GLP-1 analogs for treatment of metabolic disorders

Abstract

The present disclosure relates to methods of using GLP-1 analogs and compositions thereof to treat metabolic disorders, such as obesity, diabetes, fatty liver disease associated with metabolic dysfunction (MASLD), steatohepatitis associated with metabolic dysfunction (MASH), and hypertriglyceridemia. More specifically, the present disclosure relates to a method for treating obesity in a subject comprising administering to the subject a therapeutically effective amount of GL0034. The disclosure also relates to a method for treating a metabolic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of GL0034. The disclosure further relates to compositions comprising GL0034 for use in the treatment of obesity, diabetes, or other metabolic disorders in a subject.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of Indian Application No. 202321042015, filed on June 20, 2023, and Indian Application No. 202421015451, filed on March 1, 2024, the disclosure of each of which is incorporated herein by reference in its entirety.

[0003] sequence list

[0004] This application contains a sequence list that has been submitted electronically and is hereby adopted in its entirety. The sequence list submitted herewith is contained in an XML file named “23-0927-WO_ Sequence-Listing.xml” created on June 6, 2024, and is 4,096 bytes in size. Technical Field

[0005] This disclosure relates to methods of treating metabolic disorders such as obesity, diabetes, metabolic dysfunction-associated fatty liver disease (MASLD) (sometimes referred to in the literature as non-alcoholic fatty liver disease (NAFLD)), metabolic dysfunction-associated steatohepatitis (MASH) (sometimes referred to in the literature as non-alcoholic steatohepatitis (NASH)), and hypertriglyceridemia using GLP-1 analogs and compositions thereof. More specifically, this disclosure relates to a method for treating obesity in a subject, the method comprising administering a therapeutically effective amount of GL0034 to the subject. This disclosure also relates to a method for treating metabolic disorders in a subject in need, the method comprising administering a therapeutically effective amount of GL0034 to the subject. This disclosure further relates to compositions containing GL0034 for treating obesity, diabetes, or other metabolic disorders in a subject. Background Technology

[0006] As of 2016, obesity was estimated to affect 13% of adults, with its prevalence nearly tripling since 1975. World Health Organization, 2021, “Obesity and Overweight,” available on the WHO website (accessed June 18, 2023). An estimated 2% of obese U.S. adults received drug therapy for obesity in 2015. Xia et al., Obesity (… Obesity ) (Silver Spring) 23(8): 1721-28 (2015); Samaranayake et al., Annals of Epidemiology ( Ann. EpidemiolObesity significantly increases all-cause mortality in affected individuals, primarily due to its association with increased risk of cardiovascular disease and diabetes. Global BMI Mortality Collaboration et al., *The Lancet* (2012). Lancet )》 388(10046): 776-86 (2016); GBD 2015 Obesity Collaborators et al., The New England Journal of Medicine ( N. Engl. J. Med .)》 377(1): 13-27 (2017); Powell-Wiley et al., Circulation ( Circulation )》 143(21): e984-e1010 (2021); Khan et al., JAMA Cardiology ( JAMA Cardiol. )》 3(4): 280-87 (2018); Nguyen et al., "Obesity Surgery ( Obes. Surg .)》 21(3): 351-55 (2011).

[0007] Diabetes is a chronic metabolic disease that affects approximately 422 million people worldwide and causes 1.5 million deaths annually. World Health Organization, “Diabetes,” available on the WHO website (accessed June 18, 2023). Diabetes is characterized by elevated blood sugar levels, which over time lead to serious damage to the heart, blood vessels, eyes, kidneys, and nerves. Ibid. The most common type of diabetes is type 2 diabetes, which occurs when the body develops resistance to insulin or is unable to produce enough insulin. Ibid.

[0008] Nonalcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated fatty liver disease (MASLD), and nonalcoholic steatohepatitis (NASH), now known as metabolic dysfunction-associated steatohepatitis (MASH), are highly associated with obesity and type 2 diabetes. Boland et al., *Nature Metabolism* (… Nat. Metab .)》 2(5):413-31 (2020), Rinella et al., Hepatology ( Heptaology )》, 78(6): 1966-86 (2023). NAFLD is very common in patients with type 2 diabetes, as approximately two-thirds of such patients are diagnosed with the disease. Cusi et al., Recent Perspectives on Endocrinology, Diabetes and Obesity ( Curr. Opin. Endocrinol. Diabetes Obes .)》 16(2): 141-49 (2009). Furthermore, type 2 diabetes is a contributing factor to NAFLD because it increases the risk of NASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma. El-Serag et al, Hepatology (Hepatology )》 60(5): 1767-75 (2014). Currently, the only proven treatment for NAFLD is weight loss.

[0009] Glucagon-like peptide-1 (GLP-1) is a hormone primarily produced in enteroendocrine L cells of the intestine and secreted into the bloodstream when food containing fats, protein hydrolysates, and / or glucose enters the duodenum. GLP-1 originates from cell-specific post-translational processing of the proglucagon gene. Initially, the peptide GLP-1(1-37) was identified from this process, but it is actually two N-terminally truncated products, GLP-1(7-37) and GLP-1(7-36) amide, which were found to recognize pancreatic receptors and were identified as the active species in vivo. GLP-1 has been found to stimulate insulin secretion, thereby causing glucose uptake through cells and a reduction in serum glucose levels.

[0010] Glucagon-like peptide-1 (GLP-1) receptor agonists have been shown to provide reductions in glycated hemoglobin (HbA1c) and weight loss in type 2 diabetes. Andersen et al., *Nature Reviews Endocrinology* Nat. Rev. Endocrinol .)》 14(7): 390-403 (2018). Some GLP-1 receptor agonists have been shown to improve glycemic control in adults with type 2 diabetes. Zhao et al., Frontiers in Endocrinology ( Front. Endocrinol. ) (Lausanne) Mol. Metab 12: 721135 (2021); Nauck et al., Molecular Metabolism ( Diabetes Care GLP-1 receptor agonists reduce glucose by a combination of multiple effects, including direct action on GLP-1 receptors in pancreatic β cells, which enhances glucose-stimulated insulin secretion, inhibits glucagon release, sensitizes insulin due to weight loss, and reduces hepatic glucose output mediated by neurons. Müller et al., Molecular Metabolism 30: 72-130 (2019). Therefore, GLP-1 receptor agonists have been shown to be an appropriate therapy for individuals with type 2 diabetes. Buse et al., Diabetes Care ( Diabetes Obes. Metab )》 43(2): 487-93 (2020).

[0011] GLP-1 agonists such as semaglutide and tirzepatide are typically prescribed for patients with at least one weight-related metabolic comorbidity who are overweight (≥ 27 kg / m²). 2), which aims to reduce body weight and associated risks due to metabolic conditions. Treatment is performed with subcutaneous administration once weekly in the abdomen, thigh, or upper arm. The initial dosing for semaglutide (WEGOVY ) is 0.25 mg once weekly for 4 weeks, followed by a titration every 4 weeks to achieve a maintenance dose, where the maintenance dose is between 1.7 mg and 2.4 mg (see WEGOVY label). The initial dosing for tirzepatide (ZEPBOUND ) is 2.5 mg once weekly for 4 weeks, followed by an increase in dose by 2.5 mg after at least 4 weeks, where the maintenance dose is 5 mg, 10 mg, or 15 mg (see ZEPBOUND label).

[0012] Treatment with GLP-1 receptor agonists also provides additional beneficial metabolic effects, such as improvements in lipid profiles and resolution of hepatic steatosis. Jones et al., Diabetes, Obesity and Metabolism 24(11): 2090-101 (2022). Animal model studies suggest that certain GLP-1 receptor agonists can have beneficial effects on liver fat content and nonalcoholic steatohepatitis (NASH), while recent human studies evaluating GLP-1 receptor agonists in populations with type 2 diabetes and obesity suggest that treatment with certain GLP-1 receptor agonists can represent a new alternative for the management of nonalcoholic fatty liver disease (NAFLD) and NASH. Newsome et al., Journal of Clinical Gastroenterology 50(2): 193-203 (2019); Newsome et al., New England Journal of Medicine, 384(12): 1113-24 (2021). Certain GLP-1 receptor agonists have also been shown to reduce body weight in obese individuals. Ma et al., International Journal of Biological Sciences 17(8): 2050-68 (2021); Ard et al., Therapeutic Advances in Chronic Disease 38(6): 2821-39 (2021). Aliment. Pharmacol. Ther Int. J. Biol. Sci Adv. Ther Figure 1

[0013] ​​​​GL0034 is a novel incretin analog based on the sequence of native GLP-1 that has potent G protein-biased long-acting agonist activity at the GLP-1 receptor that efficiently lowers glucose and triglyceride levels and body weight in mice. Jones et al., Diabetes, Obesity and Metabolism 24(11): 2090-101 (2022). This agonist shares some structural homology with another GLP-1 receptor agonist, but it has a different linker sequence between the polypeptide chain and the acyl group of albumin binding, which can affect its pharmacological properties. Id. The performance of GL0034 has been described in vitro and in vivo compared to other commercially available compounds using various models. Id. International Publication No. WO 2019 / 193576 Al discloses a group of novel GLP-1 receptor agonists (or analogs) that have an amino acid sequence with a leucine or isoleucine residue at the C-terminus (SEQ ID NO: 1, shown below in Formula I), and are also acylated with a prolonging moiety to further improve their potency and duration of action, which is incorporated by reference herein in its entirety. GL0034 (see Compound #16 in Table 2 of International Publication No. WO 2019 / 193576 Al) can be represented by the following Formula I compound: SUMMARY

[0014] The present disclosure relates to methods and compositions for treating obesity. The present disclosure also relates to methods and compositions for treating metabolic disorders, such as metabolic dysfunction-associated steatohepatitis (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), diabetes, and hypertriglyceridemia. More specifically, the present disclosure relates to methods for treating obesity in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034. The present disclosure also relates to methods for treating a metabolic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of GL0034. The present disclosure further relates to methods for treating hypertension in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034. The present disclosure further relates to compositions comprising GL0034 for treating obesity or a metabolic disorder or hypertension in a subject.

[0015] Provided herein is a method of treating obesity in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034. Also provided herein is a method of treating a metabolic disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034. Further provided herein is a method of treating hypertension in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034.

[0016] Further provided herein is a pharmaceutical composition for treating obesity in a subject, the pharmaceutical composition comprising GL0034. Further provided herein is a pharmaceutical composition for treating a metabolic disorder in a subject, the pharmaceutical composition comprising GL0034. Further provided herein is a pharmaceutical composition for treating hypertension in a subject, the pharmaceutical composition comprising GL0034.

[0017] Further provided herein is the use of GL0034 for the manufacture of a medicament for treating obesity in a subject. Further provided herein is the use of GL0034 for the manufacture of a medicament for treating a metabolic disorder in a subject. Further provided herein is the use of GL0034 for the manufacture of a medicament for treating hypertension in a subject.

[0018] These and other features and advantages of the present disclosure will become more fully apparent from the following detailed description, the appended claims and the accompanying drawings. It should be noted that the description and specific examples herein are intended for purposes of illustration only and are not intended to limit the scope of the claims. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 2A is a study design depicting the selection, randomization, and treatment of lean males with multiple ascending doses of GL0034. AE, adverse event; ALT, alanine aminotransferase; BMI, body mass index; HbAlC, hemoglobin AlC; HOMA-IR, homeostatic model assessment of insulin resistance; PD, pharmacodynamics.

[0020] Figure 2B A bar graph depicting the mean change in body weight in kilograms on Day 29 is shown. Changes in body weight over time were analyzed using a paired Student's t-test using GraphPad Prism 9 (version 9.5.1), GraphPad Software, Inc., San Diego, CA. Missing data were not imputed. Data tab shows mean absolute / % change from baseline. Day 29 comparison for Cohorts 1 and 2 is shown. Relative to the corresponding Day 1 value, P < 0.001.

[0021] Figure 3AA bar graph depicting the mean change in body weight in kilograms at Day 52 is shown. Changes in body weight over time were analyzed using a paired Student's t-test with GraphPad Prism 9 (version 9.5.1), Boston, MA, LLC. Missing data were not imputed. Data tab shows mean absolute / % change from baseline. Day 52 comparisons for Cohort 3 are shown. Relative to corresponding Day 1 values, P < 0.001.

[0022] Figure 3B A bar graph depicting the mean change in alanine aminotransferase (ALT) levels (U / L) at Day 23 is shown. Changes in ALT over time were analyzed using a paired Student's t-test with GraphPad Prism 9 (version 9.5.1), Boston, MA, LLC. Missing data were not imputed. Data tab shows mean absolute / % change from baseline. Day 23 comparisons for Cohorts 1 and 2 are shown. Relative to corresponding Day 1 values, P < 0.05.

[0023] Figure 4A A bar graph depicting the mean change in alanine aminotransferase (ALT) levels (U / L) at Day 51 is shown. Changes in ALT over time were analyzed using a paired Student's t-test with GraphPad Prism 9 (version 9.5.1), Boston, MA, LLC. Missing data were not imputed. Data tab shows mean absolute / % change from baseline. Day 51 comparisons for Cohort 3 are shown. Relative to corresponding Day 1 values, P < 0.05.

[0024] Figure 4B A bar graph depicting the mean change in fasting insulin in all three cohorts at Day 23 is shown. Changes in fasting insulin over time were analyzed using a paired Student's t-test with GraphPad Prism 9 (version 9.5.1), Boston, MA, LLC. Missing data were not imputed. Data tab shows mean absolute / % change from baseline. Day 23 comparisons for Cohorts 1 and 2 are shown.

[0025] Figure 5A A bar graph depicting the mean change in fasting insulin in all three cohorts at Day 51 is shown. Changes in fasting insulin over time were analyzed using a paired Student's t-test with GraphPad Prism 9 (version 9.5.1), Boston, MA, LLC. Missing data were not imputed. Data tab shows mean absolute / % change from baseline. Day 51 comparisons for Cohort 3 are shown.

[0026] Figure 5B A bar graph showing the change in homeostatic model assessment of insulin resistance (HOMA-IR) levels at Day 23 is shown. Changes in HOMA-IR over time were analyzed using a paired Student's t-test using GraphPad Prism 9 (version 9.5.1), Boston, MA LLC. Missing data were not imputed. HOMA-IR < 1.0 indicates optimal insulin sensitivity; HOMA-IR > 1.9 indicates early insulin resistance; HOMA-IR > 2.9 indicates clinically significant insulin resistance. Data labels show the mean HOMA-IR. Day 23 comparisons for Cohorts 1 and 2 are shown.

[0027] Figure 6 A bar graph showing the change in homeostatic model assessment of insulin resistance (HOMA-IR) levels at Day 51 is shown. Changes in HOMA-IR over time were analyzed using a paired Student's t-test using GraphPad Prism 9 (version 9.5.1), Boston, MA LLC. Missing data were not imputed. HOMA-IR < 1.0 indicates optimal insulin sensitivity; HOMA-IR > 1.9 indicates early insulin resistance; HOMA-IR > 2.9 indicates clinically significant insulin resistance. Data labels show the mean HOMA-IR. Day 51 comparisons for Cohort 3 are shown.

[0028] Figure 7 is a study design depicting the selection, randomization, and treatment of individuals with obesity with a single ascending dose of GL0034. BMI, body mass index; HbAlC, hemoglobin AlC; PD, pharmacodynamics; PK, pharmacokinetics.

[0029] Figure 8 is a plasma concentration-time curve depicting the mean concentration of GL0034 in plasma over time in hours.

[0030] Figure 9A A graph showing the mean change in body weight (kg) at Day 8, Day 15, and Day 22 (EOS - end of study) is shown. Changes in body weight over time were analyzed using a one-way ANOVA with a paired Dunnett's posthoc test using GraphPad Prism 9 (version 9.5.1), Boston, MA LLC. Missing data were not imputed. Data labels show the mean absolute change in kg from baseline. Relative to the corresponding Day 1 body weight, P < 0.05, P < 0.01, P < 0.001.

[0031] Figure 9B A bar graph showing the mean change in triglyceride levels (ng / ml) for all participants is shown. #P < 0.05, ##P < 0.01 vs. respective Day 1 values; analyzed with paired Student’s t test using GraphPad Prism 9 (version 9.5.1); missing values were not imputed; data tab shows mean absolute / % change from baseline.

[0032] For example A bar graph showing the mean change in leptin levels (ng / ml) for all participants is shown. #P < 0.05, ##P < 0.01 vs. respective Day 1 values; analyzed with paired Student’s t test using GraphPad Prism 9 (version 9.5.1); missing values were not imputed; data tab shows mean absolute / % change from baseline. DETAILED DESCRIPTION

[0033] The present disclosure relates to methods and compositions for treating obesity. The present disclosure also relates to methods and compositions for treating metabolic disorders, such as metabolic dysfunction-associated steatohepatitis (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), diabetes, and hypertriglyceridemia. More specifically, the present disclosure relates to methods for treating obesity in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034. The present disclosure also relates to methods for treating a metabolic disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of GL0034. The present disclosure also relates to methods for treating hypertension in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034. The present disclosure further relates to compositions comprising GL0034 for treating obesity or a metabolic disorder or hypertension in a subject.

[0034] As utilized in accordance with the present disclosure, unless otherwise indicated or defined, all technical and scientific terms used herein are to be understood as having the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide one of ordinary skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0035] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. For example, the terms "a," "an," and "the" as used herein, unless otherwise indicated or specified, shall be understood to encompass the singular or plural of the referenced component. It will be further understood that the terms "comprising," "including," and "having," when used herein, shall be understood to encompass the various combinations of elements that are specifically listed, as well as combinations of those elements with others not specifically listed. It will be further understood that terms, such as "coupled," "connected," and "with," among others, as used herein, are understood to be used in their broadest, ordinary sense, unless otherwise specifically noted.

[0036] As used herein, the terms "comprise" and "comprising" can have the meaning ascribed to them in U.S. patent law and can mean "include," "including," "contain," "containing," "characterized by," "characterized by," "have," "having," and the like. The term "comprise," "comprising," and grammatical variations thereof, as used herein, unless otherwise stated, indicate the inclusion of an integer or step, but not to the exclusion of any other integer or step, notwithstanding any common meaning of the term "comprise" and "comprising" under U.S. patent law. As used herein, the term "consisting essentially of, or "consists essentially of," likewise has the meaning ascribed to it in U.S. patent law and allows for the presence of additional components so long as the basic or novel properties of the composition are not changed by the presence of the additional components.

[0037] Any of the methods or compositions provided herein can be combined with one or more of any other method or composition provided herein.

[0038] In the present disclosure, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range is to be understood to include the values within the range and, where appropriate, fractions of the minimum and maximum values within the range (e.g. one-tenth and one-hundredth of an integer). A range provided herein is to be understood to include all values and subranges within the range. For example, a range of 1 to 50 is to be understood to include any number, combination of numbers, or sub-range between 1 and 50, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0039] The terms "about" and "approximately," as used herein, unless otherwise indicated or otherwise evident from context, are understood to mean within normal tolerances for the relevant measurement or determination, for example within 2 standard deviations of the mean, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on the measurement or determination being made, i.e., the limitations of the measurement system. "About" can be understood as meaning within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.

[0040] It should be noted that terms such as "preferably," "commonly," and "typically" are used herein not to restrict the scope of the claimed subject matter but to describe a particular example of an implementation. For example, a feature that is "preferably" included can be included or not, depending on the implementation.

[0041] For purposes of describing and defining the present disclosure, it is noted that the term "substantially" is used herein to represent an extent of deviation that can be attributed to inherent variability in any quantitative comparison, value, measurement, or other representation. The term "substantially" is also used herein to represent an extent of deviation that a quantitative representation can vary from a stated reference without causing a change in the basic function of the subject matter at issue.

[0042] Methods and compositions

[0043] In one embodiment, the present disclosure provides a method of treating obesity in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034. In another embodiment, the present disclosure provides a method of treating a metabolic disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034.

[0044] In one embodiment, the present disclosure provides a pharmaceutical composition for use in treating obesity in a subject, the pharmaceutical composition comprising GL0034. In another embodiment, the present disclosure provides a pharmaceutical composition for use in treating a metabolic disorder in a subject, the pharmaceutical composition comprising GL0034.

[0045] In one embodiment, the present disclosure provides use of GL0034 for the manufacture of a medicament for treating obesity in a subject. In another embodiment, the present disclosure provides use of GL0034 for the manufacture of a medicament for treating a metabolic disorder in a subject.

[0046] As used herein, the terms "subject" and "patient" are interchangeable. In some embodiments, the subject or patient is a mammal. In some embodiments of the methods, compositions, and medicaments of the disclosure, the subject has diabetes. In some embodiments of the methods, compositions, and medicaments of the disclosure, the subject does not have diabetes. In some embodiments of the methods, compositions, and medicaments of the disclosure, the subject has a body mass index (BMI) of at least 18 kg / m2. 2 .

[0047] As used herein, "diabetes" or "diabetes mellitus" or "diabetic" is a metabolic condition / disorder associated with elevated blood glucose levels. The term also includes all types of diabetes, non-limiting three major types of diabetes are: type 1 diabetes (T1DM), type 2 diabetes (T2DM), and gestational diabetes.

[0048] As used herein, a "disorder" is any condition that would benefit from treatment with GL0034. The terms "disorder" and "condition" are used interchangeably herein and include chronic and acute disorders or diseases including those pathological conditions which predispose a patient to the disorder in question.

[0049] As used herein, the terms "treatment" or "treat" refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those who have obesity, metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated steatohepatitis (MASH), or diabetes.

[0050] In some embodiments of the methods, compositions, and medicaments of the disclosure, the metabolic disorder is metabolic dysfunction-associated steatohepatitis (MASH). In certain embodiments of the methods, compositions, and medicaments of the disclosure, the MASLD is metabolic dysfunction-associated steatohepatitis (MASH). In some embodiments of the methods, compositions, and medicaments of the disclosure, the metabolic disorder is diabetes. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the metabolic disorder is type 2 diabetes. In other embodiments, the metabolic disorder is hypertriglyceridemia.

[0051] As used herein, the term "pharmaceutical composition" or "therapeutic composition" refers to a compound or composition that is capable of inducing a desired therapeutic effect when properly administered to a patient. One embodiment of the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of GL0034.

[0052] As used herein, the terms “pharmaceuticalally acceptable carrier” or “physiologically acceptable carrier” refer to one or more formulation materials suitable for completing or enhancing the delivery of GL0034.

[0053] Pharmaceutical compositions comprising GL0034, alone or in combination with preventative agents, therapeutic agents, and / or pharmaceutically acceptable carriers, are provided herein. The pharmaceutical compositions comprising GL0034 provided herein are intended for, but not limited to, prevention, treatment, management, or relief of a condition or one or more of its symptoms. Formulations of pharmaceutical compositions, alone or in combination with preventative agents, therapeutic agents, and / or pharmaceutically acceptable carriers, are known to those skilled in the art.

[0054] As used herein, the terms "administration" or "administering" mean the provision, contact, and / or delivery of GL0034 through any appropriate route to achieve the desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral, or intravenous administration. Figure 1 It can be administered intravenously, subcutaneously, intradermally, intramuscularly, intra-articularly, intra-arterially, intrasynovially, intrasternally, intrathecally, intralesionally, intracranially, transdermally, topically, buccally, rectally, vaginally, nasally, ocularly, by inhalation, and via implantation. In some embodiments of the methods, compositions, and agents of this disclosure, GL0034 (or a composition or agent containing GL0034) is administered subcutaneously to the subject. In some embodiments of the methods, compositions, and agents of this disclosure, administration is performed by subcutaneous injection. In some embodiments of the methods, compositions, and agents of this disclosure, administration is performed subcutaneously using an auto-injector or a pre-filled syringe.

[0055] In some embodiments of the methods, compositions, and pharmaceuticals disclosed herein, the dose of GL0034 (or a composition or pharmaceutical agent containing GL0034) administered to the subject is between 200 μg and 8000 μg, between 300 μg and 6000 μg, between 400 μg and 4000 μg, or between 1000 μg and 3000 μg. In some embodiments of the methods, compositions, and pharmaceuticals disclosed herein, the dose of GL0034 (or a composition or pharmaceutical agent containing GL0034) administered to the subject is 450 μg, 680 μg, 900 μg, 1520 μg, 2000 μg, or 2520 μg of GL0034. In some embodiments of the methods, compositions, and agents disclosed herein, a single dose of GL0034 (or a composition or agent containing GL0034) is administered to the subject, wherein the dose of GL0034 (or a composition or agent containing GL0034) is 1520 μg, 2000 μg, or 2520 μg of GL0034.

[0056] In some embodiments of the methods, compositions, and agents disclosed herein, GL0034 (or a composition or agent containing GL0034) is administered daily, every other day, every three days, every four days, every five days, every six days, once a week, or every two weeks. In one embodiment of the methods, compositions, and agents disclosed herein, GL0034 (or a composition or agent containing GL0034) is administered once a week. As used herein, the term "day 1" refers to the first day that the subject receives GL0034 (or a composition or agent containing GL0034).

[0057] In some embodiments of the methods, compositions, and agents of this disclosure, GL0034 (or a composition or agent containing GL0034) is administered over a two-week, four-week, six-week, or eight-week treatment period. In one embodiment of the methods, compositions, and agents of this disclosure, GL0034 (or a composition or agent containing GL0034) is administered to the subject once weekly for up to four weeks. In another embodiment of the methods, compositions, and agents of this disclosure, GL0034 (or a composition or agent containing GL0034) is administered to the subject once weekly for up to eight weeks.

[0058] In one embodiment of the methods, compositions, and reagents disclosed herein, the average maximum concentration (C) of GL0034 is... maxThe concentrations ranged between 226.9 ± 57.3 ng / mL and 367.0 ± 152.0 ng / mL. In certain embodiments of the methods, compositions, and agents disclosed herein, administration of GL0034 (or a composition or agent containing GL0034) provided between 47,151.5 ± 16,838.6 ng / mL over a 22-day period. h / mL vs. 62,265.9 ± 20,816.5 ng The area under the concentration-time curve (AUC) of GL0034 between h / mL 0-t In certain embodiments of the methods, compositions, and agents disclosed herein, administration of GL0034 (or a composition or agent containing GL0034) provides a plasma drug half-life (t) of GL0034 between 98.5 ± 13.0 hours and 113.5 ± 22.9 hours. 1 / 2 In certain embodiments of the methods, compositions, and agents disclosed herein, administration of GL0034 (or a composition or agent containing GL0034) provides a maximum plasma concentration (T0) of GL0034 from administration to delivery between 22.0 ± 6.9 hours and 31.0 ± 13.5 hours. max (Time)

[0059] In one embodiment of the methods, compositions, and agents disclosed herein, GL0034 (or a composition or agent containing GL0034) is administered at a dose of 450 μg GL0034 once weekly for 4 weeks, and the mean maximum concentration (C) of GL0034 is... max The concentrations ranged between 100.5 ± 22.0 ng / mL and 141.7 ± 34.6 ng / mL. In certain embodiments of the methods, compositions, and agents disclosed herein, administration of GL0034 (or a composition or agent containing GL0034) provided between 12814.3 ± 2652.1 ng / mL over a 22-day period. h / mL and 18536.8 ± 4608.0 ng The area under the concentration-time curve (AUC) of GL0034 between h / mL 0-t In certain embodiments of the methods, compositions, and agents disclosed herein, administration of GL0034 (or a composition or agent containing GL0034) provides a plasma drug half-life (t) of GL0034 of 102.3 ± 15.4 hours prior to day 22. 1 / 2). In certain embodiments of the methods, compositions, and medicaments of the disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) provides a time from administration to maximum plasma concentration (T max ) of GL0034 of between 36.0 ± 12.0 hours and 47.0 ± 16.0 hours.

[0060] In one embodiment of the methods, compositions, and medicaments of the disclosure, GL0034 (or a composition or medicament comprising GL0034) is administered at a dose of 680 pg GL0034 once weekly for 4 weeks, and the mean maximum concentration (C max ) of GL0034 is between 169.0 ± 49.5 ng / mL and 267.0 ± 60.9 ng / mL. In certain embodiments of the methods, compositions, and medicaments of the disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) provides an area under the concentration-time curve (AUC ) of GL0034 of between 24575.9 ± 3391.3 ng h / mL and 34536.6 ± 6445.0 ng 0-t h / mL over a 22-day period. In certain embodiments of the methods, compositions, and medicaments of the disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) provides a plasma drug half-life (t 1 / 2 ) of GL0034 of 122.9 ± 16.5 hours prior to day 22. In certain embodiments of the methods, compositions, and medicaments of the disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) provides a time from administration to maximum plasma concentration (T max ) of GL0034 of between 39.0 ± 21.0 hours and 54.0 ± 27.0 hours.

[0061] In one embodiment of the methods, compositions, and medicaments of the disclosure, (i) a dose of 450 pg GL0034 is administered to the subject once weekly for 2 weeks; followed by (ii) a dose of 900 pg GL0034 is administered to the subject once weekly for 2 weeks; and followed by (iii) a dose of 1520 pg GL0034 is administered to the subject once weekly for 4 weeks. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the mean maximum concentration (C maxbetween 12942.2 ± 1517.5 ng h / mL and 76320.4 ± 23334.6 ng h / mL over a 50-day period. In certain embodiments of the methods, compositions, and medicaments of the present disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) provides a plasma drug half-life (t½) of GL0034 of 106.8 ± 33.8 hours prior to day 50. In certain embodiments of the methods, compositions, and medicaments of the present disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) provides a time from administration to the maximum plasma concentration (Tmax) of GL0034 of between 22.0 ± 16.0 hours and 41.0 ± 8.0 hours. 0-t 1 / 2 max

[0062] In some embodiments of the methods, compositions, and medicaments of the present disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) results in one or more clinically meaningful changes in the subject relative to baseline, wherein the clinically meaningful change relative to baseline is a decrease in alanine aminotransferase (ALT) values, a decrease in aspartate aminotransferase (AST) values, a decrease in gamma-glutamyl transferase (GGT) values, a decrease in fasting insulin levels, a decrease in fasting glucose levels, a decrease in glycosylated hemoglobin (HbAlc%), a decrease in homeostatic model assessment of insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin levels, a decrease in triglyceride (TG) levels, a decrease in total cholesterol (TC) levels, a decrease in low-density lipoprotein (LDL) levels, an increase in high-density lipoprotein (HDL) levels, and / or a decrease in TG / HDL ratio.

[0063] ​​​​​In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in ALT value from baseline persists for up to 23 days, up to 52 days, or up to 78 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in ALT value from baseline is at least -8.8 ± 13.1 U / L over a period of about 23 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -3.1 ± 5.8 U / L over a period of about 23 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -7.4 ± 10.3 U / L over a period of about 51 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -1.0 ± 9.4 U / L over a period of about 78 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0064] In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in AST value from baseline persists for up to 23 days, up to 51 days, or up to 78 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in AST value from baseline is at least -4.0 ± 7.5 U / L over a period of about 51 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -1.1 ± 6.7 U / L over a period of about 78 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0065] In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in GGT value from baseline persists for up to 23 days, up to 51 days, or up to 78 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in GGT value from baseline is at least -3.4 ± 3.5 U / L over a period of about 51 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -1.0 ± 2.7 U / L over a period of about 78 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0066] In one embodiment of the methods, compositions, and medicaments of the disclosure, the reduction in fasting insulin level persists for up to 23 days or up to 51 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in fasting insulin level relative to baseline is at least -4.6 ± 23.0 pmol / L over a period of about 23 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -11.3 ± 16.5 pmol / L over a period of about 51 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0067] In one embodiment of the methods, compositions, and medicaments of the disclosure, the reduction in fasting glucose persists for up to 23 days or up to 51 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the reduction in fasting glucose is at least -2.8 ± 3.7 mg / dL over a period of about 23 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -4.6 ± 2.7 mg / dL over a period of about 23 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -7.7 ± 9.9 mg / dL over a period of about 51 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0068] In one embodiment of the methods, compositions, and medicaments of the disclosure, the reduction in HbAlc is at least -0.25 ± 0.2 over a period of about 78 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0069] In one embodiment of the methods, compositions, and medicaments of the disclosure, the reduction in HOMA-IR is achieved 23 days after administration of GL0034 (or a composition or medicament comprising GL0034) or 51 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0070] In one embodiment of the methods, compositions, and medicaments of the disclosure, the reduction in body weight lasts for at most 8 days, at most 15 days, at most 22 days, at most 29 days, at most 50 days, at most 52 days, or at most 78 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the reduction in body weight is at least -1.8 ± 2.4 kg over a period of about 22 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -2.4 ± 2.2 kg over a period of about 22 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -3.1 ± 1.7 kg over a period of about 22 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -3.4 ± 1.8 kg over a period of about 29 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -4.1 ± 1.0 kg over a period of about 29 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -7.7 ± 1.9 kg over a period of about 52 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -6.4 ± 2.1 kg over a period of about 78 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0071] In one embodiment of the methods, compositions, and medicaments of the disclosure, the reduction in leptin levels relative to baseline is dose-dependent. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in leptin levels relative to baseline is at least -6.9 ± 5.1 ng / mL over a period of about 8 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -10.9 ± 8.6 ng / mL over a period of about 8 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -11.6 ± 12.8 ng / mL over a period of about 8 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0072] In one embodiment of the methods, compositions, and medicaments of the disclosure, a decrease in TG from baseline is observed at day 8 after administration of GL0034 (or a composition or medicament comprising GL0034) and the decrease in TG from baseline continues for up to 51 days or up to 78 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in TG level from baseline is at least -0.4 ± 0.4 mmol / L over a period of about 8 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -0.5 ± 0.5 mmol / L over a period of about 22 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -0.8 ± 0.5 mmol / L over a period of about 8 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -21.0 ± 27.5 mg / dL over a period of about 51 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -11.0 ± 55.3 mg / dL over a period of about 78 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0073] In one embodiment of the methods, compositions, and medicaments of the disclosure, the change in TC level from baseline is at least -29.1 ± 23.3 mg / dL over a period of about 51 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -5.8 ± 12.6 mg / dL over a period of about 78 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0074] In one embodiment of the methods, compositions, and medicaments of the disclosure, the change in LDL level from baseline is at least -24.0 ± 24.3 mg / dL over a period of about 51 days after administration of GL0034 (or a composition or medicament comprising GL0034), or at least -19.5 ± 35.8 mg / dL over a period of about 78 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0075] In one embodiment of the methods, compositions, and medicaments of the disclosure, the increase in HDL level from baseline is at least 2.9 ± 3.1 mg / dL over a period of about 78 days after administration of GL0034 (or a composition or medicament comprising GL0034).

[0076] In one embodiment of the methods, compositions, and medicaments of the disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) achieves a reduction in the frequency of adverse events (AEs) in the subject over time. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the AEs are one or more of nausea, vomiting, and / or decreased appetite. In other embodiments of the methods, compositions, and medicaments of the disclosure, the reduction in the frequency of AEs is dose-dependent.

[0077] As used herein, the terms "set" and "group" have the same meaning.

[0078] EMBODIMENT: EMBODIMENT 1: A pharmaceutical composition for treating obesity in a subject, the pharmaceutical composition comprising GL0034.

[0079] EMBODIMENT 2: The pharmaceutical composition of embodiment 1, wherein the subject does not have diabetes.

[0080] EMBODIMENT 3: The pharmaceutical composition of embodiment 1 or embodiment 2, wherein the subject has a body mass index (BMI) of at least 28 kg / m 2 or > 27 kg / m 2 with at least one weight-related comorbidity condition.

[0081] EMBODIMENT 4: A pharmaceutical composition for treating a metabolic disorder in a subject, the pharmaceutical composition comprising GL0034.

[0082] EMBODIMENT 5: The pharmaceutical composition of embodiment 4, wherein the metabolic disorder is metabolic dysfunction-associated steatohepatitis (MASLD).

[0083] EMBODIMENT 6: The pharmaceutical composition of embodiment 5, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

[0084] EMBODIMENT 7: The pharmaceutical composition of embodiment 4, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

[0085] EMBODIMENT 8: The pharmaceutical composition of embodiment 7, wherein the metabolic disorder is type 2 diabetes.

[0086] EMBODIMENT 9: The pharmaceutical composition of any one of embodiments 1-8, wherein the subject has hypertension.

[0087] EMBODIMENT 10: The pharmaceutical composition of any one of embodiments 1-9, wherein the pharmaceutical composition is administered subcutaneously to the subject.

[0088] Example 11: The pharmaceutical composition of Example 10, wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.

[0089] Example 12: The pharmaceutical composition of Example 11, wherein the pharmaceutical composition is administered to the subject using an auto-injector or a pre-filled syringe.

[0090] Example 13: The pharmaceutical composition of any one of Examples 1-12, wherein a dose of the pharmaceutical composition comprises between 200 pg and 8000 pg of GL0034.

[0091] Example 14: The pharmaceutical composition of Example 13, wherein the dose of the pharmaceutical composition comprises between 300 pg and 6000 pg of GL0034.

[0092] Example 15: The pharmaceutical composition of Example 14, wherein the dose of the pharmaceutical composition comprises between 400 pg and 4000 pg of GL0034.

[0093] Example 16: The pharmaceutical composition of Example 15, wherein the dose of the pharmaceutical composition comprises between 1000 pg and 3000 pg of GL0034.

[0094] Example 17: The pharmaceutical composition of any one of Examples 1-16, wherein the dose of the pharmaceutical composition is administered to the subject once a week or once every two weeks.

[0095] Example 18: The pharmaceutical composition of any one of Examples 1-16, wherein administration of the pharmaceutical composition to the subject achieves a mean maximum concentration (C max max) of GL0034 of between 75 ng / mL and 1200 ng / mL.

[0096] Example 19: The pharmaceutical composition of any one of Examples 1-16, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUC ) of GL0034 of between 6200 ng h / mL and 406300 ng 0-t h / mL over a 22-day period.

[0097] Example 20: The pharmaceutical composition of Example 16, wherein the dose of the pharmaceutical composition comprises 1520 pg, 2000 pg, or 2520 pg of GL0034.

[0098] Example 21: The pharmaceutical composition of Example 20, wherein administration of the pharmaceutical composition to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 227 ng / mL and 367 ng / mL. max ).

[0099] Example 22: The pharmaceutical composition of Example 20, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUC) of GL0034 of between 30313 ng h / mL and 83082 ng h / mL over a 22-day period. 0-t ).

[0100] Example 23: The pharmaceutical composition of any one of Examples 1-21, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t½) of GL0034 of between 90 hours and 120 hours. 1 / 2 ).

[0101] Example 24: The pharmaceutical composition of Example 21, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t½) of GL0034 of between 98 hours and 113 hours. 1 / 2 ).

[0102] Example 25: The pharmaceutical composition of any one of Examples 1-12, wherein administration of the pharmaceutical composition to the subject is once a week or once every two weeks.

[0103] Example 26: The pharmaceutical composition of any one of Examples 1-12 or 25, wherein a dose of the pharmaceutical composition comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034.

[0104] Example 27: The pharmaceutical composition of Example 26, wherein the dose of the pharmaceutical composition is administered once a week or once every two weeks.

[0105] Example 28: The pharmaceutical composition of Example 26, wherein the dose of the pharmaceutical composition comprises 450 pg GL0034, and wherein administration of the pharmaceutical composition to the subject once a week for at least 4 weeks achieves a mean maximum concentration (Cmax) of GL0034 of between 101 ng / mL and 142 ng / mL. max ).

[0106] Example 29: The pharmaceutical composition of Example 28, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUCo-22) of GL0334 of between 12814 ng h / mL and 18537 ng h / mL over a 22-day period. 0-t ).

[0107] Example 30: The pharmaceutical composition of Example 28, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t 1 / 2 ) of GL0034 of 102 hours prior to day 22.

[0108] Example 31 : The pharmaceutical composition of Example 26, wherein the dose of the pharmaceutical composition comprises 680 pg GL0034, and wherein administration of the pharmaceutical composition to the subject once a week for at least 4 weeks achieves a mean maximum concentration (C max ) of GL0034 of between 169 ng / mL and 267 ng / mL.

[0109] Example 32: The pharmaceutical composition of Example 31, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUCo-22) of GL0034 of between 24576 ng h / mL and 34537 ng h / mL over a 22-day period. 0-t ).

[0110] Example 33: The pharmaceutical composition of Example 31, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t 1 / 2 ) of GL0034 of 123 hours prior to day 22.

[0111] Example 34: The pharmaceutical composition of any one of examples 1-12, wherein: (i) the subject is administered a dose of the pharmaceutical composition comprising between 50 pg and 200 pg of GL0034 once a week for at least 2 weeks; (ii) the subject is administered a dose of the pharmaceutical composition comprising between 200 pg and 400 pg of GL0034 once a week for at least 2 weeks; (iii) the subject is administered a dose of the pharmaceutical composition comprising between 500 pg and 700 pg of GL0034 once a week for at least 2 weeks; (iv) the subject is administered a dose of the pharmaceutical composition comprising between 1200 pg and 1500 pg of GL0034 once a week for at least 2 weeks; and (v) the subject is administered a dose of the pharmaceutical composition comprising between 2000 pg and 3000 pg of GL0034 once a week for at least 4 weeks.

[0112] Example 35: The pharmaceutical composition of any one of examples 1-12, wherein: (i) the subject is administered a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) the subject is administered a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) the subject is administered a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0113] Example 36: The pharmaceutical composition of example 35, wherein administration of the pharmaceutical composition to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 112 ng / mL and 708 ng / mL. max ).

[0114] Example 37: The pharmaceutical composition of example 35, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUC ) of GL0034 of between 12942 ng h / mL and 76320 ng 0-t h / mL over a 50-day period.

[0115] Example 38: The pharmaceutical composition of example 35, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t 1 / 2 ) of GL0034 of 106.8 ± 33.7 hours prior to day 50.

[0116] Example 39: The pharmaceutical composition of any one of Examples 1-12, wherein: (i) the pharmaceutical composition comprising between 200 pg and 680 pg of GL0034 is administered to the subject for at least 4 weeks as an initial dose; (ii) the pharmaceutical composition comprising between 680 pg and 900 pg of GL0034 is administered to the subject once a week for at least 2 weeks as an escalation dose; and (iii) the pharmaceutical composition comprising between 1500 pg and 2000 pg of GL0034 is administered to the subject once a week for at least 2 weeks as a maintenance dose.

[0117] Example 40: The pharmaceutical composition of any one of Examples 1-12, wherein: (i) the pharmaceutical composition comprising between 450 pg and 680 pg of GL0034 is administered to the subject for at least 4 weeks as an initial dose; and (ii) the pharmaceutical composition comprising between 680 pg and 900 pg of GL0034 is administered to the subject once a week for at least 2 weeks as an escalation dose.

[0118] Example 41: The pharmaceutical composition of any one of Examples 1-12, wherein: (i) the pharmaceutical composition comprising between 450 pg and 680 pg of GL0034 is administered to the subject for at least 4 weeks as an initial dose; (ii) the pharmaceutical composition comprising between 680 pg and 900 pg of GL0034 is administered to the subject once a week for at least 2 weeks as an escalation dose; and (iii) the pharmaceutical composition comprising between 1520 pg and 2000 pg of GL0034 is administered to the subject once a week for at least 2 weeks as a maintenance dose.

[0119] Example 42: The pharmaceutical composition of any one of examples 1-41, wherein administration of the pharmaceutical composition to the subject results in one or more clinically meaningful changes in the subject relative to baseline, wherein the clinically meaningful change relative to baseline is a decrease in alanine aminotransferase (ALT) value, a decrease in aspartate aminotransferase (AST) value, a decrease in gamma-glutamyl transferase (GGT) value, a decrease in fasting insulin level, a decrease in fasting glucose level, a decrease in glycated hemoglobin (HbAlc%), a decrease in homeostatic model assessment of insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin level, a decrease in triglyceride (TG) level, a decrease in total cholesterol (TC) level, a decrease in low-density lipoprotein (LDL) level, an increase in high-density lipoprotein (HDL) level, a decrease in TG / HDL ratio, an increase in FGF-21 in the liver, an increase in uncoupling protein-1 level (UCP-1) in brown adipose tissue (BAT) and / or white adipose tissue (WAT), and / or a decrease in blood pressure.

[0120] Example 43: The pharmaceutical composition of example 42, wherein the decrease in ALT value relative to baseline persists for at least 23 days, at least 52 days, or at least 78 days after administration of the pharmaceutical composition to the subject.

[0121] Example 44: The pharmaceutical composition of example 42, wherein: (a) the change in ALT value relative to baseline is at least -9 U / L within a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 450 pg GL0034 to the subject, or at least -3 U / L within a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034 to the subject; or (b) the change in ALT value is at least -7 U / L within a period of about 51 days or at least -1 U / L within a period of about 78 days after administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks, to the subject.

[0122] Example 45: The pharmaceutical composition of example 42, wherein the decrease in AST value relative to baseline persists for at least 23 days, at least 51 days, or at least 78 days after administration of the pharmaceutical composition to the subject.

[0123] Example 46: The pharmaceutical composition of Example 42, wherein the change in AST value from baseline is at least -4 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0124] Example 47: The pharmaceutical composition of Example 42, wherein the reduction in GGT value from baseline persists for at least 23 days, at least 51 days, or at least 78 days after administration of the pharmaceutical composition to the subject.

[0125] Example 48: The pharmaceutical composition of Example 42, wherein the change in GGT value from baseline is at least -3 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0126] Example 49: The pharmaceutical composition of Example 42, wherein the reduction in fasting insulin level from baseline persists for at least 23 days or at least 51 days after administration of the pharmaceutical composition to the subject.

[0127] Example 50: The pharmaceutical composition of Example 42, wherein the change in fasting insulin level from baseline is at least -5 pmol / L over a period of about 23 days after administration to the subject of 680 pg GL0034 once weekly for at least 4 weeks; or at least -11 pmol / L over a period of about 51 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0128] Example 51: The pharmaceutical composition of Example 42, wherein the reduction in fasting glucose is sustained for at least 23 days or at least 51 days after administration of the pharmaceutical composition to the subject.

[0129] Example 52: The pharmaceutical composition of Example 42, wherein the reduction in fasting glucose is at least -3 mg / dL over a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 4 weeks to the subject; or at least -5 mg / dL over a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034 once a week for at least 4 weeks to the subject; or at least -8 mg / dL over a period of about 51 days after administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks to the subject.

[0130] Example 53: The pharmaceutical composition of Example 42, wherein the reduction in body weight is sustained for at least 8 days, at least 15 days, at least 22 days, at least 29 days, at least 50 days, at least 52 days, or at least 78 days after administration of the pharmaceutical composition to the subject.

[0131] Example 54: The pharmaceutical composition of Example 42, wherein: (a) the reduction in body weight is at least -2 kg over a period of about 22 days after administration to the subject of a dose of the pharmaceutical composition comprising 2000 pg GL0034; or at least -2 kg over a period of about 22 days after administration to the subject of a dose of the pharmaceutical composition comprising 1520 pg GL0034; or at least -3 kg over a period of about 22 days after administration to the subject of a dose of the pharmaceutical composition comprising 2520 pg GL0034; or at least -3 kg over a period of about 29 days after administration to the subject of a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 4 weeks; or at least -4 kg over a period of about 29 days after administration to the subject of a dose of the pharmaceutical composition comprising 680 pg GL0034 once a week for at least 4 weeks; or (b) the reduction in body weight is at least -8 kg over a period of about 52 days or at least -6 kg over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0132] Example 55: The pharmaceutical composition of Example 42, wherein the reduction in leptin levels relative to baseline is dose dependent.

[0133] Example 56: The pharmaceutical composition of Example 42, wherein the change in leptin levels relative to baseline is at least -7 ng / mL over a period of about 8 days after administration to the subject of a dose of the pharmaceutical composition comprising 1520 pg GL0034; or at least -11 ng / mL over a period of about 8 days after administration to the subject of a dose of the pharmaceutical composition comprising 2000 pg GL0034; or at least -12 ng / mL over a period of about 8 days after administration to the subject of a dose of the pharmaceutical composition comprising 2520 pg GL0034.

[0134] Example 57: The pharmaceutical composition of Example 42, wherein a reduction in the TG level relative to baseline is observed at Day 8 and the reduction in the TG level relative to baseline persists for at least 51 days or at least 78 days after administration of the pharmaceutical composition to the subject.

[0135] Example 58: The pharmaceutical composition of Example 42, wherein: (a) the change in the TG level relative to baseline is at least -1 mmol / L over a period of about 8 days after administration of a dose of the pharmaceutical composition comprising 2000 pg GL0034 to the subject, or at least -1 mmol / L over a period of about 22 days after administration of a dose of the pharmaceutical composition comprising 2520 pg GL0034 to the subject; or (b) the change in the TG value is at least -21 mg / dL over a period of about 51 days or at least -11 mg / dL over a period of about 78 days after administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks to the subject.

[0136] Example 59: The pharmaceutical composition of Example 42, wherein the reduction in the TC level relative to baseline is at least -29 mg / dL over a period of about 51 days or at least -6 mg / dL over a period of about 78 days after administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks to the subject.

[0137] Example 60: The pharmaceutical composition of claim 42, wherein the change in LDL levels from baseline is at least -24 mg / dL over a period of about 51 days or at least -20 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0138] Example 61: The pharmaceutical composition of claim 42, wherein the increase in HDL levels from baseline is at least 3 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0139] Example 62: The pharmaceutical composition of claim 42, wherein the clinically meaningful change in the subject relative to baseline is a decrease in blood pressure.

[0140] Example 63: The pharmaceutical composition of claim 62, wherein the decrease in blood pressure is a decrease in systolic blood pressure.

[0141] Example 64: The pharmaceutical composition of claim 62, wherein the decrease in blood pressure is a decrease in diastolic blood pressure.

[0142] Example 65: The pharmaceutical composition of claim 63, wherein the decrease in systolic blood pressure from baseline is at least about 18 mmHg or at least about 14% over a period of about 23 days after administration to the subject of a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 4 weeks.

[0143] Example 66: The pharmaceutical composition of claim 64, wherein the decrease in diastolic blood pressure from baseline is at least about 12 mmHg or at least about 14% over a period of about 23 days after administration to the subject of a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 4 weeks.

[0144] Example 67: The pharmaceutical composition of claim 62, wherein the reduction in blood pressure in the subject is greater compared to the reduction in blood pressure following administration of: (a) 1.7 mg to 2.4 mg of semaglutide once weekly; or (b) 5 mg to 15 mg of tirzepatide once weekly.

[0145] Example 68: The pharmaceutical composition of any one of claims 1 to 67, wherein administration of the pharmaceutical composition to the subject achieves a reduction in the frequency of adverse events (AEs) in the subject over time.

[0146] Example 69: The pharmaceutical composition of claim 68, wherein the AE is one or more of nausea, vomiting, and / or decreased appetite.

[0147] Example 70: The pharmaceutical composition of claim 68, wherein the reduction in the frequency of the AE is dose-dependent.

[0148] Example 71: The pharmaceutical composition of any one of claims 1 to 12, wherein administration of a higher dose of the pharmaceutical composition to the subject does not cause an increase in severe treatment-emergent adverse events (TEAEs).

[0149] Example 72: A pharmaceutical composition for treating hypertension in a subject, the pharmaceutical composition comprising GL0034, wherein a therapeutically effective dose of the pharmaceutical composition is administered to the subject.

[0150] Example 73: The pharmaceutical composition of claim 72, wherein the subject is obese.

[0151] Example 74: The pharmaceutical composition of claim 73, wherein the subject does not have diabetes.

[0152] Example 75: The pharmaceutical composition of claim 72, wherein the subject has a metabolic disorder.

[0153] Example 76: The pharmaceutical composition of claim 75, wherein the metabolic disorder is metabolic dysfunction-associated fatty liver disease (MASLD).

[0154] Example 77: The pharmaceutical composition of claim 76, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

[0155] Example 78: The pharmaceutical composition of claim 75, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

[0156] Example 79: The pharmaceutical composition of Example 78, wherein the metabolic disorder is type 2 diabetes.

[0157] Example 80: The pharmaceutical composition of any one of Examples 72-79, wherein the pharmaceutical composition is administered subcutaneously to the subject.

[0158] Example 81: The pharmaceutical composition of Example 80, wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.

[0159] Example 82: The pharmaceutical composition of Example 81, wherein the pharmaceutical composition is administered to the subject using an auto-injector or a pre-filled syringe.

[0160] Example 83: The pharmaceutical composition of any one of Examples 72-82, wherein the subject is administered a dose of the pharmaceutical composition comprising 450 pg GL0034.

[0161] Example 84: The pharmaceutical composition of Example 83, wherein administration of the pharmaceutical composition achieves a reduction in systolic blood pressure in the subject of at least about 18 mmHg or at least about 14% relative to baseline over a period of about 23 days after administration of the pharmaceutical composition.

[0162] Example 85: The pharmaceutical composition of Example 83, wherein administration of the pharmaceutical composition achieves a reduction in diastolic blood pressure in the subject of at least about 12 mmHg or at least about 14% relative to baseline over a period of about 23 days after administration of the pharmaceutical composition.

[0163] Example 86: The pharmaceutical composition of any one of Examples 72-85, wherein the reduction in blood pressure in the subject is greater than a reduction in blood pressure after administration of: (a) 1.7 mg to 2.4 mg semaglutide; or (b) 5 mg to 15 mg tirzepatide once weekly.

[0164] Example 87: A method of treating obesity in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034.

[0165] Example 88: The method of Example 87, wherein the subject does not have diabetes.

[0166] Example 89: The method of Example 87 or Example 88, wherein the subject has a body mass index (BMI) of at least 28 kg / m 2 or > 27 kg / m 2 with at least one weight-related comorbid condition.

[0167] Embodiment 90: A method of treating a metabolic disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034.

[0168] Embodiment 91 : The method of Embodiment 90, wherein the metabolic disorder is metabolic dysfunction-associated fatty liver disease (MASLD).

[0169] Embodiment 92: The method of Embodiment 91, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

[0170] Embodiment 93: The method of Embodiment 90, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

[0171] Embodiment 94: The method of Embodiment 93, wherein the metabolic disorder is type 2 diabetes.

[0172] Embodiment 95: The method of any one of Embodiments 87-94, wherein the subject has hypertension.

[0173] Embodiment 96: The method of any one of Embodiments 87-95, wherein GL0034 is administered to the subject subcutaneously.

[0174] Embodiment 97: The method of Embodiment 96, wherein GL0034 is administered to the subject by subcutaneous injection.

[0175] Embodiment 98: The method of Embodiment 97, wherein GL0034 is administered to the subject using an auto-injector or a pre-filled syringe.

[0176] Embodiment 99: The method of any one of Embodiments 87-98, wherein the subject is administered a dose comprising between 200 pg and 8000 pg of GL0034.

[0177] Embodiment 100: The method of Embodiment 99, wherein the dose comprises between 300 pg and 6000 pg of GL0034.

[0178] Embodiment 101 : The method of Embodiment 100, wherein the dose comprises between 400 pg and 4000 pg of GL0034.

[0179] Embodiment 102: The method of Embodiment 101, wherein the dose comprises between 1000 pg and 3000 pg of GL0034.

[0180] Example 103: The method of any one of examples 87-102, wherein the dose of GL0034 is administered to the subject once a week or once every two weeks.

[0181] Example 104: The method of any one of examples 87-102, wherein administration of GL0034 to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 75 ng / mL and 1200 ng / mL. max ).

[0182] Example 105: The method of any one of examples 87-102, wherein administration of GL0034 to the subject achieves an area under the concentration-time curve (AUC0-22) of GL0034 of between 6200 ng h / mL and 406300 ng h / mL over a 22-day period. 0-t ).

[0183] Example 106: The method of example 102, wherein the dose comprises 1520 pg, 2000 pg, or 2520 pg GL0034.

[0184] Example 107: The method of example 106, wherein administration of GL0034 to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 227 ng / mL and 367 ng / mL. max ).

[0185] Example 108: The method of example 106, wherein administration of GL0034 to the subject achieves an area under the concentration-time curve (AUC0-22) of GL0034 of between 30313 ng h / mL and 83082 ng h / mL over a 22-day period. 0-t ).

[0186] Example 109: The method of any one of examples 87-107, wherein administration of GL0034 to the subject achieves a plasma drug half-life (t½) of GL0034 of between 90 hours and 120 hours. 1 / 2 ).

[0187] Example 110: The method of example 107, wherein administration of GL0034 to the subject achieves a plasma drug half-life (t½) of GL0034 of between 98 hours and 113 hours. 1 / 2 ).

[0188] Example 111: The method of any one of examples 87-98, wherein the subject is administered GL0034 once a week or once every two weeks.

[0189] Example 112: The method of any one of examples 87-98 or 111, wherein the subject is administered a dose comprising 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034.

[0190] Example 113: The method of example 112, wherein the subject is administered the dose of GL0034 once a week or once every two weeks.

[0191] Example 114: The method of example 112, wherein the subject is administered GL0034 at a dose of 450 pg once a week for at least 4 weeks, and wherein the mean maximum concentration (C max ) of GL0034 is between 101 ng / mL and 142 ng / mL.

[0192] Example 115: The method of example 114, wherein the subject is administered GL0034 achieves an area under the concentration-time curve (AUC ) of GL0334 between 12814 ng h / mL and 18537 ng 0-t h / mL over a 22-day period.

[0193] Example 116: The method of example 114, wherein the subject is administered GL0034 achieves a plasma drug half-life (t 1 / 2 ) of GL0034 of 102 hours prior to day 22.

[0194] Example 117: The method of example 112, wherein the subject is administered GL0034 at a dose of 680 pg once a week for at least 4 weeks, and wherein the mean maximum concentration (C max ) of GL0034 is between 169 ng / mL and 267 ng / mL.

[0195] Example 118: The method of example 117, wherein the subject is administered GL0034 achieves an area under the concentration-time curve (AUC ) of GL0034 between 24576 ng h / mL and 34537 ng 0-t h / mL over a 22-day period.

[0196] Embodiment 119: The method of Embodiment 117, wherein administration of GL0034 to the subject achieves a plasma drug half-life (t 1 / 2 ).

[0197] Embodiment 120: The method of any one of Embodiments 87-98, wherein: (i) GL0034 is administered to the subject at a dose of between 50 pg and 200 pg once a week for at least 2 weeks; (ii) GL0034 is administered to the subject at a dose of between 200 pg and 400 pg once a week for at least 2 weeks; (iii) GL0034 is administered to the subject at a dose of between 500 pg and 700 pg once a week for at least 2 weeks; (iv) GL0034 is administered to the subject at a dose of between 1200 pg and 1500 pg once a week for at least 2 weeks; and (v) GL0034 is administered to the subject at a dose of between 2000 pg and 3000 pg once a week for at least 4 weeks.

[0198] Embodiment 121: The method of any one of Embodiments 87-98, wherein: (i) GL0034 is administered to the subject at a dose of 450 pg once a week for at least 2 weeks; (ii) GL0034 is administered to the subject at a dose of 900 pg once a week for at least 2 weeks; and (iii) GL0034 is administered to the subject at a dose of 1520 pg once a week for at least 4 weeks.

[0199] Embodiment 122: The method of Embodiment 121, wherein administration of GL0034 to the subject achieves a mean maximum concentration (C max ).

[0200] Embodiment 123: The method of Embodiment 121, wherein administration of GL0034 to the subject achieves an area under the concentration-time curve (AUC ) of GL0034 of between 12942 ng h / mL and 76320 ng 0-t ).

[0201] Embodiment 124: The method of Embodiment 121, wherein administration of GL0034 to the subject achieves a plasma drug half-life (t 1 / 2 ).

[0202] Embodiment 125: The method of any one of embodiments 87-98, comprising: (i) administering to the subject an initial dose comprising between 200 pg and 680 pg of GL0034 for at least 4 weeks; (ii) administering to the subject an escalation dose comprising between 680 pg and 900 pg of GL0034 once a week for at least 2 weeks; and (iii) administering to the subject a maintenance dose comprising between 1500 pg and 2000 pg of GL0034 once a week for at least 2 weeks.

[0203] Embodiment 126: The method of any one of embodiments 87-98, comprising: (i) administering to the subject an initial dose comprising between 450 pg and 680 pg of GL0034 for at least 4 weeks; and (ii) administering to the subject an escalation dose comprising between 680 pg and 900 pg of GL0034 once a week for at least 2 weeks.

[0204] Embodiment 127: The method of any one of embodiments 87-98, comprising: (i) administering to the subject an initial dose comprising between 450 pg and 680 pg of GL0034 for at least 4 weeks; (ii) administering to the subject an escalation dose comprising between 680 pg and 900 pg of GL0034 once a week for at least 2 weeks; and (iii) administering to the subject a maintenance dose comprising between 1520 pg and 2000 pg of GL0034 once a week for at least 2 weeks.

[0205] Example 128: The method of any one of examples 87-127, wherein administration of GL0034 to the subject produces one or more clinically meaningful changes in the subject relative to baseline, wherein the clinically meaningful change relative to baseline is a decrease in alanine aminotransferase (ALT) value, a decrease in aspartate aminotransferase (AST) value, a decrease in gamma-glutamyl transferase (GGT) value, a decrease in fasting insulin level, a decrease in fasting glucose level, a decrease in glycosylated hemoglobin (HbAlc%), a decrease in homeostatic model assessment of insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin level, a decrease in triglyceride (TG) level, a decrease in total cholesterol (TC) level, a decrease in low-density lipoprotein (LDL) level, an increase in high-density lipoprotein (HDL) level, a decrease in TG / HDL ratio, an increase in FGF-21 in the liver, an increase in uncoupling protein-1 level (UCP-1) in brown adipose tissue (BAT) and / or white adipose tissue (WAT), and / or a decrease in blood pressure.

[0206] Example 129: The method of example 128, wherein the decrease in ALT value relative to baseline persists for at least 23 days, at least 52 days, or at least 78 days after administration of GL0034 to the subject.

[0207] Example 130: The method of example 128, wherein: (a) the change in ALT value relative to baseline is at least -9 U / L over a period of about 23 days after administration of a dose comprising 450 pg GL0034 to the subject, or at least -3 U / L over a period of about 23 days after administration of a dose comprising 680 pg GL0034 to the subject; or (b) the change in ALT value is at least -7 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks, to the subject.

[0208] Example 131: The method of example 128, wherein the decrease in AST value relative to baseline persists for at least 23 days, at least 51 days, or at least 78 days after administration of GL0034 to the subject.

[0209] Example 132: The method of Example 128, wherein the change from baseline in AST value is at least -4 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0210] Example 133: The method of Example 128, wherein the reduction from baseline in GGT value lasts for at least 23 days, at least 51 days, or at least 78 days after administration of GL0034 to the subject.

[0211] Example 134: The method of Example 128, wherein the change from baseline in GGT value is at least -3 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0212] Example 135: The method of Example 128, wherein the reduction from baseline in fasting insulin level lasts for at least 23 days or at least 51 days after administration of GL0034 to the subject.

[0213] Example 136: The method of Example 128, wherein the change from baseline in fasting insulin level is at least -5 pmol / L over a period of about 23 days after administration to the subject of a dose comprising 680 pg GL0034 once a week for at least 4 weeks; or at least -11 pmol / L over a period of about 51 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0214] Example 137: The method of Example 128, wherein the reduction in fasting glucose lasts for at least 23 days or at least 51 days after administration of GL0034 to the subject.

[0215] Embodiment 138: The method of Embodiment 128, wherein the reduction in fasting glucose is at least -3 mg / dL over a period of about 23 days after administration to the subject of a dose comprising 450 pg GL0034 once a week for at least 4 weeks; or at least -5 mg / dL over a period of about 23 days after administration to the subject of a dose comprising 680 pg GL0034 once a week for at least 4 weeks; or at least -8 mg / dL over a period of about 51 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0216] Embodiment 139: The method of Embodiment 128, wherein the reduction in body weight persists for at least 8 days, at least 15 days, at least 22 days, at least 29 days, at least 50 days, at least 52 days, or at least 78 days after administration of GL0034 to the subject.

[0217] Embodiment 140: The method of Embodiment 128, wherein: (a) the reduction in body weight is at least -2 kg over a period of about 22 days after administration to the subject of a dose comprising 2000 pg GL0034; or at least -2 kg over a period of about 22 days after administration to the subject of a dose comprising 1520 pg GL0034; or at least -3 kg over a period of about 22 days after administration to the subject of a dose comprising 2520 pg GL0034; or at least -3 kg over a period of about 29 days after administration to the subject of a dose comprising 450 pg GL0034 once a week for at least 4 weeks; or at least -4 kg over a period of about 29 days after administration to the subject of a dose comprising 680 pg GL0034 once a week for at least 4 weeks; or (b) the reduction in body weight is at least -8 kg over a period of about 52 days or at least -6 kg over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0218] Example 141: The method of Example 128, wherein the reduction in leptin level relative to baseline is dose-dependent.

[0219] Example 142: The method of Example 128, wherein the change in leptin level relative to baseline is at least -7 ng / mL over a period of about 8 days after administration to the subject of a dose comprising 1520 pg GL0034; or at least -11 ng / mL over a period of about 8 days after administration to the subject of a dose comprising 2000 pg GL0034; or at least -12 ng / mL over a period of about 8 days after administration to the subject of a dose comprising 2520 pg GL0034.

[0220] Example 143: The method of Example 128, wherein a reduction in TG level relative to baseline is observed at day 8 after administration of GL0034 to the subject and the reduction in TG level relative to baseline persists for at least 51 days or at least 78 days.

[0221] Example 144: The method of Example 128, wherein: (a) the change in TG level relative to baseline is at least -1 mmol / L over a period of about 8 days after administration to the subject of a dose comprising 2000 pg GL0034, or at least -1 mmol / L over a period of about 22 days after administration of a dose comprising 2520 pg GL0034; or (b) the change in TG value is at least -21 mg / dL over a period of about 51 days or at least -11 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0222] Example 145: The method of Example 128, wherein the reduction in TC level relative to baseline is at least -29 mg / dL over a period of about 51 days or at least -6 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0223] Example 146: The method of Example 128, wherein the change from baseline in LDL levels is at least -24 mg / dL over a period of about 51 days or at least -20 mg / dL over a period of about 78 days following administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0224] Example 147: The method of Example 128, wherein the increase from baseline in HDL levels is at least 3 mg / dL over a period of about 78 days following administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0225] Example 148: The method of Example 128, wherein the clinically meaningful change from baseline in the subject is a reduction in blood pressure.

[0226] Example 149: The method of Example 148, wherein the reduction in blood pressure is a reduction in systolic blood pressure.

[0227] Example 150: The method of Example 148, wherein the reduction in blood pressure is a reduction in diastolic blood pressure.

[0228] Example 151: The method of Example 149, wherein the reduction from baseline in systolic blood pressure is at least about 18 mmHg or at least about 14% over a period of about 23 days following administration to the subject of a dose comprising 450 pg GL0034 once a week for at least 4 weeks.

[0229] Example 152: The method of Example 150, wherein the reduction from baseline in diastolic blood pressure is at least about 12 mmHg or at least about 14% over a period of about 23 days following administration to the subject of a dose comprising 450 pg GL0034 once a week for at least 4 weeks.

[0230] Example 153: The method of Example 148, wherein the reduction in blood pressure in the subject is greater compared to the reduction in blood pressure following administration of: (a) 1.7 mg to 2.4 mg of semaglutide once weekly; or (b) 5 mg to 15 mg of tirzepatide once weekly.

[0231] Example 154: The method of any one of Examples 87-153, wherein administration of GL0034 to the subject achieves a reduction in the frequency of adverse events (AEs) in the subject over time.

[0232] Example 155: The method of Example 154, wherein the AE is one or more of nausea, vomiting, and / or decreased appetite.

[0233] Example 156: The method of Example 154, wherein the reduction in the frequency of the AE is dose-dependent.

[0234] Example 157: The method of any one of Examples 87-98, wherein administration of a higher dose of GL0034 to the subject does not cause an increase in severe treatment-emergent adverse events (TEAEs).

[0235] Example 158: A method of treating hypertension in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034.

[0236] Example 159: The method of Example 158, wherein the subject is obese.

[0237] Example 160: The method of Example 159, wherein the subject does not have diabetes.

[0238] Example 161: The method of Example 158, wherein the subject has a metabolic disorder.

[0239] Example 162: The method of Example 161, wherein the metabolic disorder is metabolic dysfunction-associated fatty liver disease (MASLD).

[0240] Example 163: The method of Example 162, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

[0241] Example 164: The method of Example 161, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

[0242] Example 165: The method of Example 164, wherein the metabolic disorder is type 2 diabetes.

[0243] Embodiment 166: The method of any one of embodiments 158-165, wherein GL0034 is administered to the subject subcutaneously.

[0244] Embodiment 167: The method of embodiment 166, wherein GL0034 is administered to the subject by subcutaneous injection.

[0245] Embodiment 168: The method of embodiment 167, wherein GL0034 is administered to the subject using an auto-injector or a pre-filled syringe.

[0246] Embodiment 169: The method of any one of embodiments 158-168, wherein the subject is administered a dose comprising 450 pg GL0034.

[0247] Embodiment 170: The method of embodiment 169, wherein administration of GL0034 achieves a reduction in systolic blood pressure in the subject of at least about 18 mmHg or at least about 14% relative to baseline over a period of about 23 days following administration of GL0034.

[0248] Embodiment 171: The method of embodiment 169, wherein administration of GL0034 achieves a reduction in diastolic blood pressure in the subject of at least about 12 mmHg or at least about 14% relative to baseline over a period of about 23 days following administration of GL0034.

[0249] Embodiment 172: The method of any one of embodiments 158-171, wherein the reduction in blood pressure in the subject is greater than a reduction in blood pressure following administration of: (a) 1.7 mg to 2.4 mg semaglutide; or (b) 5 mg to 15 mg tirzepatide once weekly.

[0250] Embodiment 173: Use of GL0034 for the manufacture of a medicament for the treatment of obesity in a subject.

[0251] Embodiment 174: The use of embodiment 173, wherein the subject does not have diabetes.

[0252] Embodiment 175: The use of embodiment 173 or embodiment 174, wherein the subject has a body mass index (BMI) of at least 28 kg / m 2 or > 27 kg / m 2 with at least 1 weight-related co-morbid condition.

[0253] Embodiment 176: Use of GL0034 for the manufacture of a medicament for the treatment of a metabolic disorder in a subject.

[0254] Embodiment 177: The use of any one of Embodiments 176, wherein the metabolic disorder is metabolic dysfunction-associated fatty liver disease (MASLD).

[0255] Embodiment 178: The use of Embodiment 177, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

[0256] Embodiment 179: The use of Embodiment 176, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

[0257] Embodiment 180: The use of Embodiment 179, wherein the metabolic disorder is type 2 diabetes.

[0258] Embodiment 181: The use of any one of Embodiments 173-180, wherein the subject has hypertension.

[0259] Embodiment 182: The use of any one of Embodiments 173-181, wherein the medicament is administered subcutaneously to the subject.

[0260] Embodiment 183: The use of Embodiment 182, wherein the medicament is administered to the subject by subcutaneous injection.

[0261] Embodiment 184: The use of Embodiment 183, wherein the medicament is administered to the subject using an auto-injector or a pre-filled syringe.

[0262] Embodiment 185: The use of any one of Embodiments 173-184, wherein a dose of the medicament comprises between 200 pg and 8000 pg of GL0034.

[0263] Embodiment 186: The use of Embodiment 185, wherein the dose of the medicament comprises between 300 pg and 6000 pg of GL0034.

[0264] Embodiment 187: The use of Embodiment 186, wherein the dose of the medicament comprises between 400 pg and 4000 pg of GL0034.

[0265] Embodiment 188: The use of Embodiment 187, wherein the dose of the medicament comprises between 1000 pg and 3000 pg of GL0034.

[0266] Embodiment 189: The use of any one of Embodiments 173-188, wherein the dose of the medicament is administered to the subject once a week or once every two weeks.

[0267] Embodiment 190: The use of any one of embodiments 173-188, wherein administration of the medicament to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 75 ng / mL and 1200 ng / mL. max ).

[0268] Embodiment 191: The use of any one of embodiments 173-188, wherein administration of the medicament to the subject achieves an area under the concentration-time curve (AUC) of GL0034 of between 6200 ng h / mL and 406300 ng h / mL over a 22-day period. 0-t ).

[0269] Embodiment 192: The use of embodiment 188, wherein the dose of the medicament comprises 1520 pg, 2000 pg, or 2520 pg GL0034.

[0270] Embodiment 193: The use of embodiment 192, wherein administration of the medicament to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 227 ng / mL and 367 ng / mL. max ).

[0271] Embodiment 194: The use of embodiment 192, wherein administration of the medicament to the subject achieves an area under the concentration-time curve (AUC) of GL0034 of between 30313 ng h / mL and 83082 ng h / mL over a 22-day period. 0-t ).

[0272] Embodiment 195: The use of any one of embodiments 173-193, wherein administration of the medicament to the subject achieves a plasma drug half-life (t½) of GL0034 of between 90 hours and 120 hours. 1 / 2 ).

[0273] Embodiment 196: The use of embodiment 193, wherein administration of the medicament to the subject achieves a plasma drug half-life (t½) of GL0034 of between 98 hours and 113 hours. 1 / 2 ).

[0274] Embodiment 197: The use of any one of embodiments 173-184, wherein the medicament is administered to the subject once a week or once every two weeks.

[0275] Example 198: The use of any one of examples 173-184 or 197, wherein the dose of the medicament comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg of GL0034.

[0276] Example 199: The use of example 198, wherein the dose of the medicament is administered once per week or once every two weeks.

[0277] Example 200: The use of example 198, wherein the dose of the medicament comprises 450 pg of GL0034, and wherein the medicament is administered to the subject once per week for at least 4 weeks to achieve a mean maximum concentration (Cmax) of GL0034 of between 101 ng / mL and 142 ng / mL. max ).

[0278] Example 201: The use of example 200, wherein the administration of the medicament to the subject achieves an area under the concentration-time curve (AUC0-22) of GL0334 of between 12814 ng h / mL and 18537 ng h / mL over a 22-day period. 0-t ).

[0279] Example 202: The use of example 200, wherein the administration of the medicament to the subject achieves a plasma drug half-life (t½) of GL0034 of 102 hours prior to day 22. 1 / 2 ).

[0280] Example 203: The use of example 198, wherein the dose of the medicament comprises 680 pg of GL0034, and wherein the medicament is administered to the subject once per week for at least 4 weeks to achieve a mean maximum concentration (Cmax) of GL0034 of between 169 ng / mL and 267 ng / mL. max ).

[0281] Example 204: The use of example 203, wherein the administration of the medicament to the subject achieves an area under the concentration-time curve (AUC0-22) of GL0034 of between 24576 ng h / mL and 34537 ng h / mL over a 22-day period. 0-t ).

[0282] Embodiment 205: The use of Embodiment 203, wherein administration of the medicament to the subject achieves a plasma drug half-life (t 1 / 2 ).

[0283] Embodiment 206: The use of any one of Embodiments 173-184, wherein: (i) the medicament comprising between 50 pg and 200 pg of GL0034 is administered to the subject once weekly for at least 2 weeks; (ii) the medicament comprising between 200 pg and 400 pg of GL0034 is administered to the subject once weekly for at least 2 weeks; (iii) the medicament comprising between 500 pg and 700 pg of GL0034 is administered to the subject once weekly for at least 2 weeks; (iv) the medicament comprising between 1200 pg and 1500 pg of GL0034 is administered to the subject once weekly for at least 2 weeks; and (v) the medicament comprising between 2000 pg and 3000 pg of GL0034 is administered to the subject once weekly for at least 4 weeks.

[0284] Embodiment 207: The use of any one of Embodiments 173-184, wherein: (i) the medicament comprising 450 pg GL0034 is administered to the subject once weekly for at least 2 weeks; (ii) the medicament comprising 900 pg GL0034 is administered to the subject once weekly for at least 2 weeks; and (iii) the medicament comprising 1520 pg GL0034 is administered to the subject once weekly for at least 4 weeks.

[0285] Embodiment 208: The use of Embodiment 207, wherein administration of the medicament to the subject achieves a mean maximum concentration (C max ).

[0286] Embodiment 209: The use of Embodiment 207, wherein administration of the medicament to the subject achieves an area under the concentration-time curve (AUC ) of GL0034 of between 12942 ng h / mL and 76320 ng 0-t ).

[0287] Example 210: The use of any one of Examples 207, wherein administration of the medicament to the subject achieves a plasma drug half-life (t½) of GL0034 of 106.8 ± 33.7 hours prior to day 50 1 / 2 .

[0288] Example 211: The use of any one of Examples 173-184, wherein: (i) the medicament comprising an initial dose of between 200 μg and 680 μg of GL0034 is administered to the subject for at least 4 weeks; (ii) the medicament comprising an escalation dose of between 680 μg and 900 μg of GL0034 is administered to the subject once weekly for at least 2 weeks; and (iii) the medicament comprising a maintenance dose of between 1500 μg and 2000 μg of GL0034 is administered to the subject once weekly for at least 2 weeks.

[0289] Example 212: The use of any one of Examples 173-184, wherein: (i) the medicament comprising an initial dose of between 450 μg and 680 μg of GL0034 is administered to the subject for at least 4 weeks; and (ii) the medicament comprising an escalation dose of between 680 μg and 900 μg of GL0034 is administered to the subject once weekly for at least 2 weeks.

[0290] Example 213: The use of any one of Examples 173-184, wherein: (i) the medicament comprising an initial dose of between 450 μg and 680 μg of GL0034 is administered to the subject for at least 4 weeks; (ii) the medicament comprising an escalation dose of between 680 μg and 900 μg of GL0034 is administered to the subject once weekly for at least 2 weeks; and (iii) the medicament comprising a maintenance dose of between 1520 μg and 2000 μg of GL0034 is administered to the subject once weekly for at least 2 weeks.

[0291] Example 214: The use of any one of examples 173-213, wherein administration of the medicament to the subject produces one or more clinically meaningful changes in the subject relative to baseline, wherein the clinically meaningful changes relative to baseline are a decrease in alanine aminotransferase (ALT) values, a decrease in aspartate aminotransferase (AST) values, a decrease in gamma-glutamyl transferase (GGT) values, a decrease in fasting insulin levels, a decrease in fasting glucose levels, a decrease in glycated hemoglobin (HbAlc%), a decrease in homeostatic model assessment of insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin levels, a decrease in triglyceride (TG) levels, a decrease in total cholesterol (TC) levels, a decrease in low-density lipoprotein (LDL) levels, an increase in high-density lipoprotein (HDL) levels, a decrease in TG / HDL ratio, an increase in FGF-21 in the liver, an increase in uncoupling protein-1 levels (UCP-1) in brown adipose tissue (BAT) and / or white adipose tissue (WAT), and / or a decrease in blood pressure.

[0292] Example 215: The use of example 214, wherein the decrease in ALT values relative to baseline persists for at least 23 days, at least 52 days, or at least 78 days after administration of the medicament to the subject.

[0293] Example 216: The use of example 214, wherein: (a) the change in ALT values relative to baseline is at least -9 U / L over a period of about 23 days after administration of a dose of the medicament to the subject comprising 450 pg GL0034, or at least -3 U / L over a period of about 23 days after administration of a dose of the medicament to the subject comprising 680 pg GL0034; or (b) the change in ALT values is at least -7 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration of: (i) a dose of the medicament comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once a week for at least 4 weeks, to the subject.

[0294] Example 217: The use of example 214, wherein the decrease in AST values relative to baseline persists for at least 23 days, at least 51 days, or at least 78 days after administration of the medicament to the subject.

[0295] Example 218: The use of Example 214, wherein the change from baseline in AST value is at least -4 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose of the medicament comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0296] Example 219: The use of Example 214, wherein the reduction from baseline in GGT value lasts for at least 23 days, at least 51 days, or at least 78 days after administration to the subject of the medicament.

[0297] Example 220: The use of Example 214, wherein the change from baseline in GGT value is at least -3 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose of the medicament comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0298] Example 221: The use of Example 214, wherein the reduction from baseline in fasting insulin level lasts for at least 23 days or at least 51 days after administration to the subject of the medicament.

[0299] Example 222: The use of Example 214, wherein the change from baseline in fasting insulin level is at least -5 pmol / L over a period of about 23 days after administration to the subject of 680 pg GL0034 once weekly for at least 4 weeks; or at least -11 pmol / L over a period of about 51 days after administration to the subject of: (i) a dose of the medicament comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0300] Embodiment 223: Use according to Embodiment 214, wherein the reduction in fasting glucose is sustained for at least 23 days or at least 51 days after administration of the medicament to the subject.

[0301] Embodiment 224: Use according to Embodiment 214, wherein the reduction in fasting glucose is at least -3 mg / dL over a period of about 23 days after administration to the subject of a dose of the medicament comprising 450 pg GL0034 once weekly for at least 4 weeks; or at least -5 mg / dL over a period of about 23 days after administration to the subject of a dose of the medicament comprising 680 pg GL0034 once weekly for at least 4 weeks; or at least -8 mg / dL over a period of about 51 days after administration to the subject of: (i) a dose of the medicament comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0302] Embodiment 225: Use according to Embodiment 214, wherein the reduction in body weight is sustained for at least 8 days, at least 15 days, at least 22 days, at least 29 days, at least 50 days, at least 52 days, or at least 78 days after administration of the medicament to the subject.

[0303] Example 226: The use of Example 214, wherein: (a) the reduction in body weight is at least -2 kg over a period of about 22 days after administration to the subject of a dose of the medicament comprising 2000 pg GL0034; or at least -2 kg over a period of about 22 days after administration to the subject of a dose of the medicament comprising 1520 pg GL0034; or at least -3 kg over a period of about 22 days after administration to the subject of a dose of the medicament comprising 2520 pg GL0034; or at least -3 kg over a period of about 29 days after administration to the subject of a dose of the medicament comprising 450 pg GL0034 once weekly for at least 4 weeks; or at least -4 kg over a period of about 29 days after administration to the subject of a dose of the medicament comprising 680 pg GL0034 once weekly for at least 4 weeks; or (b) the reduction in body weight is at least -8 kg over a period of about 52 days or at least -6 kg over a period of about 78 days after administration to the subject of: (i) a dose of the medicament comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0304] Example 227: The use of Example 214, wherein the reduction in leptin level relative to baseline is dose dependent.

[0305] Example 228: The use of Example 214, wherein the change in leptin level relative to baseline is at least -7 ng / mL over a period of about 8 days after administration to the subject of a dose of the medicament comprising 1520 pg GL0034; or at least -11 ng / mL over a period of about 8 days after administration to the subject of a dose of the medicament comprising 2000 pg GL0034; or at least -12 ng / mL over a period of about 8 days after administration to the subject of a dose of the medicament comprising 2520 pg GL0034.

[0306] Example 229: The use of Example 214, wherein the reduction in TG level relative to baseline is observed on day 8 and the reduction in TG level relative to baseline persists for at least 51 days or at least 78 days after administration of the medicament to the subject.

[0307] Example 230: The use of Example 214, wherein: (a) the change in TG level from baseline is at least -1 mmol / L over a period of about 8 days after administration to the subject of a dose of the medicament comprising 2000 pg GL0034, or at least -1 mmol / L over a period of about 22 days after administration to the subject of a dose of the medicament comprising 2520 pg GL0034; or (b) the change in TG value is at least -21 mg / dL over a period of about 51 days or at least -11 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the medicament comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0308] Example 231: The use of Example 214, wherein the reduction in TC level from baseline is at least -29 mg / dL over a period of about 51 days or at least -6 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the medicament comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0309] Example 232: The use of Example 214, wherein the change in LDL level from baseline is at least -24 mg / dL over a period of about 51 days or at least -20 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the medicament comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once weekly for at least 4 weeks.

[0310] Example 233: The use of Example 214, wherein the increase in HDL levels relative to baseline is at least 3 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the medicament comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 once a week for at least 4 weeks.

[0311] Example 234: The use of Example 214, wherein the clinically meaningful change in the subject relative to baseline is a reduction in blood pressure.

[0312] Example 235: The use of Example 234, wherein the reduction in blood pressure is a reduction in systolic blood pressure.

[0313] Example 236: The use of Example 234, wherein the reduction in blood pressure is a reduction in diastolic blood pressure.

[0314] Example 237: The use of Example 235, wherein the reduction in systolic blood pressure relative to baseline is at least about 18 mmHg or at least about 14% over a period of about 23 days after administration to the subject of a dose of the medicament comprising 450 pg GL0034 once a week for at least 4 weeks.

[0315] Example 238: The use of Example 236, wherein the reduction in diastolic blood pressure relative to baseline is at least about 12 mmHg or at least about 14% over a period of about 23 days after administration to the subject of a dose of the medicament comprising 450 pg GL0034 once a week for at least 4 weeks.

[0316] Example 239: The use of Example 234, wherein the reduction in blood pressure in the subject is greater than the reduction in blood pressure after administration of: (a) 1.7 mg to 2.4 mg semaglutide once a week; or (b) 5 mg to 15 mg tirzepatide once a week.

[0317] Example 240: The use of any one of Examples 173-239, wherein administration of the medicament to the subject achieves a reduction in the frequency of adverse events (AEs) in the subject over time.

[0318] Example 241: The use of Example 240, wherein the AE is one or more of nausea, vomiting, and / or decreased appetite.

[0319] Embodiment 242: The use of any one of embodiments 240, wherein the reduction in frequency of AEs is dose dependent.

[0320] Embodiment 243: The use of any one of embodiments 173-184, wherein administration of a higher dose of the medicament to the subject does not cause an increase in severe treatment-emergent adverse events (TEAEs).

[0321] Embodiment 244: Use of GL0034 for the manufacture of a medicament for treating hypertension in a subject, wherein a therapeutically effective dose of the medicament is administered to the subject.

[0322] Embodiment 245: The use of embodiment 244, wherein the subject is obese.

[0323] Embodiment 246: The use of embodiment 245, wherein the subject does not have diabetes.

[0324] Embodiment 247: The use of embodiment 244, wherein the subject has a metabolic disorder.

[0325] Embodiment 248: The use of embodiment 247, wherein the metabolic disorder is metabolic dysfunction-associated steatohepatitis (MASLD).

[0326] Embodiment 249: The use of embodiment 248, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

[0327] Embodiment 250: The use of embodiment 247, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

[0328] Embodiment 251: The use of embodiment 250, wherein the metabolic disorder is type 2 diabetes.

[0329] Embodiment 252: The use of any one of embodiments 244-251, wherein the medicament is administered to the subject subcutaneously.

[0330] Embodiment 253: The use of embodiment 252, wherein the medicament is administered to the subject by subcutaneous injection.

[0331] Embodiment 254: The use of embodiment 253, wherein the medicament is administered to the subject using an auto-injector or a pre-filled syringe.

[0332] Example 255: The use of any one of examples 244-254, wherein the subject is administered a dose of the medicament comprising 450 pg GL0034.

[0333] Example 256: The use of example 255, wherein administration of the medicament achieves a reduction in systolic blood pressure in the subject of at least about 18 mmHg or at least about 14% relative to baseline over a period of about 23 days after administration of the medicament.

[0334] Example 257: The use of example 255, wherein administration of the medicament achieves a reduction in diastolic blood pressure in the subject of at least about 12 mmHg or at least about 14% relative to baseline over a period of about 23 days after administration of the medicament.

[0335] Example 258: The use of any one of examples 244-257, wherein the reduction in blood pressure in the subject is greater than a reduction in blood pressure after administration of: (a) 1.7 mg to 2.4 mg semaglutide; or (b) 5 mg to 15 mg

[0336] Example 259: A method of treating obesity in a subject, the method comprising administering to the subject a dose of 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034.

[0337] Example 260: A method of treating a metabolic disorder in a subject, the method comprising administering to the subject a dose of 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034.

[0338] Example 261: The method of example 260, wherein the metabolic disorder is MASH, MASLD, diabetes, or hypertriglyceridemia.

[0339] Example 262: The method of example 259 or example 260, wherein GL0034 is administered to the subject subcutaneously.

[0340] Example 263: The method of example 259 or example 260, wherein GL0034 is administered to the subject in a single dose of 1520 pg, 2000 pg, or 2520 pg.

[0341] Example 264: The method of Example 263, wherein the administration provides a mean maximum concentration (Cmax) of GL0034 of between 226.9 ± 57.3 ng / mL and 367.0 ± 152.0 ng / mL. max .

[0342] Example 265: The method of Example 263, wherein the administration provides an area under the concentration-time curve (AUC) over a 22-day period of between 47,151.5 ± 16,838.6 ng h / mL and 62,265.9 ± 20,816.5 ng h / mL. 0-t .

[0343] Example 266: The method of Example 263, wherein the administration provides a plasma drug half-life (t½) of between 98.5 ± 13.0 hours and 113.5 ± 22.9 hours. 1 / 2 .

[0344] Example 267: The method of Example 263, wherein the administration provides a time from administration to maximum plasma concentration (Tmax) of between 22.0 ± 6.9 hours and 31.0 ± 13.5 hours. max .

[0345] Example 268: The method of Example 259 or Example 260, wherein GL0034 is administered to the subject in multiple doses of 450 μg, 680 μg, 900 μg, 1520 μg, 2000 μg, or 2520 μg over a period of up to 8 weeks.

[0346] Example 269: The method of Example 268, wherein GL0034 is administered to the subject in a dose of 450 μg once a week for 4 weeks.

[0347] Example 270: The method of Example 269, wherein the administration provides a mean maximum concentration (Cmax) of GL0034 of between 100.5 ± 22.0 ng / mL and 141.7 ± 34.6 ng / mL. max .

[0348] Example 271: The method of Example 269, wherein the administration provides an area under the concentration-time curve (AUC) over a 22-day period of between 12,814.2 ± 2,652.1 ng h / mL and 18,536.8 ± 4,608.2 ng area under the concentration-time curve (AUC 0-t ).

[0349] Example 272: The method of Example 269, wherein the administration provides a plasma drug half-life (t 1 / 2 ).

[0350] Example 273: The method of Example 269, wherein the administration provides a time from administration to maximum plasma concentration (T max ).

[0351] Example 274: The method of Example 268, wherein GL0034 is administered to the subject at a dose of 680 μg once a week for 4 weeks.

[0352] Example 275: The method of Example 274, wherein the administration provides a mean maximum concentration (C max ).

[0353] Example 276: The method of Example 274, wherein the administration provides an area under the concentration-time curve (AUC ) between 24575.9 ± 3391.2 ng h / mL and 34536.6 ± 6445.0 ng 0-t ).

[0354] Example 277: The method of Example 274, wherein the administration provides a plasma drug half-life (t 1 / 2 ).

[0355] Example 278: The method of Example 274, wherein the administration provides a time from administration to maximum plasma concentration (T max ).

[0356] Example 279: The method of Example 268, wherein GL0034 is administered as follows: (i) a dose of 450 μg once a week for at least 2 weeks; (ii) a dose of 900 μg once a week for at least 2 weeks; and (iii) a dose of 1520 μg once a week for at least 4 weeks.

[0357] Embodiment 280: The method of Embodiment 279, wherein the administration provides a mean maximum concentration (Cmax) of GL0034 of between 111.7 ± 23.7 ng / mL and 707.6 ± 251.7 ng / mL. max ).

[0358] Embodiment 281 : The method of Embodiment 279, wherein the administration provides an area under the concentration-time curve (AUC) of between 12942.2 ± 1517.5 ng h / mL and 76320.4 ± 23334.6 ng h / mL over a 50-day period. 0-t ).

[0359] Embodiment 282: The method of Embodiment 279, wherein the administration provides a plasma drug half-life (t½) of 106.8 ± 33.7 hours on day 50. 1 / 2 ).

[0360] Embodiment 283: The method of Embodiment 279, wherein the administration provides a time from administration to maximum plasma concentration (Tmax) of between 22.0 ± 16.0 hours and 41.0 ± 8.0 hours. max ).

[0361] Embodiment 284: The method of Embodiment 259 or Embodiment 260, wherein administration of GL0034 results in one or more clinically meaningful changes in the subject relative to baseline, wherein the clinically meaningful change relative to baseline is a reduction in body weight, a reduction in glycosylated hemoglobin (HbAlc %), an increase in high-density lipoprotein (HDL) level, a reduction in alanine aminotransferase (ALT) value, a reduction in aspartate aminotransferase (AST) value, a reduction in gamma-glutamyl transferase (GGT) value, a reduction in triglyceride (TG) level, a reduction in total cholesterol (TC) level, a reduction in low-density lipoprotein (LDL) level, a reduction in TG / HDL ratio, a reduction in fasting insulin level, a reduction in fasting glucose level, a reduction in homeostatic model assessment of insulin resistance (HOMA-IR), and / or a reduction in leptin level.

[0362] Embodiment 285: The method of Embodiment 284, wherein the change in fasting plasma glucose level relative to baseline is at least about -2.8 ± 3.7 mg / dL over a period of about 23 days after administration of 450 μg GL0034 once a week for 4 weeks.

[0363] Example 286: The method of Example 284, wherein the change from baseline in fasting plasma glucose levels is at least about -4.6 ± 2.7 mg / dL over a period of about 23 days after administration of 680 pg GL0034 once a week for 4 weeks.

[0364] Example 287: The method of Example 284, wherein the change from baseline in fasting plasma glucose levels is at least about -7.7 ± 9.9 mg / dL over a period of about 51 days after administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0365] Example 288: The method of Example 284, wherein the change from baseline in fasting insulin levels is at least about -4.6 ± 23.0 pmol / L over a period of about 23 days after administration of 680 pg GL0034 once a week for 4 weeks.

[0366] Example 289: The method of Example 284, wherein the change from baseline in fasting insulin levels is at least about -11.3 ± 16.5 pmol / L over a period of about 51 days after administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0367] Example 290: The method of Example 284, wherein the change from baseline in ALT values is at least about -8.8 ± 13.1 U / L over a period of about 23 days after administration of 450 pg GL0034 once a week for 4 weeks.

[0368] Example 291: The method of Example 284, wherein the change from baseline in ALT values is at least about -3.1 ± 5.8 U / L over a period of about 23 days after administration of 680 pg GL0034 once a week for 4 weeks.

[0369] Example 292: The method of Example 284, wherein the change from baseline in ALT values is at least about -7.4 ± 10.3 U / L over the period of about 51 days after administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0370] Example 293: The method of Example 284, wherein the change from baseline in ALT values is at least about -1.0 ± 9.4 U / L over the period of about 78 days after administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0371] Example 294: The method of Example 284, wherein the change from baseline in AST values is at least about -4.0 ± 7.5 U / L over the period of about 51 days after administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0372] Example 295: The method of Example 284, wherein the change from baseline in AST values is at least about -1.1 ± 6.7 U / L over the period of about 78 days after administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0373] Example 296: The method of Example 284, wherein the change from baseline in GGT values is at least about -3.4 ± 3.5 U / L over the period of about 51 days after administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0374] Example 297: The method of Example 284, wherein the change from baseline in GGT value is at least about -1.0 ± 2.7 U / L over a period of about 78 days following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0375] Example 298: The method of Example 284, wherein the change from baseline in body weight is at least about -3.4 ± 1.8 kg over a period of about 29 days following administration of 450 pg GL0034 once a week for 4 weeks.

[0376] Example 299: The method of Example 284, wherein the change from baseline in body weight is at least about -4.1 ± 1.0 kg over a period of about 29 days following administration of 680 pg GL0034 once a week for 4 weeks.

[0377] Example 300: The method of Example 284, wherein the change from baseline in body weight is at least about -7.7 ± 1.9 kg over a period of about 52 days following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0378] Example 301: The method of Example 284, wherein the change from baseline in body weight is at least about -6.4 ± 2.1 kg over a period of about 78 days following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0379] Example 302: The method of Example 284, wherein the change from baseline in HbAlc% is at least about -0.25 ± 0.2 over a period of about 78 days following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0380] Example 303: The method of Example 284, wherein the change from baseline in TG levels is at least about -21.0 ± 27.5 mg / dL over the period of about 51 days following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0381] Example 304: The method of Example 284, wherein the change from baseline in TG levels is at least about -11.0 ± 55.3 mg / dL over the period of about 78 days following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0382] Example 305: The method of Example 284, wherein the change from baseline in TC levels is at least about -29.1 ± 23.3 mg / dL over the period of about 51 days following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0383] Example 306: The method of Example 284, wherein the change from baseline in TC levels is at least about -5.8 ± 12.6 mg / dL over the period of about 78 days following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0384] Example 307: The method of Example 284, wherein the change from baseline in LDL levels is at least about -24.0 ± 24.3 mg / dL over the period of about 51 days following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0385] Example 308: The method of Example 284, wherein the change from baseline in LDL levels over the period of about 78 days is at least about -19.5 ± 35.8 mg / dL following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0386] Example 309: The method of Example 846, wherein the change from baseline in HDL levels over the period of about 78 days is at least about 2.9 ± 3.1 mg / dL following administration of GL0034 in the following manner: (i) a dose of 450 pg once a week for 2 weeks; (ii) a dose of 900 pg once a week for 2 weeks; and (iii) a dose of 1520 pg once a week for 4 weeks.

[0387] Example 310: The method of Example 284, wherein the change from baseline in body weight over the period of about 22 days is at least about -2.4 ± 2.2 kg following administration of GL0034 in a single dose of 1520 pg.

[0388] Example 311: The method of Example 284, wherein the change from baseline in body weight over the period of about 22 days is at least about -1.8 ± 2.4 kg following administration of GL0034 in a single dose of 2000 pg.

[0389] Example 312: The method of Example 284, wherein the change from baseline in body weight over the period of about 22 days is at least about -3.1 ± 1.7 kg following administration of GL0034 in a single dose of 2520 pg.

[0390] Example 313: The method of Example 284, wherein the change from baseline in TG levels over the period of about 8 days is at least about -0.4 ± 0.4 mmol / L following administration of GL0034 in a single dose of 1520 pg.

[0391] Example 314: The method of Example 284, wherein the change from baseline in TG levels over the period of about 8 days is at least about -0.8 ± 0.5 mmol / L following administration of GL0034 in a single dose of 2000 pg.

[0392] Example 315: The method of Example 284, wherein the change from baseline in TG levels is at least about -0.5 ± 0.5 mmol / L over a period of about 22 days following administration of GL0034 in a single dose of 2520 μg.

[0393] Example 316: The method of Example 284, wherein the change from baseline in leptin levels is at least about -6.9 ± 5.1 ng / mL over a period of about 8 days following administration of GL0034 in a single dose of 1520 μg.

[0394] Example 317: The method of Example 284, wherein the change from baseline in leptin levels is at least about -10.9 ± 8.6 ng / mL over a period of about 8 days following administration of GL0034 in a single dose of 2000 μg.

[0395] Example 318: The method of Example 284, wherein the change from baseline in leptin levels is at least about -11.6 ± 12.8 ng / mL over a period of about 8 days following administration of GL0034 in a single dose of 2520 μg.

[0396] Example 319: The method of Example 259 or Example 260, comprising: administering an initial dose for at least about 2 weeks; administering an escalation dose once a week for at least about 2 weeks; and administering a maintenance dose once a week for at least about 4 weeks; wherein the initial dose is about 450 μg or about 680 μg; the escalation dose is about 680 μg or about 900 μg; and the maintenance dose is about 1520 μg or about 2000 μg.

[0397] Example 320: The method of Example 259 or Example 260, comprising: administering an initial dose for at least about 4 weeks; and administering an escalation dose once a week for at least about 2 weeks; wherein the initial dose is about 450 μg or about 680 μg; and the escalation dose is about 680 μg or about 900 μg.

[0398] Example 321: The method of Example 259 or Example 260, comprising: administering an initial dose for at least about 4 weeks; administering an escalation dose once a week for at least about 2 weeks; and administering a maintenance dose once a week for at least about 2 weeks; wherein the initial dose is about 450 μg or about 680 μg; the escalation dose is about 680 μg or about 900 μg; and the maintenance dose is about 1520 μg or about 2000 μg.

[0399] Embodiment 322: A pharmaceutical composition of GL0034 for use in treating obesity in a subject, wherein a dose of the pharmaceutical composition comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034.

[0400] Embodiment 323: A pharmaceutical composition of GL0034 for use in treating a metabolic disorder in a subject, wherein a dose of the pharmaceutical composition comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034.

[0401] Embodiment 324: The pharmaceutical composition of Embodiment 323, wherein the metabolic disorder is MASH, MASLD, diabetes, or hypertriglyceridemia.

[0402] Embodiment 325: The pharmaceutical composition of Embodiment 322 or Embodiment 323, wherein the pharmaceutical composition is administered subcutaneously to the subject.

[0403] Embodiment 326: The pharmaceutical composition of Embodiment 322 or Embodiment 323, wherein the dose of the pharmaceutical composition comprises 1520 pg, 2000 pg, or 2520 pg GL0034, and wherein a single dose of the pharmaceutical composition is administered to the subject.

[0404] Embodiment 327: The pharmaceutical composition of Embodiment 326, wherein administration of the pharmaceutical composition achieves a mean maximum concentration (C max max) of GL0034 of between 226.9 ± 57.3 ng / mL and 367.0 ± 152.0 ng / mL.

[0405] Embodiment 328: The pharmaceutical composition of Embodiment 326, wherein administration of the pharmaceutical composition achieves an area under the concentration-time curve (AUC ) of between 47,151.5 ± 16,838.6 ng h / mL and 62,265.9 ± 20,816.5 ng 0-t h / mL over a 22-day period.

[0406] Embodiment 329: The pharmaceutical composition of Embodiment 326, wherein administration of the pharmaceutical composition achieves a plasma drug half-life (t 1 / 2 ) of between 98.5 ± 13.0 hours and 113.5 ± 22.9 hours.

[0407] Example 330: The pharmaceutical composition of Example 326, wherein administration of the pharmaceutical composition achieves a time from administration to maximum plasma concentration (T max ) of between 22.0 ± 6.9 hours and 31.0 ± 13.5 hours.

[0408] Example 331: The pharmaceutical composition of Example 322 or Example 323, wherein the dose of the pharmaceutical composition comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg of GL0034, and wherein a plurality of doses of the pharmaceutical composition is administered to the subject over a period of up to 8 weeks.

[0409] Example 332: The pharmaceutical composition of Example 331, wherein GL0034 is administered to the subject at a dose of 450 pg once a week for 4 weeks.

[0410] Example 333: The pharmaceutical composition of Example 332, wherein administration of the pharmaceutical composition achieves a mean maximum concentration (C max ) of GL0034 of between 100.5 ± 22.0 ng / mL and 141.7 ± 34.6 ng / mL.

[0411] Example 334: The pharmaceutical composition of Example 332, wherein administration of the pharmaceutical composition achieves an area under the concentration-time curve (AUC ) of between 12814.2 ± 2652.1 ng h / mL and 18536.8 ± 4608.2 ng 0-t h / mL over a period of 22 days.

[0412] Example 335: The pharmaceutical composition of Example 332, wherein administration of the pharmaceutical composition achieves a plasma drug half-life (t 1 / 2 ) of 102.3 ± 15.4 on day 22.

[0413] Example 336: The pharmaceutical composition of Example 332, wherein administration of the pharmaceutical composition achieves a time from administration to maximum plasma concentration (T max ) of between 36.0 ± 12.0 hours and 47.0 ± 16.0 hours.

[0414] Example 337: The pharmaceutical composition of Example 331, wherein a dose of the pharmaceutical composition comprises 680 pg, and wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0415] Embodiment 338: The pharmaceutical composition of Embodiment 337, wherein administration of the pharmaceutical composition achieves a mean maximum concentration (Cmax) of GL0034 of between 169.0 ± 49.5 ng / mL and 267.0 ± 60.9 ng / mL. max ).

[0416] Embodiment 339: The pharmaceutical composition of Embodiment 337, wherein administration of the pharmaceutical composition achieves an area under the concentration-time curve (AUC ) of between 24575.9 ± 3391.2 ng h / mL and 34536.6 ± 6445.0 ng 0-t h / mL over a 22-day period.

[0417] Embodiment 340: The pharmaceutical composition of Embodiment 337, wherein administration of the pharmaceutical composition achieves a plasma drug half-life (t 1 / 2 ) of 122.9 ± 16.5 on day 22.

[0418] Embodiment 341: The pharmaceutical composition of Embodiment 337, wherein administration of the pharmaceutical composition achieves a time from administration to maximum plasma concentration (T max ) of between 39.0 ± 21.0 hours and 54.0 ± 27.0 hours.

[0419] Embodiment 342: The pharmaceutical composition of Embodiment 331, wherein: (i) a first dose of the pharmaceutical composition comprises 450 μg GL0034, wherein the first dose of the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a second dose of the pharmaceutical composition comprises 900 μg GL0034, wherein the second dose of the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a third dose of the pharmaceutical composition comprises 1520 μg GL0034, wherein the third dose of the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0420] Embodiment 343: The pharmaceutical composition of Embodiment 342, wherein administration of the pharmaceutical composition achieves a mean maximum concentration (C max ) of GL0034 of between 111.7 ± 23.7 ng / mL and 707.6 ± 251.7 ng / mL.

[0421] Example 344: The pharmaceutical composition of Example 342, wherein administration of the pharmaceutical composition achieves an area under the concentration-time curve (AUCo-50) of between 12942.2 ± 1517.5 ng h / mL and 76320.4 ± 23334.6 ng h / mL over a 50-day period. 0-t .

[0422] Example 345: The pharmaceutical composition of Example 342, wherein administration of the pharmaceutical composition achieves a plasma drug half-life (t½) of 106.8 ± 33.7 on day 50. 1 / 2 .

[0423] Example 346: The pharmaceutical composition of Example 342, wherein administration of the pharmaceutical composition achieves a time from administration to maximum plasma concentration (Tmax) of between 22.0 ± 16.0 hours and 41.0 ± 8.0 hours. max .

[0424] Example 347: The pharmaceutical composition of Example 322 or Example 323, wherein administration of the pharmaceutical composition pharmaceutical composition produces one or more clinically meaningful changes in the subject relative to baseline, wherein the clinically meaningful changes relative to baseline are a reduction in body weight, a reduction in glycated hemoglobin (HbAlc %), an increase in high-density lipoprotein (HDL) levels, a reduction in alanine aminotransferase (ALT) values, a reduction in aspartate aminotransferase (AST) values, a reduction in gamma-glutamyl transferase (GGT) values, a reduction in triglyceride (TG) levels, a reduction in total cholesterol (TC) levels, a reduction in low-density lipoprotein (LDL) levels, a reduction in TG / HDL ratio, a reduction in fasting insulin levels, a reduction in fasting glucose levels, a reduction in homeostatic model assessment of insulin resistance (HOMA-IR), and / or a reduction in leptin levels.

[0425] Example 348: The pharmaceutical composition of Example 347, wherein the change in fasting plasma glucose levels relative to baseline is at least about -2.8 ± 3.7 mg / dL over a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0426] Example 349: The pharmaceutical composition of Example 347, wherein the change from baseline in fasting plasma glucose levels is at least about -4.6 ± 2.7 mg / dL over a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0427] Example 350: The pharmaceutical composition of Example 347, wherein the change from baseline in fasting plasma glucose levels is at least about -7.7 ± 9.9 mg / dL over a period of about 51 days after administration of each of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0428] Example 351: The pharmaceutical composition of Example 347, wherein the change from baseline in fasting insulin levels is at least about -4.6 ± 23.0 pmol / L over a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0429] Example 352: The pharmaceutical composition of Example 347, wherein the change from baseline in fasting insulin levels is at least about -11.3 ± 16.5 pmol / L over a period of about 51 days after administration of each of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0430] Example 353: The pharmaceutical composition of Example 347, wherein the change from baseline in ALT value is at least about -8.8 ± 13.1 U / L over a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0431] Example 354: The pharmaceutical composition of Example 347, wherein the change from baseline in ALT value is at least about -3.1 ± 5.8 U / L over a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0432] Example 355: The pharmaceutical composition of Example 347, wherein the change from baseline in ALT value is at least about -7.4 ± 10.3 U / L over a period of about 51 days after administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0433] Example 356: The pharmaceutical composition of Example 347, wherein the change from baseline in ALT value is at least about -1.0 ± 9.4 U / L over a period of about 78 days after administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0434] Example 357: The pharmaceutical composition of Example 347, wherein the change from baseline in AST value is at least about -4.0 ± 7.5 U / L over a period of about 51 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0435] Example 358: The pharmaceutical composition of Example 347, wherein the change from baseline in AST value is at least about -1.1 ± 6.7 U / L over a period of about 78 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0436] Example 359: The pharmaceutical composition of Example 347, wherein the change from baseline in GGT value is at least about -3.4 ± 3.5 U / L over a period of about 51 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0437] Example 360: The pharmaceutical composition of Example 347, wherein the change from baseline in GGT value is at least about -1.0 ± 2.7 U / L over a period of about 78 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0438] Example 361: The pharmaceutical composition of Example 347, wherein the change from baseline in body weight is at least about -3.4 ± 1.8 kg over a period of about 29 days following administration of a dose of the pharmaceutical composition comprising 450 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0439] Example 362: The pharmaceutical composition of Example 347, wherein the change from baseline in body weight is at least about -4.1 ± 1.0 kg over a period of about 29 days following administration of a dose of the pharmaceutical composition comprising 680 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0440] Example 363: The pharmaceutical composition of Example 347, wherein the change from baseline in body weight is at least about -7.7 ± 1.9 kg over a period of about 52 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 μg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0441] Example 364: The pharmaceutical composition of Example 347, wherein the change from baseline in body weight is at least about -6.4 ± 2.1 kg over a period of about 78 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0442] Example 365: The pharmaceutical composition of Example 347, wherein the change from baseline in HbAlc% is at least about -0.25 ± 0.2 over a period of about 78 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0443] Example 366: The pharmaceutical composition of Example 347, wherein the change from baseline in TG level is at least about -21.0 ± 27.5 mg / dL over a period of about 51 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0444] Example 367: The pharmaceutical composition of Example 347, wherein the change from baseline in TG levels is at least about -11.0 ± 55.3 mg / dL over a period of about 78 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0445] Example 368: The pharmaceutical composition of Example 347, wherein the change from baseline in TC levels is at least about -29.1 ± 23.3 mg / dL over a period of about 51 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0446] Example 369: The pharmaceutical composition of Example 347, wherein the change from baseline in TC levels is at least about -5.8 ± 12.6 mg / dL over a period of about 78 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0447] Example 370: The pharmaceutical composition of Example 347, wherein the change from baseline in LDL levels is at least about -24.0 ± 24.3 mg / dL over a period of about 51 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0448] Example 371: The pharmaceutical composition of Example 347, wherein the change from baseline in LDL levels is at least about -19.5 ± 35.8 mg / dL over a period of about 78 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0449] Example 372: The pharmaceutical composition of Example 347, wherein the change from baseline in HDL levels is at least about 2.9 ± 3.1 mg / dL over a period of about 78 days following administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034, wherein the pharmaceutical composition is administered to the subject once a week for 4 weeks.

[0450] Example 373: The pharmaceutical composition of Example 347, wherein the change from baseline in body weight is at least about -2.4 ± 2.2 kg over a period of about 22 days following administration of a single dose of the pharmaceutical composition comprising 1520 pg GL0034.

[0451] Embodiment 374: The pharmaceutical composition of Embodiment 347, wherein the change in body weight from baseline over a period of about 22 days is at least about -1.8 ± 2.4 kg following administration of a single dose of the pharmaceutical composition comprising 2000 pg GL0034.

[0452] Embodiment 375: The pharmaceutical composition of Embodiment 347, wherein the change in body weight from baseline over a period of about 22 days is at least about -3.1 ± 1.7 kg following administration of a single dose of the pharmaceutical composition comprising 2520 pg GL0034.

[0453] Embodiment 376: The pharmaceutical composition of Embodiment 347, wherein the change in TG level from baseline over a period of about 8 days is at least about -0.4 ± 0.4 mmol / L following administration of a single dose of the pharmaceutical composition comprising 1520 pg GL0034.

[0454] Embodiment 377: The pharmaceutical composition of Embodiment 347, wherein the change in TG level from baseline over a period of about 8 days is at least about -0.8 ± 0.5 mmol / L following administration of a single dose of the pharmaceutical composition comprising 2000 pg GL0034.

[0455] Embodiment 378: The pharmaceutical composition of Embodiment 347, wherein the change in TG level from baseline over a period of about 22 days is at least about -0.5 ± 0.5 mmol / L following administration of a single dose of the pharmaceutical composition comprising 2520 pg GL0034.

[0456] Embodiment 379: The pharmaceutical composition of Embodiment 347, wherein the change in leptin level from baseline over a period of about 8 days is at least about -6.9 ± 5.1 ng / mL following administration of a single dose of the pharmaceutical composition comprising 1520 pg GL0034.

[0457] Embodiment 380: The pharmaceutical composition of Embodiment 347, wherein the change in leptin level from baseline over a period of about 8 days is at least about -10.9 ± 8.6 ng / mL following administration of a single dose of the pharmaceutical composition comprising 2000 pg GL0034.

[0458] Example 381: The pharmaceutical composition of Example 347, wherein the change from baseline in leptin levels is at least about -11.6 ± 12.8 ng / mL over the period of about 8 days following administration of a single dose of the pharmaceutical composition comprising 2520 pg GL0034.

[0459] Example 382: The pharmaceutical composition of Example 322 or Example 323, wherein the subject is administered an initial dose of the pharmaceutical composition comprising about 450 pg or about 680 pg GL0034 for at least about 2 weeks; wherein the subject is administered an escalation dose of the pharmaceutical composition comprising about 680 pg or about 900 pg GL0034 once a week for at least about 2 weeks; and wherein the subject is administered a maintenance dose of the pharmaceutical composition comprising about 1520 pg or about 2000 pg GL0034 once a week for at least about 4 weeks.

[0460] Example 383: The pharmaceutical composition of Example 322 or Example 323, wherein the subject is administered an initial dose of the pharmaceutical composition comprising about 450 pg or about 680 pg GL0034 for at least about 4 weeks; and wherein the subject is administered an escalation dose of the pharmaceutical composition comprising about 680 pg or about 900 pg GL0034 once a week for at least about 2 weeks.

[0461] Example 384: The pharmaceutical composition of Example 322 or Example 323, wherein the subject is administered an initial dose of the pharmaceutical composition comprising about 450 pg or about 680 pg GL0034 for at least about 4 weeks; wherein the subject is administered an escalation dose of the pharmaceutical composition comprising about 680 pg or about 900 pg GL0034 once a week for at least about 2 weeks; and wherein the subject is administered a maintenance dose of the pharmaceutical composition comprising about 1520 pg or about 2000 pg GL0034 once a week for at least about 2 weeks.

[0462] Example 385: Use of GL0034 for the manufacture of a medicament for the treatment of obesity in a subject, wherein a dose of the medicament comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034.

[0463] Example 386: Use of GL0034 for the manufacture of a medicament for treating a metabolic disorder in a subject, wherein a dose of the medicament comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034.

[0464] Example 387: The use of Example 386, wherein the metabolic disorder is MASH, MASLD, diabetes, or hypertriglyceridemia.

[0465] Example 388: The use of Example 385 or Example 386, wherein the medicament is administered subcutaneously to the subject.

[0466] Example 389: The use of Example 385 or Example 386, wherein the dose of the medicament comprises 1520 pg, 2000 pg, or 2520 pg GL0034, and wherein a single dose of the medicament is administered to the subject.

[0467] Example 390: The use of Example 389, wherein administration of the medicament achieves a mean maximum concentration (Cmax) of GL0034 of between 226.9 ± 57.3 ng / mL and 367.0 ± 152.0 ng / mL. max ).

[0468] Example 391: The use of Example 389, wherein administration of the medicament achieves an area under the concentration-time curve (AUC ) of between 47,151.5 ± 16,838.6 ng h / mL and 62,265.9 ± 20,816.5 ng h / mL over a 22-day period. 0-t ).

[0469] Example 392: The use of Example 389, wherein administration of the medicament achieves a plasma drug half-life (t 1 / 2 ) of between 98.5 ± 13.0 hours and 113.5 ± 22.9 hours.

[0470] Example 393: The use of Example 389, wherein administration of the medicament achieves a time from administration to maximum plasma concentration (T max ) of between 22.0 ± 6.9 hours and 31.0 ± 13.5 hours.

[0471] ​Example 394: The use according to Example 385 or Example 386, wherein the dosage of the agent comprises 450 μg, 680 μg, 900 μg, 1520 μg, 2000 μg or 2520 μg GL0034, and wherein multiple doses of the agent are administered to the subject over a period of up to 8 weeks.

[0472] Example 395: GL0034 was administered to the subject at a dose of 450 μg once a week for 4 weeks, according to the use described in Example 394.

[0473] Example 396: According to the use described in Example 395, wherein the application of the agent achieves an average maximum concentration (C0034) between 100.5 ± 22.0 ng / mL and 141.7 ± 34.6 ng / mL. max ).

[0474] Example 397: According to the use described in Example 395, wherein the agent is applied over a period of 22 days to achieve a concentration between 12814.2 ± 2652.1 ng. h / mL and 18536.8 ± 4608.2 ng The area under the concentration-time curve (AUC) between h / mL 0-t ).

[0475] Example 398: According to the use described in Example 395, wherein the administration of the agent achieves a plasma drug half-life of 102.3 ± 15.4 on day 22 (t). 1 / 2 ).

[0476] Example 399: According to the use described in Example 395, the administration of the agent achieves a time between 36.0 ± 12.0 hours and 47.0 ± 16.0 hours from administration to maximum plasma concentration (T0). max (Time)

[0477] Example 400: According to the use described in Example 394, a certain dose of the agent contains 680 μg, and the agent is administered to the subject once a week for 4 weeks.

[0478] Example 401: According to the use described in Example 400, wherein the application of the agent achieves an average maximum concentration (C0034) between 169.0 ± 49.5 ng / mL and 267.0 ± 60.9 ng / mL. max ).

[0479] Example 402: The use according to Example 400, wherein administration of the medicament achieves an area under the concentration-time curve (AUC ) between 24575.9 ± 3391.2 ng h / mL and 34536.6 ± 6445.0 ng h / mL over a 22-day period. 0-t .

[0480] Example 403: The use according to Example 400, wherein administration of the medicament achieves a plasma drug half-life (t 1 / 2 ) of 122.9 ± 16.5 on day 22.

[0481] Example 404: The use according to Example 400, wherein administration of the medicament achieves a time from administration to maximum plasma concentration (T max ) of between 39.0 ± 21.0 hours and 54.0 ± 27.0 hours.

[0482] Example 405: The use according to Example 394, wherein: (i) the first dose of the medicament comprises 450 μg GL0034, wherein the first dose of the medicament is administered to the subject once a week for 2 weeks; (ii) the second dose of the medicament comprises 900 μg GL0034, wherein the second dose of the medicament is administered to the subject once a week for 2 weeks; and (iii) the third dose of the medicament comprises 1520 μg GL0034, wherein the third dose of the medicament is administered to the subject once a week for 4 weeks.

[0483] Example 406: The use according to Example 405, wherein administration of the medicament achieves a mean maximum concentration (C max ) of GL0034 of between 111.7 ± 23.7 ng / mL and 707.6 ± 251.7 ng / mL.

[0484] Example 407: The use according to Example 405, wherein administration of the medicament achieves an area under the concentration-time curve (AUC ) between 12942.2 ± 1517.5 ng h / mL and 76320.4 ± 23334.6 ng 0-t h / mL over a 50-day period.

[0485] Example 408: The use according to Example 405, wherein administration of the medicament achieves a plasma drug half-life (t 1 / 2 ) of 106.8 ± 33.7 on day 50.

[0486] Embodiment 409: The use of Embodiment 327, wherein administration of the medicament achieves a time from administration to maximum plasma concentration (T max

[0487] Embodiment 410: The use of Embodiment 385 or Embodiment 386, wherein administration of the medicament produces one or more clinically meaningful changes in the subject relative to baseline, wherein the clinically meaningful changes relative to baseline are a reduction in body weight, a reduction in glycated hemoglobin (HbAlc%), an increase in high-density lipoprotein (HDL) levels, a reduction in alanine aminotransferase (ALT) values, a reduction in aspartate aminotransferase (AST) values, a reduction in gamma-glutamyl transferase (GGT) values, a reduction in triglyceride (TG) levels, a reduction in total cholesterol (TC) levels, a reduction in low-density lipoprotein (LDL) levels, a reduction in TG / HDL ratio, a reduction in fasting insulin levels, a reduction in fasting glucose levels, a reduction in homeostatic model assessment of insulin resistance (HOMA-IR), and / or a reduction in leptin levels.

[0488] Embodiment 411: The use of Embodiment 410, wherein the change in fasting plasma glucose levels relative to baseline is at least about -2.8 ± 3.7 mg / dL over a period of about 23 days after administration of a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0489] Embodiment 412: The use of Embodiment 410, wherein the change in fasting plasma glucose levels relative to baseline is at least about -4.6 ± 2.7 mg / dL over a period of about 23 days after administration of a dose of the medicament comprising 680 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0490] ​Example 413: The use of Example 410, wherein the change from baseline in fasting plasma glucose levels is at least about -7.7 ± 9.9 mg / dL over a period of about 51 days following administration of: (i) a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered once a week for 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034, wherein the medicament is administered once a week for 2 weeks to the subject; and (iii) a dose of the medicament comprising 1520 pg, wherein the medicament is administered once a week for 4 weeks to the subject.

[0491] Example 414: The use of Example 410, wherein the change from baseline in fasting insulin levels is at least about -4.6 ± 23.0 pmol / L over a period of about 23 days following administration of a dose of the medicament comprising 680 pg GL0034, wherein the medicament is administered once a week for 4 weeks to the subject.

[0492] Example 415: The use of Example 410, wherein the change from baseline in fasting insulin levels is at least about -11.3 ± 16.5 pmol / L over a period of about 51 days following administration of: (i) a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered once a week for 2 weeks to the subject; (ii) a dose of the medicament comprising 900 pg GL0034, wherein the medicament is administered once a week for 2 weeks to the subject; and (iii) a dose of the medicament comprising 1520 pg GL0034, wherein the medicament is administered once a week for 4 weeks to the subject.

[0493] Example 416: The use of Example 410, wherein the change from baseline in ALT values is at least about -8.8 ± 13.1 U / L over a period of about 23 days following administration of a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered once a week for 4 weeks to the subject.

[0494] Example 417: The use of Example 410, wherein the change from baseline in ALT values is at least about -3.1 ± 5.8 U / L over a period of about 23 days following administration of a dose of the medicament comprising 680 pg GL0034, wherein the medicament is administered once a week for 4 weeks to the subject.

[0495] Example 418: The use of Example 410, wherein the change from baseline in ALT value is at least about -7.4 ± 10.3 U / L over a period of about 51 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0496] Example 419: The use of Example 410, wherein the change from baseline in ALT value is at least about -1.0 ± 9.4 U / L over a period of about 78 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0497] Example 420: The use of Example 410, wherein the change from baseline in AST value is at least about -4.0 ± 7.5 U / L over a period of about 51 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0498] Example 421: The use of Example 410, wherein the change from baseline in AST value is at least about -1.1 ± 6.7 U / L over a period of about 78 days after administration of: (i) a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0499] Example 422: The use of Example 410, wherein the change from baseline in GGT value is at least about -3.4 ± 3.5 U / L over a period of about 51 days after administration of: (i) a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0500] Example 423: The use of Example 410, wherein the change from baseline in GGT value is at least about -1.0 ± 2.7 U / L over a period of about 78 days after administration of: (i) a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0501] Example 424: The use of Example 410, wherein the change from baseline in body weight is at least about -3.4 ± 1.8 kg over a period of about 29 days after administration of a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0502] Example 425: The use of Example 410, wherein the change from baseline in body weight is at least about -4.1 ± 1.0 kg over a period of about 29 days after administration of a dose of the medicament comprising 680 pg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0503] Example 426: The use of Example 410, wherein the change from baseline in body weight is at least about -7.7 ± 1.9 kg over a period of about 52 days after administration of: (i) a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0504] Example 427: The use of Example 410, wherein the change from baseline in body weight is at least about -6.4 ± 2.1 kg over a period of about 78 days after administration of: (i) a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0505] Example 428: The use of Example 410, wherein the change from baseline in HbAlc% is at least about -0.25 ± 0.2 over a period of about 78 days after administration of: (i) a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0506] Example 429: The use according to Example 410, wherein the change from baseline in TG levels is at least about -21.0 ± 27.5 mg / dL over the period of about 51 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0507] Example 430: The use according to Example 410, wherein the change from baseline in TG levels is at least about -11.0 ± 55.3 mg / dL over the period of about 78 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0508] Example 431: The use according to Example 410, wherein the change from baseline in TC levels is at least about -29.1 ± 23.3 mg / dL over the period of about 51 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0509] Example 432: The use according to Example 410, wherein the change from baseline in the TC level is at least about -5.8 ± 12.6 mg / dL over a period of about 78 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0510] Example 433: The use according to Example 410, wherein the change from baseline in the LDL level is at least about -24.0 ± 24.3 mg / dL over a period of about 51 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0511] Example 434: The use according to Example 410, wherein the change from baseline in the LDL level is at least about -19.5 ± 35.8 mg / dL over a period of about 78 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0512] Example 435: The use of Example 410, wherein the change from baseline in HDL levels is at least about 2.9 ± 3.1 mg / dL over a period of about 78 days following administration of: (i) a dose of the medicament comprising 450 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; (ii) a dose of the medicament comprising 900 μg GL0034, wherein the medicament is administered to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 μg GL0034, wherein the medicament is administered to the subject once a week for 4 weeks.

[0513] Example 436: The use of Example 410, wherein the change from baseline in body weight is at least about -2.4 ±2.2 kg over a period of about 22 days following administration of a single dose of the medicament comprising 1520 μg GL0034.

[0514] Example 437: The use of Example 410, wherein the change from baseline in body weight is at least about -1.8 ±2.4 kg over a period of about 22 days following administration of a single dose of the medicament comprising 2000 μg GL0034.

[0515] Example 438: The use of Example 410, wherein the change from baseline in body weight is at least about -3.1 ±1.7 kg over a period of about 22 days following administration of a single dose of the medicament comprising 2520 μg GL0034.

[0516] Example 439: The medicament of Example 410, wherein the change from baseline in TG levels is at least about -0.4 ±0.4 mmol / L over a period of about 8 days following administration of a single dose of the medicament comprising 1520 μg GL0034.

[0517] Example 440: The use of Example 410, wherein the change from baseline in TG levels is at least about -0.8 ±0.5 mmol / L over a period of about 8 days following administration of a single dose of the medicament comprising 2000 μg GL0034.

[0518] Example 441: The use of Example 410, wherein the change from baseline in TG levels is at least about -0.5 ± 0.5 mmol / L over a period of about 22 days following administration of a single dose of the medicament comprising 2520 μg GL0034.

[0519] Example 442: The use of Example 410, wherein the change in leptin level from baseline over the period of about 8 days is at least about -6.9 ± 5.1 ng / mL following administration of a single dose of the medicament comprising 1520 pg GL0034.

[0520] Example 443: The use of Example 410, wherein the change in leptin level from baseline over the period of about 8 days is at least about -10.9 ± 8.6 ng / mL following administration of a single dose of the medicament comprising 2000 pg GL0034.

[0521] Example 444: The use of Example 410, wherein the change in leptin level from baseline over the period of about 8 days is at least about -11.6 ± 12.8 ng / mL following administration of a single dose of the medicament comprising 2520 pg GL0034.

[0522] Example 445: The use of Example 385 or Example 386, wherein the subject is administered an initial dose of the medicament comprising about 450 pg or about 680 pg GL0034 for at least about 2 weeks; wherein the subject is administered an escalation dose of the medicament comprising about 680 pg or about 900 pg GL0034 once a week for at least about 2 weeks; and wherein the subject is administered a maintenance dose of the medicament comprising about 1520 pg or about 2000 pg GL0034 once a week for at least about 4 weeks.

[0523] Example 446: The use of Example 385 or Example 386, wherein the subject is administered an initial dose of the medicament comprising about 450 pg or about 680 pg GL0034 for at least about 4 weeks; and wherein the subject is administered an escalation dose of the medicament comprising about 680 pg or about 900 pg GL0034 once a week for at least about 2 weeks.

[0524] Example 447: The use of Example 385 or Example 386, wherein the subject is administered an initial dose of the medicament comprising about 450 pg or about 680 pg GL0034 for at least about 4 weeks; wherein the subject is administered an escalation dose of the medicament comprising about 680 pg or about 900 pg GL0034 once a week for at least about 2 weeks; and wherein the subject is administered a maintenance dose of the medicament comprising about 1520 pg or about 2000 pg GL0034 once a week for at least about 2 weeks.

[0525] Examples

[0526] The following examples illustrate specific embodiments of the present disclosure and various uses thereof. They are set forth for explanatory purposes only, and should not be construed in any way to limit the scope of the present disclosure.

[0527] GL0034 was administered in the abdominal wall by subcutaneous injection. Qualitative and quantitative compositions are represented as follows:

[0528] Example 1: Safety, tolerability, pharmacodynamics, and pharmacokinetics of GL0034 in normal weight subjects

[0529] A randomized, double-blind, placebo-controlled study was conducted to assess the safety, tolerability of GL0034 after single and repeated ascending subcutaneous doses in healthy volunteers. Healthy young men (BMI between about 18 kg / m 2 and about 28 kg / m 2 were administered repeated ascending doses of GL0034 by subcutaneous injection.

[0530] Nine healthy male subjects (between 18 and 40 years of age) received GL0034, were injected subcutaneously in the abdomen at each dose level, and three subjects received placebo. Eighteen subjects received four doses one week apart, and nine subjects received eight doses one week apart. A total of twenty-seven healthy subjects received multiple doses of GL0034, and nine subjects received placebo.

[0531] Subjects were randomly assigned to receive one of three doses: Group 1 : single subcutaneous injection of GL0034 (450 μg) or placebo in the abdominal wall weekly for 4 weeks; Group 2: single subcutaneous injection of GL0034 (680 μg) or placebo in the abdominal wall weekly for 4 weeks; or Group 3: single subcutaneous injection of two doses of GL0034 (450 μg) or placebo in the abdominal wall weekly for 2 weeks. Subsequently, single subcutaneous injection of two doses of GL0034 (900 μg) or placebo in the abdominal wall weekly for 2 weeks. Subsequently, single subcutaneous injection of four doses of GL0034 (1520 μg) or placebo in the abdominal wall weekly for 4 weeks following a two-step up-titration scheme (i.e., 8 administrations, one week apart, for 8 weeks).

[0532] Safety and tolerability of multiple ascending doses of GL0034 were determined in Cohorts 1-3 as described above and further outlined in the timelines as shown below. Figure 1 Safety biomarkers including fasting insulin and glucose, alanine aminotransferase, and weight and key exploratory pharmacodynamic effects were assessed.

[0533] Results

[0534] GL0034-related adverse effects were gastrointestinal with dose-dependent nausea, vomiting, and decreased appetite. Fasting insulin (Table 1) decreased in Cohorts 2 and 3 on Day 23 and Day 51, respectively, following treatment with GL0034, with a corresponding decrease in homeostatic model assessment of insulin resistance (HOMA-IR) (Figures 4, 5). Alanine aminotransferase levels decreased in Cohort 3 relative to baseline and increased relative to placebo on Day 51 (Figure 3, Table 1). Dose-dependent decreases in body weight were measured in all cohorts compared to baseline and persisted to Day 50 and Day 78 (Figure 2). The results support the good tolerability and efficacy of GL0034 in healthy individuals of normal weight. Results are summarized in Table 1.

[0535] Table 1. Summary of safety, tolerability, pharmacodynamics, and pharmacokinetics of multiple ascending GL0034 doses

[0536] BMI - body mass index; BW - body weight; ALT - alanine aminotransferase; HOMA-IR - homeostatic model assessment-insulin resistance; relative to respective Day 1 levels, P < 0.05, p < 0.01, P < 0.001; paired Student's t-test; BL = baseline; CBL = change from baseline; comparisons on Day 23, Day 29 for Cohorts 1 and 2, and on Day 51, Day 52 for Cohort 3

[0537] Example 2: MASLD / MASH pharmacodynamic (PD) and safety results of a multiple ascending dose Phase 1 study in healthy individuals

[0538] A randomized, double-blind, placebo-controlled study was conducted to assess the safety and tolerability of GL0034 in healthy volunteers following single and repeated ascending subcutaneous doses. Healthy young men (BMI between about 18 kg / m 2 and about 28 kg / m 2 were administered repeated ascending doses of GL0034 by subcutaneous injection.

[0539] Nine healthy male subjects (between the ages of 18 and 40 years) received GL0034, subcutaneous injection in the abdomen at each dose level, and three subjects received placebo. Eighteen subjects received four doses one week apart, and nine subjects received eight doses one week apart. A total of twenty-seven healthy subjects received multiple doses of GL0034, and nine subjects received placebo.

[0540] Subjects were randomly assigned to receive one of three doses: Group 1 : single subcutaneous injection in the abdominal wall of GL0034 (450 μg) or placebo weekly for 4 weeks; Group 2: single subcutaneous injection in the abdominal wall of GL0034 (680 μg) or placebo weekly for 4 weeks; or Group 3: single subcutaneous injection in the abdominal wall of two doses of GL0034 (450 μg) or placebo weekly for 2 weeks. Followed by single subcutaneous injection in the abdominal wall of two doses of GL0034 (900 μg) or placebo weekly for 2 weeks. Followed by single subcutaneous injection in the abdominal wall of four doses of GL0034 (1520 μg) or placebo weekly for 4 weeks (i.e., 8 administrations, one week apart, for 8 weeks) following a two-step escalation titration regimen.

[0541] Safety and tolerability of multiple ascending doses of GL0034 were determined in Groups / cohorts 1-3, as described above, and further indicated in the timeline, as shown below. Figure 6 Safety biomarkers evaluated included body weight, glycosylated hemoglobin Alc (HbAlc), liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT)), and lipid profile (triglycerides, total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)).

[0542] Results

[0543] GL0034 was generally well tolerated, and the adverse effects associated were primarily gastrointestinal with dose-dependent nausea, vomiting, and decreased appetite. Adverse events became less frequent over time despite increasing dosing of GL0034. Clinically meaningful changes in body weight, HbAlc, and lipid profile were observed when compared to baseline (Table 2). An increase in HDL (Table 2) and decreases in ALT, AST, and GGT were observed with GL0034 relative to placebo (Table 2).

[0544] Table 2. Tolerability of multiple ascending doses of GL0034

[0545] Conclusions

[0546] An effective, long-acting GLP-1 receptor agonist, GL0034, was safe, well-tolerated and had improved liver function in healthy individuals. The observed PD effects reflect therapeutic benefits in MASLD / MASH patients.

[0547] Tables 3 to 7 convey various data from repeated ascending doses of GL0034 in healthy young men (BMI between about 18 kg / m 2 and about 28 kg / m 2 ).

[0548] Subject data - repeated ascending doses of GL0034 in healthy young men

[0549] Table 3. Demographics and baseline characteristics of the study population

[0550] Table 4. Summary of treatment-emergent adverse events

[0551] Table 5. Pharmacokinetic parameters - descriptive statistics for GL0034 PK parameters following once-weekly subcutaneous injection of GL0034 on Day 1 in Cohort 1 (fixed-dose regimen: 450 μg)

[0552] Table 6. Descriptive statistics for GL0034 PK parameters following once-weekly subcutaneous injection of GL0034 on Day 1 in Cohort 2 (fixed-dose regimen: 680 μg)

[0553] Table 7. Descriptive statistics for GL0034 PK parameters following once-weekly subcutaneous injection of GL0034 on Day 1 in Cohort 3 (two-step ascending titration regimen: 450 μg on Days 1 and 8; 900 μg on Days 15 and 22; 1520 μg on Days 29, 36, 43, and 50)

[0554] Example 3: Safety and tolerability of single ascending doses of GL0034 in obese subjects without diabetes

[0555] A randomized, double-blind, placebo-controlled, 4-part study was conducted in overweight and / or obese subjects. Safety, tolerability, pharmacodynamics, and pharmacokinetics of GL0034 were evaluated in healthy overweight and / or obese volunteers following single and repeat ascending subcutaneous doses Figure 8 、 7 )。

[0556] Single ascending doses of GL0034 were administered by subcutaneous injection in healthy young male overweight and / or obese (BMI greater than or equal to 28 kg / m 2 ) subjects. Six healthy male subjects, 18 years to 40 years of age, received abdominal subcutaneous injections of GL0034 (1520 μg, 2000 μg, and 2520 μg per subject) at each dose level. Two subjects received placebo at each dose level. A total of 18 healthy overweight / obese male subjects received a single dose of GL0034, while 6 subjects received placebo. GL0034 pharmacokinetics and key exploratory pharmacodynamic parameters (triglyceride, leptin levels, and body weight) were evaluated (Table 8).

[0557] Results

[0558] The most common GL0034-related adverse events were gastrointestinal with dose-dependent nausea, decreased appetite, and vomiting. No injection site reactions or any other adverse events were noted. GL0034 maximum concentrations ranged from 227 ± 57 ng / mL to 367 ± 152 ng / mL, and mean half-lives ranged from 99 hours to 118 hours. Triglyceride levels were reduced relative to baseline following treatment with GL0034 2000 μg and 2520 μg doses on Day 8 (Figure 9). Reductions in leptin levels were dose-dependent (Figure 9). Body weight reduction relative to baseline reached a maximum of 3.3 kg with the 2520 μg dose on Day 8, and this effect was sustained through Day 22 with each GL0034 dose ​ , Table 8).

[0559] In the pooled data (n = 18), 28% of subjects achieved greater than 3% weight loss following a single dose of GL0034 at both day 8 and day 22 compared to 0% change in subjects receiving placebo. An increase was observed over time with 11% of subjects losing greater than 5% of body weight at day 22. Significant reductions in triglycerides were also observed in all three cohorts. At day 8, cohorts 1, 2, and 3 reduced by 17.5%, 40.7%, and 28.0% respectively, and at day 22 by 21.2%, 25.4%, and 12.5%. In comparison to the three cohorts, subjects receiving placebo experienced an increase in triglycerides of 9.9% and 7.6% at day 8 and day 22, respectively. TG levels (mg / dL) greater than 150 mg / dL at baseline (n = 9) also demonstrated robust reductions. Subjects with a baseline of 194.7 ± 29.1 mg / dL saw a 38.9% reduction at day 8 (p < 0.05 vs. placebo), while subjects with a baseline of 212 ± 100.8 mg / dL (n = 4) saw a 4.1% reduction vs. placebo. During the OGTT at day 8, the area under the glucose curve was reduced in the three cohorts by 16.7% (p < 0.05), 21.5% (p < 0.01), and 26.4% (p < 0.05) respectively, while placebo was reduced by only 7.4%.

[0560] Table 8. Safety and tolerability of single ascending doses of GL0034 in obese non-diabetic subjects

[0561] Conclusions

[0562] In summary, GL0034 once weekly demonstrated clinically relevant reductions in body weight, triglycerides, and area under the glucose curve during an OGTT in obese individuals and was well tolerated.

[0563] Example 4: Safety and tolerability of single ascending doses of GL0034 in obese subjects

[0564] A randomized, double-blind, placebo (PB) controlled, 4-part study was conducted in overweight and / or obese subjects. Safety, tolerability, pharmacodynamics, and pharmacokinetics of GL0034 were evaluated in healthy overweight and / or obese volunteers following single and repeated ascending subcutaneous doses.

[0565] Healthy young male overweight and / or obese (BMI greater than or equal to 30 kg / m 2Single ascending doses of GL0034 were administered by subcutaneous injection in subjects. Six healthy male subjects, 18 to 40 years of age, received abdominal subcutaneous injections of GL0034 at each dose level (1520, 2000, and 2520 pg per subject). Two subjects received placebo at each dose level. A total of 18 healthy overweight / obese male subjects received a single dose of GL0034, while 6 subjects received placebo. GL0034 pharmacokinetics and key exploratory pharmacodynamic parameters (triglyceride, leptin levels, and body weight) were assessed (Table 9).

[0566] Results

[0567] GL0034 had no apparent safety concerns and tolerability was limited to dose-dependent gastrointestinal events, including nausea, decreased appetite, and vomiting, class effects for GLP-1 receptor agonists. Body weight loss relative to baseline (BL) was observed on Day 8 [respective to -0.3 ± 0.5 kg PB, 2.4 ± 1.3 (p < 0.01), 2.2 ± 1.1 (p < 0.05), 3.3 ± 1.9 (p < 0.01)]; on Day 15 [respective to -0.1 ± 2.0 kg PB, 1.7 ± 1.6 (p < 0.05), 2.4 ± 2.0 (p < 0.05), 2.7 ± 1.9 (p < 0.05) (BMI at BL was 34.5 ± 3.0 kg / m 2 , 34.4 ± 4.0 kg / m 2 , 38.9 ± 7.3 kg / m 2 , and 31.8 ± 3.1 kg / m 2 , respectively)].

[0568] Changes in lipids were observed at day 8 and the following levels were detected at day 15: triglycerides [vs. 24.5 ± 71.0 mg / dL PB, -42.2 ± 48.3, -44.7 ± 43.7, -18.7 ± 46.9, respectively]; total cholesterol [vs. -3.7 ± 10.2 mg / dL PB, -23.7 ± 11.2, -28.5 ± 19.1 (p < 0.01), -27.8 ± 31.5, respectively]; LDL [vs. -6.3 ± 2.6 mg / dL PB, -19.0 ± 10.6, -23.8 ± 21.5 (p < 0.05), -28.0 ± 25.3, respectively]; HDL [vs. -0.2 ± 3.4 mg / dL PB, -6.0 ± 2.3 (p < 0.01), -3.7 ± 5.9, -1.8 ± 3.3, respectively]. The TG / HDL ratio improved at day 15 vs. BL ratio was 3.1 ± 1.4, 3.1 ± 1.0, 4.3 ± 3.2, respectively, vs. 5.3 ± 4.3 PB, and 3.6 ± 1.6, 4.1 ± 1.7, 4.5 ± 2.3, respectively, vs. 4.5 ± 2.9 PB.

[0569] Table 9. Safety and tolerability of single ascending doses of GL0034 in obese subjects

[0570] Conclusion

[0571] GL0034 was safe and well tolerated in adults with obesity once weekly. GL0034 reduced body weight in obese individuals in a maintenance manner at all doses and showed a beneficial effect on the lipid profile, improving the TG / HDL ratio. The TG / HDL ratio is a predictor of many potential clinical conditions. An improved TG / HDL ratio can translate clinically into: reduced risk of heart attack and stroke; improved atherogenic lipid profile and thus reduced risk of developing coronary artery disease such as coronary atherosclerosis; reduced risk of cerebrospinal vascular disease such as asymptomatic cerebral infarction, etc.

[0572] The following Tables 10 to 13 provide a summary of various data sets.

[0573] Table 10. Demographics and baseline characteristics data

[0574] Table 11. Summary of treatment-emergent adverse events

[0575] Table 12. Pharmacokinetic properties

[0576] Table 13. Dose-dependent pharmacokinetic properties and adverse event frequencies

[0577] Example 5: Safety and tolerability of multiple ascending doses of GL0034 in obese subjects

[0578] A double-blind, placebo (PB) controlled study was conducted in obese subjects. Tolerability and metabolic effects were assessed in obese subjects following multiple ascending doses of GL0034.

[0579] Multiple ascending doses of GL0034 were administered by subcutaneous injection in healthy young male obese (BMI > 28 kg / m 2 ) subjects. Two cohorts of nine subjects received GL0034 treatment, while three subjects per cohort received placebo treatment. Cohort 1 received a single 680 pg dose once weekly for four weeks, while cohort 2 received increasing doses of 680 pg, 900 pg, 1520 pg, and 2000 pg over four weeks. Safety, tolerability, and metabolic effects following GL0034 treatment were assessed.

[0580] Results

[0581] The most common adverse effects (AEs) were gastrointestinal (GI) with dose-dependent nausea, decreased appetite, and vomiting. One individual with a serious GI-related AE recovered rapidly following intravenous fluid replacement. On Day 23, reductions from baseline (BL) were observed in all parameters. Significant reductions included area under the curve for glucose (177.5 ± 12.1 mg h / dL) and percent HbAlc in both groups. Cohort 1 experienced reductions to 5.3 ± 0.4%, and cohort 2 to 4.9 ± 0.1%. In cohorts 1 and 2, reductions from BL on Day 29 were 2.9 kg and 4.6 kg, respectively (Table 14). The complete findings of this study are shown in Table 14 below.

[0582] Table 14. Metabolic properties of multiple ascending doses (mean ± SD)

[0583] Conclusion

[0584] GL0034 was found to be safe and well-tolerated once weekly in obese adults. GL0034 reduced body weight in individuals receiving treatment and lowered OGTT glucose AUC and HbA1c levels in treated subjects. These results translate into lower blood glucose levels, indicating control of diabetes and weight loss, which are important indicators of reducing chronic inflammatory symptoms exacerbated by obesity.

[0585] Example 6: Phase 1 Multiple Elevation-Dose (MAD) Study of GL0034 in Obese Individuals

[0586] Subjects: A randomized, double-blind, placebo (PBO) controlled study was conducted to evaluate the safety, tolerability, and pharmacodynamics of a multi-escalation dose study. BMI ≥ 28 kg / m² was required. 2 Individuals (n = 12) were randomized (9:3) to receive subcutaneous doses of GL or placebo (680 μg, 900 μg, 1520 μg, or 2000 μg) once weekly for four weeks. Biomarker measurements included body weight, lipid profiles (triglycerides (TG), total cholesterol), and total cholesterol.

[0587] (TC and low-density lipoprotein (LDL)) and liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT)), free fatty acids (FFA), homeostasis model assessment-insulin resistance (HOMA-IR) and leptin.

[0588] result

[0589] The most common adverse effects (AEs) were gastrointestinal (GI) with dose-dependent nausea, decreased appetite, and vomiting. An individual with a severe GI-related AE recovered rapidly after intravenous rehydration. The mean BMI (kg / m²) at baseline in subjects treated with GL0034 was 32.4 ± 4.6 kg / m². 2 Furthermore, the mean BMI at baseline for subjects receiving the placebo was 27.9 ± 1.3 kg / m². 2At day 29, subjects lost 4.6 ± 1.5 kg (p < 0.001) relative to placebo subjects (0.0 ± 0.9 kg). Consistently, subjects receiving GL0034 also saw a significant reduction in triglycerides. At day 23, subjects saw a reduction of 47.1 ± 54.2 mg / dL (p < 0.05) compared to a reduction of 16.7 ± 28.7 mg / dL in the placebo group relative to baseline. Further, total cholesterol was reduced by 20.0 ± 26.8 mg / dL (8.7 ± 26.9 mg / dL relative to placebo) and LDL levels similarly reduced by 5.7 ± 23.9 mg / dL, while the placebo group experienced an increase of 11.3 ± 19.6 mg / dL relative to baseline. Reductions in ALT, AST, and GGT were also achieved with GL0034 treatment. ALT levels were reduced by 9.1 U / L (± 13.9 U / L) compared to an increase of 6.3 U / L (± 43 U / L) in subjects receiving placebo. AST was reduced by 2.7 U / L (± 4.2 U / L) compared to an increase of 1.7 U / L (± 18.7 U / L) in subjects receiving placebo. At day 23, the reduction in GGT relative to baseline was significant, with a reduction of 4.2 U / L (± 2.4 U / L, p < 0.001) compared to an increase of 4.3 U / L (± 15.3 U / L) in the placebo group. Free fatty acid levels were unchanged in both GL0034 and placebo groups. At day 23 and day 50, HOMA-IR improved from 2.3 (± 1.2) to 1.7 (± 1.0) and 1.7 (± 0.4) relative to baseline, respectively. At day 23 and day 50, the placebo group improved from 3.2 (± 0.5) to 2.1 (± 0.1) and 2.6 (± 0.9) relative to baseline, respectively. Finally, a reduction in leptin was observed at day 23 and day 50. Treated subjects saw a reduction of 5.7 (± 5.9) and 4.5 (± 10.2) compared to a reduction of 3.7 (± 5.3) and an increase of 5.1 (± 16.4) in subjects receiving placebo at day 23 and day 50, respectively.

[0590] Conclusions

[0591] GLP-1 RA, GL0034, was safe and well tolerated. GL0034 treatment demonstrated significant weight loss in individuals with obesity as well as improvements in lipids, liver injury, and metabolic biomarkers. The observed PD effects suggest potential therapeutic benefits in MASLD patients.

[0592] Example 7: Study to evaluate efficacy of GLP-1 analog after multiple subcutaneous injections in db / db mice

[0593] Materials and Methods

[0594] db / db (C57BL / KsJ-db / db) male / female mice (age 8-10 weeks; body weight 45-65 g) generated from the Laboratory Animal Resources Department of Sun Pharma Advanced Research Company Ltd. were housed in individual ventilated cages with free access to food and water and maintained on a 12-hour light / 12-hour dark cycle. Mice were acclimatized for 3 days. On day 0, each animal was weighed using a digital weighing balance and 10 μL of blood was collected by retro-orbital plexus puncture under light isoflurane anesthesia. Blood glucose levels were measured using a hand-held blood glucose meter (One Touch™ Ultra™; LIFESCAN, Johnson & Johnson, Malvern, Pennsylvania) and HbAlc% was measured using A1CNow + ® kit (PTS Diagnostics, Indianapolis, Indiana). Mice were divided into treatment groups (n = 8 per group; four males, four females) with matching baseline HbAlc levels. Vehicle GL0034 (21 nmol / kg), semaglutide (21 nmol / kg), or tirzepatide (21 nmol / kg) was injected subcutaneously into the neck region of mice every third day for 4 weeks.

[0595] Body weight and food intake were monitored continuously. On days 14 and 28 of the study, 24 hours after the last dose, blood was collected for measurement of HbAlc and insulin.

[0596] On day 28, mice (n = 5) were sacrificed after blood collection for measurement of HbAlc, insulin, C-peptide, and glucagon, triglycerides, total cholesterol, low-density cholesterol (LDL), and amylase. Liver was removed for measurement of fibroblast growth factor-21 (FGF-21) while white and brown adipose tissue (WAT, BAT) was removed to estimate uncoupling protein-1 levels (UCP-1).

[0597] Statistical comparisons were made using one-way ANOVA or two-way ANOVA as appropriate. Bonferroni’s post-test was used. Statistical significance was assigned where P < 0.05. Data are expressed as mean ± standard deviation (SD).

[0598] Results

[0599] GL0034 demonstrated a stronger trend in percent reduction of HbAlc and a higher percent change in body weight at day 14 and day 28 compared to the proglucagon-like peptide 1 receptor agonists, semaglutide and tirzepatide. These changes were statistically significant compared to semaglutide treatment. Similar trends in reduction of glucagon, triglycerides, total cholesterol, and LDL were observed at day 28. Insulin secretion response was better for GL0034 compared to semaglutide and tirzepatide at day 14 and day 28. Increases in FGF-21 protein in the liver and UCP-1 in BAT and WAT were significantly greater than those observed for semaglutide. Increases in UCP-1 in BAT were significantly more than both semaglutide and tirzepatide. Complete results from this study are shown in Table 15 below.

[0600] Table 15. Changes in biomarkers after treatment with GL0034 (Utreglutide) (mean ± SD)

[0601] Conclusions

[0602] GL0034 demonstrated a strong anti-diabetic effect in db / db mice compared to semaglutide and tirzepatide, which indicates that GL0034 can act as a GLP-1 RA in obese patients with type 2 diabetes because it significantly increased UCP-1 levels in brown adipose tissue.

[0603] Example 8: Utreglutide (GL0034) at a once-weekly 4 x 450 pg dose reduces blood pressure, lipids, and body weight in postmenopausal women

[0604] In a randomized, double-blind, placebo-controlled study, 12 postmenopausal, overweight / obese women aged 18 to 65 years and body mass index (BMI) > 26 kg / m were randomized (9:3) to receive subcutaneous utreglutide at a fixed dose (4 x 450 pg) or placebo once weekly for four weeks. Safety, tolerability, and key cardiometabolic parameters were assessed.

[0605] Biomarker measurements included oral glucose tolerance test (OGTT) insulin and glucose area under the curve (AUC), systolic and diastolic BP, lipid profile (triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL), creatinine, potassium, BW, and leptin.

[0606] Results

[0607] Utroglutide was well tolerated, and the main adverse effects were gastrointestinal, including dose-dependent nausea, vomiting, and decreased appetite. Insulin levels were observed on day 23 after four weeks of treatment with uttroglutide. p < 0.05) and glucose ( p The OGTT AUC decreased by < 0.01. This was accompanied by a decrease in mean systolic and diastolic blood pressure (BP) relative to baseline (BL) on day 23. p < 0.001). TC was observed on day 23. p < 0.01), LDL ( p < 0.05) and non-HDL ( p < 0.05) significantly decreased. At day 29 and the end of the study (EoS), the decrease in BW relative to BL ( p < 0.001) were 2.0 kg and 1.8 kg respectively. On day 23 ( p < 0.01) and EoS ( p When leptin levels were < 0.001, leptin levels were significantly lower relative to BL. No significant changes were observed in TG, creatinine, and potassium (see Table 16).

[0608] Table 16. Effects of uroglutide (4 × 450 μg) on ​​cardiometabolic biomarkers in postmenopausal, overweight, and obese women (all values ​​are mean ± SD)

[0609] in conclusion

[0610] In overweight and obese postmenopausal women, a weekly dose of 450 μg utroglutide for four weeks demonstrated a clinically relevant reduction in systolic and diastolic blood pressure. This was associated with improved performance of OGTT AUC for insulin, glucose, lipids, blood pressure wobble (BW), and leptin, with high tolerability and demonstrated cardiometabolic benefits.

[0611] Having described the subject matter of this disclosure in detail and with reference to its specific embodiments, it will be apparent that modifications and variations are possible without departing from the scope of the claimed subject matter.

Claims

1. A pharmaceutical composition for treating obesity in a subject, the pharmaceutical composition comprising GL0034.

2. The pharmaceutical composition of claim 1, wherein the subject does not have diabetes.

3. The pharmaceutical composition of claim 1 or claim 2, wherein the subject has a body mass index (BMI) of at least 28 kg / m 2 or > 27 kg / m 2 with at least one weight-related comorbid condition.

4. A pharmaceutical composition for treating a metabolic disorder in a subject, the pharmaceutical composition comprising GL0034.

5. The pharmaceutical composition of claim 4, wherein the metabolic disorder is metabolic dysfunction-associated fatty liver disease (MASLD).

6. The pharmaceutical composition of claim 5, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

7. The pharmaceutical composition of claim 4, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

8. The pharmaceutical composition of claim 7, wherein the metabolic disorder is type 2 diabetes.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the subject has hypertension.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition is administered subcutaneously to the subject.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is administered to the subject using an auto-injector or a pre-filled syringe.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein a dose of the pharmaceutical composition comprises between 200 pg and 8000 pg of GL0034.

14. The pharmaceutical composition of claim 13, wherein the dose of the pharmaceutical composition comprises between 300 pg and 6000 pg of GL0034.

15. The pharmaceutical composition of claim 14, wherein the dose of the pharmaceutical composition comprises between 400 pg and 4000 pg of GL0034.

16. The pharmaceutical composition of claim 15, wherein the dose of the pharmaceutical composition comprises between 1000 pg and 3000 pg of GL0034.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the dose of the pharmaceutical composition is administered to the subject once a week or once every two weeks.

18. The pharmaceutical composition of any one of claims 1 to 16, wherein administration of the pharmaceutical composition to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 75 ng / mL and 1200 ng / mL. max ).

19. The pharmaceutical composition of any one of claims 1 to 16, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUCo-2o) of GL0034 of between 6200 ng h / mL and 406300 ng h / mL over a period of 22 days. 0-t ​ 20. The pharmaceutical composition of claim 16, wherein the dose of the pharmaceutical composition comprises 1520 pg, 2000 pg, or 2520 pg of GL0034.

21. The pharmaceutical composition of claim 20, wherein administration of the pharmaceutical composition to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 227 ng / mL and 367 ng / mL. max ).

22. The pharmaceutical composition of claim 20, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUCo-2o) for GL0034 of between 30313 ng h / mL and 83082 ng h / mL over a period of 22 days. 0-t ​ 23. The pharmaceutical composition of any one of claims 1 to 21, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t½) of GL0034 of between 90 hours and 120 hours. 1 / 2 ).

24. The pharmaceutical composition of claim 21, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t½) of GL0034 of between 98 hours and 113 hours. 1 / 2 ).

25. The pharmaceutical composition of any one of claims 1 to 12, wherein the pharmaceutical composition is administered to the subject once a week or once every two weeks.

26. The pharmaceutical composition of any one of claims 1 to 12 or 25, wherein a dose of the pharmaceutical composition comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg of GL0034.

27. The pharmaceutical composition of claim 26, wherein the dose of the pharmaceutical composition is administered once a week or once every two weeks.

28. The pharmaceutical composition of claim 26, wherein the dose of the pharmaceutical composition comprises 450 μg GL0034, and wherein the pharmaceutical composition is administered to the subject once a week for at least 4 weeks achieves a mean maximum concentration (Cmax) of GL0034 of between 101 ng / mL and 142 ng / mL. max ).

29. The pharmaceutical composition of claim 28, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUCo-22) of GL0334 of between 12814 ng h / mL and 18537 ng h / mL over a period of 22 days. 0-t ​ 30. The pharmaceutical composition of claim 28, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t½) of GL0034 of 102 hours prior to day 22 1 / 2}.

31. The pharmaceutical composition of claim 26, wherein the dose of the pharmaceutical composition comprises 680 pg GL0034, and wherein administration of the pharmaceutical composition to the subject once a week for at least 4 weeks achieves a mean maximum concentration (Cmax) of GL0034 of between 169 ng / mL and 267 ng / mL. max ).

32. The pharmaceutical composition of claim 31, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUCo-22) of GL0034 of between 24576 ng h / mL and 34537 ng h / mL over a 22-day period. 0-t ​ 33. The pharmaceutical composition of claim 31, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t½) of GL0034 of 122.9 ± 16.5 hours before day 22. 1 / 2 ).

34. The pharmaceutical composition according to any one of claims 1 to 12, wherein: (i) administering to the subject a dose of the pharmaceutical composition comprising between 50 pg and 200 pg of GL0034 once a week for at least 2 weeks; (ii) administering to the subject a dose of the pharmaceutical composition comprising between 200 pg and 400 pg of GL0034 once a week for at least 2 weeks; (iii) administering to the subject a dose of the pharmaceutical composition comprising between 500 pg and 700 pg of GL0034 once a week for at least 2 weeks; (iv) administering to the subject a dose of the pharmaceutical composition comprising between 1200 pg and 1500 pg of GL0034 once a week for at least 2 weeks; and (v) administering to the subject a dose of the pharmaceutical composition comprising between 2000 pg and 3000 pg of GL0034 once a week for at least 4 weeks.

35. The pharmaceutical composition according to any one of claims 1 to 12, wherein: (i) administering to the subject a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) administering to the subject a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) administering to the subject a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

36. The pharmaceutical composition of claim 35, wherein administration of the pharmaceutical composition to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 112 ng / mL and 708 ng / mL. max ).

37. The pharmaceutical composition of claim 35, wherein administration of the pharmaceutical composition to the subject achieves an area under the concentration-time curve (AUCo-50) of GL0034 of between 12942 ng h / mL and 76320 ng h / mL over a 50-day period. 0-t ​ 38. The pharmaceutical composition of claim 35, wherein administration of the pharmaceutical composition to the subject achieves a plasma drug half-life (t½) of GL0034 of 106.8 ± 33.7 hours before day 50. 1 / 2 ).

39. The pharmaceutical composition according to any one of claims 1 to 12, wherein: (i) administering to the subject an initial dose of the pharmaceutical composition comprising between 200 pg and 680 pg of GL0034 for at least 4 weeks; (ii) administering to the subject an escalation dose of the pharmaceutical composition comprising between 680 pg and 900 pg of GL0034 once a week for at least 2 weeks; and (iii) administering to the subject a maintenance dose of the pharmaceutical composition comprising between 1500 pg and 2000 pg of GL0034 once a week for at least 2 weeks.

40. The pharmaceutical composition according to any one of claims 1 to 12, wherein: (i) administering to the subject an initial dose of the pharmaceutical composition comprising between 450 pg and 680 pg of GL0034 for at least 4 weeks; and (ii) administering to the subject an escalation dose of the pharmaceutical composition comprising between 680 pg and 900 pg of GL0034 once a week for at least 2 weeks.

41. The pharmaceutical composition according to any one of claims 1 to 12, wherein: (i) administering to the subject an initial dose of the pharmaceutical composition comprising between 450 pg and 680 pg of GL0034 for at least 4 weeks; (ii) administering to the subject an escalation dose of the pharmaceutical composition comprising between 680 pg and 900 pg of GL0034 once a week for at least 2 weeks; and (iii) administering to the subject a maintenance dose of the pharmaceutical composition comprising between 1520 pg and 2000 pg of GL0034 once a week for at least 2 weeks.

42. The pharmaceutical composition of any one of claims 1-41, wherein administration of the pharmaceutical composition to the subject produces one or more clinically meaningful changes in the subject relative to baseline, wherein the clinically meaningful change relative to baseline is a decrease in alanine aminotransferase (ALT) value, a decrease in aspartate aminotransferase (AST) value, a decrease in gamma-glutamyl transferase (GGT) value, a decrease in fasting insulin level, a decrease in fasting glucose level, a decrease in glycosylated hemoglobin (HbAlc%), a decrease in homeostatic model assessment of insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin level, a decrease in triglyceride (TG) level, a decrease in total cholesterol (TC) level, a decrease in low-density lipoprotein (LDL) level, an increase in high-density lipoprotein (HDL) level, a decrease in TG / HDL ratio, an increase in FGF-21 in the liver, an increase in uncoupling protein-1 level (UCP-1) in brown adipose tissue (BAT) and / or white adipose tissue (WAT), and / or a decrease in blood pressure.

43. The pharmaceutical composition of claim 42, wherein the decrease in ALT value relative to baseline persists for at least 23 days, at least 52 days, or at least 78 days after administration of the pharmaceutical composition to the subject.

44. The pharmaceutical composition of claim 42, wherein: (a) the change in ALT value relative to baseline is at least -9 U / L within a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 450 pg GL0034 to the subject, or at least -3 U / L within a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034 to the subject; or (b) the change in the ALT value from baseline is at least -7 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

45. The pharmaceutical composition of claim 42, wherein the AST value is reduced from baseline for at least 23 days, at least 51 days, or at least 78 days after administration of the pharmaceutical composition to the subject.

46. The pharmaceutical composition of claim 42, wherein the change in the AST value from baseline is at least -4 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

47. The pharmaceutical composition of claim 42, wherein the GGT value is reduced from baseline for at least 23 days, at least 51 days, or at least 78 days after administration of the pharmaceutical composition to the subject.

48. The pharmaceutical composition of claim 42, wherein the change in the GGT value from baseline is at least -3 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

49. The pharmaceutical composition of claim 42, wherein the fasting insulin level is reduced from baseline for at least 23 days or at least 51 days after administration of the pharmaceutical composition to the subject.

50. The pharmaceutical composition of claim 42, wherein the change from baseline in fasting insulin level is at least -5 pmol / L over a period of about 23 days after administration of 680 pg GL0034 to the subject once weekly for at least 4 weeks; or is at least -11 pmol / L over a period of about 51 days after administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once weekly for at least 4 weeks to the subject.

51. The pharmaceutical composition of claim 42, wherein the reduction in fasting glucose lasts for at least 23 days or at least 51 days after administration of the pharmaceutical composition to the subject.

52. The pharmaceutical composition of claim 42, wherein the reduction in fasting glucose is at least -3 mg / dL over a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 450 pg GL0034 once weekly for at least 4 weeks to the subject; or is at least -5 mg / dL over a period of about 23 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034 once weekly for at least 4 weeks to the subject; or is at least -8 mg / dL over a period of about 51 days after administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once weekly for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once weekly for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once weekly for at least 4 weeks to the subject.

53. The pharmaceutical composition of claim 42, wherein the reduction in body weight lasts for at least 8 days, at least 15 days, at least 22 days, at least 29 days, at least 50 days, at least 52 days, or at least 78 days after administration of the pharmaceutical composition to the subject.

54. The pharmaceutical composition of claim 42, wherein: (a) the reduction in body weight is at least -2 kg over a period of about 22 days after administration to the subject of a dose of the pharmaceutical composition comprising 2000 pg GL0034; or at least -2 kg over a period of about 22 days after administration to the subject of a dose of the pharmaceutical composition comprising 1520 pg GL0034; or at least -3 kg over a period of about 22 days after administration to the subject of a dose of the pharmaceutical composition comprising 2520 pg GL0034; or at least -3 kg over a period of about 29 days after administration to the subject of a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 4 weeks; or at least -4 kg over a period of about 29 days after administration to the subject of a dose of the pharmaceutical composition comprising 680 pg GL0034 once a week for at least 4 weeks; or (b) the reduction in body weight is at least -8 kg over a period of about 52 days or at least -6 kg over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

55. The pharmaceutical composition of claim 42, wherein the reduction in leptin levels relative to baseline is dose dependent.

56. The pharmaceutical composition of claim 42, wherein the change in leptin levels relative to baseline is at least -7 ng / mL over a period of about 8 days after administration to the subject of a dose of the pharmaceutical composition comprising 1520 pg GL0034; or at least -11 ng / mL over a period of about 8 days after administration to the subject of a dose of the pharmaceutical composition comprising 2000 pg GL0034; or at least -12 ng / mL over a period of about 8 days after administration to the subject of a dose of the pharmaceutical composition comprising 2520 pg GL0034.

57. The pharmaceutical composition of claim 42, wherein the reduction in TG levels relative to baseline is observed on day 8 and the reduction in TG levels relative to baseline lasts for at least 51 days or at least 78 days after administration of the pharmaceutical composition to the subject.

58. The pharmaceutical composition of claim 42, wherein: (a) the change in TG level from baseline is at least -1 mmol / L over a period of about 8 days after administration to the subject of a dose of the pharmaceutical composition comprising 2000 pg GL0034; or at least -1 mmol / L over a period of about 22 days after administration to the subject of a dose of the pharmaceutical composition comprising 2520 pg GL0034; or (b) the change in TG level is at least -21 mg / dL over a period of about 51 days or at least -11 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

59. The pharmaceutical composition of claim 42, wherein the reduction in TC level from baseline is at least -29 mg / dL over a period of about 51 days or at least -6 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

60. The pharmaceutical composition of claim 42, wherein the change in LDL level from baseline is at least -24 mg / dL over a period of about 51 days or at least -20 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

61. The pharmaceutical composition of claim 42, wherein the increase in HDL levels from baseline is at least 3 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 once a week for at least 4 weeks.

62. The pharmaceutical composition of claim 42, wherein the clinically meaningful change from baseline in the subject is a reduction in blood pressure.

63. The pharmaceutical composition of claim 62, wherein the reduction in blood pressure is a reduction in systolic blood pressure.

64. The pharmaceutical composition of claim 62, wherein the reduction in blood pressure is a reduction in diastolic blood pressure.

65. The pharmaceutical composition of claim 63, wherein the reduction in systolic blood pressure from baseline is at least about 18 mmHg or at least about 14% over a period of about 23 days after administration to the subject of a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 4 weeks.

66. The pharmaceutical composition of claim 64, wherein the reduction in diastolic blood pressure from baseline is at least about 12 mmHg or at least about 14% over a period of about 23 days after administration to the subject of a dose of the pharmaceutical composition comprising 450 pg GL0034 once a week for at least 4 weeks.

67. The pharmaceutical composition of claim 62, wherein the reduction in blood pressure in the subject is greater than the reduction in blood pressure after administration of: (a) 1.7 mg to 2.4 mg semaglutide once a week; or (b) 5 mg to 15 mg tirzepatide once a week.

68. The pharmaceutical composition of any one of claims 1 to 67, wherein administration of the pharmaceutical composition to the subject achieves a reduction in the frequency of adverse events (AEs) in the subject over time.

69. The pharmaceutical composition of claim 68, wherein the AE is one or more of nausea, vomiting, and / or decreased appetite.

70. The pharmaceutical composition of claim 68, wherein the reduction in the frequency of the AE is dose-dependent.

71. The pharmaceutical composition of any one of claims 1 to 12, wherein administration of a higher dose of the pharmaceutical composition to the subject does not cause an increase in severe treatment-emergent adverse events (TEAEs).

72. A pharmaceutical composition for treating hypertension in a subject, the pharmaceutical composition comprising GL0034, wherein a therapeutically effective dose of the pharmaceutical composition is administered to the subject.

73. The pharmaceutical composition of claim 72, wherein the subject is obese.

74. The pharmaceutical composition of claim 73, wherein the subject does not have diabetes.

75. The pharmaceutical composition of claim 72, wherein the subject has a metabolic disorder.

76. The pharmaceutical composition of claim 75, wherein the metabolic disorder is metabolic dysfunction-associated fatty liver disease (MASLD).

77. The pharmaceutical composition of claim 76, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

78. The pharmaceutical composition of claim 75, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

79. The pharmaceutical composition of claim 78, wherein the metabolic disorder is type 2 diabetes.

80. The pharmaceutical composition of any one of claims 72-79, wherein the pharmaceutical composition is administered subcutaneously to the subject.

81. The pharmaceutical composition of claim 80, wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.

82. The pharmaceutical composition of claim 81, wherein the pharmaceutical composition is administered to the subject using an auto-injector or a pre-filled syringe.

83. The pharmaceutical composition of any one of claims 72-82, wherein the subject is administered a dose of the pharmaceutical composition comprising 450 pg GL0034.

84. The pharmaceutical composition of claim 83, wherein administration of the pharmaceutical composition achieves a reduction in systolic blood pressure in the subject of at least about 18 mmHg or at least about 14% relative to baseline over a period of about 23 days after administration of the pharmaceutical composition.

85. The pharmaceutical composition of claim 83, wherein administration of the pharmaceutical composition achieves a reduction in diastolic blood pressure in the subject of at least about 12 mmHg or at least about 14% relative to baseline over a period of about 23 days after administration of the pharmaceutical composition.

86. The pharmaceutical composition of any one of claims 72-85, wherein the reduction in blood pressure in the subject is greater than a reduction in blood pressure after administration of: (a) 1.7 mg to 2.4 mg semaglutide; or (b) 5 mg to 15 mg tirzepatide once a week.

87. A method of treating obesity in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034.

88. The method of claim 87, wherein the subject does not have diabetes.

89. The method of claim 87 or claim 88, wherein the subject has a body mass index (BMI) of at least 28 kg / m 2 or > 27 kg / m 2 with at least 1 weight-related comorbid condition.

90. A method of treating a metabolic disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034.

91. The method of claim 90, wherein the metabolic disorder is metabolic dysfunction-associated fatty liver disease (MASLD).

92. The method of claim 91, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

93. The method of claim 90, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

94. The method of claim 93, wherein the metabolic disorder is type 2 diabetes.

95. The method of any one of claims 87-94, wherein the subject has hypertension.

96. The method of any one of claims 87-95, wherein GL0034 is administered to the subject subcutaneously.

97. The method of claim 96, wherein GL0034 is administered to the subject by subcutaneous injection.

98. The method of claim 97, wherein GL0034 is administered to the subject using an autoinjector or a pre-filled syringe.

99. The method of any one of claims 87-98, wherein the subject is administered a dose comprising between 200 pg and 8000 pg of GL0034.

100. The method of claim 99, wherein the dose comprises between 300 pg and 6000 pg of GL0034.

101. The method of claim 100, wherein the dose comprises between 400 pg and 4000 pg of GL0034.

102. The method of claim 101, wherein the dose comprises between 1000 pg and 3000 pg of GL0034.

103. The method of any one of claims 87-102, wherein the subject is administered the dose of GL0034 once a week or once every two weeks.

104. The method of any one of claims 87-102, wherein administration of GL0034 to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 75 ng / mL and 1200 ng / mL. max}.

105. The method of any one of claims 87-102, wherein administration of GL0034 to the subject achieves an area under the concentration-time curve (AUC) of GL0034 of between 6200 ng h / mL and 406300 ng h / mL over a 22-day period. 0-t ​ 106. The method of claim 102, wherein the dose comprises 1520 pg, 2000 pg, or 2520 pg of GL0034.

107. The method of claim 106, wherein administration of GL0034 to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 227 ng / mL and 367 ng / mL. max}.

108. The method of claim 106, wherein administration of GL0034 to the subject achieves an area under the concentration-time curve (AUC) of GL0034 of between 30 313 ng h / mL and 83 082 ng h / mL over a 22 day period. 0-t ​ 109. The method of any one of claims 87-107, wherein administration of GL0034 to the subject achieves a plasma drug half-life (t½) of GL0034 of between 90 hours and 120 hours. 1 / 2}.

110. The method of claim 107, wherein administration of GL0034 to the subject achieves a plasma drug half-life (t½) of GL0034 of between 98 hours and 113 hours. 1 / 2}.

111. The method of any one of claims 87-98, wherein the subject is administered GL0034 once a week or once every two weeks.

112. The method of any one of claims 87-98 or 111, wherein the subject is administered a dose comprising 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg of GL0034.

113. The method of claim 112, wherein the subject is administered the dose of GL0034 once a week or once every two weeks.

114. The method of claim 112, wherein GL0034 is administered to the subject at a dose of 450 pg once a week for at least 4 weeks, and wherein the mean maximum concentration (C max ) of GL0034 is between 101 ng / mL and 142 ng / mL.

115. The method of claim 114, wherein administration of GL0034 to the subject achieves an area under the concentration-time curve (AUC) of GL0334 of between 12814 ng h / mL and 18537 ng h / mL over a 22 day period. 0-t ​ 116. The method of claim 114, wherein administering GL0034 to the subject achieves a plasma drug half-life (t 1 / 2 ) of GL0034 of 102 hours prior to 22 days.

117. The method of claim 112, wherein GL0034 is administered to the subject at a dose of 680 pg once a week for at least 4 weeks, and wherein the mean maximum concentration (C max ) of GL0034 is between 169 ng / mL and 267 ng / mL.

118. The method of claim 117, wherein administering GL0034 to the subject achieves an area under the concentration-time curve (AUCo-2o) of GL0034 of between 24576 ng h / mL and 34537 ng h / mL over a 22-day period. 0-t ​ 119. The method of claim 117, wherein administering GL0034 to the subject achieves a plasma drug half-life (t½) of GL0034 of 122.9 ± 16.5 hours prior to day 22 1 / 2}.

120. The method of any one of claims 87-98, wherein: (i) administering GL0034 to the subject at a dose of between 50 pg and 200 pg once a week for at least 2 weeks; (ii) administering GL0034 to the subject at a dose of between 200 pg and 400 pg once a week for at least 2 weeks; (iii) administering GL0034 to the subject at a dose of between 500 pg and 700 pg once a week for at least 2 weeks; (iv) administering GL0034 to the subject at a dose of between 1200 pg and 1500 pg once a week for at least 2 weeks; and (v) administering GL0034 to the subject at a dose of between 2000 pg and 3000 pg once a week for at least 4 weeks.

121. The method of any one of claims 87 to 98, wherein: (i) administering GL0034 to the subject at a dose of 450 pg once a week for at least 2 weeks; (ii) administering GL0034 to the subject at a dose of 900 pg once a week for at least 2 weeks; and (iii) administering GL0034 to the subject at a dose of 1520 pg once a week for at least 4 weeks.

122. The method of claim 121, wherein administration of GL0034 to the subject achieves a mean maximum concentration (Cmax) of GL0034 of between 112 ng / mL and 708 ng / mL. max}.

123. The method of claim 121, wherein administering GL0034 to the subject achieves an area under the concentration-time curve (AUCo-50) of GL0034 of between 12942 ng h / mL and 76320 ng h / mL over a 50 day period. 0-t ​ 124. The method of claim 121, wherein administration of GL0034 to the subject achieves a plasma drug half-life (t½) of GL0034 of 106.8 ± 33.7 hours prior to day 50. 1 / 2 ].

125. The method of any one of claims 87-98, comprising: (i) administering to the subject an initial dose comprising between 200 pg and 680 pg of GL0034 for at least 4 weeks; (ii) administering to the subject an escalation dose comprising between 680 pg and 900 pg of GL0034 once a week for at least 2 weeks; and (iii) administering to the subject a maintenance dose comprising between 1500 pg and 2000 pg of GL0034 once a week for at least 2 weeks.

126. The method of any one of claims 87-98, comprising: (i) administering to the subject an initial dose comprising between 450 pg and 680 pg of GL0034 for at least 4 weeks; and (ii) administering to the subject an escalation dose comprising between 680 pg and 900 pg of GL0034 once a week for at least 2 weeks.

127. The method of any one of claims 87-98, comprising: (i) administering to the subject an initial dose comprising between 450 pg and 680 pg of GL0034 for at least 4 weeks; (ii) administering to the subject an escalation dose comprising between 680 pg and 900 pg of GL0034 once a week for at least 2 weeks; and (iii) administering to the subject a maintenance dose comprising between 1520 pg and 2000 pg of GL0034 once a week for at least 2 weeks.

128. The method of any one of claims 87-127, wherein administration of GL0034 to the subject produces one or more clinically meaningful changes in the subject relative to baseline, wherein the clinically meaningful change relative to baseline is a decrease in alanine aminotransferase (ALT) value, a decrease in aspartate aminotransferase (AST) value, a decrease in gamma-glutamyl transferase (GGT) value, a decrease in fasting insulin level, a decrease in fasting glucose level, a decrease in glycosylated hemoglobin (HbAlc%), a decrease in homeostatic model assessment of insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin level, a decrease in triglyceride (TG) level, a decrease in total cholesterol (TC) level, a decrease in low-density lipoprotein (LDL) level, an increase in high-density lipoprotein (HDL) level, a decrease in TG / HDL ratio, an increase in FGF-21 in the liver, an increase in uncoupling protein- 1 level (UCP-1) in brown adipose tissue (BAT) and / or white adipose tissue (WAT), and / or a decrease in blood pressure.

129. The method of claim 128, wherein the decrease in ALT value relative to baseline persists for at least 23 days, at least 52 days, or at least 78 days after administration of GL0034 to the subject.

130. The method of claim 128, wherein: (a) the change in ALT value relative to baseline is at least -9 U / L over a period of about 23 days after administration of a dose comprising 450 pg GL0034 to the subject, or at least -3 U / L over a period of about 23 days after administration of a dose comprising 680 pg GL0034 to the subject; or (b) the change in ALT value is at least -7 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks, to the subject.

131. The method of claim 128, wherein the decrease in AST value relative to baseline persists for at least 23 days, at least 51 days, or at least 78 days after administration of GL0034 to the subject.

132. The method of claim 128, wherein the change from baseline in AST value is at least -4 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

133. The method of claim 128, wherein the reduction from baseline in GGT value lasts for at least 23 days, at least 51 days, or at least 78 days after administration of GL0034 to the subject.

134. The method of claim 128, wherein the change from baseline in GGT value is at least -3 U / L over a period of about 51 days or at least -1 U / L over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

135. The method of claim 128, wherein the reduction from baseline in fasting insulin level lasts for at least 23 days or at least 51 days after administration of GL0034 to the subject.

136. The method of claim 128, wherein the change from baseline in fasting insulin level is at least -5 pmol / L over a period of about 23 days after administration to the subject of a dose comprising 680 pg GL0034 once a week for at least 4 weeks; or at least -11 pmol / L over a period of about 51 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

137. The method of claim 128, wherein the reduction in fasting glucose lasts for at least 23 days or at least 51 days after administration of GL0034 to the subject.

138. The method of claim 128, wherein the reduction in fasting glucose is at least -3 mg / dL over a period of about 23 days after administration to the subject of a dose comprising 450 pg GL0034 once a week for at least 4 weeks; or at least -5 mg / dL over a period of about 23 days after administration to the subject of a dose comprising 680 pg GL0034 once a week for at least 4 weeks; or at least -8 mg / dL over a period of about 51 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

139. The method of claim 128, wherein the reduction in body weight persists for at least 8 days, at least 15 days, at least 22 days, at least 29 days, at least 50 days, at least 52 days, or at least 78 days after administration of GL0034 to the subject.

140. The method of claim 128, wherein: (a) the reduction in body weight is at least -2 kg over a period of about 22 days after administration to the subject of a dose comprising 2000 pg GL0034; or at least -2 kg over a period of about 22 days after administration to the subject of a dose comprising 1520 pg GL0034; or at least -3 kg over a period of about 22 days after administration to the subject of a dose comprising 2520 pg GL0034; or at least -3 kg over a period of about 29 days after administration to the subject of a dose comprising 450 pg GL0034 once a week for at least 4 weeks; or at least -4 kg over a period of about 29 days after administration to the subject of a dose comprising 680 pg GL0034 once a week for at least 4 weeks; or (b) the reduction in body weight is at least -8 kg over a period of about 52 days or at least -6 kg over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

141. The method of claim 128, wherein the reduction in leptin level relative to baseline is dose dependent.

142. The method of claim 128, wherein the change from baseline in leptin levels is at least -7 ng / mL over a period of about 8 days after administration to the subject of a dose comprising 1520 μg GL0034; or at least -11 ng / mL over a period of about 8 days after administration to the subject of a dose comprising 2000 μg GL0034; or at least -12 ng / mL over a period of about 8 days after administration to the subject of a dose comprising 2520 μg GL0034.

143. The method of claim 128, wherein a reduction from baseline in the TG levels is observed at day 8 after administration of GL0034 to the subject and the reduction from baseline in the TG levels lasts for at least 51 days or at least 78 days.

144. The method of claim 128, wherein: (a) the change from baseline in TG levels is at least -1 mmol / L over a period of about 8 days after administration to the subject of a dose comprising 2000 μg GL0034; or at least -1 mmol / L over a period of about 22 days after administration of a dose comprising 2520 μg GL0034; or (b) the change in TG levels is at least -21 mg / dL over a period of about 51 days or at least -11 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 μg GL0034 once weekly for at least 2 weeks; (ii) a dose comprising 900 μg GL0034 once weekly for at least 2 weeks; and (iii) a dose comprising 1520 μg GL0034 once weekly for at least 4 weeks.

145. The method of claim 128, wherein the reduction from baseline in TC levels is at least -29 mg / dL over a period of about 51 days or at least -6 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 μg GL0034 once weekly for at least 2 weeks; (ii) a dose comprising 900 μg GL0034 once weekly for at least 2 weeks; and (iii) a dose comprising 1520 μg GL0034 once weekly for at least 4 weeks.

146. The method of claim 128, wherein the change in LDL levels from baseline is at least -24 mg / dL over a period of about 51 days or at least -20 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

147. The method of claim 128, wherein the increase in HDL levels from baseline is at least 3 mg / dL over a period of about 78 days after administration to the subject of: (i) a dose comprising 450 pg GL0034 once a week for at least 2 weeks; (ii) a dose comprising 900 pg GL0034 once a week for at least 2 weeks; and (iii) a dose comprising 1520 pg GL0034 once a week for at least 4 weeks.

148. The method of claim 128, wherein the clinically meaningful change in the subject relative to baseline is a reduction in blood pressure.

149. The method of claim 148, wherein the reduction in blood pressure is a reduction in systolic blood pressure.

150. The method of claim 148, wherein the reduction in blood pressure is a reduction in diastolic blood pressure.

151. The method of claim 149, wherein the reduction in systolic blood pressure from baseline is at least about 18 mmHg or at least about 14% over a period of about 23 days after administration to the subject of a dose comprising 450 pg GL0034 once a week for at least 4 weeks.

152. The method of claim 150, wherein the reduction in diastolic blood pressure from baseline is at least about 12 mmHg or at least about 14% over a period of about 23 days after administration to the subject of a dose comprising 450 pg GL0034 once a week for at least 4 weeks.

153. The method of claim 148, wherein the reduction in blood pressure in the subject is greater than the reduction in blood pressure after administration of: (a) 1.7 mg to 2.4 mg semaglutide once a week; or (b) 5 mg to 15 mg tirzepatide once a week.

154. The method of any one of claims 87-153, wherein administration of GL0034 to the subject results in a reduction in the frequency of adverse events (AEs) in the subject over time.

155. The method of claim 154, wherein the AEs are one or more of nausea, vomiting, and / or decreased appetite.

156. The method of claim 154, wherein the reduction in the frequency of AEs is dose dependent.

157. The method of any one of claims 87-98, wherein administration of a higher dose of GL0034 to the subject does not cause an increase in severe treatment-emergent adverse events (TEAEs).

158. A method of treating hypertension in a subject, the method comprising administering to the subject a therapeutically effective amount of GL0034.

159. The method of claim 158, wherein the subject is obese.

160. The method of claim 159, wherein the subject does not have diabetes.

161. The method of claim 158, wherein the subject has a metabolic disorder.

162. The method of claim 161, wherein the metabolic disorder is metabolic dysfunction-associated fatty liver disease (MASLD).

163. The method of claim 162, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

164. The method of claim 161, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

165. The method of claim 164, wherein the metabolic disorder is type 2 diabetes.

166. The method of any one of claims 158-165, wherein GL0034 is administered to the subject subcutaneously.

167. The method of claim 166, wherein GL0034 is administered to the subject by subcutaneous injection.

168. The method of claim 167, wherein GL0034 is administered to the subject using an autoinjector or a pre-filled syringe.

169. The method of any one of claims 158-168, wherein the subject is administered a dose comprising 450 pg of GL0034.

170. The method of claim 169, wherein administration of GL0034 achieves a reduction in systolic blood pressure in the subject relative to baseline of at least about 18 mmHg or at least about 14% over a period of about 23 days after administration of GL0034.

171. The method of claim 169, wherein administration of GL0034 achieves a reduction in diastolic blood pressure in the subject relative to baseline of at least about 12 mmHg or at least about 14% over a period of about 23 days after administration of GL0034.

172. The method of any one of claims 158-171, wherein the reduction in blood pressure in the subject is greater than the reduction in blood pressure after administration of: (a) 1.7 mg to 2.4 mg semaglutide; or (b) 5 mg to 15 mg tirzepatide once weekly.

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