Combination therapies for weight loss and maintenance

Abstract

The present disclosure provides combinations for reducing weight and / or preventing weight gain in a subject (e.g., an obese subject) comprising three or more (e.g., three or four) of: (i) an amylin analog, (ii) a GLP-1 receptor agonist, (iii) a GIP analog, and (iv) a glucagon analog. As described herein, the combination can be administered to a subject in the same pharmaceutical composition or in separate pharmaceutical compositions (e.g., via concurrent or subsequent administration).

Description

[0001] Atty Ref. METS-036 / 01WO 350242-2269

[0002] COMBINATION THERAPIES FOR WEIGHT LOSS AND MAINTENANCE

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004]

[0001] The present application claims priority to U.S. Provisional Application 63 / 737,066, filed December 20, 2024, the contents each of which are incorporated herein by reference in their entireties.

[0005] REFERENCE TO THE ELECTRONIC SEQUENCE FILE

[0006]

[0002] The contents of the electronic sequence listing (METS_036_01WO_SeqList_ST26.xml; Size: 21,308 bytes; and Date of Creation: December 17, 2025) are herein incorporated by reference in their entirety

[0007] BACKGROUND

[0008]

[0003] Advances in peptide therapeutics for weight loss and the treatment of metabolic disorders have resulted in the development of incretin / hormone mimics which act as single and multireceptor agonists to target receptors, such as G-protein coupled receptors (e.g., glucagon-like peptide-1 receptor (GLP-1), gastric inhibitory polypeptide receptor (GIP), etc.). Current standards for injectable peptides used in the management of weight loss and metabolic disorders — such as liraglutide, semaglutide, and tirzepatide — are associated with limitations including frequent administration and adverse effects, which may negatively impact treatment adherence and patient compliance. There remains a need for next-generation therapeutics for weight loss, weight maintenance, and the treatment of metabolic disorders that not only demonstrate robust efficacy but also possess extended half-lives to enable reduced dosing frequency and / or minimized side effects.

[0009] SUMMARY

[0010]

[0004] The present disclosure provides combination therapies for inducing or maintaining weight loss or managing body weight in a subject (e.g., an obese subject) comprising three or more (e.g., three, or four) of: (i) an amylin analog, (ii) a GLP-1 receptor agonist, (iii) a GIP analog, and (iv) a glucagon analog.

[0011]

[0005] In some embodiments, provided herein are methods of inducing or maintaining weight loss or managing body weight in a subject, the method comprising administering to the subject an effective amount of a combination comprising three or more peptides selected from:

[0012] (i) a first peptide comprising the amino acid sequence of Atty Ref. METS-036 / 01WO 350242-2269

[0013] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof;

[0014] (ii) a second peptide comprising the amino acid sequence of

[0015] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof;

[0016] (iii) a third peptide comprising the amino acid sequence of

[0017] (SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof; and

[0018] (iv) a fourth peptide comprising the amino acid sequence of

[0019] (SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof.

[0020]

[0006] In some embodiments, provided herein are combinations, pharmaceutical compositions or kits comprising three or more of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof. Aty Ref. METS-036 / 01WO 350242-2269

[0007] In the methods described herein, the combination can be administered concurrently (i.e., in the same or different pharmaceutical compositions) or sequentially (i.e., in different pharmaceutical compositions). In certain embodiments of the methods described herein, a subject has obesity or is overweight. In certain embodiments of the methods described herein, the subject has a weight-related comorbid condition, for example, hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, Type 2 diabetes (T2DM), or nonalcoholic fatty liver disease (NAFLD).

[0021]

[0008] Also provided herein are methods of stimulating glucose clearance, stimulating glucose clearance, stimulating insulin release, stimulating carbohydrate metabolism, stimulating lipid metabolism, improving carbohydrate tolerance, reducing appetite, reducing food intake, or reducing caloric intake in a subject, the method comprising administering to the subject an effective amount of a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof, as described herein.

[0022] BRIEF DESCRIPTION OF THE DRAWINGS

[0023]

[0009] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the disclosure and together with the description, provide non-limiting examples.

[0010] FIG. 1 shows efficacy of two-, three-, and four-way combinations in effecting weight loss in rats. Male Sprague Dawley rats (n=6-7 / group) received repeat SC injections of vehicle, SEQ ID NO: 4, SEQ ID NOs: 4+3, SEQ ID NOs: 4+3+9, or SEQ ID NOs: 4+3+9+10, three times per week, from Day 0 to 18. For SEQ ID NOs: 4, 3, 9, and 10, doses were initiated at 0.5, 0.5, 5, and 2.5 nmol / kg, respectively. SEQ ID NO: 10 was reduced to 0.5 nmol / kg on Day 4. All doses were doubled on Day 7 and 14. Data is presented as mean ± SEM, with % change in bodyweight from baseline (Day 0) normalised to the vehicle group.

[0024] [Oil] FIG. 2 shows minipig pharmacokinetics of co-administered combination.

[0025]

[0012] FIG. 3A and FIG. 3B illustrates cumulative food intake and change in body weight over a 3 -day period of the single dose study.

[0026]

[0013] FIG. 4A and FIG. 4B illustrates cumulative food intake and change in body weight over a 3 -day period of the repeated dose study.

[0027]

[0014] FIG. 5A and FIG. 5B illustrates cumulative food intake and change in body weight over a 25-day period of the repeated dose study.

[0028]

[0015] FIG. 6A and FIG. 6B illustrate the change in body weight for each treatment group on Day 23 and the fasted plasma glucose levels for each treatment group on Day 24. Aty Ref. METS-036 / 01WO 350242-2269

[0016] FIG. 7A and FIG. 7B show the food intake and weight loss for treatment groups SEQ ID NO: 4, SEQ ID NOs: 4+3, SEQ ID NOs: 4+9+10, and SEQ ID NOs: 4+3+9+10 on Day 25 * p<0.05, ** p<0.01, *** p<0.001, ****p<0.0001.

[0029]

[0017] FIGS. 8A-8D show the food intake and weight loss for treatment groups M3 and M4 at equimolar doses to RET alone or with KBP-336 on Day 25.

[0030] DEFINITIONS

[0031]

[0018] The following definitions are general terms used throughout the present disclosure.

[0032]

[0019] The term “peptide” includes a polymer of amino acid residues linked together by peptide bonds. Typically, a peptide will be at least the length required by an amino acid sequence provided herein. Peptides provided herein can include natural amino acids and / or unnatural amino acids (z.e., compounds that do not occur in nature but that can be incorporated into a peptide chain) in any combination. One or more of the amino acids in a peptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a famesyl group, an isofarnesyl group, a faty acid group, a lipid moiety, a linker for conjugation or functionalization, or other modification. A peptide may be naturally occurring, recombinant, synthetic, or any combination of these. Peptide derivatives are also encompassed herein. A peptide derivative can, for example, comprise one or more derivatizations selected from amidation, glycosylation, carb amyl ati on, acylation, sulfation, phosphorylation, cyclization, lipidization, pegylation and fusion to another peptide or protein to form a fusion protein. A peptide structure can be modified at random positions within the molecule, or at predetermined positions within the molecule and can include one, two, three or more attached chemical moieties.

[0033]

[0020] Peptides described herein include those with an amidated C-terminus. “Amidated C- terminus” refers to peptides wherein the traditional C-terminus of the peptide (-C(=O)OH) is replaced with an amide (-C(=O)NH2). In some embodiments, a “-COOH” or an “-NH2” moiety at the C-terminus of the sequence indicates a carboxylic acid (COOH) or an amido (CONH2) group at the C-terminus, respectively. In each sequence of the disclosure, a C-terminal “-OH” moiety may be substituted for a C-terminal “-NH2” moiety, and vice-versa.

[0034]

[0021] A peptide provided herein can be of any length. In certain embodiments, a peptide is 50 amino acids or fewer in length. In certain embodiments, a peptide is 45 amino acids or fewer in length. In certain embodiments, a peptide is 41 amino acids or fewer in length. In certain embodiments, a peptide is 40 amino acids or fewer in length. In certain embodiments, a peptide is 35 amino acids or fewer in length. In certain embodiments, a peptide is 33 amino acids or fewer in length. In certain embodiments, a peptide is at least the length of an amino acid sequence Atty Ref. METS-036 / 01WO 350242-2269 provided herein. In certain embodiments, a peptide is the length of an amino acid sequence provided herein.

[0035]

[0022] The term “amino acid” includes a molecule containing both an amino group and a carboxyl group. Unless otherwise indicated, an amino acid is an alpha-amino acid (a-amino acid), the generic structure of which is depicted below (wherein each R is independently H or an amino acid sidechain, i.e., an “a-sidechain”). Unless otherwise indicated, reference to a particular amino acid implies the L-isomer of the amino acid. Each amino acid referred to herein may be denoted by a 1- to 4-letter code (e.g., L and Lys represent L-Lysine, etc. .

[0036] R R

[0037] HOHa amino acid

[0038]

[0023] Suitable amino acids include, without limitation, natural a-amino acids such as D- and L- isomers of the 20 common naturally occurring a-amino acids found in peptides (e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V, as provided below), and unnatural a-amino acids. Exemplary natural a-amino acids (with one-letter code provided in parentheses) include L-alanine (A), L-arginine (R), L-asparagine (N), L-aspartic acid (D), L-cysteine (C), L-glutamic acid (E), L-glutamine (Q), glycine (G), L-histidine (H), L-isoleucine (I), L-leucine (L), L-lysine (K), L- methionine (M), L-phenylalanine (F), L-proline (P), L-serine (S), L-threonine (T), L-tryptophan (W), L-tyrosine (Y), and L-valine (V). Exemplary unnatural a-amino acids include, without limitation, D-arginine, D-asparagine, D-aspartic acid, D-cysteine, D-glutamic acid, D-glutamine, D-histidine, D-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-proline, D- serine, D-threonine, D-tryptophan, D-tyrosine, D-valine, Di-vinyl, a-methyl-alanine (Aib), a- methyl-arginine, a-methyl-asparagine, a-methyl-aspartic acid, a-methyl-cysteine, a-methyl- glutamic acid, a-methyl-glutamine, a-methyl-histidine, a-methyl-isoleucine, a-methyl-leucine, a- methyl-lysine, a-methyl-methionine, a-methyl-phenylalanine, a-methyl-proline, a-methyl-serine, a-methyl-threonine, a-methyl-tryptophan, a-methyl-tyrosine, a-methyl-valine, norleucine, and terminally unsaturated a-amino acids. There are many known unnatural amino acids, any of which may be included in the peptides of the present disclosure. See for example, S. Hunt, The NonProtein Amino Acids: In Chemistry and Biochemistry of the Amino Acids, edited by G. C. Barrett, Chapman and Hall, 1985. Unnatural amino acids also include amino acids comprising a substituent (i.e., non-hydrogen group) on the peptide nitrogen. For example, any amino acid described herein can comprise a Ci-6 alkyl group on the peptide nitrogen (“N-alkyl”-amino acid). In certain embodiments, any amino acid described herein can comprise a methyl group on the peptide nitrogen (“N-methyl”-amino acid). Aty Ref. METS-036 / 01WO 350242-2269

[0024] Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1- 19, incorporated herein by reference. Pharmaceutically acceptable salts of the peptides of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0039]

[0025] As used herein, the term “co-administration” or “co-administered” refers to the administration of two peptides to a subject, either concurrently, sequentially, or separately, such that the therapeutic effects of the peptides overlap at least in part. “Co-administration” or “coadministered” includes administration of the peptides together in a single composition or separately as individual compositions, given at the same time or at different times, provided that both peptides are present in the subject at therapeutically effective levels during a relevant treatment period. The peptides may be co-administered by the same or different routes of administration (e.g., oral, intravenous, subcutaneous, etc.), and in any order, provided that the intended combined therapeutic effect is achieved.

[0040]

[0026] The term “neurological disease” includes any disease of the nervous system, including diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type Aty Ref. METS-036 / 01WO 350242-2269 of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease.

[0041]

[0027] A “subject” to which administration is contemplated includes a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal.

[0042]

[0028] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0043]

[0029] The term “prevent,” “preventing,” or “prevention” includes a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0044]

[0030] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0045]

[0031] An “effective amount” of a compound described herein is an amount sufficient to provide a desired effect, for example, weight loss and / or weight maintenance (e.g., preventing weight gain). An effective amount of a compound includes an amount of an agent (e.g., peptide, compound, etc.), alone or in combination with other therapies, that provides a benefit to the subject receiving the agent.

[0046] DETAILED DESCRIPTION

[0047]

[0032] The present disclosure provides, in some aspects, combination therapies for reducing weight (weight loss) and / or preventing weight gain (weight maintenance) in a subject (e.g., an obese subject) comprising three or more (e.g., three, or four) of (i) an amylin analog, (ii) a GLP-1 receptor agonist, (iii) a GIP analog, and (iv) a glucagon analog. As described herein, the three or more peptides can be administered to a subject in the same pharmaceutical composition or in Aty Ref. METS-036 / 01WO 350242-2269 separate pharmaceutical compositions (e.g., via concurrent or subsequent administration). In some aspects, the combination of a GLP-1 receptor agonist, amylin analog, GIP analog, and / or glucagon analog of the disclosure is used to treat a metabolic disorder.

[0048]

[0033] In one aspect, provided herein are combinations, pharmaceutical compositions, or kits comprising three or more peptides selected from:

[0049] (i) a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof;

[0050] (ii) a second peptide comprising the amino acid sequence of F(Aib)EGTFTSDVSKQLEEKRVREFIEWLKQGGPSSGKPPPGKK (SEQ ID NO: 2) or a pharmaceutically acceptable salt thereof, wherein Aib is 2-aminoisobutyric acid;

[0051] (iii) a third peptide comprising the amino acid sequence of Y(Aib)EGTFISDYSKALDKIHQQDFVNWLLAQKGKK (SEQ ID NO: 7) or a pharmaceutically acceptable salt thereof; and

[0052] (iv) a fourth peptide comprising the amino acid sequence of H(Aib)HGTFTSDYSKYLDAKRAQEFIEWLLQSQQHESPPPK (SEQ ID NO: 8) or a pharmaceutically acceptable salt thereof.

[0053]

[0034] In certain embodiments of the combinations described herein,

[0054] (i) the first peptide is:

[0055] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; and / or

[0056] (ii) the second peptide is:

[0057] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof; and / or

[0058] (iii) the third peptide is: Atty Ref. METS-036 / 01WO 350242-2269

[0059] (SEQ ID NO: 9), or a pharmaceutically acceptable salt thereof; and / or

[0060] (iv) the fourth peptide is:

[0061] (SEQ ID NO: 10), or a pharmaceutically acceptable salt thereof.

[0062]

[0035] In another aspect, provided herein are methods of reducing weight and / or preventing weight gain in a subject, the methods comprising administering to the subject three or more peptides selected from:

[0063] (i) a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof;

[0064] (ii) a second peptide comprising the amino acid sequence of F(Aib)EGTFTSDVSKQLEEKRVREFIEWLKQGGPSSGKPPPGKK (SEQ ID NO: 2) or a pharmaceutically acceptable salt thereof, wherein Aib is 2-aminoisobutyric acid;

[0065] (iii) a third peptide comprising the amino acid sequence of

[0066] Y(Aib)EGTFISDYSKALDKIHQQDFVNWLLAQKGKKK (SEQ ID NO: 7) or a pharmaceutically acceptable salt thereof; and

[0067] (iv) a fourth peptide comprising the amino acid sequence of

[0068] H(Aib)HGTFTSDYSKYLDAKRAQEFIEWLLQSQQHESPPPK (SEQ ID NO: 8) or a pharmaceutically acceptable salt thereof.

[0069]

[0036] In certain embodiments of the methods described herein, (i) the first peptide is SEQ ID NO: 3, or a pharmaceutically acceptable salt thereof; and / or (ii) the second peptide is SEQ ID NO: 4, or a pharmaceutically acceptable salt thereof; and / or (iii) the third peptide is Aty Ref. METS-036 / 01WO 350242-2269 SEQ ID NO: 9, or a pharmaceutically acceptable salt thereof; and / or (iv) the fourth peptide is SEQ ID NO: 10, or a pharmaceutically acceptable salt thereof.

[0070] First Peptide (Amylin)

[0071]

[0037] In some embodiments, combinations described herein comprise an amylin analog (“first peptide”). Amylin is a neuroendocrine hormone that is co-secreted with insulin as a result of nutrient ingestion and has been shown to decrease food intake, delay gastric emptying, and reduce blood glucose levels. For these reasons, amylin receptors are a target for the development of therapeutic peptides for weight loss and / or maintenance or the treatment of metabolic disorder. A related peptide hormone, calcitonin, has also been shown to increase sensitivity to insulin, inhibit gastric emptying, regulate energy expenditure, and induce feelings of satiety. See, e.g., Mathiesen etal. “Amylin and Calcitonin: Potential Therapeutic Strategies to Reduce Body Weight and Liver Fat.” Front Endocrinol (Lausanne) 2021 Jan 8; 11 :617400. Molecules which act on both the amylin, and calcitonin receptors, known as dual amylin and calcitonin receptor agonists (DACRAs), have the potential for reducing and / or maintain weight (e.g., preventing weight gain); as well as therapeutic potential in the treatment of metabolic disorder.

[0072]

[0038] As described herein, the first peptide comprises the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1), or a pharmaceutically acceptable salt thereof. In certain embodiments, the first peptide comprises a disulfide bond between the cysteine at position 3 of and the cysteine at position 8 of SEQ ID NO: 1. In certain embodiments, the first peptide comprises an amidated C-terminus. In certain embodiments, the first peptide is a peptide described in WO 2024 / 110763, published May 30, 2024, the entire contents of which is incorporated herein by reference.

[0073]

[0039] In certain embodiments, the first peptide comprises a lipid moiety. In certain embodiments, the lipid moiety is attached to N-terminus of the first peptide. In certain embodiments, the lipid moiety is attached to the alpha nitrogen of an N-terminal lysine of the first peptide. In certain embodiments, the lipid moiety is a lipid modification described in WO 2024 / 110763, published May 30, 2024, the entire contents of which is incorporated herein by reference.

[0074]

[0040] In certain embodiments, the lipid moiety comprises glutamic acid. In certain embodiments, the lipid moiety comprises a dicarboxylic acid (e.g., eicosanedioic acid). In certain embodiments, the lipid moiety comprises glutamic acid and a dicarboxylic acid (e.g., eicosanedioic acid). In certain embodiments, the lipid moiety is of the formula: certain embodiments, the lipid moiety is: Atty Ref. METS-036 / 01WO 350242-2269

[0075]

[0041] In certain embodiments, the first peptide is:

[0076] (SEQ ID NO: 5), or a pharmaceutically acceptable salt thereof.

[0077]

[0042] In certain embodiments, the first peptide is:

[0078] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof. In certain embodiments, the first peptide is an acetate salt.

[0079] Second Peptide (GLP-1 Receptor Agonist)

[0080]

[0043] In some embodiments, combinations described herein comprise a GLP-1 receptor agonist (“second peptide”). Advances in peptide therapeutics for reducing and / or maintaining weight or for the treatment of metabolic disorders (e.g., obesity) have resulted in the development of G- protein coupled receptor agonists (e.g., glucagon-like peptide-1 receptor (GLP-1), gastric inhibitory polypeptide receptor (GIP), etc.). The current standards for injectable peptides for weight loss and metabolic disorder management (e.g., liraglutide, semaglutide, tirzepatide) have drawbacks, such as daily or weekly injections and side effects which create issues with treatment adherence / patient compliance. The combination therapies described herein can help solve these challenges.

[0081]

[0044] As described herein, the second peptide comprises the amino acid sequence of F(Aib)EGTFTSDVSKQLEEKRVREFIEWLKQGGPSSGKPPPGKK (SEQ ID NO: 2), or a pharmaceutically acceptable salt thereof. In certain embodiments, the second peptide is a peptide described in WO 2022 / 123271, published June 16, 2022, the entire contents of which is incorporated herein by reference.

[0082]

[0045] In certain embodiments, the second peptide comprises a lipid moiety. In certain embodiments, the lipid moiety is attached to C-terminus of the second peptide. In certain Atty Ref. METS-036 / 01WO 350242-2269 embodiments, the lipid moiety is attached to the epsilon nitrogen of a C-terminal lysine of the second peptide. In certain embodiments, the lipid moiety is a lipid modification described in WO 2022 / 123271, published June 16, 2022, the entire contents of which is incorporated herein by reference.

[0083]

[0046] In certain embodiments, the lipid moiety comprises glutamic acid. In certain embodiments, the lipid moiety comprises a dicarboxylic acid (e.g., eicosanedioic acid). In certain embodiments, the lipid moiety comprises glutamic acid and a dicarboxylic acid (e.g., eicosanedioic acid). In certain embodiments, the lipid moiety is of the formula: certain embodiments, the lipid moiety is:

[0084]

[0047] In certain embodiments, the second peptide is:

[0085] (SEQ ID NO: 6), or a pharmaceutically acceptable salt thereof.

[0086]

[0048] In certain embodiments, the second peptide is:

[0087] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0088] Third Peptide (GIP Analog)

[0089]

[0049] In some embodiments, combinations described herein comprise a GIP analog (“first peptide”). As described herein, advances in peptide therapeutics for reducing and / or maintaining weight or for the treatment of metabolic disorders (e.g., obesity) have resulted in the development Atty Ref. METS-036 / 01WO 350242-2269 of G-protein coupled receptor agonists, including gastric inhibitory polypeptide receptor (GIP) agonists. The current standards for injectable peptides for weight loss and metabolic disorder management (e.g., liraglutide, semaglutide, tirzepatide) have drawbacks, such as daily or weekly injections and side effects which create issues with treatment adherence / patient compliance. The combination therapies described herein comprising GIP analogs can help solve these challenges.

[0050] As described herein, the first peptide comprises the amino acid sequence of Y(Aib)EGTFISDYSKALDKIHQQDFVNWLLAQKGKK (SEQ ID NO: 7), or a pharmaceutically acceptable salt thereof. In certain embodiments, the first peptide comprises an amidated C-terminus. In certain embodiments, the first peptide is a peptide described in WO 2024 / 175930, published August 29, 2024, and WO2025176999, published October 2, 2025, the entire contents of each of which are incorporated herein by reference.

[0090]

[0051] In certain embodiments, the third peptide comprises a lipid moiety. In certain embodiments, the lipid moiety is attached to C-terminus of the third peptide. In certain embodiments, the lipid moiety is attached to the epsilon nitrogen of a C-terminal lysine of the third peptide. In certain embodiments, the lipid moiety is a lipid modification described in WO 2024 / 175930, published August 29, 2024, and WO2025176999, published October 2, 2025, the entire contents of each of which are incorporated herein by reference.

[0091]

[0052] In certain embodiments, the lipid moiety comprises glutamic acid. In certain embodiments, the lipid moiety comprises a dicarboxylic acid (e.g., eicosanedioic acid). In certain embodiments, the lipid moiety comprises glutamic acid and a dicarboxylic acid (e.g., eicosanedioic acid). In certain embodiments, the lipid moiety is of the formula:

[0092]

[0053] In certain embodiments, the lipid moiety is:

[0093]

[0054] In certain embodiments, the third peptide comprises the group -K-(lipid moiety), i.e., H2

[0094] (lipid moiety) . In certain embodiments, the group -K-(lipid moiety) is linked to the epsilon nitrogen of the C-terminal lysine of the third peptide. In certain embodiments, the group Atty Ref. METS-036 / 01WO 350242-2269

[0095] -K-(lipid moiety) is of the formula: embodiments, the group -K-(lipid moiety) is:

[0096]

[0055] In certain embodiments, the first peptide is:

[0097] (SEQ ID NO: 11), or a pharmaceutically acceptable salt thereof.

[0098]

[0056] In certain embodiments, the first peptide is:

[0099] (SEQ ID NO: 9), or a pharmaceutically acceptable salt thereof. In certain embodiments, the first peptide is an acetate salt.

[0100] Fourth Peptide (Glucagon Analog)

[0101]

[0057] In some embodiments, combinations described herein comprise a glucagon analog (“fourth peptide”). The combination therapies described herein comprising glucagon analogs can help solve the challenges associated with current peptides available for weight loss and / or management described herein.

[0102]

[0058] As described herein, the fourth peptide comprises the amino acid sequence of H(Aib)HGTFTSDYSKYLDAKRAQEFIEWLLQSQQHESPPPK (SEQ ID NO: 8), or a pharmaceutically acceptable salt thereof. In certain embodiments, the fourth peptide is a Atty Ref. METS-036 / 01WO 350242-2269 peptide described in WO 2020 / 249966, published December 17, 2020, the entire contents of which is incorporated herein by reference.

[0103]

[0059] In certain embodiments, the fourth peptide comprises a lipid moiety. In certain embodiments, the lipid moiety is attached to C-terminus of the fourth peptide. In certain embodiments, the lipid moiety is attached to the epsilon nitrogen of a C-terminal lysine of the fourth peptide. In certain embodiments, the lipid moiety is a lipid modification described in WO 2020 / 249966, published December 17, 2020, the entire contents of which is incorporated herein by reference.

[0104]

[0060] In certain embodiments, the lipid moiety comprises glutamic acid. In certain embodiments, the lipid moiety comprises a dicarboxylic acid (e.g., eicosanedioic acid). In certain embodiments, the lipid moiety comprises glutamic acid and a dicarboxylic acid (e.g., eicosanedioic acid). In certain embodiments, the lipid moiety is of the formula:

[0105]

[0061] In certain embodiments, the fourth peptide is:

[0106] (SEQ ID NO: 12), or a pharmaceutically acceptable salt thereof.

[0107]

[0062] In certain embodiments, the fourth peptide is:

[0108] (SEQ ID NO: 10), or a pharmaceutically acceptable salt thereof. Atty Ref. METS-036 / 01WO 350242-2269

[0109] Peptide Derivatives

[0110]

[0063] The present disclosure provides peptides, derivatives of such peptides, and salts or solvates of such peptides and derivatives.

[0111]

[0064] The peptides, derivatives and salts may be produced by recombinant methods or synthetic methods.

[0112]

[0065] In some embodiments, a peptide (e.g., of any amino acid sequence herein, e.g., of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 7, or SEQ ID NO: 8) or a pharmaceutical composition herein is not a derivative, and in other embodiments a peptide or a pharmaceutical composition herein is a derivative (e.g., a peptide of any amino acid sequence herein, e g , of a peptide of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 7, or SEQ ID NO: 8). A derivative can, for example, comprise one or more derivatizations selected from amidation, glycosylation, carbamylation, acylation, sulfation, phosphorylation, cyclization, lipidization, pegylation and fusion to another peptide or protein to form a fusion protein. The structure may be modified at random positions within the peptide molecule, or at predetermined positions within the peptide molecule and may include one, two, three or more attached chemical moieties.

[0113]

[0066] A derivative of the disclosure can, for example, be a physiologically functional derivative of an amylin analog, GLP-1 Receptor agonist, GIP analog, or glucagon analog described herein, such as a peptide of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 7, or SEQ ID NO: 8 The term “physiologically functional derivative” is used herein to denote a chemical derivative of a amylin analog GLP-1 Receptor agonist, GIP analog, or glucagon analog described herein having the same physiological function as the corresponding unmodified peptide. For example, a physiologically functionally derivative may be convertible in the body to a peptide described herein. According to the present disclosure, non-limiting examples of physiologically functional derivatives include esters, amides, and carbamates; preferably esters and amides.

[0114]

[0067] In some embodiments, a derivatization comprises lipidization. Lipidization markedly increases the absorption of peptides relative to the rate of absorption of the corresponding unlipidized peptides, as well as prolonging blood and tissue retention of the peptides. Suitable lipid groups include, without limitation, fatty acids (e.g. lauroyl (C12H23), palmityl (C15H31), oleyl (C15H29) or stearyl (C17H35)) and bile acids (e.g. cholate or deoxycholate). Other lipid groups include, but are not limited to, dicarboxylic acids (e.g., eicosanedioic acid. In certain embodiments, the lipid moiety comprises glutamic acid. In certain embodiments, the lipid moiety comprises a dicarboxylic acid (e.g., eicosanedioic acid). In certain embodiments, the lipid moiety comprises glutamic acid and a dicarboxylic acid (e.g., eicosanedioic acid). In Aty Ref. METS-036 / 01WO 350242-2269 some embodiments, an amylin analog, GLP-1 Receptor agonist, GIP analog, or glucagon analog is linked (e.g., conjugated) to a lipid moiety, for example, selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids. The lipid moiety may be linked to any one or more amino acid of a peptide described herein (e.g., of any amino acid sequence describe herein, e g , a peptide of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 7, or SEQ ID NO: 8)

[0115] Peptide Fusions

[0116]

[0068] In certain embodiments of the pharmaceutical compositions and methods described herein, the first peptide and second peptide are fused (i.e., linked, conjugated) to one another. The first peptide and second peptide may be linked to one another via any positions on the peptides and may be linked to one another via a bond (e.g., peptide bond) or a linker. For example, the C- or N-terminus of the first peptide may be linked to C- or N-terminus of the second peptide (e.g., via a peptide bond or via a linker). Also provided herein are fusion peptides and pharmaceutically acceptable salts thereof comprising a first peptide described herein linked to a second peptide described herein, e.g., via a bond, peptide bond, or a linker.

[0117] Combination Therapies

[0118] A. Combination of SEQ ID NO: 3, SEQ ID NO: 4 and SEQ ID NO: 9

[0119]

[0069] In some embodiments, the present disclosure provide combination therapies comprising a combination of an amylin analog, a GLP-1 receptor agonist, and a GIP analog. In some embodiments, the combination therapy of the present disclosure comprises a combination of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in any weight or molar ratio as described herein. The combination may be formulated or administered in a manner that allows for flexibility in the relative amounts of each peptide, depending on the desired therapeutic effect, pharmacokinetic properties, or patient-specific needs.

[0120]

[0070] In some embodiments, the combination comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof formulated in separate pharmaceutical compositions. In some embodiments, the combination comprises the first, second, and third peptides or pharmaceutically acceptable salts thereof provided in different containers (e.g., vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the Aty Ref. METS-036 / 01WO 350242-2269 combination comprises the first, second, and third peptides or pharmaceutically acceptable salts thereof in various physical forms, including solution, lyophilized, cryopreserved preparations. In some embodiments, the combination is administered concurrently (e.g., at or near the same time) or sequentially (e.g., at different times).

[0121]

[0071] In some embodiments, the combination comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof co-formulated in the same pharmaceutical composition. In some embodiments, the combination comprises the first, second, and third peptides or pharmaceutically acceptable salts thereof co-formulated in a solution. In some embodiments, the combination comprises the first, second, and third peptides or pharmaceutically acceptable salts thereof provided in the same container (e.g., vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the combination comprises the first, second, and third peptides or pharmaceutically acceptable salts thereof in solution, lyophilized, cryopreserved. In some embodiments, the combination is co-administered concurrently.

[0122]

[0072] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g, SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g, SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a weight or molar ratio ranging from about 1 :0.1 :0.I to about 1 :50:50, for example, 1 : 1 : 10, 1 :2:10, 1 :2:6, 1 :4: 10, 1 :5: 10, or 1 : 10:20, including all values and ranges therein.

[0123]

[0073] In some embodiments, each of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in the combination of the present disclosure is independently in an amount of about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all values and ranges therein) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole. Unless otherwise indicated, percentages are by weight or by mole relative to the total amount of the first, second and third peptides.

[0124]

[0074] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 20% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about Aty Ref. METS-036 / 01WO 350242-2269 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, including all values and ranges therein) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 40% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, including all values and ranges therein) by weight or by mole, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 90% (e.g, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%, including all values and ranges therein) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0125]

[0075] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g, SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 83% to about 85% (e.g., about 84%) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0076] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 14% to about 16% (e.g., about 15%) by weight or by mole, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 76% to about 78% (e.g., about 77%) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0126]

[0077] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in an amount of about 10% to about 12% (e.g., about 11%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 21% to about 23% (e.g., about 22%) by weight or by mole, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 66% to about 68% (e.g., about 67%) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0127] B. Combination of SEQ ID NO: 4, SEQ ID NO: 9 and SEQ ID NO: 10 Aty Ref. METS-036 / 01WO 350242-2269

[0078] In some embodiments, the present disclosure provide combination therapies comprising a combination of a GLP-1 receptor agonist, a GIP analog and a glucagon analog. In some embodiments, the combination therapy of the present disclosure comprises a combination of the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in any weight or molar ratio as described herein. The combination may be formulated or administered in a manner that allows for flexibility in the relative amounts of each peptide, depending on the desired therapeutic effect, pharmacokinetic properties, or patient-specific needs.

[0128]

[0079] In some embodiments, the combination comprises the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g, SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof formulated in separate pharmaceutical compositions. In some embodiments, the combination comprises the second, third, fourth peptides or pharmaceutically acceptable salts thereof provided in different containers (e.g., vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the combination comprises the second, third, fourth peptides or pharmaceutically acceptable salts thereof in various physical forms, including solution, lyophilized, cryopreserved preparations. In some embodiments, the combination is administered concurrently (e.g., at or near the same time) or sequentially (e.g., at different times).

[0129]

[0080] In some embodiments, the combination comprises the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof co-formulated in the same pharmaceutical composition. In some embodiments, the combination comprises the second, third, fourth peptides or pharmaceutically acceptable salts thereof co-formulated in a solution. In some embodiments, the combination comprises the second, third, fourth peptides or pharmaceutically acceptable salts thereof provided in the same container (e.g., vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the combination comprises the second, third, fourth peptides or pharmaceutically acceptable salts thereof in solution, lyophilized, cryopreserved. In some embodiments, the combination is coadministered concurrently.

[0130]

[0081] In some embodiments, the combination of the present disclosure comprises the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., Aty Ref. METS-036 / 01WO 350242-2269 SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a weight or molar ratio ranging from about 1 :0.1 :0.1 to about 1 :50:50, for example 1 :5: 1, 1 : 10: 1, 1 :3:0.75, 1 :3: 1, including all values and ranges therein.

[0131]

[0082] In some embodiments, each of the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in the combination of the present disclosure is independently in an amount of about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all values and ranges therein) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole. Unless otherwise indicated, percentages are by weight or by mole relative to the total amount of the second, third, fourth peptides.

[0132]

[0083] In some embodiments, the combination of the present disclosure comprises the second peptide (e.g, SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 30% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, including all values and ranges therein) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 90% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%, including all values and ranges therein) by weight or by mole, and the fourth peptide (e.g. , SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 30% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, including all values and ranges therein) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0133]

[0084] In some embodiments, the combination of the present disclosure comprises the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, the third peptide (e.g., SEQ ID NO: Aty Ref. METS-036 / 01WO 350242-2269 9) or a pharmaceutically acceptable salt thereof in an amount of about 83% to about 85% (e.g., about 84%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0134]

[0085] In some embodiments, the combination of the present disclosure comprises the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 13% to about 15% (e.g., about 14%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 71% to about 73% (e.g., about 72%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 13% to about 15% (e.g., about 14%) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0135]

[0086] In some embodiments, the combination of the present disclosure comprises the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 20% to about 22% (e.g., about 21%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 62% to about 64% (e.g., about 63%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 15% to about 17% (e.g., about 16%) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0136]

[0087] In some embodiments, the combination of the present disclosure comprises the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 19% to about 21% (e.g., about 20%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 59% to about 61% (e.g., about 60%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 19% to about 21% (e.g., about 20%) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0137] C. Combination of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 9 and SEQ ID NO: 10

[0088] In some embodiments, the present disclosure provide combination therapies comprising a combination of an amylin analog, a GLP-1 receptor agonist, a GIP analog, and a glucagon analog. In some embodiments, the combination therapy of the present disclosure comprises a combination of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the Aty Ref. METS-036 / 01WO 350242-2269 second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in any weight or molar ratio as described herein. The combination may be formulated or administered in a manner that allows for flexibility in the relative amounts of each peptide, depending on the desired therapeutic effect, pharmacokinetic properties, or patient-specific needs.

[0138]

[0089] In some embodiments, the combination comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof formulated in separate pharmaceutical compositions. In some embodiments, the combination comprises the first, second, third, and fourth peptides or pharmaceutically acceptable salts thereof provided in different containers (e.g., vial, ampule, botle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the combination comprises the first, second, third, and fourth peptides or pharmaceutically acceptable salts thereof in various physical forms, including solution, lyophilized, cryopreserved preparations. In some embodiments, the combination is administered concurrently (e.g., at or near the same time) or sequentially (e.g., at different times).

[0139]

[0090] In some embodiments, the combination comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof co-formulated in the same pharmaceutical composition. In some embodiments, the combination comprises the first, second, third, and fourth peptides or pharmaceutically acceptable salts thereof co-formulated in a solution. In some embodiments, the combination comprises the first, second, third, and fourth peptides or pharmaceutically acceptable salts thereof provided in the same container (e.g., vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, the combination comprises the first, second, third, and fourth peptides or pharmaceutically acceptable salts thereof in solution, lyophilized, cryopreserved. In some embodiments, the combination is co-administered concurrently.

[0140]

[0091] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g, SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: Aty Ref. METS-036 / 01WO 350242-2269 10) or a pharmaceutically acceptable salt thereof at a weight or molar ratio ranging from about 1:0.1:0.1:0 1 to about 1 :50:50:50, for example, 1 : 1 : 10: 1, 1 :2: 10:2, 1:2:6:1.5, 1 :2:6:2, 1 :4: 10:4, 1 :5: 10:5, or 1 : 10:20: 10, including all values and ranges therein.

[0141]

[0092] In some embodiments, each of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in the combination of the present disclosure is independently in an amount of about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all values and ranges therein) by weight or by mole, wherein the sum of the first, second, third, fourth peptides is 100% by weight or by mole. Unless otherwise indicated, percentages are by weight or by mole relative to the total amount of the first, second, third, fourth peptides.

[0142]

[0093] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g, SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 20% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, including all values and ranges therein) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 40% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, including all values and ranges therein) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 90% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%, including all values and ranges therein) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 1% to about 20% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, including all values and ranges therein) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0143]

[0094] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in an amount of about 7% to Aty Ref. METS-036 / 01WO 350242-2269 about 9% (e.g., about 8%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 75% to about 77% (e.g., about 76%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, wherein the sum of the first, second, third and fourth peptides is 100% by weight or by mole.

[0144]

[0095] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in an amount of about 6% to about 8% (e.g., about 7%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 12% to about 14% (e.g., about 13%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 66% to about 68% (e.g., about 67%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 12% to about 14% (e.g., about 13%) by weight or by mole, wherein the sum of the first, second, third and fourth peptides is 100% by weight or by mole.

[0145]

[0096] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in an amount of about 9% to about 11% (e.g., about 10%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 18% to about 20% (e.g., about 19%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 56% to about 58% (e.g., about 57%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 13% to about 15% (e.g., about 14%) by weight or by mole, wherein the sum of the first, second, third and fourth peptides is 100% by weight or by mole.

[0146]

[0097] In some embodiments, the combination of the present disclosure comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in an amount of about 8% to about 10% (e.g., about 9%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in an amount of about 17% to about 19% (e.g., about 18%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in an amount of about 54% to about 56% (e.g., about 55%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in an amount of about 17% to about 19% (e.g., about 18%) by weight or by mole, wherein the sum of the first, second, third and fourth peptides is 100% by weight or by mole. Atty Ref. METS-036 / 01WO 350242-2269

[0147] Pharmaceutical Compositions, Administration and Kits

[0148]

[0098] As described, the present disclosure provides pharmaceutical compositions or kits comprising three or more (e.g., three or four) of: (i) a first peptide or a pharmaceutically acceptable salt thereof, (ii) a second peptide or a pharmaceutically acceptable salt thereof, (iii) a third peptide or a pharmaceutically acceptable salt thereof, and (iv) a fourth peptide or a pharmaceutically acceptable salt thereof. The pharmaceutical composition or kits can comprise one or more pharmaceutically acceptable carriers and / or excipients. In certain embodiments, the peptides are provided in effective amounts in the pharmaceutical composition or kit. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0149]

[0099] The terms “composition” and “formulation” are used interchangeably herein.

[0150]

[0100] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the peptides described herein ( / .< ., the “active ingredients”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0151]

[0101] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising predetermined amounts of the active ingredients. The amount of the active ingredients is generally equal to the dosage of the active ingredients which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0152]

[0102] Relative amounts of the active ingredients, the pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0153]

[0103] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0154]

[0104] The peptides and compositions provided herein can be administered by any route, including parenteral, enteral (e.g., oral), intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, Aty Ref. METS-036 / 01WO 350242-2269 intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol.

[0155]

[0105] Specifically contemplated routes are via injection (e.g., subcutaneous injection) or oral administration. In some embodiments, a pharmaceutical composition or peptide thereof is administered via injection (e.g., intravenously, subcutaneously, or intramuscularly). In some embodiments, a pharmaceutical composition or peptide thereof is administered orally. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agents (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0156]

[0106] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0157]

[0107] In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a ready -to-use (“RTU”) preparation that can be directly administered to a subject. In some embodiments, the RTU preparation is a suspension. In some embodiments, the RTU preparation is a solution. In some embodiments, the RTU preparation is an emulsion. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of solids that are reconstituted prior to administration. In some embodiments, the solid is a lyophilized solid. In some embodiments, injectable preparations of the compositions disclosed herein are in the form of a liquid or suspension that is diluted prior to administration.

[0158]

[0108] In certain embodiments, the first peptide and the second peptide are co-formulated in a solution. In certain embodiments, the first peptide and the second peptide are both miscible in solution. In certain embodiments, the first peptide and the second peptide are coformulated in a solution. In certain embodiments, the first peptide and the second peptide are both miscible in solution.

[0159]

[0109] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for Aty Ref. METS-036 / 01WO 350242-2269 administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0160]

[0110] Peptides provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific effective or therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the condition being treated and / or the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0161] [Hl] The exact amount of peptides required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular peptide, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject, any two doses of the multiple doses include different or substantially the same amounts of the peptides described herein.

[0162]

[0112] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). In certain embodiments, a kit comprises: the first peptide and the second peptide, or pharmaceutically acceptable salts thereof, in any combination as described herein, wherein the peptides are in different containers (e.g., vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container), optionally in solution, lyophilized, cryopreserved. In other embodiments, the first peptides are in the same container (e.g., vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container) optionally in solution, lyophilized, cryopreserved. In certain embodiments, a kit comprises: a first peptide or a pharmaceutically acceptable salt thereof described herein; and a second peptide or a pharmaceutically acceptable salt thereof described herein, wherein the first peptide and the second peptide are in different containers (e.g., vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container), optionally in solution, lyophilized, cryopreserved. In other embodiments, the first peptides are in the same container (e.g., vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container) optionally in solution, lyophilized, cryopreserved. Aty Ref. METS-036 / 01WO 350242-2269

[0163]

[0113] In some embodiments, provided kits may optionally further include an additional container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or peptides described herein. In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for reducing weight. In certain embodiments, the kits provide instructions for preventing weight gain.

[0164] Dosage and Dosing Regimens

[0165]

[0114] Unless otherwise provided herein, the stated dose amounts of the amylin analog (e.g., SEQ ID NO: 3), the GLP-1 receptor agonist (e.g., SEQ ID NO: 4), the GIP analog (e.g., SEQ ID NO: 9), and the glucagon analog (e.g., SEQ ID NO: 10), are expressed as the free base form. When a pharmaceutically acceptable salt form is administered, the salt form is administered at a dose that provides the molar equivalent of the free base.

[0166]

[0115] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof in the combination therapy is administered at a dose of about 0.05 mg to about 9.6 mg, about 0.05 mg to about 7.2 mg, about 0.05 mg to about 0.15 mg, about 0.1 mg to about 2.4 mg, about 0.1 mg to about 0.3 mg, about 0.3 mg to about 0.5 mg, about 0.5 mg to about 0.7 mg, about 0.7 mg to about 0.9 mg, about 1.1 mg to about 1.3 mg, about 1.5 mg to about 1.7 mg, about 2.3 mg to about 2.5 mg, about 4.7 mg to about 4.9 mg, or about 6.3 mg to about 6.6 mg, including all values and subranges therein. In some embodiments, a dose of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about

[0167] 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about

[0168] 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about

[0169] 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.1 Aty Ref. METS-036 / 01WO 350242-2269 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, or about 9.6 mg, including all ranges therein.

[0170]

[0116] In some embodiments, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in the combination therapy is administered at a dose of about 0.05 mg to about 9.6 mg, about 0.05 mg to about 7.2 mg, about 0.05 mg to about 0.15 mg, about 0.1 mg to about 2.4 mg, about 0.1 mg to about 0.3 mg, about 0.3 mg to about 0.5 mg, about 0.7 mg to about 0.9 mg, about 1.5 mg to about 1.7 mg, about 4.7 mg to about 4.9 mg, or about 6.3 mg to about 6.6 mg, including all values and subranges therein. In some embodiments, a dose of the second peptide (e.g. , SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about

[0171] 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about

[0172] 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about

[0173] 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about

[0174] 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about

[0175] 9.5 mg, or about 9.6 mg, including all ranges therein.

[0176]

[0117] In some embodiments, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof in the combination therapy is administered at a dose of about 1 mg to about 50 mg, about 3 mg to about 20 mg, about 3 mg to about 10 mg, about 10 mg to about 20 mg, about 2 mg to about 4 mg (e.g., about 3 mg), about 9 mg to about 11 mg (e.g., about 10 mg), or about 19 mg to about 21 mg (e.g., 20 mg), including all values and subranges therein. In some embodiments, a dose of the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, Atty Ref. METS-036 / 01WO 350242-2269 about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg, including all ranges therein.

[0177]

[0118] In some embodiments, the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof in the combination therapy is administered at a dose of at a dose of about 0.05 mg to about 9.6 mg, about 0.05 mg to about 7.2 mg, about 0.5 mg to about 5 mg, about 0.05 mg to about 0.15 mg, about 0.1 mg to about 2.4 mg, about 0.1 mg to about 0.3 mg, about 0.3 mg to about 0.5 mg, about 0.7 mg to about 0.9 mg, about 1.5 mg to about 1.7 mg, about 4.7 mg to about 4.9 mg, or about 6.3 mg to about 6.6 mg, including all values and subranges therein. In some embodiments, a dose of the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about

[0178] 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about

[0179] 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about

[0180] 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, or about 9.6 mg, including all ranges therein.

[0181]

[0119] In some embodiments, the present disclosure provides methods of administering a combination comprising three or more peptides described herein or pharmaceutically acceptable salts thereof to a subject according to any of the dosing regimens described herein. In some embodiments, the peptides described herein or pharmaceutically acceptable salts thereof are coadministered (e.g., in a single composition or dosage form) or separately administered (e.g., as separate compositions). In some embodiments, the peptides described herein, or pharmaceutically acceptable salts thereof, are separately administered within the same dosing interval and / or on the Aty Ref. METS-036 / 01WO 350242-2269 same dosing day. In some embodiments, the separate administration are staggered such that the administrations are separated by about 1 hour to about 2 days (e.g., about 1 day).

[0182]

[0120] In some embodiments, the combination of peptides or pharmaceutically acceptable salts thereof is administered on a weekly dosing schedule. In some embodiments, the combination is administered once weekly at a maintenance dose. In some embodiments, the combination is administered once weekly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 weeks (e.g., about 2 weekly administrations to about 4 weekly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, until a target maintenance dose is achieved, followed by a weekly maintenance dose.

[0183]

[0121] In some embodiments, the combination of peptides or pharmaceutically acceptable salts thereof is administered on a monthly dosing schedule. In some embodiments, the combination is administered once monthly at a maintenance dose. In some embodiments, the combination is administered once monthly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 months (e.g., about 2 monthly administrations to about 4 monthly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once monthly for about 2 to about 16 months, wherein the amount of one or more peptides is increased over about 2 to about 4 monthly escalations, and wherein each increased dose level is maintained for about 2 months to about 4 months prior to a subsequent increase, until a target maintenance dose is achieved, followed by a monthly maintenance dose.

[0184]

[0122] In some embodiments, the combination of peptides or pharmaceutically acceptable salts thereof is administered weekly for an initial period and then transitioned to monthly administration. In some embodiments, the combination of peptides or pharmaceutically acceptable salts thereof is administered once weekly in a stepwise titration regimen, wherein the administered amount is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 weeks (e.g., about 2 weekly administrations to about 4 weekly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased Aty Ref. METS-036 / 01WO 350242-2269 over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, followed by administering the combination once monthly thereafter. In some embodiments, upon reaching a target maintenance dose, the target maintenance dose is administered for about 2 weeks to about 4 weeks prior to transitioning to once monthly administration.

[0185]

[0123] In some embodiments, the combination of the peptides described herein or pharmaceutically acceptable salts thereof is administered weekly for an initial period and then transitioned to monthly administration without titration. In some embodiments, the combination of the peptides described herein or pharmaceutically acceptable salts thereof is administered once weekly for an initial period (e.g., about 2 to about 16 weeks) at a constant amount, and then switching to monthly administration at a constant maintenance dose.

[0186]

[0124] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 9.6 mg, about 0.1 mg to about 7.2 mg or about 0.1 mg to about 2.4 mg, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 9.6 mg, about 0.1 mg to about 7.2 mg, or about 0.1 mg to about 2.4 mg, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 50 mg, about 1 mg to about 30 mg, about 3 mg to about 20 mg, about 3 mg to about 10 mg, about 10 mg to about 20 mg.

[0187]

[0125] In some embodiments, the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), and the third peptide (e.g., SEQ ID NO: 9), or their pharmaceutically acceptable salts thereof, are administered at a weight or molar ratio ranging from about 1:0.1 :0.1 to about 1 :50:50, for example, 1 : 1 : 10, 1 :2: 10, 1 :2:6, 1 :4: 10, 1 :5:10, or 1 : 10:20, including all values and ranges therein.

[0188]

[0126] In some embodiments, each of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), and the third peptide (e.g., SEQ ID NO: 9), or their pharmaceutically acceptable salts thereof, is independently administered in an amount of about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all values and ranges therein) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0189]

[0127] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 20% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, Aty Ref. METS-036 / 01WO 350242-2269 about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, including all values and ranges therein) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 40% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, including all values and ranges therein) by weight or by mole, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 90% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%, including all values and ranges therein) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0190]

[0128] In some embodiments, the first peptide (e.g, SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 83% to about 85% (e.g., about 84%) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0191]

[0129] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 14% to about 16% (e.g., about 15%) by weight or by mole, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 76% to about 78% (e.g., about 77%) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0192]

[0130] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered in an amount of about 10% to about 12% (e.g., about 11%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 21% to about 23% (e.g., about 22%) by weight or by mole, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 66% to about 68% (e.g., about 67%) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0193]

[0131] In some embodiments, the combination of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), and the third peptide (e.g., SEQ ID NO: 9), or their pharmaceutically acceptable salts thereof, is administered on a weekly dosing schedule. In some Aty Ref. METS-036 / 01WO 350242-2269 embodiments, the combination is administered once weekly at a maintenance dose. In some embodiments, the combination is administered once weekly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 weeks (e.g., about 2 weekly administrations to about 4 weekly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, until a target maintenance dose is achieved, followed by a weekly maintenance dose.

[0194]

[0132] In some embodiments, the combination of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), and the third peptide (e.g., SEQ ID NO: 9), or their pharmaceutically acceptable salts thereof, is administered on a monthly dosing schedule. In some embodiments, the combination is administered once monthly at a maintenance dose. In some embodiments, the combination is administered once monthly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 months (e.g., about 2 monthly administrations to about 4 monthly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once monthly for about 2 to about 16 months, wherein the amount of one or more peptides is increased over about 2 to about 4 monthly escalations, and wherein each increased dose level is maintained for about 2 months to about 4 months prior to a subsequent increase, until a target maintenance dose is achieved, followed by a monthly maintenance dose.

[0195]

[0133] In some embodiments, the combination of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), and the third peptide (e.g., SEQ ID NO: 9), or their pharmaceutically acceptable salts thereof is administered weekly for an initial period and then transitioned to monthly administration. In some embodiments, the combination is administered once weekly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 weeks (e.g., about 2 weekly administrations to about 4 weekly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased Aty Ref. METS-036 / 01WO 350242-2269 over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, followed by administering the combination once monthly thereafter. In some embodiments, upon reaching a target maintenance dose, the target maintenance dose is administered for about 2 weeks to about 4 weeks prior to transitioning to once monthly administration.

[0196]

[0134] In some embodiments, the combination of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), and the third peptide (e.g., SEQ ID NO: 9), or their pharmaceutically acceptable salts thereof, is administered once weekly for an initial period (e.g., about 2 to about 16 weeks) at a constant amount, and then switching to monthly administration at a constant maintenance dose.

[0197]

[0135] In some embodiments, the starting dose of one or more of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), and the third peptide (e.g., SEQ ID NO: 9), or their pharmaceutically acceptable salts is lower than the corresponding maintenance dose (e.g., the first dose is titrated upward to the second dose). In some embodiments, the starting dose of one or more of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), and the third peptide (e.g., SEQ ID NO: 9), or their pharmaceutically acceptable salts is identical to the corresponding maintenance dose. In some embodiments, a starting dose may be increased by any increment described herein (e.g., by about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about

[0198] 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about

[0199] 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about

[0200] 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about

[0201] 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about

[0202] 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, about 10.9 mg, about 11.0 mg, about 12.1 mg, about 12.2 mg, about 12.3 mg, about 12.4 mg, about 12.5 mg, about 12.6 mg, Atty Ref. METS-036 / 01WO 350242-2269 about 12.7 mg, about 12.8 mg, about 12.9 mg, about 13.0 mg, about 13.1 mg, about 13.2 mg, about 13.3 mg, about 13.4 mg, about 13.5 mg, about 13.6 mg, about 13.7 mg, about 13.8 mg, about 13.9 mg, about 14.0 mg, about 14.1 mg, about 14.2 mg, about 14.3 mg, about 14.4 mg, about 14.5 mg, about 14.6 mg, about 14.7 mg, about 14.8 mg, about 14.9 mg, about 15.0 mg, about 15.1 mg, about 15.2 mg, about 15.3 mg, about 15.4 mg, about 15.5 mg, about 15.6 mg, about 15.7 mg, about 15.8 mg, about 15.9 mg, about 16.0 mg, about 16.1 mg, about 16.2 mg, about 16.3 mg, about 16.4 mg, about 16.5 mg, about 16.6 mg, about 16.7 mg, about 16.8 mg, about 16.9 mg, about 17.0 mg, about 17.1 mg, about 17.2 mg, about 17.3 mg, about 17.4 mg, about 17.5 mg, about 17.6 mg, about 17.7 mg, about 17.8 mg, about 17.9 mg, about 18.0 mg, about 18.1 mg, about 18.2 mg, about 18.3 mg, about 18.4 mg, about 18.5 mg, about 18.6 mg, about 18.7 mg, about 18.8 mg, about 18.9 mg, about 19.0 mg, about 19.1 mg, about 19.2 mg, about 19.3 mg, about 19.4 mg, about 19.5 mg, about 19.6 mg, about 19.7 mg, about 19.8 mg, about 19.9 mg, or about 20.0 mg) to an increased dose. In some embodiments, titrating comprises multiple dose increases to reach a maintenance dose. In some embodiments, each dose increase (or increased dose) is about 1.1-fold to about 8-fold of the amount of the immediately preceding dose, for example, about 1.1-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, or about 8-fold of the amount of the immediately preceding dose.

[0203]

[0136] In some embodiments, the methods of the present disclosure comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1 mg to about 3 mg (e.g., about 2 mg) for about 4 weeks. In some embodiments, on about weeks 4-8 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 3 mg to about 5 mg (e.g., about 4 mg) for about 4 weeks. In some embodiments, on about weeks 8-12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable Aty Ref. METS-036 / 01WO 350242-2269 salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 7 mg to about 9 mg (e.g., about 8 mg) for about 4 weeks. In some embodiments, starting on week 12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to 2.5 mg (e.g., about 2.4 mg), and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 9 mg to about 11 mg (e.g., about 10 mg), about 19 mg to about 21 mg (e.g., about 20 mg), or about 29 mg to about 31 mg (e.g., about 30 mg).

[0204]

[0137] In some embodiments, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 9.6 mg, about 0.1 mg to about 7.2 mg, or about 0.1 mg to about 2.4 mg, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 50 mg, about 1 mg to about 20 mg, about 3 mg to about 20 mg, about 3 mg to about 10 mg, about 10 mg to about 20 mg, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 9.6 mg, about 0.1 mg to about 7.2 mg, about 0.5 mg to about 5 mg, or about 0.5 mg to about 2.4 mg.

[0205]

[0138] In some embodiments, the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof, are administered at a weight or molar ratio ranging from about 1 :0.1 :0.1 to about 1 :50:50, for example, 1 :5: 1, 1 : 10: 1, 1 :3:0.75, 1 :3: 1, including all values and ranges therein.

[0206]

[0139] In some embodiments, each of the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salt thereof, is independently administered in an amount of about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all values and ranges therein) by weight or by mole, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole. Aty Ref. METS-036 / 01WO 350242-2269

[0207]

[0140] In some embodiments, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 30% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, including all values and ranges therein) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 90% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%, including all values and ranges therein) by weight or by mole, and the fourth peptide (e.g, SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 30% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30%, including all values and ranges therein) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0208]

[0141] In some embodiments, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 83% to about 85% (e.g., about 84%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0209]

[0142] In some embodiments, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 13% to about 15% (e.g., about 14%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 71% to about 73% (e.g., about 72%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 13% to about 15% (e.g., about 14%) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0210]

[0143] In some embodiments, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 20% to about 22% (e.g., about 21%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable Aty Ref. METS-036 / 01WO 350242-2269 salt thereof is administered in an amount of about 62% to about 64% (e.g., about 63%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 15% to about 17% (e.g., about 16%) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0211]

[0144] In some embodiments, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 19% to about 21% (e.g., about 20%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 59% to about 61% (e.g., about 60%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 19% to about 21% (e.g., about 20%) by weight or by mole, wherein the sum of the second, third, and fourth peptides is 100% by weight or by mole.

[0212]

[0145] In some embodiments, , the combination of the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof, is administered on a weekly dosing schedule. In some embodiments, the combination is administered once weekly at a maintenance dose. In some embodiments, the combination is administered once weekly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 weeks (e.g., about 2 weekly administrations to about 4 weekly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, until a target maintenance dose is achieved, followed by a weekly maintenance dose.

[0213]

[0146] In some embodiments, the combination of the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof, is administered on a monthly dosing schedule. In some embodiments, the combination is administered once monthly at a maintenance dose. In some embodiments, the combination is administered once monthly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 months (e.g., about 2 monthly administrations to about 4 monthly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once monthly for about 2 to about 16 months, Aty Ref. METS-036 / 01WO 350242-2269 wherein the amount of one or more peptides is increased over about 2 to about 4 monthly escalations, and wherein each increased dose level is maintained for about 2 months to about 4 months prior to a subsequent increase, until a target maintenance dose is achieved, followed by a monthly maintenance dose.

[0214]

[0147] In some embodiments, the combination of the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof, is administered weekly for an initial period and then transitioned to monthly administration. In some embodiments, the combination is administered once weekly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 weeks (e.g., about 2 weekly administrations to about 4 weekly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, followed by administering the combination once monthly thereafter. In some embodiments, upon reaching a target maintenance dose, the target maintenance dose is administered for about 2 weeks to about 4 weeks prior to transitioning to once monthly administration.

[0215]

[0148] In some embodiments, the combination of the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof, is administered once weekly for an initial period (e.g., about 2 to about 16 weeks) at a constant amount, and then switching to monthly administration at a constant maintenance dose.

[0216]

[0149] In some embodiments, the starting dose of one or more of the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts is lower than its maintenance dose (e.g., the first dose is titrated upward to the second dose). In some embodiments, the starting dose of one or more of the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts is identical to the maintenance dose. In some embodiments, a starting dose may be increased by any increment described herein (e.g., by about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, Atty Ref. METS-036 / 01WO 350242-2269 about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about

[0217] 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about

[0218] 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about

[0219] 7.9 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about

[0220] 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, about 10.9 mg, about 11.0 mg, about 12.1 mg, about 12.2 mg, about 12.3 mg, about 12.4 mg, about 12.5 mg, about 12.6 mg, about 12.7 mg, about 12.8 mg, about 12.9 mg, about 13.0 mg, about 13.1 mg, about 13.2 mg, about 13.3 mg, about 13.4 mg, about 13.5 mg, about 13.6 mg, about 13.7 mg, about 13.8 mg, about 13.9 mg, about 14.0 mg, about 14.1 mg, about 14.2 mg, about 14.3 mg, about 14.4 mg, about 14.5 mg, about 14.6 mg, about 14.7 mg, about 14.8 mg, about 14.9 mg, about 15.0 mg, about 15.1 mg, about 15.2 mg, about 15.3 mg, about 15.4 mg, about 15.5 mg, about 15.6 mg, about 15.7 mg, about 15.8 mg, about 15.9 mg, about 16.0 mg, about 16.1 mg, about 16.2 mg, about 16.3 mg, about 16.4 mg, about 16.5 mg, about 16.6 mg, about 16.7 mg, about 16.8 mg, about 16.9 mg, about 17.0 mg, about 17.1 mg, about 17.2 mg, about 17.3 mg, about 17.4 mg, about 17.5 mg, about 17.6 mg, about 17.7 mg, about 17.8 mg, about 17.9 mg, about 18.0 mg, about 18.1 mg, about 18.2 mg, about 18.3 mg, about 18.4 mg, about 18.5 mg, about 18.6 mg, about 18.7 mg, about 18.8 mg, about 18.9 mg, about 19.0 mg, about 19.1 mg, about 19.2 mg, about 19.3 mg, about 19.4 mg, about 19.5 mg, about 19.6 mg, about 19.7 mg, about 19.8 mg, about 19.9 mg, or about 20.0 mg) to an increased dose. In some embodiments, titrating comprises multiple dose increases to reach a maintenance dose. In some embodiments, each dose increase (or increased dose) is about 1.1-fold to about 8-fold of the amount of the immediately preceding dose, for example, about 1.1-fold, about 1.5-fold, about 2-fold, about 2.5 -fold, about 3-fold, about 3.3 -fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5- fold, about 7-fold, about 7.5-fold, or about 8-fold of the amount of the immediately preceding dose.

[0221]

[0150] In some embodiments, the methods of the present disclosure comprise administration of the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once Aty Ref. METS-036 / 01WO 350242-2269 weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1 mg to about 3 mg (e.g., about 2 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), for about 4 weeks. In some embodiments, on about weeks 4-8 of treatment, the methods comprise administration of the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 3 mg to about 5 mg (e.g., about 4 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), for about 4 weeks. In some embodiments, on about weeks 8-12 of treatment, the methods comprise administration of the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 7 mg to about 9 mg (e.g., about 8 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), for about 4 weeks. In some embodiments, starting on week 12 of treatment, the methods comprise administration of the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to 2.5 mg (e.g., about 2.4 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 9 mg to about 11 mg (e.g., about 10 mg), about 19 mg to about 21 mg (e.g., about 20 mg), or about 29 mg to about 31 mg (e.g., about 30 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to 2.5 mg (e.g., about 2.4 mg).

[0222]

[0151] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 9.6 mg, about 0.1 mg to about 7.2 mg or about 0.1 mg to about 2.4 mg, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 9.6 mg, about 0.1 mg to about 7.2 mg, or about 0.1 mg to about 2.4 mg, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 50 mg, about 1 mg to about 20 mg, about 3 mg to about 20 mg, about 3 mg to about 10 mg, about 10 mg to about 20 mg, and the fourth peptide (e.g., SEQ ID NO: 10) or a Aty Ref. METS-036 / 01WO 350242-2269 pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 9.6 mg, about 0.1 mg to about 7.2 mg, about 0.5 mg to about 5 mg, or about 0.5 mg to about 2.4 mg.

[0223]

[0152] In some embodiments, the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), or their pharmaceutically acceptable salts thereof, and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof are administered at a weight or molar ratio ranging from about 1 :0.1 :0.1:0.1 to about 1 :50:50:50, for example, 1 : 1 : 10: 1, 1 :2: 10:2, 1:2:6:1.5, 1 :2:6:2, 1 :4: 10:4, 1 :5: 10:5, or 1 : 10:20: 10, including all values and ranges therein.

[0224]

[0153] In some embodiments, each of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof, is independently administered in an amount of about 1% to about 95% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%, including all values and ranges therein) by weight or by mole, wherein the sum of the first, second, third, fourth peptides is 100% by weight or by mole.

[0225]

[0154] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 20% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, including all values and ranges therein) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 40% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, including all values and ranges therein) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 90% (e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%, including all values and ranges therein) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 1% to about 20% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, including all values and Aty Ref. METS-036 / 01WO 350242-2269 ranges therein) by weight or by mole, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0226]

[0155] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 75% to about 77% (e.g., about 76%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 7% to about 9% (e.g., about 8%) by weight or by mole, wherein the sum of the first, second, third and fourth peptides is 100% by weight or by mole

[0227]

[0156] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered in an amount of about 6% to about 8% (e.g., about 7%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 12% to about 14% (e.g., about 13%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 66% to about 68% (e.g., about 67%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 12% to about 14% (e.g., about 13%) by weight or by mole, wherein the sum of the first, second, third and fourth peptides is 100% by weight or by mole.

[0228]

[0157] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered in an amount of about 9% to about 11% (e.g., about 10%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 18% to about 20% (e.g., about 19%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 56% to about 58% (e.g., about 57%) by weight or by mole, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 13% to about 15% (e.g., about 14%) by weight or by mole, wherein the sum of the first, second, third and fourth peptides is 100% by weight or by mole.

[0229]

[0158] In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered in an amount of about 8% to about 10% (e.g., about 9%) by weight or by mole, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered in an amount of about 17% to about 19% (e.g., about 18%) by weight or by mole, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered in an amount of about 54% to about 56% (e.g., about 55%) by weight or by mole, Aty Ref. METS-036 / 01WO 350242-2269 and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered in an amount of about 17% to about 19% e.g., about 18%) by weight or by mole, wherein the sum of the first, second, third and fourth peptides is 100% by weight or by mole.

[0230]

[0159] In some embodiments, the combination of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e g , SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof, is administered on a weekly dosing schedule. In some embodiments, the combination is administered once weekly at a maintenance dose. In some embodiments, the combination is administered once weekly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 weeks (e.g., about 2 weekly administrations to about 4 weekly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, until a target maintenance dose is achieved, followed by a weekly maintenance dose.

[0231]

[0160] In some embodiments, the combination of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e g , SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof, is administered on a monthly dosing schedule. In some embodiments, the combination is administered once monthly at a maintenance dose. In some embodiments, the combination is administered once monthly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 months (e.g., about 2 monthly administrations to about 4 monthly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once monthly for about 2 to about 16 months, wherein the amount of one or more peptides is increased over about 2 to about 4 monthly escalations, and wherein each increased dose level is maintained for about 2 months to about 4 months prior to a subsequent increase, until a target maintenance dose is achieved, followed by a monthly maintenance dose.

[0232]

[0161] In some embodiments, the combination of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e g , SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof is administered weekly for an initial period and then transitioned to monthly administration. In some embodiments, the Aty Ref. METS-036 / 01WO 350242-2269 combination is administered once weekly in a stepwise titration regimen, wherein the administered amount for one or more peptides is increased from a starting dose to a subsequent higher dose, and each higher (titrated) dose is maintained for about 2 to about 4 weeks (e.g., about 2 weekly administrations to about 4 weekly administrations) before a subsequent increase to the next higher dose, until a target maintenance dose is achieved. In some embodiments, the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, followed by administering the combination once monthly thereafter. In some embodiments, upon reaching a target maintenance dose, the target maintenance dose is administered for about 2 weeks to about 4 weeks prior to transitioning to once monthly administration.

[0233]

[0162] In some embodiments, the combination of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e g , SEQ ID NO: 10), or their pharmaceutically acceptable salts thereof, is administered once weekly for an initial period (e.g., about 2 to about 16 weeks) at a constant amount, and then switching to monthly administration at a constant maintenance dose.

[0234]

[0163] In some embodiments, the starting dose of one or more the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts is lower than the corresponding maintenance dose (e.g., the first dose is titrated upward to the second dose). In some embodiments, the starting dose of one or more of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10), or their pharmaceutically acceptable salts is identical to the corresponding maintenance dose. In some embodiments, a starting dose may be increased by any increment described herein (e.g., by about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about

[0235] 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about

[0236] 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about

[0237] 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, Atty Ref. METS-036 / 01WO 350242-2269 about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg, about 10.1 mg, about 10.2 mg, about 10.3 mg, about 10.4 mg, about 10.5 mg, about 10.6 mg, about 10.7 mg, about 10.8 mg, about 10.9 mg, about 11.0 mg, about 12.1 mg, about 12.2 mg, about 12.3 mg, about 12.4 mg, about 12.5 mg, about 12.6 mg, about 12.7 mg, about 12.8 mg, about 12.9 mg, about 13.0 mg, about 13.1 mg, about 13.2 mg, about 13.3 mg, about 13.4 mg, about 13.5 mg, about 13.6 mg, about 13.7 mg, about 13.8 mg, about 13.9 mg, about 14.0 mg, about 14.1 mg, about 14.2 mg, about 14.3 mg, about 14.4 mg, about 14.5 mg, about 14.6 mg, about 14.7 mg, about 14.8 mg, about 14.9 mg, about 15.0 mg, about 15.1 mg, about 15.2 mg, about 15.3 mg, about 15.4 mg, about 15.5 mg, about 15.6 mg, about 15.7 mg, about 15.8 mg, about 15.9 mg, about 16.0 mg, about 16.1 mg, about 16.2 mg, about 16.3 mg, about 16.4 mg, about 16.5 mg, about 16.6 mg, about 16.7 mg, about 16.8 mg, about 16.9 mg, about 17.0 mg, about 17.1 mg, about 17.2 mg, about 17.3 mg, about 17.4 mg, about 17.5 mg, about 17.6 mg, about 17.7 mg, about 17.8 mg, about 17.9 mg, about 18.0 mg, about 18.1 mg, about 18.2 mg, about 18.3 mg, about 18.4 mg, about 18.5 mg, about 18.6 mg, about 18.7 mg, about 18.8 mg, about 18.9 mg, about 19.0 mg, about 19.1 mg, about 19.2 mg, about 19.3 mg, about 19.4 mg, about 19.5 mg, about 19.6 mg, about 19.7 mg, about 19.8 mg, about 19.9 mg, or about 20.0 mg) to an increased dose. In some embodiments, titrating comprises multiple dose increases to reach a maintenance dose. In some embodiments, each dose increase (or increased dose) is about 1.1-fold to about 8-fold of the amount of the immediately preceding dose, for example, about 1.1-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, about 5-fold, about 5.5-fold, about 6-fold, about 6.5-fold, about 7-fold, about 7.5-fold, or about 8-fold of the amount of the immediately preceding dose.

[0238]

[0164] In some embodiments, the methods of the present disclosure comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1 mg to about 3 mg (e.g., about 2 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), for about 4 weeks. In some Aty Ref. METS-036 / 01WO 350242-2269 embodiments, on about weeks 4-8 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 3 mg to about 5 mg (e.g., about 4 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), for about 4 weeks. In some embodiments, on about weeks 8-12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 7 mg to about 9 mg (e.g., about 8 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), for about 4 weeks. In some embodiments, starting on week 12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to 2.5 mg (e.g., about 2.4 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 9 mg to about 11 mg (e.g., about 10 mg), about 19 mg to about 21 mg (e.g., about 20 mg), or about 29 mg to about 31 mg (e.g., about 30 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to 2.5 mg (e.g., about 2.4 mg).

[0239]

[0165] In some embodiments, the methods of the present disclosure comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1 mg to about 3 mg (e.g., about 2 mg), and Aty Ref. METS-036 / 01WO 350242-2269 the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), for about 4 weeks. In some embodiments, on about weeks 4-8 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 3 mg to about 5 mg (e.g., about 4 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), for about 4 weeks. In some embodiments, on about weeks 8-12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 7 mg to about 9 mg (e.g., about 8 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), for about 4 weeks. In some embodiments, starting on week 12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 2.3 mg to 2.5 mg (e.g., about 2.4 mg), or about 3.1 mg to 3.3 mg (e.g., about 3.2 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 9 mg to about 11 mg (e.g., about 10 mg), about 19 mg to about 21 mg (e.g., about 20 mg), or about 29 mg to about 31 mg (e.g., about 30 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 2.3 mg to 2.5 mg (e.g., about 2.4 mg), or about 3.1 mg to 3.3 mg (e.g., about 3.2 mg).

[0240]

[0166] In some embodiments, the methods of the present disclosure comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), Aty Ref. METS-036 / 01WO 350242-2269 and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), for about 4 weeks. In some embodiments, on about weeks 4-8 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.5 mg to about 0.7 mg (e.g., about 0.6 mg), for about 4 weeks. In some embodiments, on about weeks 8-12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 4.7 mg to about 4.9 mg (e.g., about 4.8 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), for about 4 weeks. In some embodiments, starting on week 12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 2.3 mg to 2.5 mg (e.g., about 2.4 mg), or about 3.1 mg to 3.3 mg (e.g., about 3.2 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 9 mg to about 11 mg (e.g., about 10 mg), about 19 mg to about 21 mg (e.g., about 20 mg), or about 29 mg to about 31 mg (e.g., about 30 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 2.3 mg to 2.5 mg (e.g., about 2.4 mg), or about 3.1 mg to 3.3 mg (e.g., about 3.2 mg).

[0241]

[0167] In some embodiments, the methods of the present disclosure comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), Aty Ref. METS-036 / 01WO 350242-2269 and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), for about 4 weeks. In some embodiments, on about weeks 4-8 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), for about 4 weeks. In some embodiments, on about weeks 8-12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 4.7 mg to about 4.9 mg (e.g., about 4.8 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), for about 4 weeks. In some embodiments, starting on week 12 of treatment, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), or about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 2.3 mg to 2.5 mg (e.g., about 2.4 mg), or about 3.1 mg to 3.3 mg (e.g., about 3.2 mg), the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 9 mg to about 11 mg (e.g., about 10 mg), about 19 mg to about 21 mg (e.g., about 20 mg), or about 29 mg to about 31 mg (e.g., about 30 mg), and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 2.3 mg to 2.5 mg (e.g., about 2.4 mg), or about 3.1 mg to 3.3 mg (e.g., about 3.2 mg).

[0242]

[0168] In some embodiments, the methods comprise administration of the combination of three or more of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10) or their pharmaceutically acceptable salts thereof, concurrently (e.g., at or near the same time). In some embodiments, the methods comprise administration of the combination of three or more of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide Aty Ref. METS-036 / 01WO 350242-2269 (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10) or their pharmaceutically acceptable salts sequentially (e.g., at different times). In some embodiments, the methods comprise administration of the combination of three or more of the first peptide (e.g., SEQ ID NO: 3), the second peptide (e.g., SEQ ID NO: 4), the third peptide (e.g., SEQ ID NO: 9), and the fourth peptide (e.g., SEQ ID NO: 10) or their pharmaceutically acceptable salts sequentially at an interval of about 1 hour to about 2 days (e.g., about 1 day).

[0243] Methods of Treatment and Uses

[0244]

[0169] In some embodiments, the present disclosure provides methods of inducing or maintaining weight loss or managing body weight in a subject, wherein the method comprises administering a combination comprising three or more peptides selected from the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is obese, overweight or normal weight. Some embodiments provide a method of inducing or maintaining weight loss or managing body weight in a subject with obesity or with overweight and at least one weight-related comorbidity, wherein the method comprises administering a combination comprising three or more peptides selected from the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof. In some embodiments, the weight- related comorbidity includes hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, Type 2 diabetes (T2DM), or nonalcoholic fatty liver disease (NAFLD). In some embodiments, the comorbid condition is T2DM. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and one or more weight-related comorbid conditions. In some embodiments, the comorbid condition is type 2 diabetes. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and hypertension. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and dyslipidemia. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and low HDL-C. In some embodiments, the subject has a body mass index (BMI) of at least 27 kg / m2and T2DM. Aty Ref. METS-036 / 01WO 350242-2269

[0245]

[0170] Also provided herein are methods of reducing weight and / or preventing weight gain in a subject, the methods comprising administering to the subject an effective amount of (a) a pharmaceutical composition described herein or (b) a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof, as described herein. Further provided herein are methods of treating a disorder (e.g., metabolic disorder, cardiovascular disorder, or neurological disorder), the methods comprising administering to the subject a therapeutically effective amount of (a) a pharmaceutical composition described herein or (b) a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof, as described herein. In the methods described herein, the first and second peptide can be administered concurrently (i.e., in the same or different pharmaceutical compositions) or sequentially (i.e., in different pharmaceutical compositions). In certain embodiments of the methods described herein, the metabolic disorder is selected from obesity, prediabetes, diabetes, non-alcoholic fatty liver disease (NAFLD), and polycystic ovary syndrome (PCOS).

[0246]

[0171] Also provided herein are methods of reducing weight of a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a pharmaceutical composition described herein or (b) a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof, as described herein.

[0247]

[0172] In certain embodiments, the subject has a reduction in weight of about 5% to about 40%. In some embodiments, the subject has a reduction in weight of about 1% to about 5%. In some embodiments, the subject has a reduction in weight of about 5%. In some embodiments, the subject has a reduction in weight of about 10%. In some embodiments, the subject has a reduction in weight of about 15%. In some embodiments, the subject has a reduction in weight of about 20%. In some embodiments, the subject has a reduction in weight of about 25%. In some embodiments, the subject has a reduction in weight of about 30%. In some embodiments, the subject has a reduction in weight of about 35%. In some embodiments, the subject has a reduction in weight of about 40%. In some embodiments, the subject has a reduction in weight of about 40% or more.

[0248]

[0173] Also provided herein are methods of preventing weight gain in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a pharmaceutical composition described herein or (b) a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof, as described herein. Aty Ref. METS-036 / 01WO 350242-2269

[0249]

[0174] Also provided herein are methods of stimulating glucose clearance, stimulating glucose clearance, stimulating insulin release, stimulating carbohydrate metabolism, stimulating lipid metabolism, improving carbohydrate tolerance, reducing appetite, reducing food intake, or reducing caloric intake in a subject in need thereof, the method comprising administering to the subject an effective amount of (a) a pharmaceutical composition described herein or (b) a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof, as described herein.

[0250]

[0175] Also provided herein are methods of treating type 2 diabetes mellitus, reducing the risk of a major cardiovascular event, reducing the risk of eGFR decline or end-stage kidney disease, or treating obstructive sleep apnea, the method comprising administering to the subject an effective amount of (a) a pharmaceutical composition described herein or (b) a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof, as described herein.

[0251]

[0176] As described, in certain embodiments of the methods described herein, (a) the pharmaceutical composition is administered monthly or (b) the first peptide or a pharmaceutically acceptable salt thereof and the second peptide or a pharmaceutically acceptable salt thereof are each administered monthly.

[0252]

[0177] In certain embodiments, a method described herein comprises administering the first peptide or a pharmaceutically acceptable salt thereof and the second peptide or a pharmaceutically acceptable salt thereof.

[0253]

[0178] Also provided herein are (a) pharmaceutical compositions described herein and (b) combinations of (i) a first peptide or a pharmaceutically acceptable salt thereof and (ii) a second peptide or a pharmaceutically acceptable salt thereof, as described herein, for use in any of the methods described herein.

[0254]

[0179] Also provided herein are uses of (a) a pharmaceutical composition described herein or (b) a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof, as described herein, for the manufacture of a medicament for reducing weight and / or preventing weight gain.

[0255]

[0180] Also provided herein are uses of (a) a pharmaceutical composition described herein or (b) a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof, as described herein, for the manufacture of a medicament for the treatment or prevention of a disease (e.g., metabolic disease, cardiovascular disease, and neurological disease).

[0256]

[0181] The term “metabolic disease” or “metabolic disorder” includes any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic Aty Ref. METS-036 / 01WO 350242-2269 acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity. In certain embodiments, the metabolic disorder is a diabetic condition. In certain embodiments, the metabolic disorder is selected from obesity, prediabetes, diabetes, non-alcoholic fatty liver disease (NAFLD), and polycystic ovary syndrome (PCOS).

[0257]

[0182] A “diabetic condition” includes diabetes and pre-diabetes. Diabetes includes a group of metabolic disorders in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). There are several types of diabetes. Type I diabetes results from the body’s failure to produce insulin, and presently requires the person to inject insulin or wear an insulin pump. Type II diabetes results from insulin resistance a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. Gestational diabetes occurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level. Other forms of diabetes include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes, e.g., mature onset diabetes of the young (e.g., MODY 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Pre-diabetes indicates a condition that occurs when a person’s blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes. All forms of diabetes increase the risk of long-term complications. These typically develop after many years but may be the first symptom in those who have otherwise not received a diagnosis before that time. The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease and macrovascular diseases such as ischemic heart disease (angina, myocardial infarction), stroke, and peripheral vascular disease. Diabetes also causes microvascular complications, e.g., damage to the small blood vessels. Diabetic retinopathy, which affects blood vessel formation in the retina of the eye, can lead to visual symptoms, reduced vision, and potentially blindness. Diabetic nephropathy, the impact of diabetes on the kidneys, can lead to scarring changes in the kidney Aty Ref. METS-036 / 01WO 350242-2269 tissue, loss of small or progressively larger amounts of protein in the urine, and eventually chronic kidney disease requiring dialysis. Diabetic neuropathy is the impact of diabetes on the nervous system, most commonly causing numbness, tingling and pain in the feet and also increasing the risk of skin damage due to altered sensation. Together with vascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot problems, e.g., diabetic foot ulcers, that can be difficult to treat and occasionally require amputation.

[0258]

[0183] In certain embodiments, the metabolic disorder is an obesity-related condition or complication thereof. An “obesity-related condition” includes, but is not limited to, obesity, undesired weight gain (e.g., from medication-induced weight gain, from cessation of smoking) and an over-eating disorder (e.g., binge eating, bulimia, compulsive eating, or a lack of appetite control each of which can optionally lead to undesired weight gain or obesity). “Obesity” and “obese” includes class I obesity, class II obesity, class III obesity and pre-obesity (e.g., being “over-weight”) as defined by the World Health Organization.

[0259]

[0184] Reduction of storage fat is expected to provide various primary and / or secondary benefits in a subject (e.g., in a subject diagnosed with a complication associated with obesity) such as, for example, an increased insulin responsiveness (e.g., in a subject diagnosed with Type II diabetes mellitus); a reduction in elevated blood pressure; a reduction in elevated cholesterol levels; and / or a reduction (or a reduced risk or progression) of ischemic heart disease, arterial vascular disease, angina, myocardial infarction, stroke, migraines, congestive heart failure, deep vein thrombosis, pulmonary embolism, gall stones, gastroesophagael reflux disease, obstructive sleep apnea, obesity hypoventilation syndrome, asthma, gout, poor mobility, back pain, erectile dysfunction, urinary incontinence, liver injury (e.g., fatty liver disease, liver cirrhosis, alcoholic cirrhosis, endotoxin mediated liver injury) or chronic renal failure. Thus, the compositions and methods described herein are applicable to these conditions.

[0260]

[0185] In some embodiments, the methods provided herein may be used as next-step treatment following a prior amylin analog and / or a prior GLP-1 receptor agonist and / or a prior GIP analog and / or a prior glucagon analog that the subject has received. In some embodiments, the present disclosure provides methods of inducing or maintaining weight loss or managing body weight in a subject who has received a prior amylin analog and / or a prior GLP-1 receptor agonist and / or a prior GIP analog and / or a prior glucagon analog administered on a daily or weekly basis, comprising a) discontinuing the administration of a prior amylin analog and / or a prior GLP-1 receptor agonist and / or a prior GIP analog and / or a prior glucagon analog; and b) thereafter, initiating the subcutaneous administration of the combination described herein. Examples of prior amylin analogs that the subject may have received include, but are not limited Aty Ref. METS-036 / 01WO 350242-2269 to, Pramlintide, Cagrilintide, and Petrelintide (ZP8396). Examples of prior GLP-1 receptor agonists that the subject may have received include, but are not limited to, Semaglutide, liraglutide, Cagrisema, tirzepatide, amycretin, dulaglutide, retatrutide, mazdutide, exenatide, cotadutide, AZD9550, AMG-133, survodutide, efinopegdutide, pemvidutide, VK-2735, CT- 868, CT-388, utreglutide, dapiglutide, NYL-01, DD-01, vurolenatide, OPK88003, ecnoglutide, GMA102, GMA105, GMA106, efpeglenatide, HM-15211, HM- 15275, noiiglutide, HRS-17031, HRS-9531, DR-10624, SCO-094, HS-20094, AP-026, BI-3006337, supaglutide, HS-20094, GX-G6, GZR-18, BGM-0504, HEC-88473, ZT-002. Examples of prior GIP analogs that the subject may have received include, but are not limited to, Tirzepatide, and Maridebart cafraglutide. Examples of prior glucagon analogs that the subject may have received include, but are not limited to, Dasiglucagon (ZEGALOGUE®), BAQSIMI®, GVOKE®, and GlucaGen®.

[0261] NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0262]

[0186] In addition to the disclosure above, the Examples below, and the appended claims, the disclosure sets forth the following numbered embodiments.

[0263] 1. A method of inducing or maintaining weight loss or managing body weight in a subject, the method comprising administering to the subject an effective amount of a combination comprising three or more peptides selected from:

[0264] (i) a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof;

[0265] (ii) a second peptide comprising the amino acid sequence of F(Aib)EGTFTSDVSKQLEEKRVREFIEWLKQGGPSSGKPPPGKK (SEQ ID NO: 2) or a pharmaceutically acceptable salt thereof, wherein Aib is 2-aminoisobutyric acid;

[0266] (iii) a third peptide comprising the amino acid sequence of Y(Aib)EGTFISDYSKALDKIHQQDFVNWLLAQKGKK (SEQ ID NO: 7) or a pharmaceutically acceptable salt thereof; and

[0267] (iv) a fourth peptide comprising the amino acid sequence of H(Aib)HGTFTSDYSKYLDAKRAQEFIEWLLQSQQHESPPPK (SEQ ID NO: 8) or a pharmaceutically acceptable salt thereof.

[0268] 2. The method of embodiment 1, wherein the first peptide comprises a disulfide bond between the cysteine at position 3 and the cysteine at position 8 of SEQ ID NO: 1. Aty Ref. METS-036 / 01WO 350242-2269

[0269] 3. The method of embodiment 1 or 2, wherein the first peptide or a pharmaceutically acceptable salt thereof further comprises a lipid moiety.

[0270] 4. The method of embodiment 3, wherein the lipid moiety of the first peptide is linked to the alpha nitrogen of the N-terminal lysine of the first peptide.

[0271] 5. The method of any one of embodiments 1-4, wherein the second peptide further comprises a lipid moiety.

[0272] 6. The method of embodiment 5, wherein the lipid moiety of the second peptide is linked to the epsilon nitrogen of the C-terminal lysine of the second peptide.

[0273] 7. The method of any one of the preceding embodiments, wherein the third peptide or a pharmaceutically acceptable salt thereof further comprises a lipid moiety.

[0274] 8. The method of embodiment 7, wherein the lipid moiety of the third peptide or a pharmaceutically acceptable salt thereof is linked to the epsilon nitrogen of the C-terminal lysine of the third peptide.

[0275] 9. The method of any one of the preceding embodiments, wherein the fourth peptide or a pharmaceutically acceptable salt thereof further comprises a lipid moiety.

[0276] 10. The method of embodiment 9, wherein the lipid moiety of the fourth peptide or a pharmaceutically acceptable salt thereof is linked to the epsilon nitrogen of the C-terminal lysine of the fourth peptide.

[0277] 11. The method of any one of embodiments 3-10, wherein the lipid moiety is selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids.

[0278] 12. The method of any one of embodiments 3-11, wherein the lipid moiety is: Atty Ref. METS-036 / 01WO 350242-2269

[0279] 13. The method of any one of the preceding embodiments, wherein the first peptide is:

[0280] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof.

[0281] 14. The method of any one of the preceding embodiments, wherein the second peptide is:

[0282] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0283] 15. The method of any one of the preceding embodiments, wherein the third peptide is:

[0284] (SEQ ID NO: 9), or a pharmaceutically acceptable salt thereof.

[0285] 16. The method of any one of the preceding embodiments, wherein the fourth peptide is: Atty Ref. METS-036 / 01WO 350242-2269

[0286] (SEQ ID NO: 10), or a pharmaceutically acceptable salt thereof.

[0287] 17. A method of inducing or maintaining weight loss or managing body weight in a subject, the method comprising administering to the subject an effective amount of a combination comprising three or more peptides selected from:

[0288] (i) a first peptide comprising the amino acid sequence of

[0289] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof;

[0290] (ii) a second peptide comprising the amino acid sequence of

[0291] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof;

[0292] (iii) a third peptide comprising the amino acid sequence of

[0293] (SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof; and

[0294] (iv) a fourth peptide comprising the amino acid sequence of Atty Ref. METS-036 / 01WO 350242-2269

[0295] (SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof.

[0296] 18. The method of embodiment 17, wherein the combination comprises

[0297] (i) the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0298] (ii) the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0299] (iii) the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof.

[0300] 19. The method of embodiment 18, wherein the combination comprises

[0301] (i) about 1% to about 20% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0302] (ii) about 1% to about 40% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0303] (iii) about 1% to about 90% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0304] 20. The method of embodiment 19, wherein the combination comprises

[0305] (i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0306] (ii) about 7% to about 9% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0307] (iii) about 83% to about 85% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0308] 21. The method of embodiment 20, wherein the combination comprises Aty Ref. METS-036 / 01WO 350242-2269

[0309] (i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0310] (ii) about 8% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0311] (iii) about 84% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0312] 22. The method of embodiment 19, wherein the combination comprises

[0313] (i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0314] (ii) about 14% to about 16% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0315] (iii) about 76% to about 78% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0316] 23. The method of embodiment 22, wherein the combination comprises

[0317] (i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0318] (ii) about 15% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0319] (iii) about 77% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0320] 24. The method of embodiment 19, wherein the combination comprises

[0321] (i) about 10% to about 12% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0322] (ii) about 21% to about 23% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0323] (iii) about 66% to about 68% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole. Atty Ref. METS-036 / 01WO 350242-2269

[0324] 25. The method of embodiment 24, wherein the combination comprises

[0325] (i) about 11% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0326] (ii) about 22% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0327] (iii) about 67% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0328] 26. The method of any one of embodiments 18-25, wherein the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 7.2 mg, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 7.2 mg, and the third peptide (e.g. , SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 30 mg.

[0329] 27. The method of embodiment 17, wherein the combination comprises

[0330] (i) the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0331] (ii) the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0332] (iii) the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof.

[0333] 28. The method of embodiment 26, wherein the combination comprises

[0334] (i) about 1% to about 30% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0335] (ii) about 1% to about 90% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0336] (iii) about 1% to about 30% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0337] 29. The method of embodiment 27, wherein the combination comprises Aty Ref. METS-036 / 01WO 350242-2269

[0338] (i) about 7% to about 9% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0339] (ii) about 83% to about 85% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0340] (iii) about 7% to about 9% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0341] 30. The method of embodiment 28, wherein the combination comprises

[0342] (i) about 8% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0343] (ii) about 84% of the third peptide comprising the amino acid sequence of SEQ ID NO:

[0344] 9 or a pharmaceutically acceptable salt thereof; and

[0345] (iii) about 8% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0346] 31. The method of embodiment 27, wherein the combination comprises

[0347] (i) about 13% to about 15% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0348] (ii) about 71% to about 73% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0349] (iii) about 13% to about 15% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0350] 32. The method of embodiment 30, wherein the combination comprises

[0351] (i) about 14% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0352] (ii) about 72% of the third peptide comprising the amino acid sequence of SEQ ID NO:

[0353] 9 or a pharmaceutically acceptable salt thereof; and

[0354] (iii) about 14% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole. Atty Ref. METS-036 / 01WO 350242-2269

[0355] 33. The method of embodiment 27, wherein the combination comprises

[0356] (i) about 20% to about 22% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0357] (ii) about 62% to about 64% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0358] (iii) about 15% to about 17% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0359] 34. The method of embodiment 32, wherein the combination comprises

[0360] (i) about 21% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0361] (ii) about 63% of the third peptide comprising the amino acid sequence of SEQ ID NO:

[0362] 9 or a pharmaceutically acceptable salt thereof; and

[0363] (iii) about 16% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0364] 35. The method of embodiment 27, wherein the combination comprises

[0365] (i) about 19% to about 21% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0366] (ii) about 59% to about 61% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0367] (iii) about 19% to about 21% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0368] 36. The method of embodiment 34, wherein the combination comprises

[0369] (i) about 20% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0370] (ii) about 60% of the third peptide comprising the amino acid sequence of SEQ ID NO:

[0371] 9 or a pharmaceutically acceptable salt thereof; and

[0372] (iii) about 20% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole. Atty Ref. METS-036 / 01WO 350242-2269

[0373] 37. The method of any one of embodiments 27-36, wherein the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 7.2 mg, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 30 mg, and the fourth peptide e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg to about 5 mg.

[0374] 38. The method of embodiment 17, wherein the combination comprises

[0375] (i) the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0376] (ii) the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0377] (iii) the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0378] (iv) the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof.

[0379] 39. The method of embodiment 36, wherein the combination comprises

[0380] (i) about 1% to about 20% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0381] (ii) about 1% to about 40% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0382] (iii) about 1% to about 90% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0383] (iv) about 1% to about 20% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0384] 40. The method of embodiment 37, wherein the combination comprises

[0385] (i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0386] (ii) about 7% to about 9% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and Aty Ref. METS-036 / 01WO 350242-2269

[0387] (iii) about 75% to about 77% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,

[0388] (iv) about 7% to about 9% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0389] 41. The method of embodiment 38, wherein the combination comprises

[0390] (i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0391] (ii) about 8% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0392] (iii) about 76% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0393] (iv) about 8% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0394] 42. The method of embodiment 37, wherein the combination comprises

[0395] (i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0396] (ii) about 12% to about 14% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0397] (iii) about 66% to about 68% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,

[0398] (iv) about 12% to about 14% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0399] 43. The method of embodiment 40, wherein the combination comprises

[0400] (i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof; Atty Ref. METS-036 / 01WO 350242-2269

[0401] (ii) about 13% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0402] (iii) about 67% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0403] (iv) about 13% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0404] 44. The method of embodiment 37, wherein the combination comprises

[0405] (i) about 9% to about 11% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0406] (ii) about 18% to about 20% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0407] (iii) about 56% to about 58% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,

[0408] (iv) about 13% to about 15% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0409] 45. The method of embodiment 42, wherein the combination comprises

[0410] (i) about 10% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0411] (ii) about 19% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0412] (iii) about 57% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and iv) about 14% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0413] 46. The method of embodiment 37, wherein the combination comprises Aty Ref. METS-036 / 01WO 350242-2269

[0414] (i) about 8% to about 10% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0415] (ii) about 17% to about 19% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0416] (iii) about 54% to about 56% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,

[0417] (iv) about 17% to about 19% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0418] 47. The method of embodiment 44, wherein the combination comprises

[0419] (i) about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0420] (ii) about 18% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0421] (iii) about 55% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and iv) about 18% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0422] 48. The method of any one of embodiments 38-47, wherein the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 7.2 mg, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 7.2 mg, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 30 mg, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg to about 5 mg.

[0423] 49. The method of any one of the preceding embodiments, wherein the three or more peptides are co-formulated in a solution. Aty Ref. METS-036 / 01WO 350242-2269

[0424] 50. The method of any one of the preceding embodiments, wherein the three or more peptides are co-formulated in the same pharmaceutical composition.

[0425] 51. The method of embodiment 50, wherein the three or more peptides are provided in the same container.

[0426] 52. The method of any one of embodiment 49-51, wherein the three or more peptides are co-administered concurrently.

[0427] 53. The method of any one of embodiments 1-48, wherein the three or more peptides are formulated in separate pharmaceutical compositions.

[0428] 54. The method of embodiment 53, wherein the three or more peptides are provided in different containers.

[0429] 55. The method of embodiment 53 or 54, wherein the three or more peptides are administered concurrently or sequentially.

[0430] 56. The method of any one of embodiment 50-52, wherein the three or more peptides are administered sequentially at an interval of about 1 hour to about 2 days.

[0431] 57. The method of embodiment 56, wherein the three or more peptides are administered sequentially at an interval of about Iday.

[0432] 58. The method of any one of the preceding embodiments, wherein the three or more peptides are in solution, lyophilized, or cryopreserved.

[0433] 59. The method of any one of the preceding embodiments, wherein the combination is administered once weekly.

[0434] 60. The method of embodiment 59, wherein the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, followed by a weekly maintenance dose. Atty Ref. METS-036 / 01WO 350242-2269

[0435] 61. The method of any one of embodiments 1-58, wherein the combination is administered once monthly.

[0436] 62. The method of embodiment 61, wherein the combination is administered once monthly for about 2 to about 16 months, wherein the amount of one or more peptides is increased over about 2 to about 4 monthly escalations, and wherein each increased dose level is maintained for about 2 months to about 4 months prior to a subsequent increase, followed by a monthly maintenance dose.

[0437] 63. The method of any one of embodiments 1-58, wherein the combination is administered weekly for an initial period and then transitioned to monthly administration.

[0438] 64. The method of embodiment 63, wherein the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, followed by administering the combination once monthly thereafter.

[0439] 65. The method of any one of embodiments 60-64, wherein each increased weekly or monthly dose is about 1.5 fold to about 4 fold of an immediately preceding dose.

[0440] 66. The method of embodiment 65, wherein each increased weekly or monthly dose is 1.5 fold of an immediately preceding dose.

[0441] 67. The method of embodiment 65, wherein each increased weekly or monthly dose is about 2 fold of an immediately preceding dose.

[0442] 68. The method of embodiment 65, wherein each increased weekly or monthly dose is about 3 fold of an immediately preceding dose.

[0443] 69. The method of embodiment 65, wherein each increased weekly or monthly dose is about 4 fold of an immediately preceding dose. Aty Ref. METS-036 / 01WO 350242-2269

[0444] 70. The method of any one of embodiments 1-58, wherein the combination is administered once weekly for an initial period of about 2 to about 16 weeks at a constant amount, and then is administered once monthly at a constant maintenance dose.

[0445] 71. The method of embodiment 70, wherein the monthly dose is about 2 fold to about 4 fold of the weekly dose.

[0446] 72. The method of any one of the preceding embodiments, wherein the subject the subject has obesity or is overweight.

[0447] 73. The method of any one of the preceding embodiments, wherein the subject has a body mass index (BMI) of at least 27 kg / m2.

[0448] 74. The method of embodiment 72 or 73, wherein the subject has a weight-related comorbid condition.

[0449] 75. The method of embodiment 74, wherein the weight-related comorbid condition is hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, Type 2 diabetes (T2DM), or nonalcoholic fatty liver disease (NAFLD).

[0450] 76. The method of embodiment 75, wherein the weight-related comorbid condition is T2DM.

[0451] 77. The method of any one of the preceding embodiments, wherein the subject has a metabolic disorder.

[0452] 78. The method of embodiment 77, wherein the metabolic disorder is selected from obesity, prediabetes, diabetes, non-alcoholic fatty liver disease (NAFLD), and polycystic ovary syndrome (PCOS).

[0453] 79. The method of any one of the preceding embodiments, wherein the administration is subcutaneous. Atty Ref. METS-036 / 01WO 350242-2269

[0454] Additional Embodiments

[0455]

[0187] Additional embodiments of the disclosure are encompassed by the following numbered embodiments:

[0456] 1. A combination comprising three or more peptides selected from:

[0457] (i) a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof;

[0458] (ii) a second peptide comprising the amino acid sequence of F(Aib)EGTFTSDVSKQLEEKRVREFIEWLKQGGPSSGKPPPGKK (SEQ ID NO: 2) or a pharmaceutically acceptable salt thereof, wherein Aib is 2-aminoisobutyric acid;

[0459] (iii) a third peptide comprising the amino acid sequence of Y(Aib)EGTFISDYSKALDKIHQQDFVNWLLAQKGKK (SEQ ID NO: 7) or a pharmaceutically acceptable salt thereof; and

[0460] (iv) a fourth peptide comprising the amino acid sequence of H(Aib)HGTFTSDYSKYLDAKRAQEFIEWLLQSQQHESPPPK (SEQ ID NO: 8) or a pharmaceutically acceptable salt thereof.

[0461] 2. The combination of embodiment 1, wherein the first peptide comprises a disulfide bond between the cysteine at position 3 and the cysteine at position 8 of SEQ ID NO: 1.

[0462] 3. The combination of embodiment 1 or 2, wherein the first peptide or a pharmaceutically acceptable salt thereof further comprises a lipid moiety.

[0463] 4. The combination of embodiment 3, wherein the lipid moiety of the first peptide is linked to the alpha nitrogen of the N-terminal lysine of the first peptide.

[0464] 5. The combination of any one of embodiments 1-4, wherein the second peptide further comprises a lipid moiety.

[0465] 6. The combination of embodiment 5, wherein the lipid moiety of the second peptide is linked to the epsilon nitrogen of the C-terminal lysine of the second peptide.

[0466] 7. The combination of any one of the preceding embodiments, wherein the third peptide or a pharmaceutically acceptable salt thereof further comprises a lipid moiety. Atty Ref. METS-036 / 01WO 350242-2269

[0467] 8. The combination of embodiment 7, wherein the lipid moiety of the third peptide or a pharmaceutically acceptable salt thereof is linked to the epsilon nitrogen of the C-terminal lysine of the third peptide.

[0468] 9. The combination of any one of the preceding embodiments, wherein the fourth peptide or a pharmaceutically acceptable salt thereof further comprises a lipid moiety.

[0469] 10. The combination of embodiment 9, wherein the lipid moiety of the fourth peptide or a pharmaceutically acceptable salt thereof is linked to the epsilon nitrogen of the C-terminal lysine of the fourth peptide.

[0470] 11. The combination of any one of embodiments 3-10, wherein the lipid moiety is selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids.

[0471] 12. The combination of any one of embodiments 3-11, wherein the lipid moiety is:

[0472] 13. The combination of any one of the preceding embodiments, wherein the first peptide is:

[0473] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof.

[0474] 14. The combination of any one of the preceding embodiments, wherein the second peptide is: Atty Ref. METS-036 / 01WO 350242-2269

[0475] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0476] 15. The combination of any one of the preceding embodiments, wherein the third peptide is:

[0477] (SEQ ID NO: 9), or a pharmaceutically acceptable salt thereof.

[0478] 16. The combination of any one of the preceding embodiments, wherein the fourth peptide is:

[0479] (SEQ ID NO: 10), or a pharmaceutically acceptable salt thereof.

[0480] 17. A combination comprising three or more peptides selected from:

[0481] (i) a first peptide comprising the amino acid sequence of Atty Ref. METS-036 / 01WO 350242-2269

[0482] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof;

[0483] (ii) a second peptide comprising the amino acid sequence of

[0484] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof;

[0485] (iii) a third peptide comprising the amino acid sequence of

[0486] (SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof; and

[0487] (iv) a fourth peptide comprising the amino acid sequence of

[0488] (SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof.

[0489] 18. The combination of embodiment 17, wherein the combination comprises

[0490] (i) the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof; Aty Ref. METS-036 / 01WO 350242-2269

[0491] (ii) the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0492] (iii) the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof.

[0493] 19. The combination of embodiment 18, wherein the combination comprises

[0494] (i) about 1% to about 20% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0495] (ii) about 1% to about 40% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0496] (iii) about 1% to about 90% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0497] 20. The combination of embodiment 19, wherein the combination comprises

[0498] (i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0499] (ii) about 7% to about 9% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0500] (iii) about 83% to about 85% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0501] 21. The combination of embodiment 20, wherein the combination comprises

[0502] (i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0503] (ii) about 8% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0504] (iii) about 84% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0505] 22. The combination of embodiment 19, wherein the combination comprises

[0506] (i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof; Aty Ref. METS-036 / 01WO 350242-2269

[0507] (ii) about 14% to about 16% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0508] (iii) about 76% to about 78% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0509] 23. The combination of embodiment 22, wherein the combination comprises

[0510] (i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0511] (ii) about 15% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0512] (iii) about 77% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0513] 24. The combination of embodiment 19, wherein the combination comprises

[0514] (i) about 10% to about 12% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0515] (ii) about 21% to about 23% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0516] (iii) about 66% to about 68% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0517] 25. The combination of embodiment 24, wherein the combination comprises

[0518] (i) about 11% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0519] (ii) about 22% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0520] (iii) about 67% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

[0521] 26. The combination of any one of embodiments 18-25, wherein the combination comprises about 0.1 mg to about 7.2 mg of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically Aty Ref. METS-036 / 01WO 350242-2269 acceptable salt thereof of, about 0.1 mg to about 7.2 mg of the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof of, and about 1 mg to about 30 mg of the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof.

[0522] 27. The combination of embodiment 17, wherein the combination comprises

[0523] (i) the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0524] (ii) the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0525] (iii) the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof.

[0526] 28. The combination of embodiment 26, wherein the combination comprises

[0527] (i) about 1% to about 30% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0528] (ii) about 1% to about 90% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0529] (iii) about 1% to about 30% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0530] 29. The combination of embodiment 27, wherein the combination comprises

[0531] (i) about 7% to about 9% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0532] (ii) about 83% to about 85% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0533] (iii) about 7% to about 9% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0534] 30. The combination of embodiment 28, wherein the combination comprises

[0535] (i) about 8% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0536] (ii) about 84% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and Aty Ref. METS-036 / 01WO 350242-2269

[0537] (iii) about 8% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0538] 31. The combination of embodiment 27, wherein the combination comprises

[0539] (i) about 13% to about 15% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0540] (ii) about 71% to about 73% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0541] (iii) about 13% to about 15% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0542] 32. The combination of embodiment 30, wherein the combination comprises

[0543] (i) about 14% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0544] (ii) about 72% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0545] (iii) about 14% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0546] 33. The combination of embodiment 27, wherein the combination comprises

[0547] (i) about 20% to about 22% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0548] (ii) about 62% to about 64% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0549] (iii) about 15% to about 17% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0550] 34. The combination of embodiment 32, wherein the combination comprises

[0551] (i) about 21% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; Aty Ref. METS-036 / 01WO 350242-2269

[0552] (ii) about 63% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0553] (iii) about 16% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0554] 35. The combination of embodiment 27, wherein the combination comprises

[0555] (i) about 19% to about 21% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0556] (ii) about 59% to about 61% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0557] (iii) about 19% to about 21% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0558] 36. The combination of embodiment 34, wherein the combination comprises

[0559] (i) about 20% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0560] (ii) about 60% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0561] (iii) about 20% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

[0562] 37. The combination of any one of embodiments 27-36, wherein the combination comprises about 0.1 mg to about 7.2 mg of the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, about 1 mg to about 30 mg of the third peptide (e.g, SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and about 0.5 mg to about 5 mg of the fourth peptide (e.g, SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof.

[0563] 38. The combination of embodiment 17, wherein the combination comprises

[0564] (i) the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0565] (ii) the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; Aty Ref. METS-036 / 01WO 350242-2269

[0566] (iii) the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0567] (iv) the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof.

[0568] 39. The combination of embodiment 36, wherein the combination comprises

[0569] (i) about 1% to about 20% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0570] (ii) about 1% to about 40% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0571] (iii) about 1% to about 90% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0572] (iv) about 1% to about 20% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0573] 40. The combination of embodiment 37, wherein the combination comprises

[0574] (i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0575] (ii) about 7% to about 9% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0576] (iii) about 75% to about 77% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,

[0577] (iv) about 7% to about 9% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0578] 41. The combination of embodiment 38, wherein the combination comprises

[0579] (i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0580] (ii) about 8% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; Aty Ref. METS-036 / 01WO 350242-2269

[0581] (iii) about 76% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0582] (iv) about 8% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0583] 42. The combination of embodiment 37, wherein the combination comprises

[0584] (i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0585] (ii) about 12% to about 14% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0586] (iii) about 66% to about 68% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,

[0587] (iv) about 12% to about 14% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0588] 43. The combination of embodiment 40, wherein the combination comprises

[0589] (i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0590] (ii) about 13% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0591] (iii) about 67% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and

[0592] (iv) about 13% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0593] 44. The combination of embodiment 37, wherein the combination comprises

[0594] (i) about 9% to about 11% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof; Atty Ref. METS-036 / 01WO 350242-2269

[0595] (ii) about 18% to about 20% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0596] (iii) about 56% to about 58% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,

[0597] (iv) about 13% to about 15% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0598] 45. The combination of embodiment 42, wherein the combination comprises

[0599] (i) about 10% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0600] (ii) about 19% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0601] (iii) about 57% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and iv) about 14% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0602] 46. The combination of embodiment 37, wherein the combination comprises

[0603] (i) about 8% to about 10% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0604] (ii) about 17% to about 19% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and

[0605] (iii) about 54% to about 56% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,

[0606] (iv) about 17% to about 19% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0607] 47. The combination of embodiment 44, wherein the combination comprises Aty Ref. METS-036 / 01WO 350242-2269

[0608] (i) about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;

[0609] (ii) about 18% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;

[0610] (iii) about 55% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and iv) about 18% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

[0611] 48. The combination of any one of embodiments 38-47, wherein the combination comprises about 0.1 mg to about 7.2 mg of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, about 0.1 mg to about 7.2 mg of the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, about 1 mg to about 30 mg of the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof, and about 0.5 mg to about 5 mg of the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof.

[0612] 49. The combination of any one of the preceding embodiments, wherein the three or more peptides are co-formulated in a solution.

[0613] 50. The combination of any one of the preceding embodiments, wherein the three or more peptides are co-formulated in the same pharmaceutical composition.

[0614] 51. The combination of embodiment 50, wherein the three or more peptides are provided in the same container.

[0615] 52. The combination of any one of embodiment 49-51, wherein the three or more peptides are co-administered concurrently.

[0616] 53. The combination of any one of embodiments 1-48, wherein the three or more peptides are formulated in separate pharmaceutical compositions.

[0617] 54. The combination of embodiment 53, wherein the three or more peptides are provided in different containers. Atty Ref. METS-036 / 01WO 350242-2269

[0618] 55. The combination of embodiment 53 or 54, wherein the three or more peptides are administered concurrently or sequentially.

[0619] EXAMPLES

[0620]

[0188] In order that the present disclosure may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the peptides, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope.

[0621] Example 1: Efficacy of Two-, Three-, and Four-way Combinations in Rats

[0622]

[0189] Husbandry. 11 -week-old male Sprague Dawley rats (Charles River, UK) were housed in individually ventilated cages (Tecniplast, UK), identified by cage number. Cages had wood shavings (Datesand, UK) for bedding, and 30 mm Aspen balls (LBS, UK) and cardboard Play Tunnels (LBS, UK) for enrichment. Ad libitum access to standard chow diet (Tekland Global 2014X; Inotiv, UK) and water was provided throughout, and the room was maintained at 21-23 °C with a normal 12: 12 hour light cycle (on at 07:00). Animals were allocated to treatment groups randomly and stratified by body weight, such that the average body weight of each group was ± 5g (average starting body weight, 282g; IQR, 265-296g).

[0623]

[0190] Study Schedule-. SC injections of vehicle, SEQ ID NO: 4, M2 (SEQ ID NO: 4 + SEQ ID NO: 3), M3 (SEQ ID NO: 4 + SEQ ID NO: 3 + SEQ ID NO: 9), or M4 (SEQ ID NO: 4 + SEQ ID NO: 3 + SEQ ID NO: 9 + SEQ ID NO: 10) (n=6-7 / group) were administered three times per week from Day 0 to 18 using 31G x 5mm BD Micro-Fine Insulin Syringes (Medisave, UK). Treatments were prepared using 0.02% polysorbate 80 (Merck, UK) in PBS, pH7.2 (Thermofisher, UK) (v / v) to the target concentrations with body weight adjusted injection volumes of 30-70 pL. Body weight and food intake was measured at the time of dosing and on Day 21. All treatments were dose titrated on Days 7 and 14 by a 2-fold increase, with treatment doses for individual components - SEQ ID NO: 4 + SEQ ID NO: 3 + SEQ ID NO: 9 + SEQ ID NO: 10 - initiated at 0.5, 0.5, 5, 2.5 nmol / kg, respectively. The dose of SEQ ID NO: 10 was reduced on Day 4 to 0.5 nmol / kg (from 2.5 nmol / kg), such that the SEQ ID NO:4 to SEQ ID NO: 10 ratio in all treatment groups was 1 : 1 (instead of 1 :5) for all subsequent injections.

[0624]

[0191] Data-. Data was analysed and presented as mean ± SEM using GraphPad Prism v 10.0.0 for Windows (GraphPad, USA). Body weight change data is presented as a percentage change from baseline (Day 0), normalised to the body weight change of the vehicle group. Atty Ref. METS-036 / 01WO 350242-2269

[0625]

[0192] Results: FIG. 1 shows efficacy of two-, three-, and four-way combinations in effecting weight loss in rats. Combinations of SEQ ID NO: 4, SEQ ID NO: 3, SEQ ID NO: 9, and SEQ ID NO: 10 led to significant body weight reduction in mice compared to monotherapy.

[0626] Example 2: Pharmacokinetics in Minipigs

[0627]

[0193] For each peptide (2 mg), the following ratio of diluent [0.02% (w / v) Polysorbate 80 (PS 80) in 0.9% w / v Sodium Chloride] to IM HC1 should be used to form homogeneous stock solutions (2 mg / mL) of each peptide (Table 1).

[0628] Table 1. Stock solutions for Example 2

[0629]

[0194] Formulation steps: (1) Prepared required volume of each diluent according to table above; (2) Reconstituted each peptide in the required volume of its own buffer i.e. SEQ ID NO: 9 in Diluent A; (3) Mixed reconstituted peptide solutions in a ratio of 1 : 1 : 1 : 1, combining SEQ ID NO: 9 and SEQ ID NO: 10 first before adding SEQ ID NO: 3 and SEQ ID NO: 4. After the four stock solutions are combined, the concentration of each TA will be 0.5 mg / mL.

[0630]

[0195] Animal Specifications

[0631] Species Barna Miniature Swine

[0632] History of Dosing Naive animals

[0633] Body Weight Range 7~17kg

[0634] Age > 3 months

[0635] Sex Male

[0636] Number of Animals for Acclimation 6 males

[0637] Number of Animals for Dosing 4 males

[0638]

[0196] Animal Care

[0639]

[0197] Environmental Conditions: The room(s) were controlled and monitored for relative humidity (targeted mean range 40% to 70%, and any excursion from this range for more than 3 hours will be documented as a deviation) and temperature (targeted mean range 18° to 26°C, and any excursion from this range will be documented as a deviation) with no less than 10 air Aty Ref. METS-036 / 01WO 350242-2269 changes / hour. The room was on a 12-hour light / dark cycle except when interruptions are necessitated by study activities.

[0640]

[0198] Housing: Animals were individually housed in stainless-steel mesh cages during in-life. Animals are in fasted condition for each dosing: minipigs will be fasted overnight, then food will be provided 4 hour after dosing.

[0641]

[0199] Drinking Water: RO (reverses osmosis) water is available to all animals, ad libitum.

[0642]

[0200] Administration of Dose Formulation

[0643] Administration Route: Subcutaneous

[0644] Dose Administration: Subcutaneous (SC): The SC dose is administered to the back of the neck via subcutaneous injection

[0645]

[0201] Pharmacokinetics in Male Barna Minipigs

[0646]

[0202] The pharmacokinetics of example compounds were evaluated following single subcutaneous administration of 50 pg / kg to male Barna minipigs. Blood samples were collected over 264 hours and resulting individual plasma concentrations were used to calculate standard pharmacokinetic parameters. Plasma concentrations are shown in FIG. 2. Mean pharmacokinetic parameters are shown in Table 2.

[0647] Table 2. Mean pharmacokinetic parameters

[0648] Example 3: Combination Therapies Single Dose Study in Mice

[0649]

[0203] The study aimed to demonstrate the acute effects of the combined therapies on food intake (FI) and body weight (BW) compared to the individual therapies.

[0650]

[0204] Single subcutaneous (SC) injections of vehicle, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 14, M2 (SEQ ID NO: 4 + SEQ ID NO: 3), M3 (SEQ ID NO: 4 + SEQ ID NO: 3 + SEQ ID NO: 9), and M4 (SEQ ID NO: 4 + SEQ ID NO: 3 + SEQ Aty Ref. METS-036 / 01WO 350242-2269

[0651] ID NO: 9 + SEQ ID NO: 10) (n=6 / group) were administered to C57BL6 / J male mice. Food intake and body weight were measured on day 0, 1, 2, and 3. Table 3 provides detailed dosing for each treatment group.

[0652] Table 3. Dose for each treatment group for Example 3

[0653]

[0205] FIG. 3A illustrates cumulative food intake over a 3 -day study period, and FIG. 3B illustrates the corresponding change in body weight during the same period.

[0654] Example 4: Combination Therapies Repeated Dose Study in Mice

[0655]

[0206] The study aimed to demonstrate the acute effects of the combined therapies on food intake (FI) and body weight (BW) compared to the individual therapies.

[0656]

[0207] Repeated daily subcutaneous (SC) injections of vehicle, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 14, M2 (SEQ ID NO: 4 + SEQ ID NO: 3), M3 (SEQ ID NO: 4 + SEQ ID NO: 3 + SEQ ID NO: 9), and M4 (SEQ ID NO: 4 + SEQ ID NO: 3 + SEQ ID NO: 9 + SEQ ID NO: 10) (n=6 / group) were administered to C57BL6 / J male mice on day 0, 1, 2 and 3. Food intake and body weight were measured concurrently on the same day. Table 4 provides detailed dosing for each treatment group.

[0657] Table 4. Dose for each treatment group for Example 4 Atty Ref. METS-036 / 01WO 350242-2269

[0658]

[0208] FIG. 4A illustrates cumulative food intake over a 3 -day study period, and FIG. 4B illustrates the corresponding change in body weight during the same period.

[0659] Example 5: Combination Therapies Repeated Dose Study in Rats

[0660]

[0209] These studies aimed to demonstrate the effects of the combined therapies on food intake (FI) and body weight (BW) compared to Retatrutide (RET) alone or RET and KBP-336 combination (Ret + KBP-336).

[0661]

[0210] Repeated subcutaneous (SC) injections of vehicle, SEQ ID NO: 4, RET, RET + KBP-336, M2 (SEQ ID NO: 4 + SEQ ID NO: 3), M3 (SEQ ID NO: 4 + SEQ ID NO: 9 + SEQ ID NO: 10), and M4 (SEQ ID NO: 4 + SEQ ID NO: 3 + SEQ ID NO: 9 + SEQ ID NO: 10) (n=7 / group) were administered to Sprague Dawley male rats three days a week (i.e., on Monday, Wednesday and Friday (MWF)) on Day 0, 3, 5, 7, 9, 11, 14, 16, 18, 21, 23, and 25). Dose for each treatment group was doubled on day 7 and afterward. Food intake and body weight were measured concurrently on the same day. Table 5 provides detailed dosing for each treatment group.

[0662] Table 5. Dose for each treatment group for Example 5 Atty Ref. METS-036 / 01WO 350242-2269

[0663]

[0211] FIG. 5A illustrates cumulative food intake over a 25-day study period, and FIG. 5B illustrates the corresponding change in body weight during the same period.

[0664]

[0212] FIG. 6A illustrates the change in body weight for each treatment group on Day 23 and FIG. 6B illustrates the fasted plasma glucose levels for each treatment group on Day 24. No deterioration of glucose relative to vehicle was observed when treated with M3 or M4.

[0665]

[0213] FIG. 7A and FIG. 7B show that weight loss for treatment group M3 was similar to weight loss for group M2, despite greater food intake in M3; weight loss for group M4 was greater than M2, even though food intake was similar. Together, these data demonstrate the enhanced energy expenditure contributes to SEQ ID NO: 10-mediated weight loss.

[0666]

[0214] FIGS. 8A-8D show that M3 and M4 at equimolar doses to RET alone or with KBP-336, respectively, exhibited increased BWL and decreased food.

[0667]

[0215] These studies illustrate that activation of multiple NuSH pathways leads to incremental increases in body weight loss (BWL) relative to approaches targeting a single pathway. Incorporation of SEQ ID NO: 10, a glucagon analog, resulted in incremental BWL without reducing food intake and without adverse effects on blood glucose at equimolar concentrations. Utilizing multiple combinations provide greater flexibility to balance engagement of individual NuSH pathways compared to unimolecular agonists, thereby potentially improving efficacy, tolerability, and safety.

[0668]

[0216] Three future studies will be conducted to evaluate improved efficacy using optimized ratios.

[0669]

[0217] In future study 1, dosing schedule will be changed from WF (Monday -Wednesday -Friday) to every other day (EoD). The starting doses for SEQ ID NO: 4 and SEQ ID NO: 10 will be doubled from 0.5 nmol / kg to 1 nmol / kg. The starting dose for SEQ ID NO: 3 will be unchanged but the ratio of SEQ ID NO: 3 to SEQ ID NO: 4 will be changed from 1 : 1 to 0.5 : 1. The starting dose for SEQ ID NO: 9 will be unchanged but the ratio of SEQ ID NO: 9 to SEQ ID NO: 4 will be changed from 10: 1 to 5: 1. Table 6 provides detailed dosing for each treatment group over the study period.

[0670] Table 6. Dosing details for each treatment group in future study 1 Atty Ref. METS-036 / 01WO 350242-2269

[0671]

[0218] In future study 2, dosing schedule will be changed from WF (Monday -Wednesday -Friday) to every other day (EoD). The starting doses for SEQ ID NO: 4 and SEQ ID NO: 10 will be increased from 0.5 nmol / kg to 1 nmol / kg (x2) or 0.75 nmol / kg (xl.5). The starting dose for SEQ ID NO: 3 will be unchanged but the ratio of SEQ ID NO: 3 to SEQ ID NO: 4 will be changed from 1 : 1 to 0.5: 1. The starting dose for SEQ ID NO: 9 will be unchanged but the ratio of SEQ ID NO: 9 to SEQ ID NO: 4 will be changed from 10: 1 to 5: 1. Table 7 provides detailed dosing for each treatment group over the study period.

[0672] Table 7. Dosing details for each treatment group in future study 2

[0673]

[0219] In future study 3, the starting doses for SEQ ID NO: 4 and SEQ ID NO: 10 will be increased from 0.5 nmol / kg to 1 nmol / kg (x2). The starting dose for SEQ ID NO: 3 will be unchanged but the ratio of SEQ ID NO: 3 to SEQ ID NO: 4 will be changed from 1 : 1 to 0.5: 1. Atty Ref. METS-036 / 01WO 350242-2269

[0674] The starting dose for SEQ ID NO: 9 will be unchanged but the ratio of SEQ ID NO: 9 to SEQ ID NO: 4 will be changed from 10:1 to 5: 1. Table 8 provides detailed dosing for each treatment group over the study period.

[0675] Table 8. Dosing details for each treatment group in future study 2

[0676] Experiment 6: Clinical study

[0677]

[0220] This is a randomized, placebo-controlled, double-blind, double-dummy, dose-ranging study to investigate the safety and efficacy of the combination of three or more peptides selected from SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 9 and SEQ ID NO: 10 co administered by subcutaneous (SC) injection in once-weekly (QW), once-monthly (QM), QW to QM dose regimens described herein, compared with the amylin analog (SEQ ID NO: 3), the GLP-1 receptor agonist (SEQ ID NO: 4), the GIP analog (SEQ ID NO: 9), and the glucagon analog (SEQ ID NO: 10) monotherapies and placebo.

[0678]

[0221] Participants will be randomized to the following treatment groups: M3 A (SEQ ID NO: 3 + SEQ ID NO: 4 + SEQ ID NO: 9), M3B (SEQ ID NO: 4 + SEQ ID NO: 9 + SEQ ID NO: 10), M4 (SEQ ID NO: 3 + SEQ ID NO: 4 + SEQ ID NO: 9+ SEQ ID NO: 10), SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 9 and SEQ ID NO: 10 monotherapies, or placebo. The ratios used for the combination in the M3 A, M3B and M4 treatment groups are any of the ratios described herein. The combinations are administered to the patients according to any of the dosing regimens described herein. Aty Ref. METS-036 / 01WO 350242-2269

[0679]

[0222] The trial population includes adults who have obesity (BMI >30.0 kg / m2 to <50.0 kg / m2) or overweight (BMI >27.0 kg / m2 to <30.0 kg / m2) with >1 weight-related comorbid condition. The weight-related comorbid condition includes: (1) Hypertension, defined as being on blood pressure-lowering medication or having systolic BP >130 mmHg or diastolic BP >80 mmHg at Screening; (2) Dyslipidemia, defined as being on lipid-lowering medication or having LDL-C >160 mg / dL (4.1 mmol / L) or triglycerides >150 mg / dL (1.7 mmol / L), orLow HDL-C, defined as <40 mg / dL (1.0 mmol / L) for men or <50 mg / dL (1.3 mmol / L) for women; or (3) clinical diagnosis of obstructive sleep apnea. Participants must also have stable body weight, defined as a selfreported change (gain or loss) of <5 kg within the 3 months prior to Screening.

[0680]

[0223] The primary endpoint includes percent change from baseline in body weight at 32 weeks of treatment in participants with obesity in the BMI range of >33.0 to <50.0 kg / m2 (Sub-population A).

[0681]

[0224] The secondary endpoints include: occurrence of achievement of a BMI <25.0 in Subpopulation A (obese with BMI of >33 to <50 kg / m2) and the Full population (overweight and obese, with BMI of 27 to 50 kg / m2); percent change from baseline in body weight, BMI and waist circumference at 32 and 60 weeks; occurrence of body weight reduction (weight loss) from baseline at 32 and 60 weeks that is >5%, >10%, >15%; occurrence, severity, and relatedness of TEAEs and AECIs (GI TEAEs of nausea, vomiting, diarrhea); occurrence of abnormal clinically significant physical examination; systolic BP as measured in mmHg; 12-lead EGG measurements; laboratory measurements; Columbia-Suicide Severity Rating Scale (C-SSRS); Patient Health Questionnaire (PHQ-9); Occurrence of anti-drug antibodies (ADAs); PK parameters including minimum observed concentration (Cmin), area under the concentration versus time curve during the dosing interval (AU O-T)), maximum observed concentration (Cmax), and time to maximum concentration (tmax).

[0682]

[0225] To evaluate glucose metabolism parameters, markers of insulin sensitivity, and markers of inflammation and / or metabolic syndrome in participants treated with the combination therapy in Sub-population A and the Full population, the exploratory endpoints include: changes from baseline in HbAlc, fasting glucose (mg / dL), fasting insulin (pmol / L), fasting C-peptide, fasting glucagon, hsCRP, triglycerides (mg / dL), HDL-C (mg / dL), LDL-C (mg / dL), VLDL-C (calculated), HOMA-IR (calculated), and diastolic BP (mmHg).

[0683]

[0226] To evaluate the impact of the combination therapy on qualitative measures of satiety, hunger / appetite, quality of life, and food-mediated cognitive distraction at all protocol-specified timepoints, the exploratory endpoints include: change from baseline in the total scores from the following PRO scale: short form-36 health survey (SF-36), 3-factor eating questionnaire revised 18-item version 2 (TFEQ-R18V2), food noise questionnaire (FNQ). Aty Ref. METS-036 / 01WO 350242-2269

[0684]

[0227] To evaluate the efficacy of the combination therapies on glycermic control, prevention of prediabetes, prevention of T2DM, remission of prediabetes, use of medication for hypertension and dyslipidemia, other cardiovascular risk factors, and physical performance in participants in Sub-population A and the Full population, the exploratory endpoints include: time to HbAlC<5.7% for participants with prediabetes (defined as HbAlC>5.7%) at baseline; achievement of HbAlC<5.7% for participants with prediabetes (defined as HbAlC>5.7%) at baseline; development of HbAlC>5.7% for participants with normoglycemia (defined as HbAlC<5.7%) at baseline; development of HbAlC>6.5% for participants with normoglycemia (defined as HbAlC<5.7%) at baseline; change in ACC / AHA 10-year ASCVD risk score; change in intensity of antihypertensive medication (decrease / no increase); change in intensity of lipid- lowering medication (decrease / no increase); and change in sit-to-stand test.

[0685]

[0228] To evaluate the feasibility and acceptability of the Waveband (Dreem 3S) and Sleep View technology for at home evaluation of OSA at protocol-specified timepoints in the OSA sub-study subset, the exploratory endpoints include: discontinuation rate of Waveband (Dreem 3S) and Sleep View; within-participant variability of OSA-related measures; estimation of effect size in participants with moderate to severe baseline AHI scores, assessing the impact of active study treatment; prevalence of mild, moderate, and severe OSA; and prevalence of other sleep disorders, as detectable by Waveband (Dreem 3S) and Sleep View device.

[0686]

[0229] To characterize the immunogenicity to the combination therapies co-administered in participants in the Full population, the exploratory endpoint includes immunogenicity assessments of titer, incidence of predose ADAs, and postdose treatment-enhanced or treatment-emergent AD As.

[0687]

[0230] To assess the effect of the combination therapies on additional safety measures compared to placebo at all protocol specified timepoints, the exploratory endpoint includes change from baseline biomarkers of malnutrition at all protocol-specified timepoint in serum albumin, transthyretin [pre-albumin], and micronutrients

[0688] EQUIVALENTS AND SCOPE

[0689]

[0231] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes Aty Ref. METS-036 / 01WO 350242-2269 embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0690]

[0232] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0691]

[0233] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0692]

[0234] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

1. Atty Ref. METS-036 / 01WO 350242-2269CLAIMSWhat is claimed is:

1. A method of inducing or maintaining weight loss or managing body weight in a subject, the method comprising administering to the subject an effective amount of a combination comprising three or more peptides selected from:(i) a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof;(ii) a second peptide comprising the amino acid sequence of F(Aib)EGTFTSDVSKQLEEKRVREFIEWLKQGGPSSGKPPPGKK (SEQ ID NO: 2) or a pharmaceutically acceptable salt thereof, wherein Aib is 2-aminoisobutyric acid;(iii) a third peptide comprising the amino acid sequence ofY(Aib)EGTFISDYSKALDKIHQQDFVNWLLAQKGKK (SEQ ID NO: 7) or a pharmaceutically acceptable salt thereof; and(iv) a fourth peptide comprising the amino acid sequence of H(Aib)HGTFTSDYSKYLDAKRAQEFIEWLLQSQQHESPPPK (SEQ ID NO: 8) or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the first peptide comprises a disulfide bond between the cysteine at position 3 and the cysteine at position 8 of SEQ ID NO: 1.

3. The method of claim 1 or 2, wherein the first peptide or a pharmaceutically acceptable salt thereof further comprises a lipid moiety.

4. The method of claim 3, wherein the lipid moiety of the first peptide is linked to the alpha nitrogen of the N-terminal lysine of the first peptide.

5. The method of any one of claims 1-4, wherein the second peptide further comprises a lipid moiety.

6. The method of claim 5, wherein the lipid moiety of the second peptide is linked to the epsilon nitrogen of the C-terminal lysine of the second peptide.

7. The method of any one of the preceding claims, wherein the third peptide or a pharmaceutically acceptable salt thereof further comprises a lipid moiety.Atty Ref. METS-036 / 01WO 350242-22698. The method of claim 7, wherein the lipid moiety of the third peptide or a pharmaceutically acceptable salt thereof is linked to the epsilon nitrogen of the C-terminal lysine of the third peptide.

9. The method of any one of the preceding claims, wherein the fourth peptide or a pharmaceutically acceptable salt thereof further comprises a lipid moiety.

10. The method of claim 9, wherein the lipid moiety of the fourth peptide or a pharmaceutically acceptable salt thereof is linked to the epsilon nitrogen of the C-terminal lysine of the fourth peptide.

11. The method of any one of claims 3-10, wherein the lipid moiety is selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids.

12. The method of any one of claims 3-11, wherein the lipid moiety is:

13. The method of any one of the preceding claims, wherein the first peptide is:(SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof.

14. The method of any one of the preceding claims, wherein the second peptide is:Atty Ref. METS-036 / 01WO 350242-2269(SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

15. The method of any one of the preceding claims, wherein the third peptide is:(SEQ ID NO: 9), or a pharmaceutically acceptable salt thereof.

16. The method of any one of the preceding claims, wherein the fourth peptide is:(SEQ ID NO: 10), or a pharmaceutically acceptable salt thereof.

17. A method of inducing or maintaining weight loss or managing body weight in a subject, the method comprising administering to the subject an effective amount of a combination comprising three or more peptides selected from:(i) a first peptide comprising the amino acid sequence ofAtty Ref. METS-036 / 01WO 350242-2269(SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof;(ii) a second peptide comprising the amino acid sequence of(SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof;(iii) a third peptide comprising the amino acid sequence of(SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof; and(iv) a fourth peptide comprising the amino acid sequence of(SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the combination comprises(i) the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;Aty Ref. METS-036 / 01WO 350242-2269(ii) the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the combination comprises(i) about 1% to about 20% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 1% to about 40% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 1% to about 90% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

20. The method of claim 19, wherein the combination comprises(i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 7% to about 9% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 83% to about 85% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

21. The method of claim 20, wherein the combination comprises(i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 8% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 84% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

22. The method of claim 19, wherein the combination comprises(i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;Aty Ref. METS-036 / 01WO 350242-2269(ii) about 14% to about 16% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 76% to about 78% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

23. The method of claim 22, wherein the combination comprises(i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 15% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 77% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

24. The method of claim 19, wherein the combination comprises(i) about 10% to about 12% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 21% to about 23% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 66% to about 68% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

25. The method of claim 24, wherein the combination comprises(i) about 11% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 22% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 67% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second and third peptides is 100% by weight or by mole.

26. The method of any one of claims 18-25, wherein the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to aboutAty Ref. METS-036 / 01WO 350242-22697.2 mg, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 7.2 mg, and the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 30 mg.

27. The method of claim 17, wherein the combination comprises(i) the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(ii) the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof.

28. The method of claim 26, wherein the combination comprises(i) about 1% to about 30% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(ii) about 1% to about 90% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) about 1% to about 30% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

29. The method of claim 27, wherein the combination comprises(i) about 7% to about 9% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(ii) about 83% to about 85% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) about 7% to about 9% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

30. The method of claim 28, wherein the combination comprises(i) about 8% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;Aty Ref. METS-036 / 01WO 350242-2269(ii) about 84% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) about 8% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

31. The method of claim 27, wherein the combination comprises(i) about 13% to about 15% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(ii) about 71% to about 73% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) about 13% to about 15% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

32. The method of claim 30, wherein the combination comprises(i) about 14% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(ii) about 72% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) about 14% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

33. The method of claim 27, wherein the combination comprises(i) about 20% to about 22% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(ii) about 62% to about 64% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) about 15% to about 17% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

34. The method of claim 32, wherein the combination comprisesAty Ref. METS-036 / 01WO 350242-2269(i) about 21% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(ii) about 63% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) about 16% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

35. The method of claim 27, wherein the combination comprises(i) about 19% to about 21% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(ii) about 59% to about 61% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) about 19% to about 21% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

36. The method of claim 34, wherein the combination comprises(i) about 20% of the second peptide comprising the amino acid sequence of SEQ ID NO:4 or a pharmaceutically acceptable salt thereof;(ii) about 60% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iii) about 20% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the second, third and fourth peptides is 100% by weight or by mole.

37. The method of any one of claims 27-36, wherein the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 7.2 mg, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 30 mg, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg to about5 mg.

38. The method of claim 17, wherein the combination comprisesAtty Ref. METS-036 / 01WO 350242-2269(i) the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(iii) the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iv) the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof.

39. The method of claim 36, wherein the combination comprises(i) about 1% to about 20% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 1% to about 40% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(iii) about 1% to about 90% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iv) about 1% to about 20% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

40. The method of claim 37, wherein the combination comprises(i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 7% to about 9% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 75% to about 77% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,(iv) about 7% to about 9% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

41. The method of claim 38, wherein the combination comprisesAty Ref. METS-036 / 01WO 350242-2269(i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 8% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(iii) about 76% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iv) about 8% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

42. The method of claim 37, wherein the combination comprises(i) about 7% to about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 12% to about 14% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 66% to about 68% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,(iv) about 12% to about 14% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

43. The method of claim 40, wherein the combination comprises(i) about 8% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 13% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(iii) about 67% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and(iv) about 13% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.Atty Ref. METS-036 / 01WO 350242-226944. The method of claim 37, wherein the combination comprises(i) about 9% to about 11% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 18% to about 20% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 56% to about 58% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,(iv) about 13% to about 15% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

45. The method of claim 42, wherein the combination comprises(i) about 10% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 19% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(iii) about 57% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and iv) about 14% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

46. The method of claim 37, wherein the combination comprises(i) about 8% to about 10% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 17% to about 19% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof; and(iii) about 54% to about 56% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof,(iv) about 17% to about 19% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.Atty Ref. METS-036 / 01WO 350242-226947. The method of claim 44, wherein the combination comprises(i) about 9% of the first peptide comprising the amino acid sequence of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof;(ii) about 18% of the second peptide comprising the amino acid sequence of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof;(iii) about 55% of the third peptide comprising the amino acid sequence of SEQ ID NO: 9 or a pharmaceutically acceptable salt thereof; and iv) about 18% of the fourth peptide comprising the amino acid sequence of SEQ ID NO: 10 or a pharmaceutically acceptable salt thereof, wherein the sum of the first, second, third, and fourth peptides is 100% by weight or by mole.

48. The method of any one of claims 38-47, wherein the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 7.2 mg, the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 7.2 mg, the third peptide (e.g., SEQ ID NO: 9) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 30 mg, and the fourth peptide (e.g., SEQ ID NO: 10) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg to about 5 mg.

49. The method of any one of the preceding claims, wherein the three or more peptides are co-formulated in a solution.

50. The method of any one of the preceding claims, wherein the three or more peptides are co-formulated in the same pharmaceutical composition.

51. The method of claim 50, wherein the three or more peptides are provided in the same container.

52. The method of any one of claim 49-51, wherein the three or more peptides are coadministered concurrently.

53. The method of any one of claims 1-48, wherein the three or more peptides are formulated in separate pharmaceutical compositions.Atty Ref. METS-036 / 01WO 350242-226954. The method of claim 53, wherein the three or more peptides are provided in different containers.

55. The method of claim 53 or 54, wherein the three or more peptides are administered concurrently or sequentially.

56. The method of any one of claim 50-52, wherein the three or more peptides are administered sequentially at an interval of about 1 hour to about 2 days.

57. The method of claim 56, wherein the three or more peptides are administered sequentially at an interval of about Iday.

58. The method of any one of the preceding claims, wherein the three or more peptides are in solution, lyophilized, or cryopreserved.

59. The method of any one of the preceding claims, wherein the combination is administered once weekly.

60. The method of claim 59, wherein the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, followed by a weekly maintenance dose.

61. The method of any one of claims 1-58, wherein the combination is administered once monthly.

62. The method of claim 61, wherein the combination is administered once monthly for about 2 to about 16 months, wherein the amount of one or more peptides is increased over about 2 to about 4 monthly escalations, and wherein each increased dose level is maintained for about 2 months to about 4 months prior to a subsequent increase, followed by a monthly maintenance dose.

63. The method of any one of claims 1-58, wherein the combination is administered weekly for an initial period and then transitioned to monthly administration.Atty Ref. METS-036 / 01WO 350242-226964. The method of claim 63, wherein the combination is administered once weekly for about 2 to about 16 weeks, wherein the amount of one or more peptides is increased over about 2 to about 4 weekly escalations, and wherein each increased dose level is maintained for about 2 weeks to about 4 weeks prior to a subsequent increase, followed by administering the combination once monthly thereafter.

65. The method of any one of claims 60-64, wherein each increased weekly or monthly dose is about 1.5 fold to about 4 fold of an immediately preceding dose.

66. The method of claim 65, wherein each increased weekly or monthly dose is 1.5 fold of an immediately preceding dose.

67. The method of claim 65, wherein each increased weekly or monthly dose is about 2 fold of an immediately preceding dose.

68. The method of claim 65, wherein each increased weekly or monthly dose is about 3 fold of an immediately preceding dose.

69. The method of claim 65, wherein each increased weekly or monthly dose is about 4 fold of an immediately preceding dose.

70. The method of any one of claims 1-58, wherein the combination is administered once weekly for an initial period of about 2 to about 16 weeks at a constant amount, and then is administered once monthly at a constant maintenance dose.

71. The method of claim 70, wherein the monthly dose is about 2 fold to about 4 fold of the weekly dose.

72. The method of any one of the preceding claims, wherein the subject the subject has obesity or is overweight.

73. The method of any one of the preceding claims, wherein the subject has a body mass index (BMI) of at least 27 kg / m2.Atty Ref. METS-036 / 01WO 350242-226974. The method of claim 72 or 73, wherein the subject has a weight-related comorbid condition.

75. The method of claim 74, wherein the weight-related comorbid condition is hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, Type 2 diabetes (T2DM), or nonalcoholic fatty liver disease (NAFLD).

76. The method of claim 75, wherein the weight-related comorbid condition is T2DM.

77. The method of any one of the preceding claims, wherein the subject has a metabolic disorder.

78. The method of claim 77, wherein the metabolic disorder is selected from obesity, prediabetes, diabetes, non-alcoholic fatty liver disease (NAFLD), and polycystic ovary syndrome (PCOS).

79. The method of any one of the preceding claims, wherein the administration is subcutaneous.

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