WO2025073288A1

WO2025073288A1 - Methods of treating adolescent obesity

Info

Publication number: WO2025073288A1
Application number: PCT/CN2024/123191
Authority: WO
Inventors: Huan DENG; Hanbo Hu
Original assignee: Innovent Biologics Suzhou Co Ltd
Current assignee: Innovent Biologics Suzhou Co Ltd
Priority date: 2023-10-03
Filing date: 2024-10-03
Publication date: 2025-04-10
Anticipated expiration: 2026-04-03
Also published as: TW202535452A

Abstract

Provided are methods of using the GLP-1R and GCGR dual targeting agonist Mazdutide or a pharmaceutically acceptable salt thereof in the treatment of adolescent obesity.

Description

METHODS OF TREATING ADOLESCENT OBESITY

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to PCT application No. PCT/CN2023/123082, filed October 3, 2023, the content of which is hereby expressly incorporated by reference in its entirety.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

The contents of the electronic sequence listing (701672000841SEQLIST. xml; Size: 3, 294 bytes; and Date of Creation: September 27, 2024) is herein incorporated by reference in its entirety.

FIELD

The present invention relates to medicine. Specifically, the present invention relates to methods of using Mazdutide in the treatment of adolescent obesity.

BACKGROUND

The alarming escalation in the prevalence of adolescent obesity has become a critical concern worldwide. These conditions not only detrimentally affect physical health but also pose substantial risks to individuals’ overall well-being and quality of life. Despite efforts to address these issues through lifestyle interventions, many patients find them insufficient for effective weight control, necessitating therapeutic intervention. While early weight-loss drugs have shown some benefits, their usage is often limited due to accompanying side effects.

As such, there remains significant unmet needs for safe and effective therapies for treatment of obesity in adolescents. The compositions and methods provided herein meet these needs and provide relative advantages.

SUMMARY

Provided herein are methods for treating obesity in an adolescent subject in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof.

In some embodiments, methods provided herein comprise administering Mazdutide or the pharmaceutically acceptable salt at a maintenance dose of about 4.0 mg once weekly. In some embodiments, methods provided herein further comprise administering Mazdutide or the pharmaceutically acceptable salt at an escalation dose of about 2.0 mg once weekly before administering the maintenance dose. In some embodiments, the escalation dose is administered for about four weeks. In some embodiments, the maintenance dose is administered for about or at least about any of eight weeks, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months.

In some embodiments, methods provided herein comprise administering Mazdutide or the pharmaceutically acceptable salt at a maintenance dose of about 6.0 mg once weekly. In some embodiments, methods provided herein further comprise administering Mazdutide or the pharmaceutically acceptable salt at a first escalation dose of about 2.0 mg once weekly, and at a second escalation dose of about 4.0 mg once weekly before administering the maintenance dose. In some embodiments, the first and second escalation doses are each administered for about four weeks. In some embodiments, the maintenance dose is administered for about four weeks. In some embodiments, the maintenance dose is administered for about or at least about any of eight weeks, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months.

In some embodiments, the subject to be treated with the methods provided herein have adolescent obesity according to the WHO Standard, the China Standard, or the United States Standard.

In some embodiments, methods provided herein result in at least about any of 5%or 10%weight loss in the subject.

Provided herein are also uses of Mazdutide or a pharmaceutically acceptable salt thereof in the treatment of adolescent obesity. Provided herein are also uses of Mazdutide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of adolescent obesity.

Provided herein are also compositions having Mazdutide or a pharmaceutically acceptable salt thereof for use in the treatment of adolescent obesity.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A shows that Mazdutide effectively reduced body weight in overweight or obese patients.

FIG. 1B shows the percentages of patients that reached weight loss goals (at least 5%, or at least 10%) in all treatment groups. In both parts, bars represent data from Mazdutide 3 mg group, Mazdutide 4.5 mg group, Mazdutide 6 mg group, and placebo group, respectively, from left to right.

FIG. 2 shows that Mazdutide effectively reduced waist circumstances in overweight or obese patients.

DETAILED DESCRIPTION

The present disclosure provides methods of treating adolescent obesity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof.

Obesity is characterized by the excessive accumulation and irregular distribution of body fat, often leading to weight gain. Over the past few decades, the prevalence of obesity among adolescents has significantly increased. In teenagers dealing with obesity, additional health issues frequently arise, such as abnormal blood glucose levels, hypertension, dyslipidemia, nonalcoholic fatty liver disease, and obstructive sleep apnea. These comorbidities collectively have a significant impact on their mental well-being and overall quality of life.

Lifestyle intervention is the primary and foundational strategy for tackling adolescent obesity, but a significant portion of individuals face obstacles when trying to achieve weight reduction due to a variety of factors. In situations where attaining the desired weight loss goals becomes challenging or elusive, pharmacological support can emerge as a viable option. Currently, the Food and Drug Administration (FDA) has approved specific medications for weight loss in adolescents, such as liraglutide, semaglutide, orlistat, and phentermine-topiramate.

Mazdutide is a synthetic peptide with an extended duration of action, designed to mimic the properties of mammalian gastric inhibitory polypeptide, oxyntomodulin (OXM) . It achieves this prolonged effect through the incorporation of a fatty acyl side chain, allowing for once-weekly dosing regimens. Notably, when administered externally, natural OXM has demonstrated its ability to improve glucose tolerance and induce weight loss. In humans, this hormone is thought to exert its biological influence by simultaneously activating both the Glucagon-Like Peptide-1 Receptor (GLP-1R) and the Glucagon Receptor (GCGR) . Without being bound by theory, as an analog of OXM, Mazdutide is presumed to function by similarly engaging both GLP-1R and GCGR receptors. By acting as a GLP-1R agonist, Mazdutide enhances insulin secretion and reduces blood glucose levels. By interacting with GCGR, Mazdutide can also promote weight loss. Clinical investigations of Mazdutide in adults who are overweight or obese have demonstrated a favorable safety profile, disclosed herein are uses of Mazdutide or pharmaceutically acceptable salts thereof in the treatment of adolescent obesity.

Before the present disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.

Definitions

Unless otherwise defined herein, scientific and technical terms used in the present disclosures shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art.

The term “a” or “an” entity refers to one or more of that entity; for example, “an antibody, ” is understood to represent one or more antibodies.

The term “and/or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B, ” “A or B, ” “A” (alone) , and B” (alone) . Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone) ; and C (alone) .

As used herein, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects. The term “about” encompasses the exact number recited. In some embodiments, “about” means within plus or minus 10%of a given value or range. In some embodiments, “about” means that the variation is ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1%of the value to which “about” refers. In some embodiments, “about” means that the variation is ±1%, ±0.5%, ±0.2%, or ±0.1%of the value to which “about” refers.

The terms “polypeptide, ” “peptide, ” “protein, ” and their grammatical equivalents as used interchangeably herein refer to polymers of amino acids of any length, which can be linear or branched. It can include unnatural or modified amino acids or be interrupted by non-amino acids. A polypeptide, peptide, or protein can also be modified with, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification.

The term “variant” as used herein in relation to a protein or a polypeptide with particular sequence features (the “reference protein” or “reference polypeptide” ) refers to a different protein or polypeptide having one or more (such as, for example, about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid substitutions, deletions, and/or additions as compared to the reference protein or reference polypeptide. The changes to an amino acid sequence can be amino acid substitutions. The changes to an amino acid sequence can be conservative amino acid substitutions. The changes to an amino acid sequence can be amino acid deletions. A variant can be a fragment of the reference protein or polypeptide. A functional variant of a protein or polypeptide maintains the basic structural and functional properties of the reference protein or polypeptide.

The term “pharmaceutically acceptable” refers to a substance (e.g., an active ingredient or an excipient) that is suitable for use in contact with the tissues and organs of a subject without excessive irritation, allergic response, immunogenicity and toxicity, is commensurate with a reasonable benefit/risk ratio, and is effective for its intended use. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to a material that is suitable for drug administration to a subject along with an active agent without causing undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition.

The term “treat” and its grammatical equivalents as used herein in connection with a disease or a condition, or a subject having a disease or a condition refer to an action that suppresses, eliminates, reduces, and/or ameliorates a symptom, the severity of the symptom, and/or the frequency of the symptom associated with the disease or disorder being treated.

The term “administer” and its grammatical equivalents as used herein refer to the act of delivering, or causing to be delivered, a therapeutic or a pharmaceutical composition to the body of a subject by a method described herein or otherwise known in the art. Administering a therapeutic or a pharmaceutical composition includes prescribing a therapeutic or a pharmaceutical composition to be delivered into the body of a subject. Exemplary forms of administration include oral dosage forms, such as tablets, capsules, syrups, suspensions; injectable dosage forms, such as intravenous (IV) , intramuscular (IM) , or intraperitoneal (IP) ; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and rectal suppositories.

The terms “effective amount, ” “therapeutically effective amount, ” and their grammatical equivalents as used herein refer to the administration of an agent to a subject, either alone or as a part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount that is capable of having any detectable, positive effect on any symptom, aspect, or characteristics of a disease, disorder or condition when administered to the subject. The therapeutically effective amount can be ascertained by measuring relevant physiological effects. The exact amount required varies from subject to subject, depending on the age, weight, and general condition of the subject, the severity of the condition being treated, the judgment of the clinician, and the like. An appropriate “effective amount” in any individual case can be determined by one of ordinary skills in the art using routine experimentation.

The term “subject” as used herein refers to any animal (e.g., a mammal) , including, but not limited to, humans, non-human primates, canines, felines, rodents, and the like, which is to be the recipient of a particular treatment. A subject can be a human. A subject can have a particular disease or condition.

Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

Exemplary genes and polypeptides are described herein with reference to GenBank numbers, GI numbers and/or SEQ ID NOS. It is understood that one skilled in the art can readily identify homologous sequences by reference to sequence sources, including but not limited to GenBank (ncbi. nlm. nih. gov/genbank/) and EMBL (embl. org/) .

Compositions

Provided herein are compositions comprising Mazdutide or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are pharmaceutical compositions comprising Mazdutide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Compositions provided herein can be also used in treating obesity in a subject in need thereof. In some embodiments, compositions provided herein can be used in treating adolescent obesity.

Mazdutide is a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor (GCGR) agonist that binds to and activates GLP-1R and GCGR. Mazdutide is also described in patent CN201680036771.3, the entire contents of which are incorporated herein by reference.

Mazdutide has the sequence shown in SEQ ID NO. 1:

His-Xaa-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Lys-Lys-Ala-Lys-Glu-Phe-Val-Glu-Trp-Leu-Leu-Glu-Gly-Gly-Gly-Pro-Ser-Ser-Gly; wherein Xaa is alpha amino isobutyric acid (Aib) ; Lys at position 20 is chemically modified through conjugation to the epsilon-amino group of the K side-chain with ( [2- (2-Amino-ethoxy) -ethoxy] -acetyl) 2- (γGlu) 1-CO-(CH2) 18-CO2H;

and the carboxyl group of the C-terminal Gly is amidated to the C-terminal primary amide.

The chemical structure of Mazdutide is shown below:

As understood by a person of ordinary skill in the art, Mazdutide can be reacted with any number of inorganic and organic bases to form pharmaceutically acceptable salts. Pharmaceutically acceptable salts and conventional methodologies for their preparation are well known in the art. See, for example, P. Stahl et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, 2nd Revision (Wiley-VCH, 2011)

A salt of Mazdutide can be formed between an acid and a basic group of Mazdutide, such as an amino functional group, or a base and an acidic group of Mazdutide, such as a carboxyl functional group.

Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present. For example, see Remington’s Pharmaceutical Sciences, 19^thed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution. Thus, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

It is also to be understood that Mazdutide can exist in unsolvated forms, solvated forms (e.g., hydrated forms) , and solid forms (e.g., crystal or polymorphic forms) , and the present disclosure is intended to encompass all such forms.

As used herein, the term “solvate” or “solvated form” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H₂O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

As used herein, the terms “crystal form” , “crystalline form” , “polymorphic forms” and “polymorphs” can be used interchangeably, and mean crystal structures in which Mazdutide or a pharmaceutically acceptable salt thereof can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of Mazdutide can be prepared by crystallization under different conditions.

Those of skill in the art will appreciate that Mazdutide may exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. The presence and concentrations of the isomeric forms will depend on the environment Mazdutide is found in and may be different depending upon, for example, whether Mazdutide is a solid or is in an organic or aqueous solution. By way of examples, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations and annular forms where a proton can occupy two or more positions of a heterocyclic system. Valence tautomers include interconversions by reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitution. Mazdutide identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

Synthesis of Mazdutide provided herein, including pharmaceutically acceptable salts thereof, are provided in Examples 1, 2, 3 and 4 of WO 2016/209707, the content of which is incorporated herein by reference. Preparation of the compounds provided herein may also be found in WO2021252829A1 and WO2023196765A1, the content of which is incorporated herein by reference in their entirety. Mazdutide provided herein may also be prepared using any known organic synthesis techniques and can be synthesized according to any possible synthetic routes.

In some embodiments, the method provided herein comprises administering a composition (e.g., a pharmaceutical composition) comprising Mazdutide or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one compound as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, and magnesium carbonate.

Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms. The pharmaceutical composition may be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport patch forms) for prolonged timed, and/or pulsed administration at a predetermined rate. In some embodiments, the pharmaceutical composition may be administered in unit dosage forms suitable for single administration of a precise dose.

Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound or a pharmaceutical salt thereof, and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of Mazdutide or a pharmaceutically acceptable salt thereof contained in such parenteral compositions depends, for example, on the physical nature of Mazdutide or a pharmaceutically acceptable salt thereof, the activity of Mazdutide or a pharmaceutically acceptable salt thereof and the needs of the subject (e.g., human) .

In some embodiments, Mazdutide or the pharmaceutically acceptable salt thereof is in a formulation (e.g., a liquid formulation) comprising tromethamine (e.g., 0.5-5 mg/mL tromethamine) , a stabilizer, a chelating agent and a solvent. In some embodiments, the stabilizer comprises one or more of mannitol, propylene glycol, arginine, arginine hydrochloride, histidine and histidine hydrochloride. In some embodiments, the stabilizer comprises mannitol and propylene glycol (e.g., at a concentration of 0.1-100 mg/mL) . In some embodiments, the chelating agent comprises edetate disodium (e.g., 0.01-5 mg/mL edetate disodium) . In some embodiments, the solvent comprises water.

In some embodiments, the formulation comprises 1-3 mg/mL tromethamine, 10-66 mg/mL stabilizer, 0.03-1 mg/mL chelating agent and a solvent. In some embodiments, the formulation comprises 1.21 mg/mL tromethamine, 20-46 mg/mL stabilizer, 0.05-0.5 mg/mL chelating agent and a solvent.

In some embodiments, the formulation comprises 1.21 mg/mL tromethamine, 46 mg/mL mannitol, 0.5 mg/mL edetate disodium and water as a solvent.

In some embodiments, the formulation comprises 1.21 mg/mL tromethamine, 20 mg/mL propylene glycol, 0.5 mg/mL edetate disodium and water as a solvent.

In some embodiments, the formulation comprises 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent.

In some embodiments, the formulation further comprises a surfactant. In some embodiments, the surfactant is tween 80.

In some embodiments, the formulation comprises Mazdutide, and the concentration of Mazdutide is about at a concentration of about 1-100 mg/mL. In some embodiments, Mazdutide has a concentration of 3-50 mg/mL. In some embodiments, Mazdutide has a concentration of 6-20 mg/mL. In some embodiments, Mazdutide has a concentration of 15-20 mg/mL. In some embodiments, Mazdutide has a concentration of 3mg/ml, 4mg/ml, 6 mg/ml, 8.37 mg/ml, 12 mg/ml, 15 mg/ml, 18 mg/ml or 20 mg/ml. In some embodiments, Mazdutide has a concentration of 18 mg/mL.

In some embodiments, the formulation has a pH of 7-9. In some embodiments, the formulation has a pH of 7.5-8.5. In some embodiments, the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 8.37 mg/mL Mazdutide, 1.21 mg/mL tromethamine, 46 mg/mL mannitol, 0.5 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 8.37 mg/mL Mazdutide, 1.21 mg/mL tromethamine, 20 mg/mL propylene glycol, 0.5 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 3 mg/mL Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 4 mg/mL Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 8mg/ml Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 6 mg/mL Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 12 mg/mL Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 15 mg/mL Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 18 mg/mL Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, the formulation comprises 20 mg/mL Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7.

In some embodiments, Mazdutide and pharmaceutically acceptable salts thereof can be formulated as pharmaceutical compositions to be used in methods disclosed herein. Exemplary pharmaceutical compositions or formulations are described in, e.g., WO2022228498A1 and WO2022140373A1, the content of which is incorporated herein by reference in their entirety.

Mazdutide and pharmaceutically acceptable salts thereof can be present at various concentrations. In some embodiments, the pharmaceutical compositions provided herein comprise Mazdutide or a pharmaceutically acceptable salt thereof at 1-100 mg/mL (e.g., 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 12 mg/ml, 14 mg/ml, 15 mg/ml, 16 mg/ml, 18 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, or 100 mg/ml) .

Pharmaceutically acceptable carriers that can be included in compositions to be used in methods provided herein include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In some embodiments, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion) .

In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of Mazdutide and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier comprises tromethamine, mannitol, propylene glycol (for injection) , disodium edetate, diluted hydrochloric acid, sodium hydroxide and water for injection.

In some embodiments, methods provided herein comprise administering a pharmaceutical composition having Mazdutide and pharmaceutically acceptable salt described herein that is suitable for local administration. In certain embodiments, the pharmaceutical compositions provided herein are suited for subcutaneous administration. In some embodiments, the pharmaceutical compositions are suitable for systemic administration. In certain embodiments, the pharmaceutical compositions are suitable for intravenous administration.

In some embodiments, the Mazdutide or a pharmaceutically acceptable salt thereof is stored in pre-filled injection pens. The injectable formulation includes Mazdutide and tromethamine, mannitol, propylene glycol (for injection) , disodium edetate, dilute hydrochloric acid, sodium hydroxide, and water for injection as excipients. In some embodiments, Mazdutide is provided in the following dosage forms: 0.5 ml: 3 mg, 0.5 ml: 6 mg, and 0.5 ml: 9 mg. In some embodiments, Mazdutide is provided in the following dosage forms: 0.5 ml: 2 mg, 0.5 ml: 4 mg, and 0.5 ml: 6 mg.

Pharmaceutical compositions disclosed herein can be delivered subcutaneously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

Methods of treatment

Obesity can disrupt the body’s normal metabolic processes and contribute to the development of various metabolic conditions, such as insulin resistance, type 2 diabetes, dyslipidemia, hypertension, etc. Obesity can also result in musculoskeletal disorders. Methods provided herein can treat obesity and address these comorbidities.

Provided herein are methods of reducing body weight in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is an adolescent. In some embodiments, provided herein are uses of compositions described herein comprising Mazdutide or a pharmaceutically acceptable salt thereof in reducing body weight in an adolescent. In some embodiments, provided herein are uses of compositions described herein comprising Mazdutide or a pharmaceutically acceptable salt thereof in the manufacture of medicament for reducing body weight in an adolescent.

Provided herein are methods of chronic weight management in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is an adolescent. In some embodiments, provided herein are uses of compositions described herein comprising Mazdutide or a pharmaceutically acceptable salt thereof for chronic weight management in an adolescent. In some embodiments, provided herein are uses of compositions described herein comprising Mazdutide or a pharmaceutically acceptable salt thereof in the manufacture of medicament for chronic weight management in an adolescent.

In some embodiments, provided herein are methods of treating obesity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is an adolescent. In some embodiments, provided herein are uses of compositions described herein comprising Mazdutide or a pharmaceutically acceptable salt thereof in treating adolescent obesity. In some embodiments, provided herein are uses of compositions described herein comprising Mazdutide or a pharmaceutically acceptable salt thereof in the manufacture of medicament for treating adolescent obesity.

In some embodiments, there is provided a method for treating obesity in a female adolescent human individual in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof, wherein the method comprises administering Mazdutide or the pharmaceutically acceptable salt a) at a maintenance dose of about 4.0 mg once weekly, and b) at an escalation dose of about 2.0 mg once weekly before administering the maintenance dose, optionally wherein the escalation dose is administered for about four weeks. In some embodiments, the maintenance dose is administered for at least about any of eight week, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months. In some embodiments, the individual is about or at least about any of 12, 13, 14, 15, 16, 17, and/or 18 years old. In some embodiments, the individual is about 12-13, 13-14, 14-15, 15-16, 16-17, and/or 17-18 years old. In some embodiments, the individual is in Tanner stage II, III, IV, or V. In some embodiments, the individual is in Tanner stage II-III, stage III-IV, and/or stage IV-V. In some embodiments, the individual has a BMI of at least about any of 23.9, 24.5, 25.0, 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual has a BMI of no more than about any of 24.5, 25.0, 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual has a BMI with a range of any of 23.9-24.5, 24.5-25.0, 25.0-25.6, 25.6-25.9, 25.9-26.3, 26.3-26.6, 26.6-26.9, 26.9-27.1, 27.1-27.4, 27.4-27.6, 27.6-27.8, 27.8-28.0, 28.0-28.3, 28.3-28.6, 28.6-28.9, 28.9-29.2, 29.2-29.5, 29.5-29.8, 29.8-30.1, 30.1-30.4, 30.4-30.7, 30.7-31, 31-31.3, 31.3-31.6, 31.6-31.9, 31.9-32.2, 32.5-32.5, and/or 32.5-32.8, or any combination thereof. In some embodiments, the individual has a BMI of about 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0 or 32.0. In some embodiments, the methods comprise administering such treatment to a plurality of the individuals described above. In some embodiments, Mazdutide or a pharmaceutically acceptable salt thereof is in a formulation comprising 4 mg/ml, 6mg/ml, 8 mg/ml, or 12 mg/ml Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7. In some embodiments, the treatment resulted in an improvement in one, two, three, four, five, six, seven, eight or nine parameters in a lipid profile (e.g., total cholesterol, HDL, LDL, and/or Triglyceride) , body weight, BMI, waist hip ratio (WHR) , HbA1c in the individual or the plurality of individuals.

In some embodiments, there is provided a method for treating obesity in a female adolescent human individual in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof, wherein the method comprises administering Mazdutide or the pharmaceutically acceptable salt a) at a maintenance dose of about 6.0 mg once weekly, and b) at a first escalation dose of about 2.0 mg once weekly (e.g., for four weeks) and at a second escalation dose of about 4.0 mg once weekly (e.g., for four weeks) following the first escalation dose and before administering the maintenance dose. In some embodiments, the maintenance dose is administered for at least about any of eight week, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months. In some embodiments, the individual is about or at least about any of 12, 13, 14, 15, 16, 17, and/or 18 years old. In some embodiments, the individual is about 12-13, 13-14, 14-15, 15-16, 16-17, and/or 17-18 years old. In some embodiments, the individual is in Tanner stage II, III, IV, or V. In some embodiments, the individual is in Tanner stage II-III, stage III-IV, and/or stage IV-V. In some embodiments, the individual has a BMI of at least about any of 23.9, 24.5, 25.0, 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual has a BMI of no more than about any of 24.5, 25.0, 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual has a BMI with a range of 23.9-24.5, 24.5-25.0, 25.0-25.6, 25.6-25.9, 25.9-26.3, 26.3-26.6, 26.6-26.9, 26.9-27.1, 27.1-27.4, 27.4-27.6, 27.6-27.8, 27.8-28.0, 28.0-28.3, 28.3-28.6, 28.6-28.9, 28.9-29.2, 29.2-29.5, 29.5-29.8, 29.8-30.1, 30.1-30.4, 30.4-30.7, 30.7-31, 31-31.3, 31.3-31.6, 31.6-31.9, 31.9-32.2, 32.5-32.5, and/or 32.5-32.8, or any combination thereof. In some embodiments, the individual has a BMI of about 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0 or 32.0. In some embodiments, the methods comprises administering such treatment to a plurality of the individuals described above. In some embodiments, Mazdutide or a pharmaceutically acceptable salt thereof is in a formulation comprising 4 mg/ml, 6mg/ml, 8 mg/ml, or 12 mg/ml Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7. In some embodiments, the treatment resulted in an improvement in one, two, three, four, five, six, seven, eight or nine parameters in a lipid profile (e.g., total cholesterol, HDL, LDL, and/or Triglyceride) , body weight, BMI, waist hip ratio (WHR) , HbA1c in the individual or the plurality of individuals.

In some embodiments, there is provided a method for treating obesity in a male adolescent human individual in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof, wherein the method comprises administering Mazdutide or the pharmaceutically acceptable salt a) at a maintenance dose of about 4.0 mg once weekly, and b) at an escalation dose of about 2.0 mg once weekly before administering the maintenance dose, optionally wherein the escalation dose is administered for about four weeks. In some embodiments, the maintenance dose is administered for at least about any of eight week, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months. In some embodiments, the individual is about or at least about any of 12, 13, 14, 15, 16, 17, and/or 18 years old. In some embodiments, the individual is about 12-13, 13-14, 14-15, 15-16, 16-17, and/or 17-18 years old. In some embodiments, the individual is in Tanner stage II, III, IV, or V. In some embodiments, the individual is in Tanner stage II-III, stage III-IV, and/or stage IV-V. In some embodiments, the individual has a BMI of at least about any of 24.1, 24.7, 25.2, 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual has a BMI of no more than about any of 24.1, 24.7, 25.2, 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual has a BMI with a range of any of 24.1-24.7, 24.7-25.2, 25.2-25.7, 25.7-26.1, 26.1-26.4, 26.4-26.6, 26.6-26.9, 26.9-27.1, 27.1-27.4, 27.4-27.6, 27.6-27.8, 27.8-28.0, 28.0-28.3, 28.3-28.6, 28.6-28.9, 28.9-29.2, 29.2-29.5, 29.5-29.8, 29.8-30.1, 30.1-30.4, 30.4-30.7, 30.7-31, 31-31.3, 31.3-31.6, 31.6-31.9, 31.9-32.2, 32.2-32.5, or 32.5-32.8, or any combination thereof. In some embodiments, the individual has a BMI of about 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0 or 32.0. In some embodiments, the methods comprise administering such treatment to a plurality of the individuals described above. In some embodiments, Mazdutide or a pharmaceutically acceptable salt thereof is in a formulation comprising 4 mg/ml, 6mg/ml, 8 mg/ml, or 12 mg/ml Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7. In some embodiments, the treatment resulted in an improvement in one, two, three, four, five, six, seven, eight or nine parameters in a lipid profile (e.g., total cholesterol, HDL, LDL, and/or Triglyceride) , body weight, BMI, waist hip ratio (WHR) , HbA1c in the individual or the plurality of individuals.

In some embodiments, there is provided a method for treating obesity in a male adolescent human individual in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof, wherein the method comprises administering Mazdutide or the pharmaceutically acceptable salt a) at a maintenance dose of about 6.0 mg once weekly, and b) at a first escalation dose of about 2.0 mg once weekly (e.g., for four weeks) and at a second escalation dose of about 4.0 mg once weekly (e.g., for four weeks) following the first escalation dose and before administering the maintenance dose. In some embodiments, the maintenance dose is administered for at least about any of eight week, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months. In some embodiments, the individual is about 12, 13, 14, 15, 16, 17, and/or 18 years old. In some embodiments, the individual is about 12-13, 13-14, 14-15, 15-16, 16-17, and/or 17-18 years old. In some embodiments, the individual is in Tanner stage II, III, IV, or IV. In some embodiments, the individual is in Tanner stage II-III, stage III-IV, and/or stage IV-V. In some embodiments, the individual has a BMI of at least about any of 24.1, 24.7, 25.2, 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual has a BMI of no more than about any of 24.1, 24.7, 25.2, 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual has a BMI with a range of 24.1-24.7, 24.7-25.2, 25.2-25.7, 25.7-26.1, 26.1-26.4, 26.4-26.6, 26.6-26.9, 26.9-27.1, 27.1-27.4, 27.4-27.6, 27.6-27.8, 27.8-28.0, 28.0-28.3, 28.3-28.6, 28.6-28.9, 28.9-29.2, 29.2-29.5, 29.5-29.8, 29.8-30.1, 30.1-30.4, 30.4-30.7, 30.7-31, 31-31.3, 31.3-31.6, 31.6-31.9, 31.9-32.2, 32.2-32.5, or 32.5-32.8, or any combination thereof. In some embodiments, the individual has a BMI of about 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0 or 32.0. In some embodiments, the methods comprise administering such treatment to a plurality of the individuals described above. In some embodiments, Mazdutide or a pharmaceutically acceptable salt thereof is in a formulation comprising 4 mg/ml, 6mg/ml, 8 mg/ml, or 12 mg/ml Mazdutide, 1.21 mg/mL tromethamine, 10 mg/mL propylene glycol, 23 mg/mL mannitol, 0.05 mg/mL edetate disodium and water as a solvent, and the formulation has a pH of 7.7. In some embodiments, the treatment resulted in an improvement in one, two, three, four, five, six, seven, eight or nine parameters in a lipid profile (e.g., total cholesterol, HDL, LDL, and/or Triglyceride) , body weight, BMI, waist hip ratio (WHR) , HbA1c in the individual or the plurality of individuals.

In some embodiments, the method results in at least about any of 5%, 6%, 7%, 8%, 9%, or 10%body weight loss in the individual or averagely (e.g., median or mean) in the plurality of the individuals. In some embodiments, the method results in a BMI decrease of at least about any of 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 kg/m² in the individual or averagely (e.g., median or mean) in the plurality of the individuals. In some embodiments, the method results in an decrease in weight hip ratio (WHR) of at least about any of about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07. 0.08, 0.09, or 0.1 in the individual or averagely (e.g., median or mean) in the plurality of the individuals. In some embodiments, the method results in a decrease in total cholesterol (e.g., in mmol/L) of at least about any of 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, and/12%in the individual or averagely (e.g., median or mean) in the plurality of the individuals. In some embodiments, the method results in a decrease in total cholesterol (e.g., in mmol/L) of at least about any of 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, and/or 15%in the individual or averagely (e.g., median or mean) in the plurality of the individuals. In some embodiments, the method results in a decrease in HDL (e.g., in mmol/L) of at least about any of 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, and/or 15%in the individual or averagely (e.g., median or mean) in the plurality of the individuals. In some embodiments, the method results in a decrease in LDL (e.g., in mmol/L) of at least about any of 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, or 18%in the individual or averagely (e.g., median or mean) in the plurality of the individuals. In some embodiments, the method results in a decrease in Triglycerides (e.g., in mmol/L) of at least about any of 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, or 18%in the individual or averagely (e.g., median or mean) in the plurality of the individuals. In some embodiments, the method results in a decrease in HbA1c of at least about any of 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%in the individual or averagely (e.g., median or mean) in the plurality of the individuals.

The pharmaceutical compositions provided herein comprising Mazdutide or a pharmaceutically acceptable salt thereof can be administered to a subject by any methods known in the art. In some embodiments, intravenous administration is adopted. In some embodiments, subcutaneous administration is adopted. In some embodiments, the subcutaneous administration is performed through an abdominal injection.

As used herein and understood in the art, an “adolescent” subject means that the subject is at least 12 but less than 18 years old. An adolescent subject can be male or female.

As used herein and understood in the art, “body mass index” or BMI is a measure of body fat based on height and weight. The formula for calculation is BMI = weight (kilograms) /height² (m²) .

Different countries have varying standards for adolescent obesity. In China, according to the “Health Industry Standards of the People's Republic of China” (WS/T 586-2018) the following criteria are applied (the “China Standard” ) :

The methods provided herein can be used to treat adolescent obesity according to the Chinese standard. Accordingly, for illustrative purposes, in some embodiments, subjected to be treated with methods disclosed herein can be a 12 year old male with BMI of at least 24.1. In some embodiments, subjected to be treated with methods disclosed herein can be a 12 year old female with BMI of at least 23.9. In some embodiments, subjected to be treated with methods disclosed herein can be a 13 year old male with BMI of at least 25.2. In some embodiments, subjected to be treated with methods disclosed herein can be a 13 year old female with BMI of at least 25.0. In some embodiments, subjected to be treated with methods disclosed herein can be a 14 year old male with BMI of at least 26.1. In some embodiments, subjected to be treated with methods disclosed herein can be a 14 year old female with BMI of at least 25.9. In some embodiments, subjected to be treated with methods disclosed herein can be a 15 year old male with BMI of at least 26.6. In some embodiments, subjected to be treated with methods disclosed herein can be a 15 year old female with BMI of at least 26.6. In some embodiments, subjected to be treated with methods disclosed herein can be a 16 year old male with BMI of at least 27.1. In some embodiments, subjected to be treated with methods disclosed herein can be a 16 year old female with BMI of at least 27.1. In some embodiments, subjected to be treated with methods disclosed herein can be a 17 year old male with BMI of at least 27.6. In some embodiments, subjected to be treated with methods disclosed herein can be a 17 year old female with BMI of at least 27.6. In some embodiments, subjected to be treated with methods disclosed herein can be an 18 year old male with BMI of at least 28.0. In some embodiments, subjected to be treated with methods disclosed herein can be an 18 year old female with BMI of at least 28.0.

The United States primarily uses growth charts developed by the Centers for Disease Control and Prevention (CDC) to assess and classify adolescent obesity. These growth charts are based on data collected from a nationally representative sample of children and adolescents. The specific standard used to determine obesity in adolescents is the Body Mass Index (BMI) percentile on BMI. Specifically, the BMI Percentile Categories are (the “United States Standard” ) :

Underweight: Less than the 5th percentile

Healthy weight: 5th to less than the 85th percentile

Overweight: 85th to less than the 95th percentile

Obese: Equal to or greater than the 95th percentile

Severe Obese: 20%of the 95th percentile or greater OR 35 kg/m² or greater

The following table is generated based on the charts released by CDC in December 2022.

The methods provided herein can also be used to treat adolescent obesity according to the U. S. standard. Accordingly, for illustrative purposes, in some embodiments, subjected to be treated with methods disclosed herein can be a 12 year old male with BMI of at least 26.0. In some embodiments, subjected to be treated with methods disclosed herein can be a 12 year old female with BMI of at least 27.2. In some embodiments, subjected to be treated with methods disclosed herein can be a 13 year old male with BMI of at least 27.0. In some embodiments, subjected to be treated with methods disclosed herein can be a 13 year old female with BMI of at least 28.3. In some embodiments, subjected to be treated with methods disclosed herein can be a 14 year old male with BMI of at least 27.9. In some embodiments, subjected to be treated with methods disclosed herein can be a 14 year old female with BMI of at least 29.4. In some embodiments, subjected to be treated with methods disclosed herein can be a 15 year old male with BMI of at least 28.6. In some embodiments, subjected to be treated with methods disclosed herein can be a 15 year old female with BMI of at least 30.4. In some embodiments, subjected to be treated with methods disclosed herein can be a 16 year old male with BMI of at least 29.3. In some embodiments, subjected to be treated with methods disclosed herein can be a 16 year old female with BMI of at least 31.3. In some embodiments, subjected to be treated with methods disclosed herein can be a 17 year old male with BMI of at least 30.0. In some embodiments, subjected to be treated with methods disclosed herein can be a 17 year old female with BMI of at least 32.2. In some embodiments, subjected to be treated with methods disclosed herein can be an 18 year old male with BMI of at least 30.6. In some embodiments, subjected to be treated with methods disclosed herein can be an 18 year old female with BMI of at least 33.1.

The World Health Organization (WHO) also defines adolescent obesity (or pediatric obesity) using BMI. Specifically, the following categories are defined based on BMI (the “WHO Standard” ) :

Moderate and serve underweight: more than 2 standard deviations (SD) below the median of the WHO growth reference

Mild underweight: 2 SD to more than 1 SD below the median

healthy weight: 1 SD below the median to 1 SD above the median

overweight but not obese: more than 1 SD to 2 SD above the median

obese: more than 2 SD above the median

The following table is generated based on the charts released by WHO (https: //www. who. int/tools/growth-reference-data-for-5to19-years/indicators/bmi-for-age; accessed September 26, 2023) .

The methods provided herein can also be used to treat adolescent obesity according to the WHO standard. Accordingly, for illustrative purposes, in some embodiments, subjected to be treated with methods disclosed herein can be a 12 year old male with BMI of at least 23.6. In some embodiments, subjected to be treated with methods disclosed herein can be a 12 year old female with BMI of at least 25.0. In some embodiments, subjected to be treated with methods disclosed herein can be a 13 year old male with BMI of at least 24.8. In some embodiments, subjected to be treated with methods disclosed herein can be a 13 year old female with BMI of at least 26.2. In some embodiments, subjected to be treated with methods disclosed herein can be a 14 year old male with BMI of at least 25.9. In some embodiments, subjected to be treated with methods disclosed herein can be a 14 year old female with BMI of at least 27.3. In some embodiments, subjected to be treated with methods disclosed herein can be a 15 year old male with BMI of at least 27.0. In some embodiments, subjected to be treated with methods disclosed herein can be a 15 year old female with BMI of at least 28.2. In some embodiments, subjected to be treated with methods disclosed herein can be a 16 year old male with BMI of at least 27.9. In some embodiments, subjected to be treated with methods disclosed herein can be a 16 year old female with BMI of at least 28.9. In some embodiments, subjected to be treated with methods disclosed herein can be a 17 year old male with BMI of at least 28.6. In some embodiments, subjected to be treated with methods disclosed herein can be a 17 year old female with BMI of at least 29.3. In some embodiments, subjected to be treated with methods disclosed herein can be an 18 year old male with BMI of at least 29.2. In some embodiments, subjected to be treated with methods disclosed herein can be an 18 year old female with BMI of at least 29.5.

As a person of ordinary skill in the art would understand, although standards in different countries may vary, and may change over time, the differences in detailed schedule does not affect the applicability of the claimed methods. In some embodiments, methods provided herein for reducing weight, for chronic weight management, and for treating adolescent obesity can be used worldwide according to the respective local standard. In some embodiments, the subject to be treated by methods provided herein falls under the obese category according to the Chinese standard for adolescent obesity. In some embodiments, the subject to be treated by methods provided herein falls under the obese category according to the US standard for adolescent obesity. In some embodiments, the subject to be treated by methods provided herein falls under the obese category according to the WHO standard for adolescent/pediatric obesity.

In some embodiments, the adolescent subject has been obese for at least four weeks, at least eight weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, at least twelve months, at least two years, or at least three years. In some embodiments, the subject has been obese for at least four weeks. In some embodiments, the subject has been obese for at least eight weeks. In some embodiments, the subject has been obese for at least twelve weeks. In some embodiments, the subject has been obese for at least 24 weeks. In some embodiments, the subject has been obese for at least nine months. In some embodiments, the subject has been obese for at least one year. In some embodiments, the subject has been obese for at least two years. In some embodiments, the subject has been obese for at least three years.

In some embodiments, the individual is at Tanner stage II-V. In some embodiments, the individual is at Tanner stage II. In some embodiments, the individual is at Tanner stage III. In some embodiments, the individual is at Tanner stage IV. In some embodiments, the individual is at Tanner stage V.

In some embodiments, the individual is a female. In some embodiments, the individual is a male.

In some embodiments, the individual has not been subject to a GLP-1 receptor (GLP-1R) agonist. In some embodiments, the individual has not been subject to a GLP-1R/GCGR agonist within six months or three months prior to the initiation of the treatment described herein. In some embodiments, the individual has not been subject to a GIPR/GLP-1R agonist. In some embodiments, the individual has not been subject to a GIPR/GLP-1R/GCGR agonist. In some embodiments, the individual has not been subject to any one or more of the medicines described above.

In some embodiments, the individual has not been subject to a systemic steroid hormone. In some embodiments, the individual has not been subject to metformin within six months or three months prior to the initiation of the treatment described herein. In some embodiments, the individual has not been subject to a sodium glucose cotransporter 2 (SGLT2) inhibitor. In some embodiments, the individual has not been subject to a thiazolidinedione (TZD) . In some embodiments, the individual has not been subject to a tricyclic antidepressant. In some embodiments, the individual has not been subject to a psychiatric medication. In some embodiments, the individual has not been subject to a sedative drug (such as imipramine, amitriptyline, azapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid, valproic acid derivatives, lithium salts) . In some embodiments, the individual has not been subject to any one or more of the medicines described above.

In some embodiments, the individual has not been subject to a Chinese herbal medicine, a health product, or a meal replacement that affects weight within six months or three months prior to the initiation of the treatment described herein. In some embodiments, the individual has not been subject to a weight loss drug, such as: sibutramine hydrochloride, oligosaccharide Orlistat, phenylpropanolamine, chlorpheniramine, phentermine, bupropion, lorcaserin, Phentermine/topiramate mixture, naltrexone/bupropion mixture, within six months or three months prior to the initiation of the treatment described herein. In some embodiments, the individual has not been subject to any one or more of the medicines described above.

In some embodiments, the individual is a male, is about or at least about any of 12 years old, and has a BMI of at least about any of 24.1, 24.7, 25.2, 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 12 years old, and has a BMI of no more than about any of 24.7, 25.2, 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about any of 12.5 years old, and has a BMI of at least about any of 24.7, 25.2, 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 12.5 years old, and has a BMI of no more than about any of 25.2, 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 13 years old, and has a BMI of at least about any of 25.2, 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 13 years old, and has a BMI of no more than about any of 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 13.5 years old, and has a BMI of at least about any of 25.7, 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 13.5 years old, and has a BMI of no more than about any of 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 14 years old, and has a BMI of at least about any of 26.1, 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 14 years old, and has a BMI of no more than about any of 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 14.5 years old, and has a BMI of at least about any of 26.4, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 14.5 years old, and has a BMI of no more than about any of 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 15 years old, and has a BMI of at least about any of 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 15 years old, and has a BMI of no more than about any of 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 15.5 years old, and has a BMI of at least about any of 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 15.5 years old, and has a BMI of no more than about any of 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 16 years old, and has a BMI of at least about any of 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 16 years old, and has a BMI of no more than about any of 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 16.5 years old, and has a BMI of at least about any of 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 16.5 years old, and has a BMI of no more than about any of 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 17 years old, and has a BMI of at least about any of 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 17 years old, and has a BMI of no more than about any of 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 17.5 years old, and has a BMI of at least about any of 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 17.5 years old, and has a BMI of no more than about any of 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a male, is about or at least about 18 years old, and has a BMI of at least about any of 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a male, is about or at least about 18 years old, and has a BMI of no more than about any of 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 12 years old, and has a BMI of at least about any of 23.9, 24.5, 25.0, 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 12 years old, and has a BMI of no more than about any of 24.5, 25.0, 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 12.5 years old, and has a BMI of at least about any of 24.5, 25.0, 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 12.5 years old, and has a BMI of no more than about any of 25.0, 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 13 years old, and has a BMI of at least about any of 25.0, 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 13 years old, and has a BMI of no more than about any of 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 13.5 years old, and has a BMI of at least about any of 25.6, 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 13.5 years old, and has a BMI of no more than about any of 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 14 years old, and has a BMI of at least about any of 25.9, 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 14 years old, and has a BMI of no more than about any of 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 14.5 years old, and has a BMI of at least about any of 26.3, 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 14.5 years old, and has a BMI of no more than about any of 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 15 years old, and has a BMI of at least about any of 26.6, 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 15 years old, and has a BMI of no more than about any of 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 15.5 years old, and has a BMI of at least about any of 26.9, 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 15.5 years old, and has a BMI of no more than about any of 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 16 years old, and has a BMI of at least about any of 27.1, 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 16 years old, and has a BMI of no more than about any of 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 16.5 years old, and has a BMI of at least about any of 27.4, 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 16.5 years old, and has a BMI of no more than about any of 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 17 years old, and has a BMI of at least about any of 27.6, 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 17 years old, and has a BMI of no more than about any of 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 17.5 years old, and has a BMI of at least about any of 27.8, 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 17.5 years old, and has a BMI of no more than about any of 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the individual is a female, is about or at least about 18 years old, and has a BMI of at least about any of 28.0, 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8. In some embodiments, the individual is a female, is about or at least about 18 years old, and has a BMI of no more than about any of 28.3, 28.6, 28.9, 29.2, 29.5, 29.8, 30.1, 30.4, 30.7, 31, 31.3, 31.6, 31.9, 32.2, 32.5, or 32.8.

In some embodiments, the adolescent subject to be administered Mazdutide or a pharmaceutically acceptable salt thereof has previously undergone lifestyle intervention (i.e., diet and exercise) . In some embodiments, the lifestyle intervention has lasted at least four weeks, at least eight weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least 12 months. In some embodiments, the lifestyle intervention has lasted at least four weeks. In some embodiments, the lifestyle invention has lasted at least eight weeks. In some embodiments, the lifestyle intervention has lasted at least 12 weeks. In some embodiments, the lifestyle intervention has lasted at least 24 weeks. The lifestyle intervention can be diet, exercise, or a combination thereof. In some embodiments, the subject has had at least one failed attempt at weight control with lifestyle intervention (i.e., diet and exercise) . As used herein, a “failed attempt” at weight control meaning less than 5%weight loss during the period of weight control. In some embodiments, the adolescent subject has had at least one failed attempt at weight control with lifestyle intervention (i.e., diet and exercise) for an extended period (e.g., at least eight weeks) . In some embodiments, the adolescent subject has at least one failed attempt with lifestyle intervention for at least 12 weeks.

The amount of Mazdutide or a pharmaceutically acceptable salt thereof administered to an adolescent subject according to the methods disclosed herein is, generally, a therapeutically effective amount. In some embodiments, the dosage regimens of Mazdutide or a pharmaceutically acceptable salt thereof provided herein reduce body weight in an adolescent subject in need thereof. In some embodiments, the dosage regimens of Mazdutide or a pharmaceutically acceptable salt thereof provided herein improve weight management in an adolescent subject in need thereof. In some embodiments, the dosage regimens of Mazdutide or a pharmaceutically acceptable salt thereof provided herein treat overweight in an adolescent subject in need thereof. In some embodiments, the dosage regimens of Mazdutide or a pharmaceutically acceptable salt thereof provided herein treat overweight in an adolescent subject in need thereof. In some embodiments, the dosage regimens of Mazdutide or a pharmaceutically acceptable salt thereof provided herein treat obesity in an adolescent subject in need thereof. In some embodiments, the adolescent subject has had at least one failed attempt to control weight by lifestyle intervention.

The term “maintenance dose, ” as used herein, refers to the ongoing, regular, or recurrent dosage of a medication or treatment that is administered over an extended period to achieve or maintain a desired therapeutic effect. Maintenance doses can be administered after an initial course of treatment or induction phase has been completed. Maintenance doses can often be used for chronic conditions or to prevent the recurrence of a medical condition. In some embodiment, maintenance doses can be administered for a period of at least four weeks, at least eight weeks, or at least 12 weeks, or at least any of twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months. The maintenance dose can be adjusted over time based on the patient’s response to treatment, changes in their health status, or other factors. In some embodiments, the maintenance dose used in methods disclosed herein can be about 3.0 mg. The maintenance dose can be about 3.5 mg. the maintenance dose used in methods disclosed herein can be about 4.0 mg. The maintenance dose can be about 4.5 mg. The maintenance dose can be about 5.0 mg. The maintenance dose can be about 5.5 mg. The maintenance dose can be about 6.0 mg.

In some embodiments, provided herein are dosing regimens that include an escalation dose and a maintenance dose. As used herein, the term “escalation dose” as used herein refers to a temporary dose that is usually lower than the maintenance dose and administered earlier than the maintenance dose. Escalation doses are typically used as the initial or starting dose of the medication, which in itself may be insufficient to achieve the desired therapeutic effect but helps minimizing potential side effects or adverse reactions of the treatment. Escalation doses are typically administered gradually, with incremental increases in the medication dosage over a predetermined period. This approach allows the patient’s body to adjust to the higher dose and helps minimize the risk of adverse reactions. Accordingly, in some embodiments, dosing regimens provided herein include administering an escalation dose before administering the maintenance dose. In some embodiments, dosing regimens provided herein include administering sequentially a first escalation dose, a second escalation dose, and a maintenance dose, wherein the second escalation dose is higher than the first escalation dose and lower than the maintenance dose. In some embodiments, dosing regimens provided herein include administering sequentially a first escalation dose, a second escalation dose, a third escalation dose, and a maintenance dose, wherein the third escalation dose is higher than the second escalation dose and lower than the maintenance dose, and wherein the second escalation dose is higher than the first escalation dose and lower than the third escalation dose.

In some embodiments of the methods disclosed herein that comprise at least two escalation doses, the difference between each two consecutive doses can be the same or different. For example, in some embodiments, the dosage regimens provided herein comprise a first escalation dose, a second escalation dose, and a maintenance dose, wherein the three doses are equally spaced. For illustrative purposes, the dosage regimens can comprise, e.g., 2.0 mg as the first escalation dose, 4.0 mg as the second escalation dose, and 6.0 mg as the maintenance dose. The dosage regimens provided herein can comprise a third escalation dose, and optionally a four escalation, and so on, before reaching the maintenance dose, and all these doses can be equally spaced. For illustrative purposes, the dosage regimens can comprise, e.g., 1.0 mg as the first escalation dose, 2.0 mg as the second escalation dose, 3.0 mg as the third escalation dose, and 4.0 mg as the maintenance dose. In some embodiments, the doses of the treatment regimen are not equally spaced. For example, in the methods provided herein comprise a first escalation dose, a second escalation dose, and a maintenance dose, the difference between the first and second escalation dosed can be either smaller or larger than the difference between the second escalation dose and the maintenance dose. For illustrative purposes, the dosage regimens can comprise, e.g., 1.0 mg as the first escalation dose, 2.0 mg as the second escalation dose, and 4.0 mg as the maintenance dose. For illustrative purposes, the dosage regimens can comprise, e.g., 1.5 mg as the first escalation dose, 3.0 mg as the second escalation dose, and 4.0 mg as the maintenance dose.

In some embodiments of the treatment regiments provided herein, the escalation dose (s) is (are) administered for about four weeks. Additionally, it is understood by a person of ordinary skill in the art that the period can be adjusted as appropriate, for example, between one week and eight weeks. In some embodiments, the subject to be treated with the methods disclosed herein does not need escalation dose before receiving the maintenance dose. In some embodiments, the subject to be treated with the methods disclosed herein receives an escalation dose for two weeks. In some embodiments, the subject to be treated with the methods disclosed herein receives an escalation dose for three weeks. The subject can receive an escalation dose for four weeks. The subject can receive an escalation dose for five weeks. The subject can receive an escalation dose for six weeks. The subject can receive an escalation dose for seven weeks. The subject can receive an escalation dose for eight weeks. In some embodiments, the subject to be treated with the methods disclosed herein receives two escalation doses. The two escalation doses can be administered for the same length of time (e.g., four weeks) . The two escalation doses can also be administered for different lengths of time. In some embodiments, the first escalation dose can be administered for four weeks, and the second escalation dose can be administered for six weeks. It is understood by a person of ordinary skill in the art that the specifics of the escalation doses, e.g., the dosage and the length of each escalation dose of the dosage regimens provided herein can be adjusted as appropriate such that the subject to be treated by the methods disclosed herein receives the maintenance dose with minimum risk for possible adverse effect and maximum potential for achieving the therapeutic goal.

In some embodiments, methods provided herein comprise administering Mazdutide and a pharmaceutically acceptable salt thereof once weekly. Provided herein are dosing regimens that include administering at least one escalation dose about once weekly for about four weeks and thereafter at least one maintenance dose about once weekly for about four weeks. In some embodiment, the maintenance doses can be administered for about four weeks. In certain embodiments, the maintenance doses can be administered for more than about four weeks as determined by the patient and/or health care provider. For example, a maintenance dose can be administered for about five weeks, about six weeks, about seven weeks, or about eight weeks, or about any of twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, thirty-two weeks, forty-eight weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months. In some embodiments, a maintenance dose can be increased to a higher maintenance dose if further weight loss is needed. For example, in one dosing regimen, the escalation dose is about 2.0 mg, and the maintenance dose is about 4.0 mg; the maintenance dose can be further increased to about 6.0 mg.

As such, provided herein are method of reducing body weight, methods of improving weight management, and methods of treating overweight or obesity in an adolescent subject in need thereof, comprising administering Mazdutide or a pharmaceutically acceptable salt thereof according to the following dosage regimen: an escalation dose once weekly for of about four weeks and thereafter a maintenance dose about once weekly for about four weeks. In some embodiments, the escalation dose administered about once weekly for about four weeks is about 2.0 mg and the maintenance dose administered about once weekly for about four weeks is about 4.0 mg. In some embodiments, the escalation dose administered about once weekly for about four weeks is about 2.5 mg and the maintenance dose administered about once weekly for about four weeks is about 5.0 mg. In some embodiments, the escalation dose administered about once weekly for about four weeks is about 3.0 mg and the maintenance dose administered about once weekly for about four weeks is about 6.0 mg.

In some embodiments of the dosage regimens disclosed herein, after a first maintenance dose has been administered for about four weeks, a second maintenance dose is administered about once weekly for about four weeks. In some embodiments of the dosage regimens disclosed herein, after a second maintenance dose has been administered for about four weeks, a third maintenance dose is administered about once weekly for about four weeks. In some embodiments, after a third maintenance dose is administered about once weekly for about four weeks, a fourth maintenance dose is administered about once weekly for about four weeks.

Accordingly, in some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt thereof according to the following dosage regimen: an escalation dose once weekly for about four weeks, thereafter a first maintenance dose about once weekly for about four weeks, and thereafter a second maintenance dose about once weekly for about four weeks. In some embodiments, the escalation dose administered about once weekly for about four weeks is about 2.0 mg, the first maintenance dose administered about once weekly for about four weeks is about 4.0 mg, and the second maintenance dose administered about once weekly for about four weeks is about 6.0 mg. In some embodiments, the escalation dose administered about once weekly for about four weeks is about 1.5 mg, the first maintenance dose administered about once weekly for about four weeks is about 3.0 mg, and the second maintenance dose administered about once weekly for about four weeks is about 4.5 mg.

In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt thereof according to the following dosage regimen: an escalation dose once weekly for about four weeks, thereafter a first maintenance dose about once weekly for about four weeks, thereafter a second maintenance dose about once weekly for about four weeks, and thereafter a third maintenance dose about once weekly for about four weeks. In some embodiments, the escalation dose administered about once weekly for about four weeks is about 1.5 mg, the first maintenance dose administered about once weekly for about four weeks is about 3.0 mg, the second maintenance dose administered about once weekly for about four weeks is about 4.5 mg, and the third maintenance dose administered about once weekly for about four weeks is about 6.0 mg.

In some embodiments, provided herein are method of reducing body weight, methods of improving weight management, and methods of treating obesity in an adolescent subject in need thereof, comprising administering Mazdutide or a pharmaceutically acceptable salt thereof at a maintenance dose of about 4.0 mg. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof an escalation dose of about 2.0 mg once weekly for about four weeks, and thereafter a maintenance dose of about 4.0 mg once weekly for about four weeks. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof thereafter a maintenance dose of about 4.0 mg once weekly for about four weeks. The maintenance dose can be further adjusted if greater weight loss is desired.

In some embodiments, provided herein are method of reducing body weight, methods of improving weight management, and methods of treating obesity in a subject in need thereof, comprising administering Mazdutide or a pharmaceutically acceptable salt thereof at a maintenance dose of about 5.0 mg. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof an escalation dose of about 2.5 mg once weekly for about four weeks, and thereafter a maintenance dose of about 5.0 mg once weekly for about four weeks. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof a first escalation dose of about 1.5 mg once weekly for about four weeks, a second escalation dose of about 3.0 mg once weekly for about four weeks, and thereafter a maintenance dose of about 5.0 mg once weekly for about four weeks. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof thereafter a maintenance dose of about 5.0 mg once weekly for about four weeks. The maintenance dose can be further adjusted if greater weight control is desired.

In some embodiments, provided herein are method of reducing body weight, methods of improving weight management, and methods of treating obesity in a subject in need thereof, comprising administering Mazdutide or a pharmaceutically acceptable salt thereof at a maintenance dose of about 4.5 mg. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof an escalation dose of about 1.5 mg once weekly for about four weeks, thereafter a second escalation dose of about 3 mg once weekly for about four weeks, and thereafter a maintenance dose of about 4.5 mg once weekly for about four weeks. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof an escalation dose of about 3.0 mg once weekly for about four weeks, and thereafter a maintenance dose of about 4.5 mg once weekly for about four weeks. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof thereafter a maintenance dose of about 4.5 mg once weekly for about four weeks. The maintenance dose can be further adjusted if greater weight loss is desired.

In some embodiments, provided herein are method of reducing body weight, methods of improving weight management, and methods of treating obesity in a subject in need thereof, comprising administering Mazdutide or a pharmaceutically acceptable salt thereof at a maintenance dose of about 6.0 mg. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof an escalation dose of about 2.0 mg once weekly for about four weeks, thereafter a second escalation dose of about 4.0 mg once weekly for about four weeks, and thereafter a maintenance dose of about 6.0 mg once weekly for about four weeks. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof an escalation dose of about 3.0 mg once weekly for about four weeks, and thereafter a maintenance dose of about 6.0 mg once weekly for about four weeks. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof an escalation dose of about 4.0 mg once weekly for about four weeks, and thereafter a maintenance dose of about 6.0 mg once weekly for about four weeks. In some embodiments, methods provided herein comprise administering Mazdutide or a pharmaceutically acceptable salt to a subject in need thereof thereafter a maintenance dose of about 6.0 mg once weekly for about four weeks. The maintenance dose can be further adjusted if greater weight loss is desired.

While some exemplary embodiments described above provide that escalation dose (s) is (are) administered for about four weeks, it is understood by a person of ordinary skill in the art that the period can be adjusted, for example, between on week and eight weeks. In some embodiments, the adolescent subject to be treated with the methods disclosed herein does not need escalation dose and directly receives maintenance dose. In some embodiments, the adolescent subject to be treated with the methods disclosed herein receives an escalation dose for two weeks. The adolescent subject can receive an escalation dose for four weeks. The adolescent subject can receive an escalation dose for five weeks. The adolescent subject can receive an escalation dose for six weeks. The adolescent subject can receive an escalation dose for seven weeks. The adolescent subject can receive an escalation dose for eight weeks. In some embodiments, the adolescent subject to be treated with the methods disclosed herein receives a single escalation dose. In some embodiments, the adolescent subject to be treated with the methods disclosed herein receives two escalation doses.

In some embodiments, provided herein are method of reducing body weight, methods of improving weight management, and methods of treating obesity in a subject in need thereof, comprising administering Mazdutide or a pharmaceutically acceptable salt thereof at a maintenance dose of about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg. The maintenance dose can be about 3.0 mg. The maintenance dose can be about 3.5 mg. The maintenance dose can be about 4.0 mg. The maintenance dose can be about 4.5 mg. The maintenance dose can be about 5.0 mg. The maintenance dose can be about 5.5 mg. The maintenance dose can be about 6.0 mg. In some embodiments, the maintenance dose is administered about once weekly. In some embodiments, the maintenance dose is administered for at about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about eleven weeks, or about 12 weeks, or about any of sixteen weeks, twenty weeks, twenty-four weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months. In some embodiments, the maintenance dose is administered about once weekly for about four weeks. In some embodiments, the maintenance dose is administered about once weekly for about six weeks. In some embodiments, the maintenance dose is administered about once weekly for about eight weeks. In some embodiments, the maintenance dose is administered about once weekly for about ten weeks. In some embodiments, the maintenance dose is administered about once weekly for about 12 weeks or three months. In some embodiments, the maintenance dose is administered about once weekly for about six months. In some embodiments, the maintenance dose is administered about once weekly for about a year. In some embodiments, the maintenance dose is administered about once weekly for about one and a half year. In some embodiments, the maintenance dose is administered about once weekly for about two years. In some embodiments, the maintenance dose is administered about once weekly for about 8, 9, 10, or 11 months. In some embodiments, the maintenance dose is administered about once weekly for about 20, 21, 22, or 23 months.

It is expressly contemplated herein that methods disclosed can adopt any combination or permutation of the above-mentioned dosage regimens. For exemplary purposes, in some embodiments, provided herein are methods of treating obesity in an adolescent subject in need thereof, comprising administering to the subject an escalation dosage of about 2.0 mg once weekly for about four weeks and a maintenance dose of about 4.0 mg once weekly. In some embodiments, provided herein are methods of treating obesity in a subject in need thereof, comprising administering to the subject an escalation dosage of about 2.0 mg once weekly for about four weeks and a second escalation dose of about 4.0 mg once weekly for about four weeks, and a maintenance dose of about 6.0 mg once weekly. The administration of maintenance dose can last about four weeks. In some embodiments, administration of maintenance dose last about eight weeks.

Provided herein are methods of reducing body weight in an adolescent subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof. Provided herein are methods of improving weight management in an adolescent subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof. Provided herein are methods of treating obesity in an adolescent subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof.

In some embodiments, methods provided here reduce body weight by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, or at least 25%in the treated subject. In some embodiments, methods provided herein reduce body weight by at least 5%. In some embodiments, methods provided herein reduce body weight by at least 8%. In some embodiments, methods provided herein reduce body weight by at least 10%. In some embodiments, methods provided herein reduce body weight by at least 12%. In some embodiments, methods provided herein reduce body weight by at least 15%. In some embodiments, methods provided herein reduce body weight by at least 18%. In some embodiments, methods provided herein reduce body weight by at least 20%.

In some embodiments, methods provided here reduce body weight by about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, in the treated subject. In some embodiments, methods provided herein reduce body weight by about 5%. In some embodiments, methods provided herein reduce body weight by about 8%. In some embodiments, methods provided herein reduce body weight by about 10%. In some embodiments, methods provided herein reduce body weight by about 12%. In some embodiments, methods provided herein reduce body weight by about 15%. In some embodiments, methods provided herein reduce body weight by about 18%. In some embodiments, methods provided herein reduce body weight by about 20%.

In some embodiments, the weight loss is observed in four weeks or less, five weeks or less, six weeks or less, seven weeks or less, eight weeks or less, ten weeks or less, or 12 weeks or less. In some embodiments, the therapeutic effect is observed in about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about ten weeks, or about 12 weeks of initiating treatment. In some embodiments, initiating treatment refers to the first dosing of the maintenance dose of Mazdutide or a pharmaceutically acceptable salt thereof as described herein.

For example, in some embodiments, the method is therapeutically effective to achieve at least 5%weight loss. In some embodiments, the at least 5%weight loss is achieved in 4 or less weeks of initiating treatment. In some embodiments, the at least 5%weight loss is achieved in 8 or less weeks of initiating treatment. In some embodiments, the at least 5%weight loss is achieved in 12 or less weeks of initiating treatment. In some embodiments, initiating treatment refers to the first dosing of the maintenance dose of Mazdutide or a pharmaceutically acceptable salt thereof as described herein.

In some embodiments, the weight loss achieved with the treatment disclosed herein can be maintained for at least four weeks, at least eight weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, or at least 36 weeks, after the completion of the treatment. In some embodiments, the weight loss achieved with the treatment disclosed herein can be maintained for four weeks after the completion of the treatment. In some embodiments, the weight loss achieved with the treatment disclosed herein can be maintained for eight weeks after the completion of the treatment. In some embodiments, the weight loss achieved with the treatment disclosed herein can be maintained for 12 weeks after the completion of the treatment. In some embodiments, the weight loss achieved with the treatment disclosed herein can be maintained for 24 weeks after the completion of the treatment. In some embodiments, the weight loss achieved with the treatment disclosed herein can be maintained for 36 weeks after the completion of the treatment. In some embodiments, the weight loss achieved with the treatment disclosed herein can be maintained for 48 weeks after the completion of the treatment.

In some embodiments, methods provided herein achieve reduced BMI in the treated subject. Accordingly, in some embodiments, methods provided herein reduce BMI by at least 1.0 kg/m2, at least 1.5 kg/m2, at least 2.0 kg/m2, at least 2.5 kg/m2, at least 3.0 kg/m2, at least 3.5 kg/m2, at least 4.0 kg/m2, at least 4.5 kg/m2, or at least 5.0 kg/m2, in the treated subject. In some embodiments, methods provided herein reduce BMI by at least 2.0 kg/m2 in the treated subject. In some embodiments, methods provided herein reduce BMI by at least 3.0 kg/m2 in the treated subject. In some embodiments, methods provided herein reduce BMI by about 1.0 kg/m2, about 1.5 kg/m2, about 2.0 kg/m2, about 2.5 kg/m2, about 3.0 kg/m2, about 3.5 kg/m2, about 4.0 kg/m2, about 4.5 kg/m2, or about 5.0 kg/m2, in the treated subject. In some embodiments, methods provided herein reduce BMI by about 2.0 kg/m2 in the treated subject. In some embodiments, methods provided herein reduce BMI by about 2.5 kg/m2 in the treated subject. In some embodiments, methods provided herein reduce BMI by about 3.0 kg/m2 in the treated subject. In some embodiments, methods provided herein reduce BMI by about 3.5 kg/m2 in the treated subject. In some embodiments, methods provided herein reduce BMI by about 4.0 kg/m2 in the treated subject.

In some embodiments, methods provided herein achieve reduced BMI in the treated subject. Accordingly, in some embodiments, methods provided herein reduce BMI to 24 kg/m2 or less, 25%kg/m2 or less, 26%kg/m2 or less, 27%kg/m2 or less, or 28%kg/m2 or less in the treated subject. In some embodiments, methods provided herein reduce BMI to 24 kg/m2 or less in the treated subject. In some embodiments, methods provided herein reduce BMI to 28 kg/m2 or less in the treated subject. In some embodiments, the method is therapeutically effective to achieve reduced BMI (e.g., 24 kg/m2 or less; 28 kg/m2 or less) in 4 or less, 8 or less, or 12 or less weeks of initiating treatment. In some embodiments, the method is therapeutically effective to achieve reduced BMI in 4 or less weeks of initiating treatment. In some embodiments, the method is therapeutically effective to achieve reduced BMI in 8 or less weeks of initiating treatment. In some embodiments, the method is therapeutically effective to achieve reduced BMI in 12 or less weeks of initiating treatment. In some embodiments, initiating treatment refers to the first dosing of the maintenance dose of Mazdutide or a pharmaceutically acceptable salt thereof as described herein.

In some embodiments, the reduction in BMI achieved with the treatment disclosed herein can be maintained for at least four weeks, at least eight weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, or at least 36 weeks, after the completion of the treatment.

In addition to weight control, methods provided herein can provide additional benefits for the treated subjects. In some embodiments, the subjects treated with methods disclosed herein have weight loss measurable by waist circumference, neck circumference, or hip circumference. In some embodiments, the subject has reduced waist circumference. In some embodiments, the subject has reduced neck circumference. In some embodiments, the subject has reduced hip circumference.

In some embodiments, these therapeutic benefits can be achieved in 4 or less, 8 or less, or 12 or less weeks of initiating treatment. In some embodiments, the therapeutic benefits can be maintained at least four weeks, at least eight weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, or at least 36 weeks, after the completion of the treatment.

In some embodiments, methods provided herein further comprise monitoring for adverse events during the administration of Mazdutide or a pharmaceutically acceptable salt thereof and optionally, interrupting or terminating the administration. AEs include, but are not limited to, the following: exacerbation of a pre-existing medical condition/disease (including exacerbation of symptoms, signs, or abnormal laboratory tests) ; occurrence of any new adverse medical condition (including symptoms, signs, or newly diagnosed disease) ; any abnormal laboratory test value or result that has significant clinical significance.

In some embodiments, methods provided herein further comprise monitoring vital signs (including blood pressure, pulse, respiratory rate and body temperature) and/or physical examination during the administration, or monitoring hematology and serum chemistry during the treatment cycle. In some embodiments, heart rate or heart signal is monitored. In some embodiment, heart rate or heart signal is monitored by electrocardiogram.

In some embodiments, methods provided herein result in none of the following adverse events: severe gastrointestinal reactions (nausea, vomiting, diarrhea) , hypoglycemic events, acute pancreatitis, thyroid malignancy and thyroid C-cell hyperplasia, major cardiovascular adverse events, supraventricular tachycardia and conduction block, anaphylaxis and injection site reactions, diabetic retinopathy complications, acute kidney injury, and acute gallbladder disease.

As used herein and understood in the art, a “hypoglycemic event” refers to an occurrence of 1-hour continuous glucose levels of 3.9 mmol/L. Hypoglycemic grading criteria are:

· Grade 1 hypoglycemic: 54 mg/dL (3.0 mmol/L) ≤ glucose < 70 mg/dL (3.9 mmol/L)

· Grade 2 hypoglycemic: glucose < 54 mg/dL (3.0 mmol/L)

· Grade 3 hypoglycemic (severe hypoglycemic) : The subject requires assistance from others to obtain carbohydrates, glucagon, or other rescue measures. During this period, the patient experiences changes in consciousness, is unable to self-administer the aforementioned recovery treatments, may be unconscious or semi-conscious, or may fall into a coma (regardless of whether accompanied by symptoms of seizures) and require intravenous nutritional support. In such events, blood glucose measurements may not be recorded. Because neurological symptoms recover as the blood glucose returns to normal, it is clear that such events were caused by hypoglycemia.

In some embodiments, methods provided herein result do not cause a Grade 3 hypoglycemic event. In some embodiments, methods provided herein result do not cause a Grade 2 or Grade 3 hypoglycemic event.

Methods of treatment provided herein reference certain methods of diagnosis, methods of evaluation (e.g., of severity of condition, progress of condition, or of improvement of condition) . Standard procedures of such methods are well known by and available to persons of ordinary skill in the art. For exemplary purposes, some representative methods and procedures are described here.

Weight

Standard protocol for weight measurement: weight measurement should be conducted in a standardized manner using a calibrated scale (either mechanical or electronic) . When measuring weight, participants should have urinated, and should remove any clothing or accessories that could add extra weight, such as coats, pants, hats, scarves, necklaces, belts, etc. They should be dressed in a single layer of clothing (limited to one upper garment and one lower garment) and should remove their shoes. Ensure that the weight scale is zeroed before weighing. Participant should step onto the weight scale and stand still on both feet with their arms at their sides.

Waist circumference

When measuring wait circumference, participants should take standing position, relax shoulders and abdomen, breathe steadily, and keep feet apart by 25～30 cm. Horizontal measurement is taken at the midpoint of the line connecting the anterior superior iliac spine (ASIS) and the lower edge of the 12th rib on the midaxillary line. A tape is used which wraps around the waist at the above-mentioned horizontal position. When measuring, the tape measure should be snug against the skin but not tight. During the measurement, participants should not consciously pull in or push out abdomen. The measurement should be taken at the end of a calm exhalation.

Neck circumference

When measuring neck circumference, participants should stand upright, gaze straight ahead, and shoulders down. The tape measure should be snug against the skin but not tight. Horizontal measurement of the neck (one full circle) is taken just below the Adam’s apple (thyroid cartilage) and around the middle of the neck.

Hip circumference

When measuring hip circumstance, the subject should stand naturally with relaxed shoulders, arms hanging naturally and slightly apart, legs together, weight evenly distributed on both legs, and hips relaxed while looking straight ahead. The horizontal measurement position is as follows: in front, it corresponds to the pubic symphysis, and in the back, it corresponds to the greater trochanter of the femur. Typically, this measurement is taken at the most prominent part of the hips.

Patient report outcome (PRO) questionnaires

The Patient Reported Outcome (PRO) Questionnaires should be completed by patients without external interference. This study utilizes the IWQoL-Lite-CT questionnaire and the SF-36v2 questionnaire to assess the subjects’ quality of life.

The IWQOL-Lite-CT questionnaire consists of 20 questions aimed at evaluating the impact of weight changes on the physical and psychosocial functioning of patients. It includes three composite scores (physical function, physical and psychosocial) as well as a total score.

The SF-36v2 questionnaire comprises 36 questions designed to assess the overall health-related quality of life of patients. It is divided into 8 domains: physical functioning, bodily pain, role-physical, general health, vitality, social functioning, role-emotional, and mental health. These questions can also be combined to provide two summary component scores (overall mental and physical health) .

Exemplified embodiments

Embodiment 1: A method for treating obesity in an adolescent subject in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof.

Embodiment 2: The method of Embodiment 1, comprising administering Mazdutide or the pharmaceutically acceptable salt at a maintenance dose of about 4.0 mg once weekly.

Embodiment 3: The method of Embodiment 2, comprising administering Mazdutide or the pharmaceutically acceptable salt at an escalation dose of about 2.0 mg once weekly before administering the maintenance dose.

Embodiment 4: The method of Embodiment 3, wherein the escalation dose is administered for about four weeks.

Embodiment 5: The method of any one of Embodiments 2 to 4, wherein the maintenance dose is administered for about eight weeks.

Embodiment 6: The method of Embodiment 1, comprising administering Mazdutide or the pharmaceutically acceptable salt at a maintenance dose of about 6.0 mg once weekly.

Embodiment 7: The method of Embodiment 6, comprising administering Mazdutide or the pharmaceutically acceptable salt at a first escalation dose of about 2.0 mg once weekly, and at a second escalation dose of about 4.0 mg once weekly before administering the maintenance dose.

Embodiment 8: The method of Embodiment 7, wherein the first and second escalation doses are each administered for about four weeks.

Embodiment 9: The method of any one of Embodiments 6 to 8, wherein the maintenance dose is administered for about four weeks.

Embodiment 10: The method of any one of Embodiments 1 to 9, wherein the subject has adolescent obesity according to the WHO Standard, the China Standard, or the United States Standard.

Embodiment 11: The method of any one of Embodiments 1 to 10, wherein the method results in at least 5%weight loss in the subject.

Embodiment 12: Use of Mazdutide or a pharmaceutically acceptable salt thereof in the treatment of adolescent obesity.

Embodiment 13: Use of Mazdutide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of adolescent obesity.

Embodiment 14: The use of Embodiment 12 or 13, wherein adolescent obesity is determined according to the WHO Standard, the United States Standard, or the China Standard.

Embodiment 15: The use of any one of Embodiments 12 to 14, wherein Mazdutide or the pharmaceutically acceptable salt is administered at a maintenance dose of about 4.0 mg once weekly.

Embodiment 16: The use of Embodiment 15, wherein Mazdutide or the pharmaceutically acceptable salt is administered at an escalation dose of about 2.0 mg once weekly before the maintenance dose.

Embodiment 17: The use of Embodiment 16, wherein the escalation dose is administered for about four weeks.

Embodiment 18: The use of any one of Embodiments 15 or 17, wherein the maintenance dose is administered for about eight weeks.

Embodiment 19: The use of any one of Embodiments 12 to 14, wherein Mazdutide or the pharmaceutically acceptable salt is administered at a maintenance dose of about 6.0 mg once weekly.

Embodiment 20: The use of Embodiment 19, wherein Mazdutide or the pharmaceutically acceptable salt is administered at a first escalation dose of about 2.0 mg once weekly, and a second escalation dose of about 4.0 mg once weekly before the maintenance dose.

Embodiment 21: The use of Embodiment 20, wherein the first and second escalation doses are each administered for about four weeks.

Embodiment 22: The use of any one of Embodiments 19 to 21, wherein the maintenance dose is administered for about eight weeks.

Embodiment 23: The use of any one of Embodiments 12 to 22, wherein the treatment results in at least 5%weight loss.

Embodiment 24: A composition having Mazdutide or a pharmaceutically acceptable salt thereof for use in the treatment of adolescent obesity.

Embodiment 25: The composition for use of Embodiment 24, wherein adolescent obesity is determined according to the WHO Standard, the United States Standard, or the China Standard.

Embodiment 26: The composition for use of Embodiment 24 or 25, wherein the use comprises administering Mazdutide or the pharmaceutically acceptable salt at a maintenance dose of about 4.0 mg once weekly.

Embodiment 27: The composition for use of Embodiment 26, wherein the use comprises administering an escalation dose of about 2.0 mg once weekly before administering the maintenance dose.

Embodiment 28: The composition for use of Embodiment 27, wherein the escalation dose is administered for about four weeks.

Embodiment 29: The composition for use of any one of Embodiments 26 to 28, wherein the maintenance dose is administered for about eight weeks.

Embodiment 30: The composition for use of Embodiment 24 or 25, comprising administering at a maintenance dose of about 6.0 mg once weekly.

Embodiment 31: The composition for use of Embodiment 30, wherein the use comprises administering a first escalation dose of about 2.0 mg once weekly, and a second escalation dose of about 4.0 mg once weekly before administering the maintenance dose.

Embodiment 32: The composition for use of Embodiment 31, wherein the first and second escalation doses are each administered for about four weeks.

Embodiment 33: The composition for use of any one of Embodiments 30 to 32, wherein the maintenance dose is administered for about four weeks.

Embodiment 34: The composition for use of any one of Embodiments 24 to 33, wherein the method results in at least 5%weight loss in the subject.

Examples

The examples provided below are for purposes of illustration only, which are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

The active pharmaceutical ingredient under investigation of the studies described below is Mazdutide. Briefly, results from the studies described below demonstrate at the specified regimens, Mazdutide is safe and effective in treating adolescent obesity.

Example 1: Phase I and Phase II studies in treating obesity

Phase I study: A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the safety, tolerability and PK/PD of multiple administration of Mazdutide in overweight or obese subjects. Data showed good efficacy of Mazdutide in reducing weight in obese patients. It also lowered blood sugar, blood lipids, blood pressure, and liver enzyme levels, indicating overall metabolic improvement for patients. The majority of adverse events were mild gastrointestinal events. There were no unexpected adverse events.

Phase II study: A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of Mazdutide in overweight and obese subjects. In the first phase, 248 subjects were enrolled. Qualified subjects received placebo run-in for two weeks. After a successful run-in, the subjects were randomly assigned to the 3.0 mg, 4.5 mg and 6.0 mg dosage groups. The following dosage regimens were provided (QW: once weekly) : (1) 3.0 mg dosage group: 1.5 mg QW for 4 weeks + 3.0 mg QW for 20 weeks. (2) 4.5 mg dosage group: 1.5 mg QW for 4 weeks + 3.0 mg QW for 4 weeks + 4.5 mg QW for 16 weeks. (3) 6.0 mg dosage group: 2.0 mg QW for 4 weeks + 4.0 mg QW for 4 weeks + 6.0 mg QW for 16 weeks.

Results:

Mazdutide demonstrated dose-dependent weight-reducing efficacy in obese or overweight subjects. As shown in FIG. 1A, at week 25, the least squares mean value of weight change (percentage change) from baseline were -6.35kg (-7.2%) , -9.08kg (-10.6%) , -9.86kg (-11.6%) and 1.08kg (1.0%) , in the Mazdutide 3.0 mg, Mazdutide 4.5 mg, Mazdutide 6.0 mg groups and the placebo group respectively. Compared with the placebo group, the estimated difference in relative baseline changes at week 25 were -6.70% (0.740) , -10.38% (0.724) , -11.30% (0.735) and 1.02% (0.738) , in the Mazdutide 3.0 mg, Mazdutide 4.5 mg, Mazdutide 6.0 mg, and placebo groups, respectively (p-value less than 0.0001 in all groups) . As shown in FIG. 1B, at Week 25, the percentages of subjects whose body weight decreased by at least 5%from the baseline were 58.1%, 82.5%and 80.3%, in the groups receiving Mazdutide 3.0 mg, Mazdutide 4.5 mg and Mazdutide 6.0 mg, respectively, compared to 4.8%in the placebo group; the percentages of subjects whose body weight decreased by at least 10%from the baseline were 19.4%, 49.2%and 50.8%, in the groups receiving Mazdutide 3.0 mg, Mazdutide 4.5 mg and Mazdutide 6.0 mg, respectively, compared to 0%in the placebo group; the percentages of subjects whose body weight decreased by at least 15%from the baseline were 9.7%, 15.9%, and 26.2%respectively, compared to 0%in the placebo group.

Also, at Week 25, the least squares mean value of BMI change from baseline were -2.30 kg/m², -3.30 kg/m², -3.62 kg/m², and 0.36 kg/m², in the Mazdutide 3.0 mg, Mazdutide 4.5 mg, Mazdutide 6.0 mg, and the placebo group, respectively; and the percentage of subjects whose BMI was < 24 kg/m2 were 8.1%, 17.5%and 26.2%, in the Mazdutide 3.0 mg, Mazdutide 4.5 mg and Mazdutide 6.0 mg groups, respectively, compared to 0%in the placebo group.

Additionally, at Week 25, the corrected least squares estimated means of the change in waist circumference from baseline for the Mazdutide 3.0 mg group, the Mazdutide 4.5 mg group, the Mazdutide 6.0 mg group, and the placebo group were -5.58 cm, -8.45 cm -8.75 cm, and -1.13 cm, respectively (FIG. 2) .

Mazdutide not only demonstrated significant efficacy in promoting weight loss and reduction in waist circumference, but also reduced blood lipids, blood pressure, blood uric acid and liver enzymes, bringing multiple metabolic benefits to overweight or obese subjects.

Mazdutide was generally safe and well tolerated. Treatment emergent adverse events (TEAE) were mostly mild or moderate. One subject had a TEAE that led to discontinuation of the study, which was unrelated to the study drug. Nine subjects had a serious adverse event (SAE) , including infectious pneumonia, anal abscess, disc herniation, synovitis, spontaneous abortion, ovarian cyst, vertigo, ureterolithiasis, and anal fissure, all of which were unrelated to the study drug. No severe hypoglycemic events, acute pancreatitis, or psychiatric adverse events were reported.

Example 2: Phase Ib study in treating adolescent obesity

This is a randomized, double-blind, placebo-controlled phase Ib clinical study to evaluate the safety and efficacy of Mazdutide in treating obese adolescent patients. 36 subjects are included.

Study population: Subjects must meet the following criteria to be included in this study: 1.18 > age ≥ 12 years; 2. meeting the obesity criteria described in the “WS/T586‐2018 Screening for Overweight and Obesity in School-aged Children and Adolescents” ; 3. having less than 5%weight loss after a minimum of 12 weeks of diet and exercise control, as reported by the subject, parents, or legal guardians; 4. capable of maintaining a stable diet and regular exercise during the study period; 5. signing of consent form by subject or his/her parent or legal guardian, understanding the protocol and agreeing to strictly follow the protocol. Subjects that meet one of the following criteria were excluded: pre-puberty (Tanner I) ; suspected to be allergic to the study drug or ingredients or has an allergic tendency; pre-treatment within 3 months of the screening period with one or more of: 1) GLP-1 receptor (GLP-1R) agonist, GLP-1R/GCGR agonist, GIPR/GLP-1R agonist, or GIPR/GLP-1R/GCGR agonist, 2) medicines that may affect body weight, including: systemic steroid hormones (intravenous, oral or intra-articular administration) , metformin, sodium glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones (TZD) , tricyclic antidepressants, psychiatric medications or sedative drugs (such as imipramine, amitriptyline, azapine, paroxetine, phenelzine, chlorpromazine, thioridazine, clozapine, olanzapine, valproic acid, valproic acid derivatives, lithium salts) ; 3) Chinese herbal medicines, health products, meal replacements, etc. that affect weight; 4) weight loss drugs, such as: sibutramine hydrochloride, oligosaccharide Orlistat, phenylpropanolamine, chlorpheniramine, phentermine, bupropion, lorcaserin, Phentermine/topiramate mixture, naltrexone/bupropion mixture, etc; 5) other study drugs from other clinical trial participation.

The entire study includes a 3-week screening phase, a 12-week double-blind treatment period, and a 8-week safety follow-up period.

Study drug: Mazdutide is provided in pre-filled injection pens in three dosage forms: 0.5 ml: 2 mg, 0.5 ml: 4 mg, and 0.5 ml: 6 mg. The injectable formulation includes Mazdutide and tromethamine, mannitol, propylene glycol (for injection) , disodium edetate, dilute hydrochloric acid, sodium hydroxide, and water for injection as excipients.

Placebo is also provided in pre-filled injection pens. The injectable solution consists of tromethamine, mannitol, propylene glycol (for injection) , disodium edetate, diluted hydrochloric acid, sodium hydroxide and water for injection.

The entire study includes included a 4-week screening phase, a 6-week run-in period, a 24-week double-blind treatment period, a 24-week study extension period, and a 4-week safety follow-up period.

The patents were stratified into Mazdutide 4.0 group (n=12) , Mazdutide 6.0 group (n=12) , or Placebo group (n=12) , as described below.

Treatment regimens:

Mazdutide and placebo are administered by QW abdominal subcutaneous injection. The treatment regimens are listed below.

Endpoint:

Primary endpoint:

(1) Safety, tolerability: number, incidence and relevance to the study drug or treatment of Adverse Event (AE) , Treatment Emergent Adverse Event (TEAE) , Adverse Event of Special Interest (AESI) and Severe Adverse Event (SAE) ; vital signs, investigations, laboratory tests and cardiology. AESI) and Severe Adverse Event (SAE) ; changes in vital signs, results of physical examination, laboratory tests, and electrocardiograms. (2) Maximum tolerated dose: During dose escalation, if the dose exploration is stopped when the “dose escalation stop criteria" is reached at a certain dose level, the previous dose is the maximum tolerated dose; if the “dose escalation stop criteria” is not met when the highest escalation dose is reached, then the maximum tolerated dose is greater than or equal to the highest creeping dose.

“Dose escalation stop criteria” : If any one of the following criteria is met, dose escalation is terminated for that dose or any higher dose: (1) occurrence of heart rate >110 per minute in >50%of subjects receiving the same dose; (2) occurrence of at least one treatment-related serious adverse event (other than anticipated adverse events related to the pharmacologic properties of Mazdutide, such as hypoglycemia, gastrointestinal adverse reactions, etc. ) ; (3) occurrence of Mazdutide-related symptomatic hypoglycemic events in not less than 50%of subjects (plasma or peripheral glucose levels <2.8 mmol/L) ; (4) persistent (more than one week) symptoms of acute pancreatitis in not less than 2 subjects receiving Mazdutide; and (5) occurrence of Mazdutide-related non-SAE of a severe classification in not less than 2 subjects receiving Mazdutide, whether or not associated with the same organ or system.

It is expected that both 4.0 mg and 6.0 mg are safe and well tolerated in obese adolescents.

Secondary Endpoints:

(1) PK parameters of Mazdutide in adolescent obese subjects, including, but not limited to: Time to Maximum Concentration (Tmax) , Peak Concentration (Maximum Concentration, Cmax) , Area under the Curve (AUC) , Time to Dose (Td) , and Time to Dose (Td) . the Curve (AUC) , volume of distribution (Vd) , half-life (T1/2) , and clearance (CL) . (2) Change in fasting weight, BMI, waist-to-hip ratio, blood pressure, blood lipids [total cholesterol (TC) , triglyceride (TG) , non-high density lipoprotein cholesterol (non-HDL-C) , non-high density lipoprotein (HDL-C) , low-density lipoprotein cholesterol (LDL-C) ] and HbA1c relative to baseline at week 12.

Exploratory Endpoints:

Assessment of pancreatic β-cell function using homeostasis model assessment 2 of insulin resistance (HOMA2-IR) .

Statistical analysis: This study will mainly conduct descriptive statistical analysis on the efficacy endpoints.

For continuous efficacy endpoints, means and two-sided 95%confidence intervals of the Mazdutide group and the placebo group were calculated respectively. Two-sample t-test is used to calculate the p-value of the Mazdutide group compared to the placebo group and the corresponding point estimate of the difference and 95%confidence interval. Missing values will be imputed using the LOCF method.

For categorical efficacy endpoints, the proportion within each dose group is calculated and the 95%confidence interval within the group is calculated using Clopper-Pearson. The Chi square test is used to compare the differences between the Mazdutide group and the placebo group and calculate the corresponding 95%confidence interval. Missing values for categorical endpoint will be filled using the default non-response method.

For safety analysis, system organ class, preferred terminology, and adverse event grading according to the International Medical Dictionary for Regulatory Activities (MedDRA) summarize the status of each TEAE. Number of subjects. Summarize the number and percentage of subjects with various categories of AEs (including causal relationships, serious severity, SAE, etc. ) and further summarized according to MedDRA System Organ Classification and Preferred Terminology AE in each category.

References

The following publications are hereby incorporated by reference in their entireties:

https: //www. cdc. gov/obesity/data/index. html

Bray et al., Lancet. 2016; 387 (10031) : 1947-56.

World Obesity Federation. World obesity atlas 2022.

Bray GA et al. Obes. Rev. 2017; 18: 715-23.

Daniels et al., Circulation 2005; 111: 1999-2012.

Small and Aplasca, Child Adolesc Psychiatr Clin N Am 2016; 25: 269-82.

Pocai, Mol Metab. 2014; 3 (3) : 241-51.

Tan TM et al., Diabetes. 2013; 62 (4) : 1131-8.

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

Claims

A method for treating obesity in an adolescent subject in need thereof comprising administering to the subject a therapeutically effective amount of Mazdutide or a pharmaceutically acceptable salt thereof.
The method of claim 1, comprising administering Mazdutide or the pharmaceutically acceptable salt at a maintenance dose of about 4.0 mg once weekly.
The method of claim 2, comprising administering Mazdutide or the pharmaceutically acceptable salt at an escalation dose of about 2.0 mg once weekly before administering the maintenance dose.
The method of claim 3, wherein the escalation dose is administered for about four weeks.
The method of any one of claims 2 to 4, wherein the maintenance dose is administered for at least about any of eight weeks, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, thirty-two weeks, forty-eight weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months.
The method of claim 1, comprising administering Mazdutide or the pharmaceutically acceptable salt at a maintenance dose of about 6.0 mg once weekly.
The method of claim 6, comprising administering Mazdutide or the pharmaceutically acceptable salt at a first escalation dose of about 2.0 mg once weekly, and at a second escalation dose of about 4.0 mg once weekly before administering the maintenance dose.
The method of claim 7, wherein the first and second escalation doses are each administered for about four weeks.
The method of any one of claims 6 to 8, wherein the maintenance dose is administered for about 4 weeks.
The method of any one of claims 1 to 9, wherein the subject a) has adolescent obesity according to the WHO Standard, the China Standard, or the United States Standard, b) is a female, c) is a male, d) is in Tanner stage II, III, IV, and/or V, e) is at least about or about any of 12, 13, 14, 15, 16, 17, or 18 years old, and/or f) is no more than about any of 18, 17, 16, 15, 14, 13, or 12 years old.
The method of any one of claims 1 to 10, wherein the method results in at least 5%weight loss in the subject.
Use of Mazdutide or a pharmaceutically acceptable salt thereof in the treatment of adolescent obesity.
Use of Mazdutide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of adolescent obesity.
The use of claim 12 or 13, wherein adolescent obesity is determined according to the WHO Standard, the United States Standard, or the China Standard.
The use of any one of claims 12 to 14, wherein Mazdutide or the pharmaceutically acceptable salt is administered at a maintenance dose of about 4.0 mg once weekly.
The use of claim 15, wherein Mazdutide or the pharmaceutically acceptable salt is administered at an escalation dose of about 2.0 mg once weekly before the maintenance dose.
The use of claim 16, wherein the escalation dose is administered for about four weeks.
The use of any one of claims 15 or 17, wherein the maintenance dose is administered for at least about any of or about eight weeks, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, thirty-two weeks, forty-eight weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months.
The use of any one of claims 12 to 14, wherein Mazdutide or the pharmaceutically acceptable salt is administered at a maintenance dose of about 6.0 mg once weekly.
The use of claim 19, wherein Mazdutide or the pharmaceutically acceptable salt is administered at a first escalation dose of about 2.0 mg once weekly, and a second escalation dose of about 4.0 mg once weekly before the maintenance dose.
The use of claim 20, wherein the first and second escalation doses are each administered for about four weeks.
The use of any one of claims 19 to 21, wherein the maintenance dose is administered for at least about any of or about eight weeks, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, thirty-two weeks, forty-eight weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months.
The use of any one of claims 12 to 22, wherein the treatment results in at least 5%weight loss.
A composition having Mazdutide or a pharmaceutically acceptable salt thereof for use in the treatment of adolescent obesity.
The composition for use of claim 24, wherein adolescent obesity is determined according to the WHO Standard, the United States Standard, or the China Standard.
The composition for use of claim 24 or 25, wherein the use comprises administering Mazdutide or the pharmaceutically acceptable salt at a maintenance dose of about 4.0 mg once weekly.
The composition for use of claim 26, wherein the use comprises administering an escalation dose of about 2.0 mg once weekly before administering the maintenance dose.
The composition for use of claim 27, wherein the escalation dose is administered for about four weeks.
The composition for use of any one of claims 26 to 28, wherein the maintenance dose is administered for at least about any of or about eight weeks, twelve weeks, sixteen weeks, twenty weeks, twenty-four weeks, thirty-two weeks, forty-eight weeks, six months, nine months, twelve months, fifteen months, eighteen months, twenty-one months, or twenty-four months.
The composition for use of claim 24 or 25, comprising administering at a maintenance dose of about 6.0 mg once weekly.
The composition for use of claim 30, wherein the use comprises administering a first escalation dose of about 2.0 mg once weekly, and a second escalation dose of about 4.0 mg once weekly before administering the maintenance dose.
The composition for use of claim 31, wherein the first and second escalation doses are each administered for about four weeks.
The composition for use of any one of claims 30 to 32, wherein the maintenance dose is administered for about 4 weeks.
The composition for use of any one of claims 24 to 33, wherein the method results in at least 5%weight loss in the subject.