WO2024261580A1

WO2024261580A1 - Glp-1 analog for use in the treatment of metabolic disorders

Info

Publication number: WO2024261580A1
Application number: PCT/IB2024/055560
Authority: WO
Inventors: Rajamannar Thennati; Vinod Sampatrao BURADE; Muthukumaran Natarajan; Ravishankara Madavati NAGARAJA; Pradeep Shahi; Satishbhai Tribhovanbhai PANCHAL; Sudeep Kumar Agrawal
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2023-06-20
Filing date: 2024-06-06
Publication date: 2024-12-26
Anticipated expiration: 2025-12-20

Abstract

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

Description

GLP-1 ANALOG FOR USE IN THE TREATMENT OF METABOLIC DISORDERS

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Indian Application No. 202321042015, filed on June 20, 2023, and Indian Application No. 202421015451, filed March 1, 2024, the disclosures of each of which are incorporated by reference herein in their entirety.

SEQUENCE LISTING

This application contains a sequence listing which is submitted electronically and is hereby incorporated by reference in its entirety. The sequence listing submitted herewith is contained in the XML file created June 6, 2024 entitled “23-0927-WO_Sequence- Listing.xml” and is 4,096 bytes in size.

FIELD OF THE DISCLOSURE

The disclosure relates to methods of using GLP-1 analog and composition thereof for the treatment of metabolic disorders, such as obesity, diabetes, metabolic dysfunction- associated steatotic liver disease (MASLD) (sometimes referred to as nonalcoholic fatty liver disease (NAFLD) in the literature), metabolic dysfunction-associated steatohepatitis (MASH) (sometimes referred to as nonalcoholic steatohepatitis (NASH) in the literature), and hypertriglyceridemia. More specifically, the disclosure relates to methods for treating obesity in a subject, comprising administering a therapeutically effective amount of GL0034 to the subject. The disclosure also relates to methods for treating a metabolic disorder in a subject in need thereof, comprising administering a therapeutically effective amount of GL0034 to the subject. The disclosure further relates to compositions comprising GL0034 for the treatment of obesity, diabetes, or other metabolic disorder in a subject.

BACKGROUND

As of 2016, obesity was estimated to affect 13% of adults, with an incidence that had nearly tripled since 1975. World Health Organization, 2021, "Obesity and overweight," available at World Health Organization website (accessed June 18, 2023). Approximately 2% of obese U.S. adults were estimated to receive pharmacotherapy for obesity in 2015. Xia etal., Obesity (Silver Spring) 23(8): 1721-28 (2015); Samaranayake etal., Ann. Epidemiol. 22(5): 349-53 (2012). Obesity significantly increases all-cause mortality in affected individuals, largely due to its association with increased risks of cardiovascular disease and diabetes. Global BMI Mortality Collaboration et al., Lancet 388(10046): 776-86 (2016); GBD 2015 Obesity Collaborators et al., N. Engl. J. Med. 377(1): 13-27 (2017); Powell-Wiley et al., Circulation 143(21): e984-el010 (2021); Khan et al., JAMA Cardiol. 3(4): 280-87 (2018); Nguyen et al., Obes. Surg. 21(3): 351-55 (2011).

Diabetes is a chronic, metabolic disease that affects approximately 422 million people worldwide and contributes to 1.5 million deaths each year. World Health Organization, "Diabetes," available at World Health Organization website (accessed June 18, 2023). Diabetes is characterized by elevated levels of blood glucose, which leads over time to serious damage to the heart, blood vessels, eyes, kidneys, and nerves. Id. The most common type of diabetes is type 2 diabetes, which occurs when the body becomes resistant to insulin or does not make enough insulin. Id.

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction- associated steatotic liver disease (MASLD), and nonalcoholic steatohepatitis (NASH), now referred to as metabolic dysfunction-associated steatohepatitis (MASH), are highly associated with obesity and type 2 diabetes mellitus. Boland et al., Nat. Metab. 2(5): 413-31 (2020), Rinella et al., Heptaology, 78(f)): 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., Curr. Opin. Endocrinol. Diabetes Obes. 16(2): 141-49 (2009). Moreover, type 2 diabetes is an aggravating factor for NAFLD, as it increases the risk of developing NASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma. El-Serag et al., Hepatology 60(5): 1767-75 (2014). Currently, the only validated treatment for NAFLD is weight loss.

Glucagon-like peptide- 1 (GLP-1) is a hormone that is mainly produced in the enteroendocrine L-cells of the gut and is secreted into the bloodstream when food containing fat, protein hydrolysate, or glucose enters the duodenum. GLP-1 is derived from the cellspecific post-translational processing of the preproglucagon gene. Initially, the peptide GLP- 1(1-37) was identified from this processing, but it was two N-terminally truncated products, GLP-l(7-37) and GLP-l(7-36) amide, that were found to recognize the pancreatic receptor and which were determined to be the active species in vivo. GLP-1 has been found to stimulate insulin secretion, thereby causing glucose uptake by cells and decreased serum glucose levels.

Glucagon-like peptide- 1 (GLP-1) receptor agonists have been shown to provide reductions in glycated hemoglobin (HbAlc) and body weight loss in type 2 diabetes. Andersen et al., Nat. Rev. Endocrinol. 14(7): 390-403 (2018). Certain GLP-1 receptor agonists have been shown to improve glycemic control in adults with type 2 diabetes mellitus. Zhao et al., Front. Endocrinol. (Lausanne) 12: 721135 (2021); Nauck et al., Mol. Metab. 46: 101102 (2021). Glucose lowering by GLP-1 receptor agonists is attributed to a combination of effects, including direct action on pancreatic beta-cell GLP-1 receptors that potentiates glucose-stimulated insulin secretion, suppression of glucagon release, insulin sensitization due to weight loss, and neuronally mediated reductions in hepatic glucose output. Muller et al., Mol. Metab. 30: 72-130 (2019). GLP-1 receptor agonists have therefore been shown to be appropriate therapy for individuals with type 2 diabetes. Buse et al., Diabetes Care 43(2): 487-93 (2020).

GLP-1 agonists such as semaglutide and tirzepatide are often prescribed to overweight patients (> 27 kg/m² ) having at least one weight-related metabolic comorbid condition with the intent to reduce body weight and associated risks due to metabolic conditions. Treatments are administered subcutaneously once weekly in the abdomen, thigh, or upper arm. Initial dosing for semaglutide (WEGOVY®) is 0.25 mg once weekly for 4 weeks, followed by titrating every 4 weeks to achieve the maintenance dosage, with the maintenance dosage being between 1.7 mg and 2.4 mg (see WEGOVY® label). Initial dosing for tirzepatide (ZEPBOUND®) is 2.5 mg once weekly for 4 weeks, followed by increasing the dosage in 2.5 mg increments after at least 4 weeks, with the maintenance dosage being 5 mg, 10 mg, or 15 mg (see ZEPBOUND® label).

Treatment with GLP-1 receptor agonists also provides further beneficial metabolic effects such as improvements in lipid profile and resolution of hepatic steatosis. Jones et al., Diabetes Obes. Metab. 24(11): 2090-101 (2022). Animal model studies suggest that certain GLP- 1 receptor agonists may have a beneficial effect on liver fat content and nonalcoholic steatohepatitis (NASH), while recent human studies evaluating GLP-1 receptor agonists in the type 2 diabetic and obese population suggest that treatment with certain GLP-1 receptor agonists could represent a new alternative for management of nonalcoholic fatty liver disease (NAFLD) and NASH. Newsome et al., Aliment. Pharmacol. Ther. 50(2): 193-203 (2019); Newsome et al., N. Engl. J. Med., 384(12): 1113-24 (2021). Certain GLP-1 receptor agonists have also been shown to decrease body weight in obese individuals. Ma et al., Int. J. Biol. Sci. 17(8): 2050-68 (2021); Ard et al., Adv. Ther. 38(6): 2821-39 (2021).

GL0034 is a novel incretin analogue, based on the sequence of native GLP-1, with potent, G protein-biased, long-acting agonist activity at the GLP- 1 receptor that effectively reduced glucose and triglyceride levels as well as body weight in mice. Jones et al., Diabetes Obes. Metab. 24(11): 2090-101 (2022). This agonist shares some structural homology with another GLP- 1 receptor agonist, but with a distinct linker sequence between its polypeptide chain and albumin-binding acyl group, which could potentially affect its pharmacological properties. Id. The performance of GL0034 in vitro and in vivo in comparison with other marketed compounds using a variety of models has been described. Id. International Publication No. WO 2019/193576 Al discloses a group of novel GLP-1 receptor agonists (or analogs) having an amino acid sequence (SEQ ID NO: 1 shown below in Formula I) with a leucine or isoleucine residue at the C-terminus and also been acylated with protracting moieties 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 following compound of Formula I:

Formula I

SUMMARY

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

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

Further provided herein is a pharmaceutical composition comprising GL0034 for the treatment of obesity in a subject. Further provided herein is a pharmaceutical composition comprising GL0034 for the treatment of a metabolic disorder in a subject. Further provided herein is a pharmaceutical composition comprising GL0034 for the treatment of hypertension in a subject.

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.

These and other features and advantages of the present disclosure will be more fully understood from the following detailed description taken together with the accompanying claims. It is noted that the scope of the claims is defined by the recitations therein and not by the specific discussion of features and advantages set forth in the present description.

BRIEF DESCRIPTIONS OF THE DRAWINGS

FIG. 1 is the study design depicting the selection, randomization, and treatment of lean men with multiple ascending doses of GL0034. AE, adverse event; ALT, alanine transaminase; BMI, body mass index; HbAlC, hemoglobin A1C; HOMA-IR, homeostatic model assessment of insulin resistance; PD, pharmacodynamic.

FIG. 2A shows bar graphs depicting the mean change in body weight in kilograms at Day 29. Changes in body weight over time were analyzed with paired Student’s t-tests performed using GraphPad Prism 9 (version 9.5.1), LLC, Boston, MA. Missing data were not imputed. Data labels show the mean absolute/% change from baseline. Day 29 comparisons are shown for Cohorts 1 and 2. ***P <0.001vs respective Day 1 values.

FIG. 2B shows bar graphs depicting the mean change in body weight in kilograms at Day 52. Changes in body weight over time were analyzed with paired Student’s t-tests performed using GraphPad Prism 9 (version 9.5.1), LLC, Boston, MA. Missing data were not imputed. Data labels show the mean absolute/% change from baseline. Day 52 comparisons are shown for Cohort 3. ***P O.OOlvs respective Day 1 values. FIG. 3A shows bar graphs depicting the mean change in alanine transaminase (ALT) levels (U/L) on Day 23. Changes in ALT over time were analyzed with paired Student’s t- tests performed using GraphPad Prism 9 (version 9.5.1), LLC, Boston, MA. Missing data were not imputed. Data labels show the mean absolute/% change from baseline. Day 23 comparisons are shown for Cohorts 1 and 2. *P <0.05 vs respective Day 1 values.

FIG. 3B shows bar graphs depicting the mean change in alanine transaminase (ALT) levels (U/L) on Day 51. Changes in ALT over time were analyzed with paired Student’s t- tests performed using GraphPad Prism 9 (version 9.5.1), LLC, Boston, MA. Missing data were not imputed. Data labels show the mean absolute/% change from baseline. Day 51 comparisons are shown for Cohort 3. *P <0.05 vs respective Day 1 values.

FIG. 4A shows bar graphs depicting the mean change in fasting insulin among all three cohorts at Day 23. Changes in fasting insulin over time were analyzed with paired Student’s t-tests performed using GraphPad Prism 9 (version 9.5.1), LLC, Boston, MA. Missing data were not imputed. Data labels show the mean absolute/% change from baseline. Day 23 comparisons are shown for Cohorts 1 and 2.

FIG. 4B shows bar graphs depicting the mean change in fasting insulin among all three cohorts at Day 51. Changes in fasting insulin over time were analyzed with paired Student’s t-tests performed using GraphPad Prism 9 (version 9.5.1), LLC, Boston, MA. Missing data were not imputed. Data labels show the mean absolute/% change from baseline. Day 51 comparisons are shown for Cohort 3.

FIG. 5A shows bar graphs at Day 23 depicting the change in the homeostatic model assessment for insulin resistance (HOMA-IR) levels. Changes in HOMA-IR over time were analyzed with paired Student’s t-tests performed using GraphPad Prism 9 (version 9.5.1), LLC, Boston, MA. Missing data were not imputed. HOMA-IR <1.0 indicates optimal insulin sensitivity; HOMA-IR >1.9 indicates early insulin resistance; HOMAIR >2.9 indicates clinically significant insulin resistance. Data labels show the mean HOMA-IR. Day 23 comparisons are shown for Cohorts 1 and 2.

FIG. 5B shows bar graphs at Day 51 depicting the change in the homeostatic model assessment for insulin resistance (HOMA-IR) levels. Changes in HOMA-IR over time were analyzed with paired Student’s t-tests performed using GraphPad Prism 9 (version 9.5.1), LLC, Boston, MA. Missing data were not imputed. HOMA-IR <1.0 indicates optimal insulin sensitivity; HOMA-IR >1.9 indicates early insulin resistance; HOMAIR >2.9 indicates clinically significant insulin resistance. Data labels show the mean HOMA-IR. Day 51 comparisons are shown for Cohort 3. FIG. 6 is the study design depicting the selection, randomization, and treatment of individuals with obesity with single ascending doses of GL0034. BMI, body mass index; HbAlC, hemoglobin A1C; PD, pharmacodynamics; PK, pharmacokinetics.

FIG. 7 is a plasma concentration-time curve depicting the mean concentration of GL0034 in the plasma over time in hours.

FIG. 8 shows a graph depicting the mean change in bodyweight (kg) at day 8, 15, and 22 (EOS-End of study). Changes in body weight over time were analyzed with paired Oneway ANOVA followed by Dunnett’s posthoc test using GraphPad Prism 9 (version 9.5.1), LLC, Boston, MA. Missing data were not imputed. Data labels show the mean absolute change from baseline in kg. *P <0.05, **P <0.01, ***P <0.001 vs respective Day 1 body weight.

FIG. 9A shows bar graphs depicting the mean change in triglyceride levels (ng /ml) of all participants. #P <0.05, ##P <0.01 vs respective Day 1 values; analyzed with paired Student’s t-tests performed using GraphPad Prism 9 (version 9.5.1); Missing values were not imputed; Data labels show the mean absolute/% change from baseline.

FIG. 9B shows bar graphs depicting the mean change in leptin levels (ng /ml) of all participants. #P <0.05, ##P <0.01 vs respective Day 1 values; analyzed with paired Student’s t-tests performed using GraphPad Prism 9 (version 9.5.1); Missing values were not imputed; Data labels show the mean absolute/% change from baseline.

DETAILED DESCRIPTION

The disclosure relates to methods and compositions for the treatment of obesity. The disclosure also relates to methods and compositions for the treatment of metabolic disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), diabetes, and hypertriglyceridemia. More specifically, the disclosure relates to methods for treating obesity in a subject, comprising administering a therapeutically effective amount of GL0034 to the subject. The disclosure also relates to methods for treating a metabolic disorder in a subject in need thereof, comprising administering a therapeutically effective amount of GL0034 to the subject. The disclosure also relates to methods for treating hypertension in a subject, comprising administering a therapeutically effective amount of GL0034 to the subject. The disclosure further relates to compositions comprising GL0034 for the treatment of obesity or a metabolic disorder or hypertension in a subject. As utilized in accordance with the present disclosure, unless otherwise indicated or defined, all technical and scientific terms used herein shall be understood to have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. The following references provide one of 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.

Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. For example, the terms "a," "an," and "the," as used herein, are understood to be singular or plural unless the context clearly dictates otherwise. It should be understood that the terms "a" and "an" as used herein refer to "one or more" of the enumerated components unless otherwise indicated or dictated by its context. The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives unless otherwise indicated. Thus, unless specifically stated or apparent from context, the term "or," as used herein, is understood to be inclusive.

The terms "comprises" and "comprising," as used herein, can have the meaning ascribed to them in U.S. patent law and can mean "includes," "including," "containing," "having," and the like. Thus, unless expressly specified otherwise, the terms "comprises" and "comprising," as used herein, indicate that further components or members may optionally be present in addition to the components or members of the list introduced by "comprising." The terms "consisting essentially of' or "consists essentially," as used herein, likewise have the meaning ascribed in U.S. patent law, and allow for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited are not changed by the presence of more than that which is recited.

Any of the methods or compositions provided herein can be combined with one or more of any of the other methods or compositions provided herein.

In the present disclosure, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 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.

Unless specifically stated or apparent from context, the terms "about" and "approximately," as used herein, are understood as meaning within a range of normal tolerance in the art, for example within 2 standard deviations of the mean, or mean 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 how the value is measured or determined, 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.

It is noted that terms like "preferably," "commonly," and "typically" are not utilized herein to limit the scope of the claimed subject matter or to imply that certain features are critical, essential, or even important to the structure or function of the claimed subject matter. Rather, these terms are merely intended to highlight alternative or additional features that can or cannot be utilized in a particular embodiment of the present disclosure.

For the purposes of describing and defining the present disclosure it is noted that the term "substantially" is utilized herein to represent the inherent degree of uncertainty that can be attributed to any quantitative comparison, value, measurement, or other representation. The term "substantially" is also utilized herein to represent the degree by which a quantitative representation can vary from a stated reference without resulting in a change in the basic function of the subject matter at issue.

Methods and Compositions

In one embodiment, the present disclosure provides a method of treating obesity in a subject, comprising administering a therapeutically effective amount of GU0034 to the subject. In another embodiment, the present disclosure provides a method of treating a metabolic disorder in a subject, comprising administering a therapeutically effective amount of GU0034 to the subject.

In one embodiment, the present disclosure provides a pharmaceutical composition comprising GU0034 for the treatment of obesity in a subject. In another embodiment, the present disclosure provides a pharmaceutical composition comprising GU0034 for the treatment of a metabolic disorder in a subject.

In one embodiment, the present disclosure provides use of GU0034 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.

As used herein, the terms "subject", "patient", and "participant" are interchangeable. In some embodiments, subjects or patients are mammals. In some embodiments of the methods, compositions, and medicaments of the disclosure, the subject is diabetic. In other embodiments of the methods, compositions, and medicaments of the disclosure, the subject is not diabetic. 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.

As used herein, "diabetes" or "diabetes mellitus" or "diabetic" is a metabolic condition / disorder which is related to increased blood glucose levels. The term also includes all types of diabetes, non-limiting three main types of diabetes are: Type 1 diabetes mellitus (T1DM), Type 2 diabetes mellitus (T2DM) and gestational diabetes.

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 that predispose a patient to the disorder in question.

The terms "treatment" or "treat," as used herein, refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include subjects having obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), or diabetes.

In some embodiments of the methods, compositions, and medicaments of the disclosure, the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD). 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.

The terms "pharmaceutical composition" or "therapeutic composition," as used herein, refer to a compound or composition 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. The terms "pharmaceutically acceptable carrier" or "physiologically acceptable carrier," as used herein, refer to one or more formulation materials suitable for accomplishing or enhancing the delivery of GL0034.

Pharmaceutical compositions comprising GL0034, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers are provided. The pharmaceutical compositions comprising GL0034 provided herein are for use in, but not limited to, preventing, treating, managing, or ameliorating a disorder or one or more symptoms thereof. The formulation of pharmaceutical compositions, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers, is known to one skilled in the art.

The terms "administration" or "administering," as used herein, refer to providing, contacting, and/or delivering GL0034 by any appropriate route to achieve the desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional, or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ophthalmic, via inhalation, and implants. In some embodiments of the methods, compositions, and medicaments of the disclosure, GL0034 (or a composition or medicament comprising GL0034) is administered to the subject subcutaneously. In certain embodiments of the methods, compositions, and medicaments of the disclosure, administration is by subcutaneous injection. In certain embodiments of the methods, compositions, and medicaments of the disclosure, administration is subcutaneous via an auto-injector or pre-filled syringe.

In some embodiments of the methods, compositions, and medicaments of the disclosure, the dose of GL0034 (or a composition or medicament comprising GL0034) administered to the subject is between 200 pg and 8000 pg GL0034, between 300 pg and 6000 pg GL0034, between 400 pg and 4000 pg GL0034, or between 1000 pg and 3000 pg GL0034. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the dose of GL0034 (or a composition or medicament comprising GL0034) administered to the subject is 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg of GL0034. In certain embodiments of the methods, compositions, and medicaments of the disclosure, a single dose of GL0034 (or a composition or medicament comprising GL0034) is administered to the subject, wherein the dose of GL0034 (or a composition or medicament comprising GL0034) is 1520 pg, 2000 pg, or 2520 pg of GL0034. In some embodiments of the methods, compositions, and medicaments of the disclosure, GL0034 (or a composition or medicament comprising GL0034) is administered every day, every other day, every third day, every fourth day, every fifth day, every sixth day, once a week, or once every two weeks. In one embodiment of the methods, compositions, and medicaments of the disclosure, GL0034 (or a composition or medicament comprising GL0034) is administered once a week. As used herein, the term "Day 1" refers to the first day that GL0034 (or a composition or medicament comprising GL0034) is administered to a subject.

In some embodiments of the methods, compositions, and medicaments of the disclosure, GL0034 (or a composition or medicament comprising GL0034) is administered over a two week treatment period, over a four week treatment period, over a six week treatment period, or over an eight week treatment period. In one embodiment of the methods, compositions, and medicaments of the disclosure, GL0034 (or a composition or medicament comprising GL0034) is administered to the subject once a week for up to 4 weeks. In another embodiment of the methods, compositions, and medicaments of the disclosure, GL0034 (or a composition or medicament comprising GL0034) is administered to the subject once a week for up to 8 weeks.

In one embodiment of the methods, compositions, and medicaments of the disclosure, the mean maximum concentration (Cmax) of GL0034 is between 226.9 ± 57.3 ng/mL and 367.0 ± 152.0 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 concentration-time Curve (AUCo-t) of GL0034 of between 47,151.5 ± 16,838.6 ng*h/mL and 62,265.9 ± 20,816.5 ng*h/mL over a period of 22 days. 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 (ti/2) of GL0034 between 98.5 ± 13.0 hours and 113.5 ± 22.9 hours. 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 (Tmax) of GL0034 of between 22.0 ± 6.9 hours and 31.0 ± 13.5 hours.

In one embodiment of the methods, compositions, and medicaments of the disclosure, GL0034 (or a composition or medicament comprising GL0034) is administered at dose of 450 pg of GL0034 once a week for 4 weeks, and the mean maximum concentration (Cmax) of GL0034 is between 100.5 ± 22.0 ng/mL and 141.7 ± 34.6 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 concentrationtime Curve (AUCo-t) ofGL0034 ofbetween 12814.3 ± 2652.1 ng*h/mL and 18536.8 ± 4608.0 ng*h/mL over a period of 22 days. 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 (ti/2) of GL0034 of 102.3 ± 15.4 hours by 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 (Tmax) of GL0034 ofbetween 36.0 ± 12.0 hours and 47.0 ± 16.0 hours.

In one embodiment of the methods, compositions, and medicaments of the disclosure, GL0034 (or a composition or medicament comprising GL0034) is administered at dose of 680 pg of GL0034 once a week for 4 weeks, and the mean maximum concentration (Cmax) 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 concentrationtime Curve (AUCo-t) ofGU0034 ofbetween 24575.9 ± 3391.3 ng*h/mU and 34536.6 ± 6445.0 ng*h/mU over a period of 22 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, administration of GU0034 (or a composition or medicament comprising GU0034) provides a plasma drug half-life (ti/2) of GU0034 of 122.9 ± 16.5 hours by day 22. In certain embodiments of the methods, compositions, and medicaments of the disclosure, administration of GU0034 (or a composition or medicament comprising GU0034) provides a time from administration to maximum plasma concentration (Tmax) of GU0034 ofbetween 39.0 ± 21.0 hours and 54.0 ± 27.0 hours.

In one embodiment of the methods, compositions, and medicaments of the disclosure, (i) a dose of 450 pg GU0034 is administered to the subject once a week for 2 weeks; followed by (ii) a dose of 900 pg GU0034 is administered to the subject once a week for 2 weeks; and followed by (iii) a dose of 1520 pg GU0034 is administered to the subject once a week for 4 weeks. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the mean maximum concentration (Cmax) of GU0034 is between 111.7 ± 23.7 ng/mU and 707.6 ± 251.7 ng/mU. In certain embodiments of the methods, compositions, and medicaments of the disclosure, administration of GU0034 (or a composition or medicament comprising GL0034) provides an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 12942.2 ± 1517.5 ng*h/mL and 76320.4 ± 23334.6 ng*h/mL over a period of 50 days. 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 (ti/2) of GL0034 of 106.8 ± 33.8 hours by day 50. 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 (Tmax) of GL0034 of between 22.0 ± 16.0 hours and 41.0 ± 8.0 hours.

In some embodiments of the methods, compositions, and medicaments of the disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) results in one or more clinically meaningful changes from baseline in the subject, wherein the clinically meaningful changes from baseline are a decrease in alanine transaminase (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 for insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin levels, a decrease in triglycerides (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.

In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in ALT values from baseline is sustained for up to 23 days, for up to 52 days, or for up to 78 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in ALT values 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in AST values from baseline is sustained for up to 23 days, for up to 51 days, or for up to 78 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in AST values 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in GGT values from baseline is sustained for up to 23 days, for up to 51 days, or for up to 78 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in GGT values 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in fasting insulin levels from baseline is sustained for up to 23 days or for up to 51 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in fasting insulin levels from 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in fasting glucose is sustained for up to 23 days or for up to 51 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the decrease 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease 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). In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in HOMA-IR is achieved at 23 days after administration of GL0034 (or a composition or medicament comprising GL0034) or at 51 days after administration of GL0034 (or a composition or medicament comprising GL0034). In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in body weight is sustained for up to 8 days, for up to 15 days, for up to 22 days, for up to 29 days, for up to 50 days, for up to 52 days, or for up to 78 days. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the decrease 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in leptin levels from baseline is dose dependent. In certain embodiments of the methods, compositions, and medicaments of the disclosure, the change in leptin levels from 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the decrease in TG from baseline is observed at day 8 after administration of GL0034 (or a composition or medicament comprising GL0034) and is sustained 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 levels 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the change in TC levels 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the change in LDL levels 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).

In one embodiment of the methods, compositions, and medicaments of the disclosure, the increase in HDL levels 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). In one embodiment of the methods, compositions, and medicaments of the disclosure, administration of GL0034 (or a composition or medicament comprising GL0034) results a decrease in the frequency of adverse events (AEs) overtime in the subject. 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 decrease in the frequency of AEs is dose dependent.

As used herein, the terms "group" and "cohort" have the same meaning.

Embodiments:

Embodiment 1: A pharmaceutical composition comprising GL0034 for the treatment of obesity in a subject.

Embodiment 2: The pharmaceutical composition according to embodiment 1, wherein the subject is not diabetic.

Embodiment 3 : The pharmaceutical composition according to either embodiment 1 or embodiment 2, wherein the subject has a body mass index (BMI) of at least 28 kg/m² or > 27 kg/m² with at least 1 weight-related comorbid condition. Embodiment 4: A pharmaceutical composition comprising GL0034 for the treatment of a metabolic disorder in a subject.

Embodiment 5 : The pharmaceutical composition according to embodiment 4, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD). Embodiment 6: The pharmaceutical composition according to embodiment 5, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

Embodiment 7 : The pharmaceutical composition according to embodiment 4, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Embodiment 8: The pharmaceutical composition according to embodiment 7, wherein the metabolic disorder is type 2 diabetes.

Embodiment 9: The pharmaceutical composition according to any one of embodiments 1 to

8, wherein the subject has hypertension.

Embodiment 10: The pharmaceutical composition according to any one of embodiments 1 to

9, wherein the pharmaceutical composition is administered to the subject subcutaneously.

Embodiment 11: The pharmaceutical composition according to embodiment 10, wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.

Embodiment 12: The pharmaceutical composition according to embodiment 11, wherein the pharmaceutical composition is administered to the subject using an auto-injector or prefilled syringe.

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

Embodiment 14: The pharmaceutical composition according to embodiment 13, wherein the dose of the pharmaceutical composition comprises between 300 pg and 6000 pg GL0034.

Embodiment 15: The pharmaceutical composition according to embodiment 14, wherein the dose of the pharmaceutical composition comprises between 400 pg and 4000 pg GL0034. Embodiment 16: The pharmaceutical composition according to embodiment 15, wherein the dose of the pharmaceutical composition comprises between 1000 pg and 3000 pg GL0034.

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

Embodiment 18: The pharmaceutical composition according to any one of embodiments 1 to 16, wherein administration of the pharmaceutical composition to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 75 ng/mL and 1200 ng/mL. Embodiment 19: The pharmaceutical composition according to any one of embodiments 1 to 16, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 6200 ng*h/mL and 406300 ng*h/mL over a period of 22 days.

Embodiment 20: The pharmaceutical composition according to embodiment 16, wherein the dose of the pharmaceutical composition comprises 1520 pg, 2000 pg, or 2520 pg GL0034. Embodiment 21 : The pharmaceutical composition according to embodiment 20, wherein administration of the pharmaceutical composition to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 227 ng/mL and 367 ng/mL.

Embodiment 22: The pharmaceutical composition according to embodiment 20, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 30313 ng*h/mL and 83082 ng*h/mL over a period of 22 days.

Embodiment 23 : The pharmaceutical composition according to any one of embodiments 1 to 21, wherein administration of the pharmaceutical composition to the subject results in a plasma drug half-life (ti/2) of GL0034 of between 90 hours and 120 hours.

Embodiment 24: The pharmaceutical composition according to embodiment 21, wherein administration of the pharmaceutical composition to the subject results in a plasma drug halflife (ti/2) ofGL0034 of between 98 hours and 113 hours.

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

Embodiment 26: The pharmaceutical composition according to any one of embodiments 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 GL0034.

Embodiment 27 : The pharmaceutical composition according to embodiment 26, wherein the dose of the pharmaceutical composition is administered once a week or once every two weeks.

Embodiment 28: The pharmaceutical composition according to embodiment 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 results in a mean maximum concentration (Cmax) of GL0034 of between 101 ng/mL and 142 ng/mL. Embodiment 29: The pharmaceutical composition according to embodiment 28, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0334 of between 12814 ng*h/mL and 18537 ng*h/mL over a period of 22 days.

Embodiment 30: The pharmaceutical composition according to embodiment 28, wherein administration of the pharmaceutical composition to the subject results in a plasma drug halflife (ti/2) of GL0034 of 102 hours by day 22.

Embodiment 31 : The pharmaceutical composition according to embodiment 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 results in a mean maximum concentration (Cmax) of GL0034 of between 169 ng/mL and 267 ng/mL.

Embodiment 32: The pharmaceutical composition according to embodiment 31, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 24576 ng*h/mL and 34537 ng*h/mL over a period of 22 days.

Embodiment 33: The pharmaceutical composition according to embodiment 31, wherein administration of the pharmaceutical composition to the subject results in a plasma drug halflife (ti/2) of GL0034 of 123 hours by day 22.

Embodiment 34: The pharmaceutical composition according to any one of embodiments 1 to 12, wherein: (i) a dose of the pharmaceutical composition comprising between 50 pg and 200 pg GL0034 is administered to the subject once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising between 200 pg and 400 pg GL0034 is administered to the subject once a week for at least 2 weeks; (iii) a dose of the pharmaceutical composition comprising between 500 pg and 700 pg GL0034 is administered to the subject once a week for at least 2 weeks; (iv) a dose of the pharmaceutical composition comprising between 1200 pg and 1500 pg GL0034 is administered to the subject once a week for at least 2 weeks; and (v) a dose of the pharmaceutical composition comprising between 2000 pg and 3000 pg GL0034 is administered to the subject once a week for at least 4 weeks. Embodiment 35: The pharmaceutical composition according to any one of embodiments 1 to 12, wherein: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034 is administered to the subject once a week for at least 2 weeks; (ii) a dose of the pharmaceutical composition comprising 900 pg GL0034 is administered to the subject once a week for at least 2 weeks; and (iii) a dose of the pharmaceutical composition comprising 1520 pg GL0034 is administered to the subject once a week for at least 4 weeks.

Embodiment 36: The pharmaceutical composition according to embodiment 35, wherein administration of the pharmaceutical composition to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 112 ng/mL and 708 ng/mL.

Embodiment 37: The pharmaceutical composition according to embodiment 35, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 12942 ng*h/mL and 76320 ng*h/mL over a period of 50 days.

Embodiment 38: The pharmaceutical composition according to embodiment 35, wherein administration of the pharmaceutical composition to the subject results in a plasma drug halflife (ti/2) of GL0034 of 106.8 ± 33.7 hours by day 50.

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

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

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

Embodiment 42: The pharmaceutical composition according to any one of embodiments 1 to 41, wherein administration of the pharmaceutical composition to the subject results in one or more clinically meaningful changes from baseline in the subject, wherein the clinically meaningful changes from baseline are a decrease in alanine transaminase (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 for insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin levels, a decrease in triglycerides (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 level (UCP-1) in brown adipose tissue (BAT) and/or white adipose tissue (WAT), and/or a decrease in blood pressure.

Embodiment 43 : The pharmaceutical composition according to embodiment 42, wherein the decrease in ALT values from baseline is sustained for at least 23 days, for at least 52 days, or for at least 78 days after administration of the pharmaceutical composition to the subject. Embodiment 44: The pharmaceutical composition according to embodiment 42, wherein: (a) the change in ALT values from baseline is at least -9 U/L over 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 over 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 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 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.

Embodiment 45 : The pharmaceutical composition according to embodiment 42, wherein the decrease in AST values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of the pharmaceutical composition to the subject. Embodiment 46: The pharmaceutical composition according to embodiment 42, wherein the change in AST values 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. Embodiment 47 : The pharmaceutical composition according to embodiment 42, wherein the decrease in GGT values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of the pharmaceutical composition to the subject. Embodiment 48: The pharmaceutical composition according to embodiment 42, wherein the change in GGT values 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.

Embodiment 49: The pharmaceutical composition according to embodiment 42, wherein the decrease in fasting insulin levels from baseline is sustained for at least 23 days or for at least 51 days after administration of the pharmaceutical composition to the subject.

Embodiment 50: The pharmaceutical composition according to embodiment 42, wherein the change in fasting insulin levels from baseline is at least -5 pmol/L over a period of about 23 days after administration of 680 pg GL0034 to the subject 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 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.

Embodiment 51 : The pharmaceutical composition according to embodiment 42, wherein the decrease in fasting glucose is sustained for at least 23 days or for at least 51 days after administration of the pharmaceutical composition to the subject.

Embodiment 52: The pharmaceutical composition according to embodiment 42, wherein the decrease 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 to the subject once a week for at least 4 weeks; 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 to the subject 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 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.

Embodiment 53: The pharmaceutical composition according to embodiment 42, wherein the decrease in body weight is sustained for at least 8 days, for at least 15 days, for at least 22 days, for at least 29 days, for at least 50 days, for at least 52 days, or for at least 78 days after administration of the pharmaceutical composition to the subject.

Embodiment 54: The pharmaceutical composition according to embodiment 42, wherein: (a) the decrease in body weight is at least -2 kg over a period of about 22 days after administration of a dose of the pharmaceutical composition comprising 2000 pg GL0034 to the subject; or at least -2 kg over a period of about 22 days after administration of a dose of the pharmaceutical composition comprising 1520 pg GL0034 to the subject; or at least -3 kg over a period of about 22 days after administration of a dose of the pharmaceutical composition comprising 2520 pg GL0034 to the subject; or at least -3 kg over a period of about 29 days after administration of a dose of the pharmaceutical composition comprising 450 pg GL0034 to the subject once a week for at least 4 weeks; or at least -4 kg over a period of about 29 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034 to the subject once a week for at least 4 weeks; or (b) the decrease 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.

Embodiment 55: The pharmaceutical composition according to embodiment 42, wherein the decrease in leptin levels from baseline is dose dependent.

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

Embodiment 57: The pharmaceutical composition according to embodiment 42, wherein the decrease in TG levels from baseline is observed at day 8 and is sustained for at least 51 days or for at least 78 days after administration of the pharmaceutical composition to the subject. Embodiment 58: The pharmaceutical composition according to embodiment 42, wherein: (a) the change in TG levels from 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 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 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.

Embodiment 59: The pharmaceutical composition according to embodiment 42, wherein the decrease in TC levels 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.

Embodiment 60: The pharmaceutical composition according to embodiment 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.

Embodiment 61 : The pharmaceutical composition according to embodiment 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. Embodiment 62: The pharmaceutical composition according to embodiment 42, wherein the clinically meaningful change from baseline in the subject is a decrease in blood pressure. Embodiment 63 : The pharmaceutical composition according to embodiment 62, wherein the decrease in blood pressure is a decrease in systolic blood pressure.

Embodiment 64: The pharmaceutical composition according to embodiment 62, wherein the decrease in blood pressure is a decrease in diastolic blood pressure.

Embodiment 65: The pharmaceutical composition according to embodiment 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. Embodiment 66: The pharmaceutical composition according to embodiment 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 at least GL0034 once a week for at least 4 weeks.

Embodiment 67 : The pharmaceutical composition according to embodiment 62, wherein the decrease in blood pressure in the subject is greater as compared to the decrease in blood pressure following administration of: (a) 1.7 to 2.4 mg semaglutide once weekly; or (b) 5 to 15 mg tirzepatide once weekly.

Embodiment 68: The pharmaceutical composition according to any one of embodiments 1 to 67, wherein administration of the pharmaceutical composition to the subject results a decrease in the frequency of adverse events (AEs) overtime in the subject.

Embodiment 69: The pharmaceutical composition according to embodiment 68, wherein the AEs are one or more of nausea, vomiting, and/or decreased appetite.

Embodiment 70: The pharmaceutical composition according to embodiment 68, wherein the decrease in the frequency of AEs is dose dependent.

Embodiment 71 : The pharmaceutical composition according to any one of embodiments 1 to 12, wherein administration of a higher dose of the pharmaceutical composition to the subject does not result in an increase in severe treatment-emergent adverse events (TEAEs). Embodiment 72: A pharmaceutical composition comprising GL0034 for the treatment of hypertension in a subject, wherein a therapeutically effective dose of the pharmaceutical composition is administered to the subject.

Embodiment 73: The pharmaceutical composition according to embodiment 72, wherein the subject is obese.

Embodiment 74: The pharmaceutical composition according to embodiment 73, wherein the subject is not diabetic. Embodiment 75: The pharmaceutical composition according to embodiment 72, wherein the subject has a metabolic disorder.

Embodiment 76: The pharmaceutical composition according to embodiment 75, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

Embodiment 77: The pharmaceutical composition according to embodiment 76, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

Embodiment 78: The pharmaceutical composition according to embodiment 75, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Embodiment 79: The pharmaceutical composition according to embodiment 78, wherein the metabolic disorder is type 2 diabetes.

Embodiment 80: The pharmaceutical composition according to any one of embodiments 72 to 79, wherein the pharmaceutical composition is administered to the subject subcutaneously. Embodiment 81: The pharmaceutical composition according to embodiment 80, wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.

Embodiment 82: The pharmaceutical composition according to embodiment 81, wherein the pharmaceutical composition is administered to the subject using an auto-injector or prefilled syringe.

Embodiment 83: The pharmaceutical composition according to any one of embodiments 72 to 82, wherein a dose of the pharmaceutical composition comprising 450 pg GL0034 is administered to the subject.

Embodiment 84: The pharmaceutical composition according to embodiment 83, wherein administration of the pharmaceutical composition results in a decrease in systolic blood pressure from baseline in the subject of at least about 18 mmHg or at least about 14% over a period of about 23 days after administration of the pharmaceutical composition.

Embodiment 85: The pharmaceutical composition according to embodiment 83, wherein administration of the pharmaceutical composition results in a decrease in diastolic blood pressure from baseline in the subject of at least about 12 mmHg or at least about 14% over a period of about 23 days after administration of the pharmaceutical composition.

Embodiment 86: The pharmaceutical composition according to any one of embodiments 72 to 85, wherein the decrease in blood pressure in the subject is greater as compared to the decrease in blood pressure following administration of: (a) 1.7 to 2.4 mg semaglutide; or (b) 5 to 15 mg tirzepatide once weekly.

Embodiment 87: A method of treating obesity in a subject, comprising administering a therapeutically effective amount of GL0034 to the subject. Embodiment 88: The method according to embodiment 87, wherein the subject is not diabetic.

Embodiment 89: The method according to either embodiment 87 or embodiment 88, wherein the subject has a body mass index (BMI) of at least 28 kg/m² or > 27 kg/m² with at least 1 weight-related comorbid condition.

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

Embodiment 91 : The method according to embodiment 90, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

Embodiment 92: The method according to embodiment 91, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

Embodiment 93 : The method according to embodiment 90, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Embodiment 94: The method according to embodiment 93, wherein the metabolic disorder is type 2 diabetes.

Embodiment 95: The method according to any one of embodiments 87 to 94, wherein the subject has hypertension.

Embodiment 96: The method according to any one of embodiments 87 to 95, wherein GL0034 is administered to the subject subcutaneously.

Embodiment 97: The method according to embodiment 96, wherein GL0034 is administered to the subject by subcutaneous injection.

Embodiment 98: The method according to embodiment 97, wherein GL0034 is administered to the subject using an auto-injector or prefdled syringe.

Embodiment 99: The method according to any one of embodiments 87 to 98, wherein a dose comprising between 200 pg and 8000 pg GL0034 is administered to the subject.

Embodiment 100: The method according to embodiment 99, wherein the dose comprises between 300 pg and 6000 pg GL0034.

Embodiment 101: The method according to embodiment 100, wherein the dose comprises between 400 pg and 4000 pg GL0034.

Embodiment 102: The method according to embodiment 101, wherein the dose comprises between 1000 pg and 3000 pg GL0034.

Embodiment 103: The method according to any one of embodiments 87 to 102, wherein the dose of GL0034 is administered to the subject once a week or once every two weeks. Embodiment 104: The method according to any one of embodiments 87 to 102, wherein administration of GL0034 to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 75 ng/mL and 1200 ng/mL.

Embodiment 105: The method according to any one of embodiments 87 to 102, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 6200 ng*h/mL and 406300 ng*h/mL over a period of 22 days.

Embodiment 106: The method according to embodiment 102, wherein the dose comprises 1520 pg, 2000 pg, or 2520 pg GL0034.

Embodiment 107: The method according to embodiment 106, wherein administration of GL0034 to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 227 ng/mL and 367 ng/mL.

Embodiment 108: The method according to embodiment 106, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 30313 ng*h/mL and 83082 ng*h/mL over a period of 22 days. Embodiment 109: The method according to any one of embodiments 87 to 107, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of between 90 hours and 120 hours.

Embodiment 110: The method according to embodiment 107, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of between 98 hours and 113 hours.

Embodiment 111: The method according to any one of embodiments 87 to 98, wherein GL0034 is administered to the subject once a week or once every two weeks.

Embodiment 112: The method according to any one of embodiments 87 to 98 or l l l, wherein a dose comprising 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034 is administered to the subject.

Embodiment 113: The method according to embodiment 112, wherein the dose of GL0034 is administered to the subject once a week or once every two weeks.

Embodiment 114: The method according to embodiment 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 (Cmax) of GL0034 is between 101 ng/mL and 142 ng/mL. Embodiment 115: The method according to embodiment 114, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0334 of between 12814 ng*h/mL and 18537 ng*h/mL over a period of 22 days. Embodiment 116: The method according to embodiment 114, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of 102 hours by day 22.

Embodiment 117: The method according to embodiment 112, wherein GL0034 is administered to the subject at dose of 680 pg once a week for at least 4 weeks, and wherein the mean maximum concentration (Cmax) of GL0034 is between 169 ng/mL and 267 ng/mL. Embodiment 118: The method according to embodiment 117, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 24576 ng*h/mL and 34537 ng*h/mL over a period of 22 days. Embodiment 119: The method according to embodiment 117, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of 123 hours by day 22.

Embodiment 120: The method according to any one of embodiments 87 to 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.

Embodiment 121: The method according to any one of embodiments 87 to 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.

Embodiment 122: The method according to embodiment 121, wherein administration of GL0034 to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 112 ng/mL and 708 ng/mL.

Embodiment 123: The method according to embodiment 121, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 12942 ng*h/mL and 76320 ng*h/mL over a period of 50 days. Embodiment 124: The method according to embodiment 121, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of 106.8 ± 33.7 hours by day 50. Embodiment 125: The method according to any one of embodiments 87 to 98, comprising: (i) administering an initial dose comprising between 200 pg and 680 pg GL0034 to the subject for at least 4 weeks; (ii) administering an escalation dose comprising between 680 pg and 900 pg GL0034 to the subject once a week for at least 2 weeks; and (iii) administering a maintenance dose comprising between 1500 pg and 2000 pg GL0034 to the subject once a week for at least 2 weeks.

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

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

Embodiment 128: The method according to any one of embodiments 87 to 127, wherein administration of GL0034 to the subject results in one or more clinically meaningful changes from baseline in the subject, wherein the clinically meaningful changes from baseline are a decrease in alanine transaminase (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 for insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin levels, a decrease in triglycerides (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 level (UCP-1) in brown adipose tissue (BAT) and/or white adipose tissue (WAT), and/or a decrease in blood pressure. Embodiment 129: The method according to embodiment 128, wherein the decrease in ALT values from baseline is sustained for at least 23 days, for at least 52 days, or for at least 78 days after administration of GL0034 to the subject.

Embodiment 130: The method according to embodiment 128, wherein: (a) the change in ALT values from baseline is at least -9 U/L over a period of about 23 days after administration to the subject of a dose comprising 450 pg GL0034, or at least -3 U/L over a period of about 23 days after administration to the subject of a dose 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 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.

Embodiment 131: The method according to embodiment 128, wherein the decrease in AST values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of GL0034 to the subject.

Embodiment 132: The method according to embodiment 128, wherein the change in AST values 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 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.

Embodiment 133: The method according to embodiment 128, wherein the decrease in GGT values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of GL0034 to the subject.

Embodiment 134: The method according to embodiment 128, wherein the change in GGT values 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 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.

Embodiment 135: The method according to embodiment 128, wherein the decrease in fasting insulin levels from baseline is sustained for at least 23 days or for at least 51 days after administration of GL0034 to the subject.

Embodiment 136: The method according to embodiment 128, wherein the change in fasting insulin levels from baseline 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. Embodiment 137: The method according to embodiment 128, wherein the decrease in fasting glucose is sustained for at least 23 days or for at least 51 days after administration of GL0034 to the subject.

Embodiment 138: The method according to embodiment 128, wherein the decrease 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. Embodiment 139: The method according to embodiment 128, wherein the decrease in body weight is sustained for at least 8 days, for at least 15 days, for at least 22 days, for at least 29 days, for at least 50 days, for at least 52 days, or for at least 78 days after administration of GL0034 to the subject.

Embodiment 140: The method according to embodiment 128, wherein: (a) the decrease 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 decrease 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.

Embodiment 141: The method according to embodiment 128, wherein the decrease in leptin levels from baseline is dose dependent.

Embodiment 142: The method according to embodiment 128, wherein the change in leptin levels from 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.

Embodiment 143: The method according to embodiment 128, wherein the decrease in TG levels from baseline is observed at day 8 and is sustained for at least 51 days or for at least 78 days after administration of GL0034 to the subject.

Embodiment 144: The method according to embodiment 128, wherein: (a) the change in TG levels from 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 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 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.

Embodiment 145: The method according to embodiment 128, wherein the decrease in TC levels 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 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.

Embodiment 146: The method according to embodiment 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.

Embodiment 147: The method according to embodiment 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.

Embodiment 148: The method according to embodiment 128, wherein the clinically meaningful change from baseline in the subject is a decrease in blood pressure. Embodiment 149: The method according to embodiment 148, wherein the decrease in blood pressure is a decrease in systolic blood pressure.

Embodiment 150: The method according to embodiment 148, wherein the decrease in blood pressure is a decrease in diastolic blood pressure.

Embodiment 151: The method according to embodiment 149, 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 comprising 450 pg GL0034 once a week for at least 4 weeks.

Embodiment 152: The method according to embodiment 150, 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 comprising 450 pg at least GL0034 once a week for at least 4 weeks.

Embodiment 153: The method according to embodiment 148, wherein the decrease in blood pressure in the subject is greater as compared to the decrease in blood pressure following administration of: (a) 1.7 to 2.4 mg semaglutide once weekly; or (b) 5 to 15 mg tirzepatide once weekly.

Embodiment 154: The method according to any one of embodiments 87 to 153, wherein administration of GL0034 to the subject results a decrease in the frequency of adverse events (AEs) overtime in the subject.

Embodiment 155: The method according to embodiment 154, wherein the AEs are one or more of nausea, vomiting, and/or decreased appetite.

Embodiment 156: The method according to embodiment 154, wherein the decrease in the frequency of AEs is dose dependent.

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

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

Embodiment 159: The method according to embodiment 158, wherein the subject is obese. Embodiment 160: The method according to embodiment 159, wherein the subject is not diabetic.

Embodiment 161: The method according to embodiment 158, wherein the subject has a metabolic disorder. Embodiment 162: The method according to embodiment 161, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

Embodiment 163: The method according to embodiment 162, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

Embodiment 164: The method according to embodiment 161, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Embodiment 165: The method according to embodiment 164, wherein the metabolic disorder is type 2 diabetes.

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

Embodiment 167: The method according to embodiment 166, wherein GL0034 is administered to the subject by subcutaneous injection.

Embodiment 168: The method according to embodiment 167, wherein GL0034 is administered to the subject using an auto-injector or prefilled syringe.

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

Embodiment 170: The method according to embodiment 169, wherein administration of GL0034 results in a decrease in systolic blood pressure from baseline in the subject of at least about 18 mmHg or at least about 14% over a period of about 23 days after administration of GL0034.

Embodiment 171: The method according to embodiment 169, wherein administration of GL0034 results in a decrease in diastolic blood pressure from baseline in the subject of at least about 12 mmHg or at least about 14% over a period of about 23 days after administration of GL0034.

Embodiment 172: The method according to any one of embodiments 158 to 171, wherein the decrease in blood pressure in the subject is greater as compared to the decrease in blood pressure following administration of: (a) 1.7 to 2.4 mg semaglutide; or (b) 5 to 15 mg tirzepatide once weekly.

Embodiment 173: Use of GL0034 for the manufacture of a medicament for treating obesity in a subject.

Embodiment 174: The use according to embodiment 173, wherein the subject is not diabetic. Embodiment 175: The use according to either embodiment 173 or embodiment 174, wherein the subject has a body mass index (BMI) of at least 28 kg/m² or > 27 kg/m² with at least 1 weight-related comorbid condition. Embodiment 176: Use of GL0034 for the manufacture of a medicament for treating a metabolic disorder in a subject.

Embodiment 177: The use according to embodiment 176, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

Embodiment 178: The use according to embodiment 177, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

Embodiment 179: The use according to embodiment 176, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Embodiment 180: The use according to embodiment 179, wherein the metabolic disorder is type 2 diabetes.

Embodiment 181: The use according to any one of embodiments 173 to 180, wherein the subject has hypertension.

Embodiment 182: The use according to any one of embodiments 173 to 181, wherein the medicament is administered to the subject subcutaneously.

Embodiment 183: The use according to embodiment 182, wherein the medicament is administered to the subject by subcutaneous injection.

Embodiment 184: The use according to embodiment 183, wherein the medicament is administered to the subject using an auto-injector or prefilled syringe.

Embodiment 185: The use according to any one of embodiments 173 to 184, wherein a dose of the medicament comprises between 200 pg and 8000 pg GL0034.

Embodiment 186: The use according to embodiment 185, wherein the dose of the medicament comprises between 300 pg and 6000 pg GL0034.

Embodiment 187: The use according to embodiment 186, wherein the dose of the medicament comprises between 400 pg and 4000 pg GL0034.

Embodiment 188: The use according to embodiment 187, wherein the dose of the medicament comprises between 1000 pg and 3000 pg GL0034.

Embodiment 189: The use according to any one of embodiments 173 to 188, wherein the dose of the medicament is administered to the subject once a week or once every two weeks. Embodiment 190: The use according to any one of embodiments 173 to 188, wherein administration of the medicament to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 75 ng/mL and 1200 ng/mL.

Embodiment 191: The use according to any one of embodiments 173 to 188, wherein administration of the medicament to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 6200 ng*h/mL and 406300 ng*h/mL over a period of 22 days.

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

Embodiment 193: The use according to embodiment 192, wherein administration of the medicament to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 227 ng/mL and 367 ng/mL.

Embodiment 194: The use according to embodiment 192, wherein administration of the medicament to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 30313 ng*h/mL and 83082 ng*h/mL over a period of 22 days. Embodiment 195: The use according to any one of embodiments 173 to 193, wherein administration of the medicament to the subject results in a plasma drug half-life (ti/2) of GL0034 of between 90 hours and 120 hours.

Embodiment 196: The use according to embodiment 193, wherein administration of the medicament to the subject results in a plasma drug half-life (ti/2) of GL0034 of between 98 hours and 113 hours.

Embodiment 197: The use according to any one of embodiments 173 to 184, wherein the medicament is administered to the subject once a week or once every two weeks. Embodiment 198: The use according to any one of embodiments 173 to 184 or 197, wherein a dose of the medicament comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034.

Embodiment 199: The use according to embodiment 198, wherein the dose of the medicament is administered once a week or once every two weeks.

Embodiment 200: The use according to embodiment 198, wherein the dose of the medicament comprises 450 pg GL0034, and wherein administration of the medicament to the subject once a week for at least 4 weeks results in a mean maximum concentration (Cmax) of GL0034 of between 101 ng/mL and 142 ng/mL.

Embodiment 201 : The use according to embodiment 200, wherein administration of the medicament to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0334 of between 12814 ng*h/mL and 18537 ng*h/mL over a period of 22 days. Embodiment 202: The use according to embodiment 200, wherein administration of the medicament to the subject results in a plasma drug half-life (ti/2) of GL0034 of 102 hours by day 22. Embodiment 203: The use according to embodiment 198, wherein the dose of the medicament comprises 680 pg GL0034, and wherein administration of the medicament to the subject once a week for at least 4 weeks results in a mean maximum concentration (Cmax) of GL0034 of between 169 ng/mL and 267 ng/mL.

Embodiment 204: The use according to embodiment 203, wherein administration of the medicament to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 24576 ng*h/mL and 34537 ng*h/mL over a period of 22 days. Embodiment 205: The use according to embodiment 203, wherein administration of the medicament to the subject results in a plasma drug half-life (ti/2) of GL0034 of 123 hours by day 22.

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

Embodiment 207: The use according to any one of embodiments 173 to 184, wherein: (i) a dose of the medicament comprising 450 pg GL0034 is administered to the subject once a week for at least 2 weeks; (ii) a dose of the medicament comprising 900 pg GL0034 is administered to the subject once a week for at least 2 weeks; and (iii) a dose of the medicament comprising 1520 pg GL0034 is administered to the subject once a week for at least 4 weeks.

Embodiment 208: The use n according to embodiment 207, wherein administration of the medicament to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 112 ng/mL and 708 ng/mL.

Embodiment 209: The use according to embodiment 207, wherein administration of the medicament to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 12942 ng*h/mL and 76320 ng*h/mL over a period of 50 days. Embodiment 210: The use according to embodiment 207, wherein administration of the medicament to the subject results in a plasma drug half-life (ti/2) of GL0034 of 106.8 ± 33.7 hours by day 50. Embodiment 211 : The use according to any one of embodiments 173 to 184, wherein: (i) an initial dose of the medicament comprising between 200 pg and 680 pg GL0034 is administered to the subject for at least 4 weeks; (ii) an escalation dose of the medicament comprising between 680 pg and 900 pg GL0034 is administered to the subject once a week for at least 2 weeks; and (iii) a maintenance dose of the medicament comprising between 1500 pg and 2000 pg GL0034 is administered to the subject once a week for at least 2 weeks. Embodiment 212: The use according to any one of embodiments 173 to 184, wherein: (i) an initial dose of the medicament comprising between 450 pg and 680 pg GL0034 is administered to the subject for at least 4 weeks; and (ii) an escalation dose of the medicament comprising between 680 pg and 900 pg GL0034 is administered to the subject once a week for at least 2 weeks.

Embodiment 213: The use according to any one of embodiments 173 to 184, wherein: (i) an initial dose of the medicament comprising between 450 pg and 680 pg GL0034 is administered to the subject for at least 4 weeks; (ii) an escalation dose of the medicament comprising between 680 pg and 900 pg GL0034 is administered to the subject once a week for at least 2 weeks; and (iii) a maintenance dose of the medicament comprising between 1520 pg and 2000 pg GL0034 is administered to the subject once a week for at least 2 weeks. Embodiment 214: The use according to any one of embodiments 173 to 213, wherein administration of the medicament to the subject results in one or more clinically meaningful changes from baseline in the subject, wherein the clinically meaningful changes from baseline are a decrease in alanine transaminase (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 for insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin levels, a decrease in triglycerides (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 level (UCP-1) in brown adipose tissue (BAT) and/or white adipose tissue (WAT), and/or a decrease in blood pressure.

Embodiment 215: The use according to embodiment 214, wherein the decrease in ALT values from baseline is sustained for at least 23 days, for at least 52 days, or for at least 78 days after administration of the medicament to the subject. Embodiment 216: The use according to embodiment 214, wherein: (a) the change in ALT values from baseline is at least -9 U/L over a period of about 23 days after administration of a dose of the medicament 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 of the medicament comprising 680 pg GL0034 to the subject; 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 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.

Embodiment 217: The use according to embodiment 214, wherein the decrease in AST values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of the medicament to the subject.

Embodiment 218: The use according to embodiment 214, wherein the change in AST values 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 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.

Embodiment 219: The use according to embodiment 214, wherein the decrease in GGT values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of the medicament to the subject.

Embodiment 220: The use according to embodiment 214, wherein the change in GGT values 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 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.

Embodiment 221: The use according to embodiment 214, wherein the decrease in fasting insulin levels from baseline is sustained for at least 23 days or for at least 51 days after administration of the medicament to the subject.

Embodiment 222: The use according to embodiment 214, wherein the change in fasting insulin levels from baseline is at least -5 pmol/L over a period of about 23 days after administration of 680 pg GL0034 to the subject 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 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. Embodiment 223: The use according to embodiment 214, wherein the decrease in fasting glucose is sustained for at least 23 days or for at least 51 days after administration of the medicament to the subject.

Embodiment 224: The use according to embodiment 214, wherein the decrease in fasting glucose is at least -3 mg/dL over a period of about 23 days after administration of a dose of the medicament comprising 450 pg GL0034 to the subject once a week for at least 4 weeks; or at least -5 mg/dL over a period of about 23 days after administration of a dose of the medicament comprising 680 pg GL0034 to the subject 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 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. Embodiment 225: The use according to embodiment 214, wherein the decrease in body weight is sustained for at least 8 days, for at least 15 days, for at least 22 days, for at least 29 days, for at least 50 days, for at least 52 days, or for at least 78 days after administration of the medicament to the subject.

Embodiment 226: The use according to embodiment 214, wherein: (a) the decrease in body weight is at least -2 kg over a period of about 22 days after administration of a dose of the medicament comprising 2000 pg GL0034 to the subject; or at least -2 kg over a period of about 22 days after administration of a dose of the medicament comprising 1520 pg GL0034 to the subject; or at least -3 kg over a period of about 22 days after administration of a dose of the medicament comprising 2520 pg GL0034 to the subject; or at least -3 kg over a period of about 29 days after administration of a dose of the medicament comprising 450 pg GL0034 to the subject once a week for at least 4 weeks; or at least -4 kg over a period of about 29 days after administration of a dose of the medicament comprising 680 pg GL0034 to the subject once a week for at least 4 weeks; or (b) the decrease 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 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.

Embodiment 227: The use according to embodiment 214, wherein the decrease in leptin levels from baseline is dose dependent.

Embodiment 228: The use according to embodiment 214, wherein the change in leptin levels from baseline is at least -7 ng/mL over a period of about 8 days after administration of a dose of the medicament comprising 1520 pg GL0034 to the subject; or at least -11 ng/mL over a period of about 8 days after administration of a dose of the medicament comprising 2000 pg GL0034 to the subject; or at least -12 ng/mL over a period of about 8 days after administration of a dose of the medicament comprising 2520 pg GL0034 to the subject. Embodiment 229: The use according to embodiment 214, wherein the decrease in TG levels from baseline is observed at day 8 and is sustained for at least 51 days or for at least 78 days after administration of the medicament to the subject.

Embodiment 230: The use according to embodiment 214, wherein: (a) the change in TG levels from baseline is at least -1 mmol/L over a period of about 8 days after administration of a dose of the medicament 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 medicament comprising 2520 pg GL0034 to the subject; 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 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.

Embodiment 231: The use according to embodiment 214, wherein the decrease in TC levels 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 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.

Embodiment 232: The use according to embodiment 214, 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 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. Embodiment 233: The use according to embodiment 214, 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 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.

Embodiment 234: The use according to embodiment 214, wherein the clinically meaningful change from baseline in the subject is a decrease in blood pressure.

Embodiment 235: The use according to embodiment 234, wherein the decrease in blood pressure is a decrease in systolic blood pressure.

Embodiment 236: The use according to embodiment 234, wherein the decrease in blood pressure is a decrease in diastolic blood pressure.

Embodiment 237: The use according to embodiment 235, 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 medicament comprising 450 pg GL0034 once a week for at least 4 weeks.

Embodiment 238: The use according to embodiment 236, 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 medicament comprising 450 pg at least GL0034 once a week for at least 4 weeks.

Embodiment 239: The use according to embodiment 234, wherein the decrease in blood pressure in the subject is greater as compared to the decrease in blood pressure following administration of: (a) 1.7 to 2.4 mg semaglutide once weekly; or (b) 5 to 15 mg tirzepatide once weekly.

Embodiment 240: The use according to any one of embodiments 173 to 239, wherein administration of the medicament to the subject results a decrease in the frequency of adverse events (AEs) overtime in the subject.

Embodiment 241 : The use according to embodiment 240, wherein the AEs are one or more of nausea, vomiting, and/or decreased appetite.

Embodiment 242: The use according to embodiment 240, wherein the decrease in the frequency of AEs is dose dependent.

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

Embodiment 245: The use according to embodiment 244, wherein the subject is obese.

Embodiment 246: The use according to embodiment 245, wherein the subject is not diabetic.

Embodiment 247: The use according to embodiment 244, wherein the subject has a metabolic disorder.

Embodiment 248: The use according to embodiment 247, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

Embodiment 249: The use according to embodiment 248, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

Embodiment 250: The use according to embodiment 247, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Embodiment 251: The use according to embodiment 250, wherein the metabolic disorder is type 2 diabetes.

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

Embodiment 253: The use according to embodiment 252, wherein the medicament is administered to the subject by subcutaneous injection.

Embodiment 254: The use according to embodiment 253, wherein the medicament is administered to the subject using an auto-injector or prefilled syringe.

Embodiment 255: The use according to any one of embodiments 244 to 254, wherein a dose of the medicament comprising 450 pg GL0034 is administered to the subject.

Embodiment 256: The use according to embodiment 255, wherein administration of the medicament results in a decrease in systolic blood pressure from baseline in the subject of at least about 18 mmHg or at least about 14% over a period of about 23 days after administration of the medicament.

Embodiment 257: The use according to embodiment 255, wherein administration of the medicament results in a decrease in diastolic blood pressure from baseline in the subject of at least about 12 mmHg or at least about 14% over a period of about 23 days after administration of the medicament.

Embodiment 258: The use according to any one of embodiments 244 to 257, wherein the decrease in blood pressure in the subject is greater as compared to the decrease in blood pressure following administration of: (a) 1.7 to 2.4 mg semaglutide; or (b) 5 to 15 mg a Embodiment 259: A method of treating obesity in a subject, comprising administering a dose of 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg of GL0034 to the subject.

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

Embodiment 261 : The method according to embodiment 260, wherein the metabolic disorder is MASH, MASLD, diabetes, or hypertriglyceridemia.

Embodiment 262: The method according to either embodiment 259 or embodiment 260, wherein GL0034 is administered to the subject subcutaneously.

Embodiment 263: The method according to either embodiment 259 or embodiment 260, wherein GL0034 is administered to the subject as a single dose of 1520 pg, 2000 pg, or 2520 MS

Embodiment 264: The method according to embodiment 263, wherein the administration provides a mean maximum concentration (Cmax) of GL0034 between 226.9 ± 57.3 ng/mL and 367.0 ± 152.0 ng/mL.

Embodiment 265: The method according to embodiment 263, wherein the administration provides Area Under concentration-time Curve (AUCo-t) between 47,151.5 ± 16,838.6 ng*h/mL and 62,265.9 ± 20,816.5 ng*h/mL over the period of 22 days.

Embodiment 266: The method according to embodiment 263, wherein the administration provides plasma drug half-life (ti/2) between 98.5 ± 13.0 hours and 113.5 ± 22.9 hours. Embodiment 267: The method according to embodiment 263, wherein the administration provides time from administration to maximum plasma concentration (Tmax) is between 22.0 ± 6.9 hours and 31.0 ± 13.5 hours.

Embodiment 268: The method according to either embodiment 259 or embodiment 260, wherein GL0034 is administered to the subject as a multiple dose of 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg over the period of up to 8 weeks.

Embodiment 269: The method according to embodiment 268, wherein GL0034 is administered to the subject at a dose of 450 pg once weekly for 4 weeks.

Embodiment 270: The method according to embodiment 269, wherein the administration provides mean maximum concentration (Cmax) of GL0034 between 100.5 ± 22.0 ng/mL and 141.7 ± 34.6 ng/mL.

Embodiment 271 : The method according to embodiment 269, wherein the administration provides Area Under concentration-time Curve (AUCo-t) between 12814.2 ± 2652.1 ng*h/mL and 18536.8 ± 4608.2 ng*h/mL over the period of 22 days. Embodiment 272: The method according to embodiment 269, wherein the administration provides plasma drug half-life (ti/2) of 102.3 ± 15.4 hours on day 22.

Embodiment 273: The method according to embodiment 269, wherein the administration provides time from administration to maximum plasma concentration (Tmax) is between 36.0 ± 12.0 hours and 47.0 ± 16.0 hours.

Embodiment 274: The method according to embodiment 268, wherein GL0034 is administered to the subject at a dose of 680 pg once weekly for 4 weeks.

Embodiment 275: The method according to embodiment 274, wherein the administration provides mean maximum concentration (Cmax) of GL0034 between 169.0 ± 49.5 ng/mL and 267.0 ± 60.9 ng/mL.

Embodiment 276: The method according to embodiment 274, wherein the administration provides Area Under concentration-time Curve (AUCo-t) between 24575.9 ± 3391.2 ng*h/mL and 34536.6 ± 6445.0 ng*h/mL over the period of 22 days.

Embodiment 277: The method according to embodiment 274, wherein the administration provides plasma drug half-life (ti/2) of 122.9 ± 16.5 hours on day 22.

Embodiment 278: The method according to embodiment 274, wherein the administration provides time from administration to maximum plasma concentration (Tmax) is between 39.0 ± 21.0 hours and 54.0 ± 27.0 hours.

Embodiment 279: The method according to embodiment 268, wherein GL0034 is administered as (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.

Embodiment 280: The method according to embodiment 279, wherein the administration provides mean maximum concentration (Cmax) of GL0034 between 111.7 ± 23.7 ng/mL and 707.6 ± 251.7 ng/mL.

Embodiment 281 : The method according to embodiment 279, wherein the administration provides Area Under concentration-time Curve (AUCo-t) between 12942.2 ± 1517.5 ng*h/mL and 76320.4 ± 23334.6 ng*h/mL over the period of 50 days.

Embodiment 282: The method according to embodiment 279, wherein the administration provides plasma drug half-life (ti/2) of 106.8 ± 33.7 hours on day 50.

Embodiment 283: The method according to embodiment 279, wherein the administration provides time from administration to maximum plasma concentration (Tmax) is between 22.0 ± 16.0 hours and 41.0 ± 8.0 hours.

Embodiment 284: The method according to either embodiment 259 or embodiment 260, wherein administration of GL0034 results in one or more clinically meaningful changes from baseline in the subject, wherein the clinically meaningful changes from baseline are a decrease in body weight, a decrease in glycated hemoglobin (%HbAlc), an increase in high- density lipoprotein (HDL) levels, a decrease in alanine transaminase (ALT) values, a decrease in aspartate aminotransferase (AST) values, a decrease in gamma-glutamyl transferase (GGT) values, a decrease in triglycerides (TG) levels, a decrease in total cholesterol (TC) levels, a decrease in low -density lipoprotein (LDL) levels, a decrease in TG/HDL ratio, a decrease in fasting insulin levels, a decrease in fasting glucose levels, a decrease in homeostatic model assessment for insulin resistance (HOMA-IR) and/or a decrease in leptin levels.

Embodiment 285: The method of embodiment 284, wherein the change in fasting plasma glucose levels from baseline is by at least about -2.8 ± 3.7 mg/dL over the time period of about 23 days after the administration of 450 pg of GL0034 once weekly for 4 weeks. Embodiment 286: The method of embodiment 284, wherein the change in fasting plasma glucose levels from baseline is by at least about -4.6 ± 2.7 mg/dL over the time period of about 23 days after the administration of 680 pg of GL0034 once weekly for 4 weeks. Embodiment 287: The method of embodiment 284, wherein the change in fasting plasma glucose levels from baseline is by at least about -7.7 ± 9.9 mg/dL over the time period of about 51 days after the administration of GL0034 as: (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.

Embodiment 288: The method of embodiment 284, wherein the change in fasting insulin levels from baseline is by at least about -4.6 ± 23.0 pmol/L over the time period of about 23 days after the administration of 680 pg of GL0034 once weekly for 4 weeks.

Embodiment 289: The method of embodiment 284, wherein the change in fasting insulin levels from baseline is by at least about -11.3 ± 16.5 pmol/L over the time period of about 51 days after the administration of GL0034 as: (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.

Embodiment 290: The method of embodiment 284, wherein the change in ALT values from baseline is by at least about -8.8 ± 13.1 U/L over the time period of about 23 days after the administration of 450 pg of GL0034 once weekly for 4 weeks.

Embodiment 291: The method of embodiment 284, wherein the change in ALT values from baseline is by at least about -3.1 ± 5.8 U/L over the time period of about 23 days after the administration of 680 pg of GL0034 once weekly for 4 weeks. Embodiment 292: The method of embodiment 284, wherein the change in ALT values from baseline is by at least about -7.4 ± 10.3 U/L over the time period of about 51 days after the administration of GL0034 as: (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.

Embodiment 293: The method of embodiment 284, wherein the change in ALT values from baseline is by at least about -1.0 ± 9.4 U/L over the time period of about 78 days after the administration of GL0034 as: (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.

Embodiment 294: The method of embodiment 284, wherein the change in AST values from baseline is by at least about -4.0 ± 7.5 U/L over the time period of about 51 days after the administration of GL0034 as: (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.

Embodiment 295: The method of embodiment 284, wherein the change in AST values from baseline is by at least about -1.1 ± 6.7 U/L over the time period of about 78 days after the administration of GL0034 as: (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.

Embodiment 296: The method of embodiment 284, wherein the change in GGT values from baseline is by at least about -3.4 ± 3.5 U/L over the time period of about 51 days after the administration of GL0034 as: (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.

Embodiment 297: The method of embodiment 284, wherein the change in GGT values from baseline is by at least about -1.0 ± 2.7 U/L over the time period of about 78 days after the administration of GL0034 as: (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.

Embodiment 298: The method of embodiment 284, wherein the change in body weight from baseline is by at least about -3.4 ± 1.8 kg over the time period of about 29 days after the administration of 450 pg of GL0034 once weekly for 4 weeks.

Embodiment 299: The method of embodiment 284, wherein the change in body weight from baseline is by at least about -4.1 ± 1.0 kg over the time period of about 29 days after the administration of 680 pg of GL0034 once weekly for 4 weeks.

Embodiment 300: The method of embodiment 284, wherein the change in body weight from baseline is by at least about -7.7 ± 1.9 kg over the time period of about 52 days after the administration of GL0034 as: (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. Embodiment 301: The method of embodiment 284, wherein the change in body weight from baseline is by at least about -6.4 ± 2.1 kg over the time period of about 78 days after the administration of GL0034 as: (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. Embodiment 302: The method of embodiment 284, wherein the change in %HbAlc from baseline is by at least about -0.25 ± 0.2 over the time period of about 78 days after the administration of GL0034 as: (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. Embodiment 303: The method of embodiment 284, wherein the change in TG levels from baseline is by at least about -21.0 ± 27.5 mg/dL over the time period of about 51 days after the administration of GL0034 as: (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. Embodiment 304: The method of embodiment 284, wherein the change in TG levels from baseline is by at least about -11.0 ± 55.3 mg/dL over the time period of about 78 days after the administration of GL0034 as: (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.

Embodiment 305: The method of embodiment 284, wherein the change in TC levels from baseline is by at least about -29.1 ± 23.3 mg/dL over the time period of about 51 days after the administration of GL0034 as: (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. Embodiment 306: The method of embodiment 284, wherein the change in TC levels from baseline is by at least about -5.8 ± 12.6 mg/dL over the time period of about 78 days after the administration of GL0034 as: (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. Embodiment 307: The method of embodiment 284, wherein the change in LDL levels from baseline is by at least about -24.0 ± 24.3 mg/dL over the time period of about 51 days after the administration of GL0034 as: (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. Embodiment 308: The method of embodiment 284, wherein the change in LDL levels from baseline is by at least about -19.5 ± 35.8 mg/dL over the time period of about 78 days after the administration of GL0034 as: (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.

Embodiment 309: The method of embodiment 846, wherein the change in HDL levels from baseline is by at least about 2.9 ± 3.1 mg/dL over the time period of about 78 days after the administration of GL0034 as: (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.

Embodiment 310: The method of embodiment 284, wherein the change in body weight from baseline is by at least about -2.4 ± 2.2 kg over the time period of about 22 days after the administration of GL0034 as a single dose of 1520 pg.

Embodiment 311: The method of embodiment 284, wherein the change in body weight from baseline is by at least about -1.8 ± 2.4 kg over the time period of about 22 days after the administration of GL0034 as a single dose of 2000 pg.

Embodiment 312: The method of embodiment 284, wherein the change in body weight from baseline is by at least about -3.1 ± 1.7 kg over the time period of about 22 days after the administration of GL0034 as a single dose of 2520 pg.

Embodiment 313: The method of embodiment 284, wherein the change in TG levels from baseline is by at least about -0.4 ± 0.4 mmol/L over the time period of about 8 days after the administration of GL0034 as a single dose of 1520 pg.

Embodiment 314: The method of embodiment 284, wherein the change in TG levels from baseline is by at least about -0.8 ± 0.5 mmol/L over the time period of about 8 days after the administration of GL0034 as a single dose of 2000 pg.

Embodiment 315: The method of embodiment 284, wherein the change in TG levels from baseline is by at least about -0.5 ± 0.5 mmol/L over the time period of about 22 days after the administration of GL0034 as a single dose of 2520 pg.

Embodiment 316: The method of embodiment 284, wherein the change in leptin levels from baseline is by at least about -6.9 ± 5.1 ng/mL over the time period of about 8 days after the administration of GL0034 as a single dose of 1520 pg.

Embodiment 317: The method of embodiment 284, wherein the change in leptin levels from baseline is by at least about -10.9 ± 8.6 ng/mL over the time period of about 8 days after the administration of GL0034 as a single dose of 2000 pg.

Embodiment 318: The method of embodiment 284, wherein the change in leptin levels from baseline is by at least about -11.6 ± 12.8 ng/mL over the time period of about 8 days after the administration of GL0034 as a single dose of 2520 pg.

Embodiment 319: The method according to either embodiment 259 or embodiment 260, comprising: administering an initial dose for a minimum of at least about 2 weeks; administering an escalation dose once weekly for a minimum of at least about 2 weeks; and administering a maintenance dose once weekly for a minimum of at least about 4 weeks; wherein the initial dose is about 450 pg or about 680 pg: the escalation dose is about 680 pg or about 900 pg; and the maintenance dose is about 1520 pg or about 2000 pg.

Embodiment 320: The method according to either embodiment 259 or embodiment 260, comprising: administering an initial dose for a minimum of at least about 4 weeks; and administering an escalation dose once weekly for a minimum of at least about 2 weeks; wherein the initial dose is about 450 pg or about 680 pg; and the escalation dose is about 680 pg or about 900 pg.

Embodiment 321: The method according to either embodiment 259 or embodiment 260, comprising: administering an initial dose for a minimum of at least about 4 weeks; administering an escalation dose once weekly for a minimum of at least about 2 weeks; and administering a maintenance dose once weekly for a minimum of at least about 2 weeks; wherein the initial dose is about 450 pg or about 680 pg; the escalation dose is about 680 pg or about 900 pg; and the maintenance dose is about 1520 pg or about 2000 pg.

Embodiment 322: A pharmaceutical composition of GL0034 for the treatment of 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.

Embodiment 323: A pharmaceutical composition of GL0034 for the treatment of 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.

Embodiment 324: The pharmaceutical composition according to embodiment 323, wherein the metabolic disorder is MASH, MASLD, diabetes, or hypertriglyceridemia.

Embodiment 325: The pharmaceutical composition according to either embodiment 322 or embodiment 323, wherein the pharmaceutical composition is administered to the subject subcutaneously.

Embodiment 326: The pharmaceutical composition according to either 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.

Embodiment 327: The pharmaceutical composition according to embodiment 326, wherein administration of the pharmaceutical composition results in a mean maximum concentration (Cmax) of GL0034 of between 226.9 ± 57.3 ng/mL and 367.0 ± 152.0 ng/mL.

Embodiment 328: The pharmaceutical composition according to embodiment 326, wherein administration of the pharmaceutical composition results in an Area Under concentration- time Curve (AUCo-t) ofbetween 47,151.5 ± 16,838.6 ng*h/mL and 62,265.9 ± 20,816.5 ng*h/mL over a period of 22 days.

Embodiment 329: The pharmaceutical composition according to embodiment 326, wherein administration of the pharmaceutical composition results in a plasma drug half-life (ti/2) of between 98.5 ± 13.0 hours and 113.5 ± 22.9 hours.

Embodiment 330: The pharmaceutical composition according to embodiment 326, wherein administration of the pharmaceutical composition results in a time from administration to maximum plasma concentration (Tmax) ofbetween 22.0 ± 6.9 hours and 31.0 ± 13.5 hours. Embodiment 331: The pharmaceutical composition according to either embodiment 322 or embodiment 323, wherein the dose of the pharmaceutical composition comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034, and wherein multiple doses of the pharmaceutical composition are administered to the subject over a period of up to 8 weeks. Embodiment 332: The pharmaceutical composition according to embodiment 331, wherein GL0034 is administered to the subject at a dose of 450 pg once weekly for 4 weeks. Embodiment 333: The pharmaceutical composition according to embodiment 332, wherein administration of the pharmaceutical composition results in a mean maximum concentration (Cmax) of GL0034 ofbetween 100.5 ± 22.0 ng/mL and 141.7 ± 34.6 ng/mL.

Embodiment 334: The pharmaceutical composition according to embodiment 332, wherein administration of the pharmaceutical composition results in an Area Under concentrationtime Curve (AUCo-t) ofbetween 12814.2 ± 2652.1 ng*h/mL and 18536.8 ± 4608.2 ng*h/mL over a period of 22 days.

Embodiment 335: The pharmaceutical composition according to embodiment 332, wherein administration of the pharmaceutical composition results in a plasma drug half-life (ti/2) of 102.3 ± 15.4 hours on day 22.

Embodiment 336: The pharmaceutical composition according to embodiment 332, wherein administration of the pharmaceutical composition results in a time from administration to maximum plasma concentration (Tmax) ofbetween 36.0 ± 12.0 hours and 47.0 ± 16.0 hours. Embodiment 337: The pharmaceutical composition according to embodiment 331, wherein a dose of the pharmaceutical composition comprises 680 pg, and wherein the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

Embodiment 338: The pharmaceutical composition according to embodiment 337, wherein administration of the pharmaceutical composition results in a mean maximum concentration (Cmax) of GL0034 ofbetween 169.0 ± 49.5 ng/mL and 267.0 ± 60.9 ng/mL. Embodiment 339: The pharmaceutical composition according to embodiment 337, wherein administration of the pharmaceutical composition results in an Area Under concentrationtime Curve (AUCo-t) ofbetween 24575.9 ± 3391.2 ng*h/mL and 34536.6 ± 6445.0 ng*h/mL over a period of 22 days.

Embodiment 340: The pharmaceutical composition according to embodiment 337, wherein administration of the pharmaceutical composition results in a plasma drug half-life (ti/2) of 122.9 ± 16.5 hours on day 22.

Embodiment 341: The pharmaceutical composition according to embodiment 337, wherein administration of the pharmaceutical composition results in a time from administration to maximum plasma concentration (Tmax) ofbetween 39.0 ± 21.0 hours and 54.0 ± 27.0 hours. Embodiment 342: The pharmaceutical composition according to embodiment 331, wherein: (i) a first dose of the pharmaceutical composition comprises 450 pg 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 pg 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 pg GL0034, wherein the third dose of the pharmaceutical composition is administered to the subject once a week for 4 weeks.

Embodiment 343: The pharmaceutical composition according to embodiment 342, wherein administration of the pharmaceutical composition results in a mean maximum concentration (Cmax) ofGL0034 ofbetween 111.7 ± 23.7 ng/mL and 707.6 ± 251.7 ng/mL.

Embodiment 344: The pharmaceutical composition according to embodiment 342, wherein administration of the pharmaceutical composition results in an Area Under concentrationtime Curve (AUCo-t) ofbetween 12942.2 ± 1517.5 ng*h/mL and 76320.4 ± 23334.6 ng*h/mL over a period of 50 days.

Embodiment 345: The pharmaceutical composition according to embodiment 342, wherein administration of the pharmaceutical composition results in a plasma drug half-life (ti/2) of 106.8 ± 33.7 hours on day 50.

Embodiment 346: The pharmaceutical composition according to embodiment 342, wherein administration of the pharmaceutical composition results in a time from administration to maximum plasma concentration (Tmax) ofbetween 22.0 ± 16.0 hours and 41.0 ± 8.0 hours. Embodiment 347: The pharmaceutical composition according to either embodiment 322 or embodiment 323, wherein administration of the pharmaceutical composition results in one or more clinically meaningful changes from baseline in the subject, wherein the clinically meaningful changes from baseline are a decrease in body weight, a decrease in glycated hemoglobin (%HbAlc), an increase in high-density lipoprotein (HDL) levels, a decrease in alanine transaminase (ALT) values, a decrease in aspartate aminotransferase (AST) values, a decrease in gamma-glutamyl transferase (GGT) values, a decrease in triglycerides (TG) levels, a decrease in total cholesterol (TC) levels, a decrease in low-density lipoprotein (LDL) levels, a decrease in TG/HDL ratio, a decrease in fasting insulin levels, a decrease in fasting glucose levels, a decrease in homeostatic model assessment for insulin resistance (HOMA- IR) and/or a decrease in leptin levels.

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

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

Embodiment 350: The pharmaceutical composition of embodiment 347, wherein the change in fasting plasma glucose levels from baseline is by at least about -7.7 ± 9.9 mg/dL over a time 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 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.

Embodiment 351: The pharmaceutical composition of embodiment 347, wherein the change in fasting insulin levels from baseline is by at least about -4.6 ± 23.0 pmol/L over a time 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 weekly for 4 weeks.

Embodiment 352: The pharmaceutical composition of embodiment 347, wherein the change in fasting insulin levels from baseline is by at least about -11.3 ± 16.5 pmol/L over a time period of about 51 days after administration of: (i) a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition ia 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.

Embodiment 353: The pharmaceutical composition of embodiment 347, wherein the change in ALT values from baseline is by at least about -8.8 ± 13.1 U/L over a time 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 weekly for 4 weeks.

Embodiment 354: The pharmaceutical composition of embodiment 347, wherein the change in ALT values from baseline is by at least about -3. 1 ± 5.8 U/L over a time 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 weekly for 4 weeks.

Embodiment 355: The pharmaceutical composition of embodiment 347, wherein the change in ALT values from baseline is by at least about -7.4 ± 10.3 U/L over a time 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.

Embodiment 356: The pharmaceutical composition of embodiment 347, wherein the change in ALT values from baseline is by at least about -1.0 ± 9.4 U/L over a time 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.

Embodiment 357: The pharmaceutical composition of embodiment 347, wherein the change in AST values from baseline is by at least about -4.0 ± 7.5 U/L over a time 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.

Embodiment 358: The pharmaceutical composition of embodiment 347, wherein the change in AST values from baseline is by at least about -1. 1 ± 6.7 U/L over a time 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.

Embodiment 359: The pharmaceutical composition of embodiment 347, wherein the change in GGT values from baseline is by at least about -3.4 ± 3.5 U/L over a time 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.

Embodiment 360: The pharmaceutical composition of embodiment 347, wherein the change in GGT values from baseline is by at least about -1.0 ± 2.7 U/L over a time 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.

Embodiment 361: The pharmaceutical composition of embodiment 347, wherein the change in body weight from baseline is by at least about -3.4 ± 1.8 kg over a time period of about 29 days after administration of a dose of the pharmaceutical composition comprising 450 pg GL0034, wherein the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

Embodiment 362: The pharmaceutical composition of embodiment 347, wherein the change in body weight from baseline is by at least about -4. 1 ± 1.0 kg over a time period of about 29 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034, wherein the pharmaceutical composition is administered to the subject once weekly for 4 weeks.

Embodiment 363: The pharmaceutical composition of embodiment 347, wherein the change in body weight from baseline is by at least about -7.7 ± 1.9 kg over a time period of about 52 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.

Embodiment 364: The pharmaceutical composition of embodiment 347, wherein the change in body weight from baseline is by at least about -6.4 ± 2. 1 kg over a time 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.

Embodiment 365: The pharmaceutical composition of embodiment 347, wherein the change in %HbAlc from baseline is by at least about -0.25 ± 0.2 over a time 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.

Embodiment 366: The pharmaceutical composition of embodiment 347, wherein the change in TG levels from baseline is by at least about -21.0 ± 27.5 mg/dL over a time 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.

Embodiment 367: The pharmaceutical composition of embodiment 347, wherein the change in TG levels from baseline is by at least about -11.0 ± 55.3 mg/dL over a time 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.

Embodiment 368: The pharmaceutical composition of embodiment 347, wherein the change in TC levels from baseline is by at least about -29. 1 ± 23.3 mg/dL over a time 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. Embodiment 369: The pharmaceutical composition of embodiment 347, wherein the change in TC levels from baseline is by at least about -5.8 ± 12.6 mg/dL over a time 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.

Embodiment 370: The pharmaceutical composition of embodiment 347, wherein the change in LDL levels from baseline is by at least about -24.0 ± 24.3 mg/dL over a time 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.

Embodiment 371: The pharmaceutical composition of embodiment 347, wherein the change in LDL levels from baseline is by at least about -19.5 ± 35.8 mg/dL over a time 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.

Embodiment 372: The pharmaceutical composition of embodiment 347, wherein the change in HDL levels from baseline is by at least about 2.9 ± 3. 1 mg/dL over a time 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.

Embodiment 373: The pharmaceutical composition of embodiment 347, wherein the change in body weight from baseline is by at least about -2.4 ± 2.2 kg over a time period of about 22 days after administration of a single dose of the pharmaceutical composition comprising 1520 pg GL0034.

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

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

Embodiment 376: The pharmaceutical composition of embodiment 347, wherein the change in TG levels from baseline is by at least about -0.4 ± 0.4 mmol/L over a time period of about 8 days after administration of a single dose of the pharmaceutical composition comprising 1520 pg GL0034.

Embodiment 377: The pharmaceutical composition of embodiment 347, wherein the change in TG levels from baseline is by at least about -0.8 ± 0.5 mmol/L over a time period of about 8 days after administration of a single dose of t he pharmaceutical composition comprising 2000 pg GL0034.

Embodiment 378: The pharmaceutical composition of embodiment 347, wherein the change in TG levels from baseline is by at least about -0.5 ± 0.5 mmol/L over a time period of about 22 days after administration of a single dose of the pharmaceutical composition comprising 2520 pg GL0034.

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

Embodiment 380: The pharmaceutical composition of embodiment 347, wherein the change in leptin levels from baseline is by at least about -10.9 ± 8.6 ng/mL over a time period of about 8 days after administration of a single dose of the pharmaceutical composition comprising 2000 pg GL0034. Embodiment 381: The pharmaceutical composition of embodiment 347, wherein the change in leptin levels from baseline is by at least about -11.6 ± 12.8 ng/mL over a time period of about 8 days after administration of a single dose of the pharmaceutical composition comprising 2520 pg GL0034.

Embodiment 382: The pharmaceutical composition according to either embodiment 322 or embodiment 323, wherein an initial dose of the pharmaceutical composition comprising about 450 pg or about 680 pg GL0034 is administered to the subject for at least about 2 weeks; wherein an escalation dose of the pharmaceutical composition comprising about 680 pg or about 900 pg GL0034 is administered to the subject once weekly for a minimum of at least about 2 weeks; and wherein a maintenance dose of the pharmaceutical composition comprising about 1520 pg or about 2000 pg GL0034 is administered to the subject once weekly for a minimum of at least about 4 weeks.

Embodiment 383: The pharmaceutical composition according to either embodiment 322 or embodiment 323, wherein an initial dose of the pharmaceutical composition comprising about 450 pg or about 680 pg GL0034 is administered to the subject for a minimum of at least about 4 weeks; and wherein an escalation dose of the pharmaceutical composition comprising about 680 pg or about 900 pg GL0034 is administered to the subject once weekly for a minimum of at least about 2 weeks.

Embodiment 384: The pharmaceutical composition according to either embodiment 322 or embodiment 323, wherein an initial dose of the pharmaceutical composition comprising about 450 pg or about 680 pg GL0034 is administered to the subject for a minimum of at least about 4 weeks; wherein an escalation dose of the pharmaceutical composition comprising about 680 pg or about 900 pg GL0034 is administered to the subject once weekly for a minimum of at least about 2 weeks; and wherein a maintenance dose of the pharmaceutical composition comprising about 1520 pg or about 2000 pg GL0034 is administered to the subject once weekly for a minimum of at least about 2 weeks.

Embodiment 385: Use of GL0034 for the manufacture of a medicament for treating 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.

Embodiment 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.

Embodiment 387: The use according to embodiment 386, wherein the metabolic disorder is MASH, MASLD, diabetes, or hypertriglyceridemia. Embodiment 388: The use according to either embodiment 385 or embodiment 386, wherein the medicament is administered to the subject subcutaneously.

Embodiment 389: The use according to either embodiment 385 or embodiment 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.

Embodiment 390: The use according to embodiment 389, wherein administration of the medicament results in a mean maximum concentration (Cmax) of GL0034 of between 226.9 ± 57.3 ng/mL and 367.0 ± 152.0 ng/mL.

Embodiment 391: The use according to embodiment 389, wherein administration of the medicament results in an Area Under concentration-time Curve (AUCo-t) of between 47,151.5 ± 16,838.6 ng*h/mL and 62,265.9 ± 20,816.5 ng*h/mL over a period of 22 days. Embodiment 392: The use according to embodiment 389, wherein administration of the medicament results in a plasma drug half-life (ti/2) of between 98.5 ± 13.0 hours and 113.5 ± 22.9 hours.

Embodiment 393: The use according to embodiment 389, wherein administration of the medicament results in a time from administration to maximum plasma concentration (Tmax) of between 22.0 ± 6.9 hours and 31.0 ± 13.5 hours.

Embodiment 394: The use according to either embodiment 385 or embodiment 386, wherein the dose of the medicament comprises 450 pg, 680 pg, 900 pg, 1520 pg, 2000 pg, or 2520 pg GL0034, and wherein multiple doses of the medicament are administered to the subject over a period of up to 8 weeks.

Embodiment 395: The use according to embodiment 394, wherein GL0034 is administered to the subject at a dose of 450 pg once weekly for 4 weeks.

Embodiment 396: The use according to embodiment 395, wherein administration of the medicament results in a mean maximum concentration (Cmax) of GL0034 of between 100.5 ± 22.0 ng/mL and 141.7 ± 34.6 ng/mL.

Embodiment 397: The use according to embodiment 395, wherein administration of the medicament results in an Area Under concentration-time Curve (AUCo-t) of between 12814.2 ± 2652.1 ng*h/mL and 18536.8 ± 4608.2 ng*h/mL over a period of 22 days.

Embodiment 398: The use according to embodiment 395, wherein administration of the medicament results in a plasma drug half-life (ti/2) of 102.3 ± 15.4 hours on day 22. Embodiment 399: The use according to embodiment 395, wherein administration of the medicament results in a time from administration to maximum plasma concentration (Tmax) of between 36.0 ± 12.0 hours and 47.0 ± 16.0 hours. Embodiment 400: The use according to embodiment 394, wherein a dose of the medicament comprises 680 pg, and wherein the medicament is administered to the subject once weekly for 4 weeks.

Embodiment 401 : The use according to embodiment 400, wherein administration of the medicament results in a mean maximum concentration (Cmax) of GL0034 of between 169.0 ± 49.5 ng/mL and 267.0 ± 60.9 ng/mL.

Embodiment 402: The use according to embodiment 400, wherein administration of the medicament results in an Area Under concentration-time Curve (AUCo-t) of between 24575.9 ± 3391.2 ng*h/mL and 34536.6 ± 6445.0 ng*h/mL over a period of 22 days.

Embodiment 403: The use according to embodiment 400, wherein administration of the medicament results in a plasma drug half-life (ti/2) of 122.9 ± 16.5 hours on day 22. Embodiment 404: The use according to embodiment 400, wherein administration of the medicament results in a time from administration to maximum plasma concentration (Tmax) of between 39.0 ± 21.0 hours and 54.0 ± 27.0 hours.

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

Embodiment 406: The use according to embodiment 405, wherein administration of the medicament results in a mean maximum concentration (Cmax) of GL0034 of between 111.7 ± 23.7 ng/mL and 707.6 ± 251.7 ng/mL.

Embodiment 407: The use according to embodiment 405, wherein administration of the medicament results in an Area Under concentration-time Curve (AUCo-t) of between 12942.2 ± 1517.5 ng*h/mL and 76320.4 ± 23334.6 ng*h/mL over a period of 50 days.

Embodiment 408: The use according to embodiment 405, wherein administration of the medicament results in a plasma drug half-life (ti/2) of 106.8 ± 33.7 hours on day 50. Embodiment 409: The use according to embodiment 327, wherein administration of the medicament results in a time from administration to maximum plasma concentration (Tmax) of between 22.0 ± 16.0 hours and 41.0 ± 8.0 hours.

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

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

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

Embodiment 413: The use of embodiment 410, wherein the change in fasting plasma glucose levels from baseline is by at least about -7.7 ± 9.9 mg/dL over a time period of about 51 days after 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 to the subject once a week for 2 weeks; and (iii) a dose of the medicament comprising 1520 pg, wherein the medicament is administered to the subject once a week for 4 weeks.

Embodiment 414: The use of embodiment 410, wherein the change in fasting insulin levels from baseline is by at least about -4.6 ± 23.0 pmol/L over a time period of about 23 days after administration of a dose of the medicament comprising 680 pg GL0034., wherein the medicament is administered to the subject once weekly for 4 weeks.

Embodiment 415: The use of embodiment 410, wherein the change in fasting insulin levels from baseline is by at least about -11.3 ± 16.5 pmol/L over a time period of about 51 days after administration of: (i) a dose of the medicament comprising 450 pg GL0034, wherein the medicament ia 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 Embodiment 416: The use of embodiment 410, wherein the change in ALT values from baseline is by at least about -8.8 ± 13.1 U/L over a time period of about 23 days after administration of a dose of the medicament comprising 450 pg GL0034, wherein the medicament is administered to the subject once weekly for 4 weeks.

Embodiment 417: The use of embodiment 410, wherein the change in ALT values from baseline is by at least about -3.1 ± 5.8 U/L over a time period of about 23 days after administration of a dose of the medicament comprising 680 pg GL0034, wherein the medicament is administered to the subject once weekly for 4 weeks.

Embodiment 418: The use of embodiment 410, wherein the change in ALT values from baseline is by at least about -7.4 ± 10.3 U/L over a time 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 Embodiment 419: The use of embodiment 410, wherein the change in ALT values from baseline is by at least about - 1.0 ± 9.4 U/L over a time 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 Embodiment 420: The use of embodiment 410, wherein the change in AST values from baseline is by at least about -4.0 ± 7.5 U/L over a time 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 Embodiment 421: The use of embodiment 410, wherein the change in AST values from baseline is by at least about -1.1 ± 6.7 U/L over a time 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 Embodiment 422: The use of embodiment 410, wherein the change in GGT values from baseline is by at least about -3.4 ± 3.5 U/L over a time 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 Embodiment 423: The use of embodiment 410, wherein the change in GGT values from baseline is by at least about -1.0 ± 2.7 U/L over a time 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 Embodiment 424: The use of embodiment 410, wherein the change in body weight from baseline is by at least about -3.4 ± 1.8 kg over a time 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 weekly for 4 weeks.

Embodiment 425: The use of embodiment 410, wherein the change in body weight from baseline is by at least about -4.1 ± 1.0 kg over a time 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 weekly for 4 weeks.

Embodiment 426: The use of embodiment 410, wherein the change in body weight from baseline is by at least about -7.7 ± 1.9 kg over a time 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 Embodiment 427: The use of embodiment 410, wherein the change in body weight from baseline is by at least about -6.4 ± 2.1 kg over a time 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 Embodiment 428: The use of embodiment 410, wherein the change in %HbAlc from baseline is by at least about -0.25 ± 0.2 over a time 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 Embodiment 429: The use of embodiment 410, wherein the change in TG levels from baseline is by at least about -21.0 ± 27.5 mg/dL over a time 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 Embodiment 430: The use of embodiment 410, wherein the change in TG levels from baseline is by at least about -11.0 ± 55.3 mg/dL over a time 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 Embodiment 431: The use of embodiment 410, wherein the change in TC levels from baseline is by at least about -29. 1 ± 23.3 mg/dL over a time 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 Embodiment 432: The use of embodiment 410, wherein the change in TC levels from baseline is by at least about -5.8 ± 12.6 mg/dL over a time 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 Embodiment 433: The use of embodiment 410, wherein the change in LDL levels from baseline is by at least about -24.0 ± 24.3 mg/dL over a time 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 Embodiment 434: The use of embodiment 410, wherein the change in LDL levels from baseline is by at least about -19.5 ± 35.8 mg/dL over a time 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 Embodiment 435: The use of embodiment 410, wherein the change in HDL levels from baseline is by at least about 2.9 ± 3.1 mg/dL over a time 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 Embodiment 436: The use of embodiment 410, wherein the change in body weight from baseline is by at least about -2.4 ± 2.2 kg over a time period of about 22 days after administration of a single dose of the medicament comprising 1520 pg GL0034. Embodiment 437: The use of embodiment 410, wherein the change in body weight from baseline is by at least about -1.8 ± 2.4 kg over a time period of about 22 days after administration of a single dose of the medicament comprising 2000 pg GL0034.

Embodiment 438: The use of embodiment 410, wherein the change in body weight from baseline is by at least about -3.1 ± 1.7 kg over a time period of about 22 days after administration of a single dose of the medicament comprising 2520 pg GL0034.

Embodiment 439: The medicament of embodiment 410, wherein the change in TG levels from baseline is by at least about -0.4 ± 0.4 mmol/L over a time period of about 8 days after administration of a single dose of the medicament comprising 1520 pg GL0034.

Embodiment 440: The use of embodiment 410, wherein the change in TG levels from baseline is by at least about -0.8 ± 0.5 mmol/L over a time period of about 8 days after administration of a single dose of the medicament comprising 2000 pg GL0034. Embodiment 441: The use of embodiment 410, wherein the change in TG levels from baseline is by at least about -0.5 ± 0.5 mmol/L over a time period of about 22 days after administration of a single dose of the medicament comprising 2520 pg GL0034.

Embodiment 442: The use of embodiment 410, wherein the change in leptin levels from baseline is by at least about -6.9 ± 5.1 ng/mL over a time period of about 8 days after administration of a single dose of the medicament comprising 1520 pg GL0034.

Embodiment 443: The use of embodiment 410, wherein the change in leptin levels from baseline is by at least about -10.9 ± 8.6 ng/mL over a time period of about 8 days after administration of a single dose of the medicament comprising 2000 pg GL0034.

Embodiment 444: The use of embodiment 410, wherein the change in leptin levels from baseline is by at least about -11.6 ± 12.8 ng/mL over a time period of about 8 days after administration of a single dose of the medicament comprising 2520 pg GL0034.

Embodiment 445: The use according to either embodiment 385 or embodiment 386, wherein an initial dose of the medicament comprising about 450 pg or about 680 pg GL0034 is administered to the subject for at least about 2 weeks; wherein an escalation dose of the medicament comprising about 680 pg or about 900 pg GL0034 is administered to the subject once weekly for a minimum of at least about 2 weeks; and wherein a maintenance dose of the medicament comprising about 1520 pg or about 2000 pg GL0034 is administered to the subject once weekly for a minimum of at least about 4 weeks.

Embodiment 446: The use according to either embodiment 385 or embodiment 386, wherein an initial dose of the medicament comprising about 450 pg or about 680 pg GL0034 is administered to the subject for a minimum of at least about 4 weeks; and wherein an escalation dose of the medicament comprising about 680 pg or about 900 pg GL0034 is administered to the subject once weekly for a minimum of at least about 2 weeks.

Embodiment 447: The use according to either embodiment 385 or embodiment 386, wherein an initial dose of the medicament comprising about 450 pg or about 680 pg GL0034 is administered to the subject for a minimum of at least about 4 weeks; wherein an escalation dose of the medicament comprising about 680 pg or about 900 pg GL0034 is administered to the subject once weekly for a minimum of at least about 2 weeks; and wherein a maintenance dose of the medicament comprising about 1520 pg or about 2000 pg GL0034 is administered to the subject once weekly for a minimum of at least about 2 weeks.

EXAMPLES

The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only and should not be construed as limiting the scope of the disclosure in any way.

GL0034 was administered as a subcutaneous injection in the abdominal wall. The qualitative & quantitative composition is represented as below:

Example 1: Safety, Tolerability, Pharmacodynamic, and Pharmacokinetics of GL0034 in Normal Weight Subjects

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. Repeated ascending doses of GL0034 were administered by subcutaneous injection in healthy young male (BMI between about 18 and about 28 kg/m²) subjects.

Nine healthy male subjects (aged between 18 and 40 years old) received GL0034, as 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. In total twenty-seven healthy subjects received GL0034 as multiple doses, and nine subjects received placebo.

Subjects were randomly assigned to receive one of three doses:

Group 1: GL0034 (450 pg) or placebo as a single subcutaneous injection in the abdominal wall, weekly for 4 weeks;

Group 2: GL0034 (680pg) or placebo as a single subcutaneous injection in the abdominal wall, weekly for 4 weeks; or

Group 3: Two doses of GL0034 (450 pg) or placebo as a single subcutaneous injection in the abdominal wall, weekly for 2 weeks. This was followed by two doses of GL0034 (900 pg) or placebo as a single subcutaneous injection in the abdominal wall, weekly for 2 weeks. This was followed by four doses of GL0034 (1520 pg) or placebo as a single subcutaneous injection 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).

The safety and tolerability of multiple ascending doses of GL0034 was determined in Groups 1-3, which are described above and further demonstrated in the timeline as shown in Figure 1. Safety biomarkers and key exploratory pharmacodynamic effects including fasting insulin and glucose, alanine transaminase and body weight were assessed.

Results

GL0034 related adverse effects were gastrointestinal with dose-dependent nausea, vomiting and decreased appetite. Fasting insulin (Table 1) was decreased in Group 2 and Group 3 on day 23 and 51 respectively following treatment with GL0034 with a corresponding reduction in homeostatic model assessment for insulin resistance (HOMA-IR) (Figures 4, 5). At day 51, alanine transaminase levels decreased from baseline in Group 3 versus an increase in placebo (Figure 3, Table 1). Dose-dependent decreases in body weight was measured in all groups, compared to baseline, and were sustained through days 50 and 78 (Figure 2). The results support that GL0034 is well tolerated and efficacious in healthy individuals with normal weight. The results are summarized in Table 1.

Table 1. Summary of safety, tolerability, pharmacodynamic, and pharmacokinetics of multiple ascending GL0034 doses

BMI - Body Mass Index; BW- Body Weight; ALT-Alanine transaminase; HOMA-IR - Homeostatic Model Assessment-Insulin Resistance*/¹^.05, **p<0.01, ***7’0.001, vs respective Day 1 Levels; Paired Student's t-test; BL = Baseline; CBL= Change from baseline; Day 23, 29 comparisons are for cohort 1 and 2 whereas Day 51, 52 comparisons are for cohort 3

Example 2: MASLD/MASH Pharmacodynamic (PD) and Safety Results of a Multiple Ascending Dose Phase 1 Study in Healthy Individuals

A randomized, double-blind, placebo-controlled study was conducted to assess the safety and tolerability of GL0034 after single and repeated ascending subcutaneous doses in healthy volunteers. Repeated ascending doses of GL0034 were administered by subcutaneous injection in healthy young male (BMI between about 18 and about 28 kg/m²) subjects.

Nine healthy male subjects (aged between 18 and 40 years old) received GL0034, as 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. In total, twenty-seven healthy subjects received GL0034 as multiple doses, and nine subjects received placebo.

Subjects were randomly assigned to receive one of three doses:

Group 2: GL0034 (680 pg) or placebo as a single subcutaneous injection in the abdominal wall, weekly for 4 weeks; or

Group 3: Two doses of GL0034 (450 pg) or placebo as a single subcutaneous injection in the abdominal wall, weekly for 2 weeks. This was followed by two doses of GL0034 (900 pg) or placebo as a single subcutaneous injection in the abdominal wall, weekly for 2 weeks. This was followed by four doses of GL0034 (1520 pg) or placebo as a single subcutaneous injection 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).

The safety and tolerability of multiple ascending doses of GL0034 was determined in Group/Cohorts 1-3, which are described above and further demonstrated in the timeline as shown in Figure 1. Safety biomarkers assessed included body weight, glycated haemoglobin Ale (HbAlc), liver enzymes (alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT)) and lipid profiles (triglycerides, total cholesterol, high- density lipoprotein (HDL) and low-density lipoprotein (LDL)).

Results

GL0034 was generally well tolerated and related adverse effects were mainly gastrointestinal with dose-dependent nausea, vomiting, and decreased appetite. Adverse events became less frequent over time despite increased dosing of GL0034. Clinically meaningful changes in the body weight, HbAlc, and lipid profile were observed when compared to baseline (Table 2). HDL increased (Table 2) and lower ALT, AST, and GGT were observed in GL0034 versus Placebo (Table 2).

Table 2. Tolerability of multiple ascending doses of GL0034

Conclusion

GL0034, a potent, long-acting GLP-1 receptor agonist, was safe, well tolerated, and with improved liver function in healthy individuals. The observed PD effects are reflective of therapeutic benefits in MASLD/MASH patients.

Tables 3 to 7 convey various data from repeated ascending doses of GL0034 in healthy young male (BMI between about 18 and about 28 kg/m²).

Subject Data - Repeated ascending doses of GL0034 in healthy young male

Table 3. Demographic and baseline characteristics of Study Population

Table 4. Summary of treatment-emergent adverse events

Table 5. Pharmacokinetic Parameters - Descriptive statistics of GL0034 PK parameters following subcutaneous injection of GL0034 once a week by day on Group 1 (fixed dose scheme: 450 pg)

Table 6. Descriptive statistics of GL0034 PK parameters following subcutaneous injection of GL0034 once a week by day on Group 2 (fixed dose scheme: 680 pg)

Table 7. Descriptive statistics of GL0034 PK parameters following subcutaneous injection of GL0034 once a week by day on Group 3 (two-step up-titration scheme 450 pg on Day 1 and Day 8; 900 pg on Day 15 and Day 22; 1520 pg on Day 29, Day 36, Day 43, and Day 50)

Example 3: Safety and Tolerability of Single Ascending Doses of GL0034 in Obese Subjects Without Diabetes

A randomized double-blind, placebo-controlled 4-part study was conducted in overweight and/or obese subjects. The safety, tolerability, pharmacodynamics, and pharmacokinetics of GL0034 was assessed in healthy overweight and/or obese volunteers after single and repeated ascending subcutaneous doses (Figures. 6, 7).

Single ascending doses of GL0034 were administered by subcutaneous injection in healthy young male overweight and/or obese (BMI above or equal to 28 kg/m² ) subjects. Six healthy male subjects, 18 to 40 years old, received an abdominal subcutaneous injection of GL0034 at each dose level (1520 pg, 2000 pg, and 2520 pg per subject). Two subjects received placebo at each dosage level. A total of 18 healthy overweight/obese male subjects received GL0034 as single dose, while 6 subjects received placebo. GL0034 pharmacokinetics and key exploratory pharmacodynamic parameters (triglyceride, leptin levels, and body weight) were assessed (Table 8).

Results

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 to 367 ± 152 ng/mL, and mean half-life ranged from 99 to 118 h. Triglyceride levels were reduced from baseline following treatment with GL0034 2000 and 2520 pg dose at day 8 (Figure 9).

Decreases in leptin levels were dose-dependent (Figure 9). Reductions in body weight versus baseline reached a maximum of 3.3 kg with the 2520 pg dose at day 8 and this effect was sustained through day 22 at every GL0034 dose (Figure 8, Table 8).

In the pooled data (n=18), 28% of subjects achieved weight loss greater than 3% after a single dose of GL0034 on both Day 8 and Day 22 as compared to 0% change for subjects receiving placebo. An increase overtime was observed with 11% of subjects with weight loss greater than 5% on Day 22. A significant reduction of triglycerides was also observed in all three cohorts. On day 8, there was a 17.5%, 40.7%, and 28.0% reduction in cohorts 1, 2, and 3 respectively, with a decrease of 21.2%, 25.4%, and 12.5% on day 22. In contrast with the three cohorts, subjects receiving placebo experienced a 9.9% and 7.6% increase in triglycerides on day 8 and 22, respectively. TG levels (mg/dL) with baseline greater than 150 mg/dL (n=9) also demonstrated a robust decrease. Subjects with a baseline of 194.7±29.1 mg/dL saw a 38.9% (p<0.05 versus placebo) on day 8 while subjects with a baseline value

212±100.8 mg/dL (n=4) saw a reduction of 4.1% versus placebo. Reduction in glucose area under the curve during OGTT on Day 8 was 16.7% (p<0.05), 21.5% (p<0.01), and 26.4%

(p<0.05) for the three cohorts, respectively, versus a reduction of only 7.4% for placebo.

Table 8. Safety and Tolerability of Single Ascending Doses of GL0034 in Obese Non¬

Diabetic Subjects

Conclusion

In conclusion, once-weekly GL0034 demonstrated clinically relevant reductions in body weight, triglycerides, and glucose area under the curve during OGTT in obese individuals and was well tolerated.

Example 4: Safety and Tolerability of Single Ascending Doses of GL0034 in Obese Subjects

A randomized double-blind, placebo (PB)-controlled 4-part study was conducted in overweight and/or obese subjects. The safety, tolerability, pharmacodynamics, and pharmacokinetics of GL0034 was assessed in healthy overweight and/or obese volunteers after single and repeated ascending subcutaneous doses. Single ascending doses of GL0034 were administered by subcutaneous injection in healthy young male overweight and/or obese (BMI above or equal to 30 kg/m²) subjects. Six healthy male subjects, 18 to 40 years old, received an abdominal subcutaneous injection of GL0034 at each dose level (1520 pg, 2000 pg, and 2520 pg per subject). Two subjects received placebo at each dosage level. A total of 18 healthy overweight/obese male subjects received GL0034 as single dose, while 6 subjects received placebo. GL0034 pharmacokinetics and key exploratory pharmacodynamic parameters (triglyceride, leptin levels, and body weight) were assessed (Table 9).

Results

No safety concerns were evident with GL0034 and the tolerability was limited to dosedependent gastrointestinal events including nausea, decreased appetite, and vomiting, a GLP- 1 receptor agonist class effect. Reduction in body weight was observed from baseline (BL) on day 8 [2.4 ± 1.3 (p<0.01), 2.2 ± 1.1 (p<0.05) 3.3 ± 1.9 (p<0.01) respectively (res) vs.-0.3 ± 0.5 kg PB], on day 15, [1.7 ± 1.6 (p<0.05), 2.4 ± 2.0 (p<0.05), 2.7 ± 1.9 (p<0.05) res vs. -0.1 ± 2.0 kg PB (BMI at BL 34.5 ± 3.0, 34.4 ± 4.0, 38.9 ± 7.3 and 31.8 ± 3.1 kg/m² res)]. Change in lipids were observed on day 8 and the measured levels on day 15, triglycerides [- 42.2 ± 48.3, -44.7 ± 43.7, -18.7 ± 46.9 res vs 24.5 ± 71.0 mg/dL PB]; total cholesterol [-23.7 ±11.2, -28.5 ± 19.1 (p<0.01), -27.8 ± 31.5 res vs -3.7 ± 10.2 mg/dL PB]; LDL [-19.0 ± 10.6, -23.8 ± 21.5 (p<0.05), -28.0 ± 25.3 res vs. -6.3 ± 2.6 mg/dL PB]; HDL [-6.0 ± 2.3 (p<0.01), -3.7 ± 5.9, -1.8 ± 3.3 res vs -0.2 ± 3.4 mg/dL PB], The improved TG/HDL ratio for treatment on day 15 was 3.1 ± 1.4, 3.1 ± 1.0, 4.3 ± 3.2 res vs. 5.3 ± 4.3 PB from the BL ratio of 3.6 ± 1.6, 4.1± 1.7, 4.5 ± 2.3 res vs 4.5 ± 2.9 PB.

Table 9. Safety and Tolerability of Single Ascending Doses of GL0034 in Obese Subjects

Conclusion

Once-weekly GL0034 is safe and well tolerated in adults with obesity. GL0034 reduced body weight of obese individuals at all doses with sustenance, and showed beneficial effects on lipid profile, improving TG/HDL ratio. The TG/HDL ratio is predictor of many potential clinical conditions. The improved TG/HDL ratio may clinically translate to: reduction in risk of heart attack and stroke; improved atherogenic lipid profile and thus lower the risk for development of coronary diseases such as coronary atherosclerosis; lowering the risk of cerebrospinal vascular disease like silent brain infarction etc.

Tables 10 to 13 below provides summary of various data set.

Table 10. Demographics and Baseline characteristic Data

Table 11. Summary of treatment-emergent adverse events

Table 12. Pharmacokinetic Profile

Table 13. Dose dependent Pharmacokinetic profile & Adverse Events frequencies

Example 5: Safety and Tolerability of Multiple Ascending Doses of GL0034 in Obese Subjects

A double-blind, placebo (PB) controlled study was conducted in obese subjects. The tolerability and metabolic effects were assessed in obese subjects after multiple ascending doses of GL0034.

Multiple ascending doses of GL0034 were administered by subcutaneous injection in healthy young male obese (BMI > 28 kg/m²) subjects. Two cohorts of nine subjects received GL0034 treatment while three received placebo treatment for each cohort. Cohort 1 received a single 680 pg dose once a week for four weeks, while cohort 2 received an increasing dose of 680 pg, 900 pg, 1520 pg, and 2000 pg over the four weeks. Safety, tolerability, and metabolic effects after GL0034 treatment were assessed.

Results

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

Table 14. Metabolic profile of multiple ascending doses (Mean ± SD)

Conclusion

Once-weekly GL0034 was found to be safe and well tolerated in adults with obesity. GL0034 reduced body weight of individuals undergoing GL0034 treatment, reduced OGTT glucose AUC, and HbAlc levels of treated subjects. These results translate into lower blood sugar levels, indicative of controlled diabetes as well as weight loss, an important metric in reducing the chronic inflammatory conditions that are exacerbated by obesity.

Example 6: A Phase 1 Multiple Ascending Dose (MAD) Study of GL0034 in Individuals with Obesity

Subjects: A randomized, double-blind, placebo (PBO)-controlled study was conducted to evaluate the safety, tolerability, and pharmacodynamics of multiple ascending dose study. Individuals with BMI > 28 kg/m² (n=12) were randomized (9:3) to subcutaneous increasing doses (680, 900, 1520, or 2000 pg) of GL or placebo once weekly for four weeks. Biomarker measurements included, body weight, lipid profile (triglycerides (TG), total cholesterol (TC) and low-density lipoprotein (LDL)) and liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT)), free fatty acids (FFA), homeostatic model assessment-insulin resistance (HOMA-IR), and leptin.

Results

The most common adverse effects (AE) were gastrointestinal (GI) with dose-dependent nausea, decreased appetite, and vomiting. One individual with a serious GI -related AE rapidly recovered upon treatment with intravenous rehydration. Mean BMI (kg/m2) at baseline was 32.4 ± 4.6 kg/m² for GL0034-treated subjects and 27.9 ± 1.3 kg/m² for subjects receiving placebo. Subjects lost 4.6 ± 1.5 kg (p<0.001) versus placebo subjects (0.0 ± 0.9 kg) on Day 29. Concordantly, subjects receiving GL0034 saw a significant reduction in triglycerides as well. On day 23, subjects saw a decrease of 47.1 ± 54.2 mg/dL (p<0.05) compared to a decrease of l6.7 ± 28.7 mg/dL in the placebo group from baseline. Further, total cholesterol decreased 20.0 ± 26.8 mg/dL versus placebo 8.7 ± 26.9 mg/dL, and LDL levels similarly decreased 5.7 ± 23.9 mg/dL while the placebo group experienced an increase of l l.3 ± 19.6 mg/dL from baseline. Reductions in ALT, AST, and GGT were also achieved with GL0034 treatment. ALT levels were reduced 9.1 U/L (± 13.9 U/L) as compared with subjects receiving placebo, which experienced an increase of 6.3 U/L (± 43 U/L). AST decreased by 2.7 U/L (± 4.2 U/L) as opposed to an increase of 1.7 U/L (± 18.7 U/L) in subjects receiving placebo. On Day 23, reduction of GGT from baseline was significant versus subjects receiving placebo with a decrease of 4.2 U/L (± 2.4 U/L, p<0.001) versus an increase of 4.3 U/L (± 15.3 U/L) in the placebo group. There was no change in the free fatty acid levels in GL0034 and placebo groups. HOMA-IR improved on Day 23 and Day 50 from a baseline of 2.3 (± 1.2) to 1.7 (± 1.0) and 1.7 (± 0.4) respectively. Placebo group baseline was 3.2 (± 0.5) to 2.1 (± 0.1) and 2.6 (± 0.9) on day 23 and 50, respectively. Finally, a decrease was observed in leptin on day 23 and 50. Treated subjects saw a decrease of 5.7 (± 5.9) and 4.5 (± 10.2) as compared with a decrease of 3.7 (± 5.3) and an increase of 5.1 (± 16.4) on day 23 and 50 in subjects receiving placebo.

Conclusion

GL0034, a potent, long-acting GLP-1RA, was safe and well tolerated. Treatment with GL0034 exhibited significant body weight reduction and improvements in lipids, liver injury, and metabolic biomarkers in individuals with obesity. The observed PD effects suggest potential therapeutic benefits in MASLD patients.

Example 7: Study to Evaluate Efficacy of GLP-1 Analogues Following Multiple Subcutaneous Injections in db/db Mice

Materials and Methods db/db (C57BL/KsJ-db/db) male/female mice (age 8-10 weeks; body weight 45-65 g), procured 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 pL blood was collected by retro-orbital plexus puncture under mild isoflurane anesthesia. Blood glucose level was measured using a hand-held blood glucose meter (One Touch™ Ultra™; LIFESCAN, Johnson & Johnson, Malvern, Pennsylvania) and % HbAlc was measured using AICNow + ® kits (PTS Diagnostics, Indianapolis, Indiana). The mice were divided into treatment groups (n = 8 per group; four males, four females) with matched 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 the mice on every third day for 4 weeks. Body weight and food intake were monitored serially. On Day 14 and 28 of the study, 24 hours after the last dose, blood was collected for measurement of HbAlc and insulin.

On Day 28, after blood collection for measurement of HbAlc, insulin, C-peptide and glucagon, triglycerides, total cholesterol, low-density cholesterol (LDL), and Amylase, the mice were sacrificed (n=5). The livers were removed for measurement of fibroblast growth factor-21 (FGF-21) while white and brown adipose tissues (WAT, BAT) were removed for uncoupling protein- 1 level (UCP-1) estimation.

Statistical comparisons were performed using one-way ANOVA, or two-way ANOVA as appropriate. Bonferroni's post hoc tests was used. Statistical significance was assigned where P < 0.05. Data are represented as mean ± standard deviation (SD).

Results

As compared with leading glucagon-like peptide 1 receptor agonists, semaglutide and tirzepatide, GL0034 demonstrated a stronger trend in the reduction of the percentage of HbAlc and higher percent change in body weight on day 14 and 28. The changes were statistically significant as compared with semaglutide treatment. On day 28, a similar trend was observed for reduction in glucagon, triglycerides, total cholesterol, and LDL. Insulin secretory responses were better for GL0034 as compared with semaglutide and tirzepatide on day 14 and 28. The increase in FGF-21 proteins in the liver and UCP-1 in BAT and WAT was significantly more than observed for semaglutide. The increase in UCP-1 in BAT was significantly more as compared with both semaglutide and tirzepatide. Complete results from this study are shown in Table 15 below.

Table 15. Changes in biomarkers after treatment with GL0034 (Utreglutide) (Mean ± SD)

Conclusions

GL0034 shows powerful antidiabetic effects in db/db mice as compared with semaglutide and tirzepatide, which indicates that GL0034 can serve as a GLP-1RA for obese patients with type 2 diabetes as it markedly increased the levels of UCP-1 in brown adipose tissue.

Example 8: Once Weekly Utreglutide (GL0034) at 4 x 450 pg Doses Reduces Blood Pressure, Lipids, and Body Weight in Post-menopausal Females

In a randomized, double-blind, placebo-controlled study, 12 post-menopausal, overweight/obese females aged 18 to 65 years old with a body mass index (BMI) >26 kg/m were randomized (9:3) to subcutaneous Utreglutide fixed doses (4 x 450 pg) or placebo once weekly for four weeks. Safety, tolerability, and key cardio-metabolic parameters were assessed.

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.

Results

Utreglutide was well tolerated, and related adverse effects were mainly gastrointestinal with dose-dependent nausea, vomiting, and decreased appetite. Reductions in OGTT AUCs of insulin (/?<().05) and glucose (/?<() .01 ) were noted on Day 23 after four weeks treatment with Utreglutide. This was accompanied by a decrease (p<0.001 ) in mean systolic and diastolic BP on Day 23 from baseline (BL). On Day 23, significant reductions in TC (p<0.01), LDL (p<0.05), and non-HDL (p<0.05) were observed. BW reduction versus BL (p<0.001) was 2.0 kg and 1 .8 kg respectively on Day 29 and End of Study (EoS). Leptin levels were significantly reduced from BL on Day 23 (p<0.01) and EoS (p<0.001). No significant changes were observed for TG, creatinine, and potassium (see Table 16).

Table 16. Effect of Utreglutide (4 x 450 pg) on cardiometabolic biomarkers in postmenopausal, overweight and obese females (All values are Mean ± SD)

Conclusion

Once weekly Utreglutide for four weeks at a dose of 450 pg in post-menopausal females with overweight and obesity demonstrated clinically relevant reductions of systolic and diastolic BP. This was associated with improved performance of OGTT AUC of insulin and glucose, lipids, BW, and leptin with high tolerability and demonstrated cardio-metabolic benefits.

Having described the subject matter of the disclosure in detail and by reference to specific embodiments thereof, it will be apparent that modifications and variations are possible without departing from the scope of the claimed subject matter.

Claims

WHAT IS CLAIMED IS:

Claim 1 : A pharmaceutical composition comprising GL0034 for the treatment of obesity in a subject.

Claim 2: The pharmaceutical composition according to claim 1, wherein the subject is not diabetic.

Claim 3 : The pharmaceutical composition according to either claim 1 or claim 2, wherein the subject has a body mass index (BMI) of at least 28 kg/m² or > 27 kg/m² with at least 1 weight-related comorbid condition.

Claim 4: A pharmaceutical composition comprising GL0034 for the treatment of a metabolic disorder in a subject.

Claim 5 : The pharmaceutical composition according to claim 4, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

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

Claim 7 : The pharmaceutical composition according to claim 4, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Claim 8: The pharmaceutical composition according to claim 7, wherein the metabolic disorder is type 2 diabetes.

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

Claim 10: The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition is administered to the subject subcutaneously. Claim 11 : The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.

Claim 12: The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is administered to the subject using an auto-injector or prefilled syringe.

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

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

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

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

Claim 17: The pharmaceutical composition according to 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.

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

Claim 19: The pharmaceutical composition according to any one of claims 1 to 16, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 6200 ng*h/mL and 406300 ng*h/mL over a period of 22 days. Claim 20: The pharmaceutical composition according to claim 16, wherein the dose of the pharmaceutical composition comprises 1520 pg, 2000 pg, or 2520 pg GL0034.

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

Claim 22: The pharmaceutical composition according to claim 20, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 30313 ng*h/mL and 83082 ng*h/mL over a period of 22 days.

Claim 23: The pharmaceutical composition according to any one of claims 1 to 21, wherein administration of the pharmaceutical composition to the subject results in a plasma drug half-life (ti/2) of GL0034 of between 90 hours and 120 hours.

Claim 24: The pharmaceutical composition according to claim 21, wherein administration of the pharmaceutical composition to the subject results in a plasma drug halflife (ti/2) ofGL0034 of between 98 hours and 113 hours.

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

Claim 26: The pharmaceutical composition according to 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 GL0034.

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

Claim 28: The pharmaceutical composition according to claim 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 results in a mean maximum concentration (Cmax) of GL0034 of between 101 ng/mL and 142 ng/mL.

Claim 29: The pharmaceutical composition according to claim 28, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0334 of between 12814 ng*h/mL and 18537 ng*h/mL over a period of 22 days.

Claim 30: The pharmaceutical composition according to claim 28, wherein administration of the pharmaceutical composition to the subject results in a plasma drug halflife (ti/2) of GL0034 of 102 hours by day 22.

Claim 31 : The pharmaceutical composition according to 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 results in a mean maximum concentration (Cmax) of GL0034 of between 169 ng/mL and 267 ng/mL.

Claim 32: The pharmaceutical composition according to claim 31, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 24576 ng*h/mL and 34537 ng*h/mL over a period of 22 days.

Claim 33: The pharmaceutical composition according to claim 31, wherein administration of the pharmaceutical composition to the subject results in a plasma drug halflife (ti/2) of GL0034 of 122.9 ± 16.5 hours by day 22.

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

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

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

Claim 37: The pharmaceutical composition according to claim 35, wherein administration of the pharmaceutical composition to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 12942 ng*h/mL and 76320 ng*h/mL over a period of 50 days.

Claim 38: The pharmaceutical composition according to claim 35, wherein administration of the pharmaceutical composition to the subject results in a plasma drug halflife (ti/2) of GL0034 of 106.8 ± 33.7 hours by day 50.

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

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

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

Claim 42: The pharmaceutical composition according to any one of claims 1 to 41, wherein administration of the pharmaceutical composition to the subject results in one or more clinically meaningful changes from baseline in the subject, wherein the clinically meaningful changes from baseline are a decrease in alanine transaminase (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 for insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin levels, a decrease in triglycerides (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 level (UCP-1) in brown adipose tissue (BAT) and/or white adipose tissue (WAT), and/or a decrease in blood pressure.

Claim 43 : The pharmaceutical composition according to claim 42, wherein the decrease in ALT values from baseline is sustained for at least 23 days, for at least 52 days, or for at least 78 days after administration of the pharmaceutical composition to the subject.

Claim 44: The pharmaceutical composition according to claim 42, wherein:

(a) the change in ALT values from baseline is at least -9 U/L over 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 over 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 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 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.

Claim 45 : The pharmaceutical composition according to claim 42, wherein the decrease in AST values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of the pharmaceutical composition to the subject.

Claim 46: The pharmaceutical composition according to claim 42, wherein the change in AST values 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.

Claim 47 : The pharmaceutical composition according to claim 42, wherein the decrease in GGT values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of the pharmaceutical composition to the subject.

Claim 48: The pharmaceutical composition according to claim 42, wherein the change in GGT values 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. Claim 49: The pharmaceutical composition according to claim 42, wherein the decrease in fasting insulin levels from baseline is sustained for at least 23 days or for at least 51 days after administration of the pharmaceutical composition to the subject.

Claim 50: The pharmaceutical composition according to claim 42, wherein the change in fasting insulin levels from baseline is at least -5 pmol/L over a period of about 23 days after administration of 680 pg GL0034 to the subject 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 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.

Claim 51 : The pharmaceutical composition according to claim 42, wherein the decrease in fasting glucose is sustained for at least 23 days or for at least 51 days after administration of the pharmaceutical composition to the subject.

Claim 52: The pharmaceutical composition according to claim 42, wherein the decrease 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 to the subject once a week for at least 4 weeks; 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 to the subject 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 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.

Claim 53: The pharmaceutical composition according to claim 42, wherein the decrease in body weight is sustained for at least 8 days, for at least 15 days, for at least 22 days, for at least 29 days, for at least 50 days, for at least 52 days, or for at least 78 days after administration of the pharmaceutical composition to the subject. Claim 54: The pharmaceutical composition according to claim 42, wherein:

(a) the decrease in body weight is at least -2 kg over a period of about 22 days after administration of a dose of the pharmaceutical composition comprising 2000 pg GL0034 to the subject; or at least -2 kg over a period of about 22 days after administration of a dose of the pharmaceutical composition comprising 1520 pg GL0034 to the subject; or at least -3 kg over a period of about 22 days after administration of a dose of the pharmaceutical composition comprising 2520 pg GL0034 to the subject; or at least -3 kg over a period of about 29 days after administration of a dose of the pharmaceutical composition comprising 450 pg GL0034 to the subject once a week for at least 4 weeks; or at least -4 kg over a period of about 29 days after administration of a dose of the pharmaceutical composition comprising 680 pg GL0034 to the subject once a week for at least 4 weeks; or

(b) the decrease 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.

Claim 55: The pharmaceutical composition according to claim 42, wherein the decrease in leptin levels from baseline is dose dependent.

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

Claim 57: The pharmaceutical composition according to claim 42, wherein the decrease in TG levels from baseline is observed at day 8 and is sustained for at least 51 days or for at least 78 days after administration of the pharmaceutical composition to the subject.

Claim 58: The pharmaceutical composition according to claim 42, wherein: (a) the change in TG levels from 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 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 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.

Claim 59: The pharmaceutical composition according to claim 42, wherein the decrease in TC levels 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.

Claim 60: The pharmaceutical composition according to 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.

Claim 61 : The pharmaceutical composition according to 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. Claim 62: The pharmaceutical composition according to claim 42, wherein the clinically meaningful change from baseline in the subject is a decrease in blood pressure.

Claim 63 : The pharmaceutical composition according to claim 62, wherein the decrease in blood pressure is a decrease in systolic blood pressure.

Claim 64: The pharmaceutical composition according to claim 62, wherein the decrease in blood pressure is a decrease in diastolic blood pressure.

Claim 65: The pharmaceutical composition according to 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.

Claim 66: The pharmaceutical composition according to 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 at least GL0034 once a week for at least 4 weeks.

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

Claim 68: The pharmaceutical composition according to any one of claims 1 to 67, wherein administration of the pharmaceutical composition to the subject results a decrease in the frequency of adverse events (AEs) overtime in the subject.

Claim 69: The pharmaceutical composition according to claim 68, wherein the AEs are one or more of nausea, vomiting, and/or decreased appetite.

Claim 70: The pharmaceutical composition according to claim 68, wherein the decrease in the frequency of AEs is dose dependent.

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

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

Claim 73: The pharmaceutical composition according to claim 72, wherein the subject is obese.

Claim 74: The pharmaceutical composition according to claim 73, wherein the subject is not diabetic.

Claim 75: The pharmaceutical composition according to claim 72, wherein the subject has a metabolic disorder.

Claim 76: The pharmaceutical composition according to claim 75, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

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

Claim 78: The pharmaceutical composition according to claim 75, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Claim 79: The pharmaceutical composition according to claim 78, wherein the metabolic disorder is type 2 diabetes.

Claim 80: The pharmaceutical composition according to any one of claims 72 to 79, wherein the pharmaceutical composition is administered to the subject subcutaneously. Claim 81 : The pharmaceutical composition according to claim 80, wherein the pharmaceutical composition is administered to the subject by subcutaneous injection.

Claim 82: The pharmaceutical composition according to claim 81, wherein the pharmaceutical composition is administered to the subject using an auto-injector or prefilled syringe.

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

Claim 84: The pharmaceutical composition according to claim 83, wherein administration of the pharmaceutical composition results in a decrease in systolic blood pressure from baseline in the subject of at least about 18 mmHg or at least about 14% over a period of about 23 days after administration of the pharmaceutical composition.

Claim 85: The pharmaceutical composition according to claim 83, wherein administration of the pharmaceutical composition results in a decrease in diastolic blood pressure from baseline in the subject of at least about 12 mmHg or at least about 14% over a period of about 23 days after administration of the pharmaceutical composition.

Claim 86: The pharmaceutical composition according to any one of claims 72 to 85, wherein the decrease in blood pressure in the subject is greater as compared to the decrease in blood pressure following administration of: (a) 1.7 to 2.4 mg semaglutide; or (b) 5 to 15 mg tirzepatide once weekly.

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

Claim 88: The method according to claim 87, wherein the subject is not diabetic.

Claim 89: The method according to either claim 87 or claim 88, wherein the subject has a body mass index (BMI) of at least 28 kg/m² or > 27 kg/m² with at least 1 weight-related comorbid condition. Claim 90: A method of treating a metabolic disorder in a subject, comprising administering a therapeutically effective amount of GL0034 to the subject.

Claim 91 : The method according to claim 90, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

Claim 92: The method according to claim 91, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

Claim 93 : The method according to claim 90, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Claim 94: The method according to claim 93, wherein the metabolic disorder is type 2 diabetes.

Claim 95: The method according to any one of claims 87 to 94, wherein the subject has hypertension.

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

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

Claim 98: The method according to claim 97, wherein GL0034 is administered to the subject using an auto-injector or prefdled syringe.

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

Claim 100: The method according to claim 99, wherein the dose comprises between 300 pg and 6000 pg GL0034. Claim 101: The method according to claim 100, wherein the dose comprises between 400 pg and 4000 pg GL0034.

Claim 102: The method according to claim 101, wherein the dose comprises between 1000 pg and 3000 pg GL0034.

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

Claim 104: The method according to any one of claims 87 to 102, wherein administration of GL0034 to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 75 ng/mL and 1200 ng/mL.

Claim 105: The method according to any one of claims 87 to 102, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 6200 ng*h/mL and 406300 ng*h/mL over a period of 22 days.

Claim 106: The method according to claim 102, wherein the dose comprises 1520 pg, 2000 pg, or 2520 pg GL0034.

Claim 107: The method according to claim 106, wherein administration of GL0034 to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 227 ng/mL and 367 ng/mL.

Claim 108: The method according to claim 106, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 30313 ng*h/mL and 83082 ng*h/mL over a period of 22 days.

Claim 109: The method according to any one of claims 87 to 107, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of between 90 hours and 120 hours. Claim 110: The method according to claim 107, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of between 98 hours and 113 hours.

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

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

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

Claim 114: The method according to 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 (Cmax) of GL0034 is between 101 ng/mL and 142 ng/mL.

Claim 115: The method according to claim 114, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0334 of between 12814 ng*h/mL and 18537 ng*h/mL over a period of 22 days.

Claim 116: The method according to claim 114, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of 102 hours by day 22.

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

Claim 118: The method according to claim 117, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 24576 ng*h/mL and 34537 ng*h/mL over a period of 22 days.

Claim 119: The method according to claim 117, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of 122.9 ± 16.5 hours by day 22. Claim 120: The method according to any one of claims 87 to 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.

Claim 121: The method according to any one of claims 87 to 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.

Claim 122: The method according to claim 121, wherein administration of GL0034 to the subject results in a mean maximum concentration (Cmax) of GL0034 of between 112 ng/mL and 708 ng/mL.

Claim 123: The method according to claim 121, wherein administration of GL0034 to the subject results in an Area Under concentration-time Curve (AUCo-t) of GL0034 of between 12942 ng*h/mL and 76320 ng*h/mL over a period of 50 days.

Claim 124: The method according to claim 121, wherein administration of GL0034 to the subject results in a plasma drug half-life (ti/2) of GL0034 of 106.8 ± 33.7 hours by day 50.

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

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

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

Claim 128: The method according to any one of claims 87 to 127, wherein administration of GL0034 to the subject results in one or more clinically meaningful changes from baseline in the subject, wherein the clinically meaningful changes from baseline are a decrease in alanine transaminase (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 for insulin resistance (HOMA-IR), a decrease in body weight, a decrease in leptin levels, a decrease in triglycerides (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 level (UCP-1) in brown adipose tissue (BAT) and/or white adipose tissue (WAT), and/or a decrease in blood pressure.

Claim 129: The method according to claim 128, wherein the decrease in ALT values from baseline is sustained for at least 23 days, for at least 52 days, or for at least 78 days after administration of GL0034 to the subject.

Claim 130: The method according to claim 128, wherein:

(a) the change in ALT values from baseline is at least -9 U/L over a period of about 23 days after administration to the subject of a dose comprising 450 pg GL0034, or at least -3 U/L over a period of about 23 days after administration to the subject of a dose 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 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.

Claim 131: The method according to claim 128, wherein the decrease in AST values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of GL0034 to the subject.

Claim 132: The method according to claim 128, wherein the change in AST values 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 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.

Claim 133: The method according to claim 128, wherein the decrease in GGT values from baseline is sustained for at least 23 days, for at least 51 days, or for at least 78 days after administration of GL0034 to the subject.

Claim 134: The method according to claim 128, wherein the change in GGT values 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 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.

Claim 135: The method according to claim 128, wherein the decrease in fasting insulin levels from baseline is sustained for at least 23 days or for at least 51 days after administration of GL0034 to the subject.

Claim 136: The method according to claim 128, wherein the change in fasting insulin levels from baseline 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.

Claim 137: The method according to claim 128, wherein the decrease in fasting glucose is sustained for at least 23 days or for at least 51 days after administration of GL0034 to the subject.

Claim 138: The method according to claim 128, wherein the decrease 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.

Claim 139: The method according to claim 128, wherein the decrease in body weight is sustained for at least 8 days, for at least 15 days, for at least 22 days, for at least 29 days, for at least 50 days, for at least 52 days, or for at least 78 days after administration of GL0034 to the subject.

Claim 140: The method according to claim 128, wherein:

(a) the decrease 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 decrease 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.

Claim 141: The method according to claim 128, wherein the decrease in leptin levels from baseline is dose dependent.

Claim 142: The method according to claim 128, wherein the change in leptin levels from 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.

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

Claim 144: The method according to claim 128, wherein:

(a) the change in TG levels from 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 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 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.

Claim 145: The method according to claim 128, wherein the decrease in TC levels 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 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. Claim 146: The method according to 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.

Claim 147: The method according to 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.

Claim 148: The method according to claim 128, wherein the clinically meaningful change from baseline in the subject is a decrease in blood pressure.

Claim 149: The method according to claim 148, wherein the decrease in blood pressure is a decrease in systolic blood pressure.

Claim 150: The method according to claim 148, wherein the decrease in blood pressure is a decrease in diastolic blood pressure.

Claim 151: The method according to claim 149, 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 comprising 450 pg GL0034 once a week for at least 4 weeks.

Claim 152: The method according to claim 150, 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 comprising 450 pg at least GL0034 once a week for at least 4 weeks. Claim 153: The method according to claim 148, wherein the decrease in blood pressure in the subject is greater as compared to the decrease in blood pressure following administration of: (a) 1.7 to 2.4 mg semaglutide once weekly; or (b) 5 to 15 mg tirzepatide once weekly.

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

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

Claim 156: The method according to claim 154, wherein the decrease in the frequency of AEs is dose dependent.

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

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

Claim 159: The method according to claim 158, wherein the subject is obese.

Claim 160: The method according to claim 159, wherein the subject is not diabetic.

Claim 161: The method according to claim 158, wherein the subject has a metabolic disorder.

Claim 162: The method according to claim 161, wherein the metabolic disorder is metabolic dysfunction-associated steatotic liver disease (MASLD).

Claim 163: The method according to claim 162, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH). Claim 164: The method according to claim 161, wherein the metabolic disorder is diabetes or hypertriglyceridemia.

Claim 165: The method according to claim 164, wherein the metabolic disorder is type 2 diabetes.

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

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

Claim 168: The method according to claim 167, wherein GL0034 is administered to the subject using an auto-injector or prefdled syringe.

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

Claim 170: The method according to claim 169, wherein administration of GL0034 results in a decrease in systolic blood pressure from baseline in the subject of at least about 18 mmHg or at least about 14% over a period of about 23 days after administration of GL0034.

Claim 171: The method according to claim 169, wherein administration of GL0034 results in a decrease in diastolic blood pressure from baseline in the subject of at least about 12 mmHg or at least about 14% over a period of about 23 days after administration of GL0034.

Claim 172: The method according to any one of claims 158 to 171, wherein the decrease in blood pressure in the subject is greater as compared to the decrease in blood pressure following administration of: (a) 1.7 to 2.4 mg semaglutide; or (b) 5 to 15 mg tirzepatide once weekly.