Therapeutic regimens and methods for reducing body weight and / or serum lipids using glp-1r and gcgr agonists

Abstract

The present disclosure relates to once-weekly dosing regimens of dual GLP-1R and GCGR agonists, formulations and methods of using the same for the treatment of long-term weight management and / or reduction of serum lipids in a subject in need thereof, using pharmaceutical dosage formulations comprising a peptide product according to SEQ ID NO: 1 or a peptide product that is at least 80% identical to the peptide of SEQ ID NO: 1, the subject having one or more comorbidities.

Description

[0001] Related applications This application claims priority to Provisional Application No. 63 / 564,477, filed on March 12, 2024, the entire contents of which are hereby incorporated herein by reference.

[0002] sequence list This application contains a sequence list that has been filed electronically in ASCII format via the USPTO Patent Centre and is incorporated herein by reference in its entirety. The ASCII copy was created on March 6, 2025, named MED014USPCT_ST26.xml, and is 4.20KB in size.

[0003] Areas of publicly available content This disclosure relates to the use of GLP-1R and the GCGR agonist pemvidutide (a composition comprising SEQ ID No.:1) in certain dosing regimens for reducing body weight and / or serum pathogenic lipid mediators.

[0004] Background of the publicly disclosed content Obesity is a major public health problem and a well-established risk factor for a variety of metabolic and cardiovascular (CV) diseases. Obesity is a rapidly increasing problem worldwide, with more than 65% of adults in the United States currently overweight, and the number of obese individuals doubling every year. Being overweight is strongly associated with an increased risk of cardiovascular disease, high blood pressure, dyslipidemia, dysglycemia, diabetes, prediabetes, obstructive sleep apnea, osteoarthritis, and some cancers, significantly contributing to patient morbidity, mortality, and healthcare costs.

[0005] The increasing prevalence of cardiovascular (CV) disease and CV-related deaths across various human populations, including overweight and / or obese individuals, constitutes an epidemic-level global health crisis, a major contributor to morbidity and mortality, and a significant economic burden. For example, obesity (e.g., having a body mass index (BMI, BMI kg / m²) greater than 25 (overweight) or 30 (obese) is a significant risk factor. 2Overweight is a rapidly increasing problem worldwide, and currently more than 65% of adults in the United States are overweight. Furthermore, over 80% of patients with heart failure with preserved ejection fraction (HFpEF) are overweight or obese (Kitzman et al., Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: Arandomized clinical trial). JAMA 2016;315(1):36-46). In a study of 100 elderly patients (67+ / - 5 years) with obesity and clinically stable HFpEF, 7% weight loss has been shown to increase exercise tolerance and improve other measures of diastolic cardiac function (ibid.; https: / / www.rethinkobesity.com / disease-progression / comorbidities-of-obesity.html). Most people considered overweight or obese have limited options for available FDA-approved pharmacological agents to induce weight loss, and therapies are primarily based on lifestyle interventions designed to achieve weight loss. However, long-term weight loss is difficult to achieve and maintain through lifestyle changes alone.

[0006] Excessive obesity, particularly visceral fat, is a key driver of metabolic dysfunction and cardiovascular disease (CVD) in overweight or obese individuals. Adipose tissue is not only a passive energy storage organ but also an active endocrine organ that secretes inflammatory cytokines, free fatty acids, and adipokines (which contribute to insulin resistance, dyslipidemia, and systemic inflammation). Elevated visceral fat is strongly associated with elevated levels of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), all of which are major contributors to atherosclerosis and CVD. While weight loss can improve lipid profiles, excessive loss of lean body mass (LBM) during weight loss is undesirable, as LBM is essential for maintaining metabolic health, functional capacity, and resting energy expenditure. Maintaining LBM while prioritizing fat reduction is crucial for optimizing metabolic outcomes, improving lipid metabolism, and maintaining long-term weight management. Pharmacological interventions that not only promote fat loss but also maintain or enhance LBM can provide greater cardiometabolic benefits compared to conventional weight loss methods.

[0007] Excess weight is also frequently associated with dyslipidemia, characterized by elevated levels of total cholesterol, triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c). This dyslipidemia spectrum significantly increases the risk of atherosclerosis, coronary artery disease, and other cardiovascular complications. Elevated triglycerides and LDL-c contribute to plaque formation, endothelial dysfunction, and systemic inflammation, and also exacerbate cardiovascular disease risk. While weight loss alone can lead to modest lipid improvements, pharmacological interventions that directly target both weight loss and lipid dyslipidemia can provide superior benefits in reducing the risk of cardiovascular disease in overweight and obese individuals.

[0008] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with moderate weight loss at approved doses, and these agents have become a treatment option for overweight patients. GLP-1RAs exert central effects on appetite and food intake, while GCGR agonists (GCGRAs) drive increased energy expenditure and lipid oxidation in animal models and humans. It has been shown that GCGRAs and GLP-1RAs have synergistic effects in driving greater weight loss compared to GLP-1RAs alone. GCGRAs also enhance lipolysis and inhibit hepatic lipogenesis, providing additional pathways for obesity-related conditions such as reduced hepatic steatosis, and / or providing regression or improvement in non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) (both conditions are associated with overweight, and especially obesity). However, no effect of such agonists on cardiovascular risk factors such as serum lipid levels or proportions has been shown.

[0009] Dual agonists combine GCGRA and GLP-1RA in the same molecule. In obese nonhuman primates, long-term administration of GLP-1R / GCGR dual agonists resulted in greater weight loss and improved glucose tolerance compared to GLP-1RA monoagonal administration. Clinical studies of cotadutide (a GLP-1 / GCGR dual agonist with a 5:1 GLP-1 glucagon activity bias) showed an impressive 39% reduction in hepatic steatosis within just 6 weeks, and a greater improvement in NASH-related alanine aminotransferase (ALT) reduction than liraglutide alone. However, the weight loss with cotadutide administration over 26 weeks was comparable to that with liraglutide (5.4% vs. 5.5%), suggesting that the 5:1 ratio is acceptable for hepatic steatosis reduction but suboptimal for weight loss. Balanced (1:1) agonists have been shown to be associated with greater weight loss and metabolic effects than biased ratios, with the biased ratio favoring one agonist over the other. A recent study of the balanced dual agonist JNJ 64565111 achieved an impressive 8% weight loss in just 12 weeks (NCT03586830). However, it is unclear whether the observed weight loss is associated with any CV disease-related factors (e.g., high cholesterol, triglycerides, LDL and VLDL particle concentration and / or diameter, and other relevant parameters).

[0010] Unfortunately, GLP-1RAs, as well as GLP-1-biased dual receptor agonists based on GLP-1R and GLP-1, are associated with a high proportion of nausea, vomiting, and diarrhea. These agents also require titration over a long period to reduce side effects, thus necessitating agents with improved tolerability and dosing regimens.

[0011] Therefore, there remains a need for convenient administration at therapeutic doses (e.g., weekly rather than daily) to reduce body weight and / or pathogenic plasma lipids for the prevention and / or treatment of metabolic disorders, including obesity, type 2 diabetes, and CV disease-related disorders, which do not induce or exacerbate gastrointestinal side effects at therapeutic doses. The compounds and methods presented in this paper offer a solution to such problems and have been shown in particular to have beneficial effects on body weight and serum lipid levels, both of which are factors associated with CV disease.

[0012] Overview of Public Content This document describes methods for treating long-term weight management and / or lowering serum lipids. In embodiments, this document provides methods for treating long-term weight management in humans with a corresponding need, comprising administering once weekly to the human a therapeutically effective amount of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product at least 80% identical to the peptide of SEQ ID NO:1, and wherein the human with the corresponding need has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea. In some embodiments, the treatment also lowers serum lipids.

[0013] In some embodiments, this document provides a method for long-term weight management in treating a human with a corresponding need, comprising administering, once weekly, a therapeutically effective dose of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product at least 80% identical to the peptide of SEQ ID NO:1, and wherein the treatment also reduces serum lipids. In some embodiments, the human with a corresponding need has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea.

[0014] In some embodiments, the peptide product is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the peptide of SEQ ID NO:1. In an exemplary embodiment, the peptide product is 100% identical to the peptide of SEQ ID NO:1.

[0015] In exemplary embodiments, this document provides a pemvidutide formulation and its use for inducing weight loss in humans, comprising administering a therapeutically effective dose of at least 1.2 mg and up to 2.4 mg of pemvidutide once weekly to a human subject with appropriate need for at least 48 weeks. This document also provides a pemvidutide formulation and its use for lowering serum lipids in humans, comprising administering a therapeutically effective dose of at least 1.2 mg and up to 2.4 mg of pemvidutide once weekly to a human subject with appropriate need for at least 48 weeks. In some preferred embodiments, this disclosure provides a method of weight loss comprising administering a therapeutically effective dose of at least 1.2 mg and up to 2.4 mg of pemvidutide once weekly to a human subject with appropriate need for at least 48 weeks, optionally wherein the subject has a body mass index (BMI kg / m²) greater than or equal to 25. 2(); are overweight, with subjects having a BMI > 27 kg / m². 2 Or obese, with a BMI > 30 kg / m². 2 .

[0016] In embodiments, this document provides a method for treating and reducing serum lipids in humans with a corresponding need, comprising administering, once weekly, a therapeutically effective dose of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1. In some embodiments, the human with a corresponding need has one or more comorbidities selected from obesity, cardiovascular disease, hypertension, dyslipidemia, dysglycemia, type 2 diabetes, and obstructive sleep apnea.

[0017] In an exemplary embodiment, the pharmaceutical dosage form comprises about 0.025%-0.5% (w / w) polysorbate 20, about 0.2%-0.5% (w / w) arginine, and about 3%-6% (w / w) mannitol in water (pH 7.7±0.1). In some embodiments, the pharmaceutical dosage form comprises about 0.2% (w / w) polysorbate 20, about 0.348% (w / w) arginine, and about 4.260% (w / w) mannitol in water (pH 7.7±0.1).

[0018] In an exemplary embodiment, the pharmaceutical dosage form is selected from pharmaceutical formulations comprising: a) a peptide product (2.4 mg / mL; 0.24% (w / w)), mannitol (42.6 mg / mL, 4.26% (w / w)), arginine (3.48 mg / mL; 0.348% (w / w)), and polysorbate 20 (2 mg / mL; 0.2% (w / w)) in sterile water; b) a peptide product (1.8 mg / mL; 0.18% (w / w)), mannitol (42.6 mg / mL, 4.26% (w / w)), arginine (3.48 mg / mL; 0.348% (w / w)), and polysorbate 20 (2 mg / mL; 0.2% (w / w)) in sterile water. mg / mL; 0.2% (w / w)); or c) peptide products in sterile water (1.2 mg / mL, 0.12% (w / w)), mannitol (42.6 mg / mL, 4.26% (w / w)), arginine (3.48 mg / mL; 0.348% (w / w)), and polysorbate 20 (2 mg / mL; 0.2% (w / w)).

[0019] Other implementation schemes are also envisioned, as will be understood by those skilled in the art. Brief description of the attached diagram Figure 1 The illustration shows the management of subjects in a Phase II clinical trial.

[0021] Figure 2 The figure illustrates the baseline characteristics of subjects in a Phase II clinical trial.

[0022] Figure 3 The relative weight loss achieved by 2.4 mg pemvidutide at week 48 is shown. p < 0.001, compared to placebo; repeated measures pooled model (MMRM). See Example 3.

[0023] Figure 4 The sustained weight loss achieved by 2.4 mg pemvidutide at week 48 is shown, with a near-linear trajectory of weight loss at 48 weeks for 2.4 mg.

[0024] Figure 5 The study showed the absolute weight loss achieved by 2.4 mg pemvidutide at week 48. p < 0.001, compared to placebo (MMRM). See Example 3.

[0025] Figure 6 The study showed that most participants lost >15% of their body weight by week 48. p<0.005; p<0.001; p<0.0001, compared to placebo (CMH) Cochran-Mantel-Haenszel.

[0026] Figure 7 The study showed a robust weight loss (placebo) at week 48. Figure 7 A), 1.2 mg pemvidutide ( Figure 7 B), 1.8 mg pemvidutide ( Figure 7 C) and 2.4 mg pemvidutide ( Figure 7 D)).

[0027] Figure 8The study demonstrates a significant reduction in BMI at week 48 compared to baseline for each of the three doses (1.2 mg, 18 mg, and 2.4 mg). 49% of subjects receiving the 2.4 mg dose achieved a Grade 1 reduction in BMI; 29% achieved a Grade 2 reduction; and 48% of subjects receiving the 2.4 mg dose who were obese at baseline were no longer obese by the end of treatment. Grade 1 obesity (BMI 30–35); Grade 2 obesity (BMI 35–40); and Grade 3 obesity (BMI > 40) were defined as follows: Grade 1 obesity (BMI 30–35); Grade 2 obesity (BMI 35–40); and Grade 3 obesity (BMI > 40).

[0028] Figure 9 This showed a robust reduction in serum lipids (triglycerides, total cholesterol, LDL, and VLDL) at week 48. p<0.05; p<0.005; p<0.001, compared to placebo (ANCOVA; analysis of covariance).

[0029] Figure 10 The study showed that in subjects with elevated baseline levels, triglycerides ( ) were significantly lower at week 48. Figure 10 A) Total cholesterol ( Figure 10 B), LDL cholesterol ( Figure 10 C) is reduced even more. p<0.05; p<0.005; p < 0.001, compared to placebo (ANCOVA). See Example 3.

[0030] Figure 11 Improvement in blood pressure was observed at week 48. Figure 11 A), without a clinically significant increase in heart rate ( Figure 11 B).

[0031] Figure 12 This shows the maintenance of glycemic homeostasis (fasting blood glucose) from baseline at week 48. Figure 12 A) HbA1c ( Figure 12 B)).

[0032] Figure 13 An overview of adverse events (AEs) is provided.

[0033] Figure 14 The ratio of lean body mass loss to total weight loss (lean body mass loss + fat mass loss) is shown.

[0034] Figure 15A The study compared the lean body mass reduction rate of pemvidutide with that of telpolide, retaliglutide, and semaglutide, with pemvidutide showing that only 21.9% of the weight loss came from lean body mass.

[0035] Figure 15B and Figure 15C The reduction in subcutaneous and visceral fat is shown for each of the placebo, 1.2 mg, 1.8 mg, and 2.4 mg doses of pemvidutide, with a greater percentage reduction in visceral fat (a risk factor for cardiovascular disease) compared to subcutaneous fat. See Example 4.

[0036] Figure 16 The data is presented by subject age (under 60 years old, N=38). Figure 16 A); 60 years and older, N=12 ( Figure 16 The proportion of lean body mass loss to total weight loss, as defined in section B), indicates that the proportion of lean body mass loss is lower in older subjects.

[0037] Detailed description of the publicly available information This disclosure relates to methods for long-term weight management (including weight loss and / or maintaining weight loss) in treating humans with appropriate needs, comprising administering, once weekly, a therapeutically effective amount of a pharmaceutical dosage form comprising the peptide or peptide product of this disclosure. In embodiments, the human with appropriate needs has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea. In some embodiments, the treatment also reduces pathological serum lipids (e.g., LDL or VLDL). Therefore, this disclosure also relates to methods for treating humans with appropriate needs to reduce serum lipids, comprising administering, once weekly, a therapeutically effective amount of a pharmaceutical dosage form comprising the peptide or peptide product of this disclosure.

[0038] The applicant of this document demonstrates that the peptide product of this disclosure (e.g., SEQ ID NO:1) reduces body weight, comprising a therapeutically effective pharmaceutical dosage form administered to humans once weekly, the pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1. See Example 3 and Figures 3-8 The peptide products disclosed herein are intended for use in humans with comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea. See also... Figure 1 and Figure 2The applicant of this document also demonstrates that the peptide product of this disclosure (e.g., SEQ ID NO:1) reduces serum lipids, including a therapeutically effective pharmaceutical dosage form administered to humans once weekly, the pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product at least 80% identical to the peptide of SEQ ID NO:1. See Example 3 and... Figure 9 and Figure 10 Therefore, this document provides a method for treating long-term weight management using peptides or peptide products of this disclosure, wherein the method reduces weight and / or serum lipids in humans who are obese or overweight and have one or more comorbidities (i.e., "humans in need").

[0039] This disclosure relates to pemvidutide (a preferred "dual agonist peptide"), pharmaceutical dosage forms comprising the peptide, and methods of using the peptide. As a dual agonist peptide, pemvidutide has an affinity for both glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), and in a preferred embodiment, has approximately equal affinity for both GLP-1R and GCGR, which can be determined using cellular assays. In a preferred embodiment, this disclosure provides a method of using pemvidutide (e.g., preferably a pharmaceutical dosage form comprising SEQ ID NO:1), which, upon administration to humans, induces weight loss in humans. In some embodiments, the human is overweight or obese (e.g., with a body mass index of at least about 25, ranging from at least 25 to at least 40), and has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea. In a preferred embodiment, administration of pemvidutide, as disclosed herein, results in weight loss and / or a reduction in waistline (“waist circumference”) measurements. In a preferred embodiment, the reduction in weight loss and / or waist circumference measurements is significant, as measured in untreated or control (e.g., vector-treated) individuals and / or populations. In some embodiments, this disclosure provides pharmaceutical dosage forms configured to reduce pathogenic plasma lipid mediators. As used herein, “pathogenic” serum lipid mediators include, but are not limited to, the following reactive lipid classes: malondialdehyde (MDA), isolevuglandins (IsoLG), methylglyoxal (MGO), 4-oxononal (ONE), and 4-hydroxynonenal (HNE). Oxidized phospholipids include 1-palmitoyl-2-oxovaleroyl-sn-glycerol-3-phosphocholine (POVPC), 1-O-alkyl-2-azeloyl-sn-glycerol-3-phosphocholine (azPAF), 1-(palmitoyl)-2-(5-keto-6-octen-diacyl)phosphatidylcholine (KOdiA-PC), 1-palmitoyl-2-F2-isoprostan-sn-glycerol-3-phosphocholine (F2IsoP-PC), and 1-palmitoyl-2-(5,6)-epoxyisoprostan E2-sn-glycerol-3-phosphocholine (PEIPC). In some embodiments, pharmaceutical dosage forms containing pemvidutide are administered once weekly at a therapeutically effective dose to reduce serum lipids, including total cholesterol, triglycerides, LDL, and / or VLDL.

[0040] In one embodiment, the pharmaceutical dosage form disclosed herein comprises the peptide product of this disclosure, about 0.025%-0.5% (w / w) polysorbate 20, about 0.2%-0.5% (w / w) arginine, and about 3%-6% (w / w) mannitol in water (pH 7.7±0.1). In an exemplary embodiment, the pharmaceutical dosage form disclosed herein comprises SEQ ID NO:1, about 0.2% (w / w) polysorbate 20, about 0.348% (w / w) arginine, and about 4.260% (w / w) mannitol in water (pH 7.7±0.1).

[0041] In some embodiments, the peptide product of this disclosure is administered once weekly at a therapeutically effective dose of at least 1.2 mg and at most 2.4 mg for approximately 48 weeks or longer. In some embodiments, a steady-state therapeutic dose is reached after a dose escalation period lasting approximately 2 weeks, 3 weeks, or 4 weeks, followed by administration for approximately 48 weeks. This is a preferred titration prior to administration of the 2.4 mg once-weekly dose.

[0042] In some embodiments, this disclosure provides pharmaceutical dosage forms configured to reduce weight (including for long-term weight management and treatment of related comorbidities). In some embodiments, this disclosure provides pharmaceutical dosage forms configured to induce weight loss and reduce pathogenic serum lipid mediators for the treatment of obesity (e.g., long-term weight management) and / or for the treatment of cardiovascular (CV)-related risk factors.

[0043] As used herein, the terms “treat,” “treated,” “treatment,” or “treating” mean both therapeutic and preventative measures aimed at alleviating (reducing) an undesirable physical condition, disorder, or disease, or achieving a beneficial or desired clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; reduction of the severity of the condition, disorder, or disease; stabilization (i.e., non-deterioration) of the condition, disorder, or disease; delay of the onset of the condition, disorder, or disease or ablation of its progression; improvement or remission of the condition, disorder, or disease (whether partial or complete), whether detectable or undetectable; improvement of at least one measurable physical parameter (not necessarily perceptible to the patient); or enhancement or improvement of the condition, disorder, or disease. Treatment includes side effects that elicit a clinically significant response without excessive levels. Treatment also includes prolongation of survival relative to expected survival without treatment. Therefore, "treatment for long-term weight management" means reducing or improving any primary or secondary symptoms (including, but not limited to, visceral fat, blood pressure, and serum lipids) associated with being overweight (e.g., obese or overweight) or other conditions described herein. Therefore, "treatment for lowering serum lipids" means reducing or improving any primary or secondary symptoms associated with elevated pathogenic serum lipids such as total cholesterol, triglycerides, LDL, and / or VLDL.

[0044] In some embodiments, this document provides a method for reducing weight (e.g., for treating long-term weight management), comprising administering once weekly to a human subject with appropriate need a therapeutically effective dose of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product at least 80% identical to the peptide of SEQ ID NO:1. In some embodiments, the treatment lasts for at least 48 weeks. In some embodiments, the human subject with appropriate need has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea. In some other embodiments, this document provides a method for reducing human serum lipids, comprising administering once weekly to a human subject with appropriate need a therapeutically effective dose of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product at least 80% identical to the peptide of SEQ ID NO:1. In some embodiments, the peptide product is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the peptide of SEQ ID NO:1. In an exemplary embodiment, the peptide product is 100% identical to the peptide of SEQ ID NO:1 (i.e., pemvidutide).

[0045] pemvidutide, present in pharmaceutical formulation and comprising a synthetic peptide (SEQ ID NO:1), contains naturally occurring amino acids and is a chimeric analog of two natural hormones, GLP-1 and glucagon, having predominantly glucagon residues at the N-terminus and predominantly GLP-1 residues at the C-terminus. See U.S. Patent No. 9,856,306, which is incorporated herein by reference. pemvidutide also incorporates a non-proteinogenic amino acid, 2-aminoisobutyric acid, an amide bond (lactam bridge) in the amino acid side chain, and a surfactant side chain comprising a glucuronic acid linked to an octadecane fatty acid side chain. The surfactant side chain exhibits slowed entry into circulation and can form micelles after subcutaneous (SC) injection. A lower maximum concentration (Cmax) associated with slower entry is observed. maxThis can lead to fewer GI side effects and better tolerability. This latter feature also enhances binding to plasma proteins and improves metabolic stability, extending the half-life (t1 / 2). Pemvidutide is designed to provide a co-agonist with equivalent (1:1) activity (approximately 40 pM and 100% activity) against both receptors. Compositions containing pemvidutide have been administered to humans at various doses using standard techniques and have been found not to induce side effects such as nausea, vomiting, diarrhea, abdominal pain, and / or constipation. See U.S. Patent Publication No. 2021 / 0290732 and PCT Publication No. WO 2022 / 125598, each incorporated herein by reference.

[0046] SEQ ID NO:1 has the following amino acid sequence: 1 His- 2 Aib- 3 Gln- 4 Gly- 5 Thr- 6 Phe- 7 Thr- 8 Ser- 9 Asp- 10 Tyr- 11 Ser- 12 Lys- 13 Tyr- 14 Leu- 15 Asp- 16 Glu - 17 Lys # - 18 Ala- 19 Ala- 20 Lys - 21 Glu- 22 Phe- 23 Ile- 24 Gln- 25 Trp- 26 Leu- 27 Leu- 28 Gln- 29 Thr-NH2, in The indicator shows that a lactam bridge is formed between Glu16 and Lys20, and 17Lys# indicates the attachment site of glucuronic acid C-18-COOH (“1-(17-carboxyheptadecoxy)-β-D-glucuronic acid”). In a different manner, SEQ ID NO:1 is a peptide amide consisting of 29 amino acid residues and a glucuronic acid / C18 diacid moiety attached to 17Lys, wherein... 16 Glu and 20 The side chains of Lys form intramolecular rings as shown below: In embodiments, a pharmaceutical formulation of SEQ ID NO:1 (referred to herein as pemvidutide) in an aqueous buffer solution is provided herein. pemvidutide comprises an amino acid side chain amide bond (lactam bridge) and a surfactant side chain comprising a glucuronic acid linked to a fatty acid side chain. The side chain comprises a hydrophilic sugar group and a hydrophobic alkyl chain portion covalently attached to the peptide via a linker amino acid. The synthesis of SEQ ID NO:1 is described in Example 1. In some embodiments, the dual agonist peptide may comprise one or more conserved substituted amino acids as described herein. In a preferred embodiment, SEQ ID NO:1 may comprise one or more conserved substituted amino acids, but preferably not at amino acid residues 16, 17, or 20, to provide a pemvidutide derivative. A peptide product 100% identical to SEQ ID NO:1 is provided herein. In alternative embodiments, the peptide product is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the peptide of SEQ ID NO:1. In the embodiments, the peptide product is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the peptide of SEQ ID NO:1. In the embodiments, a method is provided herein in which the peptide product, which is at least 95% identical to SEQ ID NO:1, is administered to a human in need of the pharmaceutical formulation of this disclosure.

[0047] A “peptide” (e.g., a dual agonist peptide) comprises two or more natural and / or non-natural amino acid residues typically linked via peptide bonds. Such amino acids may include naturally occurring structural variants, naturally occurring non-proteinogenic amino acids, and / or non-natural analogs of synthetic natural amino acids. The terms “peptide” and “polypeptide” are used interchangeably herein. Peptides include short peptides (about 2–20 amino acids), medium-length peptides (about 21–50 amino acids), and long peptides (> about 50 amino acids, also referred to as “proteins”). In some embodiments, the peptide product comprises a surfactant moiety covalently and stably attached to a peptide having no more than about 50, 40, or 30 amino acids. For example, synthetic peptides can be synthesized using an automated peptide synthesizer. Peptides can also be recombinantly generated in cells expressing a nucleic acid sequence encoding the peptide. Conventional notation is used herein to describe peptide sequences: the left-hand end of a peptide sequence is an amino (N) terminus, and the right-hand end is a carboxyl (C) terminus. Standard single-letter and three-letter abbreviations for common amino acids are used herein. Although the abbreviations used in the amino acid sequences disclosed herein represent L-amino acids, the corresponding D-isomers can generally be used at any position (e.g., to resist protein hydrolysis) unless otherwise specified as D-amino acids or DL-amino acids or the amino acid is achiral. Other amino acid abbreviations used herein include: Aib = α-aminoisobutyric acid (or 2-methylalanine or Cα-methylalanine); Xaa: any amino acid, usually explicitly defined in the formula.Other amino acid abbreviations that may be used as described herein include: Ac3c = 1-aminocyclopropane-1-carboxylic acid; Ac4c = 1-aminocyclobutane-1-carboxylic acid; Ac5c = 1-aminocyclopentane-1-carboxylic acid; Ac6c = 1-aminocyclohexane-1-carboxylic acid; Aib = α-aminoisobutyric acid (or 2-methylalanine or Cα-methylalanine); Bip = 3-(biphenyl-4-yl)alanine; Bip2Et = 3-(2'-ethylbiphenyl-4-yl)alanine; Bip2EtMeO = 3-(2'-ethyl-4'-methoxybiphenyl-4-yl)alanine; Cit = citrulline; Deg = 2,2-diethylglycine; Dmt = (2,6-dimethyl)tyrosine; 2FPhe = (2-fluorophenyl)alanine; 2FMePhe or 2FaMePhe = Cα-methyl-(2-fluorophenyl)alanine; hArg = high arginine; MeLys or aMeLys = Cα-methyllysine; MePhe or aMePhe = Cα-methylphenylalanine; MePro or aMePro = Cα-methylproline; Nal1 or Nal(1) = 3-(1-naphthyl)alanine; Nal2 or Nal(2) = 3-(2-naphthyl)alanine; Nle = leucine; Orn = ornithine; and Tmp = (2,4,6-trimethylphenyl)alanine; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), and the Tic-Phe dipeptide moiety (designated as Tic-Ψ[CFl2-NFl]-Ψ-Phe) with reduced amide bonds between residues has the following structure: Unless otherwise specifically stated or clearly indicated by the context, this disclosure covers any and all forms of dual agonist peptides that can be produced, whether they are synthetically produced (e.g., using a peptide synthesizer) or cellularly produced (e.g., by recombinant synthesis). Such forms of dual agonist peptides (i.e., pemvidutide derivatives) may contain one or more modifications that can be performed during the synthesis or cellular production process of the peptide, such as one or more post-translational modifications, whether or not said one or more modifications are intentional. Dual agonist peptides may have the same type of modification at two or more different positions, and / or may have two or more different types of modifications. Modifications that can be performed during the synthesis or cellular production process of dual agonist peptides include chemical and post-translational modifications, including but not limited to glycosylation (e.g., N-linked and O-linked glycosylation), lipidation, phosphorylation, sulfation, acetylation (e.g., N-terminal acetylation), amidation (e.g., C-terminal amidation), hydroxylation, methylation, formation of intramolecular or intermolecular disulfide bonds, formation of lactams between two side chains, formation of pyroglutamic acid, and ubiquitination. Dual agonist peptides can have one or more modifications anywhere, such as an N-terminus, a C-terminus, one or more amino acid side chains, or the dual agonist peptide backbone, or any combination thereof. In some embodiments, the dual agonist peptide is acetylated at the N-terminus and / or has a carboxamide (-CONH2) group at the C-terminus, which can increase the stability of the dual agonist peptide.

[0048] Possible modifications of SEQ ID NO:1 also include the deletion of one or more amino acids, the addition / insertion of one or more natural or / and non-natural amino acids, or substitution with one or more natural or / and non-natural amino acids, or any combination or all thereof. Substitutions may be conserved or non-conserved. Such modifications may be intentional, such as via site-directed mutagenesis or in the chemical synthesis of the dual agonist peptide, or may be accidental, such as via mutations occurring in the host cell that produces the dual agonist peptide or errors caused by PCR amplification. Non-natural amino acids may have the same chemical structure as their natural counterparts but with D stereochemistry, or they may have different chemical structures and D or L stereochemistry. Non-natural amino acids may be used, for example, to promote α-helix formation and / or increase the stability of the dual agonist peptide (e.g., resistance to proteolytic degradation). A dual agonist peptide having one or more modifications relative to the reference dual agonist peptide may be referred to as an “analog” or “variant” of the reference dual agonist peptide, as appropriate. “Analogs” generally retain one or more of the essential properties of the reference dual agonist peptide (e.g., receptor binding, activation of a receptor or enzyme, inhibition of a receptor or enzyme, or other biological activities). The “variant” may or may not retain the biological activity of the reference dual agonist peptide, and / or may have different biological activities. Preferably, such a variant maintains its ability to act as an agonist of GLP-1R and GCGR, and in a more preferred embodiment, has approximately equal affinity for GLP-1R and GCGR. In some embodiments, the analogue or variant of the reference peptide has a different amino acid sequence than the reference dual agonist peptide.

[0049] The term "conservative substitution" refers to the substitution of an amino acid in a dual agonist peptide with a functionally, structurally, or chemically similar natural or non-natural amino acid. In some embodiments, the following groups each contain natural amino acids that are conservedly substituted for each other: 1) glycine (Gly / G), alanine (Ala / A); 2) isoleucine (Ile / I), leucine (Leu / L), methionine (Met / M), valine (Val / V); 3) phenylalanine (Phe / F), tyrosine (Tyr / Y), tryptophan (Trp / W); 4) serine (Ser / S), threonine (Thr / T), cysteine ​​(Cys / C); 5) asparagine (Asn / N), glutamine (Gln / Q); 6) aspartic acid (Asp / D), glutamic acid (Glu / E); and 7) arginine (Arg / R), lysine (Lys / K), histidine (His / H). In another embodiment, the following groups each contain naturally occurring amino acids that are conservatively substituted for each other: 1) Nonpolar: Ala, Val, Leu, Ile, Met, Pro (proline / P), Phe, Trp; 2) Hydrophobic: Val, Leu, Ile, Phe, Trp; 3) Aliphatic: Ala, Val, Leu, Ile; 4) Aromatic: Phe, Tyr, Trp, His; 5) Uncharged polar or hydrophilic: Gly, Ala, Pro, Ser, Thr, Cys, Asn, Gln, Tyr; 6) Aliphatic containing hydroxyl or thiol groups: Ser, Thr, Cys; 7) Amide-containing: Asn, Gln; 8) Acidic: Asp, Glu; 9) Basic: Lys, Arg, His; and 10) Small: Gly, Ala, Ser, Cys. In other embodiments, amino acids may be grouped into conserved substitutions as listed below: 1) hydrophobic: Val, Leu, Ile, Met, Phe, Trp; 2) aromatic: Phe, Tyr, Trp, His; 3) neutral hydrophilic: Gly, Ala, Pro, Ser, Thr, Cys, Asn, Gln; 4) acidic: Asp, Glu; 5) basic: Lys, Arg, His; and 6) residues affecting main chain orientation: Pro.

[0050] Examples of non-natural or non-proteinogenic amino acids include, but are not limited to, alanine analogues (e.g., α-ethyl Gly [α-aminobutyric acid or Abu], α-n-propyl Gly [n-valine or Nva], α-tert-butyl Gly [Tbg], α-vinyl Gly [Vg or Vlg], α-allyl Gly [Alg], α-propynyl Gly [Prg], 3-cyclopropyl Ala). [Cpa] and Aib), leucine analogs (e.g., ortholeucine, Nle), proline analogs (e.g., α-MePro), phenylalanine analogs (e.g., Phe(2-F), Phe(2-Me), Tmp, Bip, Bip(2'-Et-4'-OMe), Nal1, Nal2, Tic, α-MePhe, α-MePhe(2-F) and α-MePhe(2-Me)), tyrosine analogs (e.g., Dmt and α-MeTyr), serine analogs (e.g., homoserine [isothreonine or hSer]), glutamine analogs (e.g., Cit), arginine analogs (e.g., hArg, N,N'-g-dialkyl-hArg), lysine analogs (e.g., homolysine [hLys], Orn and α-MeLys), α,α-disubstituted amino acids (e.g., Aib, α,α-diethylGly). [Deg], α-cyclohexylAla[2-Cha], Ac3c, Ac4c, Ac5c, and Ac6c), and other non-natural amino acids disclosed in A. Santoprete et al., Pept. Sci., 17:270-280 (2011). α,α-disubstituted amino acids can provide conformational restriction and / or α-helical stability. Reduced amide bonds between two residues (such as in, for example, Tic-Ψ[CFl2-NFl]-Ψ-Phe) increase protease tolerance and can also, for example, alter receptor binding. This disclosure covers all pharmaceutically acceptable salts of dual agonist peptides, including salts with a positive net charge, salts with a negative net charge, and salts with no net charge.

[0051] In some embodiments, for example, the dual agonist peptide can be associated with sugars, such as in pharmaceutically acceptable compositions or lyophilized products. Sugars include monosaccharides, disaccharides, and oligosaccharides (e.g., trisaccharides, tetrasaccharides, etc.). Reducing sugars exist in a balanced manner in cyclic and open-chain forms, generally favoring the cyclic form. Functionalized sugars of the surfactant moiety have functional groups suitable for forming stable covalent bonds with the amino acids of the dual agonist peptide.

[0052] The term "pharmaceuticalally acceptable" refers to a substance (e.g., an active ingredient or excipient) suitable for use in contact with the tissues and organs of a subject without excessive irritation, allergic reactions, immunogenicity, or toxicity, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. A pharmaceutically acceptable excipient or carrier of a pharmaceutical composition is also compatible with the other components of the composition. In one embodiment, pemvidutide (or a derivative thereof) may be formulated into a pharmaceutically acceptable composition comprising polysorbate 20 (e.g., about 0.2% (w / w)) in distilled (DI) water; optionally, methylparaben (e.g., about 0.300% (w / w)); arginine (about 0.348% (w / w)); and mannitol (e.g., about 4.260% (w / w)).

[0053] The term "therapeuticly effective amount" refers to an amount of a compound, when administered to a subject, such that, at least in a portion of the subject taking the compound, it is sufficient to prevent, reduce the risk of development of, delay the onset of, slow the progression of, or cause remission of, the medical condition, or to alleviate, to some extent, the medical condition or one or more symptoms or complications thereof. The term "therapeuticly effective amount" also refers to an amount of a compound sought by a physician or clinician sufficient to elicit a biological or medical response in cells, tissues, organs, or humans.

[0054] This disclosure also provides pharmaceutical compositions comprising the dual agonist peptide product described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition comprises a therapeutically effective amount of the peptide product or a suitable fraction thereof. The composition may optionally comprise additional therapeutic agents. In some embodiments, the peptide product is at least about 90%, 95%, or 98% pure. Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials, and media. Non-limiting examples of excipient types include liquid and solid fillers, diluents, binders, lubricants, flow aids, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickeners, solvents, isotonics, buffers, pH adjusters, absorption delay agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavoring agents, colorants, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. For example, conventional media and carriers include, but are not limited to, oils (e.g., vegetable oils such as olive oil and sesame oil), aqueous solvents (e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]), and isotonic solutions (e.g., Ringer's solution)), and organic solvents (e.g., dimethyl sulfoxide and alcohols [e.g., ethanol, glycerol, and propylene glycol]). Unless any conventional excipient or carrier is incompatible with the peptide product, this disclosure covers the use of conventional excipients and carriers in formulations containing peptide products. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th edition, Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd edition, Ash and Ash, eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-formulation and Formulation, Gibson, ed., CRC Press (Boca Raton, Florida) (2004).

[0055] In the embodiments, the pharmaceutical formulation comprises the peptide product of this disclosure and about 0.025%-0.5% (w / w) polysorbate 20, about 0.2%-0.5% (w / w) arginine, and about 3%-6% (w / w) mannitol in water (e.g., deionized and / or sterilized) (pH 7.7±0.1); optionally, about 0.2% (w / w) polysorbate 20, about 0.348% (w / w) arginine, and about 4.260% (w / w) mannitol in water (pH 7.7±0.1). In some embodiments, the pharmaceutical formulation comprises SEQ ID NO:1 (or at least 80% of the same peptide product as SEQ ID NO:1) and about 0.2% (w / w) polysorbate 20, about 0.348% (w / w) arginine, and about 4.260% (w / w) mannitol in water (pH 7.7 ± 0.1). In some embodiments, the pharmaceutical formulation comprises SEQ ID NO:1 (or at least 80% of the same peptide product as SEQ ID NO:1) and is configured for subcutaneous (SC) administration of a weekly therapeutically effective dose.

[0056] In some embodiments, the peptide product of this disclosure is provided at a therapeutically effective dose of 1.2 mg / mL to 2.4 mg / mL. In some embodiments, the therapeutic formulation comprises, in sterile water, the peptide product (2.4 mg / mL; 0.24% (w / w)); mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)). In some embodiments, the therapeutic formulation comprises, in sterile water, the peptide product (1.8 mg / mL; 0.18% (w / w)); mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)). In some embodiments, the therapeutic formulation comprises, in sterile water, a peptide product (1.2 mg / mL; 0.12% (w / w)); mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)). In some embodiments, the peptide product is pemvidutide. In some embodiments, the peptide product is SEQ ID NO:1. In some embodiments, the peptide product is at least 80%, at least 85%, at least 90%, or at least 95% identical to SEQ ID NO:1.

[0057] Appropriate or suitable formulations can depend on various factors, such as the chosen route of administration. Possible routes of administration for pharmaceutical compositions comprising peptide products include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavitary, and topical) and topical (including transdermal, transmucosal, intranasal (e.g., via nasal spray or drops), ocular (e.g., via eye drops), pulmonary (e.g., via oral inhalation or nasal inhalation), sublingual, sublingual, rectal (e.g., via suppositories), and vaginal (e.g., via suppositories)). In some embodiments, the dual-agonist peptide product of the present invention is administered parenterally (e.g., subcutaneously, intravenously, or intramuscularly). In other embodiments, the peptide product is administered via oral inhalation, nasal inhalation, or inhalation. In some embodiments, the carrier is an aqueous carrier, such as in parenteral (e.g., subcutaneous, intravenous, or intramuscular) formulations. In other embodiments, the carrier is a nonaqueous-based carrier. In some embodiments, the non-aqueous carrier is a hydrofluorocarbon (HFA) or HFA-like solvent that may include submicron anhydrous α-lactose and / or other excipients, such as in formulations intended for oral inhalation, nasal inhalation, or blow-through administration.

[0058] In some implementations, the peptide product is administered parenterally via injection (e.g., subcutaneously, intravenously, or intramuscularly). Parenterical administration bypasses the highly acidic environment of the stomach, gastrointestinal (GI) absorption, and first-pass metabolism. Excipients and carriers that can be used to prepare parenteral formulations include, but are not limited to, solvents (e.g., aqueous solvents such as water, saline, physiological saline, buffered saline [e.g., PBS], balanced salt solutions [e.g., Ringer's BSS] and aqueous dextran solutions), isotonic / iso-osmotic agents (e.g., salts [e.g., NaCl, KCl and CaCl2] and sugars [e.g., sucrose]), buffers and pH adjusters (e.g., sodium dihydrogen phosphate, monobasic sodium phosphate] / di sodium hydrogen phosphate, citric acid / sodium citrate and L-histidine / L-histidine HCl), and emulsifiers (e.g., nonionic surfactants such as polysorbates [e.g., polysorbate 20 and polysorbate 80] and poloxamer [e.g., poloxamer 188]). Peptide formulations and delivery systems are discussed, for example, in AJ Banga, Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems, 3rd Edition, CRC Press (Boca Raton, Florida) (2015). Excipients may optionally include one or more substances, or any combination or all of them, that increase peptide stability, increase peptide solubility, inhibit peptide aggregation, or reduce solution viscosity. Such substances include, but are not limited to, hydrophilic amino acids (e.g., arginine and histidine), polyols (e.g., inositol, mannitol, and sorbitol), sugars (e.g., glucose (including D-glucose [dextrose]), lactose, sucrose, and trehalose), penetrants (e.g., trehalose, taurine, amino acids [e.g., glycine, sarcosine, alanine, proline, serine, β-alanine, and GABA] and betaine [e.g., trimethylglycine and trimethylamine N-oxide]), and nonionic surfactants (e.g., alkyl polysaccharides, ProTek® alkyl sugars (e.g., monosaccharides [e.g., glucose] or disaccharides [e.g., maltose or sucrose] coupled to long-chain fatty acids or corresponding long-chain alcohols), and polypropylene glycol / polyethylene glycol block copolymers (e.g., poloxamer [e.g., Pluronic™ F-68] and Genapol® PF-10 and their variants). Because such substances increase the solubility of peptides, they can be used to increase the peptide concentration in formulations.A higher peptide concentration in the formulation is particularly advantageous for subcutaneous administration, which has a limited bolus volume (e.g., <1.5 mL). Furthermore, such a substance can be used to stabilize the peptide during preparation, storage, and reconstitution of the lyophilized peptide. Exemplary parenteral formulations comprise the peptide product, mannitol, methionine, sodium thioglycolate, polysorbate 20, a pH adjuster (e.g., NaOH and / or HCl), and deionized water. Excipients suitable for use in parenteral formulations with the dual agonist peptides described herein (e.g., various combinations of excipients comprising NaCl, etc.) are well known and available to those skilled in the art.

[0059] For parenteral (e.g., subcutaneous, intravenous, or intramuscular) administration, the peptide product can be pre-prepared in a sterile solution or suspension in an aqueous solvent containing one or more excipients and can be provided in a pre-filled syringe, such as a single-use pen or a pen with a dose counter. Optionally, the peptide product can be dissolved or suspended in an aqueous solvent that may optionally contain one or more excipients prior to lyophilization (freeze-drying). Shortly before parenteral administration, the lyophilized peptide product stored in a suitable container (e.g., vial) can be reconstituted with sterile water, for example, that may optionally contain one or more excipients.

[0060] Peptide products can also be administered via other routes, such as oral administration. Oral formulations may contain peptide products known in the art and conventional excipients, as well as optional absorption enhancers, such as sodium V-[8-(2-hydroxybenzoyl)aminooctanoic acid] (SNAC). SNAC prevents enzymatic degradation via local buffering and enhances GI absorption. Oral dosage forms (e.g., tablets, capsules, or pills) may optionally have an enteric coating to protect their contents from the strong acid and proteolytic enzymes of the stomach. In some embodiments, the peptide product is delivered from a sustained-release composition. As used herein, the term "sustained-release composition" encompasses sustained-release, prolonged-release, extended-release, delayed-release, slow-release, and controlled-release compositions, systems, and devices. In some embodiments, the sustained-release composition delivers the peptide product over a period of at least about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or longer. In other embodiments, the sustained-release composition is in the form of a reservoir produced when a mixture of peptide product and polymer is injected intramuscularly or subcutaneously into a subject. In some embodiments, the polymer is or includes PEG, polylactic acid (PLA) or polyglycolic acid (PGA), or copolymers thereof (e.g., PLGA or PLA-PEG).

[0061] Pharmaceutical compositions can be presented as unit dosage forms for a single dose, wherein all active and inactive ingredients are combined in a suitable system and the components do not need to be mixed to form the composition to be administered. Unit dosage forms typically contain a therapeutically effective dose of the drug, but may also contain appropriate proportions such that multiple unit dosage forms are taken to achieve a therapeutically effective dose. Examples of unit dosage forms include tablets, capsules, or pills for oral ingestion; solutions in pre-filled syringes of single-use pens or pens with dose counters for parenteral (e.g., intravenous, subcutaneous, or intramuscular) injection; and capsules, cartridges, or blister packs pre-loaded or manually loaded into inhalers. Optionally, pharmaceutical compositions can be presented as kits in which the active ingredient, excipients, and carriers (e.g., solvents) are provided in two or more separate containers (e.g., ampoules, vials, tubes, bottles, or syringes) and need to be combined to form the composition to be administered. Kits may include instructions for storing, preparing, and administering the composition (e.g., a solution for parenteral injection). The kit may contain all active and inactive ingredients in a single dosage form, or contain active and inactive ingredients in two or more separate containers, and may include instructions for administering or using the pharmaceutical composition to treat the medical conditions disclosed herein. The kit may also include a device for delivering the composition, such as an injection pen or inhaler. In some embodiments, the kit contains a peptide product or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the peptide product or a pharmaceutically acceptable salt thereof, and instructions for administering or using the peptide product or the composition to treat the medical conditions disclosed herein, such as insulin resistance, diabetes, metabolic syndrome, cardiovascular disease, obesity (including “chronic obesity,” which means obesity lasting more than one year or causing obesity-related conditions such as, but not limited to, insulin resistance, diabetes, metabolic syndrome, and / or cardiovascular disease), or conditions associated therewith. In some embodiments, the kit also includes a device for delivering the peptide product or composition, such as an injection pen.

[0062] Treatment This document provides a method for treating long-term weight management, comprising administering a peptide product of this disclosure (e.g., SEQ ID NO:1) to a subject with appropriate need. In some embodiments, this document provides a method for treating long-term weight management in a human with appropriate need, comprising administering once weekly to the human a therapeutically effective amount of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product at least 80% identical to the peptide of SEQ ID NO:1, and wherein the human with appropriate need has comorbidities selected from one or more of cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea. In embodiments, the treatment method lowers serum lipids. In embodiments, the human with appropriate need has abnormal serum lipid levels. In some embodiments, the human with appropriate need has elevated serum triglyceride, serum cholesterol, serum LDL, and / or serum VLDL levels.

[0063] In some embodiments, this document provides a method for long-term weight management in treating a human with a corresponding need, comprising administering to the human once weekly a therapeutically effective amount of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product at least 80% identical to the peptide of SEQ ID NO:1, and wherein the treatment also reduces serum lipids. In embodiments, the human with a corresponding need has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea. As used herein, dyslipidemia is characterized by abnormally high (or low) levels of one or more serum lipids. In embodiments, dyslipidemia is selected from the group consisting of: hypercholesterolemia, hypertriglyceridemia, high / low-density lipoprotein cholesterolemia, high non-high-density lipoprotein cholesterolemia, and low / high-density lipoprotein cholesterolemia.

[0064] The term "cardiovascular-related disease" in this article refers to any disease or disorder of the heart or blood vessels (i.e., arteries and veins) or any symptoms thereof, or any disease or condition that causes or contributes to cardiovascular disease. Non-limiting examples of cardiovascular-related diseases include: acute myocardial ischemia, acute myocardial infarction, angina pectoris, arrhythmia, atrial fibrillation, arteriosclerosis, arterial fibrillation, heart failure, cardiovascular disease, chronic heart failure, chronic stable angina, congestive heart failure, coronary artery disease, coronary artery disease, deep vein thrombosis, diabetes mellitus. Mellitus, diabetic neuropathy, diastolic dysfunction in diabetic patients, edema, essential hypertension, eventual pulmonary embolism, fatty liver disease, heart disease, heart failure, homozygous familial hypercholesterolemia (HoFH), homozygous familial sitosterolemia, hypercholesterolemia, hyperlipidemia, hyperlipidemia in HIV-positive individuals, hypertension, hypertriglyceridemia, ischemic complications in unstable angina and myocardial infarction, hypotension, metabolic syndrome, mixed dyslipidemia, moderate to mild heart failure, myocardial infarction, obesity management, paroxysmal atrial / arterial fibrillation / fibrillary fibrillation / flutter. Fibrillation / fibrulation / flutter), paroxysmal supraventricular tachycardia (PSVT), particularly severe or rapid episodes of edema, platelet aggregation, primary hypercholesterolemia, primary hyperlipidemia, pulmonary hypertension, pulmonary hypertension, recurrent hemodynamically unstable ventricular tachycardia (VT), recurrent ventricular arrhythmias, recurrent ventricular fibrillation (VF), ruptured aneurysm, sitosterolemia, stroke, supraventricular tachycardia, symptomatic atrial fibrillation / flutter, tachycardia, type II diabetes, vascular disease, venous thromboembolism, ventricular arrhythmias, and other cardiovascular events.

[0065] As used herein, a "preventive" treatment for a disease or condition refers to a compound that, in a statistical sample, reduces the occurrence of a disease or condition in a treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of a disease or condition or reduces its severity relative to an untreated control sample. As used herein, the term "treatment" includes prevention of the specified condition, or improvement or elimination of the condition once identified. As used herein, the term "obesity" refers to a disease, medical condition, or disorder, and is defined as a body mass index (BMI) > 30. A BMI of 25–30 is pre-obesity (also referred to herein as "overweight"). As used herein, methods for treating long-term weight management refer to the treatment of obesity and pre-obesity.

[0066] The application of the “effective amount” of the formulations and peptide products described herein is defined as the amount effective within the dose and time period required to achieve the desired results. In one embodiment, the composition may be administered or used weekly to provide a therapeutically effective dose in the treatment of long-term weight management and also to reduce serum lipids and / or treat obesity-related comorbidities.

[0067] According to the present invention, regulating (controlling) weight can refer to reducing or increasing weight, reducing or increasing the rate of weight gain, or increasing or decreasing the rate of weight loss, and also includes actively maintaining or not significantly altering weight (e.g., in response to external or internal influences that may otherwise increase or decrease weight) (“treatment for long-term weight management”). One embodiment of the present invention relates to regulating weight by administering a pharmaceutical formulation comprising a peptide product of the present disclosure to a human with a corresponding need.

[0068] In some embodiments, the present invention relates to methods and preparations for reducing body fat mass in humans and / or reducing increases in body fat mass in humans, and more specifically, to methods and preparations for treating or improving obesity in patients at risk of or suffering from obesity or overweight. Such methods are effective in reducing body weight and / or achieving weight loss, or in improving conditions associated with overweight and / or abnormal lipid levels.

[0069] In some implementations, the corresponding human need is defined as a disease or disorder characterized by increased cholesterol accumulation in serum and / or tissues leading to pathology or having excessive cholesterol as a risk factor. Cholesterol disorders include familial hypercholesterolemia or hereditary cholesterol disorders (ICD), defects in genetic products of cholesterol metabolism (e.g., 7-α-hydroxylase), and various forms of xanthoma. Elevated serum cholesterol levels may indicate atherosclerosis, biliary cirrhosis, familial hyperlipidemia, high-cholesterol diets, hypothyroidism, myocardial infarction, nephrotic syndrome, and uncontrolled diabetes. “Excess cholesterol” means outside the typical (normal) cholesterol range. Typical cholesterol levels are below 200 mg / dL. The borderline high level is 200–239 mg / dL, and any value exceeding 240 mg / dL is considered high.

[0070] There are two types of cholesterol: HDL cholesterol (sometimes called good cholesterol) and LDL cholesterol (sometimes called bad cholesterol). "Excess cholesterol" can also be determined relative to LDL. For example, treatment is provided to humans with corresponding needs when LDL cholesterol is >100 mg / dL (e.g., the goal is to lower LDL cholesterol to <100 mg / dL), at least 130 mg / dL (e.g., the goal is to lower LDL cholesterol to below 130 mg / dL), at least 160 mg / dL (e.g., the goal is to lower LDL cholesterol to below 130 mg / dL), or at least 190 mg / dL (e.g., the goal is to lower LDL cholesterol to below 160 mg / dL).

[0071] In some embodiments, after treatment with the compositions of the present invention, for example within a time period of about 1 week to about 200 weeks, about 1 week to about 100 weeks, about 1 week to about 80 weeks, about 1 week to about 50 weeks, about 1 week to about 40 weeks, about 1 week to about 20 weeks, about 1 week to about 15 weeks, about 1 week to about 12 weeks, about 1 week to about 10 weeks, about 1 week to about 5 weeks, about 1 week to about 2 weeks, or about 1 week, the desired human subject exhibits one or more of the following: reduced weight, weight maintenance, reduced serum lipid levels (e.g., cholesterol, LDL, VLDL, or triglycerides), reduced blood pressure, and / or reduced symptoms of one or more cardiovascular diseases.

[0072] As detailed in Example 3, weekly treatment with the peptide product of this disclosure (e.g., SEQ ID NO:1) produced statistically significant weight loss in a dose-dependent manner, with participants in the 2.4 mg cohort experiencing an average weight loss of 15.6%. Not wishing to be bound by theory, the addition of glucagon to GLP-1 may provide additional weight loss due to increased energy expenditure compared to a single GLP-1R agonist (e.g., semaglutide). Sustained weight loss at week 48 suggests that the addition of glucagon may have recalibrated the metabolic set point. Weight loss of 15% or more can improve many obesity-related comorbidities, including reversal of T2DM and regression of MASH. In the 2.4 mg pemvidutide cohort, over 50% of participants experienced a weight loss of ≥15%, and 32% experienced a weight loss of ≥20%. Other comorbidities with positive outcomes when reduced or improved include cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea. Waist circumference, and extended to visceral obesity, are indicators of cardiovascular disease risk. A reduction of 5–10 cm was associated with improved serum lipid profiles and reduced diastolic blood pressure. All pemvidutide dose cohorts had a mean reduction of >6 cm, suggesting that these cardiovascular risk factors may be improved. Therefore, this article provides a method for treating long-term weight management in humans with corresponding needs, comprising administering once weekly to a human a therapeutically effective dose of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product at least 80% identical to the peptide of SEQ ID NO:1, and wherein the method also treats one or more of cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and / or obstructive sleep apnea.

[0073] As detailed in Example 3, in addition to inducing significant weight loss, pemvidutide treatment also resulted in an improved lipid profile, with significant reductions in triglycerides and total cholesterol, and a meaningful decrease in serum LDL. The glucagon agonist activity of the peptide product of the present invention provides a significant effect on serum lipids due to the well-established role of glucagon in hepatic lipid metabolism, as it reduces hepatic lipogenesis, upregulates fatty acid β-oxidation, increases LDL receptor (LDL-R) expression, and enhances mitochondrial oxidative function. The lipid reduction observed here is greater than that seen in other obesity trials involving glucagon-free, enterokinin-based single and dual agonists. The combination of GLP-1R / GCGR signaling also produced a significant reduction in visceral fat. See Figure 15.

[0074] This disclosure also provides for the use of the dual agonist peptide products described herein for the prevention and / or treatment of conditions associated with GLP1R and / or GCGR, such as, but not limited to, insulin resistance, diabetes, obesity, metabolic syndrome, and cardiovascular disease, as well as related conditions such as NASH and PCOS. In some implementations, the dual-agonist peptide product can be used to treat hyperglycemia, insulin resistance, hyperinsulinemia, prediabetes, diabetes (including type 1 and type 2 diabetes, gestational diabetes, and juvenile diabetes), diabetic complications, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, elevated blood levels of free fatty acids, obesity, metabolic syndrome, syndrome X, cardiovascular disease (including coronary artery disease), atherosclerosis, acute cardiovascular syndrome, ischemia (including myocardial ischemia and cerebral ischemia / stroke), ischemia-reperfusion injury (including myocardial and cerebral IRI), infarction (including myocardial and cerebral infarction), angina pectoris, heart failure (e.g., congestive heart failure), peripheral vascular disease, thrombosis (e.g., deep vein thrombosis), embolism (e.g., pulmonary embolism), systemic inflammation (e.g., inflammation characterized by elevated blood levels of C-reactive protein), and hypertension. Dual agonist peptides can exert their therapeutic effects through various mechanisms, including stimulating glucose-dependent insulin secretion, increasing insulin sensitivity, stimulating fat burning, and reducing weight. Dual agonist peptides can also promote, for example, pancreatic β-cell protection, cardioprotection, and wound healing.

[0075] The peptide products described herein may be used to treat other conditions associated with insulin resistance and / or obesity and / or be administered in conjunction with medications for treating said conditions. Other conditions associated with insulin resistance and / or obesity include, but are not limited to, arthritis (e.g., osteoarthritis), lower back pain, respiratory disorders (e.g., asthma, obesity-induced hypoventilation syndrome [Pickwickian syndrome], and obstructive sleep apnea), dermatological disorders (e.g., diabetic ulcers, acanthosis nigricans, cellulitis, hirsutism, erosions, and lymphedema), gastrointestinal disorders (e.g., gallstones, gastroesophageal reflux disease [GERD], and gastroparesis), gout, Cushing's syndrome (e.g., Cushing's syndrome), kidney disorders (e.g., chronic kidney disease), and liver disorders (e.g., fatty liver disease [FLD], including alcoholism). The treatment options include: seminal and non-alcoholic flak disease (FLD), neurological disorders (e.g., carpal tunnel syndrome, dementia [e.g., Alzheimer's disease and vascular dementia], paresthetoid femoral pain, migraine, and multiple sclerosis), urinary disorders (e.g., erectile dysfunction, hypogonadism, and urinary incontinence), polycystic ovary syndrome (PCOS), infertility, menstrual disorders, mood disorders (e.g., depression), and cancers (e.g., endometrial cancer, esophageal cancer, colorectal cancer, gallbladder cancer, kidney cancer, liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer, and skin cancer [e.g., melanoma] and leukemia). In some embodiments, the dual-agonist peptide product described herein is used to treat polycystic ovary syndrome (PCOS). In other embodiments, the peptide product is used to treat chronic kidney disease (CKD), also known as chronic kidney / renal failure (CKF / CRF). The most common causes of CKD are diabetes and long-term uncontrolled hypertension. In yet another embodiment, the dual-agonist peptide product described herein is used to treat fatty liver disease (FLD). In some implementations, FLD is non-alcoholic fatty liver disease (NAFLD), which should also be understood to include metabolic fatty liver disease (MFLD). In some implementations, NAFLD is non-alcoholic steatohepatitis (NASH). FLD, also known as hepatic steatosis, is characterized by excessive fat accumulation in the liver. FLD includes alcoholic fatty liver disease (AFLD) and NAFLD. Chronic alcoholism causes fatty liver due to the production of toxic metabolites such as aldehydes during the metabolism of alcohol in the liver. NAFLD is described below. FLD is associated with diabetes, obesity, and metabolic syndrome. Fatty liver can develop into cirrhosis or liver cancer (e.g., hepatocellular carcinoma [HCC]). Less than about 10% of people with cirrhotic AFLD develop HCC, but up to about 45% of people with non-cirrhotic NASH may develop HCC. HCC is the most common type of primary liver cancer in adults and occurs against a background of chronic liver inflammation.NAFLD is characterized by fatty liver, which occurs when fat, particularly free fatty acids and triglycerides, accumulates in hepatocytes (hepatic steatosis) due to factors other than excessive alcohol consumption, such as overnutrition, high calorie intake, and metabolic dysfunction (e.g., dyslipidemia and impaired glycemic control). The liver can remain fatty without interfering with liver function, but fatty liver can progress to NASH, a condition characterized by steatosis with inflammation, hepatocellular ballooning degeneration, and cell damage, with or without liver fibrosis. Fibrosis is the strongest predictor of mortality from NASH. NAFLD can be characterized by: steatosis alone; steatosis with lobular or portal inflammation, but without ballooning degeneration; steatosis with ballooning degeneration but without inflammation; or steatosis with inflammation and ballooning degeneration. NASH is the most extreme form of NAFLD. NASH is a progressive disease; approximately 20% of patients develop cirrhosis, and approximately 10% die from liver diseases such as cirrhosis or liver cancer (e.g., HCC). Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in developed countries, and NASH is projected to surpass hepatitis C as the leading cause of liver transplantation in the United States by 2020. Approximately 12%–25% of Americans have NAFLD, with NASH affecting approximately 2%–5% of them. NAFLD, including NASH, is associated with insulin resistance, obesity, and metabolic syndrome. For example, insulin resistance contributes to the progression of fatty liver to liver inflammation and fibrosis, and thus NASH. Furthermore, obesity drives and exacerbates NASH, and weight loss can alleviate NASH. Therefore, the peptide products described herein, including GLP-1 receptor (GLP1R) agonists, glucagon receptor (GCGR) agonists, and GLP1R / GCGR dual agonists, can be used to treat NAFLD, including NASH. In some embodiments, the dual agonist peptide products disclosed herein for treating conditions associated with insulin resistance and / or obesity, such as fatty liver disease, including NAFLD and NASH, are pemvidutide and / or derivatives thereof and their pharmaceutically acceptable salts.

[0076] In some embodiments, one or more dual-agonist peptides of the present invention can be used to control blood glucose while reducing one or more adverse events (i.e., unintended events that negatively impact patient and / or animal welfare). Exemplary non-limiting adverse events may include nausea, vomiting, diarrhea, abdominal pain, and / or constipation. Adverse events may also include any event known to those skilled in the art, such as those listed in industry resources and / or otherwise known to those skilled in the art (see, for example, Medical Dictionary for Regulatory Activities (MedDRA) (Pharm., Med. Transl. Med. 2018) and / or Clark, MJ Biomed. Inf., 54, April 2015, pp. 167-173). Such adverse events can be identified in humans using standard techniques commonly used in clinical trials (e.g., doctor visits, surveys / questionnaires). Compared to the frequency and / or severity of such adverse events following administration of agonists with unbalanced affinities to GLP-1R and GCGR (e.g., smegglutide), the dual agonist peptides of this disclosure (e.g., any of SEQ ID NO. 1 or its derivatives) can reduce the frequency and / or severity of such adverse events by, for example, 5%, 10%, 20%, 40%, 50%, 60%, 70%, 80%, 90%, or higher (up to 100%). In some embodiments, the dual agonist peptides of this disclosure (e.g., pemvidutide) do not cause any adverse events.

[0077] The dual-agonist peptide products of the present invention can be administered via any suitable route for the treatment of the conditions disclosed herein. Possible routes of administration of the peptide products include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavitary, and surface) and surface (including transdermal, transmucosal, intranasal (e.g., via nasal spray or drops), ocular (e.g., via eye drops), pulmonary (e.g., via oral inhalation or nasal inhalation), sublingual, sublingual, rectal (e.g., via suppositories), and vaginal (e.g., via suppositories)). In some embodiments, the peptide products are administered parenterally, such as subcutaneously, intravenously, or intramuscularly. In other embodiments, the peptide products are administered via oral inhalation, nasal inhalation, or inhalation. The therapeutically effective amount and frequency of administration of the peptide products for the treatment of the conditions disclosed herein, as well as the duration of treatment with the peptide products, can depend on various factors, including the nature and severity of the condition, the potency of the compound, the route of administration, the subject's age, weight, general health condition, sex, diet, and the subject's response to treatment, and can be determined by the treating physician. In some embodiments, the peptide product is administered parenterally (e.g., subcutaneously (sc), intravenously (iv), or intramuscularly (IM)) over a period of about one week at a dose of about 0.01 mg to about 0.1 mg, 1 mg, 5 mg, or 10 mg, or about 0.1 mg-1 mg or 1 mg-10 mg, for the treatment of the conditions disclosed herein (e.g., conditions associated with insulin resistance and / or obesity, such as NASH or NAFLD). In other embodiments, the peptide product is administered parenterally (e.g., sc, iv, or IM) over a period of about one week at a dose of about 0.1 mg-0.5 mg, 0.5 mg-1 mg, 1 mg-5 mg, or 5 mg-10 mg. In some embodiments, the peptide product is administered parenterally (e.g., subcutaneously (SC), intravenously (IV), or intramuscularly (IM)) over a period of about one week at a dose of about 0.1 mg-1 mg, or about 0.1 mg-0.5 mg or 0.5 mg-1 mg. Those skilled in the art will understand that effective doses in mice or other preclinical animal models can be scaled for humans. Thus, through allometric scaling (also known as bioscaling), the dose for a larger animal can be inferred from the dose in a mouse to obtain an equivalent dose based on the animal's body weight or body surface area.

[0078] Pemvidutide formulations may be taken substantially with food (e.g., with a meal or about 1 hour or 30 minutes before or after a meal) or substantially without food (e.g., at least 1 hour or 2 hours before or after a meal). The duration of treatment with the dual-agonist peptide product for a medical condition may be based on, for example, the nature and severity of the condition and the subject's response to treatment, and may be determined by the treating physician. In some embodiments, pemvidutide formulations are administered long-term to treat the conditions disclosed herein, such as at least about 2 months, 3 months, 6 months, 1 year, 1.5 years, 2 years, 3 years, 5 years, 10 years, or longer. Pemvidutide formulations may also be taken as needed (as required) until the clinical manifestations of the condition disappear or clinical goals are achieved, such as blood glucose levels, blood pressure, blood lipid levels, weight or body mass index, waist-to-hip ratio, or body fat percentage, or any combination thereof. If the clinical manifestations of the condition recur or clinical goals are not maintained, administration of the dual-agonist peptide product may be resumed. This disclosure provides a method of treating the medical condition described herein, comprising administering to a subject requiring treatment a therapeutically effective amount of the pemvidutide formulation described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the pemvidutide formulation described herein or a pharmaceutically acceptable salt thereof. This disclosure also provides the pemvidutide formulation described herein or a pharmaceutically acceptable salt thereof, or a composition comprising the pemvidutide formulation described herein or a pharmaceutically acceptable salt thereof, for use as a medicament. Furthermore, this disclosure provides the use of the pemvidutide formulation described herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament. Medications comprising pemvidutide may be used to treat any of the medical conditions described herein. Pemvidutide may optionally be used in combination with one or more other therapeutic agents.

[0079] Pemvidutide (e.g., as a formulation) may be administered as the sole active agent, or optionally in combination with one or more other dual-agonist peptide products and / or additional therapeutic agents, to induce weight loss and / or treat any of the conditions disclosed herein, such as insulin resistance, diabetes, obesity, metabolic syndrome, or cardiovascular disease (e.g., heart failure with preserved ejection fraction (HFpEF)), or any conditions associated therewith, such as high cholesterol, triglycerides, LDL and / or VLDL particle concentration and / or diameter, and / or other relevant parameters (e.g., serum phosphatidylethanolamine, phosphatidylcholine, lysophosphatidylethanolamine, sphingolipids, and / or lysophosphatidylcholine). In some embodiments, one or more additional therapeutic agents are selected from antidiabetic agents, antiobesity agents (including lipid-lowering agents and satiety agents), antiatherosclerotic agents, anti-inflammatory agents, antioxidants, antifibrotic agents, antihypertensive agents, and combinations thereof.Antidiabetic agents include, but are not limited to: AMP-activated protein kinase (AMPK) agonists, including biguanides (e.g., buformin and metformin); peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, including thiazolidinediones (e.g., bamaglytein, cycloglitazone, dapagliflozin, empagliflozin, lobegliflozin, neiglitazone, pioglitazone, linaglitazone, rosiglitazone, and trogliflozin), MSDC-0602K, and saroglitazar (a dual PPAR-α / γ agonist); and glucagon-like peptide-1 (GLP-1) receptor agonists, including agonistin-4. (exendin-4), abiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, smegglutide, tasglutide, CNT0736, CNT03649, HM11260C (LAPS-Exendin), NN9926 (OG9S7GT), TT401 and ZYOGl; dipeptidyl peptidase 4 (DPP-4) inhibitors, including alogliptin, anagliptin, dulagliptin, evogliptin, gigliptin, gosogliptin, linagliptin, omarigliptin, septagliptin, sitagliptin, teneligliptin, tregliptin and vildagliptin; sodium-glucose transporter 2 (SGLT2) inhibitors, including canagliflozin (which also inhibits SGLT1), dapagliflozin, empagliflozin, etaggliflozin, ruggliflozin, remogliflozin etabonate, soggliflozin (which also inhibits SGLT1), and toggliflozin; ATP-dependent K+ (KA) on pancreatic β-cells. TPChannel blockers, including meglitinides (e.g., miglitol, nateglinide, and repaglinide) and sulfonylureas {including first-generation (e.g., acesulfame potassium, amiloride, chlorpropamide, glicyclohexamide, metahexamide, tolazoline, and tolbutamide) and second-generation (e.g., glibenclamide, glyburide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glipeilide, and glipizide); insulin and its analogues, including rapid-acting insulin (e.g., insulin aspart, insulin insulinglulisine, and insulin lispro), intermediate-acting insulin (e.g., NPH insulin), and long-acting insulin (e.g., insulin degludec). (degludec), insulin detemir, and insulin glargine; and / or their analogues, derivatives, and salts. In some embodiments, the antidiabetic agent is or includes biguanides (e.g., metformin), thiazolidinediones (e.g., pioglitazone or rosiglitazone), or SGLT2 inhibitors (e.g., empagliflozin or tolagliflozin), or any combination thereof. Anti-obesity agents include, but are not limited to: appetite suppressants (anorectics), including amphetamine, dextroamphetamine, amfepramone, clobenzylrexate, masindole, phentermine (with or without topiramate), and lorcaserin; satiety promoters, including ciliary neurotrophic factor (e.g., axokine) and long-acting analogues of amylin, calcitonin, cholecystokinin (CCK), GLP-1, leptin, gastrin, pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY); and lipase inhibitors, including caulerpenyne, cetilistat, ebelactone A and ebelactone B, esterastin, lipresstatin, orlistat, percyquinin, and panclicin. AE, valilactone, and vibralactone; antihyperlipidemic agents; and their analogues, derivatives, and salts. Antihyperlipidemic agents include, but are not limited to: HMG-CoA reductase inhibitors, including statins (e.g., atorvastatin, cerivastatin, fluvastatin, mevastatin), monacolins (e.g., monacolin K (lovastatin), pitavastatin, pravastatin, rosuvastatin, and simvastatin), and flavanones (e.g., naringenin);Squalene synthase inhibitors, including lapaquistat, zaragozic acid, and RPR-107393; acetyl-CoA carboxylase (ACC) inhibitors, including anthocyanins, avenaciolides, chloroacetylated biotin, cyclodim, diclofop, haloxyfop, and soraphens (e.g., soraphen). Ala), 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), CP-640186, GS-0976, NDI-010976; 7-(4-propoxy-phenylethynyl)-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxane-heptene; N-ethyl-N'-(3-{[4-(3,3-dimethyl-1-oxo-2-oxa-7-azaspiro[4.5]dec-7-yl)piperidin-1-yl]carbonyl}-1-benzothia phen-2-yl)urea; 5-(3-acetaminobut-1-ynyl)-2-(4-propoxyphenoxy)thiazole; and 1-(3-{[4-(3,3-dimethyl-1-oxo-2-oxa-7-azaspiro[4.5]dec-7-yl)piperidin-1-yl]carbonyl}-5-(pyridin-2-yl)-2-thienyl)-3-ethylurea; PPAR-α agonists, including fibrates (e.g., bezafibrate, ciprofibrate, crifibrate, clofibrate, clofibrate, aluminum clofibrate). Clofibrate (aluminum clofibrate), clofibride, etofibrate, fenofibrate, fenofibrate, gemfibrozil, clofibrate, and difibrate), isoflavones (e.g., daidzein and genistein), and perfluoroalkanoic acids (e.g., perfluorooctanoic acid and perfluorononanoic acid); PPAR-δ agonists, including elafibranor (PPAR-α / γ dual agonist), GFT505 (PPAR-α / γ dual agonist), GW0742, GW501516 (PPAR-β / δ dual agonist), sogreza (GW677954), MBX-8025, and isoflavones (e.g., daidzein and genistein);PPAR-γ agonists include thiazolidinediones (as above), sarograza (a dual PPAR-α / γ agonist), 4-oxo-2-thiothiazoline derivatives (e.g., rhodanine), berberine, magnolol, perfluorononanoic acid, cyclopentenone prostaglandins (e.g., cyclopentenone 15-deoxy-A-prostaglandin J2 [15d-PGJ2]), and isoflavones (e.g., daidzein and genistein); liver X receptor (LXR) agonists include endogenous ligands (e.g., oxysterols such as 22(S)-hydroxycholesterol, 24(R)-hydroxycholesterol, 27-hydroxycholesterol, and cholesteric acid) and synthetic agonists (e.g., acetyl-rohanpiperate dimer, hypochondriacamide, A(X-dimethyl-3-oxo-2 ... β-hydroxycholenamide [A(X-dimethyl-3b-hydroxy-cholenamide, DMHCA), GW3965, and T0901317]; retinoid X receptor (RXR) agonists, including endogenous ligands (e.g., 9-cis-retinoic acid) and synthetic agonists (e.g., bexarotene, AGN 191659, AGN 191701, AGN 192849, BMS649, LG100268, LG100754, and LGD346); inhibitors of acyl-CoA cholesterol acyltransferases (ACAT, also known as sterol G-acyltransferases [SOAT], including ACAT1 [SOAT1] and ACAT2 [SOAT2]), including avamidib, pactimibe, pellitorine, and terpendole. C and flavanones (e.g., naringenin); inhibitors of stearoyl-CoA desaturase-1 (SCD-1, also known as stearoyl-CoA δ-9 desaturase) activity or expression, including aramchol, CAY-10566, CVT-11127, SAR-224, SAR-707, XEN-103; 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazolyl-2-yl]benzamide and 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazolyl]benzamide. [5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine]; 5-fluoro-1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine];6-[5-(cyclopropylmethyl)-4,5-dihydro-1'H,3H-spiro[1,5-benzoxazine-2,4'-piperidin]-1'-yl]-N-(2-hydroxy-2-pyridin-3-ylethyl)pyridazine-3-carboxamide; 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide; 4-(2-chlorophenoxy)-N-[3-(methylcarbamoyl)phenyl]piperidin-1-carboxamide; cis-9, trans-11 isomers and trans-10, cis-12 isomers of conjugated linoleic acid, WO 2009 / 129625 The substituted heteroaryl compounds disclosed in A1, antisense polynucleotides and peptide nucleic acids (PNAs) targeting SCD-1 mRNA, and siRNAs targeting SCD-1; cholesterol ester transfer protein (CETP) inhibitors, including anacetrapib, dalcetrapib, evacetrapib, torcetrapib, and AMG 899 (TA-8995); inhibitors of microsomal triglyceride transfer protein (MTTP) activity or expression, including impetapide, lometabide, dirlotapide, mitratapide, CP-346086, JTT-130, SLx-4090, antisense polynucleotides and PNAs targeting MTTP mRNA, microRNAs targeting MTTP (e.g., miRNA-30c), and siRNAs targeting MTTP; GLP-1 receptor agonists; fibroblast growth factor 21 (FGF21) and its analogues and derivatives, including BMS-986036 (polyethylene glycolated FGF21); inhibitors of the activity or expression of the proprotein convertase subtilisin / kexin type 9 (PCSK9), including berberine (reducing PC8K9 levels), annexin A2 (inhibiting PCSK9 activity), anti-PCSK9 antibodies (e.g., alirocumab, bococizumab, evolocumab, LGT-209, LY3015014, and RG7652), peptides mimicking the epidermal growth factor A (EGF-A) domain of the LDL receptor that binds to PCSK9, PCSK9-binding adnectins (e.g., BMS-962476), antisense polynucleotides and PNAs targeting PCSK9 mRNA, and PCSK9-targeting siRNAs. (For example, inclisiran [ALN-PCS] and ALN-PCS02);Apolipoprotein mimic peptides, including apoA-I mimics (e.g., 2F, 3F, 3F-1, 3F-2, 3F-14, 4F, 4F-P-4F, 4F-IHS-4F, 4F2, 5F, 6F, 7F, 18F, 5A, 5A-C1, 5A-CH1, 5A-CH2, 5A-H1, 18A, 37pA [18A-P-18A], ELK, ELK-1A, ELK-1F, ELK-1K1A1E, ELK-1L1K, ELK-1W, ELK-2A, ELK-2A2K2E, ELK-2E2K, ELK-2F, ELK-3 E3EK, ELK-3E3K3A, ELK-3E3LK, ELK-PA, ELK-P2A, ELKA, ELKA-CH2, ATI-5261, CS-6253, ETC-642, FAMP, FREL, and KRES, as well as apoE analogs (e.g., Ac-hEl8A-NH2, AEM-28, Ac-[R]hEl8A-NH2, AEM-28-14, EpK, hEp, mRl8L, COG-112, COG-133, and COG- 1410); ω-3 fatty acids, including docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), alpha-linolenic acid (ALA), fish oil (which contains, for example, DHA and EPA), and their esters (e.g., glycerides and ethyl esters); and their analogues, derivatives, and salts. In some embodiments, the anti-obesity agent is or includes a lipase inhibitor (e.g., orlistat) and / or an antihyperlipidemic agent (e.g., statins such as atorvastatin, or / and fibrates such as fenofibrate). Antihypertensive agents include, but are not limited to, the renin-angiotensin-aldosterone system (RA system). Antagonists of angiotensin II receptor type 1 (ATII1) include renin inhibitors (e.g., aliskiren), angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moxipril, perindopril, quinapril, ramipril, and trandopril), angiotensin II receptor type 1 (ATII1) antagonists (e.g., azilsartan, candesartan, eprosartan, femasartan, irbesartan, losartan, olmesartanmedoxomil, olmesartan, telmisartan, and valsartan), and aldosterone receptor antagonists (e.g., eplerenone and spironolactone).Diuretics include loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, and torasemide), thiazide diuretics (e.g., benzylfluorothiazide, chlorothiazide, hydrochlorothiazide, epithiazide, meclothiazide, and porbithiazine), thiazide-like diuretics (e.g., chlorthalidone, indapamide, and metoprazone), and ciclotanine (early distal tubular diuretics). Diuretic drugs, potassium-sparing diuretics (e.g., amiloride, eplerenone, spironolactone, and triamterene), and theobromine; calcium channel blockers, including dihydropyridines (e.g., amlodipine, levamlodipine, cilnidipine, clovidin, felodipine, isradipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine, and nifedipine) and non-dihydropyridines (e.g., diltiazem and verapamil); α2-adrenergic receptor agonists, including clonidine, guanabenz, guanifaxine, methyldopa, and mosonidin; α1-adrenergic receptor antagonists (α-blockers), including doxazosin, Indolaamine, nicergoline, phenoxybenzamide, phentolamine, prazosin, terazosin, and tolazoline; β-adrenergic receptor (β1 and / or β2) antagonists (β blockers), including atenolol, betalol, bisoprolol, carteolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, oxenolol, pentbuprofenolol, indolaol, propranolol, and timolol; mixed α / β blockers, including buxinolol, carvedilol, and labetalol; endothelin receptor antagonists, including selective ETA receptor antagonists (e.g., ambesentan, atracenttan, edonantan, sitassentan, zippotentan, and BQ-123) and ET; A / ET BDual antagonists (e.g., bosentan, macitentan, and tezosentan); other vasodilators, including hydralazine, minoxidil, theobromine, sodium nitroprusside, organic nitrates (e.g., isosorbide mononitrate, isosorbide dinitrate, and nitroglycerin, which are converted to nitric oxide in vivo), endothelial nitric oxide synthase (eNOS) stimulants (e.g., ciclotanine), soluble guanylate cyclase activators (e.g., cinaciguat and riociguat), phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, benzamidenafil, dassenafil, dynafil, lodinafil, mirtinafil, sildenafil, tadalafil, udenafil, vardenafil, dipyridamole, papaverine, propentofylline, zaprist, and T-1032), and prostaglandin E1. (Prostaglandin E1) and its analogues (e.g., limaprost and misoprostol), prostacyclin and its analogues (e.g., ataprost, beprost [e.g., esuberaprost], 5,6,7-trinor-4,8-m-w-phenylene-9-fluoro-PGl2, carbacyclin, isocarbacyclin, clinprost, ciprostene, etaprost, cicarboprost, iloprost, pimiprost, SM-10906) (Desmethylpimiprost), naxaprostene, taprostene, treprostinil, CS-570, OP-2507, and TY-11223), non-prostaglandin prostacyclin receptor agonists (e.g., 1-phthalazinol, ralinepag, selexipag, ACT-333679 [MRE-269, the active metabolite of selexipag], and TRA-418), phospholipase C (PLC) inhibitors and protein kinase C (PKC) inhibitors (e.g., BIM-1, BIM-2, BIM-3, BIM-8, chelerythrine, ciclotanine, gossypol, miyabenol C, myricitrin, ruboxistaurin, and verbascoside); minerals, including magnesium and magnesium sulfate;And its analogues, derivatives and salts. In some embodiments, the antihypertensive agent is or includes thiazide or thiazide diuretics (e.g., hydrochlorothiazide or chlorothiazide), calcium channel blockers (e.g., amlodipine or nifedipine), ACE inhibitors (e.g., benazepril, captopril or perindopril) or angiotensin II receptor antagonists (e.g., olmesartan medoxomil, olmesartan, telmisartan or valsartan), or any combination thereof. In some embodiments, the peptide product described herein is used in combination with one or more additional therapeutic agents to prevent and / or treat CV disease-related conditions such as high cholesterol, triglycerides, LDL and / or VLDL particle concentration and / or diameter, and / or other relevant parameters (e.g., serum phosphatidylethanolamine, phosphatidylcholine, lysophosphatidylethanolamine, sphingolipids and / or lysophosphatidylcholine). In some implementations, one or more additional therapeutic agents are selected from antidiabetic agents, antiobesity agents, anti-inflammatory agents, antifibrotic agents, antioxidants, antihypertensive agents, and combinations thereof. Therapeutic agents that can be used to treat NAFLD (e.g., NASH) include, but are not limited to: PPAR agonists, including PPAR-δ agonists (e.g., MBX-8025, elafibranor [PPAR-α / δ dual agonist] and GW501516 [PPAR-β / δ dual agonist]) and PPAR-γ agonists (e.g., thiazolidinediones, such as pioglitazone and sarograza [PPAR-α / γ dual agonists]) – PPAR-δ and PPAR-γ agonists increase insulin sensitivity, PPAR-α agonists reduce hepatic steatosis, and PPAR-δ agonists inhibit the activation of macrophages and Kupffer cells; farnesoid X receptor (FXR) agonists, such as obeticholic acid, and nonsteroidal FXR agonists, such as GS-9674, reduce hepatic gluconeogenesis, adipogenesis, steatosis, and fibrosis; fibroblast growth factor 19 (FGF19) and its analogues and derivatives, such as NGM-282—FGF19 analogues reduce hepatic gluconeogenesis and steatosis; fibroblast growth factor 21 (FGF21) and its analogues and derivatives, such as BMS-986036 (pegylated FGF21)—FGF21 analogues reduce hepatic steatosis, cell damage, and fibrosis; HMG-CoA reductase inhibitors, including statins (e.g., rosuvastatin)—statins reduce steatohepatitis and fibrosis; ACC inhibitors, such as NDI-010976 (targeting the liver) and GS-0976—ACC inhibitors reduce neoadipogenesis and hepatic steatosis; SCD-1 inhibitors, such as aramchol—SCD-1 inhibitors reduce hepatic steatosis and increase insulin sensitivity; SGLT2 inhibitors, such as canagliflozin, ioggliflozin, and rugliflozin—SGLT2 inhibitors reduce body weight, hepatic ALT levels, and fibrosis;CCR2 and / or CCR5 antagonists, such as cenicriviroc—antagonists of CCR2 (binding to CCL2 [MCP1]) and CCR5 (binding to CCL5 [RANTES]) inhibit the activation and migration of inflammatory cells (e.g., macrophages) to the liver and reduce liver fibrosis; apoptosis inhibitors, including apoptosis signal-regulated kinase 1 (ASK1) inhibitors (e.g., selonsertib) and caspase inhibitors (e.g., emricasan [pan-cysteine ​​inhibitor])—apoptosis inhibitors reduce hepatic steatosis and fibrosis; lysyl oxidase-like 2 (LOXL2) inhibitors, such as simtuzumab—LOXL2 is a key matrix enzyme in collagen formation and is highly expressed in the liver; galactagogue-3 inhibitors, such as GR-MD-02 and TD139—galactagogue-3 is essential for the development of liver fibrosis; antioxidants, including vitamin E. (e.g., α-tocopherol) and scavengers of reactive oxygen species (ROS) and free radicals (e.g., cysteine, glutathione, melatonin, and pentoxifylline [also anti-inflammatory via inhibition of TNF-α and phosphodiesterase]) – vitamin E – reduce hepatic steatosis, hepatocellular ballooning degeneration, and lobular inflammation; and their analogues, derivatives, and salts. In some embodiments, the peptide products described herein are used in combination with PPAR agonists (e.g., PPAR-δ agonists such as elafibranor and / or PPAR-γ agonists such as pioglitazone), HMG-CoA reductase inhibitors (e.g., statins such as rosuvastatin), FXR agonists (e.g., obeticholic acid), or antioxidants (e.g., vitamin E) or any combination thereof to treat NAFLD (e.g., NASH). In some embodiments, one or more additional therapeutic agents for treating NAFLD (e.g., NASH) are or include vitamin E and / or pioglitazone. Other combinations may also be used, as will be understood by those skilled in the art.

[0080] Pharmacokinetic (“PK”) parameters can be estimated using Phoenix® WinNonlin® version 8.1 or later (Certara USA, Inc., Princeton, New Jersey). Non-compartmental methods consistent with extravascular administration can be used for parameter estimation. Individual plasma concentration-time data can be used for pharmacokinetic calculations. In addition to parameter estimation for individual animals, descriptive statistics (e.g., mean, standard deviation, coefficient of variation, median, minimum, maximum) can be determined as appropriate. For the determination of descriptive statistics and pharmacokinetic analysis, concentration values ​​below the limit of quantitation (LOQ) can be considered zero. Embedded concentration values ​​below the LOQ can be excluded from pharmacokinetic analysis. All parameters can be derived from the concentration of a single dual agonist peptide (or its derivatives and / or metabolites) in the plasma of the treatment group of the test article on the day of administration (Day 1). Parameters can be estimated using nominal dose levels unless analysis of a dose formulation exceeding the specification is obtained, in which case the actual dose level can be used. Parameters can be estimated using the nominal sampling time; if bioanalytical sample collection bias is recorded, the actual sampling time can be used at the affected time points. Bioanalytical data can be used for pharmacokinetic analysis as received and can be presented in tables and figures in the units provided. Pharmacokinetic parameters can be calculated and presented in units provided by the analytical laboratory (the order of magnitude can be appropriately adjusted for presentation in the report, e.g., h). ng / mL to h μg / mL). Descriptive statistics (e.g., mean, standard deviation, coefficient of variation, median, minimum, maximum) and pharmacokinetic parameters may be determined to three significant figures, as appropriate. Additional data processing items may be recorded as needed. Where data permits, the PK parameters to be determined may include, but are not limited to, the following: C max Maximum observed concentration; DNC max The dose-normalized maximum concentration is calculated as C. max / Dosage; T max Time to maximum observed concentration; AUC 0-t The area under the curve from time 0 to the last measurable concentration, calculated using the linear trapezoidal rule; AUC 0-96 The area under the curve from time 0 to 96 hours is calculated using the linear trapezoidal rule; DN AUC 0-96 Dose-normalized AUC 0-96 Calculated as AUC 0-96 / Dosage; AUC 0-infThe area under the curve from time 0 to infinity (day 1 only) is calculated as AUC. 0-inf =AUC 0-t +C t / λ z C t It is the last observed quantifiable concentration and λ z It eliminates the rate constant; t 1 / 2 Eliminating the half-life, it is calculated as ln(2) / λ z Other parameters and comparisons (e.g., sex ratio, proportionality ratio, etc.) may also be determined, as will be understood by one of ordinary skill in the art.

[0081] In some embodiments, this disclosure provides one or more pharmaceutical dosage forms comprising pemvidutide, wherein the peptide product is modified with a hydrophobic surfactant; the dosage is configured to induce weight loss upon administration to a mammal, while reducing one or more adverse events, wherein the subject is at risk of and / or has a CV disease-related condition (and / or CV disease) and may also be overweight, obese, and / or have type 2 diabetes, wherein the adverse events are selected from nausea, vomiting, diarrhea, abdominal pain, and constipation. In some embodiments, the formulation comprises 1.8 mg of pemvidutide as a therapeutic dose. In some embodiments, the formulation comprises 1.2 mg, 1.8 mg, or 2.4 mg of pemvidutide as a weekly therapeutic dose (the 2.4 mg dose is preferably continued for four weeks before titration to 2.4 mg, preferably 0.6 mg during week 1, 1.2 mg weekly during week 2, 1.8 mg weekly during week 3, and 1.8 mg weekly during week 4), preferably once weekly for 48 weeks.

[0082] "Reducing" or "reducing" an adverse effect or event refers to a reduction in the extent, duration, and / or frequency of the adverse effect experienced by a subject, and its incidence in a cohort of subjects, following administration of an agonist with approximately balanced affinity for GLP1R and GCGR. Such a reduction includes prevention of some adverse effects that a subject would otherwise experience in response to an agonist with unbalanced affinity for GLP1R and GCGR. Such a reduction also includes the elimination of adverse effects previously experienced by a subject following administration of an agonist with unbalanced affinity for GLP1R and GCGR. In some embodiments, "reducing" an adverse effect or "reduction of" an adverse effect includes a reduction in gastrointestinal side effects, wherein the adverse event is reduced to zero or undetectable levels. In other embodiments, the adverse effect is reduced to levels equivalent to those of untreated subjects, but not completely eliminated. In other embodiments, the adverse effect is reduced to levels equivalent to those of untreated subjects, but not completely eliminated. Furthermore, administration of analogues with unbalanced affinity for GLP-1R or GCGR to mammals may result in the need for excessively high doses to maximally activate receptors with weaker sensitivity to the ligand, potentially leading to doses exceeding the bioeffective dose level of the other ligand and causing dose-related undesirable side effects.

[0083] In a preferred embodiment, this disclosure provides a method for reducing human weight, wherein the method comprises administering pemvidutide once weekly to a human with appropriate need in an amount of at least 1.2 mg to 2.4 mg (preferably 1.2 mg, 1.8 mg, or 2.4 mg, titrated to 2.4 mg); and wherein the human is overweight, obese, and / or may also have type 2 diabetes (and, in some preferred embodiments, exhibits symptoms of cardiovascular (CV) disease or markers associated with cardiovascular (CV) disease). In some preferred embodiments of such a method, pemvidutide is administered once weekly in an amount of 2.4 mg (after titration to a 2.4 mg dose), and the human's weight is reduced by at least about 15% (e.g., preferably at least about 15.6%) (i.e., "robust average weight loss"). In a preferred embodiment, the patient exhibits a substantial and clinically significant reduction in one or more of total cholesterol, low-density lipoprotein, triglycerides, and / or blood pressure. In a preferred embodiment, in the patient population already receiving a 2.4 mg weekly dose, at least about 30% or more of the patients lose about 20% or more of their body weight by week 48. In a preferred embodiment, the 2.4 mg weekly dose is continued, or in some embodiments, a smaller dose, to continue inducing weight loss until the desired weight is reached. In some embodiments, a maintenance dose (e.g., in a preferred embodiment, 1.2 mg, 1.8 mg, or 2.4 mg weekly) may be administered to the patient after the initial 48 weeks of administration or after the desired weight is reached. In a preferred embodiment, the patient does not experience gastrointestinal (GI) or cardiac (e.g., arrhythmia, increased heart rate) adverse events. In a preferred embodiment, when a patient experiences a GI adverse event, the severity of such an event is considered mild to moderate by the patient and / or attending medical professional. In a preferred embodiment, the patient also exhibits stable glycemic homeostasis.

[0084] In some preferred embodiments of this method, administration of pemvidutide (preferably 2.4 mg weekly for 48 weeks, including 4-week titrations) induces a significant reduction in the number of atherosclerotic lipids and / or lipoproteins compared to baseline. In some preferred embodiments of this method, after 43 and / or 84 days of pemvidutide administration, the concentration of atherosclerotic lipoproteins decreases by at least -0.2 log2 compared to baseline; after 43 and / or 84 days of pemvidutide administration, the subject's total serum triglyceride concentration decreases by at least -0.2 log2 relative to placebo; wherein serum lipids are selected from glycerolipids, sterols, glycerophospholipids, and sphingolipids, optionally wherein the reduction is at least -0.2 log2. In some preferred embodiments of this method, a reduction in serum phosphatidylethanolamine, phosphatidylcholine, lysophosphatidylethanolamine, sphingolipids, and / or lysophosphatidylcholine is induced.

[0085] In some embodiments of the method, the human body weight of a person administered pemvidutide at a therapeutically effective dose of about 1.2 mg to 2.4 mg once weekly for 48 weeks (including a 4-week titration of the 2.4 mg dose) decreased by at least 10% or at least 11%, or at least 12%, or at least 13%, or at least 14%, or at least 15% from baseline at week 48. In some embodiments of the method, the human has type 2 diabetes; and / or the human has a body mass index (BMI kg / m²) of at least 25, at least about 28, or at least about 30. 2 ).

[0086] In some embodiments, this document provides methods for reducing serum lipids, including administering a therapeutically effective dose of at least 1.2 mg and up to 2.4 mg of pemvidutide once weekly to a human subject with appropriate need for at least 48 weeks. In some embodiments, after 48 weeks of administration of a therapeutically effective dose of pemvidutide once weekly, serum triglycerides are reduced from baseline by at least 20%, at least 25%, or at least 30%. In some embodiments, after 48 weeks of administration of a therapeutically effective dose of pemvidutide once weekly, total serum cholesterol is reduced by at least 5%, at least 10%, or at least 15%. In some embodiments, after 48 weeks of administration of a therapeutically effective dose of pemvidutide once weekly, serum LDL is reduced by at least 10%, at least 15%, or at least 20%. In some embodiments, after 48 weeks of administration of a therapeutically effective dose of pemvidutide once weekly, serum VLDL is reduced by at least 10%, at least 15%, at least 20%, or at least 25%. In the implementation scheme, pemvidutide is administered as a liquid pharmaceutical preparation comprising SEQ ID NO:1 and about 0.20% (w / w) polysorbate 20, about 0.348% (w / w) arginine and about 4.260% (w / w) mannitol in sterile water (pH 7.7±0.1).

[0087] In some preferred embodiments, pemvidutide is administered via parenteral injection. In some preferred embodiments, pemvidutide is administered via subcutaneous injection. In some preferred embodiments, the human is overweight, obese, and / or has a body mass index (BMI kg / m²) of at least 27. 2 In some preferred embodiments, the human body mass index (BMI kg / m²) is 30 or greater. 2 In some preferred embodiments, the human patient has a parameter level of 10% or higher associated with CV disease-related conditions prior to treatment (e.g., at baseline). In some preferred embodiments, after 48 weeks of treatment, the absolute reduction in CV disease-related conditions compared to baseline measurements is any one of about 8%, 10%, 12%, or preferably about 15%. In some preferred embodiments, after 48 weeks of treatment, the relative reduction in CV disease-related conditions relative to baseline is greater than any one of about 40%, 50%, or 60%. In some preferred embodiments, pemvidutide is administered from a liquid containing at least about 1.8 mg / mL and at most 2.4 mg / mL of pemvidutide. In some embodiments, pemvidutide is administered from a pharmaceutical dosage form comprising one or more of polysorbate 20, arginine, or mannitol.

[0088] In a preferred embodiment, this disclosure relates to a method of administering pemvidutide to a patient for 48 weeks at a weekly dose of 1.2 mg, 1.8 mg, or 2.4 mg (in a preferred embodiment, including a 4-week titration of the 2.4 mg dose), preferably 2.4 mg weekly, wherein at week 48, the human body weight has decreased from baseline by at least about 15% (preferably at least 15.6%). In a preferred embodiment, administration of 2.4 mg pemvidutide to a human population is sustained for at least 48 weeks (including a 4-week titration), wherein at week 48, at least about 30% of the population's body weight has decreased from baseline by greater than or equal to about 20%. In a preferred embodiment, the patient is overweight, obese, and / or has a body mass index (BMI kg / m²) greater than or equal to 25. 2 ( ); and / or optionally have type 2 diabetes. In a preferred embodiment, weight loss is accompanied by a significant and clinically meaningful reduction in serum lipids, cholesterol, triglycerides, LDL and / or VLDL particle concentration and / or diameter, phosphatidylethanolamine, phosphatidylcholine, lysophosphatidylethanolamine, sphingolipids and / or lysophosphatidylcholine and / or blood pressure, as these parameters can be determined by a person skilled in the art using conventional techniques. In some preferred embodiments, administration of pemvidutide at 2.4 mg weekly (including 4-week titrations) reduces cardiovascular (CV) risk in patients and / or patient populations. In some embodiments, pemvidutide is administered via subcutaneous (parenteral) injection. In some preferred embodiments, pemvidutide is administered from a liquid formulation containing at least about 1.8 mg / ml pemvidutide. In some preferred embodiments, pemvidutide is administered as a liquid pharmaceutical preparation comprising SEQ ID NO:1 and about 0.20% (w / w) polysorbate 20, about 0.348% (w / w) arginine and about 4.260% (w / w) mannitol in sterile water (pH 7.7±0.1).

[0089] Specific implementation plan Specific implementation scheme 1: A method for treating long-term weight management in humans with corresponding needs, comprising administering a therapeutically effective dose of a pharmaceutical dosage form to a human once weekly, the pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1, and wherein the human with corresponding needs has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea.

[0090] Specific implementation scheme 2: According to the method of implementation scheme 1, the treatment also reduces serum lipids.

[0091] Specific embodiment 3: A method for treating long-term weight management in humans with corresponding needs, comprising administering a therapeutically effective amount of a pharmaceutical dosage form to the human once weekly, said pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1, and wherein said treatment also reduces serum lipids.

[0092] Specific implementation scheme 4: According to the method of implementation scheme 3, the human being in need has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia and obstructive sleep apnea.

[0093] Specific embodiment 5: The method according to any of the preceding embodiments, wherein the peptide product is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the peptide of SEQ ID NO:1.

[0094] Specific embodiment 6: The method according to any of the foregoing embodiments, wherein the peptide product is 100% identical to the peptide of SEQ ID NO:1.

[0095] Specific implementation scheme 7: The method according to any of the foregoing implementation schemes, wherein the drug dosage formulation is administered subcutaneously or via parenteral injection.

[0096] Specific implementation scheme 8: The method according to any of the foregoing implementation schemes, wherein the pharmaceutical dosage form is an aqueous formulation comprising one or more of polysorbate 20, arginine or mannitol.

[0097] Specific implementation scheme 9: The method according to any of the foregoing implementation schemes, wherein the pharmaceutical dosage formulation comprises about 0.025%-0.5% (w / w) of polysorbate 20, about 0.2%-0.5% (w / w) of arginine and about 3%-6% (w / w) of mannitol in water (pH 7.7±0.1).

[0098] Specific implementation scheme 10: The method according to any of the foregoing implementation schemes, wherein the pharmaceutical dosage formulation comprises about 0.2% (w / w) polysorbate 20, about 0.348% (w / w) arginine, and about 4.260% (w / w) mannitol in water (pH 7.7±0.1).

[0099] Specific implementation scheme 11: The method according to any of the foregoing implementation schemes, wherein the human being is obese or overweight.

[0100] Specific implementation scheme 12: According to the method of any of the foregoing implementation schemes, the human being in need has a body mass index (BMI kg / m²) of at least 25. 2 ).

[0101] Specific implementation scheme 13: According to the method of any of the foregoing implementation schemes, the human being in need has a body mass index (BMI kg / m²) of at least 30. 2 ).

[0102] Specific implementation scheme 14: According to the method of any of the foregoing implementation schemes, the human being in need of the corresponding task has a body mass index (BMI kg / m²) of at least 35. 2 ).

[0103] Specific implementation scheme 15: According to the method of any of the foregoing implementation schemes, the human being in need has a body mass index (BMI kg / m²) of at least 40. 2 ).

[0104] Specific implementation scheme 16: The method according to any of the foregoing implementation schemes, wherein the treatment maintains weight loss.

[0105] Specific implementation scheme 17: The method according to any of the foregoing implementation schemes, wherein the treatment results in a relative weight reduction of at least about 10%, at least about 15%, or at least about 20%.

[0106] Specific implementation scheme 18: The method according to any of the foregoing implementation schemes, wherein the treatment reduces lean body mass by less than about 25%.

[0107] Specific implementation scheme 19: According to the method of any of the foregoing implementation schemes, the human being in need has an HbA1C value of approximately 5.7% to 6.4%.

[0108] Specific implementation scheme 20: According to the method of implementation schemes 1-14, the human being in need has an HbA1C value of approximately 4.0% to 5.6%.

[0109] Specific implementation scheme 21: The method according to any of the foregoing implementation schemes, wherein the pharmaceutical dosage form comprises about 1.2 mg of peptide product.

[0110] Specific implementation scheme 22: The method according to any of the foregoing implementation schemes, wherein the pharmaceutical dosage form comprises about 1.8 mg of peptide product.

[0111] Specific implementation scheme 23: The method according to any of the foregoing implementation schemes, wherein the pharmaceutical dosage form comprises about 2.4 mg of peptide product.

[0112] Specific embodiment 24: The method according to any of the foregoing embodiments, wherein the pharmaceutical dosage form comprises a peptide product (2.4 mg / mL; 0.24% (w / w)); mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)) in sterile water.

[0113] Specific embodiment 25: The method according to any of the foregoing embodiments, wherein the pharmaceutical dosage form comprises a peptide product (1.8 mg / mL; 0.18% (w / w)); mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)) in sterile water.

[0114] Specific embodiment 26: The method according to any of the foregoing embodiments, wherein the pharmaceutical dosage form comprises a peptide product (1.2 mg / mL; 0.12% (w / w)); mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)) in sterile water.

[0115] Specific implementation scheme 27: The method according to any of the foregoing implementation schemes, wherein the treatment reduces one or more serum lipids selected from serum triglycerides, total serum cholesterol, serum LDL or serum VLDL.

[0116] Specific implementation scheme 28: The method according to any of the foregoing implementation schemes, wherein the treatment reduces serum triglycerides by at least about 30% after 48 weeks.

[0117] Specific implementation scheme 29: The method according to any of the foregoing implementation schemes, wherein the treatment reduces total serum cholesterol by at least about 10% after 48 weeks.

[0118] Specific implementation scheme 30: The method according to any of the foregoing implementation schemes, wherein the treatment reduces total serum cholesterol by at least about 15% after 48 weeks.

[0119] Specific implementation scheme 31: The method according to any of the foregoing implementation schemes, wherein the treatment reduces serum LDL by at least about 10% after 48 weeks.

[0120] Specific implementation scheme 32: The method according to any of the foregoing implementation schemes, wherein the treatment reduces serum VLDL by at least about 25% after 48 weeks.

[0121] Specific implementation scheme 33: The method according to any of the foregoing implementation schemes, wherein treatment in humans with baseline triglycerides >150 mg / dL reduces serum triglycerides by at least about 30% after 48 weeks.

[0122] Specific implementation scheme 34: The method according to any of the foregoing implementation schemes, wherein treatment in appropriate human subjects with baseline triglycerides >150 mg / dL reduces serum triglycerides by at least about 50% after 48 weeks.

[0123] Specific implementation scheme 35: The method according to any of the foregoing implementation schemes, wherein treatment in appropriate human subjects with baseline cholesterol >200 mg / dL reduces serum cholesterol by at least about 15% after 48 weeks.

[0124] Specific implementation scheme 36: The method according to any of the foregoing implementation schemes, wherein treatment in humans with baseline cholesterol >200 mg / dL reduces serum cholesterol by at least about 20% after 48 weeks.

[0125] Specific implementation scheme 37: The method according to any of the foregoing implementation schemes, wherein treatment in humans with corresponding needs whose LDL is >130 mg / dL at baseline reduces serum LDL by at least about 15% after 48 weeks.

[0126] Specific implementation scheme 38: The method according to any of the foregoing implementation schemes, wherein treatment in humans with corresponding needs whose LDL is >130 mg / dL at baseline reduces serum LDL by at least about 20% after 48 weeks.

[0127] Specific implementation scheme 39: The method according to any of the foregoing implementation schemes, wherein a steady-state therapeutic dose is reached after a dose escalation phase lasting two to four weeks.

[0128] Specific embodiment 40: A method of treatment for reducing serum lipids in a human with a corresponding need, comprising administering, once weekly, a therapeutically effective amount of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1.

[0129] Specific implementation scheme 41: According to the method of implementation scheme 40, the human being in need has one or more comorbidities selected from obesity, cardiovascular disease, hypertension, dyslipidemia, dysglycemia, type 2 diabetes and obstructive sleep apnea.

[0130] Specific embodiment 42: The method according to embodiment 40 or 41, wherein the peptide product is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the peptide of SEQ ID NO:1.

[0131] Specific implementation scheme 43: The method according to implementation scheme 40 or 41, wherein the peptide product is 100% identical to the peptide of SEQ ID NO:1.

[0132] Specific implementation scheme 44: The method according to implementation schemes 40-43, wherein the drug dosage formulation is administered subcutaneously or via parenteral injection.

[0133] Specific implementation scheme 45: The method according to implementation schemes 40-44, wherein the pharmaceutical dosage formulation is an aqueous formulation comprising one or more of polysorbate 20, arginine or mannitol.

[0134] Specific implementation scheme 46: The method according to any one of implementation schemes 40-45, wherein the pharmaceutical dosage formulation comprises about 0.025%-0.5% (w / w) of polysorbate 20, about 0.2%-0.5% (w / w) of arginine and about 3%-6% (w / w) of mannitol in water (pH 7.7±0.1).

[0135] Specific implementation scheme 47: The method according to any one of implementation schemes 40-46, wherein the pharmaceutical dosage formulation comprises about 0.2% (w / w) polysorbate 20, about 0.348% (w / w) arginine, and about 4.260% (w / w) mannitol in water (pH 7.7±0.1).

[0136] Specific implementation scheme 48: The method according to any one of implementation schemes 40-47, wherein the human being is obese or overweight.

[0137] Specific implementation scheme 49: According to the method of any one of implementation schemes 40-48, the human being with the corresponding need has a body mass index (BMI kg / m²) of at least 25. 2 ).

[0138] Specific implementation scheme 50: According to the method of any one of implementation schemes 40-49, the human being with the corresponding need has a body mass index (BMI kg / m²) of at least 30. 2 ).

[0139] Specific implementation scheme 51: According to the method of any one of implementation schemes 40-50, the human being with the corresponding need has a body mass index (BMI kg / m²) of at least 35. 2 ).

[0140] Specific implementation scheme 52: According to the method of any one of implementation schemes 40-51, wherein the human being in need has a body mass index (BMI kg / m²) of at least 40. 2 ).

[0141] Specific implementation scheme 53: The method according to any one of implementation schemes 40-52, wherein the treatment maintains weight loss.

[0142] Specific implementation scheme 54: The method according to any one of implementation schemes 40-53, wherein the treatment will reduce the relative body weight by at least 10%, at least 15%, or at least 20%.

[0143] Specific implementation scheme 55: The method according to any one of implementation schemes 40-54, wherein the treatment results in a reduction of lean body mass of less than about 25%.

[0144] Specific implementation scheme 56: The method according to any one of implementation schemes 40-55, wherein the human being in need has an HbA1C value of approximately 5.7% to 6.4%.

[0145] Specific implementation scheme 57: According to the methods of implementation schemes 40-56, the human being in need has an HbA1C value of approximately 4.0% to 5.6%.

[0146] Specific implementation scheme 58: The method according to implementation schemes 40-57, wherein the pharmaceutical dosage formulation comprises approximately 1.2 mg of peptide product.

[0147] Specific implementation scheme 59: The method according to implementation schemes 40-58, wherein the pharmaceutical dosage formulation comprises approximately 1.8 mg of peptide product.

[0148] Specific implementation scheme 60: The method according to implementation schemes 40-59, wherein the pharmaceutical dosage form comprises about 2.4 mg of peptide product.

[0149] Specific implementation scheme 61: The method according to implementation schemes 40-60, wherein the pharmaceutical dosage formulation comprises, in sterile water, a peptide product (2.4 mg / mL; 0.24% (w / w)); mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)).

[0150] Specific embodiment 62: The method according to embodiments 40-61, wherein the pharmaceutical dosage formulation comprises a peptide product (1.8 mg / mL; 0.18% (w / w)); mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)) in sterile water.

[0151] Specific implementation scheme 63: The method according to embodiments 40-62, wherein the pharmaceutical dosage formulation comprises a peptide product (1.2 mg / mL; 0.12% (w / w)); mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)) in sterile water.

[0152] Specific implementation scheme 64: The method according to implementation schemes 40-63, wherein the treatment reduces one or more of serum triglycerides, total serum cholesterol, serum LDL or serum VLDL.

[0153] Specific implementation scheme 65: The method according to implementation schemes 40-64, wherein the treatment reduces serum triglycerides by at least about 20% after 48 weeks.

[0154] Specific implementation scheme 66: According to the method of implementation schemes 40-65, wherein the treatment reduces serum triglycerides by at least about 30% after 48 weeks.

[0155] Specific implementation scheme 67: According to the method of implementation schemes 40-66, wherein the treatment reduces total serum cholesterol by at least about 10% after 48 weeks.

[0156] Specific implementation scheme 68: According to the method of implementation schemes 40-67, wherein the treatment reduces total serum cholesterol by at least about 15% after 48 weeks.

[0157] Specific implementation scheme 69: The method according to implementation schemes 40-68, wherein the treatment reduces serum LDL by at least about 10% after 48 weeks.

[0158] Specific implementation scheme 70: The method according to implementation schemes 40-69, wherein the treatment reduces serum LDL by at least about 20% after 48 weeks.

[0159] Specific implementation scheme 71: According to the method of implementation schemes 40-70, wherein the treatment reduces serum VLDL by at least about 25% after 48 weeks.

[0160] Specific implementation scheme 72: The method according to implementation schemes 40-71, wherein treatment in humans with baseline triglycerides >150 mg / dL reduces serum triglycerides by at least about 30% after 48 weeks.

[0161] Specific implementation scheme 73: The method according to implementation schemes 40-72, wherein treatment in humans with baseline triglycerides >150 mg / dL reduces serum triglycerides by at least about 50% after 48 weeks.

[0162] Specific implementation scheme 74: According to the method of implementation schemes 40-73, in human subjects with corresponding needs whose baseline cholesterol is >200 mg / dL, treatment reduces serum cholesterol by at least about 15% after 48 weeks.

[0163] Specific implementation scheme 75: According to the method of implementation schemes 40-74, in human subjects with corresponding needs whose baseline cholesterol is >200 mg / dL, treatment reduces serum cholesterol by at least about 20% after 48 weeks.

[0164] Specific implementation scheme 76: According to the method of implementation schemes 40-75, in human subjects with corresponding needs whose LDL is >130 mg / dL at baseline, serum LDL is reduced by at least about 15% after 48 weeks of treatment.

[0165] Specific implementation scheme 77: According to the method of implementation schemes 40-76, in human subjects with corresponding needs whose LDL is >130 mg / dL at baseline, serum LDL is reduced by at least about 20% after 48 weeks of treatment.

[0166] Specific implementation scheme 78: The method according to implementation schemes 40-77, wherein a steady-state therapeutic dose is reached after a dose escalation phase lasting two to four weeks.

[0167] Other aspects of this disclosure are also contemplated, as will be understood by those skilled in the art.

[0168] As will be understood by those skilled in the art, other aspects of this disclosure are also contemplated. Unless otherwise defined or clearly indicated by their use herein, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this application pertains. As used in the specification and appended claims, the words “a” or “an” mean one or more. As used herein, the word “another” means a second or more. The acronym “aka” means also referred to. The term “exemplary” as used herein means “serving as an example, instance, or illustration.” Any embodiment or feature characterized as “exemplary” herein is not necessarily to be construed as preferred or advantageous over other embodiments or features. In some embodiments, the terms “about” or “approximately” mean within ±10% or 5% of the specified value. Whenever the term “about” or “approximately” precedes the first value in a series of two or more numerical values ​​or a range of two or more numerical values, the term “about” or “approximately” applies to each value in that series of numerical values ​​or the range of numerical values. A range herein may be expressed as from about one particular value, and / or about another particular value. When expressing such a range, the other side includes from one particular value and / or to another particular value. Similarly, when a value is expressed as an approximation, it can be understood that the particular value forms the other side by using the antecedent “about” or “approximately”. It will be further understood that it is meaningful for each endpoint of a range to be both associated with and independent of another endpoint. A range (e.g., 90%–100%) means including the range itself as well as each independent value within that range, as if each value were listed separately. Optionally or otherwise, it means that an event or situation subsequently described may or may not occur, and the description includes instances where the event or situation occurs as well as instances where the event or situation does not occur. All publications, patents and patent applications mentioned in this specification are incorporated herein by reference in their entirety, to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference.

[0169] Certain embodiments are further described below. These embodiments are provided by way of example only and are not intended to limit the scope of the claims in any way.

[0170] Example Example 1. Peptide Synthesis The peptides and peptide products disclosed herein can be prepared according to well-known procedures and by methods known and disclosed in the art. For example, SEQ ID NO:1 can be prepared according to the synthetic protocol provided in U.S. Patent No. 12,171,806. The contents of Example 1 of U.S. Patent No. 12,171,806 are incorporated herein by reference.

[0171] Example 2: Study Design of the 48-week Phase 2 Obesity Trial of pemvidutide (Momentum Study: NCT05295875) Introduction Obesity is a chronic disease that has risen to an epidemic level worldwide, with an estimated 3.3 billion people affected by 2035. Obesity is associated with risk factors for other conditions, including dyslipidemia, hypertension, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-related steatohepatitis (MASH). A 5% reduction in body weight is associated with improvements in cardiovascular risk factors, T2DM, steatotic liver disease, and other obesity-related complications, while a 10% to 15% reduction in body weight is associated with reduced cardiovascular mortality, T2DM regression, and histological improvements in MASH activity.

[0172] Bariatric surgery has historically been the most effective treatment for weight loss because it was pharmacologically difficult to achieve meaningful levels of weight loss. However, the emergence of glucagon-based therapies has shown the potential to achieve significantly greater weight loss compared to earlier medical interventions. Glucagon-like peptide-1 receptor (GLP-1R) agonists (such as semaglutide) have been used to treat type 2 diabetes mellitus (T2DM) for over a decade, and recently, two GLP-1R activators (such as semaglutide and telpolide) have been approved by the U.S. Food and Drug Administration (FDA) for long-term weight management.

[0173] The applicant hereby provides different strategies for achieving additional levels of weight loss by combining GLP-1R agonists with co-agonists having complementary mechanisms. GLP-1R agonists achieve weight loss through anorexia (inhibition of food consumption). G-coupled glucagon receptor (GCGR) agonists are thought to increase energy expenditure and shift metabolism toward increased lipid utilization as an energy source, potentially mimicking the effects of diet and exercise. Therefore, this document provides methods using peptide products of this disclosure (e.g., GLP-1R / GCGR dual agonists) that provide mechanisms for further weight reduction beyond GLP-1 monotherapy.

[0174] This study was a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group dose-exploration trial designed to evaluate the effects of ALT-801 (pemvidutide) on body weight, tolerability, and safety. The study was conducted at 30 study sites in the United States. The trial was conducted in accordance with the Declaration of Helsinki and the principles of the International Conference on Harmonization Good Clinical Practice. The trial protocol and revisions were approved by the relevant institutional review committee and / or ethics committee at each study site. All participants provided written informed consent prior to participation in the study.

[0175] Selection criteria Participants are eligible to participate in the study if they have provided written informed consent before entering. They must be between 18 and 75 years old and have a body weight of at least 30 kg / m². 2 Body mass index (BMI) or at least 27 kg / m² 2 Participants must have a BMI of [insert BMI here] and at least one obesity-related comorbidity, such as cardiovascular disease, hypertension, dyslipidemia, prediabetes, or obstructive sleep apnea. Prediabetes is defined as an HbA1c level between 5.7% and 6.4%, a fasting blood glucose level between 100 mg / dL and 125 mg / dL (5.5–6.9 mmol / L), or a glucose tolerance test result between 140 mg / dL and 199 mg / dL (7.7–11.0 mmol / L). Participants must have at least one unsuccessful weight loss attempt as determined by the investigator and must agree to adhere to the lifestyle interventions and treatments recommended during the study. Female participants of fertility potential are eligible if they have a negative pregnancy test, are not breastfeeding, and agree to use effective contraception during the study and for one month afterward. Acceptable methods include hormonal contraceptives or intrauterine devices (IUDs). Surgically sterilized or postmenopausal women are also eligible. Male participants with female partners of fertility potential must be surgically sterilized or have a partner who meets the study criteria. They also agreed not to donate sperm during the study and for three months after their last dose. Participants with same-sex partners or practicing abstinence were eligible.

[0176] Exclusion criteria Participants were excluded if they experienced significant weight fluctuations, particularly if they gained or lost more than 5% in the three months prior to randomization or more than 10% in the six months prior to screening. Those with any form of diabetes (including type 1, type 2, or young adult-onset diabetes (MODY)) were ineligible, although a history of gestational diabetes was permissible if blood glucose levels were currently normal. Obesity-related disorders, including those caused by genetic factors or endocrine disorders such as Cushing's syndrome or untreated hypothyroidism, led to exclusion, as did any history of bariatric surgery or other surgical weight-loss interventions. Gastrointestinal and liver conditions, including pancreatitis, significant GI disorders, surgery altering absorption or transport, inflammatory bowel disease, or cirrhosis, also led to exclusion. Additionally, those with a history of pheochromocytoma, insulinoma, or glucagonoma were ineligible. Candidates with a recent history of neoplastic disease (within five years) were excluded unless the condition was adequately treated, such as non-melanoma skin cancer or benign cervical fibroids under appropriate monitoring. A personal or family history of medullary thyroid carcinoma or multiple endocrine tumors also disqualifies participants. Mental health conditions, including untreated depression (PHQ-9 score ≥15), suicidal ideation, previous suicide attempts, or severe mental disorders such as schizophrenia or bipolar disorder, lead to exclusion. Participants with cardiovascular conditions, including poorly controlled hypertension, conduction abnormalities (QT prolongation), recent myocardial infarction, stroke, or congestive heart failure, are ineligible. Those with clinically significant laboratory abnormalities are also excluded, including impaired renal function (eGFR <60 mL / min / 1.73 mcg). 2 Elevated liver enzymes (ALT or AST > 2 × ULN), alkaline phosphatase (ALP) > 2 × ULN, total bilirubin > 1.3 mg / dL (except for Gilbert's syndrome), international normalized ratio (INR) > 1.3, fasting serum triglycerides > 500 mg / dL, hemoglobin < 11.0 g / dL, platelet count < 125,000 / µL, or any other abnormality determined by the investigator to be beyond the normal safety limits. Infectious conditions such as HIV, active hepatitis B or C, and recent COVID-19 infection are disqualifying factors. A history of drug abuse, positive toxicology screening for certain drugs, or recreational intravenous drug use also leads to exclusion. Use of drugs affecting glucose metabolism, weight loss, or herbal remedies within a specific time frame will result in disqualification unless deemed appropriate by the investigator. Participants who have received the study product within the past 90 days or have a severe allergic reaction, hypersensitivity to GLP-1 analogs, or any medical, psychiatric, or social condition that may interfere with adherence to the study are ineligible. Finally, individuals whom the researchers deem unlikely or unwilling to comply with the study protocol are excluded.

[0177] Randomization and stratification Eligible participants were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups using an Interactive Network Response System (IWRS): Group (1) ALT-801 1.2 mg subcutaneously (SC) once weekly for 48 weeks; Group (2) ALT-801 1.8 mg SC once weekly for 48 weeks; Group (3) ALT-801 0.6 mg SC for 1 week, followed by 1.2 mg SC for 1 week, then 1.8 mg SC once weekly for 2 weeks, and 2.4 mg SC once weekly for 44 weeks; or Group (4) placebo SC once weekly for 48 weeks. Treatment was based on sex and baseline body mass index (BMI < 35 kg / m²). 2 Compared to ≥35kg / m 2 Randomization was stratified, with a target of at least 25% of randomized participants being male. Participants were instructed to escalate to or maintain the target dose without discontinuing the titration protocol or reducing the dose tolerable levels. However, if intolerance was experienced, treatment could be continued for up to two weeks.

[0178] Research drugs The study drug was provided as a pre-filled syringe (PFS) for administration, and all syringes were matched in volume and appearance. Throughout the study, investigators, participants, and researchers remained unaware of treatment allocation. The pemvidutide injection in the PFS was a sterile solution in a pre-filled syringe (1 mL / syringe). Each pre-filled syringe contained 1 mL of the drug product solution of a specified strength and was intended for use in SC administration. The quantitative information for the excipients (mannitol, arginine, and polysorbate 20) in the PFS formulation was identical to that in the pemvidutide injection vial. The pemvidutide injection in the PFS was presented for SC administration in three different strengths (1.2 mg / mL, 1.8 mg / mL, and 2.4 mg / mL). Different strengths were achieved by reconstituted different concentrations of pemvidutide using the same 1 mL syringe fill volume. The quantitative composition of the three strengths is presented in Table 1.

[0179] Table 1: Quantitative Composition - Pemvidutide Injection in PFS program Throughout the study, participants attended regular visits, which were conducted telemedicine where feasible. The study product (IP) was administered according to protocol guidelines. Participants were advised to follow a reduced-calorie diet of 1200–1500 calories per day for individuals weighing <250 lb (113.6 kg) and 1500–1800 calories per day for individuals weighing ≥250 lb (113.6 kg). Gradual increase in physical activity was recommended, with a target of 150 minutes per week. Adherence to the lifestyle intervention was assessed regularly by the investigator. The investigator adhered to predetermined decision-making criteria regarding the timing and method of intervention for participants experiencing worsening abnormal liver function tests. If necessary, dose interruptions were monitored and discussed with the medical monitor for reasons including illness, inability to attend clinic visits, adverse events (AEs), and laboratory abnormalities. Participants who discontinued their dose due to safety or tolerability issues could choose to permanently discontinue treatment, while continued study evaluation was encouraged. Participants were educated on recognizing and managing hypoglycemia and instructed to use a glucometer to measure random blood glucose levels when symptoms occurred. If a participant's blood glucose reading is below 70 mg / dL (3.9 mmol / L), the participant contacts the investigator. Treatment for hyperglycemia, defined as fasting blood glucose ≥180 mg / dL (≥10 mmol / L), is administered according to the pre-defined protocol. Changes in body composition are assessed via magnetic resonance imaging (MRI) in the sub-study. Rare blood samples are collected to analyze the pharmacokinetics of ALT-801 and assess the efficacy relevance of immunogenicity and anti-drug antibody (ADA) titers. Participants who fail screening due to unacceptable prior or concomitant medications are eligible for rescreening at the discretion of the medical monitor. Laboratory values ​​outside the acceptable range may be reassessed once during the screening period. Blood pressure criteria for eligibility may be reassessed with one additional reading during the screening period. A non-blinded interim analysis is performed when approximately 160 participants complete 24 weeks of treatment or withdraw early. The safety of the study is overseen by the Independent Data Monitoring Committee (iDMC), which is responsible for adjudicating major adverse cardiac events (MACE) and AEs associated with acute pancreatitis. Their roles and responsibilities are detailed in the iDMC charter. Participants were communicated with measures to minimize COVID-19 risk. Participants were not prevented from receiving approved or emergency use authorized COVID-19 vaccines or treatments during trial participation. An IP (intra-injection) window of ±2 days was permitted if the COVID-19 vaccine administration was close to the planned dose. Height, weight, waist circumference, and vital signs (systolic and diastolic blood pressure, and heart rate) were measured at baseline and repeated every 4 weeks or less throughout the trial, except for height. Additional assessments included fasting blood glucose, HbA1c, and serum lipids.

[0180] end The primary efficacy endpoint was the relative change (%) in body weight from baseline at 48 weeks. Secondary endpoints included the proportion of subjects achieving ≥5%, ≥10%, ≥15%, and ≥20% weight loss at 48 weeks. Other secondary efficacy endpoints included changes in fasting lipids (total cholesterol, HDL, IDL, LDL, VLDL cholesterol, Apo AI, Apo AII, Apo B, lipoprotein(a), and triglycerides), glycemic homeostasis and insulin resistance (HbA1c, fasting blood glucose, fasting insulin, HOMA-IR), systolic and diastolic blood pressure from baseline, and concomitant use of antihypertensive medications. Exploratory endpoints included body composition measured by MRI in sub-studies. Metabolic and inflammatory markers were also analyzed. Additionally, patient-reported outcomes related to weight-related quality of life and general health status were assessed using IWQOL-Lite, SF-36, and PGI-C. Safety endpoints included adverse events (AEs), such as GI tolerance (nausea, vomiting, diarrhea, constipation), hyperglycemia, hypoglycemia, injection site reactions, and major adverse cardiac events (MACEs) (non-fatal stroke, non-fatal myocardial infarction, or cardiovascular death). Vital signs were monitored, including heart rate, blood pressure, and heart rate-blood pressure product. Safety laboratory tests (liver function tests, blood glucose, amylase, and lipase), 12-lead ECG, physical examination, and immunogenicity (ADA titer) were also evaluated. Pharmacokinetic (PK) endpoints included ALT-801 population PK analysis and PK-PD modeling.

[0181] Example 3: Results from the 48-week phase 2 obesity trial in pemvidutide (Momentum study: NCT05295875) The trial recruited 391 male and female participants aged 18-75 (at least approximately 25% of whom were male) who were obese (BMI). > 30kg / m 2 or overweight (BMI) > 27kg / m 2 ), has at least one obesity-related comorbidity (a history of cardiovascular disease, hypertension, dyslipidemia, prediabetes (e.g., abnormal blood glucose), and / or obstructive sleep apnea) and does not have diabetes (HbA1c). < 6.5% and fasting blood glucose < 125 mg / dl), with at least one unsuccessful attempt at weight loss, as detailed in Example 2. See also Figures 1-2 At baseline, the participants had a mean age of approximately 50 years and a mean body mass index (BMI) of approximately 37 kg / m². 2 And their average weight is about 104kg.

[0182] At week 48, subjects receiving pemvidutide (i.e., SEQ ID NO:1) achieved relative weight loss of 10.3%, 11.2%, 15.6%, and 2.2% at doses of 1.2 mg, 1.8 mg, and 2.4 mg, and placebo, respectively, with a near-linear trajectory of sustained weight loss observed at the 2.4 mg dose at the end of treatment. See also Figures 3-4 At week 48, subjects receiving pemvidutide achieved absolute weight loss of 3.5%, 20.1%, 20.7%, and 32.2% at doses of 1.2 mg, 1.8 mg, and 2.4 mg, and with placebo, respectively. See also Figure 5 At a 2.4 mg dose, over 50% of participants achieved at least 15% weight loss, and over 30% achieved at least 20% weight loss. See also Figures 6-7 A significant decrease in BMI was also observed at week 48. See also Figure 8 Weekly administration of pemvidutide for 48 weeks resulted in a significant decrease in serum lipids (see [link]). Figures 9-10 (In subjects with elevated baseline levels) and improvement in blood pressure, without any imbalance of cardiac events, arrhythmias, or clinically significant increase in heart rate. See also Figure 11 Maintaining steady-state blood glucose levels, with no significant changes in fasting blood glucose or HbA1c. See also Figure 12 More participants receiving pemvidutide remained in the study compared to those receiving placebo; 74.1% of pemvidutide participants completed the trial, compared to 61.9% of placebo participants. Nausea and vomiting constituted the majority of adverse events (AEs), and their severity was primarily mild to moderate. See also Figure 13Only one (1.0%) subject experienced a drug-related serious adverse event (SAE), namely vomiting at the 2.4 mg dose. The proportion of AEs leading to treatment discontinuation was 6.2% in subjects receiving placebo, 5.1%, 19.2%, and 19.6% in subjects receiving 1.2 mg, 1.8 mg, and 2.4 mg pemvidutide, respectively. Study drug-related discontinuation occurred in 2.1% of placebo subjects and 4.1%, 16.2%, and 15.5% of subjects receiving 1.2 mg, 1.8 mg, and 2.4 mg pemvidutide, respectively, with most discontinuations due to AEs occurring within the first 16 weeks of treatment in the pemvidutide group. No AEs of particular interest or major adverse cardiac events (MACEs) were observed, and the incidence of cardiac AEs (including arrhythmias) was low, with no imbalance between the pemvidutide and placebo groups. The efficacy results are summarized in Tables 2-5, and the safety and tolerability findings are summarized in Tables 6 and 7 below.

[0183] Table 2 Table 3 Table 4 Table 5 1 MMRM (Mixed Model of Repeated Measures), 2 CMH (Cochran Mantel Haenszel), 3 ANCOVA (Analysis of Covariance) p<0.05; p<0.005; p<0.001; p<0.0001, compared with placebo Table 6 Table 7 In summary, the data show that after weekly administration of 2.4 mg for 48 weeks, pemvidutide resulted in a robust mean weight loss of 15.6%, with a mean and maximum weight loss of 32.2 and 87.1 lbs, respectively. More than 30% of subjects experienced a weight loss of 20% or more after weekly administration of 2.4 mg for 48 weeks. Sustained weight loss was also observed after weekly administration of 2.4 mg for 48 weeks. Significant and clinically meaningful reductions in total cholesterol, LDL, triglycerides, and blood pressure were also observed. Regarding safety and tolerability, the severity of common glucagon-based adverse events (GI AEs) was predominantly mild to moderate, no imbalance of cardiac AEs (including arrhythmias) was observed, no clinically meaningful increase in heart rate was observed, and glycemic homeostasis was maintained.

[0184] This document provides, in some embodiments, a method for treating long-term weight management in a human with a corresponding need, comprising administering once weekly to the human a therapeutically effective dose of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1, and wherein the human with the corresponding need has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea.

[0185] In some embodiments, this document provides a method for treating long-term weight management in humans with corresponding needs, comprising administering to the human once weekly a therapeutically effective amount of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1, and wherein the treatment also reduces serum lipids.

[0186] In some embodiments, this document provides a method of treatment for reducing serum lipids in a human with a corresponding need, comprising administering to the human once weekly a therapeutically effective amount of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1.

[0187] Example 4: Body Composition Before and after treatment, a subgroup of 50 subjects from Example 2 underwent a comprehensive magnetic resonance imaging (MRI)-based body composition analysis. Results indicated that subjects treated with pemvidutide (SEQ ID NO:1) showed a mean lean body mass reduction rate of approximately 21.9% (defined as the change in lean mass divided by the change in total mass). See also Figure 14 This percentage is lower than those reported for diet and exercise alone, as well as other weight-loss agents such as telpolide, semaglutide, and retaloglutide. See also Figure 15A It is noteworthy that older subjects maintained similar levels of lean body mass. See also Figure 16 Reduced lean body mass in older subjects may be beneficial in reducing the risk of falls and fractures, which are known problems when lean body mass is lost to a significant degree. Maintaining lean body mass during weight loss is crucial because excessive lean body mass loss is associated with adverse consequences, including sarcopenia and fractures, particularly in women and older adults. Furthermore, body composition analysis revealed that the majority of weight loss (78.1%) was attributed to fat reduction. More specifically, visceral adipose tissue (a fat reservoir associated with cardiovascular risk) was reduced by 28.3% at a dose of 2.4 mg pemvidutide. See also Figure 15B At this dose, subcutaneous adipose tissue also decreased by 19.5%. See also Figure 15C Overall, MRI-based body composition analysis confirmed the preferential loss of adipose tissue relative to lean tissue in subjects treated with pemvidutide.

[0188] Example 5: Lipidomics Lipomics analysis was performed on plasma samples from participants in the Momentum study NCT05295875. Analysis was conducted in the placebo group (n=52), the 1.2 mg dose group (n=72), the 1.8 mg dose group (n=69), and the 2.4 mg dose group (n=61), comparing baseline, week 24, and week 48. Lipomics analysis included the use of ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) to examine changes in 470 lipid species across 63 lipid classes. Considering the scope of the dataset, Table 8 presents only the results of the log2 fold change (FC) and statistical significance (P) at weeks 24 and 48 for lipid species regrouped into the 63 lipid classes from the 2.4 mg dose group compared to baseline. Over 24 weeks of treatment, pemvidutide significantly reduced serum lipid levels across various lipid classes, particularly glycerides (diglycerides and triglycerides), glycerophospholipids (phosphatidylethanolamine, phosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylcholine), and sphingolipids (ceramides and sphingomyelin), which are associated with reduced cardiovascular (CV) risk and insulin resistance. Obesity has been shown to be associated with increased circulating levels of glycerol lipids, including diglycerides (DG) and triglycerides (TG). This could represent a potential risk factor for comorbidity, as DG is considered a lipotoxic substance associated with hepatic insulin resistance, and elevated triglyceride levels are strongly associated with inadequate glycemic control and an increased risk of diabetes, cardiovascular disease, or MASLD / MASH. Obesity is generally associated with abnormally low levels of circulating free fatty acids in the presence of pemvidutide. Pemvidutide also reduced plasma bile acids (BA), which have been shown to be positively correlated with body mass index. Pemvidutide induced a consistent decrease in most sterols, while no changes were detected in the placebo arm. Regarding PE, in both the 24-week and 48-week intervention periods, pemvidutide treatment resulted in a consistent reduction in the vast majority of diacyl-, hemolysin-, and ether-linked forms of these glycerophospholipids compared to baseline. Regarding phosphatidylcholine (PC), placebo treatment resulted in only minor, significant changes regardless of PC class. Pemvidutide treatment led to a consistent reduction across the entire PC spectrum. Pemvidutide also resulted in substantial reductions in ceramides (Cer), sphingomyelin (SM), monohexosylceramides (CMHs), and free sphingosine bases (FSB). Similar trends were observed at 1.2 mg and 1.8 mg doses, while limited to no significant changes were observed in the placebo group.

[0189] Table 8 Legend: FA = Fatty acid, Ox. FA = Oxidized fatty acid, AC = Acylcarnitine, GL = Glycerides, BA = Bile acids, ST = Sterols, GPL = Glycerophospholipids, SL = Sphingolipids, FC = Log2 robust fold change (log2), P = Wilcoxon signed rank. An underlined P-value indicates significance ≤ 0.05. Additionally, the same samples were subjected to glycoscale testing using nuclear magnetic resonance (NMR) spectroscopy. Liposcale allows for the determination of both a basic lipid profile consisting of total cholesterol, LDL-c, HDL-c, non-HDL, and triglycerides, and a more advanced lipoprotein profile, which includes the lipid composition, particle size (Z), and concentration (P) of the major lipoprotein classes (VLDL, LDL, IDL, and HDL). This comprehensive characterization of the blood lipoprotein profile addresses cardiovascular disease (CVD) risk. This comprehensive characterization of the lipoprotein profile helps in the detection of individuals at increased CVD risk. Glycoscale uses the same technique to determine the presence of glycosylated proteins in serum, an indicator of systemic inflammatory processes. More specifically, it measures protein-bound N-acetylglucosamine and N-acetylgalactosamine (Glyc-A), protein-bound N-acetylneuraminic acid (Glyc-B), and any one of the three acetyl groups not bound to the protein (Glyc-F). From these three peaks, it distinguishes their area (related to concentration) and height / width ratio (describing peak shape). Considering the scope of the dataset, Table 9 presents only the results of the log2 fold change (FC) and statistical significance (P) at weeks 24 and 48 compared to baseline for lipid species regrouped into 63 lipid classes from the 2.4 mg dose group. Pemvidutide treatment reduced cholesterol and TG concentrations. Furthermore, it reduced the HDL-TG / HDL-C ratio and the total amount of VLDL and LDL. Additionally, pemvidutide promoted an increase in VLDL particle size. All these changes suggest a reduced risk of cardiovascular events and a decrease in inflammatory characteristics. Some of these results have also been identified in other intervention studies on obesity, including some testing the effects of different bariatric surgeries, with similar trends observed for the 1.2 mg and 1.8 mg doses, while no significant changes were observed in the placebo group.

[0190] Table 9 P = number of particles, Z = particle size. H / W = height / width ratio. An underlined P value indicates significance ≤ 0.05. As will be appreciated by those skilled in the art, this document also provides other advantages of the reagents and methods of using said reagents. While certain embodiments have been described according to preferred embodiments, it should be understood that variations and modifications will occur to those skilled in the art. Therefore, the appended claims are intended to cover all such equivalent variations falling within the scope of the appended claims.

Claims

1. A method for treating long-term weight management in a human with a corresponding need, comprising administering a therapeutically effective amount of a pharmaceutical dosage form to the human once weekly, the pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1, and wherein the human with the corresponding need has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea.

2. The method of claim 1, wherein the treatment further reduces serum lipids.

3. A method for treating long-term weight management in humans with corresponding needs, comprising administering a therapeutically effective amount of a pharmaceutical dosage form to the human once weekly, said pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:1, and wherein said treatment also reduces serum lipids.

4. The method of claim 3, wherein the human being in need has one or more comorbidities selected from cardiovascular disease, hypertension, dyslipidemia, dysglycemia, and obstructive sleep apnea.

5. The method according to any of the preceding claims, wherein the peptide product is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the peptide of SEQ ID NO:

1.

6. The method according to any of the preceding claims, wherein the peptide product is 100% identical to the peptide of SEQ ID NO:

1.

7. The method according to any of the preceding claims, wherein the drug dosage form is administered subcutaneously or via parenteral injection.

8. The method according to any of the preceding claims, wherein the drug dosage is an aqueous formulation comprising one or more of polysorbate 20, arginine, or mannitol.

9. The method according to any of the preceding claims, wherein the pharmaceutical dosage formulation comprises about 0.025%-0.5% (w / w) polysorbate 20, about 0.2%-0.5% (w / w) arginine and about 3%-6% (w / w) mannitol in water (pH 7.7±0.1).

10. The method according to any of the preceding claims, wherein the pharmaceutical dosage form comprises about 0.2% (w / w) polysorbate 20, about 0.348% (w / w) arginine, and about 4.260% (w / w) mannitol in water (pH 7.7 ± 0.1).

11. The method according to any of the preceding claims, wherein the human being is obese or overweight.

12. The method according to any of the preceding claims, wherein the human being in need has a body mass index (BMI kg / m²) of at least 25. 2 ).

13. The method according to any of the preceding claims, wherein the human being in need has a body mass index (BMI kg / m²) of at least 30. 2 ).

14. The method according to any of the preceding claims, wherein the human with the corresponding need has a body mass index (BMI kg / m²) of at least 35. 2 ).

15. The method according to any of the preceding claims, wherein the human being in need has a body mass index (BMI kg / m²) of at least 40. 2 ).

16. The method according to any of the preceding claims, wherein the treatment maintains weight loss.

17. The method according to any of the preceding claims, wherein the treatment results in a relative weight reduction of at least about 10%, at least about 15%, or at least about 20%.

18. The method according to any of the preceding claims, wherein the treatment results in a reduction of lean body mass of less than about 25%.

19. The method according to any of the preceding claims, wherein the human with the corresponding need has an HbA1C value of about 5.7% to 6.4%.

20. The method according to claims 1-14, wherein the human with the corresponding need has an HbA1C value of about 4.0% to 5.6%.

21. The method according to any of the preceding claims, wherein the pharmaceutical dosage form comprises about 1.2 mg of the peptide product.

22. The method according to any of the preceding claims, wherein the pharmaceutical dosage form comprises about 1.8 mg of the peptide product.

23. The method according to any of the preceding claims, wherein the pharmaceutical dosage form comprises about 2.4 mg of the peptide product.

24. The method according to any of the preceding claims, wherein the pharmaceutical dosage form comprises a peptide product (2.4 mg / mL; 0.24% (w / w)) in sterile water; mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)).

25. The method according to any of the preceding claims, wherein the pharmaceutical dosage form comprises a peptide product (1.8 mg / mL; 0.18% (w / w)) in sterile water; mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)).

26. The method according to any one of the preceding claims, wherein the pharmaceutical dosage form comprises a peptide product (1.2 mg / mL; 0.12% (w / w)) in sterile water; mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)).

27. The method according to any of the preceding claims, wherein the treatment reduces one or more serum lipids selected from serum triglycerides, total serum cholesterol, serum LDL, or serum VLDL.

28. The method according to any of the preceding claims, wherein the treatment reduces serum triglycerides by at least about 30% after 48 weeks.

29. The method according to any of the preceding claims, wherein the treatment reduces total serum cholesterol by at least about 10% after 48 weeks.

30. The method according to any of the preceding claims, wherein the treatment reduces total serum cholesterol by at least about 15% after 48 weeks.

31. The method according to any of the preceding claims, wherein the treatment reduces serum LDL by at least about 10% after 48 weeks.

32. The method according to any of the preceding claims, wherein the treatment reduces serum VLDL by at least about 25% after 48 weeks.

33. The method according to any of the preceding claims, wherein the treatment reduces serum triglycerides by at least about 30% after 48 weeks in appropriately needed humans with baseline triglycerides >150 mg / dL.

34. The method according to any of the preceding claims, wherein the treatment reduces serum triglycerides by at least about 50% after 48 weeks in appropriately needed humans with baseline triglycerides >150 mg / dL.

35. The method according to any of the preceding claims, wherein the treatment reduces serum cholesterol by at least about 15% after 48 weeks in appropriately needed humans with baseline cholesterol >200 mg / dL.

36. The method according to any of the preceding claims, wherein the treatment reduces serum cholesterol by at least about 20% after 48 weeks in appropriately needed humans with baseline cholesterol >200 mg / dL.

37. The method according to any of the preceding claims, wherein the treatment reduces serum LDL by at least about 15% after 48 weeks in appropriately needed humans with baseline LDL >130 mg / dL.

38. The method according to any of the preceding claims, wherein the treatment reduces serum LDL by at least about 20% after 48 weeks in appropriately needed humans with baseline LDL >130 mg / dL.

39. The method according to any of the preceding claims, wherein a steady-state therapeutic dose is reached after a dose escalation phase lasting two to four weeks.

40. A method of treatment for lowering serum lipids in a human with a corresponding need, comprising administering, once weekly, a therapeutically effective amount of a pharmaceutical dosage form comprising at least 1.2 mg and up to 2.4 mg of the peptide product according to SEQ ID NO:1, or a peptide product that is at least 80% identical to the peptide of SEQ ID NO:

1.

41. The method of claim 40, wherein the human being in need has one or more comorbidities selected from obesity, cardiovascular disease, hypertension, dyslipidemia, dysglycemia, type 2 diabetes, and obstructive sleep apnea.

42. The method according to claim 40 or 41, wherein the peptide product is at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the peptide of SEQ ID NO:

1.

43. The method according to claim 40 or 41, wherein the peptide product is 100% identical to the peptide of SEQ ID NO:

1.

44. The method according to claims 40-43, wherein the drug dosage formulation is administered subcutaneously or via parenteral injection.

45. The method according to claims 40-44, wherein the drug dosage is an aqueous formulation comprising one or more of polysorbate 20, arginine, or mannitol.

46. ​​The method according to any one of claims 40-45, wherein the pharmaceutical dosage formulation comprises about 0.025%-0.5% (w / w) polysorbate 20, about 0.2%-0.5% (w / w) arginine and about 3%-6% (w / w) mannitol in water (pH 7.7 ± 0.1).

47. The method according to any one of claims 40-46, wherein the pharmaceutical dosage formulation comprises about 0.2% (w / w) polysorbate 20, about 0.348% (w / w) arginine, and about 4.260% (w / w) mannitol in water (pH 7.7 ± 0.1).

48. The method according to any one of claims 40-47, wherein the human being is obese or overweight.

49. The method according to any one of claims 40-48, wherein the human with the corresponding need has a body mass index (BMI kg / m²) of at least 25. 2 ).

50. The method according to any one of claims 40-49, wherein the human with the corresponding need has a body mass index (BMI kg / m²) of at least 30. 2 ).

51. The method according to any one of claims 40-50, wherein the human with the corresponding need has a body mass index (BMI kg / m²) of at least 35. 2 ).

52. The method according to any one of claims 40-51, wherein the human with the corresponding need has a body mass index (BMI kg / m²) of at least 40. 2 ).

53. The method according to any one of claims 40-52, wherein the treatment maintains weight loss.

54. The method according to any one of claims 40-53, wherein the treatment reduces relative body weight by at least 10%, at least 15%, or at least 20%.

55. The method according to any one of claims 40-54, wherein the treatment results in a reduction of lean body mass of less than about 25%.

56. The method according to any one of claims 40-55, wherein the human with the corresponding need has an HbA1C value of about 5.7% to 6.4%.

57. The method according to claims 40-56, wherein the human with the corresponding need has an HbA1C value of about 4.0% to 5.6%.

58. The method according to claims 40-57, wherein the pharmaceutical dosage form comprises about 1.2 mg of the peptide product.

59. The method according to claims 40-58, wherein the pharmaceutical dosage form comprises about 1.8 mg of the peptide product.

60. The method according to claims 40-59, wherein the pharmaceutical dosage form comprises about 2.4 mg of the peptide product.

61. The method according to claims 40-60, wherein the pharmaceutical dosage formulation comprises a peptide product (2.4 mg / mL; 0.24% (w / w)) in sterile water; mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)).

62. The method according to claims 40-61, wherein the pharmaceutical dosage formulation comprises a peptide product (1.8 mg / mL; 0.18% (w / w)) in sterile water; mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)).

63. The method according to claims 40-62, wherein the pharmaceutical dosage formulation comprises a peptide product (1.2 mg / mL; 0.12% (w / w)) in sterile water; mannitol (42.6 mg / mL; 4.26% (w / w)); arginine (3.48 mg / mL; 0.348% (w / w)); and polysorbate 20 (2 mg / mL; 0.2% (w / w)).

64. The method according to claims 40-63, wherein the treatment reduces one or more of serum triglycerides, total serum cholesterol, serum LDL, or serum VLDL.

65. The method according to claims 40-64, wherein the treatment reduces serum triglycerides by at least about 20% after 48 weeks.

66. The method according to claims 40-65, wherein the treatment reduces serum triglycerides by at least about 30% after 48 weeks.

67. The method according to claims 40-66, wherein the treatment reduces total serum cholesterol by at least about 10% after 48 weeks.

68. The method according to claims 40-67, wherein the treatment reduces total serum cholesterol by at least about 15% after 48 weeks.

69. The method according to claims 40-68, wherein the treatment reduces serum LDL by at least about 10% after 48 weeks.

70. The method according to claims 40-69, wherein the treatment reduces serum LDL by at least about 20% after 48 weeks.

71. The method according to claims 40-70, wherein the treatment reduces serum VLDL by at least about 25% after 48 weeks.

72. The method according to claims 40-71, wherein the treatment reduces serum triglycerides by at least about 30% after 48 weeks in eligible humans with baseline triglycerides >150 mg / dL.

73. The method according to claims 40-72, wherein the treatment reduces serum triglycerides by at least about 50% after 48 weeks in eligible humans with baseline triglycerides >150 mg / dL.

74. The method according to claims 40-73, wherein the treatment reduces serum cholesterol by at least about 15% after 48 weeks in eligible humans with baseline cholesterol >200 mg / dL.

75. The method according to claims 40-74, wherein the treatment reduces serum cholesterol by at least about 20% after 48 weeks in eligible humans with baseline cholesterol >200 mg / dL.

76. The method according to claims 40-75, wherein the treatment reduces serum LDL by at least about 15% after 48 weeks in correspondingly needy humans with baseline LDL >130 mg / dL.

77. The method according to claims 40-76, wherein the treatment reduces serum LDL by at least about 20% after 48 weeks in correspondingly needy humans with baseline LDL >130 mg / dL.

78. The method according to claims 40-77, wherein a steady-state therapeutic dose is reached after a dose escalation phase lasting two to four weeks.

Images