amylin analog that does not affect gastric emptying rate to the subject, and (b) administering a co-administered agent to the subject comprising, the amylin analog and the co-administered agent are administered to the subject within about 120 minutes of each other, and the amylin analog comprises or consists of a peptide of the formula: R 1 -Z-R 2 or a pharmaceutically acceptable salt and / or derivative thereof, wherein, R 1 is hydrogen, C 1-4 acyl, benzoyl or C 1-4 alkyl, or a half-life extending moiety M, where M may be linked to Z via a linker moiety L, R 2 is OH or NHR 3 wherein R 3 is hydrogen or C 1-3 alkyl, and Z is 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) is the amino acid sequence of, wherein, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. Provide a method.

[0164] In some embodiments, the present invention is a method for inhibiting weight gain and / or reducing weight in a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 3) A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, Gly(Me): N-methylglycine [also known as sarcosine (Sar)] Ile(Me):N-methylisoleucine Aad: 2-aminoadipic acid, also known as homoglutamic acid, e.g., (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid] Hyp: 4-hydroxyproline, e.g., (2S,4R)-4-hydroxyproline [also written as (4R)-4-hydroxy-L-proline] [19CD]-isoGlu: The nitrogen of the Arg residue backbone (located at position X1 of the Z peptide sequence of the amyrin analog) is covalently bonded to the carboxyl group of the side chain of the Glu moiety via an amide bond, and the 19-carboxy-nonadecanoyl group is covalently bonded to the alpha-amino group of the Glu linker via an amide bond (as described herein), Provide a method.

[0165] The suppression of glucagon secretion and food intake associated with amylin and amylin analogs can promote weight loss or at least slow down (i.e., reduce or inhibit) weight gain. Therefore, the methods of the present invention can be described as methods for inhibiting or reducing weight gain, methods for promoting weight loss, methods for reducing food intake, and / or methods for reducing weight in a subject.

[0166] Non-therapeutic use The amyrin analogs of the present invention can be used for non-therapeutic purposes. In this regard, for example, for cosmetic reasons, it may be desirable for a subject to reduce food intake and lose weight (or inhibit weight gain) even if the subject is not overweight, obese, or diabetic, and does not suffer from any other weight-related disease. Administration of amyrin analogs can achieve these desired effects (reduction of food intake, weight loss, and / or inhibition of weight gain). In such embodiments, the administration of amyrin analogs is not therapeutic, as the disease or disorder is not treated by the amyrin analogs.

[0167] Similarly, concomitant medications do not need to be pharmaceuticals, nor do they necessarily need to have a therapeutic effect. For example, a concomitant medication that is a nutritional supplement does not have a therapeutic effect.

[0168] Therefore, in some embodiments, the dosing regimen of the present invention is a non-therapeutic dosing regimen. The present invention is therefore a non-therapeutic dosing regimen for a subject, (a) The step of administering an amylin analog that does not affect the gastric emptying rate of the present invention, and (b) Steps to administer concomitant medications Includes, This provides a non-therapeutic administration regimen in which the amylin analog and the concomitant agent are administered to the subject within approximately 120 minutes of each other.

[0169] In some embodiments, the method for inhibiting weight gain and / or reducing weight in a subject is a non-therapeutic method. The present invention therefore provides a non-therapeutic method for inhibiting weight gain and / or reducing weight in a subject, (a) The step of administering an amylin analog that does not affect the gastric emptying rate of the present invention, and (b) Steps to administer concomitant medications Includes, Provided is a non-therapeutic method in which an amylin analog and a co-administered agent are each administered to a subject within about 120 minutes of each other.

[0170] In some embodiments, a method of inhibiting weight gain and / or reducing weight in a subject is a cosmetic method.

[0171] When an amylin analog is used for therapeutic and non-therapeutic purposes, the considerations regarding gastric content excretion and co-administered agents (i.e., the second medicament) outlined herein apply equally.

[0172] Such non-therapeutic methods are intended to reduce the weight of subjects who are neither obese nor morbidly obese.

[0173] In some embodiments of the non-therapeutic method of the invention, the subject is a healthy weight subject. In other words, in some embodiments, the subject is neither overweight, obese, nor morbidly obese. In some embodiments, the subject has a BMI of 18.5 - 24.9 kg / m 2 corresponding to a healthy weight.

[0174] In some embodiments of the non-therapeutic method of the invention, the subject is overweight. In other words, in some embodiments, the subject is not a healthy weight subject, but is neither obese nor morbidly obese. In some embodiments, the subject has a BMI of 25.0 - 29.9 kg / m 2 corresponding to overweight.

[0175] Therapeutic Use In accordance with the surprising discovery that the amylin analogs described herein do not stimulate the delay of gastric content excretion, the amylin analogs are utilized in many therapeutic settings. The amylin analogs of the invention are useful in the treatment or prevention of diseases.

[0176] More specifically, the amylin analogs of the present invention are useful, in particular, in reducing food intake, promoting weight loss, and inhibiting or reducing weight gain. These may therefore provide attractive therapeutic options, in particular, for obesity and metabolic diseases caused by, characterized by, or associated with excess body weight. Treatment can be achieved, for example, by controlling appetite, eating, food intake, calorie intake, and / or energy expenditure.

[0177] As used in the context of this invention, the term “treatment” (and “treating” and other grammatical variations thereof) refers to an approach to obtain a favorable or desired clinical outcome. For the purposes of this invention, favorable or desired clinical outcomes include, but are not limited to, symptom reduction, disease severity reduction, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or reduction of the condition, and remission (partial or complete), whether detectable or undetectable. “Treatment” may also refer to an extension of survival compared to expected survival in the absence of treatment. “Treatment” is an intervention undertaken with the aim of preventing the onset of a disability or altering the pathology of a disability. Thus, “treatment” refers to both therapeutic treatment and prophylactic or preventive measures. When used in the context of prophylactic or preventive measures, amylin analogs or combination agents do not need to completely prevent the onset of the disease or disability. Subjects requiring treatment include subjects already suffering from the disability and subjects for whom the onset of the disability is to be prevented. "Treatment" also means inhibiting or reducing the increase of a pathology or symptom (e.g., weight gain or hypoglycemia) compared to the absence of treatment, and does not necessarily mean the complete cessation or cure of the condition in question. The term "prevention" (as well as "preventing" and other grammatical variations thereof) refers to the prevention of a disease, for example, by reducing the symptoms of the disease.

[0178] The subject may be administered any number of other medicaments (i.e., not amylin analogs as described herein) for preventing or treating any number of the diseases or disorders described herein or, indeed, any other disease or disorder. Thus, the amylin analogs described herein are particularly advantageous because they do not interfere with the administration of such other medicaments described elsewhere herein.

[0179] Method of treatment Thus, the present invention is a method of treating or preventing a disease in a subject, comprising: (a) administering to the subject an amylin analog that does not affect gastric emptying rate, and (b) administering to the subject a co - administered agent wherein the amylin analog and the co - administered agent are each administered to the subject within about 120 minutes of each other, and the amylin analog comprises or consists of a peptide of the formula: R 1 -Z-R 2 or a pharmaceutically acceptable salt and / or derivative thereof, wherein R 1 is hydrogen, C 1-4 acyl, benzoyl or C 1-4 alkyl, or a half - life extending moiety M, where M may be linked to Z via a linker moiety L, R 2 is OH or NHR 3 wherein R 3 is hydrogen or C 1-3 alkyl, and Z is an amino acid sequence of formula I: X1 - X2 - X3 - X4 - X5 - X6 - X7 - Ala - Thr - X10 - Arg - Leu - Ala - X 14 - Phe - Leu - X17 - Arg - X19 - X20 - Phe - Gly(Me) - Ala - Ile(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, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. Provide a method.

[0180] In some embodiments, the present invention is a method for treating or preventing a disease in a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 3) A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, Gly(Me): N-methylglycine [also known as sarcosine (Sar)] Ile(Me):N-methylisoleucine Aad: 2-aminoadipic acid, also known as homoglutamic acid, e.g., (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid] Hyp: 4-hydroxyproline, e.g., (2S,4R)-4-hydroxyproline [also written as (4R)-4-hydroxy-L-proline] [19CD]-isoGlu: The nitrogen of the Arg residue backbone (located at position X1 of the Z peptide sequence of the amyrin analog) is covalently bonded to the carboxyl group of the side chain of the Glu moiety via an amide bond, and the 19-carboxy-nonadecanoyl group is covalently bonded to the alpha-amino group of the Glu linker via an amide bond (as described herein), Provide a method.

[0181] In some embodiments, the present invention provides a method for treating a subject without altering (e.g., delaying) gastric emptying, comprising the step of administering an amylin analog according to the present invention to a subject in need thereof.

[0182] In some embodiments, the present invention provides a method for maintaining the normal dosing regimen of one or more concomitant administered medicaments in a subject requiring treatment with an amylin analog, the method comprising administering an amylin analog according to the present invention to the subject.

[0183] Medical use The present invention also provides an amylin analog that does not affect gastric emptying rate for use in a method of treating or preventing a disease in a subject, the method comprising: (a) administering an amylin analog to the subject, and (b) administering a concomitant agent to the subject and the amylin analog and the concomitant agent are each administered to the subject within about 120 minutes of each other, and the amylin analog comprises or consists of a peptide of the formula: R 1 -Z-R 2 or a pharmaceutically acceptable salt and / or derivative thereof, wherein R 1 is hydrogen, C 1-4 acyl, benzoyl or C 1-4 alkyl, or a half-life extending moiety M, where M may be linked to Z via a linker moiety L, R 2 is OH or NHR 3 wherein R 3 is hydrogen or C 1-3 alkyl, and Z is of the 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-Ile(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, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. We offer Amilin analog.

[0184] The present invention also relates to the use of an amylin analog that does not affect gastric emptying rate for the manufacture of a pharmacopoeia for use in a method of treating or preventing a disease in a subject, and the method is (a) A step of administering an amylin analog, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: R 1 -ZR 2 A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3 However, hydrogen or C 1-3 It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. Provides usage.

[0185] In some embodiments, the present invention provides an amylin analog for therapeutic use that does not alter gastric emptying.

[0186] In some embodiments, the present invention provides an amylin analog for therapeutic use that does not delay gastric emptying.

[0187] In some embodiments, the present invention provides amylin analogs for use in methods of treating or preventing obesity, overweight, and / or diabetes while maintaining normal gastric emptying.

[0188] In some embodiments, the present invention provides amylin analogs according to the present invention for use in methods of treating or preventing obesity, overweight, and / or diabetes without delaying gastric emptying.

[0189] The subject's weight may be stated using the Body Mass Index (BMI), which for human subjects is calculated by dividing the subject's weight in kilograms by the square of the subject's height in meters.

[0190] In some embodiments, the subjects are obese. In some embodiments, the subjects are obese, with a weight of 30.0 to 39.9 kg / m². 2 He has a BMI of [value missing].

[0191] In some embodiments, the subject is morbidly obese. In some embodiments, the subject is 40.0 kg / m², which corresponds to morbidly obese. 2 They have the above BMI.

[0192] In some embodiments, the present invention provides amylin analogs for use in a method of treating a subject in need of one or more concomitantly administered pharmaceuticals.

[0193] disease The terms “disease,” “disorder,” and “condition” are synonymous and are used interchangeably herein to refer to any state of physical dysfunction.

[0194] The amylin analogs of the present invention can be used to treat obesity and related diseases, disorders, and health conditions, such as, but not limited to, morbid obesity, pre-surgical obesity, obesity-related inflammation, obesity-related gallbladder disease, and obesity-induced sleep apnea and respiratory problems, cartilage degeneration, osteoarthritis, and reproductive health complications of obesity or overweight, such as infertility.

[0195] Therefore, in some embodiments of the administration regimens, methods, and medical uses of the present invention, the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes. In other words, in some embodiments of the administration regimens, methods, and medical uses of the present invention, the subject is overweight, has obesity, has morbid obesity, has diabetes, or has a disease associated with obesity or diabetes. Diabetes may be type 1 diabetes or type 2 diabetes.

[0196] In some embodiments of the administration regimens, methods, and medical uses of the present invention, diseases associated with obesity or diabetes are selected from the group consisting of obesity-related inflammation, obesity-related gallbladder disease, obesity-induced sleep apnea, obesity-related respiratory problems, cartilage degeneration, osteoarthritis, infertility, Alzheimer's disease, pre-diabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), conditions associated with elevated blood glucose levels, metabolic diseases, metabolic syndrome, hyperglycemia, hypertension, atherosclerosis, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal failure, arteriosclerosis, macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a complication of diabetes, coronary heart disease, peripheral artery disease, and stroke.

[0197] The compound may also be useful in reducing circulating LDL levels and / or increasing the HDL / LDL ratio.

[0198] The effects of the above compounds may be mediated, in whole or in part, by an effect on body weight, or they may be unrelated to an effect on body weight.

[0199] Metabolic syndrome is characterized by a group of metabolic risk factors in an individual. These include abdominal obesity (excess adipose tissue around internal organs), atherosclerosis (high triglycerides, low HDL cholesterol, and / or high LDL cholesterol, which promote plaque buildup in arterial walls), elevated blood pressure (hypertension), insulin resistance and glucose intolerance, pro-thrombogenic conditions (e.g., high levels of fibrinogen or plasminogen activator-1 in the blood), and inflammatory conditions (e.g., elevated levels of C-reactive protein in the blood).

[0200] Individuals with metabolic syndrome have an increased risk of coronary heart disease, as well as other diseases associated with other signs of arteriosclerosis (e.g., stroke and peripheral vascular disease). Abdominal obesity is considered to be the primary underlying risk factor for this syndrome.

[0201] Pharmaceutical composition This specification describes pharmaceutical compositions comprising amylin analogs. As in all aspects of the present invention, references to amylin analogs are understood to also include references to pharmaceutically acceptable salts and solvates.

[0202] The amylin analog of the present invention can be formulated as a pharmaceutical composition suitable for administration with or without storage, and such pharmaceutical composition typically comprises a therapeutically effective amount of at least one peptide of the present invention together with a pharmaceutically acceptable carrier, excipient, or medium.

[0203] The term “pharmaceutically acceptable carrier” includes any standard pharmaceutically acceptable carrier. pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical field 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 salines and phosphate-buffered salines of slightly acidic or physiological pH can be used. Suitable pH buffers may be, for example, phosphates, citrates, acetates, tris(hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine, or acetates (e.g., sodium acetate), or mixtures thereof. The term further encompasses all carriers listed in the United States Pharmacopeia for use in animals, including humans.

[0204] The pharmaceutical compositions of the present invention may be in unit dosage form. In such form, the composition is divided into unit doses containing an appropriate amount of one or more active components. The unit dosage form may be provided as a packaged preparation, the packaging containing individual amounts of the preparation, for example, packaged tablets, capsules, or powder in vials or ampoules. The unit dosage form may also be itself, for example, a capsule, cachet, or tablet, or an appropriate number of any of these packaged forms. The unit dosage form may also be provided in a single-dose injectable form, for example, in the form of a pen-type device containing a liquid-phase (typically aqueous) composition. The composition can be formulated for any appropriate route and means of administration. Pharmaceutically acceptable carriers or diluents include, for example, those used in formulations suitable for oral, intravitreal, rectal, vaginal, nasal, topical, intestinal, or parenteral administration (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal administration), or inhalation. The formulations can be conveniently provided in unit dose forms and can be prepared by any method well known in the field of pharmaceutical formulations.

[0205] Subcutaneous or transdermal administration may be suitable for the peptide of the present invention in some cases.

[0206] Further embodiments relate to devices, dosage forms, and packaging used to deliver the pharmaceutical formulations of the present invention. Thus, at least one peptide in a stable or stored formulation or solution described herein can be administered to a patient in accordance with the present invention by various delivery methods, including by SC or IM injection, or by transdermal, pulmonary, or transmucosal administration, or by implantation, or by the use of an osmotic pump, cartridge, micropump, or other means recognized by those skilled in the art.

[0207] Further embodiments relate to oral formulations and oral administration. Formulations for oral administration may rely on the co-administration of an adjuvant (e.g., resorcinol and / or a nonionic surfactant, e.g., polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) to artificially increase the permeability of the intestinal wall, and / or on the co-administration of an enzyme inhibitor (e.g., a pancreatic trypsin inhibitor, diisopropyl fluorophosphate (DFF), or trazilol) to inhibit enzymatic degradation. The active constituent compound of a solid-type dosage form for oral administration may be mixed with at least one additive, e.g., sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, acacia gum, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer, or glyceride. These dosage forms may also contain other types of additives, such as inert diluents, lubricants (e.g., magnesium stearate), parabens, preservatives (e.g., sorbic acid, ascorbic acid, or alpha-tocopherol), antioxidants (e.g., cysteine), disintegrants, binders, thickeners, buffers, pH adjusters, sweeteners, flavorings, or fragrances.

[0208] Devices and kits In some embodiments, the present invention relates to a device for delivering an amylin analog or pharmaceutical composition of the present invention to a subject. Through such a device, the amylin analog can be administered to a subject by a variety of delivery methods, including intravenous, subcutaneous, intramuscular, or intraperitoneal injection; oral administration; transdermal administration; pulmonary or mucosal administration; administration by implant, osmotic pump, cartridge, or micropump; or other means recognized by those skilled in the art.

[0209] In some embodiments, the present invention relates to a kit comprising the amylin analog or a pharmaceutical composition thereof and one or more second pharmaceuticals. In certain embodiments, the kit further comprises packaging and / or instructions for use.

[0210] Embodiments of the present invention The present invention is described by the following numbered embodiments.

[0211] Appearance 1. A dosage regimen for the subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: R 1 -ZR 2 A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3 However, hydrogen or C 1-3 It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. Administration regimen.

[0212] Embodiment 2. The dosing regimen according to Embodiment 1, which is a non-therapeutic dosing regimen.

[0213] Appearance 3. The subject is, (i) being overweight, (ii) Having obesity, (iii) Having morbid obesity, (iv) Having diabetes, and / or (v) Having a disease related to obesity or diabetes, A dosage regimen as described in Embodiment 1 or Embodiment 2.

[0214] Appearance 4. A method for inhibiting weight gain and / or reducing weight in a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: R 1 -ZR 2 A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3 However, hydrogen or C 1-3 It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. method.

[0215] Embodiment 5. The method according to Embodiment 4, which is a non-therapeutic method.

[0216] Appearance 6. The subject is, (i) being overweight, (ii) Having obesity, (iii) Having morbid obesity, (iv) Having diabetes, and / or (v) Having a disease related to obesity or diabetes, The method according to embodiment 4 or embodiment 5.

[0217] Appearance 7. A method for treating or preventing a disease in the subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: R 1 -ZR 2 A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3 However, hydrogen or C 1-3 It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. method.

[0218] Appearance 8. An amylin analog for use in methods of treating or preventing diseases in a subject, which does not affect the rate of gastric emptying, and the method is (a) A step of administering an amylin analog, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: R 1 -ZR 2 A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3 However, hydrogen or C 1-3 It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. Amilin analog.

[0219] Appearance 9. The use of an amylin analog that does not affect the gastric emptying rate for manufacturing a pharmaceutical product for use in a method of treating or preventing a disease in a subject, and the method is (a) A step of administering an amylin analog, and (b) Steps to administer concomitant medications Includes, Amylin analogs and concomitant agents are administered to the subject within approximately 120 minutes of each other, and Amilin analog, formula: R 1 -ZR 2 A peptide or a pharmaceutically acceptable salt and / or derivative thereof, comprising or composed thereof, in the formula, R 1 is hydrogen, C 1-4 Acyl, benzoyl, or C 1-4 Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R 2 OH or NHR 3 And in the formula, R 3 However, hydrogen or C 1-3 It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Gln. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro. X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. use.

[0220] Apparatus 10. The method according to Apparatus 7, the amylin analog for use as described in Apparatus 8, or the use as described in Apparatus 9, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes.

[0221] Apparatus 11. The administration regimen described in Apparatus 3, the method described in Apparatus 6, or the method described in Apparatus 10, an amylin analog for use, or use, wherein the diabetes is type 1 or type 2 diabetes.

[0222] Apparatus 12. A dosing regimen according to Apparatus 3, the method according to Apparatus 6, or the method according to Apparatus 10, an amylin analog for use, or use, wherein the disease associated with obesity or diabetes is selected from the group consisting of obesity-related inflammation, obesity-related gallbladder disease, obesity-induced sleep apnea, obesity-related respiratory problems, cartilage degeneration, osteoarthritis, infertility, Alzheimer's disease, prediabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), conditions associated with elevated blood glucose levels, metabolic diseases, metabolic syndrome, hyperglycemia, hypertension, atherosclerosis, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal failure, arteriosclerosis, macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a complication of diabetes, coronary heart disease, peripheral artery disease, and stroke.

[0223] Embodiment 13. Amilin analog, formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2(Sequence ID 3) An administration regimen, method, use of an amylin analog, or use according to any one of embodiments 1 to 12, comprising or consisting of the peptide or a pharmaceutically acceptable salt and / or derivative thereof, wherein parentheses () indicate an intramolecular lactam crosslink formed between the side chains of residues at sequence positions X2 and X7.

[0224] Embodiment 14. An administration regimen, method, use of an amylin analog, or use according to any one of Embodiments 1 to 13, wherein the amylin analog and the concomitant agent are administered to the subject within 90 minutes of each other, within 60 minutes of each other, within 45 minutes of each other, within 30 minutes of each other, within 15 minutes of each other, and / or substantially simultaneously with each other.

[0225] Appearance 15. An administration regimen, method, use of an amylin analog, or use according to any of Appearances 1 to 14, wherein the amylin analog is administered to the subject in doses of approximately 0.04 mg to approximately 10 mg, for example, approximately 0.04 mg to 7 mg, approximately 0.04 mg to approximately 6 mg, approximately 0.04 mg to approximately 4.4 mg, approximately 0.04 mg to approximately 2.4 mg, approximately 0.6 mg to approximately 6 mg, approximately 0.6 mg to approximately 4.4 mg, approximately 0.6 mg to approximately 2.4 mg.

[0226] Appearance 16. An administration regimen, method, use of an amylin analog, or use according to any of Appearances 1 to 15, wherein the amylin analog is administered to the subject in doses of approximately 10 mg, approximately 9.5 mg, approximately 9 mg, approximately 8.5 mg, approximately 8 mg, approximately 7.5 mg, approximately 7 mg, approximately 6.5 mg, approximately 6 mg, approximately 4.4 mg, approximately 3.4 mg, approximately 2.4 mg, approximately 1.4 mg, approximately 0.7 mg, approximately 0.35 mg, approximately 0.16 mg, approximately 0.08 mg, and / or approximately 0.04 mg.

[0227] Embodiment 17. An administration regimen, method, use of an amylin analog, or use according to any one of Embodiments 1 to 16, wherein the amylin analog is administered to a subject at regular intervals.

[0228] Embodiment 18. An administration regimen, method, amylin analog for use, or use according to any one of Embodiments 1 to 17, wherein the amylin analog is administered to the subject once daily, once every two days, once a week, once every two weeks, once every three weeks, or once every four weeks.

[0229] Embodiment 19. An administration regimen, method, amylin analog for use, or use according to any one of Embodiments 1 to 18, wherein the administration of the amylin analog is the same in each administration.

[0230] Embodiment 20. An administration regimen, method, use of an amylin analog, or use according to any one of Embodiments 1 to 18, wherein the administration of the amylin analog differs for each dose.

[0231] Embodiment 21. An administration regimen, method, use of an amylin analog, or use according to any one of Embodiments 1 to 20, wherein the amylin analog is administered intravenously.

[0232] Embodiment 22. An administration regimen, method, use of an amylin analog, or use according to any one of Embodiments 1 to 20, wherein the amylin analog is administered subcutaneously.

[0233] Embodiment 23. An administration regimen, method, amylin analog for use, or use according to any one of Embodiments 1 to 22, wherein the activity of the concomitant agent is affected by the gastric emptying rate.

[0234] Embodiment 24. An administration regimen, method, use of an amylin analog, or use according to any of Embodiments 1 to 23, wherein the administration of the concomitant agent is affected by or dependent on the gastric emptying rate.

[0235] Embodiment 25. An administration regimen, method, amylin analog for use, or use according to any of Embodiments 1 to 24, wherein the dose of the concomitant agent administered is affected by or dependent on the gastric emptying rate.

[0236] Appearance 26. An administration regimen, method, amylin analog for use, or use according to any one of Appearances 1 to 25, wherein the concomitant agent is an oral drug.

[0237] Embodiment 27. An administration regimen, method, amylin analog for use, or use according to any one of Embodiments 1 to 26, wherein the concomitant agent is a parenteral drug.

[0238] Embodiment 28. An administration regimen, method, amylin analog for use, or use according to any one of Embodiments 1 to 29, wherein the concomitant agent is selected from the group consisting of analgesics, antibiotics, anticoagulants, contraceptives, antihypotensives, statins, antifungals, hypoglycemic agents, contraceptives, oral medicines with a narrow therapeutic index, and nutritional supplements.

[0239] Embodiment 29. An administration regimen, method, amylin analog for use, or use according to any one of Embodiments 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.

[0240] Embodiment 30. An administration regimen, method, amylin analog for use, or use according to any one of Embodiments 1 to 29, wherein the concomitant agent is insulin.

[0241] Embodiment 31. An administration regimen, method, amylin analog for use, or use according to any of Embodiments 1 to 30, wherein the subject is a human subject.

[0242] Appearance 32. A dosage regimen for the target, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications A dosage regimen that includes this.

[0243] Appearance 33. A method for treating or preventing a disease in the subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications A method that includes this.

[0244] Appearance 34. An amylin analog for use in methods of treating or preventing diseases in a subject, which does not affect the rate of gastric emptying, and the method is (a) A step of administering an amylin analog, and (b) Steps to administer concomitant medications Amilin analogs, including

[0245] Apparatus 35. Use of an amylin analog that does not affect gastric emptying rate for manufacturing a pharmaceutical for use in a method of treating or preventing a disease in a subject, wherein the method is (a) A step of administering an amylin analog, and (b) Steps to administer concomitant medications Includes, use.

[0246] Appearance 36. A method for inhibiting weight gain and / or reducing weight in a subject, (a) A step of administering an amylin analog that does not affect the rate of gastric emptying, and (b) Steps to administer concomitant medications A method that includes this.

[0247] Embodiment 37. An embodiment according to any of Embodiments 32 to 36, which includes one or more of the features described in any of Embodiments 1 to 31. [Examples]

[0248] The following examples are provided to illustrate preferred embodiments of the present invention and are not intended to limit the scope of the invention.

[0249] Materials and methods Mixed Test Meal (MTM) In the dose cohort using a single dose of ≥0.7 mg, the same mixed test meal (MTM) was administered on day -1 and day 5 (Example 1). In the dose cohort using multiple doses of ≥0.6 mg, the same mixed test meal (MTM) was administered on day -1, day 5, and day 40 (Example 2).

[0250] A predetermined number of MTMs (see below) were served for breakfast, which were standardized according to the characteristics of the average subject (using two BMI classes). The mixed test meals consisted of a fixed nutritional content.

[0251] Time point 0 (t=0) was defined as the start of intake of acetaminophen tablets and the liquid components of the mixed test meal.

[0252] Participants were required to be in a fasted state prior to the test. A meal of a fixed composition was provided as the mealtime meal (MTM), and was consumed by the participants within 15 minutes of time 0 in a predetermined order.

[0253] During the consumption of the mixed meal, the subjects were permitted to remain seated.

[0254] Participants were advised to avoid eating until after the meal test (240 minutes).

[0255] Aside from the water provided with the test meal, no water consumption was observed during the first two hours after the start of meal intake. After that, participants were free to drink water as they wished.

[0256] Participants were asked to lie in a semi-supine position for at least 4 hours after administration of MTM / acetaminophen, and then in a supine or semi-supine position until the final blood sample was taken according to the blood sampling schedule (see Table 1 below) to determine postprandial glucose (PPG), insulin, glucagon, and acetaminophen concentrations.

[0257] Acetaminophen concentration was used as a marker of postprandial gastric emptying.

[0258] After the meal test procedure was completed, the subjects were provided with a meal. In cases where each meal test was completed early, the reason for termination was recorded in the case report. [Table 1]

[0259] 1. Samples for acetaminophen, plasma glucose, insulin, and glucagon were collected within the following time window: -30 minutes before ingestion at t=0, and within the time window: ±2 minutes from t=15 minutes to t=120 minutes, and ±5 minutes at t=180 minutes and 240 minutes.

[0260] Time point t=0 is defined as the start of acetaminophen intake (2 x 500 mg) with the liquid component of MTM. The test meal is consumed within 15 minutes. [Table 2] [Table 3]

[0261] The ingredients of the mixed meal are examples and may vary depending on flavor, aversion, or allergies to the target group, but the nutritional ratios were the same. [Table 4] [Table 5]

[0262] The ingredients of the mixed meal are examples and may vary depending on flavor, aversion, or allergies to the target group, but the nutritional ratios were the same.

[0263] Acetaminophen absorption test Two 500 mg acetaminophen tablets (1000 mg total) were administered with a pre-specified solid mealtime medication (MTM). Participants were instructed to take the tablets with the liquid component of the meal at the start of the meal test. Frequent blood samples were taken to check acetaminophen levels as described above. [Examples]

[0264] Phase 1a clinical trial evaluating single dose escalation A first-in-human, randomized, single-dose escalation-dose (SAD) study was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the amyrin analog of SEQ ID NO: 3 administered to healthy subjects.

[0265] The subjects were healthy men with normal weight and overweight (BMI: 21.0-29.9 kg / m²). 2 ).

[0266] Test design The study was a single-center, randomized, double-blind, placebo-controlled, single-dose escalation study in normal-weight and overweight, otherwise healthy male subjects, who were randomized within each cohort to receive either the amylin analog of SEQ ID NO: 3 or placebo (randomization ratio 3:1, n=6 and n=2). Fifty-six subjects were assigned to the following seven escalation dose levels via subcutaneous (SC) administration, as shown in Figure 1: 0.04, 0.08, 0.16, 0.35, 0.7, 1.4, and 2.4 mg. An IV cohort of eight subjects was assigned to a single 0.35 mg dose level.

[0267] A sentinel chain approach (sequential administration) was applied within the cohort. The entire observation period was 50 days, beginning with a stay at our facility (days -1 to 8), followed by discharge on day 8, six outpatient visits, and finally an end-of-trial (EOT) visit on day 50.

[0268] Based on the suspension rules applied to the trial, blinded evaluations of each cohort were performed by the Trial Safety Group (TSG) to determine whether to proceed to the next dose level.

[0269] Table 4 below shows the formulations of the amylin analog (4 mg / mL) and placebo of Sequence ID No. 3. [Table 6]

[0270] The manufacture of the above-mentioned pharmaceuticals and compatible placebos was carried out by Rechon Life Science AB in Limhan, Sweden, on behalf of Zealand Pharma A / S. Klifo A / S in Glostrup, Denmark, is responsible for the secondary packaging and labeling of the pharmaceuticals and compatible placebos.

[0271] The subjects received a single dose consisting 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 amylin analog or placebo administered subcutaneously, or 0.35 mg administered intravenously, as shown in the table below. [Table 7]

[0272] All demographic attributes were balanced across the healthy subject cohort.

[0273] The characteristics of the baseline are as follows: [Table 8]

[0274] The subjects were tested according to the mixed meal test and acetaminophen absorption test described in the Methods section.

[0275] result Subjects treated with amylin analogs showed dose-dependent and sustained weight loss (Figure 3).

[0276] The results of the mixed meal test show that subjects administered with the amyrin analogs specified herein exhibited dose-dependent inhibition of glucagon secretion (Figure 4). Amyrin is known to affect glucagon secretion, inhibit amino acid-stimulated glucagon secretion, and reduce endogenous glucose production during the postprandial period.

[0277] Surprisingly, no dose-related correlation was observed between the administered amylin analog and acetaminophen (Figure 5 and Table 7).

[0278] In acetaminophen absorption tests, neither the maximum concentration of acetaminophen (Cmax) nor the time required to reach that maximum concentration (Tmax) changed significantly with the amylin analog compared to placebo. [Table 9]

[0279] Therefore, these data indicate that amylin analogs do not alter gastric emptying rate compared to placebo at all doses.

[0280] Amylin analogs were well tolerated, and there were no serious or severe adverse events (AEs) or discontinuations.

[0281] The most common adverse events (AEs) were loss of appetite, nausea, and vomiting. Most AEs were mild and temporary.

[0282] Furthermore, no anti-drug antibodies were detected. [Table 10]

[0283] From the first action related to the study after the subject signed informed consent, to the end of the post-treatment follow-up period, all events that met the definition of an adverse event (AE) were collected and reported. Subjects were questioned about AEs at each contact with the site (visits or phone calls (e.g., laboratory visits), excluding safety visits in which the subject did not meet the principal investigator or site staff). All AEs observed by the principal investigator or reported by the subject were recorded and evaluated by the principal investigator.

[0284] The principal investigator recorded the diagnosis whenever possible. If a diagnosis could not be made, the principal investigator recorded each sign and symptom as an individual adverse event (AE).

[0285] The maximum intensity (severity) of all adverse events (AEs) was assessed and recorded by the principal investigator.

[0286] If the outcome of an adverse event (AE) was known, its severity was graded according to the following: - Mild: A type of adverse event that is usually temporary and may require only minimal treatment or therapeutic intervention. The event generally does not interfere with normal daily activities. - Moderate: A type of adverse event that is usually mitigated by additional specific therapeutic interventions. The event interferes with normal daily activities and causes discomfort, but does not pose a significant or permanent risk of harm to the study participant. - Severe: An adverse event type that interferes with normal daily activities, significantly affects the clinical condition, or may require intensive therapeutic intervention. A “severe” reaction does not necessarily mean that an AE is “serious,” and SAEs are not inherently “severe.”

[0287] Observed, consistent, dose-dependent weight loss is an indicator of the suitability of amylin analogs for treating obesity or aiding weight loss.

[0288] Furthermore, the remarkable lack of effect on gastric emptying may facilitate dosing regimens and concomitant administrations that are not recommended or effective with other amylin analogs.

[0289] Summary of Example 1 The amylin analog of the present invention is a long-acting amylin analog, originally designed for weekly administration, that has demonstrated the ability to reduce body weight and improve glycosylation in animal models of obesity and diabetes.

[0290] The objective of this embodiment was to provide a first-in-human study to evaluate the safety, tolerability, pharmacokinetics (PK), and PD of the amylin analog of Sequence ID No. 3, with the primary endpoint being adverse events (AEs) and the secondary endpoints being the PL parameters of the amylin analog and pharmacodynamic parameters in relation to the mixed test meal (MTM).

[0291] The amilin analog of sequence number 3 may sometimes be listed as ZP8396.

[0292] The aforementioned trial was a randomized, double-blind, placebo-controlled study to evaluate the safety, pharmacokinetic (PK), and PD of a single subcutaneous injection of the amylin analog SEQ ID NO: 3 in healthy, lean, and overweight men. A total of 56 participants were included (mean age 38.1 years, mean BMI 25.6 kg / m²). 2 Patients were randomized (6:2) to receive either an amylin analog or placebo within seven dose cohorts ranging from 0.04 to 2.4 mg.

[0293] After one week of observation, mean body weight decreased by -0.6%, 2.6%, 3.6%, and 4.2% from baseline after single doses of placebo, 0.7 mg, 1.4 mg, and 2.4 mg, respectively. Amylin analogs were well-tolerated, with no serious or severe adverse events (AEs) or discontinuations. The number and severity of gastrointestinal AEs increased with dose. The mean half-life of amylin analogs was approximately 10 days (Figure 2), and a dose-dependent reduction in glucagon release was observed (Figure 4). Furthermore, no anti-drug antibodies were detected.

[0294] The data demonstrate that amylin analogs were well-tolerated at single doses up to 2.4 mg. The most common associated adverse events were decreased appetite, nausea, and vomiting, but most events were mild and temporary (Table 8). The approximately 10-day half-life is suitable for weekly administration. Furthermore, single-dose amylin analogs resulted in dose-dependent and consistent weight loss (Figure 2), supporting their potential as a treatment for obesity.

[0295] Importantly, the data from this example demonstrate that the amylin analog ZP8396 does not alter gastric emptying rate compared to placebo at all doses tested. [Examples]

[0296] Phase 1 clinical trial evaluating repeated dose escalation (Part 1) A first-in-human, randomized, repeated-dose escalation (MAD) study was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the amylin analog of SEQ ID NO: 3 administered to healthy subjects.

[0297] The subjects were healthy men with normal weight and overweight (BMI: 21.0-29.9 kg / m2).

[0298] Test design The study was a single-center, cohort-based, randomized, double-blind, placebo-controlled, sequential, repeated-dose escalation study in normal-weight and overweight but otherwise healthy subjects, where subjects were randomized within each cohort to receive either the amylin analog of SEQ ID NO: 3 or placebo (randomization ratio 7:3). Subjects were assigned to receive six weekly doses of either the amylin analog or placebo at two escalation levels via subcutaneous (sc) administration, as shown in Figure 6: 0.6 mg or 1.2 mg.

[0299] A sentinel chain approach (sequential administration) was applied within the cohort. The entire observation period was 92 days, beginning with the first stay at the company facility (-1 to 2 days) with planned discharge on day 2, followed by one outpatient visit (day 5), a second stay at the company facility (days 8 to 12) with planned discharge on day 12, a third stay at the company facility (days 15 to 19) with planned discharge on day 19, a fourth stay at the company facility (days 22 to 24) with planned discharge on day 24, followed by one outpatient visit (day 26), a fifth stay at the company facility (days 29 to 31) with planned discharge on day 31, a sixth stay at the company facility (days 36 to 38) with planned discharge on day 38, followed by five outpatient visits (days 40, 43, 50, 64, and 75), and finally an outpatient visit on day 92 for end-of-trial treatment (EOT).

[0300] Based on the specific withdrawal rules applied to the trial, blinded assessments of each cohort were performed by the Study Safety Group (TSG) to determine whether to proceed to the next dose level.

[0301] Table 9 below shows the formulations of the amylin analog (4 mg / mL) and placebo of Sequence ID No. 3. [Table 11]

[0302] The manufacture of the above-mentioned pharmaceuticals and compatible placebos was carried out by Rechon Life Science AB in Limhan, Sweden, on behalf of Zealand Pharma A / S. Klifo A / S in Grostrup, Denmark, was responsible for the secondary packaging and labeling of the pharmaceuticals and compatible placebos.

[0303] The subjects received a single dose of either 0.6 mg or 1.2 mg of amylin analog or placebo, administered subcutaneously once a week, as shown in the table below. [Table 12]

[0304] All demographic attributes were balanced across the healthy cohort. Baseline characteristics of the subjects are shown in Table 11 below. [Table 13]

[0305] The average weight is 82 kg and the BMI is 25.4 kg / m². 2 Twenty participants took part in the trial. Two participants did not receive the sixth dose. All 20 randomized participants completed the trial.

[0306] The subjects were tested according to the mixed meal test and acetaminophen absorption test described in the "Materials and Methods" section of this specification.

[0307] result In accordance with the study design detailed above, data from the continuous-dose cohort (i.e., the cohort receiving escalating doses, relative to the aforementioned cohort) became continuously available.

[0308] Initial data show favorable results consistent with the SAD trial.

[0309] Participants receiving amylin analogs showed weight loss of 0.4%, 5.3%, and 5.1% from baseline after six weekly doses of placebo, 0.6 mg, and 1.2 mg, respectively. Figure 7 shows individual and mean (thick line) weight loss during the study. [Table 14]

[0310] The results of the mixed meal test further demonstrate that subjects administered with the amylin analogs specified herein did not show a significant difference in acetaminophen concentration compared to baseline or placebo, either after a single dose (day 5) or after six doses (day 40) (Table x and Figure 8). [Table 15]

[0311] The results of the mixed test meal showed that subjects administered with the amyrin analogs specified herein had a significant difference in the change in glucagon concentration from baseline compared to placebo on day 5, and on day 40, the magnitude of the variation in glucagon concentration within individuals was not affected compared to placebo (Figure 9). Amyrin is known to affect glucagon secretion, inhibit amino acid-stimulated glucagon secretion, and reduce endogenous glucose production during the postprandial period.

[0312] Amylin analogs were well tolerated, and there were no serious or severe adverse events (AEs) or discontinuations. [Table 16]

[0313] Summary of Example 2 SEQ ID NO: 3, an amyrin analog designed for once-weekly administration, demonstrated the ability to reduce body weight and improve glycosylation in animal models of obesity and diabetes. Dose-dependent and consistent weight reduction was demonstrated in healthy subjects after a single dose of the amyrin analog, supporting its potential as a treatment for obesity.

[0314] Part 1 of a randomized, double-blind, placebo-controlled trial to evaluate the safety, pharmacokinetics, and pharmacodynamics of six weekly subcutaneous injections of the amylin analog SEQ ID NO: 3 in healthy, lean, and overweight subjects has been completed. A total of 20 subjects (mean weight 82 kg, BMI 25.4 kg / m²) were included. 2 Patients were randomized (7:3) to receive either the amylin analog of SEQ ID NO: 3 or placebo within two dose cohorts.

[0315] Mean body weight decreased by 0.4%, 5.3%, and 5.1% from baseline after six weekly doses of placebo, 0.6 mg, and 1.2 mg, respectively.

[0316] The amylin analog of Sequence ID No. 3 was well-tolerated, with no serious or severe adverse events (AEs) or discontinuations. The most frequent associated AEs were decreased appetite, early satiety, aversion to food, and nausea, all of which were mild and temporary. Nausea occurred in only three patients treated with the amylin analog, and one patient also reported vomiting. No injection site reactions were reported, and no anti-drug antibodies were detected.

[0317] Treatment with six doses of the amyrin analog SEQ ID NO: 3 was safe, well-tolerated, and resulted in meaningful weight loss. The most common associated adverse events were related to the glycemic index (GI) system, all of which were mild and mostly occurred within two days of the initial dose. These data support the findings of weight loss after a single dose of the amyrin analog, and are similar to the weight loss observed after six weeks with other weight loss treatments. A dose-escalation titration cohort exploring longer treatment durations and amyrin analog doses exceeding 1.2 mg is ongoing to further evaluate the clinical potential of the amyrin analog SEQ ID NO: 3.

[0318] Importantly, the data from this example demonstrate that the amylin analog ZP8396 does not alter gastric emptying rate compared to placebo at all doses tested. [Examples]

[0319] Phase 1 clinical trial evaluating repeated dose escalation (Part 2) A randomized, repeated-dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the amylin analog of SEQ ID NO: 3 administered to healthy subjects.

[0320] The target group is individuals with a Body Mass Index (BMI) of 27.0 to 39.9 kg / m². 2 The subjects were overweight and obese but otherwise healthy, healthy men, or women who were not of pregnancy potential.

[0321] Test design Part 2 of the MAD trial was a single-center, cohort-randomized, double-blind, placebo-controlled, sequential repeated-dose escalation study in overweight and obese but otherwise healthy subjects, where subjects were randomized within each cohort to receive either the amylin analog of SEQ ID NO: 3 or placebo (randomization ratio 3:1). The use of dose-escalation titration was investigated to achieve greater exposure to the amylin analog of SEQ ID NO: 3.

[0322] A steady state is achieved in a given cohort after six weekly doses of a maintenance dose of the amyrin analog of SEQ ID NO: 3. Participants were assigned to three different cohorts, each targeting one of three different maintenance doses with 16 weekly subcutaneous (sc) doses of either the amyrin analog of SEQ ID NO: 3 or placebo (as shown in Figure 10): 1. Cohort 1: 0.6, 0.6, 1.2, and 1.2 mg, followed by a 12-week maintenance dose of 2.4 mg. 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 over 8 weeks. 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 over 6 weeks.

[0323] The 48 subjects were randomized into three cohorts of 16 subjects each, with a 3:1 ratio within each cohort. Twelve subjects received the amylin analog (SEQ ID NO: 3), and four subjects received a placebo.

[0324] The entire observation period was 25 weeks, beginning with an initial stay at our facility (-1 to 2 days) with planned discharge on day 2, followed by three outpatient visits for weekly administration, and then 13 subsequent visits to our facility for 1 to 4 nights, depending on the dose level. After 16 weekly doses (days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, and 106), the first cohort had 6 outpatient visits (days 108, 110, 113±1, 120±1, 134±1, and 148±1), while the second and third cohorts had 5 outpatient visits (days 110, 113±1, 120±1, 134±1, and 148±1), followed by an end-of-trial (EOT) visit on day 169±2. To determine whether the current dose level is considered safe and whether dose escalation can be continued in subsequent cohorts based on the discontinuation rules, blinded evaluations for each cohort were performed by the Study Safety Group (TSG) using data up to the pre-administration evaluation of the fifth maintenance dose (Cohort 1: day 57, Cohort 2: day 85, and Cohort 3: day 99).

[0325] The formulations of the amylin analog (4 mg / mL) and placebo of Sequence ID No. 3 are shown in Table 15 below. [Table 17]

[0326] The manufacture of the above-mentioned pharmaceuticals and compatible placebos was carried out by Rechon Life Science AB in Limhan, Sweden, on behalf of Zealand Pharma A / S. Klifo A / S in Grostrup, Denmark, was responsible for the secondary packaging and labeling of the pharmaceuticals and compatible placebos.

[0327] The subjects were tested on day 1 and day 110 according to the mixed meal test and acetaminophen absorption test described in the "Materials and Methods" section of this specification.

[0328] result In accordance with the study design detailed above, data from the continuous-dose cohort (i.e., the cohort receiving escalating doses, relative to the aforementioned cohort) became continuously available.

[0329] The initial data show favorable results that are broadly consistent with the SAD test of Example 1 and Part 1 of the MAD test of Example 2 herein.

[0330] All publications described in the above specification are incorporated herein by reference. Various modifications and variations of the methods and systems described in the present invention will be obvious to those skilled in the art, without departing from the scope and spirit of the invention. Although the present invention has been described in terms of specific preferred embodiments, it should be understood that the invention described in the claims should not be unduly limited to such specific embodiments. In fact, various modifications of the described embodiments for carrying out the present invention, which will be obvious to those skilled in the art in biochemistry, molecular biology, or related fields, are included within the scope of the following embodiments.

Claims

1. An amylin analog for use in methods of treating or preventing diseases in a subject, which does not affect the rate of gastric emptying, wherein the method is (a) the step of administering the amylin analog to the subject, and (b) Step of administering the concomitant agent to the subject. Includes, The amylin analog and the concomitant agent are administered to the subject within approximately 120 minutes of each other, and The amylin analog is given by formula: R １ -Z-R ２ The peptide or its pharmaceutically acceptable salts and / or derivatives comprises or consists thereof, wherein the formula includes, R １ is hydrogen, C １－４ Acyl, benzoyl, or C １－４ Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R ２ is OH or NHR ３ wherein R ３ is hydrogen or C １－３ alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Glun. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro, X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. The aforementioned amilin analog.

2. A non-therapeutic administration regimen for the target, (a) The step of administering an amylin analog that does not affect the rate of gastric emptying to the subject, (b) Step of administering the concomitant agent to the subject. Includes, The amylin analog and the concomitant agent are administered to the subject within approximately 120 minutes of each other, and The amylin analog is given by formula: R １ -Z-R ２ The peptide or its pharmaceutically acceptable salts and / or derivatives comprises or consists thereof, wherein the formula includes, R １ is hydrogen, C １－４ Acyl, benzoyl, or C １－４ Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R ２ OH or NHR ３ And in the formula, R ３ is hydrogen or C １－３ It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Glun. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro, X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. The aforementioned non-therapeutic administration regimen.

3. A non-therapeutic method for inhibiting weight gain and / or reducing weight in a subject, (a) The step of administering an amylin analog that does not affect the rate of gastric emptying to the subject, (b) The step of administering the concomitant agent. Includes, The amylin analog and the concomitant agent are administered to the subject within approximately 120 minutes of each other, and The amylin analog is given by formula: R １ -Z-R ２ The peptide or its pharmaceutically acceptable salts and / or derivatives comprises or consists thereof, wherein the formula includes, R １ is hydrogen, C １－４ Acyl, benzoyl, or C １－４ Alkyl or half-life extension portion M, where M may be linked to Z via a linker portion L. R ２ OH or NHR ３ And in the formula, R ３ is hydrogen or C １－３ It is alkyl, and Z is given by equation 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-Ile(Me)-X27-Ser-Ser-Thr-Glu-X32-Gly-Ser-X35-Thr-X37 (SEQ ID NO: 4) The amino acid sequence is as follows, in the formula, X1 is selected from the group consisting of Arg, Lys, and Glu. X3 is selected from the group consisting of Gly, Gln, 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 Glun. X14 is selected from the group consisting of Aad, His, Asp, Asn, and Arg. X17 is selected from the group consisting of Gln, His, and Thr. X19-X20 are selected from Ser-Ser, Thr-Thr, Ala-Thr, Ala-Ala, Gly-Thr, Gly-Gly, and Ala-Asn, or are not present. X27 is selected from the group consisting of Leu and Pro, X32 is selected from the group consisting of Val 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 crosslink. Gly(Me) is N-methylglycine [also known as sarcosine (Sar)], Ile(Me) is N-methylisoleucine, Aad is 2-aminoadipic acid, also known as homoglutamic acid, for example, (2S)-2-aminoadipic acid [also known as (2S)-2-aminohexanediic acid]. The aforementioned non-therapeutic methods.

4. The administration regimen according to claim 2 or the method according to claim 3, wherein the subject is overweight, obese, or morbidly obese.

5. The amylin analog for use according to claim 1, wherein the disease is overweight, obesity, morbid obesity, diabetes, or a disease associated with obesity or diabetes.

6. Amylin analog for use according to claim 5, wherein the diseases associated with obesity or diabetes are selected from the group consisting of obesity-related inflammation, obesity-related gallbladder disease, obesity-induced sleep apnea, obesity-related respiratory problems, cartilage degeneration, osteoarthritis, infertility, Alzheimer's disease, prediabetes, insulin resistance syndrome, impaired glucose tolerance (IGT), conditions associated with elevated blood glucose levels, metabolic diseases, metabolic syndrome, hyperglycemia, hypertension, atherosclerosis, hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal failure, arteriosclerosis, macrovascular disease, microvascular disease, diabetic heart disease, diabetic cardiomyopathy, heart failure as a complication of diabetes, coronary heart disease, peripheral artery disease, and stroke.

7. Amilin analog, formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH2 (Sequence ID 3) an amyrin analog for use according to any one of claims 1, 5, and 6, comprising or comprising a peptide or a pharmaceutically acceptable salt and / or derivative thereof, a dosage regimen according to claim 2 or claim 4, or the method according to claim 3 or claim 4.

8. Amilin analog, formula: [19CD]-isoGlu-RD()GTATK()ATERLA-Aad-FLQRSSF-Gly(Me)-A-Ile(Me)-LSSTEVGSNT-Hyp-NH 2 (Sequence No. 3) Petrelintide, which is a compound having [a certain property], or a pharmaceutically acceptable salt thereof, In the formula, the intramolecular lactam crosslink is formed between the side chains of the residues indicated by parentheses "()", and [19CD]-isoGlu is a 19-carboxynonadecanoyl group covalently bonded to the alpha-amino group of the isoglutamic acid linker, as described in claim 7, an amylin analog, administration regimen, or method for use.

9. Amylin analog, administration regimen, or method for use according to any one of claims 1 to 8, wherein the amylin analog and the concomitant agent are administered to a subject within approximately 90 minutes of each other, within approximately 60 minutes of each other, within approximately 45 minutes of each other, within approximately 30 minutes of each other, within approximately 15 minutes of each other, and / or substantially simultaneously of each other.

10. An amylin analog for use, an administration regimen, or a method for use according to any one of claims 1 to 9, wherein the amylin analog is administered to a subject in doses of approximately 0.04 mg to approximately 10 mg, for example, approximately 0.04 mg to 7 mg, approximately 0.04 mg to approximately 6 mg, approximately 0.04 mg to approximately 4.4 mg, approximately 0.04 mg to approximately 2.4 mg, approximately 0.6 mg to approximately 6 mg, approximately 0.6 mg to approximately 4.4 mg, approximately 0.6 mg to approximately 2.4 mg, approximately 0.7 mg to approximately 6 mg, approximately 0.7 mg to approximately 4.4 mg, or approximately 0.7 mg to approximately 2.4 mg.

11. An amylin analog, administration regimen, or method for use according to any one of claims 1 to 10, wherein the amylin analog is administered to a subject in doses of approximately 10 mg, approximately 9.5 mg, approximately 9 mg, approximately 8.5 mg, approximately 8 mg, approximately 7.5 mg, approximately 7 mg, approximately 6.5 mg, approximately 6 mg, approximately 4.4 mg, approximately 3.4 mg, approximately 2.4 mg, approximately 1.4 mg, approximately 0.7 mg, approximately 0.35 mg, approximately 0.16 mg, approximately 0.08 mg, and / or approximately 0.04 mg.

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

13. (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 on the gastric emptying rate, and / or (iii) The dose of the concomitant drug administered is affected by or dependent on the gastric emptying rate, An amylin analog, administration regimen, or method for use according to any one of claims 1 to 12.

14. The amylin analog, administration regimen, or method for use according to any one of claims 1 to 13, wherein the concomitant agent is an oral or parenteral drug.

15. The amylin analog, administration regimen, or method for use according to any one of claims 1 to 14, wherein the concomitant agent is a pharmaceutical selected from the group consisting of analgesics, antibiotics, anticoagulants, contraceptives, antihypertensive drugs, statins, antifungals, hypoglycemic agents, oral pharmaceuticals with a narrow therapeutic index, and nutritional supplements.

16. An amylin analog, administration regimen, or method for use according to 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.

Images