Methods for inducing satiety and treating metabolic disorders

Abstract

The present invention provides methods for inducing satiety and treating metabolic disorders, diabetes, obesity, and obesity-related conditions, comprising administration of metabolic hormones via nasal, topical gastrointestinal, or intrarectal routes.

Description

[Background technology]

[0001] The prevalence of obesity continues to increase worldwide.However, there is still a lack of effective long-term non-invasive treatment for obesity and other metabolic disorders.Existing therapeutic agents induce satiety and treat metabolic syndrome, diabetes, obesity, and obesity-related disorders often do not provide suitable therapeutic effects.Therefore, new treatments are needed. Summary of the Invention

[0002] In one aspect, the invention features a method for inducing satiety or treating a disease or disorder selected from metabolic syndrome, obesity, obesity-related disorders, diabetes, fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome, cardiovascular disease, obstructive sleep apnea, retinopathy, peripheral vascular disease, peripheral arterial disease, and neuropathy (e.g., diabetic neuropathy) in a subject in need of such treatment. The method includes administering to the subject a composition comprising an agent selected from peptide YY (PYY), glucagon-like peptide 1 (GLP-1), leptin, amylin, insulin, and calcitonin, or an analog, variant, or biologically active fragment thereof. The composition is administered intranasally, topically to the gastrointestinal (GI) tract, or rectally. The composition provides treatment without substantially altering the concentration of the agent in the subject's blood.

[0003] In some embodiments, the composition is administered intranasally. The composition may be formulated, for example, as a spray, a semi-solid, a microparticle, or in a lipid-based carrier.

[0004] In some embodiments, the composition is administered locally to the GI tract. The composition may be formulated, for example, as a GI patch.

[0005] In some embodiments, the composition is administered rectally. The composition may be formulated, for example, as a suppository.

[0006] In some embodiments, the dose of the agent (e.g., PYY, GLP-1, leptin, amylin, insulin, or calcitonin, or an analog, variant, or biologically active fragment thereof) is 1 ng to 20 mg per 100 kg of body weight. For example, the dose of the agent may be from 1 ng to 10 ng per 100 kg body weight, such as 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng per 100 kg body weight, for example 10 ng to 100 ng per 100 kg body weight, for example 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng per 100 kg body weight, for example 100 ng to 1 μg per 100 kg body weight, for example 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1 μg per 100 kg body weight, for example 1 μg to 10 μg per 100 kg body weight, for example 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, or 10 μg per 100 kg of body weight, for example, 10 μg to 100 μg per 100 kg of body weight, for example, 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, or 100 μg per kg of body weight, for example, 100 μg to 1 mg per kg of body weight, for example, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, or 1 mg per kg of body weight, or for example, 1 mg to 20 mg per 100 kg of body weight, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg per 100 kg of body weight, It can be 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.

[0007] In some embodiments, the composition comprises PYY, or an analog, variant, or biologically active fragment thereof. The PYY fragment can be, for example, PYY(3-36).

[0008] In some embodiments, the composition comprises GLP-1, or an analog, variant, or biologically active fragment thereof.

[0009] In some embodiments, the composition comprises leptin, or an analog, variant, or biologically active fragment thereof.

[0010] In some embodiments, the composition comprises amylin, or an analog, variant, or biologically active fragment thereof.

[0011] In some embodiments, the composition comprises insulin, or an analog, variant, or biologically active fragment thereof.

[0012] In some embodiments, the composition does not include insulin, or an analog, variant, or biologically active fragment thereof.

[0013] In some embodiments, the composition comprises calcitonin, or an analog, variant, or biologically active fragment thereof.

[0014] definition To facilitate understanding of the present invention, certain terms are defined below. Terms defined herein have meanings commonly understood by those skilled in the art to which the present invention pertains. Terms such as "a", "an", and "the" are not intended to refer to a singular entity only, but are intended to include the general category within which a specific example may be used for illustration. Although the terms herein are used to describe certain embodiments of the present invention, their use does not limit the present invention, except as outlined in the claims.

[0015] As used herein, the term "about" refers to a value within 10% above or below the stated value.

[0016] The term "metabolic disorder", as used herein, refers to a human or animal condition or disease associated with and / or resulting from abnormal function or regulation of the metabolic system (e.g., obesity, diabetes, fatty liver disease, nonalcoholic steatohepatitis, polycystic ovary syndrome, elevated blood glucose levels, chronic kidney disease, cardiovascular disease, obstructive sleep apnea, retinopathy, neuropathy (e.g., diabetic neuropathy), peripheral arterial disease, and / or peripheral vascular disease). The term "disorder" generally refers to a disruption of normal body structure and function, or a pathophysiological response to internal or external factors.

[0017] As used herein, the term "subject" refers to a human or non-human animal (eg, a mammal). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] In general, the invention features methods for inducing satiety and treating conditions that affect metabolism, such as metabolic syndrome, diabetes, obesity, and obesity-related disorders. The present invention is based, in part, on the surprising discovery that metabolic hormones, such as PYY, can be administered via nasal, topical GI, or rectal routes to activate neuroreceptors in the central nervous system to effectively treat diseases or disorders.

[0019] By administering metabolic hormones via one of these routes, the composition can provide treatment to a subject without substantially altering the concentration of the agent in the subject's blood.Furthermore, these routes of administration avoid systemic administration, which is known to produce undesirable side effects such as nausea, injection site pain, or fatigue.

[0020] In general, by administering metabolic hormones via non-systemic routes, the hormones can target specific pleasure centers in the brain, activate important brain regions, and avoid neural or non-neural targets that may cause clinical risks (e.g., toxicity) or side effects such as nausea. For example, systemic administration of metabolic hormones activates neuroreceptors in the hypothalamus, nucleus tractus solitarius (NTS), and area postrema, while non-systemic administration routes described herein activate neuroreceptors in the hypothalamus and NTS but substantially avoid the area postrema. For example, by targeting neuroreceptors in the nose, rectum, or GI tract, the neuroreceptors and binding can fully activate pleasure centers in the CNS that control satiety. Thus, activation of these pleasure centers can provide treatment for metabolic or satiety disorders associated with dysregulation of pleasure centers in the brain. Methods are described in more detail below.

[0021] Metabolic Hormones Composition The methods described herein include administration of a metabolic hormone, or a biologically active fragment or variant thereof. The metabolic hormone targets (e.g., binds to, associates with, or interacts with) the Y2 receptor in the nasal cavity, GI tract, or rectum of a subject. In some embodiments, the metabolic hormone is PYY, PYY(3-36), leptin, amylin, insulin, calcitonin, or GLP-1, or a variant, analog, or biologically active fragment thereof.

[0022] In some embodiments, the dose of the metabolic hormone, or biologically active fragment, variant, or analog thereof, is from 0.1 ng to 20 mg. For example, the dose of the agent may be from 0.1 ng to 1 ng, for example, 0.2 ng, 0.3 ng, 0.4 ng, 0.5 ng, 0.6 ng, 0.7 ng, 0.8 ng, 0.9 ng, or 1 ng, for example, 1 ng to 10 ng, for example, 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 6 ng, 7 ng, 8 ng, 9 ng, or 10 ng, for example, 10 ng to 100 ng, for example, 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng, for example, 100 ng to 1 μg, for example, 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1 μg, for example, 1 μg to 10 μg, for example, 2 μg to 3 μg. g, 3, μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, or 10 μg, for example, 10 μg to 100 μg, for example, 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, or 100 μg, for example, 100 μg to 1 mg, for example, 100 μg, 200 μg, 300 μg, 400 μg , 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, or 1 mg, for example, 1 mg to 20 mg, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.

[0023] In some embodiments, the metabolic hormone is PYY, or an analog, variant, or biologically active fragment thereof. In some embodiments, the variant, analog, or biologically active fragment thereof has at least 70% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:1. In some embodiments, PYY has the amino acid sequence set forth in SEQ ID NO:1. In some embodiments, the methods described herein comprise administration of PYY, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein comprise administration of PYY, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein comprise administration of a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of PYY, or a variant, analog, or biologically active fragment thereof.

[0024] In some embodiments, the PYY fragment is PYY(3-36), or a variant, analog, or biologically active fragment thereof. In some embodiments, the PYY(3-36), or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:2. In some embodiments, the PYY(3-36) has the amino acid sequence set forth in SEQ ID NO:2. In some embodiments, the methods described herein comprise administration of a dose of about 2.5 μg to about 2.5 mg of PYY(3-36), or a variant, analog, or biologically active fragment thereof. In some embodiments, the methods described herein comprise administration of a dose of about 10 μg to about 1 mg of PYY(3-36), or a variant, analog, or biologically active fragment thereof. In some embodiments, the methods described herein comprise administration of a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of PYY(3-36), or a variant, analog, or biologically active fragment thereof.

[0025] In some embodiments, the PYY variant is [Pro34]PYY. In some embodiments, [Pro34]PYY, or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 11. In some embodiments, [Pro34]PYY has the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the PYY analog is NNC065-1273, which comprises a PYY(3-36) polypeptide having a beta-homo-arginine at position 35. In some embodiments, the PYY analog is NNC0165-1875. In some embodiments, the PYY analog is NNC0165-1562. In some embodiments, the PYY analogs are described, for example, in Lear et al. J. of Med. Chem. 63: 9660-9671, 2020 (incorporated herein by reference in its entirety). In some embodiments, the PYY analogs are PYY-antibodies, for example, as described in Rangwala et al. Cell Metab. 29: 837-843, 2019 (incorporated herein by reference in its entirety), and PYY conjugated to one or more PEG moieties. In some embodiments, the PYY analogs or variants are described in U.S. Patent No. 8,217,001 (the disclosure of which is incorporated herein by reference in its entirety).

[0026] In some embodiments, the PYY(3-36) variant, analog, or biologically active fragment thereof is selected from the group consisting of those described in Balasubramaniam et al., Pept Res. 1:32-35,1998;Liu et al., J.Gastrointest Surg. 5:147-152, 2001, which is incorporated herein by reference in its entirety, PYY(26-36), PYY(25-36), PYY(24-36), PYY(23-36), PYY(22-36), PYY(21-36), PYY(20-36), PYY(19-36), PYY(18-36), PYY(20-36), PYY(21-36), PYY(22-36), PYY(21 ... In some embodiments, the PYY(3-36) variant, analog, or fragment thereof is a single point mutation, e.g., a single point mutation in PYY(25-36), e.g., [Lys 25 ]PPY(25-36), [Thr 27 ]PPY(25-36), [Phe 21 ]PPY(25-36), [Ile 28 ]PYY(25-36), [Val 28 ]PYY(25-36), [Gln 29 ]PYY(25-36), [Ile 30 ]PYY(25-36), [Val 30 ]PYY(25-36), [Ile 31 ]PYY(25-36), [Leu 31 ]PYY(25-36), [Ser 32 ]PYY(25-36), [Lys 33 ]PYY(25-36), [Asn 34 ]PYY(25-36), [Lys 35 ]PYY(25-36), [Thr 36 ]PYY(25-36) or [Phe 36 ]PYY(25-36), or single point mutations in PYY(24-36), e.g., [Ile 24In some embodiments, the PYY(3-36) variant, analog, or biologically active fragment thereof can be a fragment having a double point mutation, such as a double point mutation in PYY(25-36), such as [Lys25,Thr27]PPY(25-36), [Lys25,Phe27]PPY(25-36), [Lys25,Ile28]PPY(25-36), [Lys25,Val28]PPY(25-36), [Lys25,Gln29]PPY(25-36), [Lys 25 ,Ile 30 ]PPY(25-36), [Lys 25 ,Val 30 ]PPY(25-36), [Lys 25 ,Ile 31 ]PPY(25-36), [Lys 25 ,Leu 31 ]PPY(25-36), [Lys 25 ,Ser 32 ]PPY(25-36), [Lys 25 ,Lys 33 ]PPY(25-36), [Lys 25 ,Asn 34 ]PPY(25-36), [Lys 25 ,Lys 35 ]PPY(25-36), [Lys 25 ,Thr 36 ]PPY(25-36), [Lys 25 ,Phe 36 ]PPY(25-36), [Thr 27 ,Ile 28 ]PPY(25-36), [Thr 27 ,Val 28 ]PPY(25-36), [Thr 27 ,Gln 29 ]PPY(25-36), [Thr 27 ,Ile 30 ]PPY(25-36), [Thr 27 ,Val 30 ]PPY(25-36), [Thr 27 ,Ile 31 ]PPY(25-36), [Thr 27 ,Leu31 ]PPY(25-36)、[Thr 27 ,Ser 32 ]PPY(25-36)、[Thr 27 ,Lys 33 ]PPY(25-36)、[Thr 27 ,Asn 34 ]PPY(25-36)、[Thr 27 ,Lys 35 ]PPY(25-36)、[Thr 27 ,Thr 36 ]PPY(25-36)、[Thr 27 ,Phe 36 ]PPY(25-36)、[Phe 27 ,Ile 28 ]PPY(25-36)、[Phe 27 ,Val 28 ]PPY(25-36)、[Phe 27 ,Gln 29 ]PPY(25-36)、[Phe 27 ,Ile 30 ]PPY(25-36)、[Phe 27 ,Val 30 ]PPY(25-36)、[Phe 27 ,Ile 31 ]PPY(25-36)、[Phe 27 ,Leu 31 ]PPY(25-36)、[Phe 27 ,Ser 32 ]PPY(25-36)、[Phe 27 ,Lys 33 ]PPY(25-36)、[Phe 27 ,Asn 34 ]PPY(25-36)、[Phe 27 ,Lys 35 ]PPY(25-36)、[Phe 27 ,Thr 36 ]PPY(25-36)、[Phe 27 ,Phe 36 ]PPY(25-36)、[Gln 29 ,Ile 30 ]PYY(25-36)、[Gln 29 ,Val 30 ]PYY(25-36)、[Gln29 ,Ile 31 ]PYY(25-36),[Gln 29 ,Leu 31 ]PYY(25-36),[Gln 29 ,Ser 32 ]PYY(25-36),[Gln 29 ,Leu 33 ]PYY(25-36),[Gln 29 ,Asn 34 ]PYY(25-36),[Gln 29 ,Leu 33 ]PYY(25-36),[Gln 29 ,Thr 36 ]PYY(25-36),[Gln 29 ,Phe 30 ]PYY(25-36),[Ile 30 ,Ile 31 ]PYY(25-36),[Ile 30 ,Leu 31 ]PYY(25-36),[Ile 30 ,Ser 32 ]PYY(25-36),[Ile 30 ,Lys 33 ]PYY(25-36),[Ile 30 ,Asn 34 ]PYY(25-36),[Ile 30 ,Lys 33 ]PYY(25-36),[Ile 30 ,Thr 30 ]PYY(25-36),[Ile 30 ,Phe 30 ]PYY(25-36),[Val 30 ,Ile 31 ]PYY(25-36),[Val 30 ,Leu 31 ]PYY(25-36),[Val 30 ,Ser 32 ]PYY(25-36),[Val 30 ,Lys 33 ]PYY(25-36),[Val 30 ,Asn 34 ]PYY(25-36),[Val 30 ,Lys35 ]PYY(25-36),[Val 30 ,Thr 30 ]PYY(25-36),[Val 30 ,Phe 30 ]PYY(25-36),[Ile 31 ,Ser 32 ]PYY(25-36),[Ile 31 ,Lys 33 ]PYY(25-36),[Ile 31 ,Asn 34 ]PYY(25-36),[Ile 31 ,Lys 33 ]PYY(25-36),[Ile 31 ,Thr 30 ]PYY(25-36),[Leu 31 ,Phe 30 ]PYY(25-36),[Leu 31 ,Ser 32 ]PYY(25-36),[Val 31 ,Lys 33 ]PYY(25-36),[Leu 31 ,Asn 34 ]PYY(25-36),[Leu 31 ,Lys 33 ]PYY(25-36),[Leu 31 ,Thr 30 ]PYY(25-36),[Leu 31 ,Phe 30 ]PYY(25-36),[Ser 32 ,Lys 33 ]PYY(25-36),[Ser 32 ,Asn 34 ]PYY(25-36),[Ser 32 ,Lys 35 ]PYY(25-36),[Ser 32 ,Thr 36 ]PYY(25-36),[Ser 32 ,Phe 36 ]PYY(25-36),[Lys 33 ,Asn 34 ]PYY(25-36),[Lys 33 ,Lys 35 ]PYY(25-36),[Lys33 ,Thr 36 ]PYY(25-36), [Lys 33 ,Phe 36 ]PYY(25-36), [Asn 34 ,Lys 35 ]PYY(25-36), [Asn 34 ,Thr 36 ]PYY(25-36), [Asn 34 ,Phe 36 ]PYY(25-36), [Lys 35 ,Thr 36 ]PYY(25-36), or [Lys 35 ,Phe 36 ]PYY(25-36).

[0027] In some embodiments, the metabolic hormone is leptin, or an analog, variant, or biologically active fragment thereof. In some embodiments, leptin, or a variant or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:6. In some embodiments, leptin has the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the analog of leptin is recombinant analog metreleptin (MYALEPT®), which comprises a polypeptide having the sequence set forth in SEQ ID NO:9, including a disulfide bridge linking amino acid residues 97 and 147. In some embodiments, the analog of leptin is a mouse leptin analog, e.g., as described in Peters et al. Endocrinol. 148:2878-2885, 2007, which is incorporated herein by reference in its entirety. In some embodiments, the methods described herein comprise administering leptin, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein comprise administering leptin, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg. In some embodiments, the methods described herein comprise administering leptin, or a variant, analog, or biologically active fragment thereof, at a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0028] In some embodiments, the metabolic hormone is amylin, or a variant or biologically active fragment thereof. The variant, analog, or biologically active fragment has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:7. In some embodiments, the amylin has the amino acid sequence set forth in SEQ ID NO:7. In some embodiments, the variant of amylin is pramlintide (SYMLIN®), which comprises a polypeptide having a sequence set forth in SEQ ID NO:8. In some embodiments, the methods described herein comprise administration of a dose of about 2.5 μg to about 2.5 mg of amylin, or a variant, analog, or biologically active fragment thereof. In some embodiments, the methods described herein comprise administration of a dose of about 10 μg to about 1 mg of amylin, or a variant, analog, or biologically active fragment thereof. In some embodiments, the methods described herein include administration of a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of amylin, or a variant, analog, or biologically active fragment thereof.

[0029] In some embodiments, the metabolic hormone is GLP-1, or an analog, variant, or biologically active fragment thereof. In some embodiments, the GLP-1, or a variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:3. In some embodiments, the GLP-1 has the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the GLP-1 fragment is GLP-1(7-36), or a variant, analog, or biologically active fragment thereof. In some embodiments, the GLP-1(7-36), or a variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO:4. In some embodiments, the GLP-1(7-36) has an amino acid sequence set forth in SEQ ID NO:4. In some embodiments, the GLP-1 fragment is GLP-1(7-37), or a variant, analog, or biologically active fragment thereof. In some embodiments, the GLP-1(7-37), or a variant, analog, or biologically active fragment thereof, has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100%) sequence identity to SEQ ID NO:5. In some embodiments, the GLP-1(7-37) has an amino acid sequence set forth in SEQ ID NO:5. In some embodiments, the methods described herein include administration of GLP-1, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg. In some embodiments, the methods described herein include administration of GLP-1, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg.In some embodiments, the methods described herein include administration of a dose of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg) of GLP-1, or a variant, analog, or biologically active fragment thereof.

[0030] In some embodiments, the metabolic hormone is calcitonin, or an analog, variant, or biologically active fragment thereof. In some embodiments, the calcitonin, or a variant, analog, or biologically active fragment thereof has at least 70% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 10. In some embodiments, the calcitonin has the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the methods described herein comprise administration of a dose of about 2.5 μg to about 2.5 mg of calcitonin, or a variant, analog, or biologically active fragment thereof. In some embodiments, In some embodiments, the methods described herein include administration of a dose of calcitonin, or a variant, analog, or biologically active fragment thereof, of about 10 μg to about 1 mg. In some embodiments, the methods described herein include administration of a dose of calcitonin, or a variant, analog, or biologically active fragment thereof, of about 25 μg to about 250 μg (e.g., a dose of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, or 250 μg).

[0031] In some embodiments, the metabolic hormone is insulin, or an analog thereof (e.g., insulin aspart (NOVOLOG®), insulin glargine (LANTUS®), insulin lispro (LYUMJEV™), insulin glulisine (APIDRA®), or insulin detemir (LEVEMIR®), insulin degludec (TRESIBA®), NPH insulin (HUMULIN®N or NOVOLIN®N), variant, or biologically active fragment. In some embodiments, insulin, or a variant, analog, or biologically active fragment thereof has at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) sequence identity to SEQ ID NO: 12. In some embodiments, the insulin has the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the analog of insulin is insulin aspart (NOVOLOG®), which has the sequence set forth in SEQ ID NO: 13. In some embodiments, the insulin analog is insulin glargine (LANTUS®) having an A chain having a sequence set forth in SEQ ID NO: 15 and a B chain having a sequence set forth in SEQ ID NO: 16. In some embodiments, the insulin analog is insulin lispro (LYUMJEV™) having an A chain having a sequence set forth in SEQ ID NO: 17 and a B chain having a sequence set forth in SEQ ID NO: 18. In some embodiments, the insulin analog is insulin glulisine (APIDRA®) having an A chain having a sequence set forth in SEQ ID NO: 19 and a B chain having a sequence set forth in SEQ ID NO: 20. In some embodiments, the insulin analog is insulin detemir (LEVEMIR®) having an A chain having a sequence set forth in SEQ ID NO: 21 and a B chain having a sequence set forth in SEQ ID NO: 22. In some embodiments, the methods described herein comprise administration (e.g., topically) of insulin, or a variant, analog, or biologically active fragment thereof, at a dose of about 2.5 μg to about 2.5 mg.In some embodiments, the methods described herein involve administration (e.g., topically) of insulin, or a variant, analog, or biologically active fragment thereof, at a dose of about 10 μg to about 1 mg.

[0032] Pharmaceutical Compositions and Routes of Administration The metabolic hormones described herein, or variants or biologically active fragments thereof, can be formulated as pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo.

[0033] The compositions described herein can be administered to a subject (e.g., a human) in various forms depending on the route of administration selected, as will be understood by those skilled in the art.The compositions described herein can be administered by any route that allows the composition (e.g., metabolic) to reach the target receptor without substantially changing the concentration of metabolic hormone in the subject's blood.The compositions can be administered, for example, nasally, rectally, or locally via GI route.

[0034] In some embodiments, the compositions described herein are formulated for nasal delivery. Nasal compositions can be formulated, for example, as a spray, semi-solid, microparticles, or in a lipid-based carrier. The formulation can be, for example, a solution, suspension, powder, or gel. Suitable nasal formulations are described, for example, in Marx et al. Drug Discov Dev. 299-320,2015, which is incorporated herein by reference in its entirety. In some preferred embodiments, the compositions described herein are administered by inhalation, for example by nasal inhalation. The inhalable compositions described herein can be provided as a liquid formulation or a dry powder formulation. The dry powder composition can be administered by inhalation, for example, as is, or after reconstitution with a vehicle, for example, saline (e.g., isotonic saline), phosphate buffered saline, or water.

[0035] In some embodiments, the compositions described herein are formulated for local administration to the GI tract.Topical compositions can be formulated, for example, as GI patch.Suitable GI patch formulations are described, for example, in Tao, et al Drug discovery Today 10:909-915,2005 (incorporated herein in its entirety by reference).

[0036] In some embodiments, the compositions described herein are formulated for rectal delivery. The rectal composition may be formulated, for example, as a suppository, an enema, an ointment, or an enema foam. Suitable rectal formulations are described, for example, in Hua Front. Pharmacol.10:1196,2019, which is incorporated herein by reference in its entirety. The composition for rectal administration may be in the form of a suppository containing a conventional suppository base, such as cocoa butter.

[0037] Solutions of the compositions described herein can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. These formulations may contain a preservative to prevent the growth of microorganisms under normal storage and use conditions. Conventional procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2012, 22nd ed.) and The United States Pharmacopeia: The National Formulary (USP 41 NF 36), published in 2018.

[0038] The compositions described herein, as described herein, can be administered to animals, e.g., humans, alone or in combination with a pharma- ceutically acceptable carrier, the proportions of which will be determined by the solubility and chemical properties of the composition, the chosen route of administration, and standard pharmaceutical practice.

[0039] In some embodiments, the composition includes an excipient that increases the contact time of the metabolic hormone (e.g., PYY(3-36)) with the mucosa (e.g., nasal, GI, or rectal mucosa). The excipient may provide viscosity enhancement, encapsulation, and controlled release. Without being bound by theory, it is believed that increasing the contact time of the pharmaceutical formulation with the mucosa increases the binding of the metabolic hormone to its receptor. Suitable excipients for viscosity enhancement include rheology modifiers, which may also be mucoadhesives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, alginic acid, polyvinylpyrrolidone, and sodium carboxymethylcellulose. Suitable excipients for modulating the release of the metabolic hormone at the mucosa include mucoadhesive permeation enhancers, such as 23-lauryl ether, aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, and lauric acid. Other suitable mucoadhesive polymers for use in the compositions described herein include agarose, chitosan, gelatin, hyaluronic acid, gums (e.g., guar, haecea, xanthan, gellan, carrageenan, pectin, and sodium alginate), cellulose derivatives (e.g., CMC, thiolated CMC, sodium CMC, HEC, HPMC, MC, methylcellulose ... hydroxyethyl cellulose), poly(acrylic acid)-based polymers (e.g., CP, PC, PAA, polyacrylates, poly(methyl vinyl ether-co-methacrylic acid), poly(2-hydroxyethyl methacrylate), poly(alkyl cyanoacrylates), poly(isohexyl cyanoacrylate), poly(isobutyl cyanoacrylate), copolymers of acrylic acid and PEG, poly(N-2-hydroxypropyl methacrylamide), PHPMAm, polyoxyethylene, PVA, PVP, and other thiolated polymers; scleroglucan, PVA, steroid detergents, nonionic surfactants, laureth-9, sodium fusidate, included sodium lauryl, sodium laurate (e.g., pH 8.9), palmitoyl carnitine, lauric acid / propylene glycol vehicle, Brij 78, sodium deoxycholate, sodium lauryl sulfate, lecithin, and PVP. See, e.g., International Journal of Pharmaceutics, Volume 10, 1999. 53, Issue 3, 1 August 1989, Pages 227-235.

[0040] Compositions containing the metabolic hormones described herein may include one or more pharma- ceutically acceptable excipients, such as propylene glycol, potassium sorbate, L-arginine, edetate disodium, monosodium phosphate, and polysorbate 20. Additionally, the compositions described herein can include a co-solvent stabilizer such as propylene glycol or other suitable co-solvent stabilizer (e.g., low molecular weight polyethylene glycols (PEGs) such as PEG 200 and 400, glycerin, and ethanol. In some embodiments, the compositions described herein can include an amino acid stabilizer such as L-arginine or other suitable amino acid stabilizer (e.g., alanine, aspartic acid, glycine, lysine, proline, or methionine). In some embodiments, the compositions described herein can include a preservative such as potassium sorbate or other suitable preservative (e.g., ascorbic acid, benzyl alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol, glutathione, methionine, methylparaben, propylparaben, sodium sulfite, parahydroxybenzoic acid esters (methyl hydroxybenzoate and propyl hydroxybenzoate), phosphatase, phosphatase inhibitors ... The compositions described herein may include an antioxidant, such as disodium edetate or another suitable antioxidant (e.g., sodium formaldehyde sulfoxylate, butylated hydroxyanisole, and butylated hydroxytoluene). In some embodiments, the compositions described herein include a buffer (e.g., acetate, carbonate, citrate, citrate-phosphate, glycine, HEPES, histidine, maleate, phosphate, succinate, tartrate, and triethanolamine (Tris)). In some embodiments, the compositions described herein may include a surfactant, such as polysorbate 20 or other suitable surfactant (e.g., poloxamer 188 / 407, polysorbate 40 or 80, or sodium lauryl sulfate).

[0041] In some embodiments, the pharmaceutical composition may be administered in unit dosage form or as a dose per patient mass or weight, from 0.01 ng / kg to 250 μg / kg (e.g., for a human weighing 75 kg). For example, the dose of metabolic hormone may be from 0.01 ng / kg to 0.1 ng / kg, e.g., 0.01 ng / kg, 0.02 ng / kg, 0.03 ng / kg, 0.04 ng / kg, 0.05 ng / kg, 0.06 ng / kg, 0.07 ng / kg, 0.08 ng / kg, 0.09 ng / kg, or 0.1 ng / kg, e.g., from 0.1 ng / kg to 1 ng / kg, e.g., 0.1 ng / kg. g, 0.2ng / kg, 0.3ng / kg, 0.4ng / kg, 0.5ng / kg, 0.6ng / kg, 0.7ng / kg, 0.8ng / kg, 0.9ng / kg, or 1ng / kg, e.g., 1ng / kg to 10ng / kg, e.g., 1ng / kg, 2ng / kg, 3ng / kg, 4ng / kg, 5ng / kg, 6ng / kg, 7ng / kg, 8ng / kg, 9ng / kg, if or 10ng / kg, for example, 10ng / kg to 100ng / kg, for example, 10ng / kg, 20ng / kg, 30ng / kg, 40ng / kg, 50ng / kg, 60μg / kg, 70ng / kg, 80ng / kg, 90ng / kg, or 100ng / kg, for example, 100ng / kg to 1μg / kg, for example, 100ng / kg, 200ng / kg, 300ng / kg, 400ng / kg, 500ng / kg, 600ng / kg, 700ng / kg, 800ng / kg, 900ng / kg, or 1μg / kg, for example, 1μg / kg to 10μg / kg, for example, 1μg / kg, 2μg / kg, 3μg / kg, 4μg / kg, 5μg / kg , 6 μg / kg, 7 μg / kg, 8 μg / kg, 9 μg / kg, or 10 μg / kg, or such as 10 μg / kg to 250 μg / kg, such as 10 μg / kg, 20μg / kg, 30μg / kg, 40μg / kg, 50μg / kg, 60μg / kg, 70μg / kg, 80μg / kg, 90ng / kg, 100μg / kg kg, 110μg / kg, 120μg / kg, 130μg / kg, 140μg / kg, 150μg / kg, 160μg / kg, 170μg / kg, 180μg / k g, 190 μg / kg, 200 μg / kg, 210 μg / kg, 220 μg / kg, 230 μg / kg, 240 μg / kg, or 250 μg / kg.

[0042] In general, the dosage of a pharmaceutical composition, or an active agent therein (e.g., a metabolic hormone, e.g., PYY (e.g., PYY(3-36)), GLP-1, leptin, amylin, insulin, or calcitonin, or a variant, analog, or biologically active fragment thereof) can be in the range of about 10 ng to about 200 μg per kg of body weight, e.g., in the range of about 100 ng to about 10 μg per kg of body weight, or, e.g., in the range of about 100 ng to about 2.5 μg per kg of body weight, e.g., a dose of about 100 ng, 200 ng, 300 ng, 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, 1 μg, 2 μg, or 2.5 μg per kg of body weight (e.g., for a human weighing 75 kg).

[0043] Furthermore, it is understood that the dosage of analogs, variants, or biologically active fragments of active substances can be administered as the molar equivalent of active substances.Those skilled in the art will understand that, for example, metabolic hormone analogs that contain post-translational modifications or half-life extending moieties may require increased dosages (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300% or more) than the dosage of the corresponding metabolic hormone that does not contain post-translational modifications or half-life extending moieties.

[0044] The pharmaceutical composition may also be administered as a dose per patient mass or weight per day (e.g., 0.01 ng / kg / day to 250 μg / kg / day). In some embodiments, the pharmaceutical composition is administered at a dose of 10 ng / kg / day to 200 μg / kg / day (e.g., 50 ng / kg / day to 100 μg / kg / day, 100 ng / kg / day to 50 μg / kg / day, 500 ng / kg / day to 1 μg / kg / day). In some embodiments, the pharmaceutical composition comprises a dose of 100 ng / kg / day to 10 μg / kg / day (e.g., 100 ng / kg / day, 110 ng / kg / day, 120 ng / kg / day, 130 ng / kg / day, 140 ng / kg / day, 150 ng / kg / day, 160 ng / kg / day, 170 ng / kg / day, 180 ng / kg / day, 190 ng / kg / day, 200 ng / kg / day, 210 ng / kg / day, 220 ng / kg / day, 230 ng / kg / day, 240 ng / kg / day, 250 ng / kg / day, 260 ng / kg / day, 270 ng / kg / day, 280 ng / kg / day, 290 ng / kg / day, 300 ng / kg / day, 310 ng / kg / day, 320 ng / kg / day, 330 ng / kg / day, 340 ng / kg / day, 350 ng / kg / day, 360 ng / kg / day, 370 ng / kg / day, 380 ng / kg / day, 390 ng / kg / day, 400 ng / kg / day, 410 ng / kg / day, 420 ng / kg / day, 430 ng / kg / day, 440 ng / kg / day, 450 ng / kg / day, 460 ng / kg / day, 470 ng / kg / day, 480 ng / kg / day, 490 ng / kg / day, 500 ng / kg / day, 510 ng / kg / day, 520 ng / kg / day, g / kg / day, 290ng / kg / day, 300ng / kg / day, 310ng / kg / day, 320ng / kg / day, 330ng / kg / day, 340ng / kg / day, 350ng / kg / day, 360ng / kg / day, 370ng / kg / day, 380ng / kg / day, 390ng / kg / day kg / day, 400ng / kg / day, 410ng / kg / day, 420ng / kg / day, 430ng / kg / day, 440ng / kg / day, 450ng / kg / day, 460ng / kg / day, 470ng / kg / day, 480ng / kg / day, 490ng / kg / day, 500ng / kg / day, 510ng / kg / day, 520ng / kg / day, 530ng / kg / day, 540ng / kg / day, 550ng / kg / day, 560ng / kg / day, 570ng / kg / day, 580ng / kg / day, 590ng / kg / day, 600ng / kg / day, 610ng / kg / day, 620ng / kg / day, 630ng / kg / day, 640ng / kg / day, 650ng g / kg / day, 660ng / kg / day, 670ng / kg / day, 680ng / kg / day, 690ng / kg / day, 700ng / kg / day, 710ng / kg / day, 720ng / kg / day, 730ng / kg / day, 740ng / kg / day, 750ng / kg / day, 760ng / kg / day, 770ng / kg / day, 780ng / kg / day, 790ng / kg / day, 8 00ng / kg / day, 810ng / kg / day, 820ng / kg / day, 830ng / kg / day, 840ng / kg / day, 850ng / kg / day, 860ng / kg / day, 870n g / kg / day, 880ng / kg / day, 890ng / kg / day, 900ng / kg / day, 910ng / kg / day, 920ng / kg / day, 930ng / kg / day, 940ng / kg / day, 950ng / kg / day, 960ng / kg / day, 970ng / kg / day, 980ng / kg / day, 990ng / kg / day, 1μg / kg / day, 2μg / kg / day, 3μg / kg / day, 4μg / kg / day, 5μg / kg / day, 6μg / kg / day, 7μg / kg / day, 8μg / kg / day, 9μg / kg / day, or 10μg / kg / day). In some embodiments, the pharmaceutical composition provides a dose of about 100 ng / kg / day to about 2.5 μg / kg / day (e.g., 100 ng / kg / day, 110 ng / kg / day, 120 ng / kg / day, 130 ng / kg / day, 140 ng / kg / day, 150 ng / kg / day, 160 ng / kg / day, 170 ng / kg / day, 180 ng / kg / day, 190 ng / kg / day, 200 ng / kg / day, 210 ng / kg / day, day, 220ng / kg / day, 230ng / kg / day, 240ng / kg / day, 250ng / kg / day, 260ng / kg / day, 270ng / kg / day, 280ng / kg / day, 290ng / kg / day , 300ng / kg / day, 310ng / kg / day, 320ng / kg / day, 330ng / kg / day, 340ng / kg / day, 350ng / kg / day, 360ng / kg / day, 370ng / kg / day,380ng / kg / day, 390ng / kg / day, 400ng / kg / day, 410ng / kg / day, 420ng / kg / day, 430ng / kg / day, 440ng / kg / day, 450ng / kg / day, 460ng / kg / day, 470ng / kg / day day, 480ng / kg / day, 490ng / kg / day, 500ng / kg / day, 510ng / kg / day, 520ng / kg / day, 530ng / kg / day, 540ng / kg / day, 550ng / kg / day, 560ng / kg / day, 570ng / k g / day, 580ng / kg / day, 590ng / kg / day, 600ng / kg / day, 610ng / kg / day, 620ng / kg / day, 630ng / kg / day, 640ng / kg / day, 650ng / kg / day, 660ng / kg / day, 670ng / kg / day, 680ng / kg / day, 690ng / kg / day, 700ng / kg / day, 710ng / kg / day, 720ng / kg / day, 730ng / kg / day, 740ng / kg / day, 750ng / kg / day, 760ng / kg / day, 770n g / kg / day, 780ng / kg / day, 790ng / kg / day, 800ng / kg / day, 810ng / kg / day, 820ng / kg / day, 830ng / kg / day, 840ng / kg / day, 850ng / kg / day, 860ng / kg / day, 87 0ng / kg / day, 880ng / kg / day, 890ng / kg / day, 900ng / kg / day, 910ng / kg / day, 920ng / kg / day, 930ng / kg / day, 940ng / kg / day, 950ng / kg / day, 960ng / kg / day, 9 The drug is administered at a dose of 70 ng / kg / day, 980 ng / kg / day, 990 ng / kg / day, 1 μg / kg / day, 1.1 μg / kg / day, 1.2 μg / kg / day, 1.3 μg / kg / day, 1.4 μg / kg / day, 1.5 μg / kg / day, 1.6 μg / kg / day, 1.7 μg / kg / day, 1.8 μg / kg / day, 1.9 μg / kg / day, 2 μg / kg / day, 2.1 μg / kg / day, 2.2 μg / kg / day, 2.3 μg / kg / day, 2.4 μg / kg / day, or 2.5 μg / kg / day.

[0045] The dosage of the compositions described herein (e.g., compositions comprising a metabolic hormone) will depend on the pharmacodynamic properties of the metabolic hormone, the mode of administration, the age, health, and weight of the subject to be treated, and the nature and severity of the condition. The dosage may depend on many factors, such as the degree, frequency of treatment, and type of concurrent treatment (if any), as well as the clearance rate of the composition in the treated animal. The compositions described herein may be initially administered at a suitable dose, which may be adjusted as necessary depending on the clinical response. In some embodiments, the dose of the composition (e.g., the composition comprising a metabolic hormone) is a prophylactically or therapeutically effective amount. It is further understood that all doses may be given continuously or divided into doses given per given time frame. The composition may be administered, for example, hourly, daily, weekly, monthly, or yearly. In some embodiments, the composition may be administered continuously. For example, a rectal formulation or GI patch may be present in the subject for a sustained period of time (e.g., at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, or more).

[0046] The pharmaceutical compositions described herein (e.g., including metabolic hormones) can be provided in a kit that includes the pharmaceutical composition (e.g., in a container) and instructions for its use. The kit can include one or more containers, each container including a different composition of the invention. The instructions included with the kit can be used to instruct a user to practice the methods described herein.

[0047] The methods described herein include locally administering a metabolic hormone (e.g., PYY, PYY(3-36), leptin, amylin, insulin, GLP-1, or an analog, variant, or biologically active fragment thereof) to the rectum, nasal cavity, or GI tract of a subject, wherein the local administration does not result in a substantial change in the level of the metabolic hormone in the subject's blood and / or plasma. Generally, the metabolic hormone level in the subject's blood and / or plasma is not increased by more than up to 10% (e.g., 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less) of the pre-administration level of the metabolic hormone. In some embodiments, the blood and / or plasma levels of PYY(3-36) are increased by more than ... After administration (e.g., topically) of PYY(3-36), the blood and / or plasma levels of leptin do not substantially exceed preprandial levels of about 15 pmol / l to about 25 pmol / l, as reported in Metabolism, 4:223-233, 2006, which is incorporated herein by reference in its entirety. In some embodiments, after administration (e.g., topically) of leptin, the blood and / or plasma levels do not substantially exceed preprandial levels of about 5 ng / ml to about 35 ng / ml, as reported in Considine et al, N. Engl. J. Med. 334:292-295, 1996, which is incorporated herein by reference in its entirety. In some embodiments, the blood and / or plasma levels of amylin do not substantially exceed preprandial levels of about 5 ng / ml to about 35 ng / ml, as reported in Cooper et al. As reported by al., Hypertension, 26:460-464, 1995 (hereby incorporated by reference in its entirety), following administration of amylin (eg, topically), preprandial levels of about 20 pmol / l are not substantially exceeded.

[0048] Indications The methods described herein include the administration of metabolic hormones to induce satiety and / or treat metabolic syndrome, diabetes, obesity, or any obesity-related disorder.

[0049] In some embodiments, the subject in need of treatment has been diagnosed with or is at risk for metabolic syndrome, obesity, obesity-related disorders, diabetes, fatty liver disease, nonalcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome, cardiovascular disease, obstructive sleep apnea, retinopathy, peripheral vascular disease, peripheral arterial disease, and neuropathy (e.g., diabetic neuropathy). In some embodiments, the method is used to maintain weight or prevent weight gain.

[0050] array PYY SEQ ID NO:1 MVFVRRPWPALTTVLLALLVCLGALVDAYPIKPEAPREDASPEELNRYYASLRHYLNLVTRQRYGKRDGPDTLLSKTFFPDGEDRPVRSRSEGPDLW PYY(3-36) SEQ ID NO:2 IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY GLP-1 SEQ ID NO:3 MKSIYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNEDKRHSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIAKRHDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAIVEELGRRHADGSFSDEMNTILDNLAARDFINWLIQTKITDRK GLP-1(7-36) SEQ ID NO:4 HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR GLP-1(7-37) SEQ ID NO:5 HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG Leptin SEQ ID NO:6 MHWGTLCGFLWLWPYLFYVQAVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGYSTEVVALSRLQGSLQDMLWQLDLSPGC Amylin SEQ ID NO:7 MGILKLQVFLIVLSVALNHLKATPIESHQVEKRKCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTYGKRNAVEVLKREPLNYLPL Pramlintide SEQ ID NO:8 KCNTATCATQRLANFLVHSSNNFGPILPTNVGSNTY Metreleptin SEQ ID NO:9 MVPIQKVQDDTKTLIKTIVTRINDISHTQSVSSKQKVTGLDFIPGLHPILTLSKMDQTLAVYQQILTSMPSRNVIQISNDLENLRDLLHVLAFSKSCHLPWASGLETLDSLGGVLEASGYSTEVVALSRLQGSLQDMLWQLDLSPGC (Disulfide bridge: 97-147) Calcitonin SEQ ID NO:10 CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP [Pro34]PYY SEQ ID NO:11 YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRPRY Insulin SEQ ID NO:12 MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQVGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN Insulin Aspart A chain SEQ ID NO:13 GIVEQCCTSICSLYQLENYCN Insulin Aspart B chain SEQ ID NO:14 FVNQHLCGSHLVEALYLVCGERGFFYTDKT Insulin glargine A chain SEQ ID NO:15 GIVEQCCTSICSLYQLENYCG Insulin glargine B chain SEQ ID NO:16 FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR Insulin lispro A chain SEQ ID NO:17 GIVEQCCTSICSLYQLENYCN Insulin lispro B chain SEQ ID NO:18 FVNQHLCGSHLVEALYLVCGERGFFYTKPT Insulin glulisine A chain SEQ ID NO:19 GIVEQCCTSICSLYQLENYCN Insulin glulisine B chain SEQ ID NO:20 FVKQHLCGSHLVEALYLVCGERGFFYTPET Insulin detemir A chain SEQ ID NO:21 GIVEQCCTSICSLYQLENYCN Insulin detemir B chain SEQ ID NO:22 FVNQHLCGSHLVEALYLVCGERGFFYTPK

[0051] Other embodiments While the invention has been described in connection with specific embodiments thereof, it is capable of further modifications, and this application generally covers any variations, uses, or adaptations of the invention which follow the principles of the invention and which become known in the art to which the invention pertains or which come within the customary practice of the art. It will be understood that the present invention is intended to include departures from the invention that may be practically practiced and are applicable to the essential features described above and pursuant to the scope of the appended claims. Other embodiments are within the scope of the appended claims.

Claims

1. A composition comprising an agent selected from glucagon-like peptide 1 (GLP-1), calcitonin, peptide YY (PYY), leptin, amylin, and insulin, or an analog, variant, or biologically active fragment thereof, for use in inducing satiety or treating a disease or disorder selected from metabolic syndrome, obesity, obesity-related disorders, diabetes, fatty liver disease, non-alcoholic steatohepatitis, chronic kidney disease, polycystic ovary syndrome, cardiovascular disease, obstructive sleep apnea, retinopathy, peripheral vascular disease, peripheral arterial disease, and neuropathy, in a subject in need thereof, wherein the composition is formulated to be administered to the subject nasally, locally to the gastrointestinal (GI) tract, or rectally.

2. The composition for use according to claim 1, wherein the composition is formulated for nasal administration.

3. The composition for use according to claim 2, wherein the composition is formulated for administration as a spray, semi-solid, administration as microparticles, or in a lipid-based carrier.

4. The composition for use according to claim 1, wherein the composition is formulated for local administration to the GI tract.

5. The composition for use according to claim 4, wherein the composition is formulated for administration as a GI patch.

6. The composition for use according to claim 1, wherein the composition is formulated for rectal administration.

7. The composition for use according to claim 6, wherein the composition is formulated for administration as a suppository.

8. The composition for use according to any one of claims 1 to 7, wherein the dose of the agent is from 1 ng to 20 mg per 100 kg body weight.

9. The dose of the agent is (a) from 1 ng to 1 μg per 100 kg body weight, (b) from 1 μg to 1 mg per 100 kg body weight, or (c) from 1 mg to 20 mg per 100 kg body weight for the composition for use according to claim 8.

10. The composition for use according to any one of claims 1 to 7, wherein the composition comprises GLP-1, calcitonin, PYY, leptin, leptin, or insulin.

11. The composition for use according to claim 10, wherein the PYY is PYY(3-36).