Methods for treating melanocortin 4 receptor pathway-associated disorders

Abstract

To provide methods for treating melanocortin 4 receptor pathway-associated disorders.SOLUTION: The disclosure is based, at least in part, on the discovery that the use of an MC4R agonist as replacement therapy targeting defects in the POMC-MC4R pathway, e.g., targeting defects upstream of MC4R, led to significant weight loss, decrease in hunger, and / or increase in energy expenditure in obese subjects. The disclosure relates to a method for treating disorders such as Prader Willi Syndrome (PWS), obesity or hyperphagia using a melanocortin 4 receptor (MC4R)-agonist. Also disclosed are a method for treating a subject having a deficiency in pro-opiomelanocortin (POMC)-MC4R pathway, for example, a POMC-null or PCSK-null subject, using an MC4R agonist.SELECTED DRAWING: Figure 1A

Description

[Background technology]

[0001] The melanocortin 4 receptor (MC4R) is a heterotrimeric G protein-coupled receptor that signals by activating adenylate cyclase. Expressed in the hypothalamic nucleus and other neuronal and non-neuronal tissues, MC4R regulates feeding behavior and energy homeostasis. MC4R integrates agonist (appetite-suppressing) signals mediated by α-melanocyte-stimulating hormone (α-MSH) with antagonist (appetite-stimulating) signals mediated by agouti-related peptide (AGPR).

[0002] MC4R is part of the leptin-melanocortin pathway or POMC-MC4R pathway, which includes several proteins, including leptin, leptin receptor, proopiomelanocortin (POMC), prohormone convertases including PCSK1, and α-MSH, among others. AGPR binding to MC4R inhibits MC4R activity, while α-MSH binding stimulates MC4R. Inhibition of receptor activity generates orexigenic signals, while stimulation of receptor activity generates anorectic signals. Signals from MC4R regulate feeding behavior through secondary effector neurons.

[0003] In humans, the hypothalamic POMC-MC4R pathway is part of the appetite and weight control network. Single gene defects in this pathway have been described to lead to severe, early-onset obesity. For example, patients with POMC loss-of-function mutations suffer from severe, early-onset obesity, hyperphagia, and adrenocorticotropic hormone (ACTH) deficiency. These patients also have hypopigmented skin and body hair. Prader-Willi syndrome (PWS) is thought to be caused by the loss of function of several genes, including one or more genes in the POMC-MC4R pathway, on human chromosome 15, specifically 15q11-q13. PWS patients suffer from severe hyperphagia, which leads to severe obesity and other complications. There are currently no approved treatments for obesity and hyperphagia associated with POMC-MC4R pathway gene-deficient disorders, such as PWS and POMC null obesity. Deficiency of MSH, the cleavage product of the POMC and MC4R ligand, contributes to early-onset obesity and hyperphagia in these disorders associated with defects in the POMC-MC4R pathway. There is a need for therapies, such as MSH replacement therapy, that effectively treat obesity and hyperphagia associated with POMC-MC4R pathway gene deficiency disorders and have fewer safety issues. Summary of the Invention [Means for solving the problem]

[0004] In one aspect, there is provided a method of treating Prader-Willi syndrome (PWS) in a subject in need thereof, comprising: administering an agonist of the melanocortin 4 receptor (MC4R) at a daily dose of about 0.1 mg (e.g., 0.1 mg + / - 5%) to about 10 mg (e.g., 10 mg + / - 5%); The agonist is an MC4R agonist as described herein, for example, the agonist is an MC4R agonist (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9)-A 10 -R 1 (I) wherein: A 1 Acc, HN-(CH2) m -C(O), an L-amino acid or a D-amino acid, or a deletion; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, a D-amino acid, or a deletion, A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O), A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), an L-amino acid or a D-amino acid, or a deletion; R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, substituted (C1-C 30 ) Acyl, Substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C1-C 40 ) acyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40) acyl, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are respectively, independently in each case, H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN; Methods for treating PWS are thereby provided herein.

[0005] In embodiments, the subject has, or is identified as having, a loss-of-function mutation in the 15q11-q13 region of chromosome 15.

[0006] In some embodiments, the subject has or is identified as having a mutation (eg, a loss-of-function mutation) in the MAGEL2 gene.

[0007] In various embodiments, the daily dose is 0.1 mg to 10 mg. In various embodiments, the daily dose is about 0.1 mg to about 7.5 mg. In various embodiments, the daily dose is about 0.1 mg to about 5 mg. In various embodiments, the daily dose is about 0.1 mg to about 2.5 mg. In various embodiments, the daily dose is about 0.1 mg to about 2 mg. In various embodiments, the daily dose is about 0.1 mg to about 1 mg. In various embodiments, the daily dose is about 0.2 mg to about 10 mg. In various embodiments, the daily dose is about 0.2 mg to about 7.5 mg. In various embodiments, the daily dose is about 0.2 mg to about 5 mg. In various embodiments, the daily dose is about 0.2 mg to about 2.5 mg. In various embodiments, the daily dose is about 0.2 mg to about 2 mg. In various embodiments, the daily dose is about 0.2 mg to about 1.5 mg. In various embodiments, the daily dose is about 0.2 mg to about 1 mg. In various embodiments, the daily dose is about 0.3 mg to about 10 mg. In various embodiments, the daily dose is about 0.3 mg to about 7.5 mg. In various embodiments, the daily dose is about 0.3 mg to about 5 mg. In various embodiments, the daily dose is about 0.3 mg to about 2.5 mg. In various embodiments, the daily dose is about 0.3 mg to about 2 mg. In various embodiments, the daily dose is about 0.3 mg to about 1.5 mg. In various embodiments, the daily dose is about 0.3 mg to about 1 mg. In various embodiments, the daily dose is about 0.25 mg (e.g., 0.25 mg) to about 0.5 mg (e.g., 0.5 mg). In various embodiments, the daily dose is about 0.5 mg (e.g., 0.5 mg) to about 0.75 mg (e.g., 0.75 mg). In various embodiments, the daily dose is about 0.25 mg (e.g., 0.25 mg). In some embodiments, the daily dosage is about 0.5 mg (e.g., 0.5 mg). In some embodiments, the daily dosage is about 0.75 mg (e.g., 0.75 mg) to about 1.25 mg (e.g., 1.25 mg). In some embodiments, the daily dosage is about 1 mg (e.g., 1 mg). In some embodiments, the daily dosage is about 1.25 mg (e.g., 1.25 mg) to about 2 mg (e.g., 2 mg). In some embodiments, the daily dosage is about 1.5 mg (e.g., 1.5 mg).In some embodiments, the daily dose is about 2 mg (eg, 2 mg).

[0008] In embodiments, the methods include administering the agonist to the subject in a unit dosage suitable for injection, for example subcutaneous injection.

[0009] In embodiments, the unit dose comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of the agonist.

[0010] In embodiments, the unit dosage is disposed in a delivery device, for example, a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system.

[0011] In embodiments, the agonist is administered subcutaneously, for example, by subcutaneous injection.

[0012] In embodiments, the agonist is administered daily for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or for a period of at least 1, 2, 3, 4 years or more.

[0013] In embodiments, the subject is obese, eg, severely obese.

[0014] In embodiments, the subject has early-onset severe obesity.

[0015] In embodiments, the subject has an excess of appetite.

[0016] In embodiments, the subject has a body weight of 25 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0017] In embodiments, the subject has a weight of 35 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0018] In embodiments, the subject has a weight of 40 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0019] In some embodiments, the patient has a blood pressure of 45 kg / m 2 or higher prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0020] In embodiments, the subject has a BMI greater than the 85th-95th percentile prior to administration of the agonist, eg, at the time the agonist is prescribed or at the time of the first administration.

[0021] In various embodiments, the subject has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapy, prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration.

[0022] In embodiments, the subject has a lower body weight after administration of the agonist than before administration of the agonist.

[0023] In various embodiments, administration of the agonist reduces the subject's weight by about 1 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment, compared to the subject's weight before treatment.

[0024] In various embodiments, administration of the agonist reduces the subject's body weight at a rate of about 1-2 kg / week, e.g., about 2 kg / week, for a period of, e.g., 1-2 weeks or more of treatment, 2-4 weeks or more of treatment, 4-8 weeks or more of treatment, 8-16 weeks or more of treatment, 16-32 weeks or more of treatment, or 32-64 weeks or more of treatment.

[0025] In various embodiments, administration of the agonist reduces the subject's hunger level (e.g., reduces the Likert hunger scale score, e.g., reduces the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points) compared to the subject's hunger level before treatment, e.g., results in the subject's lack of hunger (e.g., a score of 0 on the Likert hunger scale), e.g., after 1-2 weeks or more of treatment, 2-4 weeks or more of treatment, 4-8 weeks or more of treatment, or 8-16 weeks or more of treatment.

[0026] In various embodiments, administration of the agonist does not detectably / significantly reduce the resting energy expenditure (REE) of the subject, e.g., compared to a control REE (e.g., the REE of the subject before treatment, or a predetermined REE, e.g., when expressed as REE per kg of lean body mass, e.g., of a subject with a similar pre-treatment BMI), e.g., over a period of 24 hours, 1 week, or 30 days or more.

[0027] In various embodiments, administration of the agonist increases the subject's resting energy expenditure (REE), e.g., over a period of 24 hours, 1 week, 30 days or more, e.g., compared to a control REE (e.g., compared to the subject's REE before treatment, or compared to a predetermined REE, e.g., expressed as REE per kg of lean body mass, for a subject with a similar pre-treatment BMI, e.g., after a similar level of weight loss has been achieved by fasting).

[0028] In various embodiments, administration of the agonist reduces food intake by the subject compared to a control (e.g., the subject's food intake before treatment), e.g., food intake is daily food intake or food intake over a 24-hour period or a week.

[0029] In various embodiments, administration of the agonist reduces food intake by at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories, or more, compared to a control (e.g., the subject's food intake before treatment or a predetermined food intake level), e.g., food intake is daily food intake or food intake over a 24-hour period or a week.

[0030] In some embodiments, administration of the agonist reduces food intake by at least 5 kcal / kg / day, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 kcal / kg / day or more. In some embodiments, the reduction in food intake is relative to baseline food intake. In some embodiments, the baseline food intake is at least 100 kcal / kg / day, e.g., in a pediatric subject about 1 year old. In some embodiments, the baseline food intake is at least 40 kcal / kg / day, e.g., in a pediatric subject in late adolescence.

[0031] In embodiments, administration of the agonist reduces the subject's waist circumference when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to a control (e.g., the subject's waist circumference before treatment).

[0032] In various embodiments, administration of the agonist reduces the subject's waist circumference by at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm, or more) compared to a control (e.g., the subject's waist circumference before treatment) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks, or more, after initiation of treatment.

[0033] In various embodiments, administration of the agonist does not detectably increase the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to the subject's blood pressure before treatment.

[0034] In various embodiments, administration of the agonist reduces the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment.

[0035] In various embodiments, administration of the agonist reduces the subject's systolic blood pressure by at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment.

[0036] In various embodiments, administration of the agonist reduces the subject's diastolic blood pressure by at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment.

[0037] In embodiments, the subject is a mammal, for example a human.

[0038] In some embodiments, the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0039] In embodiments, the method further comprises obtaining knowledge of the subject's genotype, for example obtaining knowledge of the genotype of the 15q11-q13 region of chromosome 15 or the MAGEL2 gene.

[0040] In embodiments, the agonist is administered in response to detection of a predetermined sequence, eg, a mutation, in the 15q11-q13 region of chromosome 15 or in the MAGEL2 gene.

[0041] In embodiments, the knowledge is obtained directly from, for example, a sample from a subject (eg, a blood, serum, urine, or tissue (eg, biopsy) sample).

[0042] In embodiments, the predetermined sequence, e.g., mutation, is detected in the nucleic acid by a method selected from one or more of a nucleic acid hybridization assay, an amplification-based assay, a PCR-RFLP assay, real-time PCR, sequencing, screening analysis, FISH, spectral karyotyping or MFISH, comparative genomic hybridization, in situ hybridization, SSP, HPLC, or mass spectrometry genotyping.

[0043] In embodiments, a predetermined sequence, eg, a mutation, is detected in a subject.

[0044] In embodiments, a predetermined sequence, eg, a mutation, is detected in a nucleic acid molecule or polypeptide in a sample from a subject.

[0045] In embodiments, the sample comprises blood, serum, urine, or cells from a tissue (eg, a biopsy) from the subject.

[0046] In embodiments, the knowledge is obtained from another party, for example, the party is a subject, a caregiver, a physician, an endocrinologist, a hospital, a clinic, a third party payer, an insurance company, or a government agency.

[0047] In embodiments, the method comprises: Upon determining the presence or absence of a given sequence, e.g., a mutation, in a subject, (1) identifying or selecting a subject as having Prader-Willi syndrome (PWS); and / or (2) identifying or selecting subjects as likely or unlikely to respond to an agonist; Contains one or more of the following:

[0048] In some embodiments, the presence of a predetermined sequence, e.g., a mutation, is detected in the subject, and in response to that determination, the method includes identifying the subject as having Prader-Willi syndrome (PWS).

[0049] In embodiments, the presence of a predetermined sequence, e.g., a mutation, is detected in a subject, and in response to that determination, the method includes identifying the subject as likely to respond to an agonist.

[0050] In some embodiments, the subject has or is identified as having PWS.

[0051] In one aspect, there is provided a method of treating a disorder in a subject in need thereof, comprising: administering an agonist of the melanocortin 4 receptor (MC4R) at a daily dose of about 0.1 mg (e.g., 0.1 mg + / - 5%) to about 10 mg (e.g., 10 mg + / - 5%); The disorder is (i) Prader-Willi syndrome (PWS), (ii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the POMC gene; (iii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; (iv) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; (v) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene; (vi) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin gene; (vii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the 5-HT2c receptor gene; (viii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the nescient Helix-Loop-Helix 2 (NhHL2) gene; (ix) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in a prohormone convertase gene; (x) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the carboxypeptidase E (CPE) gene; (xi) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the single-minded 1 (SIM1) gene; (xii) a disorder characterized by a hypermethylated POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing one or more methylated cytosines, e.g., a 5' methylcytosine); or (xiii) A disorder characterized by a defect in the POMC-MC4R pathway, (a) heterozygous POMC mutations characterized by the presence of one functional and one non-functional POMC allele; (b) a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele; (c) a melanocortin 4 receptor (MC4R) mutation (e.g., a loss-of-function mutation), or (d) Prohormone convertase mutations (e.g., loss-of-function mutations) is selected from The agonist is an MC4R agonist as described herein, for example, the agonist is an MC4R agonist (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) where: A 1 Acc, HN-(CH2) m -C(O), an L-amino acid or a D-amino acid, or a deletion; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, a D-amino acid, or a deletion, A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O), A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), an L-amino acid or a D-amino acid, or a deletion; R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) acyl, (C2-C 30) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, substituted (C1-C 30 ) acyl, substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C1-C 40 ) acyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X4 , and X 8 are respectively, independently in each case, H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.

[0052] In embodiments, the subject comprises one or more mutations, for example, in one or more of the genes described herein.

[0053] In some embodiments, the disorder is Prader-Willi syndrome (PWS).

[0054] In embodiments, the subject has, or is identified as having, a loss-of-function mutation in the paternal allele of chromosome 15 in the 15q11-q13 region.

[0055] In embodiments, the subject has or is identified as having a mutation, eg a loss-of-function mutation, in the MAGEL2 gene.

[0056] In embodiments, the disorder is characterized by one or more mutations (eg, loss-of-function mutations) in the POMC gene.

[0057] In embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), eg, having one functional and one non-functional POMC allele.

[0058] In embodiments, the subject is, or is identified as being, a compound heterozygous carrier of the mutation(s), e.g., having two different non-functional POMC alleles, e.g., having a POMC null genotype.

[0059] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), eg, having a homozygous POMC null genotype.

[0060] In embodiments, the disorder is characterized by one or more mutations (eg, loss-of-function mutations) in the PCSK1 gene.

[0061] In embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), e.g., having one functional and one non-functional PCSK1 allele.

[0062] In embodiments, the subject is, or is identified as being, a compound heterozygous carrier of the mutation(s), e.g., having two non-functional PCSK1 alleles, e.g., having a PCSK1 null genotype.

[0063] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), eg, having a homozygous PCSK1 null genotype.

[0064] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the MAGEL2 gene.

[0065] In some embodiments, the subject is or is identified as being a heterozygous carrier of the mutation(s), including, for example, a subject who has one functional MAGEL2 allele and one non-functional MAGEL2 allele, with the remaining functional allele silenced by maternal imprinting, resulting in the subject being a functional MAGEL2 null patient.

[0066] In embodiments, the subject is, or is identified as being, a compound heterozygous carrier of the mutation(s), e.g., having two mutant non-functional MAGEL2 alleles, e.g., having a MAGEL2 null genotype.

[0067] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), for example, having a MAGEL2 null genotype.

[0068] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the leptin receptor gene.

[0069] In various embodiments, the subject is or is identified as being a heterozygous carrier of the mutation(s), e.g., having one functional leptin receptor allele and one non-functional leptin receptor allele.

[0070] In embodiments, the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional leptin receptor alleles, e.g., having a leptin receptor null genotype.

[0071] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), e.g., having a leptin receptor null genotype.

[0072] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the leptin gene.

[0073] In embodiments, the subject is or is identified as being a heterozygous carrier of the mutation(s), e.g., having one functional leptin allele and one non-functional leptin allele.

[0074] In embodiments, the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional leptin alleles, e.g., having a leptin null genotype.

[0075] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), e.g., having a leptin null genotype.

[0076] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the 5-HT2c receptor gene.

[0077] In various embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), e.g., having one functional and one non-functional 5-HT2c receptor allele.

[0078] In various embodiments, the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional 5-HT2c receptor alleles, e.g., having a 5-HT2c receptor null genotype.

[0079] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), eg, having a 5-HT2c receptor null genotype.

[0080] In some embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the native Helix-Loop-Helix 2 (NhHL2) gene.

[0081] In embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), e.g., having one functional NhHL2 allele and one non-functional NhHL2 receptor allele.

[0082] In embodiments, the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional NhHL2 alleles, e.g., having an NhHL2 null genotype.

[0083] In embodiments, the subject is or is identified as being a homozygous carrier of the mutation(s), for example, having an NhHL2 null genotype.

[0084] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in a prohormone convertase gene.

[0085] In embodiments, the subject is, or is identified as, a heterozygous carrier of the mutation(s), e.g., having one functional prohormone convertase allele and one non-functional prohormone convertase allele.

[0086] In embodiments, the subject is, or is identified as being, a compound heterozygous carrier of the mutation(s), e.g., having two non-functional prohormone convertase alleles, e.g., having a prohormone convertase null genotype.

[0087] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), for example, having a prohormone convertase null genotype.

[0088] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the carboxypeptidase E (CPE) gene.

[0089] In embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), for example, having one functional and one non-functional CPE allele.

[0090] In embodiments, the subject is, or is identified as being, a compound heterozygous carrier of the mutation(s), e.g., having two non-functional CPE alleles, e.g., having a CPE null genotype.

[0091] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), eg, having a CPE null genotype.

[0092] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the single-minded 1 (SIM1) gene.

[0093] In embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), for example, having one functional and one non-functional SIM1 allele.

[0094] In embodiments, the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional SIM1 alleles, e.g., having a SIM1 null genotype.

[0095] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), eg, having a SIM1 null genotype.

[0096] In some embodiments, the disorder is characterized by a hypermethylated POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing a methylated cytosine, e.g., a 5' methylcytosine).

[0097] In embodiments, the disorder is: (a) heterozygous POMC mutations characterized by the presence of one functional and one non-functional POMC allele; (b) a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele; (c) a heterozygous melanocortin 4 receptor (MC4R) mutation characterized by the presence of one functional and one non-functional MC4R allele, or (d) characterized by a defect in the POMC-MC4R pathway other than a prohormone convertase mutation (e.g., a loss-of-function mutation).

[0098] In various embodiments, the daily dose is 0.1 mg to 10 mg. In various embodiments, the daily dose is about 0.1 mg to about 7.5 mg. In various embodiments, the daily dose is about 0.1 mg to about 5 mg. In various embodiments, the daily dose is about 0.1 mg to about 2.5 mg. In various embodiments, the daily dose is about 0.1 mg to about 2 mg. In various embodiments, the daily dose is about 0.1 mg to about 1 mg. In various embodiments, the daily dose is about 0.2 mg to about 10 mg. In various embodiments, the daily dose is about 0.2 mg to about 7.5 mg. In various embodiments, the daily dose is about 0.2 mg to about 5 mg. In various embodiments, the daily dose is about 0.2 mg to about 2.5 mg. In various embodiments, the daily dose is about 0.2 mg to about 2 mg. In various embodiments, the daily dose is about 0.2 mg to about 1.5 mg. In various embodiments, the daily dose is about 0.2 mg to about 1 mg. In various embodiments, the daily dose is about 0.3 mg to about 10 mg. In various embodiments, the daily dose is about 0.3 mg to about 7.5 mg. In various embodiments, the daily dose is about 0.3 mg to about 5 mg. In various embodiments, the daily dose is about 0.3 mg to about 2.5 mg. In various embodiments, the daily dose is about 0.3 mg to about 2 mg. In various embodiments, the daily dose is about 0.3 mg to about 1.5 mg. In various embodiments, the daily dose is about 0.3 mg to about 1 mg. In various embodiments, the daily dose is about 0.25 mg (e.g., 0.25 mg) to about 0.5 mg (e.g., 0.5 mg). In various embodiments, the daily dose is about 0.5 mg (e.g., 0.5 mg) to about 0.75 mg (e.g., 0.75 mg). In various embodiments, the daily dose is about 0.25 mg (e.g., 0.25 mg). In some embodiments, the daily dosage is about 0.5 mg (e.g., 0.5 mg). In some embodiments, the daily dosage is about 0.75 mg (e.g., 0.75 mg) to about 1.25 mg (e.g., 1.25 mg). In some embodiments, the daily dosage is about 1 mg (e.g., 1 mg). In some embodiments, the daily dosage is about 1.25 mg (e.g., 1.25 mg) to about 2 mg (e.g., 2 mg). In some embodiments, the daily dosage is about 1.5 mg (e.g., 1.5 mg).In some embodiments, the daily dose is about 2 mg (eg, 2 mg).

[0099] In embodiments, the methods include administering the agonist to the subject in a unit dosage suitable for injection, for example subcutaneous injection.

[0100] In embodiments, the unit dose comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of the agonist.

[0101] In embodiments, the unit dosage is disposed in a delivery device, for example, a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system.

[0102] In embodiments, the agonist is administered subcutaneously, for example, by subcutaneous injection.

[0103] In embodiments, the agonist is administered daily for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or for a period of at least 1, 2, 3, 4 years or more.

[0104] In embodiments, the subject is obese, eg, severely obese.

[0105] In embodiments, the subject has early-onset severe obesity.

[0106] In embodiments, the subject has an excess of appetite.

[0107] In embodiments, the subject has a body weight of 25 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0108] In embodiments, the subject has a weight of 35 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0109] In embodiments, the subject has a weight of 40 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0110] In embodiments, the subject has a weight of 45 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0111] In embodiments, the subject has a BMI greater than the 85th-95th percentile prior to administration of the agonist, eg, at the time the agonist is prescribed or at the time of the first administration.

[0112] In various embodiments, the subject has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapy, prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration.

[0113] In embodiments, the subject has a lower body weight after administration of the agonist than before administration of the agonist.

[0114] In various embodiments, administration of the agonist reduces the subject's weight by about 1 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment, compared to the subject's weight before treatment.

[0115] In various embodiments, administration of the agonist reduces the subject's body weight at a rate of about 1-2 kg / week, e.g., about 2 kg / week, for a period of, e.g., 1-2 weeks or more of treatment, 2-4 weeks or more of treatment, 4-8 weeks or more of treatment, 8-16 weeks or more of treatment, 16-32 weeks or more of treatment, or 32-64 weeks or more of treatment.

[0116] In various embodiments, administration of the agonist reduces the subject's hunger level (e.g., reduces the Likert hunger scale score, e.g., reduces the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points) compared to the subject's hunger level before treatment, e.g., results in the subject's lack of hunger (e.g., a score of 0 on the Likert hunger scale), e.g., after 1-2 weeks or more of treatment, 2-4 weeks or more of treatment, 4-8 weeks or more of treatment, or 8-16 weeks or more of treatment.

[0117] In various embodiments, administration of the agonist does not detectably / significantly reduce the resting energy expenditure (REE) of the subject, e.g., compared to a control REE (e.g., the REE of the subject before treatment, or a predetermined REE, e.g., when expressed as REE per kg of lean body mass, e.g., of a subject with a similar pre-treatment BMI), e.g., over a period of 24 hours, 1 week, or 30 days or more.

[0118] In various embodiments, administration of the agonist increases the subject's resting energy expenditure (REE), e.g., over a period of 24 hours, 1 week, 30 days or more, e.g., compared to a control REE (e.g., compared to the subject's REE before treatment, or compared to a predetermined REE, e.g., expressed as REE per kg of lean body mass, for a subject with a similar pre-treatment BMI, e.g., after a similar level of weight loss has been achieved by fasting).

[0119] In various embodiments, administration of the agonist reduces food intake by the subject compared to a control (e.g., the subject's food intake before treatment), e.g., food intake is daily food intake or food intake over a 24-hour period or a week.

[0120] In various embodiments, administration of the agonist reduces food intake by at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories, or more, compared to a control (e.g., the subject's food intake before treatment or a predetermined food intake level), e.g., food intake is daily food intake or food intake over a 24-hour period or a week.

[0121] In some embodiments, administration of the agonist reduces food intake by at least 5 kcal / kg / day, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 kcal / kg / day or more. In some embodiments, the reduction in food intake is relative to baseline food intake. In some embodiments, the baseline food intake is at least 100 kcal / kg / day, e.g., in a pediatric subject about 1 year old. In some embodiments, the baseline food intake is at least 40 kcal / kg / day, e.g., in a pediatric subject in late adolescence.

[0122] In embodiments, administration of the agonist reduces the subject's waist circumference when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to a control (e.g., the subject's waist circumference before treatment).

[0123] In various embodiments, administration of the agonist reduces the subject's waist circumference by at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm, or more) compared to a control (e.g., the subject's waist circumference before treatment) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks, or more, after initiation of treatment.

[0124] In various embodiments, administration of the agonist does not detectably increase the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to the subject's blood pressure before treatment.

[0125] In various embodiments, administration of the agonist reduces the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment.

[0126] In various embodiments, administration of the agonist reduces the subject's systolic blood pressure by at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment.

[0127] In various embodiments, administration of the agonist reduces the subject's diastolic blood pressure by at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment.

[0128] In embodiments, the subject is a mammal, for example a human.

[0129] In some embodiments, the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0130] In embodiments, the method further comprises obtaining knowledge of the subject's genotype, e.g., POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, prohormone convertase gene, Carboxypeptidase E (CPE) gene, single-minded 1 (SIM1) gene, or This involves obtaining knowledge of the genotype of mutations in POMC-MC4R pathway genes.

[0131] In embodiments, the agonist is administered in response to the detection of a predetermined sequence, eg, a mutation, in a gene described herein.

[0132] In embodiments, the method comprises obtaining knowledge of the methylation status of a POMC gene (e.g., one that is hypermethylated in a POMC intron, e.g., one that contains a methylated cytosine, e.g., a 5' methylcytosine, e.g., one that is hypermethylated in a CpG island of the POMC gene).

[0133] In embodiments, the agonist is administered in response to detection of hypermethylation.

[0134] In embodiments, the knowledge is obtained directly from, for example, a sample from a subject (eg, a blood, serum, urine, or tissue (eg, biopsy) sample).

[0135] In embodiments, the predetermined sequence, e.g., mutation, is detected in the nucleic acid by a method selected from one or more of a nucleic acid hybridization assay, an amplification-based assay, a PCR-RFLP assay, real-time PCR, sequencing, screening analysis, FISH, spectral karyotyping or MFISH, comparative genomic hybridization, in situ hybridization, SSP, HPLC, or mass spectrometry genotyping.

[0136] In embodiments, a predetermined sequence, eg, a mutation, is detected in a subject.

[0137] In embodiments, a predetermined sequence, eg, a mutation, is detected in a nucleic acid molecule or polypeptide in a sample from a subject.

[0138] In embodiments, the methylation, e.g., hypermethylation, e.g., methylated cytosine status, is detected by a method selected from one or more of mass spectrometry, methylation-specific PCR, sequencing of bisulfite-treated DNA, HpaII small fragment enrichment by ligation-mediated PCR assay, ChIP-on-chip assay, restriction enzyme landmark genomic scanning, methylated DNA immunoprecipitation, molecular cleavage photoassay of DNA adenine methyltransferase activity, methyl-sensitive Southern blotting, or high-resolution melting analysis.

[0139] In embodiments, hypermethylation, eg, methylated cytosine, is detected in the subject.

[0140] In embodiments, hypermethylation, eg, methylated cytosine, is detected in nucleic acid molecules in a sample from a subject.

[0141] In embodiments, the sample comprises blood, serum, urine, or cells from a tissue (eg, a biopsy) from the subject.

[0142] In embodiments, the knowledge is obtained from another party, for example, the party is a subject, a caregiver, a physician, an endocrinologist, a hospital, a clinic, a third party payer, an insurance company, or a government agency.

[0143] In embodiments, the detection of the predetermined sequence results from a collaboration with another party.

[0144] In embodiments, the method comprises: In response to determining the presence or absence of (a) a predetermined sequence, e.g., a mutation, and / or (b) hypermethylation in the subject, (1) identifying or selecting a subject as having Prader-Willi syndrome (PWS); (2) identifying or selecting a subject as having a disorder characterized by one or more mutations in the POMC gene, e.g., POMC deficiency; (3) identifying or selecting a subject as having a disorder characterized by one or more mutations in the PCSK1 gene, e.g., PCSK1 deficiency; (4) identifying or selecting a subject as having a disorder characterized by one or more mutations in the MAGEL2 gene, e.g., MAGEL2 deficiency; (5) identifying or selecting a subject as having a disorder characterized by one or more mutations in the leptin receptor gene, e.g., leptin receptor deficiency; (6) identifying or selecting a subject as having a disorder characterized by one or more mutations in the leptin gene, e.g., leptin deficiency; (7) identifying or selecting a subject as having a disorder characterized by one or more mutations in a 5-HT2c receptor gene, e.g., 5-HT2c receptor deficiency; (8) identifying or selecting a subject as having a disorder characterized by one or more mutations in the NhHL2 gene, e.g., NhHL2 deficiency; (9) identifying or selecting a subject as having a disorder characterized by one or more mutations in a prohormone convertase gene, e.g., prohormone convertase deficiency; (10) identifying or selecting a subject as having a disorder characterized by one or more mutations in the CPE gene, e.g., CPE deficiency; (11) identifying or selecting a subject as having a disorder characterized by one or more mutations in the SIM1 gene, e.g., SIM1 deficiency; (12) identifying or selecting a subject as having a disorder characterized by a hypermethylated POMC gene, e.g., POMC deficiency; (13) identifying or selecting a subject as having a disorder characterized by one or more mutations in a POMC-MC4R pathway gene, e.g., a POMC-MC4R pathway deficiency; and / or (14) Identifying or selecting subjects as likely or unlikely to respond to an agonist. Contains one or more of the following:

[0145] In some embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in MAGEL2 and / or a mutation in the paternal allele of the 15q11-q13 region of chromosome 15) is detected in the subject, and in response to that determination, the method includes identifying the subject as having Prader-Willi syndrome (PWS).

[0146] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the POMC gene), is detected in the subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the POMC gene, e.g., POMC deficiency.

[0147] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the PCSK1 gene), is detected in the subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the PCSK1 gene, e.g., PCSK1 deficiency.

[0148] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in a leptin receptor gene), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the leptin receptor gene, e.g., a leptin receptor deficiency.

[0149] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the leptin gene), is detected in the subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the leptin gene, e.g., leptin deficiency.

[0150] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the 5-HT2c receptor gene), is detected in the subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the 5-HT2c receptor gene, e.g., 5-HT2c receptor deficiency.

[0151] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the NhHL2 gene), is detected in the subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the NhHL2 gene, e.g., NhHL2 deficiency.

[0152] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in a prohormone convertase gene), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in a prohormone convertase gene, e.g., a prohormone convertase deficiency.

[0153] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the CPE gene), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the CPE gene, e.g., CPE deficiency.

[0154] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the SIM1 gene), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the SIM1 gene, e.g., SIM1 deficiency.

[0155] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in a gene described herein), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in a POMC-MC4R pathway gene, e.g., a POMC-MC4R pathway deficiency.

[0156] In various embodiments, the presence of hypermethylation in the POMC gene is detected in the subject, and in response to the determination, the method includes identifying the subject as having a disorder characterized by a hypermethylated POMC gene, e.g., POMC deficiency.

[0157] In embodiments, the presence of a predetermined sequence, e.g., a mutation, or hypermethylation, is detected in a subject, and in response to that determination, the method includes identifying the subject as likely to respond to an agonist.

[0158] In embodiments, the subject has or is identified as having PWS or a disorder characterized by one or more mutations in POMC, PCSK1, MAGEL2, leptin receptor, leptin, 5-HT2c receptor, NhHL2, prohormone convertase, CPE, SIM1, or other POMC-MC4R pathway genes, e.g., a POMC-MC4R pathway deficiency.

[0159] In one aspect, there is provided a method of treating a disorder in a subject in need thereof, the disorder comprising: (i) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; (ii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; (iii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene; (iv) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the 5-HT2c receptor gene; (v) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the nescient Helix-Loop-Helix 2 (NhHL2) gene; (vi) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the carboxypeptidase E (CPE) gene; (vii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the single-minded 1 (SIM1) gene; (viii) a disorder characterized by a hypermethylated POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing a methylated cytosine, e.g., a 5' methylcytosine); (ix) A disorder characterized by a defect in the POMC-MC4R pathway, (a) a POMC mutation, e.g., a heterozygous POMC mutation characterized by the presence of one functional and one non-functional POMC allele; (b) a leptin mutation, e.g., a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele; (c) melanocortin 4 receptor (MC4R) mutation, or (d) disorders characterized by defects in the POMC-MC4R pathway other than prohormone convertase mutations; (x) a disorder characterized by a homozygous POMC mutation (e.g., a loss-of-function mutation), e.g., a disorder characterized by a POMC null genotype; (xi) a disorder characterized by a compound heterozygous POMC mutation (e.g., characterized by the presence of two non-functional alleles), e.g., a disorder characterized by a POMC null genotype; (xii) a disorder characterized by a homozygous leptin mutation (e.g., a loss-of-function mutation), e.g., a disorder characterized by a leptin null genotype; (xiii) Disorders characterized by compound heterozygous leptin mutations (e.g., characterized by the presence of two non-functional alleles), e.g., disorders characterized by a leptin null genotype; wherein the method comprises administering an agonist of the melanocortin 4 receptor (MC4R); The agonist is an MC4R agonist as described herein, for example, the agonist is (R 2 R 3 )-A 1 -c(A 2 -A3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) wherein: A 1 Acc, HN-(CH2) m -C(O), an L-amino acid or a D-amino acid, or a deletion; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, a D-amino acid, or a deletion, A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O), A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2)s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), an L-amino acid or a D-amino acid, or a deletion; R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, substituted (C1-C 30 ) acyl, substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C1-C 40) acyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are respectively, independently in each case, H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.

[0160] In embodiments, the disorder is characterized by a homozygous POMC mutation (eg, loss of the mutation), eg, a POMC null genotype.

[0161] In embodiments, the disorder is characterized by a compound heterozygous POMC mutation (eg, characterized by the presence of two non-functional alleles), eg, characterized by a POMC null genotype.

[0162] In embodiments, the mutation is a mutation described herein, for example, p.Lys51Term g.A6851>T and p.Arg145ProfsX12 g.7134delG.

[0163] In embodiments, the disorder is characterized by one or more mutations (eg, loss-of-function mutations) in the PCSK1 gene.

[0164] In embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), e.g., having one functional and one non-functional PCSK1 allele.

[0165] In embodiments, the subject is, or is identified as being, a compound heterozygous carrier of the mutation(s), e.g., having two non-functional PCSK1 alleles, e.g., having a PCSK1 null genotype.

[0166] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), eg, having a PCSK1 null genotype.

[0167] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the MAGEL2 gene.

[0168] In embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), for example having one functional and one non-functional MAGEL2 allele.

[0169] In embodiments, the subject is, or is identified as being, a compound heterozygous carrier of the mutation(s), e.g., having two non-functional MAGEL2 alleles, e.g., having a MAGEL2 null genotype.

[0170] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), for example, having a MAGEL2 null genotype.

[0171] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the leptin receptor gene.

[0172] In various embodiments, the subject is or is identified as being a heterozygous carrier of the mutation(s), e.g., having one functional leptin receptor allele and one non-functional leptin receptor allele.

[0173] In embodiments, the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional leptin receptor alleles, e.g., having a leptin receptor null genotype.

[0174] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), e.g., having a leptin receptor null genotype.

[0175] In embodiments, the disorder is characterized by a homozygous leptin mutation (eg, loss of mutation), eg, a leptin null genotype.

[0176] In embodiments, the disorder is characterized by a compound heterozygous leptin mutation (eg, characterized by the presence of two non-functional alleles), eg, characterized by a leptin null genotype.

[0177] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the 5-HT2c receptor gene.

[0178] In various embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), e.g., having one functional and one non-functional 5-HT2c receptor allele.

[0179] In various embodiments, the subject is, or is identified as, a compound heterozygous carrier of the mutation(s), e.g., having two non-functional 5-HT2c receptor alleles, e.g., having a 5-HT2c receptor null genotype.

[0180] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), eg, having a 5-HT2c receptor null genotype.

[0181] In some embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the native Helix-Loop-Helix 2 (NhHL2) gene.

[0182] In embodiments, the subject is or is identified as being a heterozygous carrier of the mutation(s), e.g., having one functional NhHL2 allele and one non-functional NhHL2 receptor allele.

[0183] In embodiments, the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional NhHL2 alleles, e.g., having an NhHL2 null genotype.

[0184] In embodiments, the subject is or is identified as being a homozygous carrier of the mutation(s), for example, having an NhHL2 null genotype.

[0185] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the carboxypeptidase E (CPE) gene.

[0186] In embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), for example, having one functional and one non-functional CPE allele.

[0187] In embodiments, the subject is, or is identified as being, a compound heterozygous carrier of the mutation(s), e.g., having two non-functional CPE alleles, e.g., having a CPE null genotype.

[0188] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), eg, having a CPE null genotype.

[0189] In embodiments, the disorder is characterized by a mutation (eg, a loss-of-function mutation) in the single-minded 1 (SIM1) gene.

[0190] In embodiments, the subject is, or is identified as being, a heterozygous carrier of the mutation(s), for example, having one functional and one non-functional SIM1 allele.

[0191] In embodiments, the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional SIM1 alleles, e.g., having a SIM1 null genotype.

[0192] In embodiments, the subject is, or is identified as being, a homozygous carrier of the mutation(s), eg, having a SIM1 null genotype.

[0193] In some embodiments, the disorder is characterized by a hypermethylated POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing a methylated cytosine, e.g., a 5' methylcytosine).

[0194] In embodiments, the subject has, or is identified as having, a hypermethylated CpG island in the POMC gene, for example, at the intron 2-exon 3 boundary of the POMC gene.

[0195] In embodiments, the disorder is characterized by a defect in the POMC-MC4R pathway other than a POMC mutation, eg, a heterozygous POMC mutation characterized by the presence of one functional and one non-functional POMC allele.

[0196] In embodiments, the disorder is characterized by a defect in the POMC-MC4R pathway other than a leptin mutation, e.g., a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele.

[0197] In some embodiments, the disorder is characterized by a defect in the POMC-MC4R pathway other than an MC4R mutation, e.g., a heterozygous melanocortin 4 receptor (MC4R) mutation characterized by the presence of one functional MC4R allele and one non-functional MC4R allele.

[0198] In embodiments, the disorder is characterized by a defect in the POMC-MC4R pathway other than a prohormone convertase mutation.

[0199] In embodiments, the methods include administering the agonist to the subject in a unit dosage suitable for injection, for example subcutaneous injection.

[0200] In embodiments, the unit dose comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of the agonist.

[0201] In embodiments, the unit dosage is disposed in a delivery device, for example, a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system.

[0202] In embodiments, the agonist is administered subcutaneously, for example, by subcutaneous injection.

[0203] In embodiments, the agonist is administered daily for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or for a period of at least 1, 2, 3, 4 years or more.

[0204] In embodiments, the subject is obese, eg, severely obese.

[0205] In embodiments, the subject has early-onset severe obesity.

[0206] In embodiments, the subject has an excess of appetite.

[0207] In embodiments, the subject has a body weight of 25 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0208] In embodiments, the subject has a weight of 35 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0209] In embodiments, the subject has a weight of 40 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2Over (e.g., ≥ 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0210] In some embodiments, the patient has a blood pressure of 45 kg / m 2 or higher prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 have a body mass index (BMI) of 18.5 or higher.

[0211] In embodiments, the subject has a BMI greater than the 85th-95th percentile prior to administration of the agonist, eg, at the time the agonist is prescribed or at the time of the first administration.

[0212] In various embodiments, the subject has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapy, prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration.

[0213] In embodiments, the subject has a lower body weight after administration of the agonist than before administration of the agonist.

[0214] In various embodiments, administration of the agonist reduces the subject's weight by about 1 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment, compared to the subject's weight before treatment.

[0215] In various embodiments, administration of the agonist reduces the subject's body weight at a rate of about 1-2 kg / week, e.g., about 2 kg / week, for a period of, e.g., 1-2 weeks or more of treatment, 2-4 weeks or more of treatment, 4-8 weeks or more of treatment, 8-16 weeks or more of treatment, 16-32 weeks or more of treatment, or 32-64 weeks or more of treatment.

[0216] In various embodiments, administration of the agonist reduces the subject's hunger level (e.g., reduces the Likert hunger scale score, e.g., reduces the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points) compared to the subject's hunger level before treatment, e.g., results in the subject's lack of hunger (e.g., a score of 0 on the Likert hunger scale), e.g., after 1-2 weeks or more of treatment, 2-4 weeks or more of treatment, 4-8 weeks or more of treatment, or 8-16 weeks or more of treatment.

[0217] In various embodiments, administration of the agonist does not detectably / significantly reduce the resting energy expenditure (REE) of the subject, e.g., compared to a control REE (e.g., the REE of the subject before treatment, or a predetermined REE, e.g., when expressed as REE per kg of lean body mass, e.g., of a subject with a similar pre-treatment BMI), e.g., over a period of 24 hours, 1 week, or 30 days or more.

[0218] In various embodiments, administration of the agonist increases the subject's resting energy expenditure (REE), e.g., over a period of 24 hours, 1 week, 30 days or more, e.g., compared to a control REE (e.g., compared to the subject's REE before treatment, or compared to a predetermined REE, e.g., expressed as REE per kg of lean body mass, for a subject with a similar pre-treatment BMI, e.g., after a similar level of weight loss has been achieved by fasting).

[0219] In various embodiments, administration of the agonist reduces food intake by the subject compared to a control (e.g., the subject's food intake before treatment), e.g., food intake is daily food intake or food intake over a 24-hour period or a week.

[0220] In various embodiments, administration of the agonist reduces food intake by at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories, or more, compared to a control (e.g., the subject's food intake before treatment or a predetermined food intake level), e.g., food intake is daily food intake or food intake over a 24-hour period or a week.

[0221] In some embodiments, administration of the agonist reduces food intake by at least 5 kcal / kg / day, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 kcal / kg / day or more. In some embodiments, the reduction in food intake is relative to baseline food intake. In some embodiments, the baseline food intake is at least 100 kcal / kg / day, e.g., in a pediatric subject about 1 year old. In some embodiments, the baseline food intake is at least 40 kcal / kg / day, e.g., in a pediatric subject in late adolescence.

[0222] In embodiments, administration of the agonist reduces the subject's waist circumference when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to a control (e.g., the subject's waist circumference before treatment).

[0223] In various embodiments, administration of the agonist reduces the subject's waist circumference by at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm, or more) compared to a control (e.g., the subject's waist circumference before treatment) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks, or more, after initiation of treatment.

[0224] In various embodiments, administration of the agonist does not detectably increase the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to the subject's blood pressure before treatment.

[0225] In various embodiments, administration of the agonist reduces the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment.

[0226] In various embodiments, administration of the agonist reduces the subject's systolic blood pressure by at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment.

[0227] In various embodiments, administration of the agonist reduces the subject's diastolic blood pressure by at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment.

[0228] In embodiments, the subject is a mammal, for example a human.

[0229] In some embodiments, the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0230] In embodiments, the method further comprises obtaining knowledge of the subject's genotype, e.g., POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, the carboxypeptidase E (CPE) gene, or This involves obtaining knowledge of the genotype of mutations in the single-minded 1 (SIM1) gene.

[0231] In embodiments, the agonist is administered in response to the detection of a predetermined sequence, eg, a mutation, in a gene described herein.

[0232] In embodiments, the method comprises obtaining knowledge of the methylation status of a POMC gene (e.g., one that is hypermethylated in a POMC intron, e.g., one that contains a methylated cytosine, e.g., a 5' methylcytosine, e.g., one that is hypermethylated in a CpG island of the POMC gene).

[0233] In embodiments, the agonist is administered in response to detection of hypermethylation.

[0234] In embodiments, the knowledge is obtained directly from, for example, a sample from a subject (eg, a blood, serum, urine, or tissue (eg, biopsy) sample).

[0235] In embodiments, the predetermined sequence, e.g., mutation, is detected in the nucleic acid by a method selected from one or more of a nucleic acid hybridization assay, an amplification-based assay, a PCR-RFLP assay, real-time PCR, sequencing, screening analysis, FISH, spectral karyotyping or MFISH, comparative genomic hybridization, in situ hybridization, SSP, HPLC, or mass spectrometry genotyping.

[0236] In embodiments, a predetermined sequence, eg, a mutation, is detected in a subject.

[0237] In embodiments, a predetermined sequence, eg, a mutation, is detected in a nucleic acid molecule or polypeptide in a sample from a subject.

[0238] In embodiments, the methylation, e.g., hypermethylation, e.g., methylated cytosine status, is detected by a method selected from one or more of mass spectrometry, methylation-specific PCR, sequencing of bisulfite-treated DNA, HpaII small fragment enrichment by ligation-mediated PCR assay, ChIP-on-chip assay, restriction enzyme landmark genomic scanning, methylated DNA immunoprecipitation, molecular cleavage photoassay of DNA adenine methyltransferase activity, methyl-sensitive Southern blotting, or high-resolution melting analysis.

[0239] In embodiments, hypermethylation, eg, methylated cytosine, is detected in the subject.

[0240] In embodiments, hypermethylation, eg, methylated cytosine, is detected in nucleic acid molecules in a sample from a subject.

[0241] In embodiments, the sample comprises blood, serum, urine, or cells from a tissue (eg, a biopsy) from the subject.

[0242] In embodiments, the knowledge is obtained from another party, for example, the party is a subject, a caregiver, a physician, an endocrinologist, a hospital, a clinic, a third party payer, an insurance company, or a government agency.

[0243] In embodiments, the detection of the predetermined sequence results from a collaboration with another party.

[0244] In embodiments, the detection of hypermethylation results from a collaboration with another party.

[0245] In embodiments, the method comprises: In response to determining the presence or absence of (a) a predetermined sequence, e.g., a mutation, and / or (b) hypermethylation in the subject, (1) identifying or selecting a subject as having a disorder characterized by one or more mutations in the PCSK1 gene, e.g., PCSK1 deficiency; (2) identifying or selecting a subject as having a disorder characterized by one or more mutations in the MAGEL2 gene, e.g., MAGEL2 deficiency; (3) identifying or selecting a subject as having a disorder characterized by one or more mutations in the leptin receptor gene, e.g., leptin receptor deficiency; (4) identifying or selecting a subject as having a disorder characterized by one or more mutations in the 5-HT2c receptor gene, e.g., 5-HT2c receptor deficiency; (5) identifying or selecting a subject as having a disorder characterized by one or more mutations in the NhHL2 gene, e.g., NhHL2 deficiency; (6) identifying or selecting a subject as having a disorder characterized by one or more mutations in the CPE gene, e.g., CPE deficiency; (7) identifying or selecting a subject as having a disorder characterized by one or more mutations in the SIM1 gene, e.g., SIM1 deficiency; (8) identifying or selecting a subject as having a disorder characterized by a hypermethylated POMC gene, e.g., POMC deficiency; (9) identifying or selecting a subject as having a disorder characterized by one or more mutations in a POMC-MC4R pathway gene, e.g., a POMC-MC4R pathway deficiency; (10) identifying or selecting a subject as having a disorder characterized by a defect in the POMC-MC4R pathway other than a POMC mutation; (11) identifying or selecting a subject as having a disorder characterized by a defect in the POMC-MC4R pathway other than a leptin mutation; (12) identifying or selecting a subject as having a disorder characterized by a defect in the POMC-MC4R pathway other than an MC4R mutation; (13) Identifying or selecting a subject as having a disorder characterized by a defect in the POMC-MC4R pathway other than a prohormone convertase mutation; (14) identifying or selecting a subject as having a disorder characterized by a homozygous POMC mutation; (15) Identifying or selecting a subject as having a disorder characterized by a compound heterozygous POMC mutation; (16) identifying or selecting a subject as having a disorder characterized by a homozygous leptin mutation; (17) identifying or selecting a subject as having a disorder characterized by a compound heterozygous leptin mutation; and / or (18) Identifying or selecting subjects as likely or unlikely to respond to an agonist. Contains one or more of the following:

[0246] In some embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a MAGEL2 mutation), is detected in a subject, and in response to that determination, the method includes identifying the subject as having Prader-Willi syndrome (PWS).

[0247] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the PCSK1 gene), is detected in the subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the PCSK1 gene, e.g., PCSK1 deficiency.

[0248] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in a leptin receptor gene), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the leptin receptor gene, e.g., a leptin receptor deficiency.

[0249] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the 5-HT2c receptor gene), is detected in the subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the 5-HT2c receptor gene, e.g., 5-HT2c receptor deficiency.

[0250] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the NhHL2 gene), is detected in the subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the NhHL2 gene, e.g., NhHL2 deficiency.

[0251] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the CPE gene), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the CPE gene, e.g., CPE deficiency.

[0252] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the SIM1 gene), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in the SIM1 gene, e.g., SIM1 deficiency.

[0253] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in a gene described herein), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by one or more mutations in a POMC-MC4R pathway gene, e.g., a POMC-MC4R pathway deficiency.

[0254] In various embodiments, the presence of hypermethylation in the POMC gene is detected in the subject, and in response to the determination, the method includes identifying the subject as having a disorder characterized by a hypermethylated POMC gene, e.g., POMC deficiency.

[0255] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a homozygous POMC mutation), is detected in the subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by a homozygous POMC mutation, e.g., a POMC deficiency.

[0256] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a compound heterozygous POMC mutation), is detected in the subject, and in response to the determination, the method includes identifying the subject as having a disorder characterized by the compound heterozygous POMC mutation, e.g., POMC deficiency.

[0257] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a homozygous leptin mutation), is detected in a subject, and in response to that determination, the method includes identifying the subject as having a disorder characterized by the homozygous leptin mutation, e.g., leptin deficiency.

[0258] In various embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a compound heterozygous leptin mutation), is detected in the subject, and in response to the determination, the method includes identifying the subject as having a disorder characterized by the compound heterozygous leptin mutation, e.g., leptin deficiency.

[0259] In embodiments, the presence of a predetermined sequence, e.g., a mutation, or hypermethylation, is detected in a subject, and in response to that determination, the method includes identifying the subject as likely to respond to an agonist.

[0260] In embodiments, the subject has or is identified as having a disorder characterized by one or more mutations in PCSK1, MAGEL2, leptin receptor, 5-HT2c receptor, NhHL2, prohormone convertase, CPE, SIM1, or other POMC-MC4R pathway genes, e.g., a POMC-MC4R pathway deficiency.

[0261] In embodiments, the subject has or is identified as having a disorder characterized by homozygous or compound heterozygous mutations in one or more of the POMC or leptin genes, e.g., POMC deficiency or leptin deficiency.

[0262] In one aspect, provided herein is a unit dosage of an agonist described herein, wherein the unit dosage comprises 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of the agonist.

[0263] In embodiments, the unit dose comprises 0.5 mg of the agonist.

[0264] In embodiments, the unit dose comprises 1.0 mg of the agonist.

[0265] In embodiments, the unit dose comprises 1.5 mg of the agonist.

[0266] In embodiments, the unit dosage is suitable for injection, for example subcutaneous injection.

[0267] In embodiments, the unit dosage is disposed in a delivery device suitable for injection, for example subcutaneous injection.

[0268] In embodiments, the unit dosage is disposed in a syringe or pen-type injector suitable for injection, for example subcutaneous injection.

[0269] In some embodiments, the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0270] In one aspect, there is provided a method of evaluating a subject, comprising: obtaining information that identifies the subject as having or not having a predetermined sequence, e.g., a mutation, in the 15q11-q13 region of chromosome 15 or in the MAGEL2 gene; Provided herein are methods in which identifying a subject as having a mutation identifies the patient as more likely to have symptomatic improvement after treatment with an MC4R agonist (e.g., an MC4R agonist described herein), and identifying a subject as not having a mutation in the 15q11-q13 region of chromosome 15 or the MAGEL2 gene identifies the patient as less likely to have symptomatic improvement after treatment with an MC4R agonist, e.g., an MC4R agonist described herein.

[0271] In another aspect, there is provided a method of evaluating a subject, comprising: POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, the carboxypeptidase E (CPE) gene, or single-minded 1 (SIM1) gene obtaining information identifying the subject as having or not having a predetermined sequence, e.g., a mutation, in one or more of: Provided herein are methods in which identifying a subject as having a predetermined sequence, e.g., a mutation, identifies the patient as more likely to have symptomatic improvement after treatment with an MC4R agonist (e.g., an MC4R agonist described herein), and identifying a subject as not having a predetermined sequence, e.g., a mutation, identifies the patient as less likely to have symptomatic improvement after treatment with an MC4R agonist, e.g., an MC4R agonist described herein.

[0272] According to any of the methods described herein, in embodiments, the improvement in symptoms is determined by: (a) weight loss, (b) a decrease in waist circumference; (c) decreased hunger levels; (d) reduced levels of food intake, and / or (e) No decrease or increase in resting energy expenditure Contains one or more of the following:

[0273] In embodiments, the mutation is a loss-of-function mutation.

[0274] In embodiments, the mutation is a homozygous mutation, for example a homozygous loss-of-function mutation.

[0275] In embodiments, the mutation is a heterozygous mutation.

[0276] In embodiments, the heterozygous mutation is a compound heterozygous mutation (eg, characterized by the presence of two non-functional alleles).

[0277] In some embodiments, a heterozygous mutation is characterized by the presence of one functional and one non-functional allele.

[0278] In embodiments, the method further includes providing the report to another party, for example, the party is a subject, a caregiver, a physician, an oncologist, a hospital, a clinic, a third party payer, an insurance company, or a governmental agency.

[0279] In embodiments, the report is in electronic, web-based, or paper form.

[0280] In embodiments, the report identifies the presence or absence of a mutation in the subject, and optionally includes an identifier for the subject from whom the information was obtained.

[0281] In embodiments, the report comprises: information regarding the genotype of a subject (e.g., the presence or absence of a given sequence, e.g., a mutation); information on prognosis or proposed treatment options, e.g., MC4R agonists; information regarding the likely effectiveness of a treatment option, e.g., an MC4R agonist, the tolerability of the treatment option, or the advisability of applying the treatment option to the subject; and / or Information or recommendations regarding the administration of treatment options (e.g., MC4R agonists) Includes.

[0282] In some embodiments, the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0283] In one aspect, there is provided a method for selecting a subject with Prader-Willi syndrome (PWS), comprising: obtaining knowledge of the subject's genotype, for example, obtaining knowledge of the paternal allele of the 15q11-q13 region of chromosome 15 or the genotype of the MAGEL2 gene; the obtaining step includes determining the presence or absence of a predetermined sequence, e.g., a mutation, in the paternal allele of the 15q11-q13 region of chromosome 15 or the MAGEL2 gene; Provided herein are methods in which the presence of a given sequence, e.g., a mutation, identifies a subject as having PWS.

[0284]

[0010] In one aspect, provided herein is a method for selecting a subject having a POMC-MC4R pathway deficiency, the method comprising: (i) Obtaining knowledge of the subject's genotype, e.g. POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, the carboxypeptidase E (CPE) gene, or Obtaining knowledge of the genotype of a mutation in the single-minded 1 (SIM1) gene, The presence of the mutation identifies or obtains a subject as having a POMC-MC4R pathway defect; or (ii) obtaining knowledge of the methylation status of the POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing a methylated cytosine, e.g., a 5' methylcytosine), wherein the presence of hypermethylation in the POMC intron identifies the subject as having a POMC-MC4R pathway deficiency.

[0285] According to any of the methods described herein, in embodiments, the method further comprises administering to the subject an agonist of the melanocortin 4 receptor (MC4R), e.g., an agonist described herein, e.g., setmelanotide.

[0286] In embodiments, the mutation is a loss-of-function mutation.

[0287] In embodiments, the mutation is a homozygous mutation, for example a homozygous loss-of-function mutation.

[0288] In embodiments, the mutation is a heterozygous mutation.

[0289] In embodiments, the heterozygous mutation is a compound heterozygous mutation (eg, characterized by the presence of two different non-functional alleles).

[0290] In some embodiments, a heterozygous mutation is characterized by the presence of one functional and one non-functional allele.

[0291] In some embodiments, the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0292] Also provided herein is the use of an MC4R agonist, such as an MC4R agonist described herein, in the treatment of, or the manufacture of a medicament for, Prader-Willi syndrome (PWS), wherein the MC4R agonist is administered in a daily dose of about 0.1 mg (e.g., 0.1 mg + / - 5%) to about 10 mg (e.g., 10 mg + / - 5%).

[0293] Also provided is the use of an MC4R agonist, such as an MC4R agonist described herein, in the treatment of, or the manufacture of a medicament for, a disorder, wherein the disorder is (i) Prader-Willi syndrome (PWS), (ii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the POMC gene; (iii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; (iv) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; (v) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene; (vi) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin gene; (vii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the 5-HT2c receptor gene; (viii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the nescient Helix-Loop-Helix 2 (NhHL2) gene; (ix) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in a prohormone convertase gene; (x) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the carboxypeptidase E (CPE) gene; (xi) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the single-minded 1 (SIM1) gene; (xii) a disorder characterized by a hypermethylated POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing one or more methylated cytosines, e.g., a 5' methylcytosine); or (xiii) A disorder characterized by a defect in the POMC-MC4R pathway, (a) heterozygous POMC mutations characterized by the presence of one functional and one non-functional POMC allele; (b) a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele; (c) a melanocortin 4 receptor (MC4R) mutation (e.g., a loss-of-function mutation), or (d) Prohormone convertase mutations (e.g., loss-of-function mutations) is selected from Optionally, also provided herein is a use wherein the agonist is administered in a daily dosage of about 0.1 mg (eg, 0.1 mg + / - 5%) to about 10 mg (eg, 10 mg + / - 5%).

[0294] Further embodiments according to any of the methods described herein include the following.

[0295] In embodiments, the MC4R agonist is a compound of formula I, wherein: A 1 is A6c, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, Ile, Leu, hLeu, Met, β-hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Val, or deletion; A 2 is Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or D-Pen, A 3is D-Abu, Aib, Ala, β-Ala, D-Ala, D-Cha, Gaba, D-Glu, Gly, D-Ile, D-Leu, D-Tle, D-Val, or a deletion; A 4 is His or 3-Pal, A 5 is D-Bal, D-1-Nal, D-2-Nal, D-Phe, D-Trp, or D-(Et)Tyr; A 6 is Arg or hArg, A 7 are Bal, BiP, 1-Nal, 2-Nal, Trp, and D-Trp, A 8 is A6c, D-Ala, Aha, Ahx, Ala, β-Ala, Apn, Gaba, Gly, or a deletion; A 9 is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen, A 10 is Thr or a deletion, A 3 ~A 8 is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein at least one of but not both of is a deletion.

[0296] In some embodiments, the MC4R agonist is not adrenocorticotropic hormone (ACTH).

[0297] In some embodiments, the MC4R agonist is not Melanotan-II (MT-II) (Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2) (SEQ ID NO: 562).

[0298] In embodiments, the MC4R agonist comprises eight or more amino acids.

[0299] In some embodiments, the MC4R agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140) or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, the MC4R agonist is hydantoin (C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 500) or a pharmaceutically acceptable salt thereof.

[0301] In embodiments, the MC4R agonist is the tripeptide D-Phe-Arg-Trp (SEQ ID NO: 560) or a pharmaceutical salt thereof.

[0302] In some embodiments, the MC4R agonist is a peptide comprising D-Phe-Arg-Trp (SEQ ID NO: 560) or a pharmaceutical salt thereof.

[0303] In some embodiments, the MC4R agonist is a peptide comprising the acetylated tripeptide Ac-D-Phe-Arg-Trp-NH2 (SEQ ID NO: 561) or a pharmaceutical salt thereof.

[0304] In some embodiments, the MC4R agonist is c[hydantoin (C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2 (sequence number 496) or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the MC4R agonist is hydantoin (C(O)-(Nle-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 501) or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the MC4R agonist is hydantoin (C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2 SEQ ID NO: 506) or a pharmaceutically acceptable salt thereof.

[0307] In some embodiments, the MC4R agonist is hydantoin (C(O)-(Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 507) or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the MC4R agonist is hydantoin (C(O)-(D-Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (sequence number 515) or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the MC4R agonist is hydantoin (C(O)-(Gly-D-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 535) or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the MC4R agonist is hydantoin (C(O)-(Gly-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 531) or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-NH2 (sequence number 468) or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-NH2 (sequence number 470) or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-NH2 (sequence number 471) or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-β-Ala-Cys)-(Pro)2-Lys-Asp-NH2 (sequence number 472) or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Aib-Cys)-(Pro)2-Lys-Asp-NH2 (sequence number 473) or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the MC4R agonist is c[hydantoin (C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH2 (SEQ ID NO: 492) or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the MC4R agonist is c[hydantoin (C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH2 (sequence number 489) or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the MC4R agonist is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2( SEQ ID NO: 139) or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the MC4R agonist is Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2 (SEQ ID NO: 36) or a pharmaceutically acceptable salt thereof.

[0320] In some embodiments, the MC4R agonist is D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2 (SEQ ID NO: 81) or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, the MC4R agonist is D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2 (SEQ ID NO: 83) or a pharmaceutically acceptable salt thereof.

[0322] In some embodiments, the MC4R agonist is D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2 (SEQ ID NO: 84) or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, the MC4R agonist is D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2 (sequence number 82) or a pharmaceutically acceptable salt thereof.

[0324] In embodiments, the MC4R agonist is any of the MC4R agonists described in US 2014 / 0329743 A1, which is incorporated herein by reference.

[0325] In embodiments, the MC4R agonist is any of the MC4R agonists described in WO2014 / 144260 A1, which is incorporated herein by reference.

[0326] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting. Headings, subheadings, or numbered or lettered elements, e.g., (a), (b), (i), etc., are presented for ease of reading only. The use of headings or numbered or lettered elements in this document does not require that the steps or elements be performed in alphabetical order or that the steps or elements are necessarily separated from one another. Other features, objects, and advantages of the present invention will become apparent from the specification and drawings, and from the claims. The present invention provides, for example, the following items. (Item 1) 1. A method of treating Prader-Willi syndrome (PWS) in a subject in need thereof, comprising: administering an agonist of the melanocortin 4 receptor (MC4R) at a daily dose of about 0.1 mg (e.g., 0.1 mg + / - 5%) to about 10 mg (e.g., 10 mg + / - 5%); The agonist is an MC4R agonist as described herein, for example, the agonist is (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) wherein: A 1 Acc, HN-(CH2) m-C(O), an L-amino acid or a D-amino acid, or a deletion; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, a D-amino acid, or a deletion, A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O), A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), an L-amino acid or a D-amino acid, or a deletion; R1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, substituted (C1-C 30 ) acyl, substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C1-C 40 ) acyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are respectively, independently in each case, H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN; How to treat PWS. (Item 2) Item 10. The method of item 1, wherein the subject has or is identified as having a loss-of-function mutation in the 15q11-q13 region of chromosome 15. (Item 3) 3. The method of claim 2, wherein the subject has or is identified as having a mutation (e.g., a loss-of-function mutation) in the MAGEL2 gene. (Item 4) 4. The method according to any one of items 1 to 3, wherein the daily dose is 0.1 mg to 10 mg. (Item 5) 5. The method according to Item 4, wherein the daily dose is about 0.1 mg to about 7.5 mg. (Item 6) Item 5. The method according to Item 4, wherein the daily dose is about 0.1 mg to about 5 mg. (Item 7) 5. The method according to Item 4, wherein the daily dose is about 0.1 mg to about 2.5 mg. (Item 8) 5. The method according to item 4, wherein the daily dose is about 0.1 mg to about 2 mg. (Item 9) 5. The method according to item 4, wherein the daily dose is about 0.1 mg to about 1 mg. (Item 10) 4. The method according to any one of items 1 to 3, wherein the daily dose is about 0.2 mg to about 10 mg. (Item 11) Item 11. The method according to item 10, wherein the daily dose is about 0.2 mg to about 7.5 mg. (Item 12) Item 11. The method according to Item 10, wherein the daily dose is about 0.2 mg to about 5 mg. (Item 13) Item 11. The method according to Item 10, wherein the daily dose is about 0.2 mg to about 2.5 mg. (Item 14) Item 11. The method according to Item 10, wherein the daily dose is about 0.2 mg to about 2 mg. (Item 15) Item 11. The method according to Item 10, wherein the daily dose is about 0.2 mg to about 1.5 mg. (Item 16) Item 11. The method according to Item 10, wherein the daily dose is about 0.2 mg to about 1 mg. (Item 17) 4. The method according to any one of items 1 to 3, wherein the daily dose is about 0.3 mg to about 10 mg. (Item 18) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 7.5 mg. (Item 19) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 5 mg. (Item 20) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 2.5 mg. (Item 21) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 2 mg. (Item 22) Item 18. The method according to item 17, wherein the daily dose is about 0.3 mg to about 1.5 mg. (Item 23) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 1 mg. (Item 24) 4. The method according to any one of items 1 to 3, wherein the daily dose is about 0.25 mg (e.g., 0.25 mg) to about 0.5 mg (e.g., 0.5 mg). (Item 25) 4. The method according to any one of items 1 to 3, wherein the daily dose is from about 0.5 mg (e.g., 0.5 mg) to about 0.75 mg (e.g., 0.75 mg). (Item 26) 25. The method of claim 24, wherein the daily dose is about 0.25 mg (e.g., 0.25 mg). (Item 27) 26. The method of item 24 or 25, wherein the daily dose is about 0.5 mg (e.g., 0.5 mg). (Item 28) 4. The method according to any one of items 1 to 3, wherein the daily dose is from about 0.75 mg (e.g., 0.75 mg) to about 1.25 mg (1.25 mg). (Item 29) 29. The method of claim 28, wherein the daily dose is about 1 mg (e.g., 1 mg). (Item 30) 4. The method according to any one of items 1 to 3, wherein the daily dose is from about 1.25 mg (e.g., 1.25 mg) to about 2 mg (e.g., 2 mg). (Item 31) The method according to Item 30, wherein the daily dose is about 1.5 mg (e.g., 1.5 mg). (Item 32) 31. The method of claim 30, wherein the daily dose is about 2 mg (e.g., 2 mg). (Item 33) 33. The method of any one of items 1 to 32, comprising administering the agonist to the subject in a unit dosage suitable for injection, for example subcutaneous injection. (Item 34) 34. The method of claim 33, wherein the unit dose comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of the agonist. (Item 35) 35. The method of claim 33 or 34, wherein the unit dose is disposed in a delivery device, such as a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system. (Item 36) 36. The method according to any one of items 1 to 35, wherein the agonist is administered subcutaneously, for example by subcutaneous injection. (Item 37) 38. The method of any one of claims 1 to 36, wherein the agonist is administered daily for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or for at least 1, 2, 3, 4 years or more. 38. The method of any one of items 1 to 37, wherein the subject is obese, such as severely obese. (Item 39) 39. The method of any one of items 1 to 38, wherein the subject has early-onset severe obesity. (Item 40) 40. The method according to any one of items 1 to 39, wherein the subject has an excess of appetite. (Item 41) The subject has a blood pressure of 25 kg / m 2 or less prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 41. The method according to any one of items 1 to 40, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 42) The subject has a body weight of 35 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2Over (e.g., ≥ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 42. The method according to any one of items 1 to 41, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 43) The subject has a blood pressure of 40 kg / m 2 or less prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 The method according to any one of items 1 to 42, wherein the subject has a body mass index (BMI) of 0.05 or higher. (Item 44) The subject has a body weight of 45 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 44. The method according to any one of items 1 to 43, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 45) 45. The method of any one of items 1 to 44, wherein the subject has failed one or more previous therapies, e.g., exercise therapy, diet therapy, or behavioral therapy, prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. (Item 46) 46. ​​The method of any one of items 1 to 45, wherein the subject has a lower body weight after administration of the agonist than before administration of the agonist. (Item 47) 47. The method of any one of items 1 to 46, wherein administration of the agonist reduces the subject's body weight by about 1 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment, compared to the subject's body weight before treatment. (Item 48) 48. The method of any one of items 1 to 47, wherein administration of the agonist reduces the subject's body weight at a rate of about 1 to 2 kg / week, e.g., about 2 kg / week, for a period of 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to 8 weeks or more of treatment, 8 to 16 weeks or more of treatment, 16 to 32 weeks or more of treatment, or 32 to 64 weeks or more of treatment. (Item 49) 49. The method of any one of items 1-48, wherein administration of the agonist reduces the subject's hunger level (e.g., reduces the score on the Likert hunger scale, e.g., reduces the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points) compared to the subject's hunger level before treatment, e.g., results in a loss of hunger in the subject (e.g., a score of 0 on the Likert hunger scale), e.g., after 1-2 weeks or more of treatment, 2-4 weeks or more of treatment, 4-8 weeks or more of treatment, or 8-16 weeks or more of treatment. (Item 50) 50. The method of any one of items 1 to 49, wherein administration of the agonist does not detectably / significantly reduce the resting energy expenditure (REE) of the subject, e.g., compared to a control REE (e.g., the REE of the subject before treatment, or a predetermined REE, e.g., when expressed as REE per kg of lean body mass, e.g., of a subject with a similar pre-treatment BMI), e.g., over a period of 24 hours, 1 week, or 30 days or more. (Item 51) 51. The method of claim 50, wherein administration of the agonist increases the resting energy expenditure (REE) of the subject, e.g., over a period of 24 hours, 1 week, 30 days or more, e.g., compared to a control REE (e.g., compared to the REE of the subject before treatment, or compared to a predetermined REE of a subject with a similar pre-treatment BMI, e.g., when expressed as REE per kg of lean body mass after a similar level of weight loss has been achieved by fasting). (Item 52) 52. The method of any one of items 1 to 51, wherein administration of the agonist reduces food intake by the subject compared to a control (e.g., the subject's food intake before treatment), e.g., the food intake is daily food intake or food intake over a 24-hour period or a week. (Item 53) 53. The method of claim 52, wherein administration of the agonist reduces food intake by at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories or more, compared to a control (e.g., the subject's food intake before treatment or a predetermined food intake level), e.g., wherein the food intake is daily food intake or food intake over a 24-hour period or a week. (Item 54) 54. The method of any one of paragraphs 1 to 53, wherein administration of the agonist reduces the subject's waist circumference when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to a control (e.g., the subject's waist circumference before treatment). (Item 55) 55. The method of item 54, wherein administration of the agonist reduces the subject's waist circumference by at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm, or more) compared to a control (e.g., the subject's waist circumference before treatment) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. (Item 56) 56. The method of any one of items 1 to 55, wherein administration of the agonist does not detectably increase the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to the subject's blood pressure before treatment. (Item 57) 57. The method of any one of items 1 to 56, wherein administration of the agonist reduces the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment. (Item 58) 58. The method of claim 57, wherein administration of the agonist reduces the subject's systolic blood pressure by at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. (Item 59) 58. The method of item 57, wherein administration of the agonist reduces the subject's diastolic blood pressure by at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. (Item 60) The method according to any one of items 1 to 59, wherein the subject is a mammal, for example, a human. 61. The method according to any one of items 1 to 60, wherein the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140). (Item 62) 62. The method according to any one of items 1 to 61, comprising obtaining knowledge of the genotype of said subject, for example obtaining knowledge of the genotype of the 15q11-q13 region of chromosome 15 or the MAGEL2 gene. (Item 63) 63. The method of item 62, wherein the agonist is administered in response to detection of a predetermined sequence, e.g., a mutation, in the 15q11-q13 region of chromosome 15 or in the MAGEL2 gene. (Item 64) 1. A method of treating a disorder in a subject in need thereof, comprising: administering an agonist of the melanocortin 4 receptor (MC4R) at a daily dose of about 0.1 mg (e.g., 0.1 mg + / - 5%) to about 10 mg (e.g., 10 mg + / - 5%); The disorder is (i) Prader-Willi syndrome (PWS), (ii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the POMC gene; (iii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; (iv) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; (v) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene; (vi) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin gene; (vii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the 5-HT2c receptor gene; (viii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the nescient Helix-Loop-Helix 2 (NhHL2) gene; (ix) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in a prohormone convertase gene; (x) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the carboxypeptidase E (CPE) gene; (xi) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the single-minded 1 (SIM1) gene; (xii) a disorder characterized by a hypermethylated POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing one or more methylated cytosines, e.g., a 5' methylcytosine); or (xiii) A disorder characterized by a defect in the POMC-MC4R pathway, (e) a heterozygous POMC mutation characterized by the presence of one functional and one non-functional POMC allele; (f) a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele; (g) melanocortin 4 receptor (MC4R) mutations (e.g., loss-of-function mutations), (h) prohormone convertase mutations (e.g., loss-of-function mutations), (i) Mutations in genes associated with Bardet-Biedl syndrome (e.g., mutations in BBS1 to BBS20), or (j) Disorders characterized by defects in the POMC-MC4R pathway other than mutations in genes associated with Alström syndrome is selected from The agonist is an MC4R agonist as described herein, for example, the agonist is (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) where: A 1 Acc, HN-(CH2) m -C(O), an L-amino acid or a D-amino acid, or a deletion; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, a D-amino acid, or a deletion, A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O), A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), an L-amino acid or a D-amino acid, or a deletion; R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30) heteroalkyl, substituted (C1-C 30 ) acyl, substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C1-C 40 ) acyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are respectively, independently in each case, H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN. (Item 65) 65. The method of item 64, wherein the disorder is Prader-Willi syndrome (PWS). (Item 66) 66. The method of item 64 or 65, wherein the subject has or is identified as having a loss-of-function mutation in the paternal allele of the 15q11-q13 region of chromosome 15. (Item 67) 67. The method of item 65 or 66, wherein the subject has or is identified as having a mutation, e.g., a loss-of-function mutation, in the MAGEL2 gene. (Item 68) 65. The method of item 64, wherein the disorder is characterized by one or more mutations (e.g., loss-of-function mutations) in the POMC gene. (Item 69) 69. The method of claim 68, wherein the subject is or is identified as being a heterozygous carrier of the mutation(s), e.g., having one functional and one non-functional POMC allele. (Item 70) 69. The method of claim 68, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two different non-functional POMC alleles, e.g., having a POMC null genotype. (Item 71) 69. The method of claim 68, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a homozygous POMC null genotype. (Item 72) 65. The method of item 64, wherein the disorder is characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene. (Item 73) 73. The method of claim 72, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional and one non-functional PCSK1 allele. (Item 74) 73. The method of claim 72, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional PCSK1 alleles, e.g., having a PCSK1 null genotype. (Item 75) 73. The method of claim 72, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a homozygous PCSK1 null genotype. (Item 76) 65. The method of item 64, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the MAGEL2 gene. (Item 77) 77. The method of claim 76, wherein the subject is or is identified as being a heterozygous carrier of the mutation(s), including, for example, a subject who has one functional and one non-functional MAGEL2 allele, and the remaining functional allele is silenced by maternal imprinting, such that the subject is a functional MAGEL2 null patient. (Item 78) 77. The method of claim 76, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two mutant non-functional MAGEL2 alleles, e.g., having a MAGEL2 null genotype. (Item 79) 77. The method of claim 76, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a MAGEL2 null genotype. (Item 80) 65. The method of item 64, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the leptin receptor gene. (Item 81) 81. The method of claim 80, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional leptin receptor allele and one non-functional leptin receptor allele. (Item 82) 81. The method of claim 80, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional leptin receptor alleles, e.g., having a leptin receptor null genotype. (Item 83) 81. The method of claim 80, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a leptin receptor null genotype. (Item 84) 65. The method of item 64, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the leptin gene. (Item 85) 85. The method of claim 84, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional leptin allele and one non-functional leptin allele. (Item 86) 85. The method of claim 84, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional leptin alleles, e.g., having a leptin null genotype. (Item 87) 85. The method of claim 84, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a leptin null genotype. (Item 88) 65. The method of item 64, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the 5-HT2c receptor gene. (Item 89) 89. The method of claim 88, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional and one non-functional 5-HT2c receptor allele. (Item 90) 89. The method of claim 88, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional 5-HT2c receptor alleles, e.g., having a 5-HT2c receptor null genotype. (Item 91) 89. The method of claim 88, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a 5-HT2c receptor null genotype. (Item 92) 65. The method of item 64, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the native Helix-Loop-Helix 2 (NhHL2) gene. (Item 93) 93. The method of claim 92, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional NhHL2 allele and one non-functional NhHL2 receptor allele. (Item 94) 93. The method of claim 92, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional NhHL2 alleles, e.g., having an NhHL2 null genotype. (Item 95) 93. The method of claim 92, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having an NhHL2 null genotype. (Item 96) 65. The method of claim 64, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in a prohormone convertase gene. (Item 97) 97. The method of claim 96, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional prohormone convertase allele and one non-functional prohormone convertase allele. (Item 98) 97. The method of claim 96, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional prohormone convertase alleles, e.g., having a prohormone convertase null genotype. (Item 99) 97. The method of claim 96, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a prohormone convertase null genotype. (Item 100) 65. The method of item 64, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the carboxypeptidase E (CPE) gene. (Item 101) 101. The method of claim 100, wherein the subject is, or is identified as, a heterozygous carrier of the mutation(s), e.g., having one functional CPE allele and one non-functional CPE allele. (Item 102) 101. The method of claim 100, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional CPE alleles, e.g., having a CPE null genotype. (Item 103) 101. The method of claim 100, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a CPE null genotype. (Item 104) 65. The method of item 64, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the single-minded 1 (SIM1) gene. (Item 105) 105. The method of claim 104, wherein the subject is or is identified as being a heterozygous carrier of the mutation(s), e.g., having one functional and one non-functional SIM1 allele. (Item 106) 105. The method of claim 104, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional SIM1 alleles, e.g., having a SIM1 null genotype. (Item 107) 105. The method of claim 104, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a SIM1 null genotype. (Item 108) 65. The method of claim 64, wherein the disorder is characterized by a hypermethylated POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing a methylated cytosine, e.g., a 5' methylcytosine). (Item 109) The disorder is (e) a heterozygous POMC mutation characterized by the presence of one functional and one non-functional POMC allele; (f) a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele; (g) a heterozygous melanocortin 4 receptor (MC4R) mutation characterized by the presence of one functional and one non-functional MC4R allele; (h) prohormone convertase mutations (e.g., loss-of-function mutations), (i) Mutations in genes associated with Bardet-Biedl syndrome (e.g., mutations in BBS1 to BBS20), or (j) The method according to Item 64, characterized by a defect in the POMC-MC4R pathway other than a mutation in a gene associated with Alström syndrome. (Item 110) 109. The method according to any one of items 64 to 109, wherein the daily dose is 0.1 mg to 10 mg. (Item 111) Item 111. The method according to item 110, wherein the daily dose is about 0.1 mg to about 7.5 mg. (Item 112) Item 111. The method according to item 110, wherein the daily dose is about 0.1 mg to about 5 mg. (Item 113) Item 111. The method according to item 110, wherein the daily dose is about 0.1 mg to about 2.5 mg. (Item 114) Item 111. The method according to Item 110, wherein the daily dose is about 0.1 mg to about 2 mg. (Item 115) Item 111. The method according to item 110, wherein the daily dose is about 0.1 mg to about 1 mg. (Item 116) 109. The method according to any one of items 64 to 109, wherein the daily dose is about 0.2 mg to about 10 mg. (Item 117) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 7.5 mg. (Item 118) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 5 mg. (Item 119) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 2.5 mg. (Item 120) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 2 mg. (Item 121) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 1.5 mg. (Item 122) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 1 mg. (Item 123) 109. The method according to any one of items 64 to 109, wherein the daily dose is about 0.3 mg to about 10 mg. (Item 124) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 7.5 mg. (Item 125) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 5 mg. (Item 126) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 2.5 mg. (Item 127) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 2 mg. (Item 128) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 1.5 mg. (Item 129) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 1 mg. (Item 130) 109. The method according to any one of items 64 to 109, wherein the daily dose is from about 0.25 mg (e.g., 0.25 mg) to about 0.5 mg (e.g., 0.5 mg). (Item 131) 109. The method according to any one of items 64 to 109, wherein the daily dose is from about 0.5 mg (e.g., 0.5 mg) to about 0.75 mg (e.g., 0.75 mg). (Item 132) Item 131. The method of item 130, wherein the daily dose is about 0.25 mg (e.g., 0.25 mg). (Item 133) 132. The method of claim 130 or 131, wherein the daily dose is about 0.5 mg (e.g., 0.5 mg). (Item 134) 109. The method according to any one of items 64 to 109, wherein the daily dose is from about 0.75 mg (e.g., 0.75 mg) to about 1.25 mg (1.25 mg). (Item 135) Item 135. The method of item 134, wherein the daily dose is about 1 mg (e.g., 1 mg). (Item 136) 109. The method according to any one of items 64 to 109, wherein the daily dose is from about 1.25 mg (e.g., 1.25 mg) to about 2 mg (e.g., 2 mg). (Item 137) Item 137. The method of item 136, wherein the daily dose is about 1.5 mg (e.g., 1.5 mg). (Item 138) Item 137. The method of item 136, wherein the daily dose is about 2 mg (e.g., 2 mg). (Item 139) 139. The method of any one of items 64 to 138, comprising administering the agonist to the subject in a unit dosage suitable for injection, for example subcutaneous injection. (Item 140) 140. The method of claim 139, wherein the unit dose comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of the agonist. (Item 141) 141. The method of claim 139 or 140, wherein the unit dose is disposed in a delivery device, such as a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system. (Item 142) 142. The method according to any one of items 64 to 141, wherein the agonist is administered subcutaneously, for example by subcutaneous injection. (Item 143) 143. The method of any one of paragraphs 64 to 142, wherein the agonist is administered daily for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or for at least 1, 2, 3, 4 years or more. (Item 144) 144. The method of any one of items 64 to 143, wherein the subject is obese, such as severely obese. (Item 145) 145. The method of any one of items 64 to 144, wherein the subject has early-onset severe obesity. (Item 146) 146. The method of any one of items 64 to 145, wherein the subject has an excess of appetite. (Item 147) The subject has a blood pressure of 25 kg / m 2 or less prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 147. The method according to any one of items 64 to 146, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 148) The subject has a body weight of 35 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 148. The method according to any one of items 64 to 147, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 149) The subject has a blood pressure of 40 kg / m 2 or less prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 149. The method according to any one of items 64 to 148, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 150) The subject has a body weight of 45 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m2 149. The method according to any one of items 64 to 149, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 151) 151. The method of any one of items 64 to 150, wherein the subject has failed one or more previous therapies, e.g., exercise therapy, diet therapy, or behavioral therapy, prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. (Item 152) 152. The method of any one of items 64 to 151, wherein the subject has a lower body weight after administration of the agonist than before administration of the agonist. (Item 153) 153. The method of any one of items 64 to 152, wherein administration of the agonist reduces the subject's body weight by about 1 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment, compared to the subject's body weight before treatment. (Item 154) 154. The method of any one of items 64 to 153, wherein administration of the agonist reduces the subject's body weight at a rate of about 1 to 2 kg / week, e.g., about 2 kg / week, for a period of 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to 8 weeks or more of treatment, 8 to 16 weeks or more of treatment, 16 to 32 weeks or more of treatment, or 32 to 64 weeks or more of treatment. (Item 155) 155. The method of any one of items 64 to 154, wherein administration of the agonist reduces the subject's hunger level (e.g., reduces the score on the Likert hunger scale, e.g., reduces the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points) compared to the subject's hunger level before treatment, e.g., results in a loss of hunger in the subject (e.g., a score of 0 on the Likert hunger scale), e.g., after 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to 8 weeks or more of treatment, or 8 to 16 weeks or more of treatment. (Item 156) 156. The method of any one of items 64 to 155, wherein administration of the agonist does not detectably / significantly reduce the resting energy expenditure (REE) of the subject, e.g., compared to a control REE (e.g., the REE of the subject before treatment, or a predetermined REE, e.g., when expressed as REE per kg of lean body mass, e.g., of a subject with a similar pre-treatment BMI), e.g., over a period of 24 hours, 1 week, or 30 days or more. (Item 157) 157. The method of claim 156, wherein administration of the agonist increases the resting energy expenditure (REE) of the subject, e.g., over a period of 24 hours, 1 week, 30 days or more, e.g., compared to a control REE (e.g., compared to the REE of the subject before treatment, or compared to a predetermined REE, e.g., when expressed as REE per kg of lean body mass, e.g., of a subject with a similar pre-treatment BMI, e.g., after a similar level of weight loss has been achieved by fasting). (Item 158) 158. The method of any one of items 64 to 157, wherein administration of the agonist reduces food intake by the subject compared to a control (e.g., the subject's food intake before treatment), e.g., the food intake is daily food intake or food intake over a 24-hour period or a week. (Item 159) 159. The method of claim 158, wherein administration of the agonist reduces food intake by at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories or more compared to a control (e.g., the subject's food intake before treatment or a predetermined food intake level), e.g., wherein the food intake is daily food intake or food intake over a 24-hour period or a week. (Item 160) 159. The method of any one of paragraphs 64 to 159, wherein administration of the agonist reduces the subject's waist circumference when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to a control (e.g., the subject's waist circumference before treatment). (Item 161) 161. The method of claim 160, wherein administration of the agonist reduces the subject's waist circumference by at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm, or more) compared to a control (e.g., the subject's waist circumference before treatment) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. (Item 162) 162. The method of any one of items 64 to 161, wherein administration of the agonist does not detectably increase the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to the subject's blood pressure before treatment. (Item 163) 163. The method of any one of items 64 to 162, wherein administration of the agonist reduces the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment. (Item 164) Item 165. The method of item 163, wherein administration of the agonist reduces the subject's systolic blood pressure by at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. 164. The method of claim 163, wherein administration of the agonist reduces the subject's diastolic blood pressure by at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. (Item 166) 166. The method of any one of items 64 to 165, wherein the subject is a mammal, such as a human. (Item 167) 167. The method according to any one of items 64 to 166, wherein the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140). (Item 168) Obtaining knowledge of the subject's genotype, e.g., Prohormone convertase genes, including the POMC gene and PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, Carboxypeptidase E (CPE) gene, single-minded 1 (SIM1) gene, POMC-MC4R pathway genes, BBS1~BBS20), ALMS1, BDNF, MCH1R, MCH, NTRK2, SIM1, ENPP1, COH1, CNR1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood), SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, INSIG2, KCTD15, NROB2, and 16p11.2 deletions 168. The method of any one of items 64 to 167, comprising obtaining knowledge of the genotype of a mutation in (including the SH2B1 gene). (Item 169) 169. The method of claim 168, wherein the agonist is administered in response to detection of a predetermined sequence, e.g., a mutation, in the gene of claim 168. (Item 170) 1. A method of treating a disorder in a subject in need thereof, wherein the disorder comprises: (i) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; (ii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; (iii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene; (iv) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the 5-HT2c receptor gene; (v) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the nescient Helix-Loop-Helix 2 (NhHL2) gene; (vi) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the carboxypeptidase E (CPE) gene; (vii) a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the single-minded 1 (SIM1) gene; (viii) a disorder characterized by a hypermethylated POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing a methylated cytosine, e.g., a 5' methylcytosine); (ix) A disorder characterized by a defect in the POMC-MC4R pathway, (e) a POMC mutation, e.g., a heterozygous POMC mutation characterized by the presence of one functional and one non-functional POMC allele; (f) a leptin mutation, e.g., a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele; (g) melanocortin 4 receptor (MC4R) mutation, or (h) disorders characterized by defects in the POMC-MC4R pathway other than prohormone convertase mutations; (x) a disorder characterized by a homozygous POMC mutation (e.g., a loss-of-function mutation), e.g., a disorder characterized by a POMC null genotype; (xi) a disorder characterized by a compound heterozygous POMC mutation (e.g., characterized by the presence of two non-functional alleles), e.g., a disorder characterized by a POMC null genotype; (xii) a disorder characterized by a homozygous leptin mutation (e.g., a loss-of-function mutation), e.g., a disorder characterized by a leptin null genotype; (xiii) Disorders characterized by compound heterozygous leptin mutations (e.g., characterized by the presence of two non-functional alleles), e.g., disorders characterized by a leptin null genotype; (xiv) a disorder characterized by a mutation in a gene associated with Bardet-Biedl syndrome (e.g., a mutation in BBS1 to BBS20), or (xv) Disorders characterized by mutations in genes associated with Alström syndrome wherein the method comprises administering an agonist of the melanocortin 4 receptor (MC4R); The agonist is an MC4R agonist as described herein, for example, the agonist is (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) wherein: A 1 Acc, HN-(CH2) m -C(O), an L-amino acid or a D-amino acid, or a deletion; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, a D-amino acid, or a deletion, A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O), A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), an L-amino acid or a D-amino acid, or a deletion; R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, substituted (C1-C 30 ) acyl, substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C1-C 40 ) acyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are respectively, independently in each case, H, F, Cl, Br, I, (C 1-10) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN. (Item 171) 171. The method of claim 170, wherein the disorder is characterized by a homozygous POMC mutation (e.g., loss of mutation), e.g., a POMC null genotype. (Item 172) 171. The method of claim 170, wherein the disorder is characterized by a compound heterozygous POMC mutation (e.g., characterized by the presence of two non-functional alleles), e.g., characterized by a POMC null genotype. (Item 173) 173. The method of claim 172, wherein the mutations are p.Lys51Term g.A6851>T and p.Arg145ProfsX12 g.7134delG. (Item 174) 171. The method of claim 170, wherein the disorder is characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene. (Item 175) 175. The method of claim 174, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional and one non-functional PCSK1 allele. (Item 176) 175. The method of claim 174, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional PCSK1 alleles, e.g., having a PCSK1 null genotype. (Item 177) 175. The method of claim 174, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a PCSK1 null genotype. (Item 178) 171. The method of item 170, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the MAGEL2 gene. (Item 179) 179. The method of claim 178, wherein the subject is or is identified as being a heterozygous carrier of the mutation(s), e.g., having one functional and one non-functional MAGEL2 allele. (Item 180) 179. The method of claim 178, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional MAGEL2 alleles, e.g., having a MAGEL2 null genotype. (Item 181) 179. The method of claim 178, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a MAGEL2 null genotype. (Item 182) 171. The method of claim 170, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the leptin receptor gene. (Item 183) 183. The method of claim 182, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional leptin receptor allele and one non-functional leptin receptor allele. (Item 184) 183. The method of claim 182, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional leptin receptor alleles, e.g., having a leptin receptor null genotype. (Item 185) Item 186. The method of item 182, wherein the subject is, or is identified as, a homozygous carrier of the mutation(s), e.g., having a leptin receptor null genotype. 171. The method of claim 170, wherein the disorder is characterized by a homozygous leptin mutation (e.g., loss of mutation), e.g., a leptin null genotype. (Item 187) 171. The method of claim 170, wherein the disorder is characterized by a compound heterozygous leptin mutation (e.g., characterized by the presence of two non-functional alleles), e.g., characterized by a leptin null genotype. (Item 188) 171. The method of claim 170, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the 5-HT2c receptor gene. (Item 189) 189. The method of claim 188, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional and one non-functional 5-HT2c receptor allele. (Item 190) 189. The method of claim 188, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional 5-HT2c receptor alleles, e.g., having a 5-HT2c receptor null genotype. (Item 191) 189. The method of claim 188, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a 5-HT2c receptor null genotype. (Item 192) 171. The method of claim 170, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the native Helix-Loop-Helix 2 (NhHL2) gene. (Item 193) 193. The method of claim 192, wherein the subject is or is identified as being a heterozygous carrier of the mutation(s), e.g., having one functional NhHL2 allele and one non-functional NhHL2 receptor allele. (Item 194) 193. The method of claim 192, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional NhHL2 alleles, e.g., having an NhHL2 null genotype. (Item 195) 193. The method of claim 192, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having an NhHL2 null genotype. (Item 196) 171. The method of claim 170, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the carboxypeptidase E (CPE) gene. (Item 197) 197. The method of claim 196, wherein the subject is, or is identified as, a heterozygous carrier of the mutation(s), e.g., having one functional and one non-functional CPE allele. (Item 198) 197. The method of claim 196, wherein the subject is, or is identified as, a compound heterozygous carrier of the mutation(s), e.g., having two non-functional CPE alleles, e.g., having a CPE null genotype. (Item 199) 197. The method of claim 196, wherein the subject is, or is identified as, a homozygous carrier of the mutation(s), e.g., having a CPE null genotype. (Item 200) 171. The method of claim 170, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the single-minded 1 (SIM1) gene. (Item 201) 201. The method of claim 200, wherein the subject is or is identified as being a heterozygous carrier of the mutation(s), e.g., having one functional and one non-functional SIM1 allele. (Item 202) 201. The method of claim 200, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional SIM1 alleles, e.g., having a SIM1 null genotype. (Item 203) 201. The method of claim 200, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having a SIM1 null genotype. (Item 204) 171. The method of claim 170, wherein the disorder is characterized by a hypermethylated POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., containing a methylated cytosine, e.g., a 5' methylcytosine). (Item 205) 205. The method of claim 204, wherein the subject has or is identified as having a hypermethylated CpG island in the POMC gene, for example, at the intron 2-exon 3 boundary of the POMC gene. (Item 206) 171. The method of claim 170, wherein the disorder is characterized by a defect in the POMC-MC4R pathway other than a POMC mutation, e.g., a heterozygous POMC mutation characterized by the presence of one functional POMC allele and one non-functional POMC allele. (Item 207) 171. The method of claim 170, wherein the disorder is characterized by a defect in the POMC-MC4R pathway other than a leptin mutation, e.g., a heterozygous leptin mutation characterized by the presence of one functional leptin allele and one non-functional leptin allele. (Item 208) 171. The method of claim 170, wherein the disorder is characterized by a defect in the POMC-MC4R pathway other than an MC4R mutation, e.g., a heterozygous melanocortin 4 receptor (MC4R) mutation characterized by the presence of one functional and one non-functional MC4R allele. (Item 209) 171. The method of claim 170, wherein the disorder is characterized by a defect in the POMC-MC4R pathway other than a prohormone convertase mutation. (Item 210) 209. The method of any one of items 170 to 209, comprising administering the agonist to the subject in a unit dosage suitable for injection, for example subcutaneous injection. (Item 211) 211. The method of claim 210, wherein the unit dose comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of the agonist. (Item 212) 212. The method of claim 210 or 211, wherein the unit dose is disposed in a delivery device, such as a syringe (e.g., a pre-filled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system. (Item 213) 212. The method according to any one of items 170 to 211, wherein the agonist is administered subcutaneously, for example by subcutaneous injection. (Item 214) 214. The method of any one of paragraphs 170 to 213, wherein the agonist is administered daily for a period of at least 3 weeks, such as at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or at least 1, 2, 3, 4 years or more. (Item 215) 215. The method according to any one of items 170 to 214, wherein the subject is obese, such as severely obese. (Item 216) 216. The method of any one of items 170 to 215, wherein the subject has early-onset severe obesity. (Item 217) 217. The method of any one of items 170 to 216, wherein the subject has an excess of appetite. (Item 218) The subject has a blood pressure of 25 kg / m 2 or less prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 218. The method according to any one of items 170 to 217, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 219) The subject has a body weight of 35 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 219. The method according to any one of items 170 to 218, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 220) The subject has a blood pressure of 40 kg / m 2 or less prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 219. The method according to any one of items 170 to 219, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 221) The subject has a body weight of 45 kg / m prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 Over (e.g., ≥ 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 221. The method according to any one of items 170 to 220, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 222) 222. The method of any one of items 170 to 221, wherein the subject has failed one or more previous therapies, e.g., exercise therapy, diet therapy, or behavioral therapy, prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. (Item 223) 223. The method of any one of items 170 to 222, wherein the subject has a lower body weight after administration of the agonist than before administration of the agonist. (Item 224) 224. The method of any one of items 170 to 223, wherein administration of the agonist reduces the subject's body weight by about 1 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment, compared to the subject's body weight before treatment. (Item 225) 225. The method of any one of paragraphs 170 to 224, wherein administration of the agonist reduces the subject's body weight at a rate of about 1 to 2 kg / week, e.g., about 2 kg / week, for a period of 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to 8 weeks or more of treatment, 8 to 16 weeks or more of treatment, 16 to 32 weeks or more of treatment, or 32 to 64 weeks or more of treatment. (Item 226) 226. The method of any one of paragraphs 170 to 225, wherein administration of the agonist reduces the subject's hunger level (e.g., reduces the score on the Likert hunger scale, e.g., reduces the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points) compared to the subject's hunger level before treatment, e.g., results in a loss of hunger in the subject (e.g., a score of 0 on the Likert hunger scale), e.g., after 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to 8 weeks or more of treatment, or 8 to 16 weeks or more of treatment. (Item 227) 227. The method of any one of items 170 to 226, wherein administration of the agonist does not detectably / significantly reduce the resting energy expenditure (REE) of the subject, e.g., compared to a control REE (e.g., the REE of the subject before treatment, or a predetermined REE, e.g., when expressed as REE per kg of lean body mass, e.g., of a subject with a similar pre-treatment BMI), e.g., over a period of 24 hours, 1 week, or 30 days or more. (Item 228) 228. The method of claim 227, wherein administration of the agonist increases the resting energy expenditure (REE) of the subject, e.g., over a period of 24 hours, 1 week, 30 days or more, e.g., compared to a control REE (e.g., compared to the REE of the subject before treatment, or compared to a predetermined REE, e.g., when expressed as REE per kg of lean body mass, e.g., of a subject with a similar pre-treatment BMI, e.g., after a similar level of weight loss has been achieved by fasting). (Item 229) 29. The method of any one of paragraphs 170 to 228, wherein administration of the agonist reduces food intake by the subject compared to a control (e.g., the subject's food intake before treatment), e.g., the food intake is daily food intake or food intake over a 24-hour period or a week. (Item 230) 229. The method of claim 229, wherein administration of the agonist reduces food intake by at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories or more compared to a control (e.g., the subject's food intake before treatment or a predetermined food intake level), e.g., wherein the food intake is daily food intake or food intake over a 24-hour period or a week. (Item 231) 231. The method of any one of paragraphs 170 to 230, wherein administration of the agonist reduces the subject's waist circumference when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to a control (e.g., the subject's waist circumference before treatment). (Item 232) 232. The method of claim 231, wherein administration of the agonist reduces the subject's waist circumference by at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm, or more) compared to a control (e.g., the subject's waist circumference before treatment) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. (Item 233) 233. The method of any one of paragraphs 170 to 232, wherein administration of the agonist does not detectably increase the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to the subject's blood pressure before treatment. (Item 234) 234. The method of any one of paragraphs 170 to 233, wherein administration of the agonist reduces the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to the subject's blood pressure before treatment. (Item 235) Item 236. The method of item 234, wherein administration of the agonist reduces the subject's systolic blood pressure by at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. 235. The method of claim 234, wherein administration of the agonist reduces the subject's diastolic blood pressure by at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. (Item 237) 237. The method according to any one of items 170 to 236, wherein the subject is a mammal, such as a human. (Item 238) 238. The method according to any one of items 170 to 237, wherein the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140). (Item 239) Obtaining knowledge of the subject's genotype, e.g., POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, Carboxypeptidase E (CPE) gene, single-minded 1 (SIM1) gene, Any of the BBS1 to BBS20 genes ALMS1 gene, or the method of any one of items 170 to 238, comprising obtaining knowledge of the genotype of a mutation in the BDNF, MCH1R, MCH, NTRK2, SIM1, ENPP1, COH1, CNR1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood), SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, INSIG2, KCTD15, or NROB2 gene, or a 16p11.2 deletion (including the SH2B1 gene). (Item 240) 239. The method of claim 239, wherein the agonist is administered in response to detection of a predetermined sequence, e.g., a mutation, in the gene of claim 239. (Item 241) 239. The method of any one of items 170 to 238, comprising obtaining knowledge of the methylation status of the POMC gene (e.g., hypermethylated in a POMC intron, e.g., hypermethylated in a CpG island of the POMC gene, e.g., comprising a methylated cytosine, e.g., a 5' methylcytosine). (Item 242) 242. The method of claim 241, wherein the agonist is administered in response to detection of hypermethylation. (Item 243) A unit dose of an agonist described herein, wherein the unit dose comprises 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of the agonist. (Item 244) The unit dose according to item 243, containing 0.5 mg of agonist. (Item 245) The unit dose according to item 243 containing 1.0 mg of agonist. (Item 246) The unit dose according to item 243 containing 1.5 mg of agonist. (Item 247) 247. A unit dose according to any one of items 243 to 246, suitable for injection, e.g. subcutaneous injection. (Item 248) 248. The unit dose according to any one of items 243 to 247, disposed in a delivery device suitable for injection, for example subcutaneous injection. (Item 249) 249. The unit dose according to any one of items 243 to 248, disposed in a syringe suitable for injection, for example subcutaneous injection. (Item 250) 249. The unit dosage according to any one of items 243 to 249, wherein the agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140). (Item 251) 65. The method of item 64, wherein the disorder is characterized by one or a mutation (e.g., a loss-of-function mutation) in a BBS1-19 or 20 gene. (Item 252) 97. The method of claim 96, wherein the subject is, or is identified as, a heterozygous carrier of a mutation(s), e.g., having one functional BBS1-19 or 20 allele and one non-functional BBS1-19 or 20 allele. (Item 253) 97. The method of claim 96, wherein the subject is, or is identified as, a compound heterozygous carrier of the mutation(s), e.g., having two non-functional BBS1-19 or 20 alleles, e.g., having a BBS1-19 or 20 null genotype. (Item 254) 97. The method of claim 96, wherein the subject is, or is identified as, a homozygous carrier of the mutation(s), e.g., having a BBS1-19 or 20 null genotype. (Item 255) 65. The method of item 64, wherein the disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the ALMS1 gene. (Item 256) 256. The method of claim 255, wherein the subject is or is identified as being a heterozygous carrier of a mutation(s), e.g., having one functional and one non-functional ALM1 allele. (Item 257) 257. The method of claim 256, wherein the subject is or is identified as being a compound heterozygous carrier of the mutation(s), e.g., having two non-functional ALMS1 alleles, e.g., having an ALMS1 null genotype. (Item 258) 257. The method of claim 256, wherein the subject is or is identified as being a homozygous carrier of the mutation(s), e.g., having an ALMS1 null genotype. (Item 259) 65. The method of item 64, wherein the disorder is characterized by one or more mutations (e.g., loss-of-function mutations) in BDNF, MCH1R, MCH, NTRK2, SIM1, ENPP1, COH1, CNR1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood), SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, INSIG2, KCTD15, or NROB2 genes, or a 16p11.2 deletion (including the SH2B1 gene). (Item 260) 251. The method of claim 250, wherein the subject is, or is identified as, a heterozygous carrier of a mutation(s), e.g., having one functional allele and one non-functional allele in BDNF, MCH1R, MCH, NTRK2, SIM1, ENPP1, COH1, CNR1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood), SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, INSIG2, KCTD15, or NROB2 genes, or a 16p11.2 deletion (including the SH2B1 gene). (Item 261) 251. The method of claim 250, wherein the subject is or is identified as being a compound heterozygous carrier of mutation(s), e.g., having two non-functional alleles, e.g., having a null genotype for a BDNF, MCH1R, MCH, NTRK2, SIM1, ENPP1, COH1, CNR1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood), SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, INSIG2, KCTD15, or NROB2 gene, or a 16p11.2 deletion (including the SH2B1 gene). [Brief explanation of the drawings]

[0327] The following detailed description of the preferred embodiments of the invention will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0328] [Figure 1A] 1A and 1B are graphs showing the effect on suppression of cumulative food intake after treatment with setomelanotide (RM-493 at 0.1 mg / kg (mpk)) compared to vehicle in Magel2 null (Magel2) and wild-type (WT) mice. Figure 1A is an expanded version of the inset in Figure 1B, showing cumulative food intake over a 3-hour period after dosing. Figure 1B shows cumulative food intake overnight. [Figure 1B] 1A and 1B are graphs showing the effect on suppression of cumulative food intake after treatment with setomelanotide (RM-493 at 0.1 mg / kg (mpk)) compared to vehicle in Magel2 null (Magel2) and wild-type (WT) mice. Figure 1A is an expanded version of the inset in Figure 1B, showing cumulative food intake over a 3-hour period after dosing. Figure 1B shows cumulative food intake overnight. [Figure 2] FIG. 1 is a set of graphs showing the change in body weight in wild-type obese humans after 2 or 4 weeks of treatment with setomelanotide. [Figure 3A] 1 shows food intake over time for wild-type and db / db mice administered vehicle or setomelanotide.FIG. 1 is a graph showing food intake as a function of time for wild-type and db / db mice at various setomelanotide concentrations. [Figure 3B] 1 shows food intake over time in wild-type and db / db mice treated with vehicle or setomelanotide. [Figure 3C] 1 shows food intake over time in wild-type and db / db mice treated with vehicle or setomelanotide. [Figure 3D] 1 shows food intake over time for wild-type and db / db mice administered vehicle or setomelanotide.FIG. 1 is a graph showing food intake as a function of time for wild-type and db / db mice at various setomelanotide concentrations. [Figure 3E] FIG. 1 is a graph showing food intake as a function of time in wild-type and db / db mice at various concentrations of setomelanotide. [Figure 3F] FIG. 1 is a graph showing food intake as a function of time in wild-type and db / db mice at various concentrations of setomelanotide. DETAILED DESCRIPTION OF THE INVENTION

[0329] The present disclosure is based, at least in part, on the discovery that targeting defects in the POMC-MC4R pathway, e.g., targeting defects upstream of MC4R, using an MC4R agonist as a replacement therapy led to significant weight loss, decreased hunger, and / or demonstrated increased energy expenditure in obese subjects. The present disclosure is also based, in part, on the discovery that obese subjects with defects (e.g., genetic defects) in one or more genes upstream of MC4R in the POMC-MC4R pathway are likely to exhibit a significantly greater response (e.g., decreased body weight and / or hunger and / or increased energy expenditure) to an MC4R agonist than obese subjects without such defects. For example, as described herein, subjects with a non-functional Magel2 gene (e.g., Magel2 null obesity) may be significantly more responsive (e.g., reduced food intake) following exposure to an MC4R agonist than obese subjects without such genetic disorders (e.g., wild-type obesity).

[0330] As described herein, subjects with a non-functional POMC gene (e.g., POMC-null obese) exhibited significantly greater responses (e.g., decreased body weight and / or hunger and / or increased energy expenditure) to MC4R agonists than obese subjects without such a genetic disorder (e.g., wild-type obese). Specifically, MC4R agonists led to a weight loss of approximately 2-2.5 kg per week over the 26-week course of treatment (a total weight loss of approximately 36 kg after 26 weeks, representing approximately 23% of initial body weight). This weight loss in POMC-deficient subjects was more than double that observed in wild-type obese subjects (who exhibited a weight loss of approximately 0.6-0.9 kg per week over 2-4 weeks after MC4R agonist treatment). Furthermore, the greater weight loss observed in POMC-deficient subjects was sustained over time and did not appear to desensitize.

[0331] The dramatic weight loss and duration of weight loss observed in POMC-deficient subjects is not only significantly greater than that observed in wild-type obese subjects treated with MC4R agonists, but also significantly greater than the weight loss seen in obese subjects treated with currently available therapeutic agents. In clinical studies, commercially available therapeutic agents such as Belviq® (lorcaserin HCl tablets), Qsymia® (phentermine and topiramate extended-release capsules), Contrave® (naltrexone HCl and bupropion HCl extended-release tablets), and Saxenda® (liraglutide injection) at prescription doses resulted in a placebo-corrected weight loss of less than 5 kg in obese subjects after one year of treatment. The hyperresponsiveness of POMC-MC4R pathway-deficient subjects (e.g., POMC-deficient subjects) to MC4R agonists, such as the MC4R agonists described herein, is surprising because weight loss in obese subjects is thought to reach a limit of approximately 5% once the subject appears to desensitize and adapt to the effects of the therapy due to physiological and compensatory changes, including a decrease in energy expenditure, that accompany weight loss in a subject. Surprisingly, this limit in continued weight loss was not observed in POMC-deficient subjects, who continued to lose well over 5% weight even after 13-26 weeks of treatment.

[0332] Without being bound by theory, MC4R agonists such as setomelanotide may act to replace the missing MC4R signaling step in subjects with genetic defects in the POMC-MC4R pathway (e.g., genetic disorders such as PWS and POMC-null obesity). Therefore, it is believed that MC4R agonists such as setomelanotide may provide even greater efficacy in these patient populations than in patient populations with typical (e.g., wild-type) obesity. Thus, the methods and compositions described herein provide an optimized approach for restoring MC4R pathway function in subjects with genetic disorders such as PWS, POMC-null, and PCSK-null obesity (e.g., genetic defects in one or more genes in the POMC-MC4R pathway), thereby reducing the extreme hyperphagia and obesity seen in these subjects. Provided herein are methods for treating subjects having genetic defects in one or more genes in the POMC-MC4R pathway, as well as methods for identifying / selecting subjects having such defects and / or who are more likely to respond to an MC4R agonist (e.g., more likely to respond to an MC4R agonist than wild-type obese subjects).

[0333] definition As used herein, "about" and "approximately" generally refer to an acceptable degree of error for the quantity measured given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0334] As used herein, the terms "obtain" or "obtaining" refer to gaining ownership of a genotype or nucleic acid or polypeptide physical entity, or a value, e.g., a numerical value, or knowledge (e.g., knowledge of a sequence or mutational status), by "directly obtaining" or "indirectly obtaining" that physical entity, value, or knowledge. "Directly obtaining" means performing a physical process (e.g., performing a synthetic or analytical method) to obtain the physical entity, value, or knowledge. "Indirectly obtaining" refers to receiving a physical entity, value, or knowledge from another party or source (e.g., a third-party laboratory that directly obtained the physical entity, value, or knowledge). Directly obtaining a physical entity includes performing a process that involves a physical transformation of a physical substance, e.g., a starting material. Exemplary transformations include creating a physical entity from two or more starting materials, shearing or fragmenting a material, separating or purifying a material, combining two or more separate entities into a mixture, and performing a chemical reaction that involves breaking or forming a covalent or non-covalent bond. Directly obtaining a value or knowledge includes performing a process that involves a physical change of a sample or another substance. Examples include performing an analytical process (sometimes referred to herein as a "physical analysis") that involves a physical change of a substance, e.g., a sample, analyte, or reagent; performing an analytical method, e.g., a method that involves one or more of the following: separating or purifying a substance, e.g., an analyte, or a fragment or other derivative thereof, from another substance; combining an analyte, or a fragment or other derivative thereof, with another substance, e.g., a buffer, solvent, or reactant; or altering the structure of an analyte, or a fragment or other derivative thereof, e.g., by cleaving or forming a covalent or non-covalent bond between a first atom and a second atom of the analyte, or by altering the structure of a reagent, or a fragment or other derivative thereof, e.g., by cleaving or forming a covalent or non-covalent bond between a first atom and a second atom of the reagent.

[0335] As used herein, the term "obesity" refers to a subject having a body mass index (BMI) within the range defined by the Center for Disease Control as "obese" (see, e.g., URL.cdc.gov / obesity / defining.html and www.cdc.gov / obesity / childhood / defining.html (last accessed August 19, 2015)) or the National Institutes of Health's "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults." BMI can be obtained, for example, by dividing the subject's weight in kilograms (kg) by the subject's height in meters (m), for example, squared. For example, 30 kg / m 2 Adults with a BMI above 25.0-29.9 kg / m are considered obese. 2 Adults with a BMI of 18.5 to 24.9 kg / m are considered overweight. 2 An adult with a BMI of 18.5 kg / m is considered to be in the normal or healthy weight range. 2 An adult with a BMI below 203 pounds is considered underweight. For example, an adult who is 5 feet 9 inches tall and weighs 203 pounds or more is considered obese. For children and teens, obesity refers to a subject having a BMI at or above the 85th-95th percentile for children and teens of the same age and sex.

[0336] A "severely obese" subject or subject with "severe obesity" is defined as having a body mass index (BMI) of 35 kg / m 2 or more, for example, 40 kg / m 2 For example, a severely obese subject is one who is 100% over their ideal (normal, healthy) weight.

[0337] As used herein, "early onset," e.g., as in early onset obesity, refers to an onset (e.g., the first occurrence of one or more symptoms of a disorder, e.g., a disorder described herein, e.g., obesity, PWS, POMC null obesity) that occurs before adulthood, e.g., in a subject during childhood, e.g., when the subject is 18 years of age or younger (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age or younger, or during adolescence, e.g., when the child is under 12 years of age, or when the child is under 6 years of age).

[0338] As used herein, the term "metabolic syndrome" refers to a group of conditions that occur together and increase the risk of coronary artery disease, stroke, and type 2 diabetes. According to the American Heart Association and the National Heart, Lung, and Blood Institute, metabolic syndrome, also known as Syndrome X, is present when a subject has three or more of the following symptoms: 1) Blood pressure of 130 / 85 mmHg or higher, 2) fasting blood sugar (glucose) of 100 mg / dL or more; 3) Large waist circumference (length around the waist): - Men - 40 inches and above, - Women - 35 inches and above, 4) Low HDL cholesterol: - Men - less than 40 mg / dL, - Women - less than 50 mg / dL 5) Triglycerides greater than 150 mg / dL. Metabolic syndrome can be diagnosed by testing a subject's blood pressure, blood glucose levels, HDL cholesterol levels, LDL cholesterol levels, total cholesterol levels, and triglyceride levels.

[0339] As used herein, the term "agonist" refers to any chemical compound, whether naturally occurring or synthetic, that, upon interacting with (e.g., binding to) its target, e.g., MC4R, increases the signaling activity of MC4R above its basal level. An agonist may be a superagonist (i.e., a compound that can produce a maximal response at the target receptor that is higher than the endogenous agonist and thus has greater than 100% efficacy), a full agonist (i.e., a compound that elicits a maximal response after receptor occupation and activation), or a partial agonist (i.e., a compound that can activate the receptor but is unable to elicit the maximal response of the receptor system).

[0340] As used herein, "treating" includes achieving one or more of the following results: e.g., a reduction in weight (e.g., as measured by body mass index (BMI) and / or weight) compared to a control (e.g., pre-treatment weight or a predetermined weight); e.g., a reduction in waist circumference compared to a control (e.g., pre-treatment waist circumference or a predetermined waist circumference); e.g., a reduction in hunger levels compared to a control (e.g., pre-treatment hunger level or a predetermined hunger level); e.g., an increase in resting energy expenditure (REE) compared to a control (e.g., pre-treatment REE or a predetermined REE); e.g., an increase in resting energy expenditure (REE) compared to a control level (e.g., pre-treatment or a predetermined REE); or a predetermined food intake); amelioration or improvement of clinical symptoms or indicators associated with a disorder described herein, e.g., obesity, PWS, POMC-null obesity, e.g., type II diabetes, a prediabetic state, a blood hemoglobin A1C (Hb1Ac) level greater than 6%, hyperinsulimenia, hyperlipidemia, insulin insensitivity, or glucose intolerance; delaying, inhibiting, or preventing the progression of obesity and / or obesity-related symptoms; or partially or completely delaying, inhibiting, or preventing the onset or development of obesity or obesity-related symptoms. Delaying, inhibiting, or preventing the progression of obesity includes, for example, delaying, inhibiting, or preventing the progression to obesity in a subject of normal weight. In various embodiments, the control is a parameter value measured before treatment with an MC4R agonist described herein, or a predetermined value. The term "treating" further includes partially or completely reducing the risk of coronary artery disease, stroke, and type 2 diabetes associated with metabolic syndrome, as well as ameliorating or improving clinical symptoms or signs of metabolic syndrome, such as any one or more of the five indicators listed above. For example, the term "treating" includes slowing, inhibiting, or preventing the progression of parameters associated with metabolic syndrome, including insulin resistance, glucose clearance, and cardiovascular disease parameters including heart rate and blood pressure.

[0341] As used herein, "inhibition" or "inhibiting" can include a reduction in a particular parameter, such as those described herein. For example, inhibition of a parameter, e.g., activity, can be at least 5%, 10%, 20%, 30%, 40%, or more and be included within the term. Thus, inhibition need not be 100%.

[0342] "Prophylactic treatment" refers to treatment prior to the onset of obesity to prevent, inhibit, or reduce the occurrence of obesity.

[0343] As used herein, the term "subject" refers to a mammal, e.g., a human. A subject can also refer to animals requiring veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0344] As used herein, the term "mutation" may refer to an altered nucleic acid sequence compared to the wild-type sequence of a gene or fragment thereof. For example, mutations may include point mutations, frameshift mutations, missense mutations, inversions, deletions, insertions, truncations, and chromosomal translocations. In various embodiments, a mutation may result in a gene or fragment thereof encoding a non-functional protein, a protein with reduced activity (or a partially functional protein), or a protein with altered activity. For example, a "loss-of-function" mutation refers to a mutation that results in a gene or fragment thereof encoding a non-functional protein with substantially reduced activity compared to its wild-type counterpart (e.g., a non-functional protein has less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less activity than its wild-type counterpart). For example, a "partial loss-of-function" mutation refers to a mutation that results in a gene or fragment thereof encoding a partially functional protein with reduced activity compared to its wild-type counterpart (e.g., a partially functional protein has less than 50% and more than 10% activity of its wild-type counterpart).

[0345] As used herein, "heterozygous" refers to the presence of two different alleles (having different nucleic acid sequences) for a given gene in a subject. In some embodiments, a "heterozygous mutation" can refer to the presence of a mutation in one allele of a given gene in a subject, and the absence of a mutation in the other allele of the same gene (e.g., one mutant allele and one wild-type allele for a given gene). In other embodiments, a "heterozygous mutation" can be a "compound heterozygous" mutation, which refers to the presence of a mutation (e.g., a loss-of-function mutation or a partial loss-of-function mutation) in one allele of a given gene, and the presence of a different (e.g., a loss-of-function mutation or a partial loss-of-function mutation) in the other allele of the same gene (e.g., two different alleles that are both mutated, e.g., non-functional or partially functional). In various embodiments, when a compound heterozygous mutation includes two non-functional alleles, the genotype can be a null genotype or a functional-deficient genotype.

[0346] As used herein, "homozygous" refers to the presence of two identical alleles for a given gene. In some embodiments, "homozygous mutation" refers to the presence of two mutant alleles for a given gene, where the two mutant alleles are identical.

[0347] As used herein, a "null genotype" refers to the presence of two non-functional alleles of a gene in a subject.

[0348] As used herein, "unit dosage" refers to physically discrete units suited as unitary dosages for subjects to be treated, each containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0349] As used herein, "dosage" refers to a quantity or amount of a therapeutic agent. In some embodiments, a dose is an amount administered to a subject in a single dose, e.g., a single injection, infusion, or administration of one or more unit doses. In various embodiments, a dose is an amount administered to a subject in multiple doses, e.g., multiple injections, infusions, or administration of one or more unit doses. In other embodiments, a dose may refer to the total amount administered to a subject over a particular period of time, e.g., per day. In such instances, the dose is typically referred to as a "daily dose" or in terms of daily doses.

[0350] As used herein, "hunger" or "hunger level" refers to a subject's appetite, desire to eat food, or perception of the need for food. In some embodiments, a subject's hunger or hunger level can be quantified by using a scale to obtain a hunger score. In some embodiments, the hunger scale assigns higher scores to subjects who experience unbearable hunger more frequently (e.g., often or always), and assigns lower scores to subjects who experience unbearable hunger less frequently (e.g., occasionally or never). See, for example, Sibilia. Psychologicol Topics 19 (2010), 2, 341-354. For example, a Likert hunger scale can be used, assigning a score of 0 to 10 (0 = no hunger, 10 = severe hunger). In another example, a Likert hunger scale may be used, assigning a score of 1 to 4, where subjects who never experience unbearable hunger are assigned a score of 1, subjects who occasionally experience unbearable hunger are assigned a score of 2, subjects who often experience unbearable hunger are assigned a score of 3, and subjects who always experience unbearable hunger are assigned a score of 4. See Id.

[0351] POMC-MC4R pathway The melanocortin system, including melanocortins (MCs), agouti, agouti-related proteins, and their receptors, integrates hormonal, metabolic, and neural signals to regulate energy homeostasis and control appetite, energy expenditure, and body weight. MCs, including alpha-melanocyte-stimulating hormone (α-MSH), β-MSH, γ-MSH, and ACTH, are a family of peptide hormones derived from a precursor protein called proopiomelanocortin (POMC). Activation of the MC4 receptor (MC4R) in the POMC-MC4R pathway increases energy expenditure and reduces food intake. See, e.g., Fan et al. Nature 1997;385:165-68. The POMC-MC4R pathway includes several proteins, including melanocortin (MC), MC4 receptor (MC4R), POMC, proprotein convertase subtilisin / kexin type 1 (PCSK1, also known as PC1 / 3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix-loop-helix 2 (NhHL2, also known as NSCL2), prohormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Sim1), which together contribute to the regulation of energy homeostasis, for example, by controlling appetite and energy expenditure. MC4R and other components of the POMC-MC4R pathway play important roles in body weight control. Mutations in the MC4R gene have been reported to result in early-onset and severe obesity. It is thought that other genetic defects in the POMC-MC4R pathway are also likely to lead to early-onset and severe obesity.

[0352] MC4R hMC4R is a protein encoded by the genomic sequence having GenBank accession number CH471077.2.

[0353] Mutations in the MC4R receptor are associated with severe childhood obesity. The carrier prevalence of MC4R mutations in the young-onset obese population is approximately 2.5%, with a maximum prevalence of 6% in severely obese children. Humans with MC4R mutations exhibit a phenotype broadly similar to that described in mice with mutations in the MC4R gene. MC4R-deficient patients exhibit hyperphagia, hyperinsulinemia, and increased fat mass accompanied by increases in lean body mass, bone mineral density, and linear growth rate, without changes in cortisol, gonadotropin, thyroid, and sex steroid levels. In contrast to MC4R deficiency, hyperphagia and hyperinsulinemia in human subjects tend to subside with age. Similar to MC4R knockout mice, the phenotype in heterozygous carriers is moderate compared to homozygous carriers. The hyperphagia observed upon test feeding is less severe than that observed in individuals with leptin deficiency. The severity of MC4R dysfunction seen in in vitro assays can predict the amount of food ingested in a test meal by subjects carrying that particular mutation and correlates with the onset and severity of the obesity phenotype. At least 90 different MC4R mutations have been associated with obesity, and it is likely that additional mutations in MC4R that lead to similar obesity phenotypes will be discovered.

[0354] Examples of MC4R mutations that cause obesity in humans are described, for example, in Farooqi et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 271-279 and Vaisse et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 253-262, the relevant portions of which are incorporated herein by reference.

[0355] Additional mutations that may cause obesity in humans include those described by Xiang et al., "Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist." Biochemistry, 2010 Jun, the relevant portions of which are incorporated herein by reference. 8;49(22):4583-600, R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, I317V, L325F, and 750DelGA.

[0356] Further examples of mutations that may cause obesity in humans can be found in the Online Mendelian Inheritance database, a database of human genes and genetic disorders. Those listed in the OMIM database under accession number 155541(MC4R) (more specifically, accession numbers 155541.0001-155541.0023) at the URL http: / / omim.org / entry / 155541. Representative examples include 4-BP DEL, NT631; 4-BP INS, NT732; TYR35TER; ASP37VAL; SER58CYS; ILE102SER; ASN274SER; 1-BP INS, 112A; 4-BP DEL, 211CTCT; ILE125LYS; ALA175THR; ILE316SER; TYR287TER; ASN97ASP; 15-BP DEL (delta 88-92 codon); and SER127LEU. Relevant portions of the OMIM database are incorporated herein by reference.

[0357] Further exemplary mutations of MC4R are described in Lee. Annals Acad. Med. 38.1 (2009):34-44.

[0358] In an exemplary embodiment, the MC4R mutation results in retention of MC4R signaling activity.

[0359] Mutations in the genomic sequence encoding MC4R can be detected by methods known to those skilled in the art, for example, by cloning the genomic sequence using nucleotide primers such as those described in Farooqi et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 271-279 and Vaisse et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 253-262, and analyzing the cloned sequence using commercially available sequencing equipment and software.

[0360] MC4R activity can be measured by methods known to those skilled in the art. For example, cloned MC4R DNA can be transiently transfected into cells, the transfected cells can be contacted with an MC4R agonist (e.g., α-MSH), and the intracellular level of cAMP, a second messenger of MC4R, can be measured, for example, by an electrochemiluminescence assay as described in Roubert et al., Journal of Endocrinology (2010) 207, pp. 177-183. Reduced MC4R signaling can be confirmed by comparing the intracellular level of cAMP produced by wild-type MC4R in response to a given agonist with that produced by mutant MC4R.

[0361] POMC POMC is a component of the POMC-MC4R pathway, which acts upstream of MC4R. POMC is a precursor protein that is cleaved by prohormone convertases to generate multiple peptide hormones (e.g., alpha-MSH, ACTH, beta-endorphin, and enkephalins). Convertases that process the POMC polypeptide include prohormone convertase 1 (PC1, also known as PC1 / 3 or PCSK1), prohormone convertase 2 (PC2), carboxypeptidase E (CPE), peptidyl alpha-amidating monooxygenase (PAM), N-acetyltransferase (N-AT), and prolylcarboxypeptidase (PRCP).

[0362] The POMC gene is located on human chromosome 2p23.3, and the gene sequence is provided in GenBank accession number NG_008997.1, which is incorporated herein by reference. An exemplary nucleic acid sequence of human POMC mRNA transcript variant X1 is provided in GenBank accession number XM_011532917.1, which is incorporated herein by reference. An exemplary amino acid sequence of human POMC isoform X1 is provided in GenBank accession number XP_011531219.1, which is incorporated herein by reference. An exemplary nucleic acid sequence of human POMC mRNA transcript variant 1 is provided in GenBank accession number NM_001035256.1, which is incorporated herein by reference. An exemplary amino acid sequence of human POMC pre-proprotein is provided in GenBank accession number NP_001030333.1. An exemplary nucleic acid sequence of human POMC mRNA transcript variant 2 is provided in GenBank Accession No. NM_000939.2, which is incorporated herein by reference. An exemplary amino acid sequence of human POMC pre-proprotein is provided in GenBank Accession No. NP_000930.1.

[0363] POMC-expressing POMC neurons suppress appetite by secreting POMC neuropeptides, which reduces body weight and food intake. Loss-of-function mutations in the POMC gene have been reported to result in obesity, red hair, and adrenal insufficiency. For example, POMC deficiency (e.g., loss-of-function mutation(s) or hypermethylation) has been associated with obesity and ACTH deficiency. See, for example, Mendiratta et al. Intl. J. Ped. Endocrinol. 2011:5, and Kuehnen See, e.g., Mendiratta et al. PLoS Genetics. 8.3 (2012): e1002543. It has been reported that a homozygous codon 231 cytosine to adenosine (c.231C>A) change in POMC results in a premature stop codon and causes POMC functional deficiency associated with excessive weight gain, congenital adrenal insufficiency, and hypoglycemia. See, e.g., Mendiratta et al. Intl. J. Ped. Endocrinol. 2011: 5. In various embodiments, exemplary mutations of POMC are described in Lee. Annals Acad. Med. 38.1 (2009): 34-44.

[0364] In embodiments, exemplary mutations in POMC are set forth below in Table 1. In embodiments, homozygous and / or heterozygous (e.g., compound heterozygous) mutations in Table 1 are contemplated. [Table 1]

[0365] In certain embodiments, for example, the POMC amino acid sequence referenced in Table 1 is that set forth in Takahashi, et al. 1981 Febs Letters 135(1)97, copied below (the 26 amino acid signal peptide is underlined): [ka]

[0366] In certain embodiments, for example, the POMC gene nucleotide sequence referenced in Table 1 is that described in Takahashi et al. Nucl Acids Res. 1983, 11(19)6847, e.g., as provided in GenBank Accession No. V01510.1 and copied below. [ka] [ka] [ka]

[0367] In some embodiments, exemplary mutations in POMC that lead to, for example, homozygous POMC deficiency are described, for example, in the references in Table 2, each of which is incorporated herein by reference. [Table 2-1] [Table 2-2]

[0368] Furthermore, hypermethylation of the POMC gene has been associated with childhood obesity. See, e.g., Kuehnen et al. PLoS Genetics. 8.3 (2012): e1002543. Hypermethylated variants in the CpG island at the intron 2-exon 3 boundary of the POMC gene were significantly associated with obesity compared to normal-weight children. See ibid. Exon 3 of POMC is thought to be involved in binding to the transcriptional enhancer P300, and hypermethylation of exon 3 reduces expression of POMC transcripts. See ibid.

[0369] In still other embodiments, exemplary mutations in POMC include one or more mutations described in one or more of the following: Aslan, Int J Obes(Lond). 2014 Jan; 38(1): 148-51; Krude, Nature 1998; 19; 155-157; Krude, J clin Res Metab 2003, 88(10); 4633-4640; Samuels, J Clin Endocrin Metab, 2013; 98(2); 736-742; Clement, J Clin Endocrin Metab., 2008; 93(12); 4955-4962; Creamers, J Clin Endocr Metab, 2008, 93(11); 4494-4499; Cirillo, British Assoc Derm, 2012, 167; 1390-1400; ESPE poster Barcelona 2015,R Marina et al.,Farooqi,Diabetes 2006;55;2549-2553,Mendiratta,Int J Pediatr Endocrinol.2011;2011:5,A Meloni,et al.,ESPE Poster Barcelona 2015,Hinney,J Clin Endocrin Metab,1998,10;3737-3741, Lee,Cell Metabol.,2006;3;135-140(PLOF), Dubern,Pediatric Res.2008;63(2);211-216, Philippe et al. al.Int.J.Obes.39.2.(2015):295-302, Bieberman,2006;3;141-146, or Buono, Clin Chem, 2005; 51(8); 1358-1364; Challis, Hum. Mol. Genet. 11(17): 1997; Hum. Mol. Genet. 11(17): 1998 (each of which is incorporated herein by reference in its entirety).

[0370] PCSK1 Proprotein convertase subtilisin / kexin type 1 (PCSK1, also known as PC1 / 3) is an enzyme that acts upstream of MC4R in the POMC-MC4R pathway by processing (cleaving) prohormones such as POMC to their mature forms.

[0371] A heterozygous nonsense variant in PCSK1 (p.Arg80*), encoding a propeptide truncated to less than two of 14 exons, has been reported to be associated with human obesity. See, e.g., Philippe et al. Intl. J. Obesity 39.2(2015):295-302.

[0372] The PCSK1 gene is located at cytogenetic position 5q15-q21 in humans. The human PCSK1 gene sequence is provided in GenBank accession number NG_021161.1, which is incorporated herein by reference. An exemplary nucleic acid sequence of human PCSK1 transcript variant 1 is provided in GenBank accession number NM_000439.4, which is incorporated herein by reference (see, for example, Hsiao et al. Gene 533(1), 32-37(2014)). An exemplary amino acid sequence of human PCSK1 isoform 1 is provided in GenBank accession number NP_000430.3, which is incorporated herein by reference. An exemplary nucleic acid sequence of human PCSK1 transcript variant 2 is provided in GenBank accession number NM_001177875.1, which is incorporated herein by reference. An exemplary amino acid sequence of human PCSK isoform 2 is provided in GenBank Accession No. NP_001171346.1, which is incorporated herein by reference.

[0373] In some embodiments, exemplary mutations in PCSK1 that lead to, for example, homozygous PCSK1 deficiency are described, for example, in the references in Table 3, each of which is incorporated herein by reference. [Table 3-1] [Table 3-2]

[0374] In some embodiments, exemplary mutations in PCSK1 that lead to, for example, heterozygous PCSK1 deficiency are described, for example, in the references in Table 4, each of which is incorporated herein by reference. [Table 4-1] [Table 4-2]

[0375] In still other embodiments, exemplary mutations in PCSK1 include one or more mutations described in one or more of the following: Martin, Gastroenterology 145:138-48, 2013; Creamers, Diabetes 61:383, 2012; Jackson, Nature Gen.: July 16, 1997, p. 303; Martin, Gastroenterology 145:138-48, 2013; Blanco et al. Endocrinology 156:3625-37, 2015; Jackson, J. Clin. Investigation 112:1550-51, 2003; Benzinou, Nat. Genetics 8:943, 2008; Yourshaw, Gastroenterology 57(6):759, 2013; Faroqi, J. Clin. Endocrinol. and Metab.92:3369-73,2007,Pickett,PLoS One 8:e55065,2013,Bohours-Nouet,EXPE Poster at Barcelona 2015 PWS meeting, Graeme et al.,Mol.Gen.Metabol.110:191-94,2013, Blanco et al. Endrocrinology 155:3434-47, 2014; Wilschansky PLoS ONE 9:108878, 2014; Frank, Mol. Gen Metabol. 2013; and Harter J. Pediatr. Gastroentrol Nutr. 2015 (each of which is incorporated by reference in its entirety).

[0376] MAGEL2 MAGEL2 (melanoma antigen (MAGE) family L2, or MAGE-like protein 2) is thought to be involved in the ubiquitin ligase activity of zinc finger-containing E3 ubiquitin protein ligases and possibly in the regulation of the circadian clock. MAGEL2 is a member of the MAGE family of proteins involved in pathways regulating protein degradation, protein modification, transcription, and cytoskeletal rearrangements. For example, Mercer et al. al. PLoS Genetics 9.1(2013):e1003207.

[0377] In mice, MAGEL2 is expressed in the hypothalamus, including the arcuate nucleus, which controls energy homeostasis. Mice lacking expression of the MAGEL2 gene (MAGEL2 null mice) have been reported to initially exhibit poor weight gain, followed by increased adiposity and weight gain. See, e.g., Mercer et al., PLoS Genetics 9.1 (2013): e1003207. Adult mice lacking MAGEL2 (MAGEL2 null mice) have been reported to exhibit impaired appetite suppression responses to leptin and impaired POMC neuronal responses to leptin. See, e.g., Pravdivyi et al., Hum. Mol. Genet. 2015, 1-8. Mice lacking MAGEL2 (MAGEL2 null mice) also had lower levels of alpha-MSH in the paraventricular nucleus of the hypothalamus. See Ibid. In embodiments, exemplary MAGEL2 mutations, e.g., loss-of-function MAGEL2 mutations, are those described by Schaaf et al. Nat Genet. 2013 Nov;45(11):1405-8. doi:10.1038 / ng.2776. Epub 2013 Sep 29, and Soden et al. Sci Transl Med. 2014 Dec 3;6(265):265ral68, each of which is incorporated herein by reference.

[0378] MAGEL2 is one of several genes inactivated in Prader-Willi syndrome (PWS). Inactivating mutations in MAGEL2 have been found in children with features of PWS. See Id. A heterozygous c.1652delT (p.Val551fs) mutation in MAGEL2 (NM_019066.4) was reported in a 13-year-old human subject. See, e.g., Schaaf et al. Nat. Genet. 45.11(2013):1405-09. A heterozygous c.1802delC (p.Pro601fs) mutation was also reported in an 8-year-old human subject. See Id. Additionally, a heterozygous c.3181_3182delAT (p.Ile1061fs) mutation was reported in a 5-year-old human subject. See Id. The c.3124C>T (p.Gln1024*) mutation was also reported in a 19-year-old human subject. See Ibid. PWS is discussed in further detail below.

[0379] The human MAGEL2 gene sequence is NG_016776.1, which is incorporated herein by reference. An exemplary nucleic acid sequence of a human MAGEL2 transcript is NM_019066.4, which is incorporated herein by reference. An exemplary amino acid sequence of human MAGEL2 is NP_061939.3, which is incorporated herein by reference.

[0380] Leptin and leptin-R Leptin is a hormone produced by adipocytes that acts to inhibit hunger to control energy homeostasis—food intake, body weight, and glucose homeostasis. Leptin acts upstream of MC4R in the POMC-MC4 pathway by binding to the leptin receptor (leptin-R, also known as LEP-R, OB-R, or CD295). POMC neurons are involved in mediating leptin activity in the brain, and one of the effects of leptin binding to leptin-R is stimulation of POMC expression. See, e.g., Varela et al., EMBO Reports 13.12 (2012):1079-86. Loss of leptin-R in POMC neurons leads to obesity, an effect that can be partially rescued in these leptin-R null mice by overexpressing leptin-R. Ibid. Mutations in leptin (Lep ob / ob) or leptin-R (Lep db / db) have been reported to be associated with impaired glucose homeostasis and increased body weight in mice. See Id. Additionally, fa / fa rats have been described to be leptin-R deficient. See, e.g., Cettour-Rose et al. Endocrinology: 2002; 143(6); 2277-2283.

[0381] Examples of mutant (e.g., non-functional) versions of leptin in humans have been described as being associated with obesity. A homozygous frameshift mutation that deletes a guanine nucleotide at codon 133 of the leptin gene has been associated with severe obesity in some severely obese children. See, e.g., Montague et al. Nature 387.6636(1997):903-8. A homozygous transversion (c.298G→T) in leptin, leading to an aspartic acid to tyrosine change at amino acid position 100 (p.D100Y), has been associated with early-onset severe obesity (see, e.g., Wabitsch et al. N. Engl. J. Med. 372.1(2015):47-54). Homozygous Gln223Arg and homozygous Lys656Asn mutations in leptin-R have been associated with obesity in humans. See, e.g., Masuo et al. Hypertens. Res. 31.6(2008):1093-100. Further exemplary mutations of leptin / leptin-R are described in Lee. Annals Acad. Med. 38.1(2009):34-44.

[0382] In some embodiments, exemplary mutations in the leptin receptor (LEPR) that lead to, for example, homozygous leptin receptor deficiency are described, for example, in the references in Table 5, each of which is incorporated herein by reference. [Table 5-1] [Table 5-2]

[0383] In some embodiments, exemplary mutations in the leptin receptor that lead to, for example, homozygous leptin receptor deficiency are described, for example, in the references in Table 6, each of which is incorporated herein by reference. [Table 6-1] [Table 6-2]

[0384] Exemplary nucleic acid sequences of human leptin transcripts are provided in NM_000230.2 and BC060830.1, which are incorporated herein by reference. Exemplary amino acid sequences of human leptin precursors are provided in NP_000221.1, AAH69452.1, AAH69527.1, AAH69323.1, AAH60830.1, which are incorporated herein by reference. Exemplary nucleic acid sequences of human leptin receptors are provided in GenBank Accession Nos. U66497.1, U66496.1, U66495.1, U43168.1, NM_001198689.1, NM_001198688.1, NM_001198687.1, NM_001003679.3, NM_002303.5, NM_001003680.3, which are incorporated herein by reference. Exemplary amino acid sequences of human leptin receptors are provided in GenBank Accession Nos. P48357.2, AAB09673.1, AAC23650.1, AAB07497.1, AAB07496.1, AAB07495.1, AAA93015.1, which are incorporated herein by reference.

[0385] In still other embodiments, exemplary mutations in LEPR include one or more of the mutations described in one or more of the following: Faroqui et al., N Engl J Med 356:237-24, 2007; Gill et al., Obesity 22:576-84, 2014; Kimber et al., Endocrinol. 149:6043-52, 2008; Huvenne et al. J. Clin. Endo Metab. 100:E757-66, 2015; and Mammes et al., Eur. J. Clin. Inv. 31:398-4004, 2015, each of which is incorporated by reference in its entirety.

[0386] 5HT2c receptor The 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor) is a G protein-coupled receptor (GPCR) that binds to the neurotransmitter serotonin. The 5HT2c receptor is involved in the regulation of feeding, among other physiological functions. The 5HT2c receptor acts upstream of the MC4R in the POMC-MC4R pathway. 5-HT 2C Stimulation of the receptor results in an increase in POMC in the anterior pituitary gland. By binding to serotonin receptors, including the 5HT2c receptor, serotonin increases POMC activity and reduces feeding behavior. See, e.g., Roepke et al. Am. J. Physiol. Endocrinol. Metab. 302.11 (2012):E1399-406. 5HT2c receptor agonists have been reported to reduce feeding in rats and mice. See, e.g., Bickerdike. Curr. Top. Med. Chem. 3.8 (2003):885-97. Alternative splicing of the 5-HT2c receptor is regulated by the snoRNA SNORD115. SNORD115 is inactivated in PWS. Without wishing to be bound by theory, 5HT2c polymorphisms are thought to be associated with obesity.

[0387] The human 5-HT2c receptor gene sequence is provided in GenBank accession number NG_012082.2, which is incorporated herein by reference (see, for example, Jahnsen JA et al.Eur.J.Pharmacol.684(1-3),44-50(2012)).The exemplary nucleic acid sequence of human 5-HT2c receptor is provided in GenBank accession number NM_001256761.2, NM_001256760.2, NM_000868.3, which is incorporated herein by reference.The exemplary amino acid sequence of human 5-HT2c receptor is provided in GenBank accession number NP_001243690.1, NP_001243689.1, which is incorporated herein by reference.

[0388] NhLH2 NhLH2 is a neuronal transcription factor that acts upstream of MC4R in the POMC-MC4R pathway. NhLH2 is a member of the basic helix-loop-helix (bHLH) family of transcription factors. NhLH2 is expressed in several differentiated adult neurons, including POMC neurons and MC4R neurons. NhLH2 expression can be regulated by food intake and leptin levels. See, for example, Good et al. Trends Endocrinol. Metab. 24.8(2013):385-90. Based on NhLH2 knockout mouse studies in which deletion of this gene resulted in adult-onset obesity, NhLH2 has been reported to mediate weight control and fertility. See, for example, Good et al. Nat. Genet. 15(1997):397-401. In embodiments, for example, exemplary mutations that lead to heterozygous NhLH2 deficiency are described in, for example, Rayyan et al. Gene. 2013;512(1):134-42, which is incorporated herein by reference.

[0389] NhLH2 binds to the leptin-regulated transcription factor signal transducer and activator of transcription 3 (Stat-3) to regulate PCSK1 in response to leptin or food intake. NhLH2 knockout mice have lower levels of PCSK1 than wild-type mice. This results in reduced levels of PCSK1-processed peptides, such as mature POMC. See, for example, Good et al. Trends Endocrinol. Metab. 24.8 (2013): 385-90.

[0390] Exemplary nucleic acid sequences for human NhLH2 are provided in GenBank Accession Nos. XM_006710666.2, XR_946659.1, NM_001111061.1, NM_005599.3, which are incorporated herein by reference (e.g., Al Rayyan (See, e.g., Wang et al. Gene 512(1), 134-142 (2013)). Exemplary amino acid sequences of human NhLH2 are provided in GenBank Accession Nos. XP_006710729.1, NP_001104531.1, NP_005590.1, which are incorporated herein by reference.

[0391] Prohormone convertases Prohormone convertases are serine proteases that process precursors of peptide hormones and neuropeptides. There are several types of prohormone convertases, including PCSK1 (also known as PC1, PC3, and PC1 / 3), PCSK2 (also known as PC2), PCSK3 (also known as furin, pace, and PC1), PCSK4 (also known as PC4), PCSK5 (also known as PC5, PC6, and PC5 / 6), PCSK6 (also known as PACE4), PCSK7 (also known as PC7 and PC8), PCSK8 (also known as site 1 protease, S1P, or SKI), and PCSK9 (also known as NARC-1). Prohormone convertases cleave POMC to generate alpha-MSH. For example, PC1 cleaves POMC to generate proACTH, which is then cleaved by PC2 to generate ACTH1-17. See, e.g., Pritchard et al. J. Endocrinol. 172(2002):411-21.

[0392] It is believed that defective POMC processing can lead to obesity. A patient with a compound heterozygous mutation in the PC1 gene had extreme childhood obesity, abnormal glucose homeostasis, hypocorticolism, and hypogonadotrophic hypogonadism. See Id. Another obese patient was reported to have defective POMC processing. See Id.

[0393] Exemplary sequences of PCSK1 are as described above. Exemplary nucleic acid sequences of human PCSK2 are provided under GenBank accession numbers NM_002594.4 (see, for example, van Wamelen et al. J. Neuropathol. Exp. Neurol. 72 (12), 1126-1134 (2013)), NM_001201529.2, and NM_001201528.1, which are incorporated herein by reference. Exemplary amino acid sequences of human PCSK2 are provided under GenBank accession numbers NP_001188458.1, NP_001188457.1, and NP_002585.2, which are incorporated herein by reference. Exemplary nucleic acid sequences of human PCSK3 are provided in GenBank Accession Nos. NM_001289824.1, NM_001289823.1, and NM_002569.3, which are incorporated herein by reference. Exemplary amino acid sequences of human PCSK3 are provided in GenBank Accession Nos. NP_001276753.1 (see, e.g., Dahms et al. ACS Chem. Biol. 9(5), 1113-1118 (2014)), NP_001276752.1, and NP_002560.1, which are incorporated herein by reference. An exemplary nucleic acid sequence of human PCSK4 is provided in GenBank accession number NM_017573.4, which is incorporated herein by reference (see, for example, Seidah et al. J. Biol. Chem. 288 (30), 21473-21481 (2013)). An exemplary amino acid sequence of human PCSK4 is provided in GenBank accession number NP_060043.2, which is incorporated herein by reference. A human PCSK5 gene sequence is provided in GenBank accession number NG_029445.1, which is incorporated herein by reference. Exemplary nucleic acid sequences for human PCSK5 are provided in GenBank Accession Nos. NR_120409.1, NM_006200.5, NM_001190482.1, which are incorporated herein by reference (see, e.g., Mbikay et al. Genomics 26(1), 123-129 (1995)).Exemplary amino acid sequences of human PCSK5 are provided in GenBank accession numbers NP_001177411.1 and NP_006191.2, which are incorporated herein by reference. Human PCSK6 gene sequences are provided in GenBank accession number NG_030047.3, which are incorporated herein by reference. Exemplary nucleic acid sequences of human PCSK6 are provided in GenBank accession numbers NM_138325.3, NM_001291309.1, NM_138323.2, NM_138324.2, NM_138322.3, NM_138319.3, and NM_002570.4, which are incorporated herein by reference (see, for example, Tsuji et al. J. Biochem. 122(2), 438-452 (1997)). An exemplary nucleic acid sequence of human PCSK7 is provided in GenBank accession number NM_004716.3, which is incorporated herein by reference (see, for example, Stickel et al. Hum. Mol. Genet. 23(14), 3883-3890 (2014)). An exemplary amino acid sequence of human PCSK7 is provided in GenBank accession number NP_004707.2, which is incorporated herein by reference. A human PCSK8 gene sequence is provided in GenBank accession number NG_033017.1, which is incorporated herein by reference. An exemplary nucleic acid sequence of human PCSK8 is provided in GenBank accession number NM_003791.3, which is incorporated herein by reference (see, for example, Weiss et al. J. Invest. Dermatol. 134(1), 168-175 (2014)). An exemplary amino acid sequence of human PCSK8 is provided in GenBank Accession No. NP_003782.1, which is incorporated herein by reference. A human PCSK9 gene sequence is provided in GenBank Accession No. NG_009061.1, which is incorporated herein by reference. Exemplary nucleic acid sequences of human PCSK9 are provided in GenBank Accession Nos. XM_011541193.1, NR_110451.1, and NM_174936.3, which are incorporated herein by reference (see, e.g., Brouwers et al. Clin. Sci. 126(9), 679-684(2014)).Exemplary amino acid sequences of human PCSK9 are provided in GenBank Accession Nos. XP_011539495.1 and NP_777596.2, which are incorporated herein by reference.

[0394] In some embodiments, exemplary mutations in prohormone convertases, e.g., PCSK1, that result in, e.g., homozygous deficiency, are described, e.g., in the references in Table 3, each of which is incorporated herein by reference.

[0395] In some embodiments, exemplary mutations in prohormone convertases, e.g., PCSK1, that result in, e.g., heterozygous deficiency, are described, e.g., in the references in Table 4, each of which is incorporated herein by reference.

[0396] CPE Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) or convertase, is an enzyme that catalyzes the release of C-terminal lysine or arginine residues from polypeptides. CPE is involved in the processing of many neuropeptides and peptide hormones. For example, CPE acts downstream of prohormone convertases, which generate intermediate peptide precursors, to further process the polypeptide and remove C-terminal basic residues to generate mature peptides. For example, CPE is involved in the processing of POMC. CPE mutations have been associated with obesity. For example, a morbidly obese female patient has been described to have a truncating mutation in the CPE gene (c.76_98del; p.E26RfsX68). See, e.g., Alsters et al. PloS ONE. 10.6(2015):e0131417. In embodiments, exemplary mutations in CPE that lead to, for example, homozygous CPE deficiency are described, for example, in Alsters et al. PloS One. 10.6(2015):e0131417, incorporated herein by reference.

[0397] An exemplary nucleic acid sequence of CPE is provided in GenBank Accession No. NM_001873.2, which is incorporated herein by reference (Skalka et al. Oncogene 32(23), 2836-2847(2013)). An exemplary amino acid sequence of CPE is provided in GenBank Accession No. NP_001864.1, which is incorporated herein by reference.

[0398] Sim1 Single-minded 1 (Sim1) is a transcription factor involved in the development of the paraventricular nucleus of the hypothalamus, which controls body weight, energy expenditure, and appetite. Sim1 acts on MC4R in the POMC-MC4R pathway. Loss of Sim1 function (e.g., in Sim1+ / - and Sim1- / - mice) has been reported to cause hyperphagia, obesity, and increased susceptibility to diet-induced obesity. See, e.g., Xi et al., PLoS One. 7.4(2012):e36453. Ablation of Sim1 neurons in mice led to obesity caused by increased food intake and reduced energy expenditure. See ibid. In various embodiments, exemplary mutations of Sim1 that lead to, for example, heterozygous Sim1 deficiency are described, for example, in Bonnefond et al., J. Clin. Invest. 123.7(2013):3037-41, which is incorporated herein by reference.

[0399] The human SIM1 gene sequence is provided in GenBank accession number NG_008230.1, which is incorporated herein by reference. Exemplary nucleic acid sequences of human SIM1 are provided in GenBank accession numbers XM_011536073.1 (see, for example, Ramachandrappa et al. J. Clin. Invest. 123(7), 3042-3050 (2013)), XM_011536072.1, XM_005267100.2, and NM_005068.2, which are incorporated herein by reference. Exemplary amino acid sequences of human SIM1 are provided in GenBank accession numbers XP_011534375.1, XP_011534374.1, XP_005267157.1, and NP_005059.2, which are incorporated herein by reference.

[0400] BBS1~20 BBS1 through BBS20 are 20 genes associated with Bardet-Biedl syndrome. Mutation(s) in one or more of the BBS genes have been associated with obesity, blindness, and hearing loss. Mice lacking the BBS1 gene in their nervous systems have been shown to develop obesity. See, e.g., Guo et al., PLOS Genetics 12.2 (2016): e1005890. Heterozygous carriers of mutations in BBS genes have also been described as having a higher propensity for obesity than control subjects. See, e.g., Gupta et al., J. Endocrinol. 203 (2009): 327-36.

[0401] In embodiments of any of the methods described herein, the method includes treating a subject with one or more mutations in one or more of the genes BBS1-BBS20. In embodiments, the methods described herein include use of an MC4R agonist described herein to treat a subject with one or more mutations in one or more of the genes BBS1-BBS20. Exemplary mutations include non-coding variants in one or more of the BBS genes, e.g., BBS2, BBS4, and / or BBS6. For example, SNPs in BBS6 and BBS4 have been associated with adult and childhood obesity in several reports. See, e.g., Gupta et al. J. Endocrinol. 203(2009):327-36.

[0402] ALMS1 Alström syndrome (ALMS) is an autosomal recessive genetic disorder associated with blindness, deafness, diabetes, obesity, hyperinsulinemia, and impaired glucose metabolism, which can lead to early-onset type 2 diabetes in affected subjects. ALMS is caused by mutations in the ALMS1 gene, which maps to chromosome 2p13. The progression from early-onset obesity to impaired fasting glucose or glucose tolerance and overt diabetes is thought to be primarily due to a progressive failure of beta-cell insulin secretion, even in the presence of weight loss, without further deterioration of insulin resistance with age (Bettini et al. Pediatr. Diabetes 13:59-67, 2012). Identification of ALMS1 as a cilia protein explains some of the observed phenotypes and their similarities to other cilia-related disorders, including Bardet-Biedl syndrome.

[0403] Nucleic acid sequences associated with Alström syndrome, variants of the nucleic acid sequences, proteins produced by the nucleic acid sequences, and screening methods for testing individuals to determine whether they are carriers of Alström syndrome are disclosed, for example, in U.S. Pat. No. 7,196,171.

[0404] In embodiments of any of the methods described herein, the method includes treating a subject with one or more mutations in one or more alleles of the ALMS1 gene. In embodiments, the methods described herein include use of an MC4R agonist described herein to treat a subject with one or more mutations in the gene.

[0405] Nucleic acid sequences associated with Alström syndrome, variants of the nucleic acid sequences, proteins produced by the nucleic acid sequences, and screening methods for testing individuals to determine whether they are carriers of Alström syndrome are disclosed, for example, in U.S. Pat. No. 7,196,171.

[0406] Pseudohypoparathyroidism (GNAS1) In pseudohypoparathyroidism, the body fails to respond to parathyroid hormone, a clinical condition associated with obesity and short stature. The primary symptoms are low calcium and high blood phosphate levels. Affected individuals experience cataracts, dental problems, seizures, numbness, and / or muscle stiffness (muscle spasms and cramps in the hands and feet). Symptoms typically first appear in childhood. People with this disorder are also resistant to other hormones, such as thyroid-stimulating hormone and gonadotropins. Type 1A is also associated with a group of symptoms called Albright hereditary osteodystrophy, which includes short stature, round face, obesity, and short hands. Pseudohypoparathyroidism type 1A is caused by mutations in the GNAS gene and is inherited in an autosomal dominant manner. The GNAS1 gene is described, for example, in US20060147936.

[0407] In embodiments of any of the methods described herein, the method includes treating a subject with one or more mutations in one or more alleles of the GNAS1 gene. In embodiments, the methods described herein include using an MC4R agonist described herein to treat a subject with one or more mutations in the gene.

[0408] More genes Additional genes useful in the methods disclosed herein include BDNF, MCH1R, MCH, NTRK2, SIM1 (J Clin Invest. 2013;123(7):3042-3050. doi:10.1172 / JCI68016), ENPP1, COH1, CNR1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood), SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, INSIG2, KCTD15, NROB2, and 16p11.2 deletion (including the SH2B1 gene).

[0409] In embodiments of any of the methods described herein, the method includes treating a subject with one or more mutations in one or more of these genes. In embodiments, the methods described herein include use of an MC4R agonist described herein to treat a subject with a mutation in one or more of these genes.

[0410] hindrance In accordance with the methods and compositions described herein, in some embodiments, an MC4R agonist, e.g., an MC4R agonist described herein, e.g., setomelanotide, is used to treat a metabolic disorder, e.g., a disorder such as obesity, hyperphagia, or metabolic syndrome.

[0411] In some embodiments, an MC4R agonist, such as an MC4R agonist described herein, e.g., setomelanotide, is used to treat a genetic disorder caused by a deficiency in one or more components of the POMC-MC4R pathway. In some embodiments, an MC4R agonist, such as an MC4R agonist described herein, e.g., setomelanotide, is used to treat a genetic disorder such as Prader-Willi syndrome (PWS) or POMC null obesity. In some embodiments, an MC4R agonist, such as an MC4R agonist described herein, e.g., setomelanotide, is used to treat a genetic disorder associated with a deficiency in one or more of the following genes: POMC, PCSK1, MAGEL2, leptin-R, leptin, 5-HT2c receptor, NhHL2, prohormone convertase, CPE, MC4R, or Sim1. In embodiments, an MC4R agonist, eg, an MC4R agonist described herein, eg, setomelanotide, is used to treat a genetic disorder associated with hypermethylation of the POMC gene, eg, in the POMC intron.

[0412] In some embodiments, the genetic disorder is associated with obesity, eg, severe obesity, and / or hyperphagia.

[0413] Prader-Willi syndrome (PWS) Prader-Willi syndrome (PWS) is a rare genetic disorder with a prevalence ranging from approximately 1 in 8,000 to 1 in 25,000 people in the United States. PWS is characterized by severe hyperphagia, a physiological urge to eat that overrides all other factors, leading to severe obesity and other complications. Obesity is one of the greatest health threats for individuals with PWS, and hyperphagia requires costly and constant supervision to prevent binge eating, impairing PWS individuals' ability to live independently. Without supervision, these individuals are likely to die prematurely as a result of choking, stomach rupture, or from complications caused by morbid obesity. Currently, there are no approved treatments for obesity and hyperphagia associated with PWS.

[0414] Symptoms of PWS include infantile hypotonia with failure to thrive, rapid weight gain and overeating in childhood, as well as intellectual disability, growth retardation, short stature, and hypogonadism. Diagnostic criteria for PWS are described, for example, in Holm et al. Pediatrics 91 (1993): 398-402.

[0415] The genetics underlying PWS are thought to involve the functional loss of several genes on human chromosome 15, particularly 15q11-q13. See, e.g., Schaaf et al. Nat. Genet. 45.11(2013):1405-09. Protein-coding genes in this region of chromosome 15 include MKRN3, MAGEL2, NDN, NPAP1, and SNURF-SNRPN. See ibid. Examples of MAGEL2 null deficiency syndromes are found in, e.g., Schaaf et al. and Soden et al. Sci Transl Med. 2014 Dec, 2014, incorporated herein by reference. 3;6(265):265ra168. Approximately 70% of PWS patients have a large deletion (approximately 4 Mb) in the paternal 15q11-q13 chromosomal region. See, e.g., Bervini et al. Front. Neuroendocrinol. 34(2014):107-119. Approximately 25% of PWS patients have maternal uniparental disomy. See ibid. Mice lacking MAGEL2 gene expression have POMC neuron dysfunction and develop some of the same symptoms as those exhibited by humans with PWS. It is believed that a defect in the MAGEL2 gene (found on chromosome 15 in humans) may impair the function of proopiomelanocortin (POMC) neurons, a key component of the MC4 pathway that normally promotes satiety by activating downstream MC4 receptors. This dysfunction may create a blockage in the MC4 pathway.

[0416] Without wishing to be bound by theory, it is believed that the MC4R agonists described herein, such as setomelanotide, can restore weight and appetite control in PWS subjects by bypassing defective POMC neurons and activating the MC4 pathway under MC4 pathway blockade. For example, the melanocortin receptor agonists described herein, such as setomelanotide, can act as a replacement therapy for MSH.

[0417] POMC null obesity Patients with POMC null obesity, also known as POMC deficiency syndrome, have a homozygous loss of function of the proopiomelanocortin (POMC) gene, which results in early-onset severe obesity. Patients with POMC null mutations have severe obesity, with a BMI greater than 40 and uncontrolled appetite (severe hyperphagia) beginning in childhood. This genetic disorder may also be associated with hormone deficiencies such as adrenal insufficiency, and red hair and fair skin are common. This disorder can also lead to early death. POMC null obesity is an extremely rare genetic disorder, and there are no approved treatments for the obesity and hyperphagia associated with this condition. An estimated 50 to 500 POMC null patients exist worldwide.

[0418] Bardet-Biedl syndrome (BBS) In some embodiments, the MC4R agonists described herein are used to treat Bardet-Biedl syndrome (BBS). BBS is a genetically heterogeneous disorder. BBS is a form of Laurence-Moon-Biedl syndrome and is characterized by obesity, retinopathy, learning disabilities, polydactyly, and genital hypoplasia. See, e.g., Green et al., New Engl. J. Med. 321 (1989):1002-9. Without wishing to be bound by theory, BBS is believed to be characterized by one or more mutations in one or more of 20 genes (BBS1-BBS20). Most of the BBS genes encode proteins thought to be important for cilia function, formation, and stability. Eight BBS proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, and BBS18) are believed to form a complex called the BBSome, which mediates transport to the ciliary membrane. BBS6, BBS10, and BBS12 are thought to form complexes with type II chaperonins of the CCT / TRiC family.

[0419] Mutation(s) in BBS genes(ies) are believed to lead to cilia (e.g., neurocilia) defects or ciliary regulatory dysfunction. Ciliary dysfunction is believed to cause leptin signaling abnormalities and hyperleptinemia. The role of primary cilia and ciliary proteins in energy homeostasis and obesity-related disorders is described, for example, in Gupta et al. J. Endocrinol. 203 (2009): 327-36 and Oh et al. Cell Metab. 21.1 (2015): 21-31. BBS patients have hyperleptinemia suggestive of leptin resistance, and triglycerides, leptin, diastolic BP-Z, and visceral fat mass have been found to be significantly higher in BBS patients than in controls. See, for example, Feuillan et al. J. Clin. Endocrinol. Metab. 96.3 (2011). For example, obesity in BBS mutant mice is thought to be caused by leptin resistance and defective leptin receptor trafficking. See, e.g., Berbari et al. Proc. Natl. Acad. Sci. USA 110.19(2013):7796-7801. BBS2, BB4, and BB6 mutant mice have been shown to be hyperleptinemic and fail to reduce their food intake in response to leptin. See, e.g., Berbari et al. See al. Proc. Natl. Acad. Sci. USA 110.19(2013):7796-7801.

[0420] Alström syndrome Alström syndrome (ALMS) is an autosomal recessive genetic disorder with clinical symptoms including severe obesity, hyperinsulinemia, and impaired glucose metabolism that can lead to early-onset type 2 diabetes in affected subjects. ALMS is caused by mutations in ALMS1, a gene mapped to chromosome 2p13.

[0421] The progression from early-onset obesity to impaired fasting glucose or glucose tolerance and overt diabetes is thought to occur primarily due to a progressive insufficiency of beta-cell insulin secretion without further deterioration of insulin resistance with age, even in the presence of weight loss (Bettini et al. Pediatr. Diabetes 13:59-67, 2012).

[0422] Outcome In embodiments, the methods described herein result in one or more outcomes including a reduction in weight (e.g., body weight), a reduction in hunger levels, no detectable decrease in energy expenditure (e.g., resting energy expenditure), an increase in energy expenditure (e.g., resting energy expenditure), a reduction in daily / weekly / monthly food intake, a reduction in waist circumference, no detectable increase in blood pressure, or a reduction in blood pressure in a subject, e.g., compared to a control.

[0423] In some embodiments, the control is a measurement of the subject's parameter prior to administration (treatment) of the MC4R agonist. In some embodiments, the control is a predetermined value, e.g., the value of the parameter in an average obese human population, e.g., a population of a similar age and sex as the subject, or the value of the subject's parameter measured at a previous time (e.g., a previous visit, e.g., to a doctor, medical facility, or laboratory).

[0424] In some embodiments, the outcome (e.g., a reduction, an increase, the absence of a detectable decrease, or the absence of a detectable increase in a given parameter) is measured in the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment with an MC4R agonist. In other embodiments, the outcome (e.g., a reduction, an increase, the absence of a detectable decrease, or the absence of a detectable increase in a given parameter) is measured in the subject over a period of time during the course of treatment (e.g., over a period of 1-2 weeks, 2-4 weeks, 4-6 weeks, 6-8 weeks, 8-12 weeks, or 12-16 weeks).

[0425] In embodiments, the methods described herein reduce the subject's weight (e.g., body weight) compared to a control (e.g., the subject's weight before treatment, or a predetermined value, e.g., the average weight of a population of obese humans of a similar age and sex as the subject who have not received the therapeutic intervention, or the subject's weight at a previous measurement, e.g., at a previous visit). In embodiments, the reduction is about 1 kg to 3 kg after 1 week of treatment, about 1 kg to 6 kg after 2 weeks of treatment, about 2 kg to 12 kg after 4 weeks of treatment, about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment. In embodiments, the reduction is at a rate of about 1 to 2 kg / week, e.g., about 2 kg / week, over a period of, e.g., 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to 8 weeks or more of treatment, 8 to 16 weeks of treatment, or 16 to 32 weeks or more of treatment.

[0426] Measurement of weight, eg, body weight, can be performed using methods standard in the art.

[0427] In embodiments, the methods described herein reduce the subject's hunger level compared to a control (e.g., the subject's hunger level before treatment, or a predetermined hunger level, e.g., the average hunger level of an obese human population of a similar age and sex to the subject, or the subject's hunger level at a previous measurement, e.g., at a previous visit). In embodiments, the methods described herein result in the subject's feeling of hunger disappearing.

[0428] In some embodiments, hunger is measured by a scale such as the Likert hunger scale described herein, which ranges from 0 to 10. In some embodiments, the methods described herein reduce the subject's hunger score compared to a control (e.g., the subject's hunger level before treatment, or a predetermined hunger level, e.g., the average hunger level of an obese human population of similar age and sex to the subject, or the subject's hunger level at a previous measurement, e.g., at a previous visit). In some embodiments, the methods described herein reduce the Likert hunger scale score, e.g., reduce the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points, compared to a control (e.g., the subject's hunger level before treatment, or a predetermined hunger level, e.g., the average hunger level of an obese human population of similar age and sex to the subject, or the subject's hunger level at a previous measurement, e.g., at a previous visit). In some embodiments, the methods described herein result in a score of 0 on the Likert hunger scale after treatment.

[0429] In various embodiments, the reduction in hunger levels is measured / observed after 1-2 weeks or more of treatment, 2-4 weeks or more of treatment, 4-8 weeks or more of treatment, or 8-16 weeks or more of treatment.

[0430] REE is a measure of a subject's basal metabolic rate and can be determined using methods such as those described in Chen et al. J. Clin. Endocrinol. Metab. 100.4(2015):1639-45. In some embodiments, REE can be determined at specific time points after treatment (e.g., 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4 weeks, or more) by placing the subject in a whole-room indirect calorimeter (also known as a metabolic chamber). In some embodiments, REE is measured over a 30-minute measurement period, and in some cases, REE values ​​from several 30-minute periods are averaged to generate an average REE. In some embodiments, REE may be determined after a 10-12-hour fasting period at thermoneutrality (e.g., about 25°C) while the subject is awake and without psychological or physical stress. In some embodiments, REE is measured in units of energy per unit time (e.g., kcal / hour or kcal / day). In some embodiments, REE is measured relative to kg lean body mass of a subject (eg, REE / kg lean mass), for example as described in the Examples.

[0431] In embodiments, the methods described herein do not alter or decrease the subject's energy expenditure, e.g., resting energy expenditure (REE), over a period of one hour, one day (e.g., 24 hours), one week (e.g., 7 days), or one month (e.g., 30 days), e.g., when measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment, compared to a control REE (e.g., the REE of the subject before treatment, or a predetermined REE, e.g., the mean REE of an obese human population of similar age and sex to the subject and normalized for weight, or the REE of the subject at a previous measurement, e.g., at a previous visit).

[0432] In embodiments, the methods described herein do not detectably alter or decrease the subject's energy expenditure, e.g., resting energy expenditure (REE) per kg of lean body mass, over a period of one hour, one day (e.g., 24 hours), one week (e.g., 7 days), or one month (e.g., 30 days), e.g., when measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment, compared to a control REE (e.g., the REE of the subject before treatment, or a predetermined REE, e.g., the average REE of an obese human population of a similar age and sex to the subject, or the REE of the subject at a previous measurement, e.g., a previous visit).

[0433] In embodiments, the methods described herein increase the subject's energy expenditure, e.g., resting energy expenditure (REE), over a period of one hour, one day (e.g., 24 hours), one week (e.g., 7 days), or one month (e.g., 30 days), e.g., when measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment, compared to a control REE (e.g., the REE of the subject before treatment, or a predetermined REE, e.g., the mean REE of an obese human population of similar age and sex to the subject and normalized for weight, or the REE of the subject at a previous measurement, e.g., at a previous visit).

[0434] In various embodiments, the subject's increase in REE is at least 20 kcal / day (e.g., at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150 kcal / day or more), e.g., when measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks, or more, after treatment.

[0435] In various embodiments, the increase in the subject's REE compared to the subject's REE before treatment, e.g., when measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment, is at least 2% (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or more).

[0436] In embodiments, e.g., for an adult subject, the REE of the subject (e.g., adult subject) after treatment with an MC4R agonist (e.g., 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more of treatment) is at least 1800 kcal / day (e.g., at least 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975, 2000, 2025, 2050, 2100, 2150, 2200, 2250, 2300, 2400 kcal / day, or more). In embodiments, e.g., for pediatric patients, the REE of a subject (e.g., a pediatric subject) after treatment with an MC4R agonist (e.g., 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks, or more, of treatment) is at least 200 kcal / day (e.g., at least 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500 kcal / day, or more).

[0437] In embodiments, the methods described herein reduce food intake by a subject compared to a control (e.g., the subject's food intake before treatment, or a predetermined food intake level, e.g., the food intake of an average obese human population, or the subject's food intake at a previous measurement, e.g., a previous visit), e.g., food intake measured as daily food intake or food intake over a 24-hour period or a week. In embodiments, the reduction is at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories, or more, e.g., daily food intake, or food intake over a 24-hour period, or a week, or a 30-day period, or longer, e.g., for an adult subject. In embodiments, average food intake may be reduced from a baseline of about 100 kcal / kg / day or more to about 90, 80, 70, 60, 50, 40, 30, 20, or 10 kcal / kg / day or less after treatment with an MC4R agonist, e.g., setomelanotide, in pediatric subjects, e.g., about 1 year old. In embodiments, average food intake may be reduced from a baseline of about 40 kcal / kg / day or more to about 35, 30, 20, or 10 kcal / kg / day or less after treatment with an MC4R agonist, e.g., setomelanotide, in pediatric subjects, e.g., in late adolescence.

[0438] Food intake can be determined by standard methods, for example as described in Rutishauser. Pub. Health Nutr. 8.7A(2005):1100-07.

[0439] In embodiments, the methods described herein reduce the subject's waist circumference when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to a control (e.g., the subject's waist circumference before treatment, or the subject's waist circumference at a previous measurement, e.g., at a previous visit).

[0440] In various embodiments, the reduction in waist circumference of a subject (e.g., an adult subject) compared to a control (e.g., the subject's waist circumference before treatment, or a predetermined waist circumference, e.g., the waist circumference of an average obese human population of similar age and sex, or the subject's waist circumference at a previous measurement, e.g., a previous visit) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment is at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm, or more).

[0441] In some embodiments, waist circumference is measured using standard methods. In some embodiments, waist circumference is the maximum circumference around the subject's midsection, for example, around the subject's abdomen. In other embodiments, waist circumference is measured around the natural waist (e.g., between the lowest rib and the top of the hipbone), around the navel, or at the narrowest point around the midsection.

[0442] In embodiments, the methods described herein do not detectably elevate the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment compared to a control blood pressure (e.g., the subject's blood pressure before treatment, or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of similar age and sex, or the subject's blood pressure at a previous measurement, e.g., at a previous visit).

[0443] In embodiments, the methods described herein reduce the subject's blood pressure (e.g., diastolic blood pressure and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment; control blood pressure (e.g., the subject's blood pressure before treatment, or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of similar age and sex, or the subject's blood pressure at a previous measurement, e.g., at a previous visit).

[0444] In various embodiments, the reduction in blood pressure, e.g., systolic blood pressure, compared to the subject's blood pressure before treatment, when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment, is at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more).

[0445] In various embodiments, the reduction in blood pressure, e.g., diastolic blood pressure, compared to the subject's blood pressure before treatment, when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment, is at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more).

[0446] In embodiments, the methods described herein do not have adverse effects on heart rate or blood pressure.

[0447] subject According to any method described herein, in certain embodiments, the subject is obese, for example, before the administration of the agonist described herein, for example, at the time when the agonist is prescribed or at the time of the first administration of the agonist.In various embodiments, the subject is, for example, a child or adult patient with severe obesity, for example, before the administration of the agonist described herein, for example, at the time when the agonist is prescribed or at the time of the first administration of the agonist.In various embodiments, the subject is, for example, hyperphagia, before the administration of the agonist described herein, for example, at the time when the agonist is prescribed or at the time of the first administration of the agonist.

[0448] In various embodiments, the subject (e.g., an adult subject) has a blood pressure of 25 kg / m 2 or less prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration. 2 or 30 kg / m 2 Over (e.g., ≥ 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2have a body mass index (BMI) of 18.5 or higher.

[0449] In embodiments, the subject (e.g., a pediatric subject) has a body mass index (BMI) greater than the 85th to 95th percentile prior to administration of the agonist, e.g., at the time the agonist is prescribed or at the time of the first administration.

[0450] In various embodiments, the subject weighs at least about 5 kg, e.g., at least about 5 kg, 10 kg, 20 kg, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220 kg, or more, e.g., before administration of the agonist, e.g., when the agonist is prescribed or at the time of the first administration. In various embodiments, the subject weighs at least 20 kg, at least 60 kg, or at least 100 kg, e.g., before administration of the agonist, e.g., when the agonist is prescribed or at the time of the first administration.

[0451] In embodiments, the subject is an adult, e.g., 18 years of age or older, e.g., 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or older.

[0452] In various embodiments, the subject is a pediatric subject, e.g., 18 years of age or younger (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age or younger).

[0453] In some embodiments, the subject has or is identified as having a defect, for example, a gene defect or mutation, in one or more genes of the POMC-MC4R pathway.In some embodiments, the subject has or is identified as having one or more mutations in the POMC, PCSK1, MAGEL2, leptin receptor, leptin, 5-HT2c receptor, NhHL2, prohormone convertase, CPE, MC4R, or Sim1 gene, or other genes that impair the function of the POMC-MC4R pathway.In some embodiments, the subject has or is identified as having a hypermethylated POMC gene (for example, hypermethylated in the POMC intron, for example, hypermethylated in the CpG island of the POMC gene, including methylated cytosine, for example, 5' methylcytosine).

[0454] In some embodiments, the subject has Prader-Willi syndrome.

[0455] In embodiments, the subject has, or is identified as having, a loss-of-function mutation in the 15q11-q13 region of chromosome 15, eg, the paternal allele.

[0456] In some embodiments, the subject has or is identified as having a mutation (eg, a loss-of-function mutation) in the MAGEL2 gene.

[0457] In various embodiments, the subject has or is identified as having a POMC-null, PCSK1-null genotype, MAGEL2-null genotype, leptin receptor-null genotype, leptin-null genotype, 5-HT2c receptor-null genotype, NhHL2-null genotype, prohormone convertase-null genotype, CPE-null genotype, MC4R-null genotype, and / or SIM1-null genotype. For example, the subject has or is identified as having POMC-null, PCSK1-null obesity, MAGEL2-null obesity, leptin receptor-null obesity, leptin-null obesity, 5-HT2c receptor-null obesity, NhHL2-null obesity, prohormone convertase-null genotype, CPE-null obesity, MC4R-null obesity, and / or SIM1-null obesity.

[0458] In embodiments, the subject has or is identified as having a POMC mutation described herein, e.g., a POMC mutation described in Table 1. In embodiments, the subject has or is identified as having a mutation in a POMC amino acid sequence selected from one or more of Cys28Phe, Leu37Phe, His143Glu, Phe144Leu, Tyr221Cys, Pro231Leu, Arg236Gly, or Glu244X, the numbering of which corresponds to the numbering of the protein, including the signal peptide, as described in Takahashi, et al. 1981 Febs Letters 135(1)97 (and set forth as SEQ ID NO: 563), where X indicates a premature termination.

[0459] In embodiments, the subject has or is identified as having a POMC mutation (e.g., a homozygous POMC mutation) set forth in a reference in Table 2. In embodiments, the subject has or is identified as having a POMC mutation (e.g., a heterozygous POMC mutation) set forth in a reference in Table 1.

[0460] In some embodiments, the POMC mutation is a homozygous mutation. In some embodiments, the POMC mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In some embodiments, the POMC mutation is a loss-of-function mutation. In some embodiments, the POMC mutation is a partial loss-of-function mutation.

[0461] In some embodiments, the subject has or is identified as having hypermethylation in the POMC gene, e.g., hypermethylation in exon 3 of the POMC gene, or hypermethylation at the intron 2-exon 3 boundary of the POMC gene, e.g., hypermethylation in the CpG island at the intron 2-exon 3 boundary of the POMC gene.

[0462] In embodiments, the subject has or is identified as having a PCSK1 mutation described herein, e.g., a heterozygous nonsense variant (p.Arg80*), a PCSK1 mutation (e.g., a homozygous mutation) described in a reference in Table 3, or a PCSK1 mutation (e.g., a heterozygous mutation) described in a reference in Table 4. In embodiments, the subject has or is identified as having a mutation in a PCSK1 amino acid sequence selected from Met125Ile, Thr175Met, Asn180Ser, Tyr181His, Gly262Arg, Ser325Asn, Thr558Ala, Asn221Asp, Gln665E, or S690Thr.

[0463] In some embodiments, the PCSK1 mutation is a homozygous mutation. In some embodiments, the PCSK1 mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In some embodiments, the PCSK1 mutation is a loss-of-function mutation. In some embodiments, the PCSK1 mutation is a partial loss-of-function mutation.

[0464] In some embodiments, the subject has or is identified as having a MAGEL2 mutation described herein, such as c.1652delT (p.Val551fs), c.1802delC (p.Pro601fs), c.3181_3182delAT (p.Ile1061fs), c.3124C>T (p.Gln1024*), or a mutation described in Schaaf et al. Nat. Genet. 45.11(2013):1405-09 or Soden et al. Sci Transl Med. 2014 Dec 3;6(265):265ral68. In some embodiments, the MAGEL2 mutation is a homozygous mutation. In some embodiments, the MAGEL2 mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In some embodiments, the MAGEL2 mutation is a loss-of-function mutation. In some embodiments, the MAGEL2 mutation causes a decrease in function / activity.

[0465] In some embodiments, the subject has or is identified as having a leptin mutation or leptin-R mutation described herein. In some embodiments, the subject has or is identified as having a leptin mutation described herein, e.g., a homozygous frameshift mutation that deletes a guanine nucleotide at codon 133 of the leptin gene, or a homozygous transversion (c.298G→T) that results in an aspartic acid to tyrosine change at amino acid position 100 (p.D100Y). In some embodiments, the subject has or is identified as having a leptin-R mutation described herein, e.g., a Gln223Arg or Lys656Asn mutation, or a mutation (e.g., a homozygous mutation) described in a reference in Table 5. In some embodiments, the subject has or is identified as having a leptin-R mutation (e.g., a homozygous leptin-R mutation) described in Table 6. In some embodiments, the subject has, or is identified as having, a leptin-R mutation selected from c.2396-1G>T, c.1675G>A, p.Cys604Gly, p.Leu786Pro, p.His800_Asn831del, p.Tyr422His, p.Thr711NfsX18, P.535-1G>A, p.166CfsX7, 4-bp del codon 22, 11-bp del codon 70, 66-bp del codon 514, Trp31X, Ala409Glu, Trp664Arg, His684Pro, 1-bp del codon 15, or Arg612His.

[0466] In some embodiments, the leptin or leptin-R mutation is a homozygous mutation. In some embodiments, the leptin or leptin-R mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In some embodiments, the leptin or leptin-R mutation is a loss-of-function mutation. In some embodiments, the leptin or leptin-R mutation is a partial loss-of-function mutation.

[0467] In some embodiments, the subject has or is identified as having a 5-HT2c receptor mutation described herein. In some embodiments, the 5-HT2c receptor mutation is a homozygous mutation. In some embodiments, the 5-HT2c receptor mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In some embodiments, the 5-HT2c receptor mutation is a loss-of-function mutation. In some embodiments, the 5-HT2c receptor mutation is a partial loss-of-function mutation.

[0468] In some embodiments, the subject has or is identified as having an NhLH2 mutation described herein, such as those described in Good et al. Nat. Genet. 15 (1997): 397-401. In some embodiments, the NhLH2 mutation is a homozygous mutation. In some embodiments, the NhLH2 mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In some embodiments, the NhLH2 mutation is a loss-of-function mutation. In some embodiments, the NhLH2 mutation is a partial loss-of-function mutation.

[0469] In embodiments, the subject has or is identified as having a prohormone convertase mutation described herein, such as those described in Pritchard et al. J. Endocrinol. 172 (2002):411-21, or those described in the references in Table 3 or Table 4. In embodiments, the prohormone convertase mutation is a homozygous mutation. In embodiments, the prohormone convertase mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In embodiments, the prohormone convertase mutation is a loss-of-function mutation. In embodiments, the prohormone convertase mutation is a partial loss-of-function mutation.

[0470] In some embodiments, the subject has or is identified as having a CPE mutation described herein, such as (c.76_98del; p.E26RfsX68), or one described in Alsters et al. PloS ONE. 10.6 (2015): e0131417. In some embodiments, the CPE mutation is a homozygous mutation. In some embodiments, the CPE mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In some embodiments, the CPE mutation is a loss-of-function mutation. In some embodiments, the CPE mutation is a partial loss-of-function mutation.

[0471] In some embodiments, the subject has or is identified as having a SIM1 mutation described herein, such as those described in Bonnefond et al. J. Clin. Invest. 123.7 (2013): 3037-41. In some embodiments, the SIM1 mutation is a homozygous mutation. In some embodiments, the SIM1 mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In some embodiments, the SIM1 mutation is a loss-of-function mutation. In some embodiments, the SIM1 mutation is a partial loss-of-function mutation.

[0472] In some embodiments, the methods herein may include identifying or selecting a subject having a defect, e.g., a gene defect or mutation, in one or more genes in the POMC-MC4R pathway. In some embodiments, the methods herein may include obtaining knowledge of a genotype, a predetermined sequence, or a mutation. In some embodiments, the methods herein may include obtaining knowledge of a genotype, e.g., a mutation in one or more of the genes described herein, POMC, PCSK1, MAGEL2, leptin receptor, leptin, 5-HT2c receptor, NhHL2, prohormone convertase, CPE, MC4R, Sim1, and / or other POMC-MC4R pathway genes. In some embodiments, an agonist is administered in response to obtaining knowledge, e.g., detecting or identifying, a predetermined sequence, e.g., a mutation, in one or more of the genes described herein, POMC, PCSK1, MAGEL2, leptin receptor, leptin, 5-HT2c receptor, NhHL2, prohormone convertase, CPE, MC4R, Sim1, or other POMC-MC4R pathway genes.

[0473] In embodiments, the methods herein may include obtaining knowledge of the methylation status of a POMC gene (e.g., one that is hypermethylated in a POMC intron, e.g., one that contains a methylated cytosine, e.g., a 5' methylcytosine, e.g., one that is hypermethylated in a CpG island of the POMC gene). In embodiments, an agonist is administered in response to detection of hypermethylation.

[0474] In embodiments, the methods herein may include obtaining knowledge of a subject's genotype, e.g., obtaining knowledge of the genotype of the 15q11-q13 region of chromosome 15 (e.g., paternal allele) or the MAGEL2 gene. In embodiments, the agonist is administered in response to detection of a predetermined sequence, e.g., a mutation, in the 15q11-q13 region of chromosome 15 (e.g., paternal allele) or the MAGEL2 gene.

[0475] In embodiments, identifying or selecting a subject as having a particular genotype or predetermined sequence, e.g., mutation, in a gene may involve obtaining knowledge of the particular genotype or predetermined sequence, e.g., mutation. Such knowledge can be obtained in several ways, as detailed in the "Definitions" section.

[0476] In some embodiments, a sequence is obtained by taking ownership of a nucleotide sequence, for example, by "directly obtaining" or "indirectly obtaining" the sequence. "Directly obtaining a sequence" means performing a process to obtain the sequence (e.g., performing a synthetic or analytical method), such as performing a sequencing method (e.g., next-generation sequencing (NGS)). "Indirectly obtaining a sequence" refers to receiving information or knowledge of the sequence or receiving the sequence from another party or source (e.g., a third-party laboratory that directly obtained the sequence). The sequence obtained need not be a complete sequence; for example, sequencing at least one nucleotide, or obtaining information or knowledge identifying a genotype or a predetermined sequence disclosed herein, e.g., a mutation, as present in a subject, constitutes obtaining a sequence.

[0477] In some embodiments, the sequence may be obtained directly. Directly obtaining a sequence includes performing a process that involves physical changes to a physical substance, such as a starting material, such as a tissue sample, for example, a blood sample or tissue biopsy, or analyzing an isolated nucleic acid (e.g., DNA or RNA) sample. Exemplary changes include creating a physical entity from two or more starting materials, shearing or fragmenting a substance such as genomic DNA fragments, separating or purifying a substance (e.g., isolating a nucleic acid sample from tissue), combining two or more separate entities into a mixture, or performing a chemical reaction that involves breaking or forming a covalent or non-covalent bond. Directly obtaining a value includes performing a process that involves physical changes to a sample or another substance, as described above.

[0478] In some embodiments, obtaining knowledge of a particular genotype or predetermined sequence, e.g., a mutation, can include, for example, obtaining a sample from which the genotype or predetermined sequence, e.g., a mutation, is to be determined. "Obtaining a sample," as the term is used herein, refers to taking ownership of a sample, e.g., a tissue sample or a nucleic acid sample, by "directly obtaining" or "indirectly obtaining" the sample. "Directly obtaining a sample" means performing a process to obtain the sample (e.g., performing a physical method such as surgery or extraction). "Indirectly obtaining a sample" refers to receiving the sample from another party or source (e.g., a third-party laboratory that directly obtained the sample). Directly obtaining a sample includes performing a process that involves physical transformation of a physical substance, e.g., a starting material, e.g., tissue, e.g., tissue from a human patient, or tissue previously isolated from a patient. Exemplary transformations include creating a physical entity from the starting material, dissecting or peeling tissue, separating or purifying a substance (e.g., sample tissue or nucleic acid sample), combining two or more separate entities into a mixture, or performing a chemical reaction that involves breaking or forming a covalent or non-covalent bond. Directly obtaining a sample includes, for example, performing a process, as described above, that involves a physical change of the sample or another substance.

[0479] In some aspects, methods are also provided herein for assessing a subject's likelihood of responsiveness to, for example, an MC4R agonist, such as an MC4R agonist described herein, such as setomelanotide. In some embodiments, the methods include obtaining information about the subject's genotype. In various embodiments, the methods include obtaining information about the presence or absence of a defect, such as a gene defect, in one or more genes in the POMC-MC4R pathway in the subject.

[0480] In embodiments, a subject can be identified as having a defect, eg, a gene defect, eg, a mutation, in one or more genes in the POMC-MC4R pathway using the methods described herein.

[0481] In some embodiments, identifying a subject as having a defect, e.g., a gene defect, e.g., a mutation, indicates that the subject is likely to respond (e.g., with one or more symptomatic improvements) to an MC4R agonist, e.g., an MC4R agonist described herein, e.g., setomelanotide. In some embodiments, symptomatic improvement can include outcomes described herein. For example, symptomatic improvement can include weight (e.g., body weight) reduction, hunger level reduction, no detectable decrease in energy expenditure (e.g., resting energy expenditure), increased energy expenditure (e.g., resting energy expenditure), reduced daily / weekly / monthly food intake, or reduced waist circumference, e.g., compared to a control.

[0482] In embodiments, identification of a subject as having a defect, e.g., a genetic defect, e.g., a mutation, indicates that the subject is more likely to respond (or more likely to have a greater response) to an MC4R agonist, e.g., an MC4R agonist described herein, e.g., setomelanotide, than a subject without a genetic defect in the POMC-MC4R pathway (e.g., an obese subject, e.g., a subject of similar age and / or pre-treatment weight), e.g., a wild-type obese subject. In embodiments, a subject who is more likely to respond is more likely to have improvement in one or more symptoms, e.g., a symptom described herein, compared to, e.g., a control, e.g., a subject without a genetic defect in the POMC-MC4R pathway (e.g., an obese subject, e.g., a subject of similar age and / or pre-treatment weight), e.g., a wild-type obese subject. In some embodiments, subjects who are more likely to have a greater response are more likely to have a greater improvement in a symptom, e.g., a symptom described herein, e.g., greater weight loss, greater waist circumference loss, greater increase in resting energy expenditure, greater decrease in food intake, greater decrease in hunger levels, compared to, e.g., a control, e.g., a subject without a genetic defect in the POMC-MC4R pathway (e.g., an obese subject, e.g., a subject of similar age and / or weight before treatment), e.g., a wild-type obese subject.

[0483] In embodiments, the methods described herein further include providing a report identifying the presence or absence of the genetic defect, and in some cases, an identifier for the subject. In some embodiments, the report provides a recommendation regarding potential treatment options, the likelihood of efficacy of the treatment options, and / or recommendations / instructions regarding administration of the treatment option (e.g., an MC4R agonist, e.g., an MC4R agonist described herein, e.g., setomelanotide).

[0484] MC4R agonists Examples of naturally occurring MC4R agonists include α-MSH, β-MSH, γ-MSH, and adenocorticotropic hormone (ACTH) or functional fragments thereof. Examples of synthetic MC4R agonists are detailed below.

[0485] In exemplary embodiments, the agonist used in accordance with the methods of the present invention may be any known agonist of MC4R, hi some exemplary embodiments, the MC4R agonist is not adrenocorticotropic hormone (ACTH) or a fragment thereof.

[0486] In exemplary embodiments, the MC4R agonist is any of the peptides disclosed in the international application published as WO2005 / 000339, which is incorporated herein by reference. In particular, examples include peptides of the following structural formula: [ka] are listed, During the ceremony, W is Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, Cya, or absent; R 1 is -H, -C(O)CH3, -C(O)(CH2) 1-4 CH3, -C(O)(CH2) 1-4 NHC(NH)NH2, Tyr-βArg-, Ac-Tyr-β-hArg-, gluconoyl-Tyr-Arg-, Ac-diaminobutyryl-, Ac-diaminopropionyl-, N-propionyl-, N-butyryl-, N-valeryl-, N-methyl-Tyr-Arg-, N-glutaryl-Tyr-Arg-, N-succinyl-Tyr-Arg-, R 6 -SO2NHC(O)CH2CH2C(O)-, R 6 -SO2NHC(O)CH2CH2C(O)Arg-, R 6 -SO2NHCH2CH2CH2C(O)-, C3-C7 cycloalkylcarbonyl, pheylsulfonyl, C8-C 14 Bicyclic Arylsulfonyl, Phenyl-(CH2) q C(O)-, C8-C 14 Bicyclic Aryl-(CH2) q C(O)-, [ka] (In the formula, R 2 is -H, -NH2, -NHC(O)CH3, -NHC(O)(CH2) 1-4 CH3, -NH-TyrC(O)CH3, R 6 SO2NH-, Ac-Cya-NH-, Tyr-NH-, HO-(C6H5)-CH2CH2C(O)NH-, or CH3-(C6H5)-C(O)CH2CH2C(O)NH-, R 3 is C1-C4 straight or branched alkyl, NH2-CH2-(CH2) q -, HO-CH2-, (CH3)2CHNH(CH2)4-, R 6 (CH2) q -, R 6 SO2NH-, Ser, Ile, [ka] and q is 0, 1, 2, or 3; R 6 is phenyl or C8-C 14 is a bicyclic aryl; m is 1 or 2; n is 1, 2, 3, or 4; R 9 is (CH2) p or (CH3)2C-, p is 1 or 2; R 10 is NH- or absent, R 7 is a 5- or 6-membered heteroaryl, or R 4 is a 5- or 6-membered heteroaryl ring optionally substituted with R 4 is H, C1-C4 straight or branched alkyl, phenyl, benzyl, or (C6H5)-CH2-O-CH2-; R 8 is phenyl, a phenyl ring optionally substituted with X, or cyclohexyl; X is H, Cl, F, Br, methyl, or methoxy; R 11 is -C(O) or -CH2, R 5 are -NH2, -OH, glycinol, NH2-Pro-Ser-, NH2-Pro-Lys-, HO-Ser-, HO-Pro-Ser-, HO-Lys-, Ser alcohol, -Ser-Pro alcohol, -Lys-Pro alcohol, HOCH2CH2-O-CH2CH2NH-, NH2-Phe-Arg-, NH2-Glu-, NH2CH2RCH2NH-, RHN-, RO- (where R is a C1-C4 straight or branched alkyl); L is -SS- or -S-CH2-S-.

[0487] Other examples of MC4R agonists include peptides of the following structural formula: [ka] In the formula: W is a single bond, Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, or Phe; R 1 is -H, -C(O)CH3, -C(O)(CH2) 1-4 CH3, -C(O)(CH2) 1-4 -NHC(NH)NH2, Tyr-βArg, gluconoyl-Tyr-Arg, Ac-Dab, Ac-Dap, N-succinyl-Tyr-Arg, N-propionyl, N-valeryl, N-glutaryl-Tyr-Arg, N-butyryl, [ka] (In the formula, R 2 is -H, -NH2, -NHC(O)CH3, -NHC(O)(CH2) 1-4 CH3, or -NH-TyrC(O)CH3, R 3 is C1-C4 straight or branched alkyl, Ser, Ile, [ka] and q is 0, 1, 2, or 3; m is 1 or 2; p is 1 or 2; R 4 is H or C1-C4 straight or branched alkyl; X is H, Cl, F, Br, methyl, or methoxy; R 5 are -NH2, -OH, glycinol, -Ser-Pro-NH2, -Lys-Pro-NH2, -Ser-OH, -Ser-Pro-OH, -Lys-Pro-OH-Arg-Phe-NH2, -Glu-NH2, -NHR, or -OR (wherein R is a C1-C4 straight or branched alkyl).

[0488] In yet another exemplary embodiment, the MC4R agonist can be represented by the following structural formula: [ka] During the ceremony, W is Glu, Gln, Asp, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, Cya, or absent; R 1 is -H, -C(O)CH3, -C(O)(CH2) 1-4 CH3, -C(O)(CH2) 1-4 NHC(NH)NH2, Tyr-βArg-, Ac-Tyr-β-hArg-, gluconoyl-Tyr-Arg-, Ac-diaminobutyryl-, Ac-diaminopropionyl-, N-propionyl-, N-butyryl-, N-valeryl-, N-methyl-Tyr-Arg-, N-glutaryl-Tyr-Arg-, N-succinyl-Tyr-Arg-, R 6 -SO2NHC(O)CH2CH2C(O)-, R 6 -SO2NHC(O)CH2CH2C(O)Arg-, R 6 -SO2NHCH2CH2CH2C(O)-, C3-C7 cycloalkylcarbonyl, phenylsulfonyl, C8-C 14 Bicyclic Arylsulfonyl, Phenyl-(CH2) q C(O)-, C8-C 14 Bicyclic Aryl-(CH2) q C(O)-, [ka] (In the formula, R 2 is -H, -NH2, -NHC(O)CH3, -NHC(O)(CH2) 1-4 CH3, -NH-TyrC(O)CH3, R 6 SO2NH-, Ac-Cya-NH-, Tyr-NH-, HO-(C6H5)-CH2CH2C(O)NH-, or CH3-(C6H5)-C(O)CH2CH2C(O)NH-, R 3 is C1-C4 straight or branched alkyl, NH2-CH2-(CH2) q -, HO-CH2-, (CH3)2CHNH(CH2)4-, R 6 (CH2) q -, R 6 SO2NH-, Ser, Ile, [ka] and q is 0, 1, 2, or 3; R 6 is phenyl or C8-C 14 is a bicyclic aryl; m is 1 or 2; p is 1 or 2; R 4 is H, C1-C4 straight or branched alkyl, phenyl, benzyl, or (C6H5)-CH2-O-CH2-, X is H, Cl, F, Br, methyl, or methoxy; R 5 are -NH2, -OH, glycinol, NH2-Pro-Ser-, NH2-Pro-Lys-, HO-Ser-, HO-Pro-Ser-, HO-Lys-, -Ser alcohol, -Ser-Pro alcohol, -Lys-Pro alcohol, HOCH2CH2-O-CH2CH2NH-, NH2-Phe-Arg-, NH2-Glu-, NH2CH2RCH2NH-, or RO- (where R is a C1-C4 straight chain or branched alkyl).

[0489] Further examples of MC4R agonists useful in practicing the present invention include those described in WO2011104378, WO2011104379, WO201060901, WO200887189, WO200887188, WO200887187, WO200887186, US20110065652, WO2010144341, WO2010144344, WO201065799, WO201065800, WO201065801, WO201065802, WO2010370 81, WO2009152079, WO2009151383, US20100311648, US20100280079, WO201081666, WO201034500, WO200910299, WO2008116665, WO201052256, WO201052255, WO201126015, US20100120783, WO201096854, US20100190793, WO201025142, and WO201015972. Further examples of MC4R agonists useful in practicing the present invention can be found in U.S. Patent No. 8,263,608, U.S. Patent No. 8,247,530, U.S. Patent No. 8,114,844, and U.S. Patent No. 7,968,548, the teachings of all of which are incorporated herein by reference.

[0490] In one exemplary embodiment, the MC4R agonist is the tripeptide D-Phe-Arg-Trp (SEQ ID NO: 560) or a pharmaceutical salt thereof. In another example, the agonist is any peptide comprising SEQ ID NO: 560 or a pharmaceutical salt thereof. In yet another example, the MC4R agonist is the acetylated tripeptide Ac-D-Phe-Arg-Trp-NH (SEQ ID NO: 561) or a pharmaceutical salt thereof.

[0491] In an exemplary embodiment, the MC4R agonist is of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (see International Patent Application Publication No. WO 2007 / 008704, which is incorporated by reference in its entirety). (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) In formula (I), A 1 Acc, HN-(CH2) m -C(O), an L-amino acid or a D-amino acid, or a deletion; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, a D-amino acid, or a deletion, A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4R 5 ))-C(O), A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), an L-amino acid or a D-amino acid, or a deletion; R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, substituted (C1-C 30 ) acyl, substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40) acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C1-C 40 ) acyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are respectively, independently in each case, H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 ) alkenyl, substituted (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.

[0492] In an exemplary embodiment of the agonist of Formula (I), (I)R 4 (C1-C 40 ) Acyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) acyl, substituted aryl (C1-C 40 ) acyl, (C1-C40 ) alkylsulfonyl, or -C(NH)-NH2, R 5 is H, or (C1-C 40 ) alkyl, (C1-C 40 )heteroalkyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) alkyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, or substituted aryl (C1-C 40 ) alkyl, (II)R 2 (C1-C 30 ) Acyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) acyl, or substituted aryl (C1-C 30 ) acyl, R 3 is H, (C1-C 30 ) alkyl, (C1-C 30 )heteroalkyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) alkyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) alkynyl, or substituted aryl (C1-C 30 ) alkyl, (III)A 3 Or A 8 must be present in the compound, (IV)A 2 When is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, (V)A2 When is Asp or Glu, A 9 is Dab, Dap, Orn, or Lys, (VI)A 8 When is Ala or Gly, A 1 is not NIe, (VII)A 1 When is a deletion, R 2 and R 3 cannot both be H.

[0493] In an exemplary embodiment, the agonist used in accordance with the methods described herein is a compound of Formula I, wherein: A 1 is A6c, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, Ile, Leu, hLeu, Met, β-hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Val, or deletion; A 2 is Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or D-Pen, A 3 is D-Abu, Aib, Ala, β-Ala, D-Ala, D-Cha, Gaba, D-Glu, Gly, D-Ile, D-Leu, D-Tle, D-Val, or a deletion; A 4 is His or 3-Pal, A 5 is D-Bal, D-1-Nal, D-2-Nal, D-Phe, D-Trp, or D-(Et)Tyr; A 6 is Arg or hArg, A 7 are Bal, BiP, 1-Nal, 2-Nal, Trp, and D-Trp, A 8 is A6c, D-Ala, Aha, Ahx, Ala, β-Ala, Apn, Gaba, Gly, or a deletion; A 9is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen, A 10 is Thr or a deletion, A 3 ~A 8 is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein at least one of but not both of is a deletion.

[0494] In an exemplary embodiment, an agonist of Formula (I) useful in practicing the inventions described herein is a compound of the following formula, or a pharmaceutically acceptable salt thereof: SEQ ID NO: 1 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2, SEQ ID NO: 2 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2, SEQ ID NO: 3 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2, SEQ ID NO:4 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2, SEQ ID NO:5 D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2, SEQ ID NO:6 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2, SEQ ID NO:7 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2, SEQ ID NO:8 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2, SEQ ID NO:9 Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 10 Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 11 Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 12 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 13 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 14 Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 15 Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 16 Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 17 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 18 Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 19 Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 20 Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 21 Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 22 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 23 Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 24 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 25 Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 26 Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 27 Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 28 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 29 Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 30 Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 31 Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 32 Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 33 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2, SEQ ID NO: 34 Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 35 Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 36 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 37 Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 38 Ac-D-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 39 Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 40 Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 41 Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 42 Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 43 Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 44 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 45 n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 46 n-Butyryl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, SEQ ID NO: 47 Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, Allocation number 48 Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, Allocation number 49 Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2, Allocation number 50 Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2, fl allocation number 51 Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2, Allocation number 52 Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2, Allocation number 53 Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2, Allocation number 54 Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2, Allocation number 55 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2, Allocation number 56 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH2, Allocation number 57 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2, Allocation number 58 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2, Allocation number 59 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2, SEQ ID NO: 60 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2, SEQ ID NO: 61 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2, SEQ ID NO: 62 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2, SEQ ID NO: 63 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH2, SEQ ID NO: 64 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2, SEQ ID NO: 65 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2, SEQ ID NO: 66 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2, SEQ ID NO: 67 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH2, SEQ ID NO: 68 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2, SEQ ID NO: 69 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 70 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2, SEQ ID NO:71 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH2, SEQ ID NO:72 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2, Allocation number 73 Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2, Allocation number 74 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2, Allocation number 75 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2, Allocation number 76 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, Allocation number 77 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2, Allocation number 78 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2, Allocation number 79 D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2, Allocation number 80 D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2, Allocation number 81 D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2, Allocation number 82 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2, Allocation number 83 D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2, Allocation number 84 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2, Allocation number 85 Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2、 Allocation number 86 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2, Allocation number 87 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2, Allocation number 88 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH、 Allocation number 89 Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2, Allocation number 90 Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2, Allocation number 91 Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2, Allocation number 92 Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2, Allocation number 93 Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2, Allocation number 94 Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2, Allocation number 95 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2、 Allocation number 96 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2、 SEQ ID NO:97 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2, SEQ ID NO: 98 Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 99 Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 100 Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 101 Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 102 Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 103 Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 104 Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 105 Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 106 Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 107 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH, SEQ ID NO: 108 Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2, SEQ ID NO: 109 Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2, Allocation number 110 Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2, Allocation number 111 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2, Allocation number 112 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2, Allocation number 113 Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2, Allocation number 114 Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2, Allocation number 115 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH, Allocation number 116 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH、 Allocation number 117 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH, Allocation number 118 D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH, Allocation number 119 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH, Allocation number 120 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH、 Allocation number 121 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH、 Allocation number 122 Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH, Sequence number 123 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH, Sequence number 124 Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH, Sequence number 125 Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH, Sequence number 126 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH, Sequence number 127 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH, Sequence number 128 Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH, Sequence number 129 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH, Sequence number 130 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH, Sequence number 131 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH, Sequence number 132 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH, Sequence number 133 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH, Sequence number 134 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH, SEQ ID NO: 135 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH, SEQ ID NO: 136 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH, SEQ ID NO: 137 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH, SEQ ID NO: 138 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH, SEQ ID NO: 139 Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2, SEQ ID NO: 140 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 141 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, SEQ ID NO: 142 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2, SEQ ID NO: 143 Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2, SEQ ID NO: 144 Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2, SEQ ID NO: 145 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2, SEQ ID NO: 146 Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2, or SEQ ID NO: 147 Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2, or a pharmaceutically acceptable salt thereof.

[0495] In some embodiments, the MC4R agonist is setomelanotide (also known as RM-493), which has the sequence Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140). Setomelanotide is a peptide that retains the specificity and functionality of the naturally occurring hormone that activates MC4R and has not shown adverse effects on blood pressure in clinical trials. See, e.g., Chen et al. J. Clin. Endocrinol. Metab. 2015;100(4):1639-45. The structure of setomelanotide is shown below. [ka] Setomelanotide is an 8 amino acid cyclic peptide that is effective in activating MC4R.See, for example, US 8,039,435B2, which is incorporated herein by reference.Setomelanotide is generally well tolerated, and there is little if any evidence of increased blood pressure, and it rarely affects sexual activity.

[0496] In an exemplary embodiment, an agonist of the MC4R receptor useful in practicing the methods described herein is any of the compounds set forth in Formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (see International Patent Application Publication No. WO 2007 / 008704, which is incorporated herein by reference in its entirety). (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-NH2(II) In formula (II), A 1 is Nle or deletion, A 2 is Cys or Asp, A 3 is Glu or D-Ala, A 4 is His, A 5 is D-Phe, A 6 is Arg, A 7 is Trp, 2-Nal, or Bal, A 8 is Gly, Ala, D-Ala, (3-Ala, Gaba, or Apn, A 9 is Cys or Lys, R 2 and R 3 each is independently selected from the group consisting of H or (C1-C6) acyl.

[0497] In an exemplary embodiment of Formula (II), (I)R 2 is (C1-C6) acyl, R 3 is H, (II)A 2 When is Cys, A 9 is Cys.

[0498] In an alternative exemplary embodiment of the present invention, compounds useful in practicing the methods disclosed herein are: SEQ ID NO: 148 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2, SEQ ID NO: 149 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2, SEQ ID NO: 150 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2, SEQ ID NO: 151 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2, SEQ ID NO: 152 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2, SEQ ID NO: 153 Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2, SEQ ID NO: 154 Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2, SEQ ID NO: 155 Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2, SEQ ID NO: 156 Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2, SEQ ID NO: 157 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2, or SEQ ID NO: 158 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2, or a pharmaceutically acceptable salt thereof.

[0499] In an exemplary embodiment, an agonist of MC4R useful in practicing the methods described herein is any of the compounds of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof (see International Application Publication No. WO 2007 / 008684, which is incorporated herein by reference in its entirety): (R 2 R 3 )-B 1 -A 1 -c(A 2 -A 3 -A4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -A 11 -A 12 -A 13 -B 2 -B 3 -R 1 (III)

[0500] [In formula (III), B 1 is a peptide moiety comprising 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg, and D-hArg, or B 1 is optionally a deletion, A 1 Acc, HN-(CH2) m -C(O), an L-amino acid or a D-amino acid, or a deletion; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu, A 3 is Gly, Glu, Ala, β-Ala, Gaba, Aib, a D-amino acid, or a deletion, A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X',X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, D-(Et)Tyr, D-Dip, D-Bip, or D-Bpa; A 6is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O), A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, Dip, Bpa, D-Trp, D-1-Nal, D-2-Nal, D-Bal, D-Bip, D-Dip, or...

Claims

[Claim 1] The invention as depicted in the drawings.

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