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 an amylin analog and a GLP-1 receptor agonist As described herein, the GLP-1 receptor agonist and amylin analog can be administered to a subject in the same pharmaceutical composition or in separate pharmaceutical compositions (e.g., via simultaneous or subsequent administration).

Description

[0001] Atty Ref. METS-023 / 02WO 350242-2264

[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 / 709,370, filed October 18, 2024; 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_023_02WO_SeqList_ST26.xml; Size: 203,725 bytes; and Date of Creation: October 9, 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 an amylin analog and a GLP-1 receptor agonist. As described herein, the amylin analog and the GLP-1 receptor agonist can be administered to a subject in the same pharmaceutical composition or in separate pharmaceutical compositions (e.g., via simultaneous or subsequent administration). In aspects, the combination of an amylin analog and a GLP-1 receptor agonist of the disclosure is used to treat or prevent a metabolic disorder.

[0011]

[0005] In one aspect, provided herein are pharmaceutical compositions or kits comprising: a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof; and Atty Ref. METS-023 / 02WO 350242-2264 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.

[0012]

[0006] In some embodiments, provided herein are pharmaceutical compositions or kits comprising a first peptide having the structure:

[0013] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; and a second peptide having the structure: or a pharmaceutically acceptable salt thereof.

[0014]

[0007] In some embodiments, the first peptide and the second peptide are co-formulated in a solution. In certain embodiments, the ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 4: 1 to about 1 :4. In certain embodiments, the first peptide and the second peptide are miscible in solution. In other embodiments, the first peptide and the second peptide are fused to each other (e.g., linked to each other via a bond or a linker).

[0015]

[0008] Also 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 pharmaceutical composition or kit described herein.

[0016]

[0009] In certain 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: a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof; and a second peptide comprising the amino acid sequence of F(Aib)EGTFTSDVSKQLEEKRVREFIEWLKQGGPSSGKPPPGKK (SEQ ID NO: 2) or a Atty Ref. METS-023 / 02WO 350242-2264 pharmaceutically acceptable salt thereof, wherein the first peptide and the second peptide are each administered in an effective amount, wherein Aib is 2-aminoisobutyric acid.

[0017]

[0010] In certain embodiments of the methods, the first peptide is:

[0018] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; and the second peptide is:

[0019] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0020] [OH] In the methods described herein, the first peptide and the second peptide can be administered simultaneously (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, a subject has a metabolic disorder, for example, selected from obesity, prediabetes, diabetes, non-alcoholic fatty liver disease (NAFLD), and polycystic ovary syndrome (PCOS).

[0021]

[0012] 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]

[0013] In some embodiments, the methods described herein comprise administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly or monthly dose of about 0.1 mg to about 9.6 mg and 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 9.6 mg. In some embodiments, the methods described herein comprise administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once weekly or monthly dose of about 0.1 mg to about 7.2 mg and the second peptide (e.g., SEQ Aty Ref. METS-023 / 02WO 350242-2264 ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 7.2 mg.

[0023]

[0014] In some embodiments, the methods described herein comprise administering 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 0.8 mg and 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 0.8 mg, for about 2 weeks to about 8 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher weekly dose for each peptide ranges about 0.1 mg to about 4.8 mg for a period of about 2 weeks to about 8 weeks, per titration step, and thereafter followed by administration of a once monthly dose of about 0.6 mg to about 7.2 mg for each peptide.

[0024]

[0015] In some embodiments, the methods described herein comprise administering 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 0.8 mg and 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 0.8 mg, for about 2 weeks to about 8 weeks, followed by one or more titrations to a higher once weekly dose, wherein each higher weekly dose for each peptide ranges about 0.1 mg to about 4.8 mg for a period of about 2 weeks to about 8 weeks, per titration step, and thereafter followed by administration of a once monthly dose of about 0.6 mg to about 9.6 mg for each peptide.

[0025]

[0016] In some embodiments, the methods described herein comprise administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 2 weeks to about 12 weeks, followed by administration of a once monthly dose of about 0.4 mg to about 7.2 mg for each peptide.

[0017] In some embodiments, the methods described herein comprise administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 2 weeks to about 12 weeks, followed by administration of a once monthly dose of about 0.4 mg to about 9.6 mg for each peptide.

[0026] BRIEF DESCRIPTION OF THE DRAWINGS

[0027]

[0018] 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. Aty Ref. METS-023 / 02WO 350242-2264

[0028]

[0019] FIG. 1 shows the effect of multiple doses of SEQ ID NO: 4 in combination with SEQ ID NO: 3 and CagriSema in rats.

[0029]

[0020] FIG. 2 shows the solubility profile of SEQ ID NO: 4 and SEQ ID NO: 3.

[0030]

[0021] FIG. 3 shows the pharmacokinetic (PK) profile of SEQ ID NO: 4 and SEQ ID NO: 3 following a single subcutaneous dose in pigs.

[0031]

[0022] FIG. 4 shows the study schema for Phase 2b study. QM=once monthly; QW=once weekly. Lighter shaded areas in QM dosing periods reflect the split between approximately half of participants remaining on QW dosing (A groups) and the other half switching to QM dosing (B groups). Placebo group will be randomly allocated to match titration regimens and QW versus QM treatment period dosing of the active dosing groups consistent with a double-dummy study design.

[0032] DEFINITIONS

[0033]

[0023] The following definitions are general terms used throughout the present disclosure.

[0034]

[0024] 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.

[0035]

[0025] 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).

[0036]

[0026] 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 Atty Ref. METS-023 / 02WO 350242-2264 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 provided herein. In certain embodiments, a peptide is the length of an amino acid sequence provided herein.

[0037]

[0027] 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. . a amino acid

[0038]

[0028] 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). Aty Ref. METS-023 / 02WO 350242-2264 In certain embodiments, any amino acid described herein can comprise a methyl group on the peptide nitrogen (“N-methyl”-amino acid).

[0039]

[0029] As used herein, the term “salt” includes any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the peptides of this invention include those derived from inorganic and organic acids and bases.

[0040]

[0030] The term “pharmaceutically acceptable salt” includes those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge etal. 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, hemi sulfate, 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.

[0041]

[0031] As used herein, the term “co-administration” or “co-administered” refers to the administration of two peptides to a subject, either simultaneously, sequentially, or separately, such that the therapeutic effects of the peptides overlap at least in part. “Co-administration” or “co- Aty Ref. METS-023 / 02WO 350242-2264 administered” 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.

[0042]

[0032] 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 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.

[0043]

[0033] 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.

[0044]

[0034] 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.

[0045]

[0035] 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.

[0046]

[0036] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0047]

[0037] 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). Atty Ref. METS-023 / 02WO 350242-2264

[0048] 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.

[0049] DETAILED DESCRIPTION

[0050]

[0038] 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 an amylin analog and a GLP-1 receptor agonist. As described herein, the amylin analog and the GLP-1 receptor agonist can be administered to a subject in the same pharmaceutical composition or in separate pharmaceutical compositions (e.g., via simultaneous or subsequent administration). In some aspects, the combination of an amylin analog and a GLP- 1 receptor agonist of the disclosure is used to treat a metabolic disorder.

[0051]

[0039] In one aspect, provided herein are pharmaceutical compositions or kits comprising: a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof; and 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.

[0052]

[0040] For example, provided herein are pharmaceutical compositions or kits comprising a first peptide having the structure:

[0053] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; and a second peptide having the structure:

[0054] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof. Aty Ref. METS-023 / 02WO 350242-2264

[0041] 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: a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof; and 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;

[0055]

[0042] In certain embodiments of the methods described herein, the first peptide is SEQ ID NO: 3, or a pharmaceutically acceptable salt thereof; and the second peptide is SEQ ID NO: 4, or a pharmaceutically acceptable salt thereof.

[0056] First Peptide (Amylin Analog)

[0057]

[0043] 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.

[0058]

[0044] 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.

[0059]

[0045] 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 Atty Ref. METS-023 / 02WO 350242-2264 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.

[0060]

[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:

[0061]

[0047] In certain embodiments, the lipid moiety is:

[0062]

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

[0063] (SEQ ID NO: 5), or a pharmaceutically acceptable salt thereof.

[0064]

[0049] In certain embodiments, the first peptide is:

[0065] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof. In certain embodiments, the first peptide is an acetate salt.

[0066] Second Peptide (GLP-1 Receptor Agonist)

[0067]

[0050] 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 injectable peptides for weight loss and metabolic disorder management (e.g., liraglutide, semaglutide, tirzepatide) have drawbacks, such as requiring daily or weekly injections, unfavorable weight loss or long-term weight maintenance, Aty Ref. METS-023 / 02WO 350242-2264 and side effects, which decrease treatment adherence or patient compliance. The combination therapies described herein can help solve these challenges.

[0068]

[0051] 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.

[0069]

[0052] 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 embodiments, the lipid moiety is atached 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.

[0070]

[0053] 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:

[0071]

[0054] In certain embodiments, the lipid moiety is:

[0072]

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

[0073] (SEQ ID NO: 6), or a pharmaceutically acceptable salt thereof.

[0074]

[0056] In certain embodiments, the second peptide is: Atty Ref. METS-023 / 02WO 350242-2264

[0075] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0076] Peptide Derivatives

[0077]

[0057] The present disclosure provides peptides, derivatives of such peptides, and salts or solvates of such peptides and derivatives.

[0078]

[0058] The peptides, derivatives and salts may be produced by recombinant methods or synthetic methods.

[0079]

[0059] In some embodiments, a peptide (e.g., of any amino acid sequence herein, e.g., of SEQ ID NO: 1 or SEQ ID NO: 2) 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 or SEQ ID NO: 2). 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.

[0080]

[0060] A derivative of the disclosure can, for example, be a physiologically functional derivative of an amylin analog or GLP-1 agonist herein, such as a peptide of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. The term “physiologically functional derivative” is used herein to denote a chemical derivative of a amylin analog or GLP-1 agonist 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 of any one of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6. According to the present disclosure, non-limiting examples of physiologically functional derivatives include esters, amides, and carbamates; preferably esters and amides.

[0081]

[0061] In some embodiments, a derivatization comprises lipidization. Lipidization markedly increases the absorption of peptides relative to the rate of absorption of the corresponding Aty Ref. METS-023 / 02WO 350242-2264 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 some embodiments, an amylin analogue and / or GLP-1 agonist peptide 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 if a peptide herein (e.g., of any amino acid sequence herein, e.g., a peptide of SEQ ID NO: 1 and / or a peptide of SEQ ID NO: 2)

[0082] Peptide Fusions

[0083]

[0062] 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.

[0084] Combination Therapies

[0085]

[0063] In some embodiments, the present disclosure provide combination therapies comprising a combination of an amylin analog and a GLP-1 receptor agonist. 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 and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, in any weight 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.

[0086]

[0064] In some embodiments, the combination comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof formulated in separate pharmaceutical compositions. Aty Ref. METS-023 / 02WO 350242-2264 In some embodiments, the combination comprises the first peptide and the second peptide 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 first peptide and the second peptide 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).

[0087]

[0065] In some embodiments, the combination comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof co-formulated in the same pharmaceutical composition. In some embodiments, the combination comprises the first peptide and the second peptide co-formulated in a solution. In some embodiments, the combination comprises the first peptide and the second peptide 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 peptide and the second peptide in solution, lyophilized, cryopreserved. In some embodiments, the combination is co-administered concurrently.

[0088]

[0066] 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 and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in a weight ratio ranging from about 30:1 to about 1:30 (e.g., about 30:1, about 29:1, about 28:1, about 27:1, about 26:1, about 25:1, about 24:1, about 23:1, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about

[0089] 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about

[0090] 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26, about 1:27, about 1:28, about

[0091] 1:29 or about 1:30, including all values and ranges therein). In certain embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 20:1 to about 1:20. In certain embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 10: 1 to about 1 : 10. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 5:1 to about 1:5. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 4:1 to about 1:4. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide Aty Ref. METS-023 / 02WO 350242-2264 or pharmaceutically acceptable salt thereof is about 3: 1 to about 1 :3. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 2.5: 1 to about 1:2.5. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 2: 1 to about 1 :2. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.75: 1 to about 1 : 1.75. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.5: 1 to about 1 : 1.5. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.4: 1 to about 1 : 1.4. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.35: 1 to about 1 : 1.35. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.3: 1 to about 1 : 1.3. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.25: 1 to about 1 : 1.25. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 5: 1, about 4: 1, about 3: l, about 2.5: l, about 2: l, about 1.75: 1, about 1.5: 1, about 1.4: 1, about 1.35: 1, about 1.3: 1, about 1.25: 1, about 1 : 1, about 1 : 1.25, about 1 : 1.3, about 1 : 1.35, about 1 : 1.4, about 1 : 1.5, about 1 : 1.75, about 1 :2, about 1 :2.5, about 1 :3, about 1 :4, or about 1 :5, including any values or ranges therebetween.

[0092]

[0067] In some embodiments, the combination comprises the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in a weight ratio ranging from about 4: 1 to about 1 :4. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :1. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1.35. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1:2. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second Aty Ref. METS-023 / 02WO 350242-2264 peptide or pharmaceutically acceptable salt thereof is about 1 :2.5. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :4. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.5: 1.

[0093] Pharmaceutical Compositions, Administration and Kits

[0094]

[0068] As described, the present disclosure provides pharmaceutical compositions or kits comprising a first peptide or a pharmaceutically acceptable salt thereof and a second peptide or a pharmaceutically acceptable salt thereof (“peptides”). 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.

[0095]

[0069] The terms “composition” and “formulation” are used interchangeably herein.

[0096]

[0070] 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 (z.e., 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.

[0097]

[0071] 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.

[0098]

[0072] 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.

[0099]

[0073] 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 Aty Ref. METS-023 / 02WO 350242-2264 coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0100]

[0074] 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, 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.

[0101]

[0075] 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).

[0102]

[0076] 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.

[0103]

[0077] 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.

[0104]

[0078] 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 co- Aty Ref. METS-023 / 02WO 350242-2264 formulated in a solution. In certain embodiments, the first peptide and the second peptide are both miscible in solution.

[0105]

[0079] In certain embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 30:1 to about 1:30 (e.g., about 30:1, about 29:1, about 28:1, about 27:1, about 26:1, about 25:1, about 24:1, about 23:1, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, about 1:20, about 1:21, about 1:22, about 1:23, about 1:24, about 1:25, about 1:26, about 1:27, about 1:28, about 1:29 or about 1:30, including all values and ranges therein). In certain embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 20:1 to about 1:20. In certain embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 10:1 to about 1:10.

[0106]

[0080] In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 5:1 to about 1:5. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 4:1 to about 1:4. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 3:1 to about 1:3. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 2.5:1 to about 1:2.5. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 2:1 to about 1:2. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.75:1 to about 1:1.75. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.5:1 to about 1:1.5. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.4:1 to about 1:1.4. In some embodiments, the weight ratio of the first Aty Ref. METS-023 / 02WO 350242-2264 peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.35 : 1 to about 1 : 1.35. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.3 : 1 to about 1 : 1.3. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.25: 1 to about 1 : 1.25. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 5: 1, about 4: 1, about 3 : 1, about 2.5: 1, about 2: 1, about 1.75: 1, about 1.5: 1, about 1.4: 1, about 1.35: 1, about 1.3 : 1, about 1.25: 1, about 1 : 1, about 1 : 1.25, about 1 : 1.3, about 1 : 1.35, about 1 : 1.4, about 1 : 1.5, about 1 : 1.75, about 1 :2, about 1 :2.5, about 1 :3, about 1 :4, or about 1 :5, including any values or ranges therebetween.

[0107]

[0081] In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 4: 1 to about 1 :4. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1.35. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2.5. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :4. In some embodiments, the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.5: 1.

[0108]

[0082] 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 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. Aty Ref. METS-023 / 02WO 350242-2264

[0083] 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.

[0109]

[0084] 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.

[0110]

[0085] 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.

[0111]

[0086] 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 Atty Ref. METS-023 / 02WO 350242-2264 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.

[0112] Dosage and Dosing Regimens

[0113]

[0087] Unless otherwise provided herein, the stated dose amounts of the amylin analog (e.g., SEQ ID NO: 3) and the GLP-1 receptor agonist (e.g., SEQ ID NO: 4) 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.

[0114]

[0088] 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

[0115] 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

[0116] 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

[0117] 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.

[0118]

[0089] 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 Aty Ref. METS-023 / 02WO 350242-2264 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 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

[0119] 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

[0120] 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

[0121] 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.

[0122]

[0090] 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, and 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.

[0123]

[0091] 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 0.3 mg and 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 0.3 mg. 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 and 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. 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 0.2 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.2 mg. Aty Ref. METS-023 / 02WO 350242-2264

[0124]

[0092] 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 0.3 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg to about 0.5 mg. 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 and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.4 mg.

[0125]

[0093] 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 0.3 mg to about 0.5 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg to about 0.5 mg. 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 0.3 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.4 mg. 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 0.4 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.4 mg.

[0126]

[0094] 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 0.3 mg to about 0.5 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.7 mg to about 0.9 mg. 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 0.3 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.8 mg. 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 0.4 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.8 mg.

[0127]

[0095] 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 0.5 mg to about 0.7 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg to about 0.5 mg. 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 0.6 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.4 mg. Aty Ref. METS-023 / 02WO 350242-2264

[0096] 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 0.5 mg to about 0.7 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.7 mg to about 0.9 mg. 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 0.6 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.8 mg.

[0128]

[0097] 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 0.7 mg to about 0.9 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.7 mg to about 0.9 mg. 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 0.8 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.8 mg.

[0129]

[0098] 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 0.7 mg to about 0.9 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.5 mg to about 1.7 mg. 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 0.8 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.6 mg.

[0130]

[0099] 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 1.1 mg to about 1.3 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.5 mg to about 1.7 mg. 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 1.2 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.6 mg.

[0131]

[0100] 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 1.5 mg to about 1.7 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.5 mg to about 1.7 mg. 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 1.6 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.6 mg. Aty Ref. METS-023 / 02WO 350242-2264

[0132]

[0101] 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 2.3 mg to about 2.5 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4.7 mg to about 4.9 mg. 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 2.4 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4.8 mg.

[0133]

[0102] 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 4.7 mg to about 4.8 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4.7 mg to about 4.9 mg. 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 4.8 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4.8 mg.

[0134]

[0103] 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 4.7 mg to about 4.8 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 6.3 mg to about 6.5 mg. 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 4.8 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 6.4 mg.

[0135]

[0104] 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 to about 0.2 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 to about 0.4 mg. 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 0.2 to about 0.4 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.2 to about 0.8 mg. 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 0.4 to about 1.2 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.4 to about 1.6 mg. 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 1.6 to about 4.8 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1.6 to about 6.4 mg. Aty Ref. METS-023 / 02WO 350242-2264

[0136]

[0105] In some embodiments the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof may be administered weekly, biweekly, or monthly, or any combination thereof. In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof are administered weekly. In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof are administered biweekly. In some embodiments, the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof are administered monthly.

[0137]

[0106] In some embodiments, the methods comprise administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof during a first period of treatment, and then administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof during a second period of treatment, wherein the doses and / or dosing frequency of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in the first period and the second period are the same or different, and may be any dose or frequency disclosed herein. In some embodiments, the methods comprise administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof weekly during a first period of treatment, and then administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof biweekly or monthly during a second period of treatment. In some embodiments, the doses of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof administered in the second period is greater than the doses administered in the first period.

[0138]

[0107] In some embodiments, the methods comprise administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof during an initiation phase. In some embodiments, the initiation phase comprises a single dosing period ranging from about 2 weeks to about 52 weeks (e.g., about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, about 2 to about 12 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 4 weeks, including Aty Ref. METS-023 / 02WO 350242-2264 all values and ranges therein), during which the dosage of each peptide ranges from about 0.1 mg to about 9.6 mg, or about 0.1 mg to about 7.2 mg, including all values and ranges therein, and remains constant through the period. In some embodiments, the initiation phase comprises two or more dosing periods, each ranging from about 2 weeks to about 52 weeks (e.g., about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, about 2 to about 12 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 4 weeks, including all values and ranges therein), wherein the dosage of each peptide ranges from about 0.1 mg to about 9.6 mg, or about 0.1 mg to about 7.2 mg, including all values and ranges therein, and remains constant during each dosing period, and wherein the dosage of each peptide is increased from one dosing period to the subsequent dosing period. In some embodiments, the methods comprise administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof during a maintenance phase. In some embodiments, the doses and / or dosing frequency of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in the initiation phase and maintenance phase are the same. In some embodiments, the doses and / or dosing frequency of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof in the initiation phase and maintenance phase are different, and may be any dose or frequency disclosed herein.

[0139]

[0108] In some embodiments, the methods comprise administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof weekly, at a starting dose during the initiation phase. In some embodiments, the methods comprise administering the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a maintenance dose during the maintenance phase. In some embodiments, the maintenance dose is greater than the starting dose (e.g., the first dose is titrated to the second dose). In some embodiments, the maintenance dose is administered at a different dosing frequency compared to the starting dose. In some embodiments, the maintenance dose is administered at a different dosing frequency compared to the starting dose. In some embodiments, the maintenance dose is administered biweekly or monthly. For example, 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, about 2.6 mg, about Aty Ref. METS-023 / 02WO 350242-2264

[0140] 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 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

[0141] 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 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

[0142] 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

[0143] 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, or about 9.5 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 3.5-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. The dose increase may occur after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks or months.

[0144]

[0109] In some embodiments, 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 0.1 mg to about 9.6 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg, about 1.6 mg, about 2.4 mg, about 4.8 mg, about 6.4 mg, about 7.2 mg, or about 9.6 mg, including all values and ranges therein), and 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 9.6 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg, about 1.6 mg, about 2.4 mg, about 4.8 mg, about 6.4 mg, about 7.2 mg, or about 9.6 mg, including all values and ranges therein). In some embodiments, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once biweekly (z.e., about once every two weeks) dose of about 0.1 mg to about 9.6 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg, about 1.6 mg, about 2.4 mg, about 4.8 mg, about 6.4 mg, about 7.2 mg, or about 9.6 mg, including all values and ranges therein) and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once biweekly dose of about 0.1 mg to about 9.6 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg, about 1.6 mg, about 2.4 mg, about 4.8 mg, about 6.4 mg, about 7.2 mg, or about 9.6 mg, including all values and ranges therein). In some embodiments, the methods comprise the first Aty Ref. METS-023 / 02WO 350242-2264 peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 0.1 mg to about 9.6 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg, about 1.6 mg, about 2.4 mg, about 4.8 mg, about 6.4 mg, about 7.2 mg, or about 9.6 mg, including all values and ranges therein) and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 0.1 mg to about 9.6 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg, about 1.6 mg, about 2.4 mg, about 4.8 mg, about 6.4 mg, about 7.2 mg, or about 9.6 mg, including all values and ranges therein). In some embodiments, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof at a once every 4 weeks dose of about 0.1 mg to about

[0145] 9.6 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg, about 1.6 mg, about 2.4 mg, about 4.8 mg, about 6.4 mg, about 7.2 mg, or about

[0146] 9.6 mg, including all values and ranges therein), and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once every 4 weeks dose of about 0.1 mg to about

[0147] 9.6 mg (e.g., about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1.2 mg, about 1.6 mg, about 2.4 mg, about 4.8 mg, about 6.4 mg, about 7.2 mg, or about

[0148] 9.6 mg, including all values and ranges therein).

[0149]

[0110] In some embodiments, 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 0.2 mg to about 0.4 mg (e.g., about 0.3 mg) and 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). In some embodiments, 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 and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg. In some embodiments, 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 0.5 mg to about 0.7 mg (e.g., about 0.6 mg) and 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). In some embodiments, 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 0.6 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg. In some embodiments, 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 0.1 mg to about 0.3 mg (e.g., about 0.2 mg) and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable Aty Ref. METS-023 / 02WO 350242-2264 salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg). In some embodiments, 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 0.2 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg. In some embodiments, 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 0.1 mg to about 0.3 mg (e.g., about 0.2 mg) and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.05 mg to about 0.15 mg (e.g., about 0.1 mg). In some embodiments, 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 0.2 mg and 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. In some embodiments, 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 0.05 mg to about 0.15 mg (e.g., about 0.1 mg) and 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). In some embodiments, 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 0.1 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg. In some embodiments, 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 0.2 mg to about 0.4 mg (e.g., about 0.3 mg) and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.05 mg to about 0.15 mg (e.g., about 0.1 mg). In some embodiments, 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 and 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.

[0150] [Ill] In some embodiments, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and 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 0.8 mg for each peptide for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 4 weeks, or about 4 weeks, followed by titrating to a higher once weekly dose ranging from about 0.2 mg to about 4.8 mg. In some embodiments, the titrating comprises one or more steps of increasing a dose of the first peptide (e.g., SEQ ID NO: 3) or a Aty Ref. METS-023 / 02WO 350242-2264 pharmaceutically acceptable salt thereof, and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, wherein each increasing dose is administered for a period of about 2 weeks to about 52 weeks, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, about 2 to about 12 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 4 weeks, or about 4 weeks, and thereafter followed by administration of a once biweekly or monthly dose of about 0.6 mg to about 9.6 mg for each peptide. In some embodiments, 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 O.lmg to about 0.2 mg, about 0.1 mg to about 0.15 mg (e.g., about 0.1 mg), or about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg) and the second peptide (e.g, SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about O. l mg to about 0.8 mg, about O.l mg to about 0.15 mg (e.g., about O. l mg), about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), about 0.4 mg to about 0.6 mg (e.g., about 0.5 mg), about 0.5 mg to about 0.7 mg (e.g., about 0.6 mg), about 0.6 mg to about 0.8 mg (e.g., about 0.7 mg), about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg) for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 4 weeks, about 8 weeks, or about 4 weeks, followed by titrating to a higher once weekly dose for a period of about 4 weeks to about 8 weeks, wherein a higher weekly dose for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof ranges about 0.2 mg to about 0.8 mg, about 0.1 mg to about 0.3 mg (e.g., 0.2 mg), about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), about 0.4 mg to about 0.6 mg (e.g., about 0.5 mg), about 0.5 mg to about 0.7 mg (e.g., about 0.6 mg), about 0.6 mg to about 0.8 mg (e.g., about 0.7 mg), about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg) and a higher weekly dose for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof ranges about 0.8 mg to about 1.6 mg, about 0.7 mg to about 0.9 mg (e.g., 0.8 mg), about 0.8 mg to about 1.0 mg (e.g., about 0.9 mg), about 0.9 mg to about 1.1 mg (e.g., about 1.0 mg), about 1.0 mg to about 1.2 mg (e.g., about 1.1 mg), about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), about 1.2 mg to about 1.4 mg (e.g., about 1.3 mg), about 1.3 mg to about 1.5 mg (e.g., about 1.4 mg), about 1.4 mg to about 1.6 mg (e.g., about 1.5 mg), about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), for a period of about 2 weeks to about 52 weeks, about 2 weeks to about 36 week, about 2 weeks to about 28 weeks, about 2 to about 12 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 4 weeks, about 8 weeks, or about 4 weeks, and thereafter followed by administration of a once monthly dose of about 0.6 mg to about 6.4 mg for each peptide, wherein the once monthly dose for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof ranges about 0.6 mg to about Aty Ref. METS-023 / 02WO 350242-2264 2.4 mg, about 0.5 mg to about 0.7 mg (e.g., about 0.6 mg), about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), or about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), and the once monthly dose for the second peptide e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof ranges about 0.8 mg to about 4.8 mg, about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), 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), about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), about

[0151] 4.7 mg to about 4.9 mg (e.g., about 4.8 mg), or about 6.3 mg to about 6.4 mg (e.g., about 6.4 mg). In some embodiments, each higher weekly 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 3.5-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. In some embodiments, each higher weekly dose is increased by about 0.1 to about 9.5 mg, for example, 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

[0152] 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

[0153] 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

[0154] 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 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about

[0155] 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, or about 9.5 mg, compared to an immediately preceding dose. In some embodiments, the biweekly or monthly dose is about 1.0-fold (i.e., the same) to about 8-fold, for example, about 1-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 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 weekly dose. In some embodiments, the biweekly or monthly dose is increased by about 0.1 to about 9.5 mg, for example, 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 Aty Ref. METS-023 / 02WO 350242-2264 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

[0156] 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 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about

[0157] 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 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about

[0158] 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

[0159] 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, or about 9.5 mg, compared to the immediately preceding weekly dose. In some embodiments, the initial weekly dose treatment period is for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, or more. In some embodiments, each higher weekly dose is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, or more in each titration period. In some embodiments, the biweekly or monthly dose is administered for at least about 4 weeks, for example, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, at least about 32 Aty Ref. METS-023 / 02WO 350242-2264 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 week, at least about 48 weeks, at least about 52 weeks, at least about 56 week, at least about 60 weeks, at least about 64 weeks, or more. In some embodiments, the titrating comprises one or more steps of increasing a dose of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, wherein each increasing dose is administered for a period of about 2 weeks to about 8 weeks. In some embodiments, the titrating comprises two steps of increasing a dose of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, wherein each increasing dose is administered for a period of about 4 weeks. In some embodiments, the titrating comprises two steps of increasing a dose of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof, and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, wherein a first increasing dose is administered for a period of about 4 weeks, and a second increasing dose is administered for a period of about 8 weeks.

[0160]

[0112] In some embodiments, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and 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 0.8 mg, about 0.1 mg to about 0.15 mg (e.g., about 0.1 mg), about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), for each peptide for about 2 weeks to about 12 weeks, about 2 weeks to about 8 weeks, about 3 weeks to about 5 weeks (e.g., about 4 weeks), followed by titrating to a higher once weekly dose, wherein each higher weekly dose for each peptide ranges about 0.2 mg to about 4.8 mg, about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), about 0.2 to about 0.4 mg (e.g., about 0.3 mg), about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), about 0.5 mg to about 0.7 mg (e.g., about 0.6 mg), about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), 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), for a period of about 2 weeks to about 12 weeks, about 3 weeks to about 5 week (e.g., about 4 weeks), about 7 weeks to about 9 weeks (e.g., about 8 weeks), and thereafter followed by administration of a once monthly dose of about 0.6 mg to about 7.2 mg, about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), about 4.7 mg to about 4.9 mg (e.g., about 4.8 mg) for each peptide.

[0161]

[0113] In some embodiments, 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 0.1 mg to about 0.3 mg (e.g., about 0.2 mg) and 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) for about 4 weeks. In some embodiments, on about weeks 4-8 of treatment, Aty Ref. METS-023 / 02WO 350242-2264 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 0.2 mg to about 0.4 mg (e.g., about 0.3 mg) and 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) 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 0.5 mg to about 0.7 mg (e.g., about 0.6 mg) and 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) 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 1.7 mg to about 1.9 mg (e.g., about 1.8 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 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), or about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg). In some embodiments, 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 0.2 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg for about 4 weeks, followed by a once weekly dose of about 0.3 mg for the first peptide (e.g. , SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof for about 4 weeks, and thereafter followed by a once weekly dose of about 0.6 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof.

[0162]

[0114] In some embodiments, 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. Img to about 0.15 mg (e.g., about 0.1 mg) and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.05 mg to about 0.15 mg (e.g., about 0.1 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 0.1 mg to about 0.3 mg (e.g., about 0.2 mg) and 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) for about 4 weeks. In some embodiments, on about weeks 8-12 of treatment, the methods comprise Aty Ref. METS-023 / 02WO 350242-2264 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) and 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) 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 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), or about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), or about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg). In some embodiments, 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 0.1 mg and 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 for about 4 weeks, followed by a once weekly dose of about 0.2 mg for the first peptide (e.g. , SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.2 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof for about 4 weeks, and thereafter followed by a once weekly dose of about 0.4 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof.

[0163]

[0115] In some embodiments, 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 0.1 mg to about 0.3 mg (e.g., about 0.2 mg) and 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) 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) and 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) 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 0.5 mg to about 0.7 mg (e.g., about 0.6 mg) and 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) for about 4 weeks. In some embodiments, starting on week 12 of treatment, the methods comprise administration of the first peptide (e.g., Aty Ref. METS-023 / 02WO 350242-2264 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 1.7 mg to about 1.9 mg (e.g., about 1.8 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 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), or about 3.1 mg to about 3.3 mg (e.g., about 3.2 mg). In some embodiments, 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 0.2 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg for about 4 weeks, followed by a once weekly dose of about 0.4 mg for the first peptide (e.g. , SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof for about 4 weeks, and thereafter followed by a once weekly dose of about 0.6 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof.

[0164]

[0116] In some embodiments, 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 0.1 mg to about 0.15 mg (e.g., about 0.1 mg) and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.05 mg to about 0.15 mg (e.g., about 0.1 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) and 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) 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) and 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) 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 1.5 mg to about 1.7 mg (e.g., about 1.6 mg), and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 1.5 mg to about 1.7 mg (e.g., about 1.6 mg). In some embodiments, 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 Aty Ref. METS-023 / 02WO 350242-2264 of about 0.1 mg and 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 for about 4 weeks, followed by a once weekly dose of about 0.4 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof for about 4 weeks, thereafter followed by a once weekly dose of about 0.8 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, and thereafter followed by a once monthly dose of about 1.6 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 1.6 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof.

[0165]

[0117] In some embodiments, 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 0.1 mg to about 0.15 mg (e.g., about 0.1 mg) and 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) 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 0.2 mg to about 0.4 mg (e.g., about 0.3 mg) and 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) 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) and 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) 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 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 4.7 mg to about 4.9 mg (e.g., about 4.8 mg). In some embodiments, 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 0.1 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.3 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide (e.g., SEQ ID NO: 4) Aty Ref. METS-023 / 02WO 350242-2264 or a pharmaceutically acceptable salt thereof for about 4 weeks, thereafter followed by a once weekly dose of about 0.8 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 1.6 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof, and thereafter followed by a once monthly dose of about 2.4 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 4.8 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof.

[0166]

[0118] In some embodiments, 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 0.1 mg to about 0.15 mg (e.g., about 0.1 mg) and 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) 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) and 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) 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 1.1 mg to about 1.3 mg (e.g., about 1.2 mg) and 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) 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 4.7 mg to about 4.9 mg (e.g., about 4.8 mg), and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once monthly dose of about 4.7 mg to about 4.9 mg (e.g., about 4.8 mg) or about 6.3 mg to about 6.5 mg (e.g., about 6.4 mg). In some embodiments, 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 0.1 mg and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.4 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof for about 4 weeks, thereafter followed by a once weekly dose of about 1.2 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 1.6 mg for the second peptide (e.g., SEQ ID NO: 4) or a Aty Ref. METS-023 / 02WO 350242-2264 pharmaceutically acceptable salt thereof, and thereafter followed by a once monthly dose of about 4.8 mg for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and a once weekly dose of about 4.8 mg or about 6.4 for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof.

[0167]

[0119] In some embodiments, the methods comprise administration of the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and 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 0.8 mg for each peptide for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 4 weeks, or about 4 weeks, followed by administration of a once biweekly or monthly dose of about 0.6 mg to about 7.2 mg for each peptide. In some embodiments, 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 O. lmg to about 0.2 mg, about 0.1 mg to about 0.15 mg (e.g., about 0.1 mg), or about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg) and 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 0.8 mg, about 0.1 mg to about 0.15 mg (e.g., about 0.1 mg), about 0.1 mg to about 0.3 mg (e.g., about 0.2 mg), about 0.2 mg to about 0.4 mg (e.g., about 0.3 mg), about 0.3 mg to about 0.5 mg (e.g., about 0.4 mg), about 0.4 mg to about 0.6 mg (e.g., about 0.5 mg), about 0.5 mg to about 0.7 mg (e.g., about 0.6 mg), about 0.6 mg to about 0.8 mg (e.g., about 0.7 mg), about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg) for about 2 weeks to about 52 weeks, about 2 weeks to about 36 weeks, about 2 weeks to about 28 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 4 weeks, about 8 weeks, or about 4 weeks, followed by administration of a once monthly dose of about 0.6 mg to about 6.4 mg for each peptide, wherein the once monthly dose for the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof ranges about 0.6 mg to about 2.4 mg, about 0.5 mg to about 0.7 mg (e.g., about 0.6 mg), about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), about 1.1 mg to about 1.3 mg (e.g., about 1.2 mg), or about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), and the once monthly dose for the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof ranges about 0.8 mg to about 4.8 mg, about 0.7 mg to about 0.9 mg (e.g., about 0.8 mg), 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), about 2.3 mg to about 2.5 mg (e.g., about 2.4 mg), about 4.7 mg to about 4.9 mg (e.g., about 4.8 mg), or about 6.3 mg to about 6.4 mg (e.g., about 6.4 mg). In some embodiments, the monthly dose is about 1.0-fold (i.e., the same) to about 8-fold, for example, about 1-fold, about 1.5-fold, about 2-fold, about 2.5-fold, about 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- Aty Ref. METS-023 / 02WO 350242-2264 fold, about 7.5-fold, or about 8-fold of the amount of the preceding weekly dose. In some embodiments, the monthly dose is increased by about 0.1 to about 7.1 mg, for example, 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

[0168] 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 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

[0169] 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 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

[0170] 6.8 mg, about 6.9 mg, about 7.0 mg, or about 7.1 mg, compared to the preceding weekly dose. In some embodiments, the initial weekly dose treatment period is for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, about 32 weeks, about 33 weeks, about 34 weeks, about 35 weeks, about 36 weeks, about 37 weeks, about 38 weeks, about 39 weeks, about 40 weeks, about 41 weeks, about 42 weeks, about 43 weeks, about 44 weeks, about 45 weeks, about 46 weeks, about 47 weeks, about 48 weeks, about 49 weeks, about 50 weeks, about 51 weeks, about 52 weeks, or more. In some embodiments, the monthly dose is administered for at least about 4 weeks, for example, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, at least about 24 weeks, at least about 28 weeks, at least about 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 week, at least about 48 weeks, at least about 52 weeks, at least about 56 week, at least about 60 weeks, at least about 64 weeks, or more.

[0171] Methods of Treatment and Uses

[0172]

[0120] 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 the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is obese, overweight or normal weight. Some Aty Ref. METS-023 / 02WO 350242-2264 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 the first peptide (e.g., SEQ ID NO: 3) or a pharmaceutically acceptable salt thereof and the second peptide (e.g., SEQ ID NO: 4) 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.

[0173]

[0121] 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 simultaneously (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).

[0174]

[0122] 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. Aty Ref. METS-023 / 02WO 350242-2264

[0175]

[0123] 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.

[0176]

[0124] 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.

[0177]

[0125] 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.

[0178]

[0126] 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.

[0179]

[0127] 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.

[0180]

[0128] 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. Aty Ref. METS-023 / 02WO 350242-2264

[0181]

[0129] 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.

[0182]

[0130] 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.

[0183]

[0131] 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).

[0184]

[0132] The term “metabolic disease” or “metabolic disorder” includes any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic 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).

[0185]

[0133] 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, Aty Ref. METS-023 / 02WO 350242-2264 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 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.

[0186]

[0134] 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.

[0187]

[0135] 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, Aty Ref. METS-023 / 02WO 350242-2264 endotoxin mediated liver injury) or chronic renal failure. Thus, the compositions and methods described herein are applicable to these conditions.

[0188]

[0136] In some embodiments, the methods provided herein may be used as next-step treatment following a prior GLP-1 receptor agonist and / or Amylin 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 GLP-1 receptor agonist and / or Amylin analog administered on a daily or weekly basis, comprising a) discontinuing the administration of the prior GLP-1 receptor agonist and / or Amylin analog; and b) thereafter, initiating the subcutaneous administration of the first peptide and the second peptide described herein pharmaceutically acceptable salt thereof. 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 Amylin analogs that the subject may have received include, but are not limited to, Pramlintide, Cagrilintide, and Petrelintide (ZP8396).

[0189] NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0190]

[0137] In addition to the disclosure above, the Examples below, and the appended claims, the disclosure sets forth the following numbered embodiments.

[0191] 1. A pharmaceutical composition, comprising: a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof; and 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;

[0192] 2. The pharmaceutical composition 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 Atty Ref. METS-023 / 02WO 350242-2264

[0193] 3. The pharmaceutical composition of embodiment 1 or 2, wherein the first peptide further comprises a lipid moiety.

[0194] 4. The pharmaceutical composition 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.

[0195] 5. The pharmaceutical composition of any one of the preceding embodiments, wherein the second peptide further comprises a lipid moiety.

[0196] 6. The pharmaceutical composition 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.

[0197] 7. The pharmaceutical composition of any one of embodiments 3-6, wherein the lipid moiety is selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids.

[0198] 8. The pharmaceutical composition of any one of embodiments 3-7, wherein the lipid moiety is:

[0199] 9. The pharmaceutical composition of any one of any preceding embodiments, wherein the first peptide is:

[0200] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof.

[0201] 10. The pharmaceutical composition of any one of the preceding embodiments, wherein the second peptide is: Atty Ref. METS-023 / 02WO 350242-2264

[0202] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0203] 11. The pharmaceutical composition of any one of the preceding embodiments, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 4: 1 to about 1 :4.

[0204] 12. The pharmaceutical composition of embodiment 11, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1.

[0205] 13. The pharmaceutical composition of embodiment 11, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1.35.

[0206] 14. The pharmaceutical composition of embodiment 11, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.5: 1.

[0207] 15. The pharmaceutical composition of embodiment 11, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :4.

[0208] 16. The pharmaceutical composition of embodiment 11, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2.5.

[0209] 17. The pharmaceutical composition of embodiment 11, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2. Atty Ref. METS-023 / 02WO 350242-2264

[0210] 18. The pharmaceutical composition of any one of the preceding embodiments, wherein the first peptide and the second peptide are fused to each other.

[0211] 19. The pharmaceutical composition of any one of the preceding embodiments, wherein the first peptide and the second peptide are co-formulated in a solution.

[0212] 20. The pharmaceutical composition of any one of the preceding embodiments, wherein the first peptide and the second peptide are in solution, lyophilized, or cryopreserved.

[0213] 21. A combination, comprising: a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof; and 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.

[0214] 22. The combination of embodiment 21, 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.

[0215] 23. The combination of embodiment 21 or 22, wherein the first peptide further comprises a lipid moiety.

[0216] 24. The combination of embodiment 23, wherein the lipid moiety of the first peptide is linked to the alpha nitrogen of the N-terminal lysine of the first peptide.

[0217] 25. The combination of any one of embodiments 21-24, wherein the second peptide further comprises a lipid moiety.

[0218] 26. The combination of embodiment 25, wherein the lipid moiety of the second peptide is linked to the epsilon nitrogen of the C-terminal lysine of the second peptide. Atty Ref. METS-023 / 02WO 350242-2264

[0219] 27. The combination of any one of embodiments 23-26, wherein the lipid moiety is selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids.

[0220] 28. The combination of any one of embodiments 23-27, wherein the lipid moiety is:

[0221] 29. The combination of any one of embodiments 23-28, wherein the first peptide is:

[0222] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof.

[0223] 30. The combination of any one of embodiments 23-29, wherein the second peptide is:

[0224] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0225] 31. The combination of any one of embodiments 23-30, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 4: 1 to about 1 :4.

[0226] 32. The combination of embodiment 31, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1. Aty Ref. METS-023 / 02WO 350242-2264

[0227] 33. The combination of embodiment 31, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1.35.

[0228] 34. The combination of embodiment 31, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.5: 1.

[0229] 35. The combination of embodiment 31, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :4.

[0230] 36. The combination of embodiment 31, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2.5.

[0231] 37. The combination of embodiment 31, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2.

[0232] 38. The combination of any one of embodiments 21-37, wherein the first peptide and the second peptide are formulated in separate pharmaceutical compositions.

[0233] 39. The combination of embodiment 38, wherein the first peptide and the second peptide are provided in different containers.

[0234] 40. The combination of any one of the preceding embodiments, wherein the first peptide and the second peptide are in solution, lyophilized, or cryopreserved.

[0235] 41. 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 the pharmaceutical composition of any one of embodiments 1-20 or the combination of any one of claims 21-40. Aty Ref. METS-023 / 02WO 350242-2264

[0236] 42. A method 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 the pharmaceutical composition of any one of embodiments 1-20 or the combination of any one of claims 21-40.

[0237] 43. A method of inducing or maintaining weight loss or managing body weight in a subject, the method comprising administering to the subject: first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof; and 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.

[0238] 44. The method of embodiment 43, 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.

[0239] 45. The method of embodiment 43 or 44, wherein the first peptide further comprises a lipid moiety.

[0240] 46. The method of embodiment 45, wherein the lipid moiety of the first peptide is linked to the alpha nitrogen of the N-terminal lysine of the first peptide.

[0241] 47. The method of any one of embodiments 43-46, wherein the second peptide further comprises a lipid moiety.

[0242] 48. The method of embodiment 47, wherein the lipid moiety of the second peptide is linked to the epsilon nitrogen of the C-terminal lysine of the second peptide.

[0243] 49. The method of any one of embodiments 45-48, wherein the lipid moiety is selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids. Atty Ref. METS-023 / 02WO 350242-2264

[0244] 50. The method of any one of embodiments 45-49, wherein the lipid moiety is:

[0245] 51. The method of any one of embodiments 43-50, wherein the first peptide is:

[0246] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof.

[0247] 52. The method of any one of embodiments 43-51, wherein the second peptide is:

[0248] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0249] 53. A method of inducing or maintaining weight loss or managing body weight in a subject, the method comprising administering to the subject: a first peptide comprising the amino acid sequence of

[0250] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; and Atty Ref. METS-023 / 02WO 350242-2264

[0251] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0252] 54. The method of any one of embodiments 43-53, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 4: 1 to about 1 :4.

[0253] 55. The method of embodiment 54, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1.

[0254] 56. The method of embodiment 54, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1.35.

[0255] 57. The method of embodiment 54, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.5: 1.

[0256] 58. The method of embodiment 54, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :4.

[0257] 59. The method of embodiment 54, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2.5.

[0258] 60. The method of embodiment 54, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2. Atty Ref. METS-023 / 02WO 350242-2264

[0259] 61. The method of any one of embodiments 43-60, wherein the first peptide and the second peptide are fused to each other.

[0260] 62. The method of any one of embodiments 43-61, wherein the first peptide and the second peptide are co-formulated in a solution.

[0261] 63. The method of any one of embodiments 43-62, wherein the first peptide and the second peptide are co-formulated in the same pharmaceutical composition.

[0262] 64. The method of embodiment 63, wherein the first peptide and the second peptide are provided in the same container.

[0263] 65. The method of any one of embodiment 63 or 64, wherein the first peptide and the second peptide are co-administered concurrently.

[0264] 66. The method of any one of embodiments 43-66, wherein the first peptide and the second peptide are formulated in separate pharmaceutical compositions.

[0265] 67. The method of embodiment 66, wherein the first peptide and the second peptide are provided in different containers.

[0266] 68. The method of embodiment 66 or 67, wherein the first peptide and the second peptide are administered concurrently or sequentially.

[0267] 69. The method of any one of embodiment 43-68, wherein the first peptide and the second peptide are in solution, lyophilized, or cryopreserved.

[0268] 70. The method of any one of embodiments 41-69, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 9.6 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 9.6 mg.

[0269] 71. The method of any one of embodiments 41-69, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg Aty Ref. METS-023 / 02WO 350242-2264 to about 7.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 7.2 mg.

[0270] 72. The method of embodiment 71, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg to about 0.4 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg.

[0271] 73. The method of embodiment 72, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg.

[0272] 74. The method of embodiment 71, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.5 mg to about 0.7 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg.

[0273] 75. The method of embodiment 74, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.6 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg.

[0274] 76. The method of embodiment 71, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg.

[0275] 77. The method of embodiment 76, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg.

[0276] 78. The method of embodiment 71, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.05 mg to about 0.15 mg. Aty Ref. METS-023 / 02WO 350242-2264

[0277] 79. The method of embodiment 78, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg.

[0278] 80. The method of embodiment 71, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.15 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg.

[0279] 81. The method of embodiment 80, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg.

[0280] 82. The method of embodiment 71, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg to about 0.4 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.15 mg.

[0281] 83. The method of embodiment 82, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg.

[0282] 84. The method of any one of embodiments 41-69, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once monthly dose of about 0.1 mg to about 9.6 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once monthly dose of about 0.1 mg to about 9.6 mg.

[0283] 85. The method of any one of embodiments 41-69, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once monthly dose of about 0.1 mg to about 7.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once monthly dose of about 0.1 mg to about 7.2 mg.

[0284] 86. The method of any one of embodiments 41-69, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg and the second peptide or a pharmaceutically acceptable salt Aty Ref. METS-023 / 02WO 350242-2264 thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 2 weeks to about 8 weeks, followed by titrating to a higher once weekly dose ranging from about 0.2 mg to about 4.8 mg, and thereafter followed by administration of a once monthly dose of about 0.4 mg to about 9.6 mg for each peptide.

[0285] 87. The method of any one of embodiments 41-69, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 2 weeks to about 8 weeks, followed by titrating to a higher once weekly dose ranging from about 0.2 mg to about 4.8 mg, and thereafter followed by administration of a once monthly dose of about 0.4 mg to about 7.2 mg for each peptide.

[0286] 88. The method of embodiment 86 or 87, wherein the titrating comprises one or more steps of increasing a dose of the first peptide or a pharmaceutically acceptable salt thereof, and the second peptide or a pharmaceutically acceptable salt thereof, wherein each increasing dose is administered for a period of about 2 weeks to about 8 weeks.

[0287] 89. The method of any one of embodiments 41-69, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 4 weeks, followed by titrating to a higher once weekly dose ranging from about 0.2 mg to about 4.8 mg for a period of about 4 weeks to about 8 weeks, and thereafter followed by administration of a once monthly dose of about 0.6 mg to about 6.4 mg for each peptide.

[0288] 90. The method of any one of embodiments 86-89, wherein the each higher weekly dose is about 1.5 fold to about 4 fold of an immediately preceding weekly dose.

[0289] 91. The method of embodiment 90, wherein the each higher weekly dose is about 1.5 fold of an immediately preceding weekly dose.

[0290] 92. The method of embodiment 90, wherein the each higher weekly dose is about 2 fold of an immediately preceding weekly dose. Atty Ref. METS-023 / 02WO 350242-2264

[0291] 93. The method of embodiment 90, wherein the each higher weekly dose is about 3 fold of an immediately preceding weekly dose.

[0292] 94. The method of embodiment 90, wherein the each higher weekly dose is about 4 fold of an immediately preceding weekly dose.

[0293] 95. The method of any one of embodiments 86-94, wherein the titrating comprises two steps of increasing a dose of the first peptide, or a pharmaceutically acceptable salt thereof, and the second peptide, or a pharmaceutically acceptable salt thereof, wherein each increasing dose is administered for a period of about 4 weeks.

[0294] 96. The method of any one of embodiments 86-94, wherein the titrating comprises two steps of increasing a dose of the first peptide or a pharmaceutically acceptable salt thereof, and the second peptide or a pharmaceutically acceptable salt thereof, wherein a first increasing dose is administered for a period of about 4 weeks, and a second increasing dose is administered for a period of about 8 weeks.

[0295] 97. The method of any one of embodiments 86-96, wherein the monthly dose is about 1.5 fold to about 4 fold of an immediately preceding weekly dose.

[0296] 98. The method of embodiment 97, wherein the monthly dose is about 1.5 fold of an immediately preceding weekly dose.

[0297] 99. The method of embodiment 97, wherein the monthly dose is about 2 fold of an immediately preceding weekly dose.

[0298] 100. The method of embodiment 97, wherein the monthly dose is about 3 fold of an immediately preceding weekly dose.

[0299] 101. The method of embodiment 97, wherein the monthly dose is about 4 fold of an immediately preceding weekly dose.

[0300] 102. The method of embodiment 89, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once Aty Ref. METS-023 / 02WO 350242-2264 weekly dose of about 0.2 mg, for about 4 weeks, followed by a once weekly dose of about 0.3 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, and thereafter followed by a once weekly dose of about 0.6 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof.

[0301] 103. The method of embodiment 89, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg for about 4 weeks, followed by a once weekly dose of about 0.2 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.2 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, and thereafter followed by a once weekly dose of about 0.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof.

[0302] 104. The method of embodiment 89, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg for about 4 weeks, followed by a once weekly dose of about 0.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, and thereafter followed by a once weekly dose of about 0.6 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide or a pharmaceutically acceptable salt thereof.

[0303] 105. The method of embodiment 89, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg for about 4 weeks, followed by a once weekly dose of about 0.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, thereafter followed by a once weekly dose of about 0.8 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the Aty Ref. METS-023 / 02WO 350242-2264 second peptide or a pharmaceutically acceptable salt thereof, and thereafter followed by a once monthly dose of about 1.6 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 1.6 mg for the second peptide or a pharmaceutically acceptable salt thereof.

[0304] 106. The method of embodiment 89, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.3 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, thereafter followed by a once weekly dose of about 0.8 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 1.6 mg for the second peptide or a pharmaceutically acceptable salt thereof, and thereafter followed by a once monthly dose of about 2.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 4.8 mg for the second peptide or a pharmaceutically acceptable salt thereof.

[0305] 107. The method of embodiment 89, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, thereafter followed by a once weekly dose of about 1.2 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 1.6 mg for the second peptide or a pharmaceutically acceptable salt thereof, and thereafter followed by a once monthly dose of about 4.8 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 4.8 mg or about 6.4 mg for the second peptide or a pharmaceutically acceptable salt thereof.

[0306] 108. The method of any one of embodiments 41-69, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 2 weeks to about Aty Ref. METS-023 / 02WO 350242-2264 12 weeks, followed by administration of a once monthly dose of about 0.4 mg to about 9.6 mg for each peptide.

[0307] 109. The method of any one of embodiments 41-69, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0. 1 mg to about 0.8 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 2 weeks to about 12 weeks, followed by administration of a once monthly dose of about 0.4 mg to about 7.2 mg for each peptide.

[0308] 110. The method of embodiment 108 or 109, wherein the weekly dose of the first peptide or a pharmaceutically acceptable salt thereof is about 0.1 mg to about 0.2 mg and the weekly dose of the second peptide or a pharmaceutically acceptable salt thereof is about 0. 1 mg to about 0.8 mg.

[0309] 111. The method of any one of embodiments 41-110, wherein the subject the subject has obesity or is overweight.

[0310] 112. The method of any one of embodiments 41-110, wherein the subject has a body mass index (BMI) of at least 27 kg / m2.

[0311] 113. The method of embodiment 111 or 112, wherein the subject has a weight-related comorbid condition.

[0312] 114. The method of embodiment 113, wherein the weight-related comorbid condition is hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, Type 2 diabetes (T2DM), or nonalcoholic fatty liver disease (NAFLD).

[0313] 115. The method of embodiment 114, wherein the weight-related comorbid condition is T2DM.

[0314] 116. The method of any one of embodiments 41-110, wherein the subject has a metabolic disorder. Aty Ref. METS-023 / 02WO 350242-2264

[0315] 117. The method of embodiment 116, wherein the metabolic disorder is selected from obesity, prediabetes, diabetes, non-alcoholic fatty liver disease (NAFLD), and polycystic ovary syndrome (PCOS).

[0316] 118. The method of any one of embodiments 41-117, wherein the administration is subcutaneous.

[0317] Additional Embodiments

[0318]

[0138] Additional embodiments of the disclosure are encompassed by the following numbered embodiments:

[0319] 1. A peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof.

[0320] 2. The peptide of embodiment 1, wherein the peptide comprises a disulfide bond between the cysteine at position 3 of and the cysteine at position 8 of SEQ ID NO: 1.

[0321] 3. The peptide of embodiment 1 or 2, wherein the peptide further comprises a lipid moiety.

[0322] 4. The peptide of embodiment 3, wherein one or more of the amino acids of the peptide is chemically modified, optionally through conjugation, to the lipid moiety.

[0323] 5. The peptide of embodiment 3 or 4, wherein the lipid moiety of the peptide is linked, optionally conjugated, to the alpha nitrogen of the N-terminal lysine of the peptide.

[0324] 6. The peptide of any one of embodiment 3-5, wherein the lipid moiety is selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids.

[0325] 7. The peptide of any one of embodiments 3-5, wherein the lipid moiety is: Atty Ref. METS-023 / 02WO 350242-2264

[0326] 8. The peptide of embodiment 7, wherein the first peptide is:

[0327] (SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof.

[0328] 9. A 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.

[0329] 10. The peptide of embodiment 9, wherein the peptide further comprises a lipid moiety.

[0330] 11. The peptide of embodiment 10, wherein one or more of the amino acids of the peptide is chemically modified, optionally through conjugation, to the lipid moiety.

[0331] 12. The peptide of embodiment 10 or 11, wherein the lipid moiety of the peptide is linked to the epsilon nitrogen of the C-terminal lysine of the second peptide.

[0332] 13. The peptide of any one of embodiment 10-12, wherein the lipid moiety is selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids.

[0333] 14. The peptide of any one of embodiment 10-12, wherein the lipid moiety is: Atty Ref. METS-023 / 02WO 350242-2264

[0334] 15. The peptide of embodiment 14, wherein the peptide is:

[0335] (SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

[0336] 16. A derivative of the peptide of any preceding embodiment.

[0337] 17. A pharmaceutical composition comprising two or more of the peptides, or a pharmaceutically acceptable salt thereof, of any of the preceding embodiments.

[0338] 18. A pharmaceutical composition comprising two or more of the peptides of any of the preceding embodiments.

[0339] 19. A pharmaceutical composition comprising two or more derivatives of one or more of the peptides of any of the preceding embodiments.

[0340] 20. A pharmaceutical composition comprising two or more lipidated peptides of one or more of the peptides of any of the preceding embodiments.

[0341] EXAMPLES

[0342]

[0139] 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, Aty Ref. METS-023 / 02WO 350242-2264 pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope.

[0343] Example 1: In vivo effectiveness of SEQ ID NO: 4 and SEQ ID NO: 3 in combination

[0344]

[0140] As demonstrated herein, a combination of SEQ ID NO: 4 and SEQ ID NO: 3 has promise as a monthly GLP-1 receptor agonist / amylin analog combination, owing at least to their comparable half-lives, miscibility, and overlapping solubility parameters, which also supports a single-chamber co-formulation of the two peptides. Phase 1 and 2 clinical trials of CagriSema, an existing GLP-1 receptor agonist / amylin combination, has provided human data supporting the additive effects of GLP-1 and amylin receptor agonism on metabolic parameters including body weight. However, like many clinical-stage candidates, CagriSema is studied with a weekly dosing regimen with a titration profile similar to semaglutide (consistent with the half-life of approximately one week). CagriSema is also dosed via a dual-chamber injector because cagrilintide and semaglutide likely cannot be co-formulated in a single syringe. Without wishing to be bound by any particular theory, the half-life profiles and miscibility of SEQ ID NO: 4 and SEQ ID NO: 3 enable differentiated, convenient dosing regimens as a combination therapy conducive to chronic dosing, while the potency and predicted additive efficacy of the two peptides potentially enables a differentiated impact on body weight loss and health outcomes.

[0345]

[0141] In a head-to-head repeat dose study of SEQ ID NO: 4 and SEQ ID NO: 3 versus CagriSema, rats received active drug or vehicle at matched doses, every other day through day 30. Treatments were initiated at 0.5 nmol / kg for each of the components and escalated as shown in the body weight loss figure below. This study found statistically significant superiority for the combination of SEQ ID NO: 4 and SEQ ID NO: 3 versus CagriSema (FIG. 1).

[0346]

[0142] Solubility of SEQ ID NO: 4, SEQ ID NO: 3, and the combination of the two was tested using absorbance at 600 nm to determine the solubility of the peptides. The pH dependent solubility of SEQ ID NO: 4 and SEQ ID NO: 3 was profiled at 2 mg / mL, in each case, and of the combination of the two candidates at 0.5 mg / mL and determined that all were soluble across a pH range with absorbance values less than 0.24, which was the empirically determined cut-off for acceptable solubility. FIG. 2 summarizes solubility across the pH range of 2.6 to 7.6.

[0347] Example 2: Efficacy of SEQ ID NO: 4 and SEQ ID NO: 3 combination in rats

[0348]

[0143] 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 Aty Ref. METS-023 / 02WO 350242-2264 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).

[0349]

[0144] Study Schedule-. SC injections of vehicle, SEQ ID NO: 4, M2 (SEQ ID NO: 4 + SEQ ID NO: 3) (n=6-7 / group) were administered three times per week from Day O to 18 using 31Gx 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 and SEQ ID NO: 3 - initiated at 0.5 and 0.5 nmol / kg, respectively.

[0350]

[0145] 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.

[0351]

[0146] Results: Combinations of SEQ ID NO: 4 and SEQ ID NO: 3 led to significant body weight reduction in mice (20% change in body weight normalized to vehicle) compared to monotherapy (less than 5% change in body weight normalized to vehicle) on Day 21.

[0352] Example 3: Pharmacokinetics in minipigs

[0353] Formulation Preparation

[0354]

[0147] 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

[0355]

[0148] Formulation steps: (1) Prepare required volume of each diluent according to table above;

[0356] (2) Reconstitute each peptide in the required volume of its own buffer i.e. peptide 1 in Diluent A;

[0357] (3) Mix reconstituted peptide solutions in a ratio of 1 : 1 : 1 : 1, combining peptide 1 and peptide 2 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. Atty Ref. METS-023 / 02WO 350242-2264

[0358] Animal Specifications

[0359] Species Barna Miniature Swine

[0360] History of Dosing Naive animals

[0361] Body Weight Range 7~17kg

[0362] Age > 3 months

[0363] Sex Male

[0364] Number of Animals for Acclimation 6 males

[0365] Number of Animals for Dosing 4 males

[0366] Animal Care

[0367]

[0149] Environmental Conditions: The room(s) are 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 changes / hour. The room is on a 12-hour light / dark cycle except when interruptions are necessitated by study activities.

[0368]

[0150] Housing: Animals are 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.

[0369]

[0151] Drinking Water: RO (reverses osmosis) water is available to all animals, ad libitum.

[0370] Administration of Dose Formulation

[0371] Administration Route: Subcutaneous

[0372] Dose Administration: Subcutaneous (SC): The SC dose is administered to the back of the neck via subcutaneous injection

[0373] Pharmacokinetics in Male Barna Minipigs

[0374]

[0152] 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. Mean pharmacokinetic parameters are shown in Table 1. Atty Ref. METS-023 / 02WO 350242-2264

[0375] Table 1. Mean pharmacokinetic parameters

[0376]

[0153] FIG. 3 shows a comparison of the pharmacokinetics of SEQ ID NO: 4 and SEQ ID NO: 3 in particular. Combinability is supported by in vivo evidence that SEQ ID NO: 4 and SEQ ID NO: 3 had comparable half-lives when administered as a single, co-formulated, subcutaneous injection in pigs. Overall, SEQ ID NO: 3 and SEQ ID NO: 4 had similar pharmacokinetic (PK) profiles, including half-lives of 114 and 99 hours, respectively. In this experiment, SEQ ID NO: 3 was co-formulated and co-administered with SEQ ID NO: 4, and plasma concentrations of each peptide were measured over 264 hours after injection.

[0377] Example 4: Phase l / 2a Clinical Study

[0378]

[0154] This is an on-going randomized, placebo-controlled, double-blind, double-dummy study to investigate the safety, tolerability, PK, and PD of subcutaneous (SC) doses of the amylin analog (SEQ ID NO: 3) co-administered with the GLP-1 receptor agonist (SEQ ID NO: 4) in adult participants with a BMI of 27 to 38 kg / m2, including some participants with T2DM.

[0379]

[0155] There are three parts to this study. Part A consists of single ascending dose (SAD) cohorts, PartB is multiple-ascending dose (MAD) cohorts, and Part C consists of 13 -week Dosing Cohorts. Parts A and B include only participants with overweight or obesity without type 2 diabetes (T2DM). Part C include participants with overweight or obesity who also have T2DM.

[0380]

[0156] For Part A, after the up to 4-week screening period, the study includes 1 dose and a 12-week safety follow-up after administration. Table 2 provides the doses administered in SAD Cohorts A1-A6. Atty Ref. METS-023 / 02WO 350242-2264

[0381] Table 2. Dosing in SAD Cohorts A1-A6

[0382]

[0157] For Part B and C, after the up to 4-week screening period, the study includes 12 once-weekly doses. Bl -Cl evaluated a dose-titration regimen with a single 1.5 to 4-fold dose increase over the weekly dose to assess the tolerability of switching to a pharmacologically matched, dose at monthly intervals. B4-C1 cohorts received an once monthly dose on Week 13. Table 3 provides the doses administered in MAD Cohorts B1-B6 and Cl.

[0383] Table 3. Dosing in MAD Cohorts B1-B6

[0384]

[0158] The primary endpoints include safety assessment via evaluation of adverse events (AEs), vital signs (including temperature, heart rate and blood pressure), 12-lead electrocardiogram (ECG), corrected QT (QTc) analysis, laboratory evaluations, physical examination, glucose monitoring, and injection site reactions. Tolerability will be assessed via an assessment of treatment-emergent adverse events (TEAE).

[0385]

[0159] The secondary endpoints include PK and PD measures. The PK parameters include maximum concentration (Cmax), time to maximum concentration (Tmax), area under the concentration versus time curve during the dosing interval (AUC), minimum observed Aty Ref. METS-023 / 02WO 350242-2264 concentration (Cmin), half-life T1 / 2, average concentration over the dosing interval (Cavg). The PD parameters include Percent change from baseline in weight and all other post-baseline pre-dose weekly measurements, occurrence of weight loss that is > 5%, > 10%, and > 15%, change from baseline (at all post-baseline measurements) in Body Mass Index (BMI), body weight (absolute and percent weight loss), waist circumference, change from baseline (at all post-baseline measurements) in glucose metabolism parameters (fasting insulin, hemoglobin Ale [HbAlc], fasting glucose and fasting glucagon), and change from baseline (at all post-baseline measurements) in lipid levels (triglycerides, high-density lipoprotein-cholesterol [HDL-C] and low-density lipoprotein-cholesterol [LDL-C]).

[0386]

[0160] The inclusion criteria for participants include overweight / obese but otherwise healthy adult male or female with a BMI within 27.0 kg / m2 to 38.0 kg / m2, inclusively. For participants in Part A and B, no history of clinically significant diseases or clinically significant findings from the physical examination. For participants in Part C, no clinically significant diseases except T2DM, well controlled hypertension, and / or dyslipidemia. Participants in Part C were diagnosed with T2DM for at least 3 months before screening. For participants in Part C, T2DM includes glycated hemoglobin (HbAlc) value < 10.5% at screening and treated with stable therapy for at least 30 days prior to Screening / visit 1.

[0387]

[0161] Based on the preliminary blinded safety data, all TEAEs across all cohorts were mild or moderate. No SAEs, discontinuations due to AEs, or fatal events have occurred. Across all cohorts, incidences of GI TEAEs have been approximately 50% of participants overall. The most frequently experienced TEAEs in MAD cohorts have been nausea, constipation, and vomiting.

[0388]

[0162] Table 4 provides the preliminary blinded tolerability data obtained in cohorts SAD A1-A6.

[0389] Table 4. Preliminary blinded tolerability data obtained in cohorts SAD A1-A6

[0390]

[0163] Table 5 provides the preliminary blinded tolerability data obtained in cohorts MAB B1-B6 and Cl over time. Atty Ref. METS-023 / 02WO 350242-2264

[0391] Table 5. Preliminary blinded tolerability data obtained in cohorts MAB B1-B6 and Cl

[0392]

[0164] Preliminary data demonstrate that the tolerability profile of the disclosed combination therapy is significantly influenced by the initial dose of the amylin receptor agonist (SEQ ID NO: 3), with a comparatively lower sensitivity to the starting dose of the GLP-1 receptor agonist (SEQ ID NO: 4). Specifically, administration of SEQ ID NO: 3 at an initial dose of 0.3 mg was associated with nausea incidence rates ranging from approximately 22% to approximately 50%. These findings indicate the importance of initiating treatment with a reduced dose of the amylin receptor agonist to mitigate adverse gastrointestinal effects and enhance overall tolerability of the therapeutic regimen.

[0393]

[0165] Preliminary PK data for Part A suggest that both the amylin analog (SEQ ID NO: 3) and GLP-1 receptor agonist (SEQ ID NO: 4) levels rise to a delayed and blunted peak and fall from peak levels in an approximately monophasic manner. Following a single dose of SEQ ID NO: 3 / SEQ ID NO: 4 0.6 / 0.4 mg (n=8), the geometric mean (%CV) of SEQ ID NO: 3 and SEQ ID NO: 4 AUCo-168 were 5170 (30.6%) h*ng / mL and 4880 (27.0%) h*ng / mL, and 40.8 (25.4%) ng / mL and 36.0 (23.3%) ng / mL for Cmax, respectively. Median (range) Tmax was 96 (48 to 168) hours for both SEQ ID NO: 3 and SEQ ID NO: 4; geometric mean (%CV) apparent terminal ti / 2 Aty Ref. METS-023 / 02WO 350242-2264 was 283 (11.7%) hours and 331 (12.0%) hours for SEQ ID NO: 3 and SEQ ID NO: 4, respectively.

[0394]

[0166] Preliminary PK data from Part B suggest SEQ ID NO: 3 and SEQ ID NO: 4 are independent (i.e., no drug-drug interaction is apparent). PK parameter estimates seen with SEQ ID NO: 3 and SEQ ID NO: 4 coadministration appear to be comparable to those previously seen for SEQ ID NO: 3 and SEQ ID NO: 4 monotherapies. Based on the limited available data, PK do not suggest departures from dose-proportional behavior for SEQ ID NO: 3 or SEQ ID NO: 4 based on AUCo-i68h.

[0395]

[0167] A dose-titration regimen results in superior tolerability and meaningful body weight reduction over 12 weeks of dosing.

[0396] Experiment 5: Phase 2B clinical study

[0397]

[0168] This is a phase 2B, multi-center, randomized, placebo-controlled, double-blind, doubledummy, dose-ranging study to investigate the safety and efficacy of the amylin analog (SEQ ID NO: 3) and GLP-1 receptor agonist (SEQ ID NO: 4) co-administered by subcutaneous (SC) injection in once-weekly (QW) and once-monthly (QM) dose regimens, compared with e amylin analog (SEQ ID NO: 3) and GLP-1 receptor agonist (SEQ ID NO: 4) monotherapies and placebo.

[0398]

[0169] A total of -630 participants will be randomized in a 1:1:1:1:1:1:1 ratio to 1 of 7 treatment groups (-90 participants / group) for QW dosing: 4 QW M2 (SEQ ID NO: 3 + SEQ ID NO: 4) dose level groups, SEQ ID NO: 3 and SEQ ID NO: 4 monotherapies, or placebo (FIG. 4). All treatment groups will initiate QW dosing with upward dose titration for 8 weeks, to reach a stable QW dose maintained up to 12 weeks. Target stable QW doses following titration are up to 0.8 mg SEQ ID NO: 3 and 1 6 mg SEQ ID NO: 4 At 12 weeks, all groups will be split by approximately half (-45 participants / group) to receive QW or QM dosing for the remainder of the 60-week Treatment Period for a total of 14 treatment regimen groups. Target QM doses are up to 3.2 mg SEQ ID NO: 3 and up to 6.4 mg SEQ ID NO: 4. A switch from QW to QM dosing for -50% of each treatment group allows for clinical comparisons between QM and QW dosing from 12 weeks through end of the 60-week Treatment Period. Participants in the placebo group will be randomly allocated to proportionately match regimens of active groups consistent with the double-dummy study design.

[0399]

[0170] 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 Aty Ref. METS-023 / 02WO 350242-2264 >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.

[0400]

[0171] 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).

[0401]

[0172] 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 (AUC(O-T)), maximum observed concentration (Cmax), and time to maximum concentration (tmax).

[0402]

[0173] 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).

[0403]

[0174] 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).

[0404]

[0175] To evaluate the efficacy of QW / QM combination therapy 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; Aty Ref. METS-023 / 02WO 350242-2264 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.

[0405]

[0176] 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.

[0406]

[0177] To characterize the immunogenicity to SEQ ID NO: 3 and SEQ ID NO: 4 following QW / QM dosing of SEQ ID NO: 3 and SEQ ID NO: 4 co-administered in participants in the Full population, the exploratory endpoint includes immunogenicity assessments of titer, incidence of predose AD As, and postdose treatment-enhanced or treatment-emergent AD As.

[0407]

[0178] To assess the effect of QW / QM SEQ ID NO: 3 and SEQ ID NO: 4 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

[0408] EQUIVALENTS AND SCOPE

[0409]

[0179] 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 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.

[0410]

[0180] 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 Aty Ref. METS-023 / 02WO 350242-2264 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.

[0411]

[0181] 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.

[0412]

[0182] 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

Atty Ref. METS-023 / 02WO 350242-2264CLAIMSWhat 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: a first peptide comprising the amino acid sequence of KKCSTATCATQRLAEELHKLQTYPRTPVGSNTP (SEQ ID NO: 1) or a pharmaceutically acceptable salt thereof; and 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.

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 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 claims 3-6, wherein the lipid moiety is selected from phospholipids, fatty acids, triglycerides, sterols, sphingolipids, glycerophospholipids, cationic lipids, and PEGylated lipids.

8. The method of any one of claims 3-7, wherein the lipid moiety is:

9. The method of any one of claims 1-8, wherein the first peptide is:Atty Ref. METS-023 / 02WO 350242-2264(SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1-9, wherein the second peptide is:(SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

11. A method of inducing or maintaining weight loss or managing body weight in a subject, the method comprising administering to the subject: a first peptide comprising the amino acid sequence of(SEQ ID NO: 3), or a pharmaceutically acceptable salt thereof; and(SEQ ID NO: 4), or a pharmaceutically acceptable salt thereof.

12. The method of any one of claims 1-11, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 4: 1 to about 1 :4.Atty Ref. METS-023 / 02WO 350242-226413. The method of claim 12, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1.

14. The method of claim 12, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 : 1.35.

15. The method of claim 12, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1.5: 1.

16. The method of claim 12, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :4.

17. The method of claim 12, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2.5.

18. The method of claim 12, wherein the weight ratio of the first peptide or pharmaceutically acceptable salt thereof to the second peptide or pharmaceutically acceptable salt thereof is about 1 :2.

19. The method of any one of claims 1-18, wherein the first peptide and the second peptide are co-formulated in a solution.

20. The method of any one of claims 1-18, wherein the first peptide and the second peptide are co-formulated in the same pharmaceutical composition.

21. The method of claim 20, wherein the first peptide and the second peptide are provided in the same container.Aty Ref. METS-023 / 02WO 350242-226422. The method of any one of claims 19-21, wherein the first peptide and the second peptide are co-administered concurrently.

23. The method of any one of claims 1-18, wherein the first peptide and the second peptide are formulated in separate pharmaceutical compositions.

24. The method of claim 23, wherein the first peptide and the second peptide are provided in different containers.

25. The method of claim 23 or 24, wherein the first peptide and the second peptide are administered concurrently or sequentially.

26. The method of any one of claims 1-25, wherein the first peptide and the second peptide are in solution, lyophilized, or cryopreserved.

27. The method of any one of claims 1-26, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 7.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 7.2 mg.

28. The method of claim 27, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg to about 0.4 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg.

29. The method of claim 28, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg.

30. The method of claim 27, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.5 mg to about 0.7 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg.Aty Ref. METS-023 / 02WO 350242-226431. The method of claim 30, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.6 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg.

32. The method of claim 27, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg.

33. The method of claim 32, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg.

34. The method of claim 27, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.05 mg to about 0.15 mg.

35. The method of claim 34, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg.

36. The method of claim 27, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.15 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg to about 0.5 mg.

37. The method of claim 36, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg.

38. The method of claim 27, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg to about 0.4 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.15 mg.Atty Ref. METS-023 / 02WO 350242-226439. The method of claim 38, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg.

40. The method of any one of claims 1-26, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once monthly dose of about 0.1 mg to about 7.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once monthly dose of about 0.1 mg to about 7.2 mg.

41. The method of any one of claims 1-26, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 2 weeks to about 8 weeks, followed by titrating to a higher once weekly dose ranging from about 0.2 mg to about 4.8 mg, and thereafter followed by administration of a once monthly dose of about 0.4 mg to about 7.2 mg for each peptide.

42. The method of claim 41, wherein the titrating comprises one or more steps of increasing a dose of the first peptide or a pharmaceutically acceptable salt thereof, and the second peptide or a pharmaceutically acceptable salt thereof, wherein each increasing dose is administered for a period of about 2 weeks to about 8 weeks.

43. The method of any one of claims 1-26, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.3 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 4 weeks, followed by titrating to a higher once weekly dose ranging from about 0.2 mg to about 4.8 mg for a period of about 4 weeks to about 8 weeks, and thereafter followed by administration of a once monthly dose of about 0.6 mg to about 6.4 mg for each peptide.

44. The method of any one of claims 41-43, wherein the each higher weekly dose is about 1.5 fold to about 4 fold of an immediately preceding weekly dose.Atty Ref. METS-023 / 02WO 350242-226445. The method of claim 44, wherein the each higher weekly dose is about 1.5 fold of an immediately preceding weekly dose.

46. The method of claim 44, wherein the each higher weekly dose is about 2 fold of an immediately preceding weekly dose.

47. The method of claim 44, wherein the each higher weekly dose is about 3 fold of an immediately preceding weekly dose.

48. The method of claim 44, wherein the each higher weekly dose is about 4 fold of an immediately preceding weekly dose.

49. The method of any one of claims 41-48, wherein the titrating comprises two steps of increasing a dose of the first peptide, or a pharmaceutically acceptable salt thereof, and the second peptide, or a pharmaceutically acceptable salt thereof, wherein each increasing dose is administered for a period of about 4 weeks.

50. The method of any one of claims 41-48, wherein the titrating comprises two steps of increasing a dose of the first peptide or a pharmaceutically acceptable salt thereof, and the second peptide or a pharmaceutically acceptable salt thereof, wherein a first increasing dose is administered for a period of about 4 weeks, and a second increasing dose is administered for a period of about 8 weeks.

51. The method of any one of claims 41-50, wherein the monthly dose is about 1.5 fold to about 4 fold of an immediately preceding weekly dose.

52. The method of claim 51, wherein the monthly dose is about 1.5 fold of an immediately preceding weekly dose.

53. The method of claim 51, wherein the monthly dose is about 2 fold of an immediately preceding weekly dose.

54. The method of claim 51, wherein the monthly dose is about 3 fold of an immediately preceding weekly dose.Aty Ref. METS-023 / 02WO 350242-226455. The method of claim 51, wherein the monthly dose is about 4 fold of an immediately preceding weekly dose.

56. The method of claim 43, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg, for about 4 weeks, followed by a once weekly dose of about 0.3 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, and thereafter followed by a once weekly dose of about 0.6 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof.

57. The method of claim 43, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg for about 4 weeks, followed by a once weekly dose of about 0.2 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.2 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, and thereafter followed by a once weekly dose of about 0.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof.

58. The method of claim 43, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.2 mg for about 4 weeks, followed by a once weekly dose of about 0.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, and thereafter followed by a once weekly dose of about 0.6 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide or a pharmaceutically acceptable salt thereof.

59. The method of claim 43, wherein the method comprises administeringAty Ref. METS-023 / 02WO 350242-2264 the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg for about 4 weeks, followed by a once weekly dose of about 0.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.4 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, thereafter followed by a once weekly dose of about 0.8 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide or a pharmaceutically acceptable salt thereof, and thereafter followed by a once monthly dose of about 1.6 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 1.6 mg for the second peptide or a pharmaceutically acceptable salt thereof.

60. The method of claim 43, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.3 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, thereafter followed by a once weekly dose of about 0.8 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 1.6 mg for the second peptide or a pharmaceutically acceptable salt thereof, and thereafter followed by a once monthly dose of about 2.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 4.8 mg for the second peptide or a pharmaceutically acceptable salt thereof.

61. The method of claim 43, wherein the method comprises administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.4 mg for about 4 weeks, followed by a once weekly dose of about 0.4 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 0.8 mg for the second peptide or a pharmaceutically acceptable salt thereof for about 4 weeks, thereafter followed by a once weekly dose of about 1.2 mg for the first peptide or a pharmaceutically acceptable salt thereof and a once weekly dose of about 1.6 mg for the second peptide or a pharmaceutically acceptable salt thereof, and thereafter followed by a once monthly dose of about 4.8 mg for the first peptide or a pharmaceutically acceptable saltAty Ref. METS-023 / 02WO 350242-2264 thereof and a once weekly dose of about 4.8 mg or about 6.4 mg for the second peptide or a pharmaceutically acceptable salt thereof.

62. The method of any one of claims 1-26, comprising administering the first peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0. 1 mg to about 0.8 mg and the second peptide or a pharmaceutically acceptable salt thereof at a once weekly dose of about 0.1 mg to about 0.8 mg, for about 2 weeks to about 12 weeks, followed by administration of a once monthly dose of about 0.4 mg to about 7.2 mg for each peptide.

63. The method of claim 62, wherein the weekly dose of the first peptide or a pharmaceutically acceptable salt thereof is about 0.1 mg to about 0.2 mg and the weekly dose of the second peptide or a pharmaceutically acceptable salt thereof is about 0. 1 mg to about 0.8 mg.

64. The method of any one of claims 1-63, wherein the subject the subject has obesity or is overweight.

65. The method of any one of claims 1-63, wherein the subject has a body mass index (BMI) of at least 27 kg / m2.

66. The method of claim 64 or 65, wherein the subject has a weight-related comorbid condition.

67. The method of claim 66, wherein the weight-related comorbid condition is hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease, Type 2 diabetes (T2DM), or nonalcoholic fatty liver disease (NAFLD).

68. The method of claim 67, wherein the weight-related comorbid condition is T2DM.

69. The method of any one of claims 1-63, wherein the subject has a metabolic disorder.

70. The method of claim 69, wherein the metabolic disorder is selected from obesity, prediabetes, diabetes, non-alcoholic fatty liver disease (NAFLD), and polycystic ovary syndrome (PCOS).Atty Ref. METS-023 / 02WO 350242-226471. The method of any one of claims 1-70, wherein the administration is subcutaneous.

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