Pharmaceutical composition comprising efpeglenatide as active ingredient and administration therapy thereof

Abstract

The present invention relates to a pharmaceutical composition comprising efpeglenatide as an active ingredient and a method for treating obesity using same. The administration of the composition comprising efpeglenatide according to the present invention can provide a weight loss effect in obese patients without causing side effects.

Description

Pharmaceutical composition containing efpeglenatide as an active ingredient and its administration regimen

[0001] The present invention relates to a pharmaceutical composition containing efpeglenatide as an active ingredient and a method for preventing and treating obesity using the same.

[0002]

[0003] Obesity is a metabolic disease caused by energy imbalance due to excessive nutrient intake compared to energy expenditure over a long period of time. It occurs due to a complex genetic or phenomenological relationship between various neuroendocrine substances and abnormalities in various elements related to energy metabolism. Diagnosis of obesity requires a comprehensive assessment including body mass index (BMI), bioimpedence analysis (BIA), and CT scan of waist circumference and abdominal fat. However, body mass index, which can be easily estimated using only height and weight, is generally used as a standard for diagnosing and classifying obesity stages.

[0004] The World Health Organization defines a body mass index of 25 kg / m 2 Less than normal, 25 - 29.99 kg / m 2 Overweight range, 30 kg / m 2 Obesity is classified as above, and most countries use this standard. However, because the relationship between body mass index or body fat percentage and disease morbidity or mortality varies depending on race and ethnicity, there is a need to set standards that take into account race and ethnicity rather than defining obesity uniformly. Accordingly, some Asian countries use somewhat different standards. In the case of Korea, it is not the WHO standard, but a body mass index of 25 kg / m2. 2 Less than normal, 25 - 29.99 kg / m 2 Range: Obesity stage 1, 30 kg / m 2 Obesity is diagnosed and classified based on the criteria for stage 2-3 obesity.

[0005] Currently, the primary treatment methods for obesity are diet, exercise, and behavioral therapy, with pharmacological therapy recommended as an adjunctive treatment alongside these. Recently, a new market is emerging, centered around GLP-1 agents as an obesity treatment drug.

[0006] GLP-1 (Glucagon-Like Peptide-1) is an incretin hormone secreted by L cells in the ileum and colon. It was first discovered in 1985. When blood sugar levels exceed the basal level (4.5 mM) after food intake, it binds to receptors on pancreatic β cells, stimulating insulin secretion to lower blood sugar levels. It has the characteristic of stimulating insulin secretion according to blood sugar concentration, preventing hypoglycemia. In addition, because it suppresses glucagon secretion, it has been approved and marketed worldwide, including in Korea, as a treatment for type 2 diabetes mellitus (T2DM). Subsequently, as additional effects of GLP-1 on lowering upper digestive tract motility, delaying gastric emptying, and suppressing appetite were discovered, further development as an obesity treatment was promoted, and GLP-1 analogs such as Liraglutide and Semaglutide are currently used worldwide as obesity treatment agents. However, most GLP-1 analogue preparations to date are based on the World Health Organization's criteria for diagnosing obesity, with a body mass index of 30 kg / m 2 Ideal or body mass index 27 kg / m 2 It targets obese patients with one or more comorbidities and a lower body mass index of 25 - 29.99 kg / m 2 Treatments that can be used in obese patients are still underdeveloped.

[0007]

[0008] Meanwhile, even if the effectiveness of a drug is confirmed based on test tube experiments, when administering it to an individual (especially a human), it is necessary to determine the dosage and route of administration that can be both safe and effective through clinical trials. For this reason, it is difficult to develop a drug that can pass actual clinical trials and be commercialized.

[0009] Dose translation from animal to human studies is extremely complex and difficult, and is considered one of the most challenging aspects of new drug development (Reagan-Shaw S et al., Dose translation from animal to human studies revisited. Fed Am Soc Exp Biol J 2008). This means that the optimal dosing cycle and dosage can only be derived through clinical trial design and results that take into account pharmacological effects, side effects, and tolerable dose (the dose that can be safely administered) in humans.

[0010] Another point to consider when determining the dosing cycle is the drug's duration of action, which is often predicted through its half-life. For example, if the drug's effective dose lasts for six hours, four doses per day is effective. While drug efficacy typically increases with increasing dosage, side effects also increase, making indefinitely increasing the dosage undesirable. Furthermore, most drugs tend to reach a maximum effect at a certain dosage (sigmoidal curve) and then stop increasing. In some cases, the drug's effectiveness actually decreases (biphasic effect). Therefore, determining the dosing cycle and dosage requires considering all these factors, making it by no means an easy process.

[0011] In this respect, even for drugs with known efficacy, if the therapeutic efficacy can be increased, side effects reduced, and convenience of administration increased by using a different dosage from the previously used dosage, this can be said to have value no less than that of developing a new pharmaceutical substance or pharmaceutical use.

[0012]

[0013] When administering efpeglenatide, it is necessary to identify a clinically effective dosage and regimen that can avoid both its usefulness as a medicine and critical side effects.

[0014]

[0015] One object of the present invention is to provide a pharmaceutical composition for preventing or treating obesity, which is a composition comprising efpeglenatide as an active ingredient, wherein the efpeglenatide is administered parenterally to an obese patient in an amount of 8 to 18 mg once a week.

[0016]

[0017] The composition comprising efpeglenatide according to the present invention can be applied to the treatment of obesity without side effects while ensuring the convenience of administration to patients by administering it once a week.

[0018]

[0019] Figure 1 shows the change in body weight due to efpeglenatide in an animal model. (A) shows the change in body weight over the entire period (12 weeks), (B) and (C) show the change in body weight on day 16 (D16) and day 86 (D86, the end of the trial), respectively (~E max ) (***p<0.001 vs. AMLN, vehicle by One-way ANOVA test).

[0020] Figure 2 is a diagram showing the results of estimating the weight loss rate compared to the placebo when administered once a week at different doses (0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 50 mg, 100 mg) through Population PK / PD simulation.

[0021] Figures 3a and 3b are diagrams showing the results of estimating the weight loss rate according to the time point for each administered dose (3a target dose: 2 mg, 4 mg, 6 mg, 10 mg, 14 mg, 18 mg QW / 3b target dose: 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg QW) when dose titration was performed through weight loss simulation.

[0022] Figure 4 shows the results of pharmacokinetic (PK) simulation according to dose titration up to 63 weeks. Case 1 (①): 2-2-4-4-6-6-8-8-10 mg QW, Case 2 (②): 2-2-4-4-6 mg QW, Case 4 (④): 2-2-4-4-6-6-6-6-8-8-8-8-10 mg QW (Slow Titration).

[0023] Figures 5a to 5d are diagrams showing the cumulative incidence of adverse reactions such as nausea and vomiting for each dose when there is no dose titration period.

[0024] Figure 6 is a diagram showing the simulation results of the cumulative incidence of gastrointestinal adverse reactions (nausea, vomiting) when 10 mg is administered after dose titration.

[0025] Figure 7 is a schematic diagram illustrating the clinical trial process of efpeglenatide.

[0026]

[0027] One embodiment of the present invention is a composition comprising efpeglenatide as an active ingredient.

[0028] As a specific example, the efpeglenatide is a pharmaceutical composition for preventing or treating obesity, characterized in that 8 to 18 mg of the efpeglenatide is administered parenterally to an obese patient once a week.

[0029] As another specific example, the efpeglenatide is a pharmaceutical composition for preventing or treating obesity, characterized in that 8 to 14 mg of the efpeglenatide is administered parenterally to an obese patient once a week.

[0030] A pharmaceutical composition according to any one of the preceding specific examples, wherein the efpeglenatide is administered parenterally at a dose of 8 to 10 mg once a week to an obese patient.

[0031] A pharmaceutical composition according to any one of the preceding specific examples, wherein the obese patient has a body mass index (BMI) of 25 kg / m 2 It is characterized by the following:

[0032] A pharmaceutical composition according to any one of the preceding specific examples, wherein the obese patient does not have diabetes.

[0033] A pharmaceutical composition according to any one of the preceding specific examples, wherein the obese patient

[0034] (a) BMI (Body mass index) is 30 kg / m 2 or

[0035] (b) BMI is 27 kg / m 2 Above 30 kg / m 2 It is characterized by the presence of at least one risk factor or comorbidity.

[0036] A pharmaceutical composition according to any one of the preceding specific examples, wherein the patient with the risk factor or concomitant disease is a patient with at least one of hypertension, dyslipidemia, sleep apnea, and cardiovascular disease.

[0037] A pharmaceutical composition according to any one of the preceding specific examples, wherein the patient with the risk factor or concomitant disease is a patient selected from the following (a) to (d):

[0038] (a) Hypertensive patients: If taking antihypertensive medication or if sitSBP ≥ 140 mmHg or sitDBP ≥ 90 mmHg

[0039] (b) Patients with dyslipidemia: If taking medication for dyslipidemia, or if total cholesterol is ≥ 240 mg / dL, LDL-C is ≥ 160 mg / dL, TG is ≥ 200 mg / dL, or HDL-C is < 40 mg / dL

[0040] (c) patients with sleep apnea

[0041] (d) Patients with cardiovascular disease: ischemic cardiovascular disease, heart failure of NYHA Class I to III, etc.

[0042] A pharmaceutical composition according to any one of the preceding specific examples, wherein the obese patient is a patient who has undergone a dose titration period in which 2 to 8 mg of efpeglenatide is administered for 2 to 12 weeks.

[0043] A pharmaceutical composition according to any one of the preceding specific examples, wherein the dosage titration is characterized by administering efpeglenatide in increments of 2 mg or 4 mg over 1 to 4 times.

[0044] A pharmaceutical composition according to any one of the preceding specific examples, wherein the obese patient is a patient who has undergone a dose titration period in which 2 to 14 mg of efpeglenatide is administered for 2 to 14 weeks.

[0045] A pharmaceutical composition according to any one of the preceding specific examples, wherein the dosage titration is characterized by starting with administering 2 mg of efpeglenatide once a week for 2 weeks, and sequentially administering the dosage by 2 mg or 4 mg at 2-week or 4-week intervals once a week to reach the final dosage.

[0046] A pharmaceutical composition according to any one of the preceding specific examples, wherein the dosage titration is characterized by sequentially administering 2 mg of efpeglenatide once a week for 2 weeks, 4 mg of efpeglenatide once a week for 2 weeks, 6 mg of efpeglenatide once a week for 4 weeks, and 8 mg of efpeglenatide once a week for 4 weeks.

[0047] A pharmaceutical composition according to any one of the preceding specific examples, wherein the dosage titration is characterized by sequentially administering 2 mg of efpeglenatide once a week for 2 weeks, 4 mg of efpeglenatide once a week for 2 weeks, 6 mg of efpeglenatide once a week for 4 weeks, 10 mg of efpeglenatide once a week for 4 weeks, and 14 mg of efpeglenatide once a week for 4 weeks.

[0048] A pharmaceutical composition according to any one of the preceding specific examples, wherein the dosage titration is characterized by sequentially administering efpeglenatide once a week for two weeks at a dosage titration of 2 mg or more and less than 6 mg, and efpeglenatide once a week for four weeks at a dosage titration of 6 mg or more and less than 16 mg.

[0049] A pharmaceutical composition according to any one of the preceding specific examples, wherein the pharmaceutical composition is characterized in that it is used as a dosage form for preventing or treating obesity.

[0050] A pharmaceutical composition according to any one of the preceding specific examples, characterized in that the pharmaceutical composition is administered to an arm, a thigh, or an abdomen.

[0051] A pharmaceutical composition according to any one of the preceding specific examples, characterized in that the pharmaceutical composition is administered subcutaneously.

[0052] Another embodiment of the present invention is a method for preventing or treating obesity, comprising administering to an obese patient a composition comprising efpeglenatide as an active ingredient.

[0053] As one specific example, the method comprises parenterally administering 8 to 18 mg of efpeglenatide to an obese patient once a week.

[0054] As another specific example, the method comprises parenterally administering 8 to 14 mg of efpeglenatide to an obese patient once a week.

[0055] As another specific example, the method comprises parenterally administering 10 mg of efpeglenatide to an obese patient once a week.

[0056] A method according to any one of the preceding specific examples, wherein the obese patient has a body mass index (BMI) of 25 kg / m 2 It is characterized by the following:

[0057] A pharmaceutical composition according to any one of the preceding specific examples, wherein the obese patient does not have diabetes.

[0058] As a method according to any one of the preceding specific examples, the obese patient

[0059] (a) BMI (Body mass index) is 30 kg / m 2 or

[0060] (b) BMI is 27 kg / m 2 Above 30 kg / m 2It is characterized by the presence of at least one risk factor or comorbidity.

[0061] A method according to any one of the preceding specific examples, wherein the patient with the risk factor or concomitant disease is characterized in that the patient has at least one of hypertension, dyslipidemia, sleep apnea, and cardiovascular disease.

[0062] A method according to any one of the preceding specific examples, wherein the patient with the risk factor or concomitant disease is a patient selected from the following (a) to (d):

[0063] (a) Hypertensive patients: If taking antihypertensive medication or if sitSBP ≥ 140 mmHg or sitDBP ≥ 90 mmHg

[0064] (b) Patients with dyslipidemia: If taking medication for dyslipidemia, or if total cholesterol ≥ 240 mg / dL, LDL-C ≥ 160 mg / dL, TG ≥ 200 mg / dL, or HDL-C < 40 mg / dL

[0065] (c) patients with sleep apnea

[0066] (d) Patients with cardiovascular disease: ischemic cardiovascular disease, heart failure of NYHA Class I to III, etc.

[0067] A method according to any one of the preceding specific examples, characterized in that the method comprises a dose titration step of administering 2 to 14 mg of efpeglenatide to the obese patient for 2 to 14 weeks prior to administration of 8 to 18 mg of efpeglenatide.

[0068] A method according to any one of the preceding specific examples, characterized in that the method comprises a dose titration step of administering 2 to 8 mg of efpeglenatide to the obese patient for 2 to 12 weeks prior to administering 8 to 14 mg of efpeglenatide.

[0069] A method according to any one of the preceding specific examples, wherein the dose titration step is characterized by administering efpeglenatide in an increased dose of 2 mg or 4 mg over 1 to 4 times.

[0070] A method according to any one of the preceding specific examples, characterized in that the method starts by administering 2 mg of efpeglenatide once a week for 2 weeks, and then sequentially administers the dose by 2 mg or 4 mg at intervals of 2 or 4 weeks, once a week, to reach the final dose.

[0071] A method according to any one of the preceding specific examples, wherein the dose titration step is characterized by sequentially administering 2 mg of efpeglenatide once a week for 2 weeks, 4 mg of efpeglenatide once a week for 2 weeks, 6 mg of efpeglenatide once a week for 2 weeks or 4 weeks, 10 mg of efpeglenatide once a week for 4 weeks, and 14 mg of efpeglenatide once a week for 4 weeks.

[0072] A method according to any one of the preceding specific examples, wherein the dose titration step is characterized by sequentially administering 2 mg of efpeglenatide once a week for 2 weeks, 4 mg of efpeglenatide once a week for 2 weeks, 6 mg of efpeglenatide once a week for 4 weeks, and 8 mg of efpeglenatide once a week for 4 weeks.

[0073] As a method according to any one of the preceding specific examples, the dosage titration is characterized by sequentially administering once a week for two weeks when titrating at a dosage of 2 mg or more and less than 6 mg, and once a week for four weeks when titrating at a dosage of 6 mg or more and less than 16 mg.

[0074] A method according to any one of the preceding specific examples, wherein the method is characterized by administering efpeglenatide to the arm, thigh, or abdomen of an obese patient.

[0075] A method according to any one of the preceding specific examples, wherein the method is characterized by subcutaneously administering efpeglenatide.

[0076] Another embodiment of the present invention is the use of a composition comprising efpeglenatide as an active ingredient for preventing or treating obesity.

[0077] As a specific example, the efpeglenatide is characterized in that it is administered parenterally to an obese patient at a dose of 8 to 18 mg once a week.

[0078] As another specific example, the efpeglenatide is characterized in that it is administered parenterally to an obese patient at a dose of 8 to 14 mg once a week.

[0079] As a use according to any one of the preceding specific examples, the efpeglenatide is characterized in that it is administered parenterally to an obese patient at a dose of 8 to 10 mg once a week.

[0080] For use according to any one of the preceding specific examples, the obese patient has a BMI (Body mass index) of 25 kg / m 2 It is characterized by the following:

[0081] A pharmaceutical composition according to any one of the preceding specific examples, wherein the obese patient does not have diabetes.

[0082] As a use according to any one of the preceding specific examples, the efpeglenatide is characterized in that it is administered subcutaneously.

[0083]

[0084] Hereinafter, the present invention will be described in more detail.

[0085] Meanwhile, each description and embodiment disclosed herein can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific descriptions described below.

[0086] All papers and patent documents described in this specification are incorporated herein by reference.

[0087]

[0088] Throughout this specification, the conventional one-letter and three-letter codes for naturally occurring amino acids are used, as well as the generally accepted three-letter codes for other amino acids, such as Aib (2-Aminoisobutyric acid), Sar (N-methylglycine), and α-methyl-glutamic acid. Additionally, amino acids referred to by abbreviations herein are described according to the IUPAC-IUB nomenclature.

[0089] Alanine Ala, A Arginine Arg, R

[0090] Asparagine Asn, N Aspartic acid Asp, D

[0091] Cysteine ​​Cys, C Glutamic acid Glu, E

[0092] Glutamine Gln, Q Glycine Gly, G

[0093] Histidine His, H Isoleucine Ile, I

[0094] Leucine Leu, L Lysine Lys, K

[0095] Methionine Met, M Phenylalanine Phe, F

[0096] Proline Pro, P Serine Ser, S

[0097] Threonine Thr, T Tryptophan Trp, W

[0098] Tyrosine Tyr, Y Valine Val, V

[0099]

[0100] One embodiment of the present invention provides a pharmaceutical composition for preventing or treating obesity, comprising efpeglenatide as an active ingredient, wherein 8 to 18 mg of the efpeglenatide is administered parenterally to an obese patient once a week.

[0101] The pharmaceutical composition according to the present invention has technical significance in that it can be applied to the human body by identifying a specific dosage and administration cycle that can exhibit safe and effective efficacy.

[0102] Efpeglenatide is a long-acting CA-exendin-4 derivative, and research into the development of a diabetes and obesity treatment using it is ongoing (WO 2008 / 082274 A1, WO 2009 / 011544 A2). In the present invention, a method of administering efpeglenatide through a dose titration process to reduce the risk of side effects while administering a high dose of 8 to 18 mg has been discovered.

[0103]

[0104] In one specific embodiment of the present invention, a pharmaceutical composition of the present invention comprises efpeglenatide as an active ingredient and may be used as a dosage form for the prevention or treatment of obesity. Specifically, the pharmaceutical composition may comprise a pharmacologically effective amount of efpeglenatide and a pharmaceutically acceptable excipient, but is not limited thereto.

[0105]

[0106] The efpeglenatide of the present invention is a conjugate in which an Exendin-4 analogue (CA Exendin-4) and a human-derived immunoglobulin IgG4 Fc region are linked via a propionaldehyde polyethylene glycol 3.4 kDa linker molecule (CAS No. 1296200-77-5).

[0107] CA Exendin-4 is composed of 39 amino acids and is an Exendin-4 analogue in which the first residue is substituted with (imidazol-4-yl)acetic acid (SEQ ID NO: 1).

[0108] The human immunoglobulin IgG4 Fc region is composed of a 221-amino acid monomer (SEQ ID NO: 2) that forms a homodimer (SEQ ID NO: 3) via a disulfide bond at cysteine ​​at position 3, with a molecular weight of 49.8 kDa. Each monomer contains two internal disulfide bonds, specifically, disulfide bonds exist at cysteine ​​positions 35 and 95, and 141 and 199.

[0109] The binding of CA Exendin-4 to the immunoglobulin IgG4 Fc region is mediated by aldehyde polyethylene glycol (OHC-CH2CH2O(CH2CH2O) n It is formed by forming an amine bond between lysine 27 of CH2CH2-CHO (n = 54–77) and the amino acid group of the N-terminus of the Fc region of immunoglobulin IgG4 of CA Exendin-4.

[0110] The safety of the efpeglenatide of the present invention was confirmed in patients with type 2 diabetes or obese patients without type 2 diabetes through phase 2 clinical trials (NCT01452451, NCT02057172, NCT02081118, NCT02075281), and it was confirmed that the target effect can be achieved when administered at a maximum of 6 mg once a week or 8 mg once every two weeks.

[0111]

[0112] However, in order to obtain a more effective weight loss effect, we sought to identify a high dose of efpeglenatide that ensures safety, while also identifying an administration method that reduces side effects such as vomiting, nausea, and gastrointestinal adverse reactions that commonly occur with GLP-1 analog drugs. As a result, we confirmed that such side effects can be minimized by administering a high dose of efpeglenatide of 8 to 18 mg and going through a dose titration period.

[0113]

[0114] The efpeglenatide of the present invention can be administered to an obese patient in a pharmacologically effective amount.

[0115] In the present invention, "pharmacologically effective amount" refers to a safe dosage of efpeglenatide that exhibits therapeutic effects in obese patients without causing toxicity or adverse effects. Specifically, it may refer to a dosage that can produce effects such as weight loss, BMI reduction, waist circumference reduction, and blood lipid reduction in obese patients, but is not limited thereto.

[0116] In a specific embodiment of the present invention, efpeglenatide according to the present invention is administered at a dose of about 8 to 18 mg, about 10 to 18 mg, about 8 to 14 mg, about 9 to 14 mg, about 10 to 14 mg, or about 10 to 12 mg, specifically 8.0 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, or 10.0 mg or more, and about 18 mg, 17.9 mg, 17.8 mg, 17.7 mg, It may be administered in doses of, but not limited to, 17.6 mg, 17.5 mg, 17.4 mg, 17.3 mg, 17.2 mg, 17.1 mg, 17.0 mg, 16.9 mg, 16.8 mg, 16.7 mg, 16.6 mg, 16.5 mg, 16.4 mg, 16.3 mg, 16.2 mg, 16.1 mg, or 16.0 mg or less.

[0117] Specifically, the dosage of the triple active substance sustained-release complex of the present invention may be about 8 to 18 mg, about 8 to 14 mg, about 8 to 12 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, about 16.0 mg, about 17.0 mg, or about 18.0 mg at a time, but is not limited thereto, and the single administration dosage may be appropriately adjusted at the discretion of a doctor or prescriber depending on the degree of the disease, the age of the patient, the administration period, etc. The single administration dosage refers to a dosage that should be administered at a certain cycle for the treatment of obesity.

[0118] The above efpeglenatide can be administered at a constant dose regardless of the patient's weight, but if necessary, it can be appropriately adjusted according to the patient's weight.

[0119] In the present invention, the term "about" includes all ranges including ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, ±0.05, ±0.01, etc., and includes all numerical values ​​in a range equal to or similar to the numerical value following the term "about," but is not limited thereto.

[0120] The efpeglenatide of the present invention may be administered at a single dose for a certain period of time at a certain interval to exhibit a preventive or therapeutic effect on obesity, but is not limited thereto.

[0121]

[0122] The pharmaceutical composition of the present invention comprises efpeglenatide and may be used as a dosage regimen for the prevention or treatment of obesity. Specifically, the pharmaceutical composition of the present invention may comprise efpeglenatide in the single-dose dosage described above, and may additionally comprise a pharmaceutically acceptable excipient in the required amount, but is not limited thereto.

[0123]

[0124] The efpeglenatide of the present invention has a prolonged half-life due to binding to the immunoglobulin Fc region, and thus exerts a pharmacological effect for a sufficient period of time, thereby allowing for an increase in the dosing cycle, thereby improving patient convenience.

[0125] Specifically, the efpeglenatide of the present invention may be administered once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, but is not particularly limited thereto as long as the administration cycle can maintain a body concentration capable of exerting a pharmacological effect.

[0126]

[0127] The efpeglenatide of the present invention can be administered to a patient in multiple doses over a long period of time using a fractionated treatment protocol.

[0128]

[0129] For the purposes of the present invention, the pharmaceutical composition of the present invention may be administered for a period of time sufficient to exhibit a sufficient therapeutic effect. For example, the period may be a period of time in which one or more of the abnormal indicators of an obese patient, such as weight loss, BMI reduction, waist circumference reduction, blood lipid reduction, blood pressure reduction, body composition improvement (body fat mass, lean body mass, visceral fat mass), hepatic steatosis improvement, and impaired glucose tolerance (IGT) improvement, can be returned to a normal range recognized in the art (e.g., BMI less than 23), but is not limited thereto. For example, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, It may be administered for 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, or 64 weeks or more, and the administration period may be appropriately adjusted depending on the severity of the disease.

[0130] The pharmaceutical composition according to the present invention may be administered once at one-week intervals during the administration period.

[0131]

[0132] The pharmaceutical composition according to the present invention may be administered to an obese patient who has undergone a dose titration period.

[0133] In the present invention, the dose titration refers to a process of administering a lower dose of efpeglenatide than the target dose of efpeglenatide in the initial stage of administration to reduce adverse reactions (vomiting, nausea, gastrointestinal adverse reactions, etc.) of the patient before administering a high concentration of efpeglenatide and gradually increasing the dose of efpeglenatide to ultimately reach the target dose of efpeglenatide, and the dose titration period refers to the period during which the dose titration is performed.

[0134] The efpeglenatide administered during the above dose titration may be 2 to 16 mg per dose, but is not limited thereto, and any dose lower than the final target dose may be used for dose titration. As a specific example, the efpeglenatide administered during the dose titration may be about 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, or 16 mg per dose, but is not limited thereto.

[0135] Specifically, the pharmaceutical composition according to the present invention may be characterized in that it is administered to a patient who has undergone a dose titration period in which a high dose of efpeglenatide of 8 to 18 mg is administered to increase the weight loss effect, but a low dose (e.g., 16 mg or less) of efpeglenatide is administered for a certain period of time before administration of the target dose to reduce side effects such as vomiting, nausea, and gastrointestinal adverse reactions.

[0136] Here, low-dose efpeglenatide means a dose lower than the target final efpeglenatide administration dose, and the dose increased during dose titration may be, but is not limited to, 1 mg, 2 mg, 3 mg, or 4 mg. The increased dose may be the same during the dose titration period, or may be changed (decreased or increased) during the titration period, but is not limited thereto. In addition, the dose titration period may be, but is not limited to, 1 week or more, 20 weeks or less, 18 weeks or less, 16 weeks or less, 14 weeks or less, or 12 weeks or less, and may be determined as a sufficient time to reach the final target dose. For example, when titrating the dose to less than 6 mg of efpeglenatide, administration may be performed for 2 weeks, and when titrating the dose to 6 mg or more of efpeglenatide, administration may be performed for 2 weeks or 4 weeks, but is not limited thereto.

[0137] Additionally, during the dose titration period, efpeglenatide for the above dose titration may be administered once or more, twice or more, three times or more, four times or more, five times or more, or six times or more, but is not limited thereto.

[0138] Additionally, during the above dosage titration period, efpeglenatide may be administered daily, once every two days, once a week, once every two weeks, once every three weeks, or once every four weeks, but is not limited to a specific dosage cycle as long as the final target dose of efpeglenatide can be reached while reducing side effects.

[0139] As an example, the obese patient may be a patient administered 1 to 16 mg of efpeglenatide per week for 2 to 20 weeks, but is not limited thereto. Specifically, the patient may be a patient administered 2 to 16 mg, 2 to 14 mg, 2 to 12 mg, 2 to 10 mg, or 2 to 8 mg of efpeglenatide for 2 to 20 weeks, 2 to 16 weeks, 2 to 10 weeks, or 2 to 8 weeks, but is not limited thereto.

[0140] As another example, the obese patient may be, but is not limited to, a patient administered 1 to 8 mg of efpeglenatide per week for 2 to 12 weeks.

[0141] Specifically, the patient may be administered 2 to 8 mg, 2 to 6 mg, 2 to 4 mg of efpeglenatide for 2 to 12 weeks, 2 to 10 weeks, or 2 to 8 weeks, but is not limited thereto.

[0142] As another example, the above obese patient may mean, but is not limited to, a patient who sequentially received 2 mg of efpeglenatide once a week for 2 weeks, 4 mg of efpeglenatide once a week for 2 weeks, 6 mg of efpeglenatide once a week for 4 weeks, and 8 mg of efpeglenatide once a week for 4 weeks.

[0143] As another example, when 10 mg of efpeglenatide is the target dose, it may mean a patient who sequentially received 2 mg of efpeglenatide once a week for 2 weeks, 4 mg of efpeglenatide once a week for 2 weeks, and 6 mg of efpeglenatide once a week for 2 weeks or 4 weeks before administering 10 mg of efpeglenatide, and after 6 mg, it may mean a patient who additionally received 8 mg of efpeglenatide once a week for 2 weeks or 4 weeks depending on the patient's drug tolerance, but is not limited thereto.

[0144] As another example, when 14 mg of efpeglenatide is the target dose, it may mean a patient who sequentially received 2 mg of efpeglenatide once a week for 2 weeks, 4 mg of efpeglenatide once a week for 2 weeks, 6 mg of efpeglenatide once a week for 2 weeks or 4 weeks, and 10 mg of efpeglenatide once a week for 4 weeks before administering 14 mg of efpeglenatide, and after 10 mg, it may mean a patient who additionally received 12 mg of efpeglenatide once a week for 2 weeks or 4 weeks, depending on the patient's tolerability, but is not limited thereto.

[0145] As another example, when 18 mg of efpeglenatide is the target dose, it may mean a patient who was sequentially administered 2 mg of efpeglenatide once a week for 2 weeks, 4 mg of efpeglenatide once a week for 2 weeks, 6 mg of efpeglenatide once a week for 2 weeks or 4 weeks, 10 mg of efpeglenatide once a week for 4 weeks, and 12 mg of efpeglenatide once a week for 4 weeks before administering 18 mg of efpeglenatide, and after 12 mg, it may mean a patient who was additionally administered 14 mg or 16 mg of efpeglenatide once a week for 2 weeks or 4 weeks depending on the patient's condition, but is not limited thereto.

[0146]

[0147] The pharmaceutical composition of the present invention may be administered to an obese patient.

[0148] The term "obesity" in this invention refers to a condition characterized by excessive adipose tissue in the body. Obesity is typically caused by an energy imbalance resulting from excessive nutrient intake relative to energy expenditure over a long period of time. Obesity is a metabolic disease that affects the entire body, increasing the risk of diabetes and hyperlipidemia, as well as erectile dysfunction, arthritis, and cardiovascular disease. In some cases, it is also associated with the development of cancer.

[0149] The World Health Organization defines a body mass index (BMI) of 25 kg / m 2 Less than normal, 25 - 29.99 kg / m 2 Overweight range, 30 kg / m 2 Although obesity is classified as above, a more detailed standard is needed considering racial and ethnic characteristics. In Korea, the standard is not that of the World Health Organization, but rather a body mass index of 25 kg / m2. 2 Less than normal, 25 - 29.99 kg / m 2 Range: Obesity stage 1, 30 kg / m 2 Obesity is diagnosed and classified based on the criteria for stage 2-3 obesity.

[0150]

[0151] An obese patient to whom the pharmaceutical composition according to the present invention is administered has a BMI (Body mass index) of 25 kg / m 2 Patients may be, but are not limited to, obese patients. Specifically, the obese patient has a BMI of 25 kg / m 2 Above, 26 kg / m 2 Above, 27 kg / m 2 Above, 28 kg / m 2 Above, 29 kg / m 2 or more than 30 kg / m 2 Patients may include, but are not limited to, these individuals.

[0152] Additionally, the obese patient of the present invention may be an obese patient without diabetes, particularly type 2 diabetes, but is not limited thereto.

[0153] An obese patient without diabetes of the present invention refers to an obese patient who has not been diagnosed with diabetes, and specifically, may refer to a patient who is not a patient whose blood sugar measured regardless of meal time is 200 mg / dL or higher, whose fasting blood sugar measured in a fasting state without calorie intake for 8 hours is 126 mg / dL or higher, or whose blood sugar measured 2 hours after consuming 75 mg of glucose in an oral glucose tolerance test is 200 mg / dL or higher, but is not limited thereto.

[0154] Alternatively, the non-diabetic obese patient of the present invention may refer to an obese patient with a glycated hemoglobin (HbA1c) level of less than 6.5%, but is not limited thereto.

[0155] Specifically, an obese patient to whom the pharmaceutical composition according to the present invention is administered has (a) a BMI (Body mass index) of 30 kg / m 2 or (b) BMI is 27 kg / m 2 Above 30 kg / m 2 Patients may be, but are not limited to, those with at least one risk factor or comorbidity.

[0156] Patients with the above risk factors or concomitant diseases refer to patients with one or more of hypertension, dyslipidemia, sleep apnea, and cardiovascular disease.

[0157] Specifically, patients with hypertension, dyslipidemia, sleep apnea, and cardiovascular disease may be patients who meet the following criteria, but are not limited thereto.

[0158] (a) Hypertensive patients: If taking antihypertensive medication or if sitSBP ≥ 140 mmHg or sitDBP ≥ 90 mmHg

[0159] (b) Patients with dyslipidemia: If taking medication for dyslipidemia, or if total cholesterol is ≥ 240 mg / dL, LDL-C is ≥ 160 mg / dL, TG is ≥ 200 mg / dL, or HDL-C is < 40 mg / dL

[0160] (c) patients with sleep apnea

[0161] (d) Patients with cardiovascular disease: This may refer to ischemic cardiovascular disease, heart failure of NYHA Class I to III, etc., but is not limited thereto.

[0162] Additionally, the pharmaceutical composition of the present invention may be administered to a patient diagnosed as obese based on obesity diagnostic criteria known in the art other than BMI.

[0163]

[0164] Although the efpeglenatide of the present invention is a drug of the GLP-1 analog series, which is well known as a diabetes treatment agent, it can be used for the treatment of obesity since it shows a weight loss effect in obese patients without diabetes, regardless of diabetes.

[0165]

[0166] The pharmaceutical composition of the present invention can exhibit effects such as weight loss, BMI reduction, waist circumference reduction, blood lipid reduction, blood pressure reduction, body composition improvement (body fat mass, lean body mass, visceral fat mass), hepatic steatosis improvement, and impaired glucose tolerance (IGT) improvement in obese patients.

[0167] The dosage of the pharmaceutical composition of the present invention can be adjusted according to the degree of obesity symptoms and the administration period.

[0168]

[0169] The pharmaceutical composition of the present invention may be prepared in various forms by mixing it with pharmaceutically acceptable excipients. In a specific embodiment, the pharmaceutical composition of the present invention may be formulated in a form suitable for administering efpeglenatide, particularly parenterally. Furthermore, the pharmaceutical composition of the present invention may be formulated in a stabilized form capable of maintaining pharmacological activity of efpeglenatide, but is not limited thereto.

[0170] For example, the pharmaceutical composition of the present invention may be prepared in unit dosage ampoules or multiple dosage forms. In addition, it may be formulated as a solution, suspension, tablet, pill, capsule, sustained-release preparation, etc.

[0171] Specifically, it may be formulated in the form of an injection so that it can be administered subcutaneously.

[0172] Since the injection is administered directly into the human body, either subcutaneously, through blood vessels (blood injection) or muscle (intramuscular injection), it does not undergo absorption in the gastrointestinal tract or metabolism in the liver, so solubility or absorption rate are not issues and it can take effect directly. However, since it can directly affect human tissues, extreme care must be taken regarding toxicity due to the drug components. In other words, the safety of the parenteral route of administration can be guaranteed only through the design and results of clinical trials that take into account all aspects of pharmacological action, side effects, and tolerated dose (the dose that can be safely administered) in the human body.

[0173]

[0174] In addition, the pharmaceutical composition of the present invention can be formulated into a unit dosage form suitable for administration into a patient's body according to a method conventional in the pharmaceutical field, specifically, into a form of a preparation useful for administration of a protein drug, and administered using a parenteral administration method conventionally used in the art, and as the parenteral administration method, a person skilled in the art can appropriately select a route including dermal, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, intragastric, topical, sublingual, intravaginal, or rectal. Specifically, the pharmaceutical composition of the present invention can be administered by subcutaneous administration, and more specifically, the pharmaceutical composition of the present invention can be administered subcutaneously to a patient's arm (upper arm), thigh, or abdomen, but is not limited thereto.

[0175]

[0176] For the purposes of the present invention, a subject administered with the pharmaceutical composition may exhibit one or more of the following characteristics and thus have a preventive or therapeutic effect on obesity:

[0177] Weight loss, BMI reduction,

[0178] Reduced waist circumference,

[0179] Reduced blood lipids, reduced blood pressure, improved body composition (body fat mass, lean body mass, visceral fat mass), improved liver steatosis, and improved glucose tolerance

[0180] Specifically, a patient administered the pharmaceutical composition of the present invention may experience a weight loss of about 5 to 15%, or at most 20% or more, compared to the initial administration time after two weeks, but is not limited thereto.

[0181]

[0182] The above may be applied to other specific examples or other aspects of the present invention, but is not limited thereto.

[0183]

[0184] The pharmaceutical composition of the present invention may additionally comprise a pharmaceutically acceptable carrier, excipient, or diluent. Such pharmaceutically acceptable carrier, excipient, or diluent may be non-naturally occurring.

[0185] In the present invention, the term "pharmaceutically acceptable" means a sufficient amount to exhibit a therapeutic effect and not causing side effects, and can be easily determined by those skilled in the art based on factors well known in the medical field, such as the type of disease, the patient's age, weight, health, sex, the patient's sensitivity to drugs, administration route, administration method, number of administrations, treatment period, and drugs used in combination or simultaneously.

[0186] The pharmaceutical composition of the present invention may additionally include a pharmaceutically acceptable carrier. The carrier is not particularly limited thereto, but may be used in combination with a buffer, preservative, analgesic, solubilizer, isotonic agent, stabilizer, etc.

[0187]

[0188] The pharmaceutical composition of the present invention comprises efpeglenatide in a pharmacologically effective amount, specifically 8 to 18 mg, 8 to 14 mg, 8 to 10 mg, 10 to 18 mg, 12 to 18 mg or 10 to 14 mg, and is characterized in that it is administered once a week to an obese patient.

[0189] Such administration of 8 to 18 mg, 8 to 14 mg, 8 to 10 mg, 10 to 18 mg, 12 to 18 mg or 10 to 14 mg once a week has technical significance in that it is an optimal administration cycle and dosage that can reduce side effects as well as efficacy and tolerability through clinical trials targeting actual obese patients, and administration of the pharmaceutical composition according to the present invention has a practical preventive or therapeutic effect on obesity.

[0190]

[0191] Another embodiment of the present invention provides a method for preventing or treating obesity, comprising administering to an obese patient a pharmaceutical composition comprising efpeglenatide.

[0192] The method for preventing or treating obesity of the present invention may be to administer the pharmaceutical composition in the above-described dosage and usage.

[0193] Specifically, the method for preventing or treating obesity may be, but is not limited to, parenteral administration (particularly, subcutaneous administration) of efpeglenatide to an obese patient once a week at a dose of 8 to 18 mg.

[0194] The above obese patients may be patients who have undergone a dosage titration period, but are not limited thereto.

[0195]

[0196] In another specific embodiment, the method for preventing or treating obesity may additionally include, but is not limited to, a dose titration step prior to the step of administering 8 to 18 mg of efpeglenatide.

[0197] In the present invention, the “dose titration step” refers to a step of performing the above-described dose titration, which means a step of administering a lower dose of efpeglenatide than the target dose of efpeglenatide at the beginning of administration and gradually increasing the dose of efpeglenatide to ultimately reach the target dose of efpeglenatide.

[0198] The dose to be increased may be, but is not limited to, 1 mg, 2 mg, 3 mg, or 4 mg, and the dose to be increased may be the same during the dose titration phase, or may be changed (decreased or increased) during the dose titration phase, but is not limited thereto. In addition, the dose titration phase may be, but is not limited to, a period of 20 weeks or less, 18 weeks or less, 16 weeks or less, 14 weeks or less, or 12 weeks or less, and may be determined as a sufficient time to reach the final target dose. For example, when titrating the dose to less than 6 mg of efpeglenatide, administration may be performed for 2 weeks, and when titrating the dose to 6 mg or more of efpeglenatide, administration may be performed for 2 weeks or 4 weeks, but is not limited thereto.

[0199]

[0200] As an example, the method for preventing or treating obesity may further include, but is not limited to, a step of sequentially increasing the dosage of efpeglenatide to an obese patient in a dose of 2 to 16 mg, or 2 mg to less than 16 mg, for 2 to 20 weeks.

[0201] Specifically, prior to the step of administering 8 to 18 mg of efpeglenatide, (a) a step of administering 2 mg of efpeglenatide once a week for 2 weeks, (b) a step of administering 4 mg of efpeglenatide once a week for 2 weeks, (c) a step of administering 6 mg of efpeglenatide once a week for 4 weeks, (d) a step of administering 8 mg of efpeglenatide once a week for 4 weeks, (e) a step of administering 10 mg of efpeglenatide once a week for 4 weeks, (f) a step of administering 12 mg of efpeglenatide once a week for 4 weeks, (g) a step of administering 14 mg of efpeglenatide once a week for 4 weeks, and (h) a step of administering 16 mg of It may additionally include a step of sequentially administering efpeglenatide once a week for 4 weeks, and steps (c) to (h) may include only some steps depending on the patient's drug tolerance, but is not limited thereto.

[0202]

[0203] As another example, the method for preventing or treating obesity may further include, but is not limited to, a step of sequentially increasing the dosage of efpeglenatide to an obese patient in a dose of 2 to 8 mg, or 2 mg to less than 8 mg, for 2 to 12 weeks.

[0204] Specifically, the method may further include, but is not limited to, sequentially administering (a) 2 mg of efpeglenatide once a week for two weeks, (b) 4 mg of efpeglenatide once a week for two weeks, (c) 6 mg of efpeglenatide once a week for two weeks or four weeks, and (d) 8 mg of efpeglenatide once a week for two weeks or four weeks prior to the step of administering 8 to 10 mg of efpeglenatide.

[0205]

[0206] Efpeglenatide, dosage titration period, pharmaceutical composition, obesity, and administration are as described above.

[0207]

[0208] Another embodiment of the present invention provides the use of a composition comprising efpeglenatide in the manufacture of a medicament for preventing or treating obesity.

[0209] Specifically, the efpeglenatide may be administered parenterally (particularly, subcutaneously) to an obese patient once a week at a dose of 8 to 18 mg, 8 to 14 mg, or 8 to 10 mg, but is not limited thereto.

[0210] The above obese patients may be patients who have undergone a dosage titration period, but are not limited thereto.

[0211] Efpeglenatide, dosage titration period, pharmaceutical composition, obesity, and administration are as described above.

[0212] Another embodiment of the present invention provides a formulation for preventing or treating obesity comprising efpeglenatide.

[0213] Specifically, the formulation may be administered parenterally (particularly, subcutaneously) to an obese patient once a week at a dose of 8 to 18 mg, 8 to 14 mg, or 8 to 10 mg, but is not limited thereto.

[0214] The above patient may be, but is not limited to, a patient who has undergone a dosage titration period.

[0215] Efpeglenatide, dosage titration period, pharmaceutical composition, obesity, and administration are as described above.

[0216]

[0217] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0218]

[0219] Example 1: Structure and preparation of efpeglenatide

[0220]

[0221] Efpeglenatide included in the composition of the present invention is a chemical conjugate in which an exendin-4 analogue (CA Exendin-4) and a human-derived immunoglobulin IgG4 Fc region are linked via a propionaldehyde polyethylene glycol 3.4 kDa linker molecule (CAS No. 1296200-77-5, see US 8476230 B2).

[0222] For CA Exendin-4, it is a synthetic Exendin-4 analogue consisting of 39 amino acids, with the first residue substituted with (imidazol-4-yl)acetic acid.

[0223] The human immunoglobulin IgG4 Fc region is a homodimer (SEQ ID NO: 3) with a single disulfide bond between cysteines at position 3 of the monomer (SEQ ID NO: 2) and a molecular weight of 49.8 kDa. The monomers, each consisting of 221 amino acids, are formed by two disulfide bonds between positions 35 and 95 and 141 and 199, respectively.

[0224]

[0225] The binding of CA Exendin-4 to the immunoglobulin IgG4 Fc region is achieved by forming an amine bond between aldehyde polyethylene glycol (ALD-PEG-ALD) and lysine 27 of CA Exendin-4 and the N-terminal amino acid group of the human immunoglobulin IgG4 Fc region.

[0226] The structure of efpeglenatide is as follows.

[0227]

[0228]

[0229] The purpose of this study was to confirm through nonclinical and clinical trials whether administering 8 mg to 18 mg of efpeglenatide once a week could achieve weight loss in obese patients.

[0230]

[0231] Experimental Example 1: Confirmation of the weight loss effect of efpeglenatide in an animal model.

[0232] To confirm the weight loss effect of high-dose administration of efpeglenatide, efpeglenatide was administered once a week at a human equivalent dose (HED) of 6 mg or 14 mg to obese mice induced by an AMLN diet (high fat, high fructose, high cholesterol) (Fig. 1).

[0233] Here's how to convert mouse doses to human doses:

[0234] 1. Molar concentration conversion

[0235] 2. Reflection of dosing interval - Since Q2D in mice corresponds to QW in humans and the dose to be administered for one week was divided into two doses every other day, the dose administered for one week was calculated by applying 3.5 times.

[0236] 3. Body surface area (m 2 ) when calculating human equivalent dose, mouse dose (mg / kg) = 12.3 x human dose (mg / kg)

[0237] 4. Calculated as 100 kg for obese patients

[0238]

[0239] As a result, as can be confirmed in Figure 1, gradual weight loss is confirmed for the first 2 to 3 weeks by efpeglenatide administration, and thereafter, a slight weight gain, which is typical of the weight loss profile by GLP-1 preparations, is confirmed.

[0240] Both the 6 mg and 14 mg dose groups demonstrated similar weight loss effects, with a maximum weight loss of over 30% observed on day 16 (D16). Although weight increased slightly thereafter, both dose groups maintained their normalized body weights until the end of the study.

[0241] These results suggest that efpeglenatide is effective in weight loss and weight maintenance, and furthermore, it is understood that the safety of efpeglenatide has been confirmed as it does not show excessive weight loss below normal body weight even when administered at high doses.

[0242]

[0243] A clinical trial was conducted on 8 to 10 mg of efpeglenatide, which was confirmed to have a weight loss effect in an animal model.

[0244]

[0245] Experimental Example 2: Confirmation of the weight loss effect of efpeglenatide in humans.

[0246] To determine the weight-loss effect of efpeglenatide in adult obese patients without diabetes, we conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-design clinical trial. The study assessed the "mean body weight change (%) from baseline at week 40" and the "proportion (%) of subjects with a weight loss of 5% or more from baseline at week 40" to demonstrate efpeglenatide's superiority over placebo and to compare and evaluate safety. Additionally, the weight-loss effect and safety were observed up to week 64.

[0247]

[0248] Experimental Example 2-1. Participant Selection

[0249] The 420 participants in this clinical trial were selected based on the following criteria.

[0250] On the first day of your visit (Visit 1),

[0251] - Adults aged 18 or older

[0252] - Those who meet any of the obesity criteria below

[0253] - BMI ≥ 30 kg / m 2 Person

[0254] - 27 kg / m 2 ≤ BMI < 30 kg / m 2 Those with at least one risk factor or comorbidity

[0255] Here, risk factors or comorbidities mean:

[0256] i) Hypertension: If you are taking antihypertensive medication or if sitSBP ≥ 140 mmHg or sitDBP ≥ 90 mmHg

[0257] ii) Dyslipidemia: If taking medication for dyslipidemia, or if Total Cholesterol ≥ 240 mg / dL, LDL-C ≥ 160 mg / dL, TG ≥ 200 mg / dL, or HDL-C < 40 mg / dL

[0258] iii) Sleep apnea

[0259] iv) Cardiovascular disease: ischemic cardiovascular disease, heart failure of NYHA Class I~III, etc.

[0260] However, participants were excluded if they had diabetes (type 1, type 2, etc.) or were confirmed to have HbA1c ≥ 6.5%.

[0261]

[0262] Experimental Example 2-2. Drugs and Administration Methods

[0263] (1) Test drug

[0264] ① Prefilled injection containing efpeglenatide 2 mg / 0.5 mL

[0265] ② Prefilled injection containing efpeglenatide 4 mg / 0.5 mL

[0266] ③ Prefilled injection containing efpeglenatide 6 mg / 0.5 mL

[0267] ④ Prefilled injection containing efpeglenatide 8 mg / 0.5 mL

[0268] ⑤ Prefilled injection containing efpeglenatide 10 mg / 0.5 mL

[0269]

[0270] (2) Placebo

[0271] Prefilled injection containing 0.5 mL of placebo of efpeglenatide

[0272]

[0273] (3) Administration method

[0274] Participants selected in the above Experimental Example 2-1 are randomly assigned, and the randomly assigned subjects are administered the full amount of efpeglenatide or placebo contained in the prefilled injection, 0.5 mL per injection, once a week during the clinical trial period.

[0275]

[0276] Experimental Example 2-3. Determination of Administration Dosage

[0277] A 20-week, randomized, double-blind, placebo-controlled, parallel-group, phase 2b clinical trial to evaluate the safety and efficacy of efpeglenatide on body weight in obese adults without diabetes found that doses up to 6 mg once weekly and up to 8 mg every other week were generally well tolerated.

[0278] However, as the dose of the same series of GLP-1 analogue drugs previously approved tended to increase as the dose increased (Liraglutide 1.8 mg vs. 3.0 mg approximately 1.7 times, Semaglutide 1 mg vs. 2.4 mg approximately 2.4 times), and as the pattern of a higher weight loss effect at high doses compared to low doses was confirmed in adult obese patients with efpeglenatide, the target dose was set to 10 mg, which is approximately 1.7 times that of 6 mg, to achieve additional weight loss effect.

[0279] The maximum effect size based on the weight loss rate was estimated through population PK / PD simulation, and the maximum effect (E) of efpeglenatide at 60 weeks in obese patients with a once-weekly administration regimen was max ) was estimated to be approximately -11%, and the 10 mg dose was expected to exhibit approximately 80% or more of the maximum effect (Fig. 2).

[0280]

[0281] To explain the relationship between the concentration of efpeglenatide and long-term body weight changes, pharmacodynamic modeling (a turnover model in which the concentration inhibits the response) was performed. Specifically, the simulation was conducted 100 times, assuming that 50 subjects were administered each dose using dose titration for the target doses of 4 mg, 6 mg, 10 mg, 14 mg, and 18 mg QW, and the baseline body weight of the subjects was set based on the results of the existing phase 2 clinical trial. As a result, the predicted body weight loss rates by efpeglenatide administration dose were -7.93%, -9.03%, -10.27%, -11.07%, and -11.73% for the 4 mg, 6 mg, 10 mg, 14 mg, and 18 mg doses, respectively (Fig. 3a).

[0282]

[0283] In addition, a population pharmacokinetic-pharmacodynamic (PK_PD) simulation was performed to estimate the rate of body weight loss compared to baseline when the target dose was reached at 2-week intervals for each dose in obese patients (Fig. 3b). Specifically, in order to confirm the rate of body weight loss at each time point based on the target dose of 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, and 18 mg QW, the dose was increased in 2 mg steps at 2-week intervals to reach the target dose, and repeated administration was performed once a week until week 59. The results of predicting the trend of the weight loss rate during the washout period (week 72) are shown in Table 1.

[0284]

[0285]

[0286]

[0287] Experimental Example 2-4. Determination of Dosage Cycle

[0288] Because GLP-1 analog drugs tend to have higher gastrointestinal adverse reactions at the beginning of administration and at higher doses, a slow titration period was introduced in this clinical trial as a strategy to reduce the safety risk at the initial exposure of 10 mg (Figure 4).

[0289] That is, the dose is increased more slowly to reach the target dose by administering 2 mg and 4 mg each for 2 weeks until reaching 6 mg of efpeglenatide, and then administering 6 mg and 8 mg each for 4 weeks until reaching 10 mg.

[0290] Comparing the cumulative exposure predicted through population pharmacokinetic modeling, a tendency toward a 16-21% decrease in systemic exposure was observed when dose escalation (slow titration) was performed at 2+4-week intervals compared to 2-week intervals. This could alleviate early adverse reactions.

[0291]

[0292]

[0293]

[0294] Additionally, clinical trials confirmed differences in the incidence of major gastrointestinal adverse reactions depending on the dose titration interval (no dose titration, 2-week interval, or 4-week interval).

[0295] Specifically, in a sub-analysis of the phase 2 clinical trial (HM-EXC-205) targeting adult obese patients with a BMI of 27 or more, a 6 mg once-weekly administration group (without dose titration) and a phase 3 clinical trial (AMPLITUDE-M) targeting type 2 diabetes patients with a BMI of 27 or more, the safety in the phase 3 clinical trial with dose titration was confirmed to be better (Table 3).

[0296]

[0297]

[0298]

[0299] In addition, in a phase 3 clinical trial (AMPLITUDE-M) for patients with type 2 diabetes, when comparing the sub-analysis results for obese patients with a BMI of 27 or higher with the results of another phase 3 clinical trial (AMPLITUDE-O study, patients with type 2 diabetes), it was confirmed that even at the same target dose (6 mg), when the dose was increased slowly, that is, when the dose increase interval was 4 weeks, the incidence of major gastrointestinal adverse reactions could be lower than when the interval was 2 weeks (Table 4, incidence of Nausea & Vomiting: 12.3% & 5.5% for 4-week interval titration vs. 20.22% & 7.87% for 2-week interval titration).

[0300]

[0301]

[0302]

[0303] Based on these results, a dose titration method was established in which, when the target dose is a high dose, less than 6 mg is administered for 2 weeks, and 6 mg or more is administered for 4 weeks.

[0304]

[0305] Furthermore, since nausea and vomiting are expected to be the main adverse reactions following efpeglenatide administration, a population PK / AE simulation (weekly dosing) was conducted focusing on the above adverse reactions. The adverse reaction incidence predicted by the population PK / AE model was 62.7% and 76.3% (at 18 weeks), respectively, when the target doses of 6 mg and 10 mg were administered without a dose titration period. This was confirmed to be predicted at a similar or slightly higher level compared to the 6 mg adverse reaction observed in an actual obesity clinical trial (20 weeks, 59.3%).

[0306] The predicted incidence of adverse reactions at 4, 8, 12, and 38 weeks were approximately 17%, 23%, 26%, and 30%, respectively, which was lower than the predicted incidence of adverse reactions (42% to 58%) at maintenance doses of 2 mg, 4 mg, 6 mg, and 10 mg under conditions without a dose titration period (Fig. 5).

[0307] Accordingly, the results of predicting the cumulative adverse reaction incidence when reaching and maintaining the target dose of 10 mg after dose titration (2+4 weeks) using the model are shown in Figure 6.

[0308] Specifically, the incidence of adverse reactions was found to increase rapidly until the first 4 weeks, but then gradually stabilized.

[0309]

[0310] Experimental Example 2-5. Test Method

[0311] The clinical trial is conducted in the same manner as in Figure 7.

[0312] Briefly, participants selected according to the criteria of Experimental Example 2-1 above had a body mass index (27 kg / m 2 ≤ BMI < 30 kg / m 2 , BMI ≥ 30 kg / m 2 ) and stratified by gender, and randomly assigned to the test group and control group at a ratio of 2:1.

[0313] The approximately 40-week period after randomization is the Core-Treatment Period, a period for comparative evaluation with placebo. In the experimental group, efpeglenatide will be started at 2 mg and titrated in 1-step increments (2 mg), then gradually increased at 2-week intervals until 6 mg is reached, and then at 4-week intervals until 10 mg is reached. The target dose of 10 mg of efpeglenatide should be reached by week 12, and then maintained at that dose. At all time points, the control group will be administered the same dose of placebo as the experimental group.

[0314] The Extension Period is approximately 24 weeks from the intensive treatment period to the 64th week. The experimental group maintains the existing dose administered during the intensive treatment period until the end of treatment, and the control group switches from placebo to efpeglenatide at the 40th week. At this time, the control group starts with 2 mg of efpeglenatide and titrates by one step (2 mg), gradually increasing at 2-week intervals until 6 mg is reached, and then at 4-week intervals until 10 mg is reached. Once the target dose of 10 mg of efpeglenatide is reached, that dose is maintained until the end of treatment.

[0315] Finally, a trial termination visit is conducted 6 weeks after the last IP administration to evaluate the efficacy and safety of the clinical trial drug in a washed-out state and terminate the clinical trial.

[0316]

[0317] Experimental Example 2-6. Validity Evaluation Criteria

[0318] The efficacy of efpeglenatide administration in participants was evaluated based on the following items.

[0319]

[0320] (1) Primary efficacy evaluation variable

[0321] - Percentage change in weight at 40 weeks compared to baseline

[0322] - Proportion of subjects with a weight loss rate of 5% or more compared to baseline at 40 weeks

[0323]

[0324] (2) Secondary validity evaluation variables

[0325] - Rate of weight change at 24 and 64 weeks compared to baseline

[0326] - Proportion of subjects with a weight loss rate of 5% or more compared to baseline at 24 and 64 weeks

[0327] - Proportion of subjects with a weight loss rate of 10% or more from baseline at 24, 40, and 64 weeks

[0328] - Weight change at 24, 40, and 64 weeks compared to baseline

[0329] - Changes in BMI at 24, 40, and 64 weeks compared to baseline

[0330] - Changes in waist circumference at 24, 40, and 64 weeks compared to baseline

[0331] - Changes in glucose metabolism indicators at 24, 40, and 64 weeks compared to baseline: HbA1c, FPG, fasting insulin (fasting insulin is presented as a percentage change compared to baseline)

[0332] - Changes in lipids at weeks 24, 40, and 64 compared to baseline: Total cholesterol, LDL-C, HDL-C, TG, non-HDL-C

[0333] - Changes in blood pressure at 24, 40, and 64 weeks compared to baseline: sitSBP, sitDBP

[0334] - Changes in IWQoL-Lite-CT (Physical function domain) at 24, 40, and 64 weeks compared to baseline

[0335]

[0336] Experimental Example 2-7. Safety and Exploratory Evaluation Criteria

[0337] Safety and exploratory evaluation of efpeglenatide administration in participants was conducted based on the following items.

[0338] (1) Exploratory evaluation

[0339] - Body composition evaluation (DEXA, BIA): body fat mass, lean body mass, visceral fat mass, etc.

[0340] - Immunogenicity and pharmacokinetic evaluation

[0341] - Safety evaluation including liver steatosis evaluation (2): Adverse reactions, vital signs, clinical laboratory tests, physical examination, electrocardiogram, mental health evaluation (PHQ-9, C-SSRS)

[0342]

[0343] From the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without altering its technical spirit or essential characteristics. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as encompassing all changes or modifications derived from the meaning and scope of the following claims and their equivalent concepts, rather than the detailed description above.

Claims

1. A pharmaceutical composition for preventing or treating obesity, comprising efpeglenatide as an active ingredient, characterized in that the efpeglenatide is administered parenterally in an amount of 8 to 18 mg to an obese patient once a week.

2. A pharmaceutical composition according to claim 1, characterized in that the efpeglenatide is administered parenterally at 8 to 10 mg once a week to an obese patient.

3. In paragraph 1, the obese patient has a BMI (body mass index) of 25 kg / m 2 A pharmaceutical composition characterized by the above.

4. A pharmaceutical composition according to claim 1, characterized in that the obese patient does not have diabetes.

5. In the third paragraph, the obese patient (a) BMI (Body mass index) is 30 kg / m 2 or (b) BMI is 27 kg / m 2 Above, 30 kg / m 2 A pharmaceutical composition characterized by having at least one risk factor or concomitant disease.

6. A pharmaceutical composition according to claim 5, wherein the patient with the risk factor or concomitant disease is a patient with at least one of hypertension, dyslipidemia, sleep apnea, and cardiovascular disease.

7. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that the pharmaceutical composition is used as an administration method for preventing or treating obesity.

8. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that the obese patient has undergone a dose titration period in which 2 to 16 mg of efpeglenatide is administered for 2 to 12 weeks.

9. A pharmaceutical composition according to claim 8, wherein the dose titration is sequentially administered at 2 mg of efpeglenatide once a week for 2 weeks, 4 mg of efpeglenatide once a week for 2 weeks, 6 mg of efpeglenatide once a week for 4 weeks, and 8 mg of efpeglenatide once a week for 4 weeks.

10. A pharmaceutical composition according to claim 8, characterized in that the dosage titration is sequentially administered once a week for two weeks when titrated to a dosage of 2 mg or more and less than 6 mg, and once a week for four weeks when titrated to a dosage of 6 mg or more and less than 16 mg.

11. A method for preventing or treating obesity, comprising a step of parenterally administering 8 to 18 mg of a composition containing efpeglenatide as an active ingredient to an obese patient once a week.

12. A method for preventing or treating obesity in claim 11, wherein the method for preventing or treating obesity further comprises a dose titration step of administering 2 to 16 mg of efpeglenatide for 2 to 12 weeks prior to parenteral administration of 8 to 18 mg to an obese patient once a week.

13. For the purpose of manufacturing a pharmaceutical composition containing efpeglenatide for preventing or treating obesity, The above efpeglenatide is administered parenterally at a dose of 8 to 18 mg once a week to obese patients.

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