Pharmaceutical use of GLP-1 analog

Abstract

Provided is a pharmaceutical use of a GLP-1 analog. Specifically, the present invention relates to pharmaceutical use and a method of a GLP-1 analog or a pharmaceutically acceptable salt thereof for treating, preventing, or delaying sleep apnea or apnea-related disorders.

Description

Medical uses of GLP-1 analogs

[0001] The present disclosure claims priority to the following Chinese patent applications:

[0002] CN202411129316.0, filed on August 16, 2024;

[0003] CN202510531038.X, filed on April 25, 2025. TECHNICAL FIELD

[0004] The present disclosure belongs to the field of medicine, and relates to methods and medical uses of GLP-1 analogs for preventing or treating sleep apnea. BACKGROUND

[0005] Obstructive sleep apnea (OSA) is a sleep breathing disease with snoring during sleep accompanied by apnea and daytime sleepiness as the main clinical manifestations, which can cause intermittent hypoxia, hypercapnia and sleep structure disorder, and can lead to multiple organ and system damage such as hypertension, coronary heart disease, arrhythmia, cerebrovascular disease, cognitive dysfunction, and type 2 diabetes. Obstructive sleep apnea is closely related to obesity, and obstructive sleep apnea can exacerbate obesity, and obstructive sleep apnea is even more common in obese people.

[0006] For obstructive sleep apnea, the current drugs mainly act to relieve the symptoms of OSA, such as night snoring and daytime sleepiness; the first-line treatment for OSA is continuous positive airway pressure (CPAP) treatment, the efficacy of which is closely related to compliance, and although it can relieve snoring symptoms, it has no obvious improvement on other metabolic and cardiovascular risk factors. Therefore, there is a huge unmet clinical need in the field of treatment of obstructive sleep apnea in current clinical practice. SUMMARY

[0007] The present disclosure provides methods and medical uses of GLP-1 analogs or pharmaceutically acceptable salts thereof for preventing or treating sleep apnea, or delaying the development of sleep apnea.

[0008] In one aspect, the present disclosure provides the use of a GLP-1 analog or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing sleep apnea, or delaying the development thereof, wherein the GLP-1 analog comprises or is as shown in the following structure:

[0009] H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2(SEQ ID NO. 1).

[0010] In some embodiments, the K(-OEG-OEG-γGlu-C20-OH) has the following structure:

[0011] In some embodiments, the K(-OEG-OEG-γGlu-C20-OH) has the following structure:

[0012] Dosing regimen

[0013] In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered at a dose of 0.1-20 mg, for example 1-10 mg, 2-8 mg, or 2-6 mg. In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, or about 8 mg. In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg, about 4 mg, about 6 mg, or about 8 mg.

[0014] In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered at a dose of about 8 mg or its maximum tolerated dose.

[0015] In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered by dose titration.

[0016] In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered at a frequency of about once per week.

[0017] In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered at a frequency of about once per week for at least 32 weeks, at least 52 weeks, at least 2 years, at least 3 years, at least 4 years, at least 5 years, or at least 5.5 years.

[0018] In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered starting from an initial dose, with a dose escalation of about 1 mg to about 2 mg (e.g., selected from one or more of about 1 mg and about 2.0 mg) once every 4 weeks, to gradually titrate to a maintenance dose.

[0019] In some embodiments, the initial dose is about 0.1 mg to about 2.5 mg, for example, the initial dose is about 0.5 mg, about 1.0 mg, or about 1.5 mg.

[0020] In some embodiments, the initial dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, is about 0.5 mg, about 1.0 mg, or about 1.5 mg, administered for at least about 4 weeks; then the dose is escalated by about every 4 weeks, the dose escalation being selected from one or more of about 1 mg and about 2.0 mg, titrating to a maintenance dose of 1.0 mg to 8.0 mg (e.g., about 2.0 mg, about 4.0 mg, about 6.0 mg, or about 8.0 mg).

[0021] In some embodiments, the GLP-1 analog, or pharmaceutically acceptable salt thereof, is escalated in dose about every 4 weeks, each escalation being an increase in dose from the previous dosing, e.g., an increase of 1 mg to 2 mg from the previous dosing, e.g., an increase of about 1 mg or about 2 mg from the previous dosing. In some embodiments, the magnitude of each dose escalation is the same or different, illustratively, the initial dose is about 1 mg, the second dose is about 2 mg, the dose is escalated by about 1 mg, the third dose is about 3 mg, the dose is escalated by about 1 mg, the fourth dose is about 4 mg, the dose is escalated by about 1 mg, the fifth dose is about 5 mg, the dose is escalated by about 1 mg, the sixth dose is 6 mg, the dose is escalated by about 1 mg, the maintenance dose is 8 mg, the dose is escalated by about 2 mg; illustratively, the initial dose is about 1 mg, the second dose is about 2 mg, the dose is escalated by about 1 mg, the third dose is about 3 mg, the dose is escalated by about 1 mg, the fourth dose is about 4 mg, the dose is escalated by about 1 mg, the fifth dose is about 5 mg, the dose is escalated by about 1 mg, the sixth dose is 6 mg, the maintenance dose is escalated by about 1 mg.

[0022] In some embodiments, the dosing regimen for the GLP-1 analog, or pharmaceutically acceptable salt thereof, comprises:

[0023] administering an initial dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof;

[0024] subsequently, administering a maintenance dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof;

[0025] optionally, administering an escalation dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, between the initial dose and the maintenance dose.

[0026] In some embodiments, the dosing regimen for the GLP-1 analog, or pharmaceutically acceptable salt thereof, comprises any one of the following groups:

[0027] 1)

[0028] a) administering an initial dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once a week for at least 1 week, and subsequently,

[0029] Optionally, b) administering an escalation dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once weekly for > 1 week, followed by,

[0030] c) administering a maintenance dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once weekly for > 2 weeks;

[0031] 2)

[0032] a) administering an initial dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once weekly for > 2 weeks, followed by,

[0033] Optionally, b) administering an escalation dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once weekly for > 2 weeks, followed by,

[0034] c) administering a maintenance dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once weekly for > 4 weeks;

[0035] 3)

[0036] a) administering an initial dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once weekly for about 4 weeks, followed by,

[0037] Optionally, b) administering an escalation dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once weekly for about 4 weeks, each escalation dose for about 4 weeks, followed by,

[0038] c) administering a maintenance dose of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once weekly for > 12 weeks.

[0039] In some embodiments, the initial dose is selected from 0.1 mg - 2.5 mg or 0.5 mg - 1.5 mg. In some embodiments, the initial dose is about 0.5 mg, about 1.0 mg, and / or about 1.5 mg.

[0040] In some embodiments, the escalation dose is selected from 0.5 mg - 8.0 mg, 1.0 mg - 6.0 mg, or 1.0 mg - 7.0 mg. In some embodiments, the escalation dose is about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, and / or about 6.0 mg.

[0041] In some embodiments, the maintenance dose is selected from 0.5 mg - 10.0 mg or 2.0 mg - 8.0 mg. In some embodiments, the maintenance dose is about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, and / or about 8.0 mg.

[0042] In some embodiments, the escalation dose comprises one escalation dose, two escalation doses, three escalation doses, four escalation doses, or five escalation doses.

[0043] In some embodiments, each escalation dose is the same or different independent of each other.

[0044] In some embodiments, the escalation doses comprise 4 or 5 escalation doses.

[0045] In the present disclosure, “≥1 week” or “at least 1 week” includes at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, etc. “≥2 weeks” or “at least 2 weeks” includes at least 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, etc. “≥4 weeks” or “at least 4 weeks” includes at least 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, etc. “≥12 weeks” or “at least 12 weeks” includes at least 12 weeks, 14 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, etc.

[0046] In some embodiments, the escalation doses are selected from any one of the following groups:

[0047] 1) the escalation doses comprise one escalation dose:

[0048] the first escalation dose is selected from 1.0 mg - 4.0 mg, e.g., 1.0 mg - 3.0 mg;

[0049] 2) the escalation doses comprise two escalation doses:

[0050] the first escalation dose is selected from 1.0 mg - 4.0 mg, e.g., 1.0 mg - 3.0 mg;

[0051] the second escalation dose is selected from 1.0 mg - 4.0 mg, e.g., 2.0 mg - 4.0 mg;

[0052] 3) the escalation doses comprise three escalation doses:

[0053] the first escalation dose is selected from 1.0 mg - 4.0 mg, e.g., 1.0 mg - 3.0 mg;

[0054] the second escalation dose is selected from 1.0 mg - 4.0 mg, e.g., 2.0 mg - 4.0 mg;

[0055] the third escalation dose is selected from the group consisting of 2.0 mg - 5.0 mg, for example 3.0 mg - 5.0 mg; or

[0056] 4) the escalation doses comprise four escalation doses:

[0057] the first escalation dose is selected from the group consisting of 1.0 mg - 4.0 mg, for example 1.0 mg - 3.0 mg;

[0058] the second escalation dose is selected from the group consisting of 1.0 mg - 4.0 mg, for example 2.0 mg - 4.0 mg;

[0059] the third escalation dose is selected from the group consisting of 2.0 mg - 5.0 mg, for example 3.0 mg - 5.0 mg;

[0060] the fourth escalation dose is selected from the group consisting of 3.0 mg - 6.0 mg, for example 4.0 mg - 6.0 mg;

[0061] 5) the escalation doses comprise five escalation doses:

[0062] the first escalation dose is selected from the group consisting of 1.0 mg - 4.0 mg, for example 1.0 mg - 3.0 mg;

[0063] the second escalation dose is selected from the group consisting of 1.0 mg - 4.0 mg, for example 2.0 mg - 4.0 mg;

[0064] the third escalation dose is selected from the group consisting of 2.0 mg - 5.0 mg, for example 3.0 mg - 5.0 mg;

[0065] the fourth escalation dose is selected from the group consisting of 3.0 mg - 6.0 mg, for example 4.0 mg - 6.0 mg;

[0066] the fifth escalation dose is selected from the group consisting of 4.0 mg - 7.0 mg, for example 5.0 mg - 7.0 mg.

[0067] In some embodiments, the escalation doses are selected from any one of the following groups:

[0068] 1) the escalation doses comprise one escalation dose:

[0069] the first escalation dose is selected from the group consisting of about 1.5 mg, about 2.0 mg, or about 2.5 mg;

[0070] 2) the escalation doses comprise two escalation doses:

[0071] the first escalation dose is selected from the group consisting of about 1.5 mg, about 2.0 mg, or about 2.5 mg;

[0072] the second escalation dose is selected from the group consisting of about 2.5 mg, about 3.0 mg, or about 3.5 mg;

[0073] 3) The incremental dosage includes three incremental dosages:

[0074] The first incremental dose is selected from about 1.5 mg, about 2.0 mg, or about 2.5 mg;

[0075] The second incremental dose is selected from about 2.5 mg, about 3.0 mg, or about 3.5 mg;

[0076] The third escalation dose is selected from about 3.5 mg, about 4.0 mg, or about 4.5 mg; or

[0077] 4) The incremental dosage includes four incremental dosages:

[0078] The first incremental dose is selected from about 1.5 mg, about 2.0 mg, or about 2.5 mg;

[0079] The second incremental dose is selected from about 2.5 mg, about 3.0 mg, or about 3.5 mg;

[0080] The third escalation dose is selected from about 3.5 mg, about 4.0 mg, or about 4.5 mg;

[0081] The fourth increment dose is selected from about 4.5 mg, about 5.0 mg, or about 5.5 mg; or

[0082] 5) The incremental dosage includes five incremental dosages:

[0083] The first incremental dose is selected from about 1.5 mg, about 2.0 mg, or about 2.5 mg;

[0084] The second incremental dose is selected from about 2.5 mg, about 3.0 mg, or about 3.5 mg;

[0085] The third escalation dose is selected from about 3.5 mg, about 4.0 mg, or about 4.5 mg;

[0086] The fourth increment dose is selected from about 4.5 mg, about 5.0 mg, or about 5.5 mg;

[0087] The fifth dose increment is selected from about 5.5 mg, about 6.0 mg, or about 6.5 mg.

[0088] In some implementations, the incremental dose includes four incremental doses:

[0089] The first incremental dose is approximately 2.0 mg;

[0090] The second incremental dose is approximately 3.0 mg;

[0091] The third escalation dose is approximately 4.0 mg;

[0092] the fourth escalation dose is about 5.0 mg.

[0093] In some embodiments, the escalation doses comprise five escalation doses:

[0094] the first escalation dose is about 2.0 mg;

[0095] the second escalation dose is about 3.0 mg;

[0096] the third escalation dose is about 4.0 mg;

[0097] the fourth escalation dose is about 5.0 mg;

[0098] the fifth escalation dose is about 6.0 mg.

[0099] In some embodiments, the escalation doses comprise two escalation doses:

[0100] the first escalation dose is about 2.0 mg;

[0101] the second escalation dose is about 3.0 mg.

[0102] In some embodiments, the dosing regimen of the GLP-1 analog, or pharmaceutically acceptable salt thereof, comprises any one of the following groups:

[0103] 1)

[0104] a) 0.1 mg - 2.5 mg of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once a week for > 1 week, followed by

[0105] c) 0.5 mg - 10.0 mg of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once a week for > 2 weeks;

[0106] 2)

[0107] a) 0.5 mg - 1.5 mg of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once a week for > 2 weeks, followed by

[0108] c) 2.0 mg - 8.0 mg of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once a week for > 4 weeks;

[0109] 3)

[0110] a) 1.0 mg of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once a week for about 4 weeks, followed by

[0111] c) 2.0 mg of the GLP-1 analog, or pharmaceutically acceptable salt thereof, once a week for > 12 weeks, e.g., about 28 weeks;

[0112] 4)

[0113] a) 0.1 mg - 2.5 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by

[0114] b-1) 1.0 mg - 4.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by

[0115] b-2) 1.0 mg - 4.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by

[0116] b-3) 2.0 mg - 5.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by

[0117] b-4) 3.0 mg - 6.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by

[0118] c) 0.5 mg - 10.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks;

[0119] 5)

[0120] a) 0.5 mg - 1.5 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by

[0121] b-1) 1.0 mg - 3.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by

[0122] b-2) 2.0 mg - 4.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by

[0123] b-3) 3.0 mg - 5.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by

[0124] b-4) 4.0 mg - 6.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by

[0125] c) 2.0 mg - 8.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 4 weeks;

[0126] 6)

[0127] a) about 1.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for about 4 weeks, followed by

[0128] b-1) about 2.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for about 4 weeks, followed by

[0129] b-2) about 4 weeks of about 3.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week, followed by

[0130] b-3) about 4 weeks of about 4.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week, followed by

[0131] b-4) about 4 weeks of about 5.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week, followed by

[0132] c) about 6.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 12 weeks;

[0133] 7)

[0134] a) 0.1 mg to 2.5 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 1 week, followed by

[0135] b-1) 1.0 mg to 4.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 1 week, followed by

[0136] b-2) 1.0 mg to 4.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 1 week, followed by

[0137] b-3) 2.0 mg to 5.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 1 week, followed by

[0138] b-4) 3.0 mg to 6.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 1 week, followed by

[0139] b-5) 4.0 mg to 7.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 1 week, followed by

[0140] c) 0.5 mg to 10.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 2 weeks;

[0141] 8)

[0142] a) 0.5 mg to 1.5 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 2 weeks, followed by

[0143] b-1) 1.0 mg to 3.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 2 weeks, followed by

[0144] b-2) 2.0 mg to 4.0 mg of the GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 2 weeks, followed by

[0145] b-3) 3.0 mg - 5.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for > 2 weeks, followed by

[0146] b-4) 4.0 mg - 6.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for > 2 weeks, followed by

[0147] b-5) 5.0 mg - 7.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for > 2 weeks, followed by

[0148] c) 2.0 mg - 8.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for > 4 weeks;

[0149] 9)

[0150] a) about 1.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by

[0151] b-1) about 2.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by

[0152] b-2) about 3.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by

[0153] b-3) about 4.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by

[0154] b-4) about 5.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by

[0155] b-5) about 6.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by

[0156] c) about 8.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for > 12 weeks, e.g. 28 weeks;

[0157] 10)

[0158] a) 0.1 mg - 2.5 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for > 1 week, followed by

[0159] b-1) 1.0 mg - 4.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for > 1 week, followed by

[0160] b-2) 1.0 mg - 4.0 mg of a GLP-1 analogue or a pharmaceutically acceptable salt thereof once weekly for > 1 week, followed by

[0161] c) administering 3.0 mg - 5.0 mg of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 4 weeks; or

[0162] 11)

[0163] a) administering 0.5 mg - 1.5 mg of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 2 weeks, followed by

[0164] b-1) administering 1.0 mg - 3.0 mg of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 2 weeks, followed by

[0165] b-2) administering 2.0 mg - 4.0 mg of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 2 weeks, followed by

[0166] c) administering 3.0 mg - 5.0 mg of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 4 weeks; or

[0167] 12)

[0168] a) administering about 1.0 mg of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for about 4 weeks, followed by

[0169] b-1) administering about 2.0 mg of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for about 4 weeks, followed by

[0170] b-2) administering about 3.0 mg of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for about 4 weeks, followed by

[0171] c) administering about 4.0 mg of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, once a week for > 12 weeks.

[0172] In any of the dosing regimens of the present disclosure, the dosing amount and duration can be adjusted according to the tolerance of the subject, the prevention or treatment result desired to be achieved, or other conditions determined by a physician or health care provider.

[0173] In another aspect, the present disclosure provides a GLP-1 analog, or a pharmaceutically acceptable salt thereof, for use in treating or preventing sleep apnea, or delaying progression thereof, comprising administering the GLP-1 analog, or a pharmaceutically acceptable salt thereof, to a subject in need thereof according to the foregoing dosing regimens

[0174] In another aspect, the present disclosure provides a method of preventing or treating sleep apnea, or delaying progression of sleep apnea, comprising administering to a subject in need thereof an effective amount of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, according to the foregoing dosing regimens.

[0175] In another aspect, the present disclosure provides a method of (i) improving body weight and (ii) preventing or treating sleep apnea, or delaying the development of sleep apnea, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, according to the foregoing dosage regimen.

[0176] In another aspect, the present disclosure provides a method of (i) improving body weight and (ii) preventing or treating sleep apnea, or delaying the development of sleep apnea, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, according to the foregoing dosage regimen.

[0177] In another aspect, the present disclosure provides a method of (i) improving body weight and (ii) preventing or treating sleep apnea, or delaying the development of sleep apnea, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, according to the foregoing dosage regimen.

[0178] In another aspect, the present disclosure provides a method of (i) improving body weight and (ii) preventing or treating sleep apnea, or delaying the development of sleep apnea, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a GLP-1 analog, or a pharmaceutically acceptable salt thereof, according to the foregoing dosage regimen.

[0179] In some embodiments, the sleep apnea is obstructive sleep apnea, e.g., mild, moderate, and / or severe obstructive sleep apnea.

[0180] In some embodiments, the sleep apnea subject has an AHI > 5 events / h. In some embodiments, the sleep apnea subject has an AHI > 15 events. In some embodiments, the sleep apnea subject has an AHI > 15 events / h and < 30 events / h, or an AHI > 30 events / h.

[0181] In some embodiments, the sleep apnea subject has a metabolic disorder.

[0182] In some embodiments, the sleep apnea subject is in need of improved glycemic control.

[0183] In some embodiments, the sleep apnea subject is not in need of improved glycemic control.

[0184] In some embodiments, the sleep apnea subject is in need of improved weight management, e.g., the subject is obese or overweight.

[0185] In some embodiments, the sleep apnea subject is not obese or overweight.

[0186] In some embodiments, the sleep apnea subject has a BMI > 24 kg / m 2 , for example a BMI > 28 kg / m 2 , for example a BMI of 28 kg / m 2 - 42 kg / m 2 .

[0187] In some embodiments, the sleep apnea subject has multiple cardiovascular risk factors without established cardiovascular disease.

[0188] In some embodiments, the sleep apnea subject has multiple cardiovascular risk factors with established cardiovascular disease.

[0189] In some embodiments, the sleep apnea subject is not using PAP therapy prior to and / or during administration.

[0190] In some embodiments, the sleep apnea subject has received or is receiving PAP therapy.

[0191] In some embodiments, the sleep apnea subject has obstructive sleep apnea and at the same time meets at least one of the following characteristics:

[0192] 1) in need of improved weight management, for example the subject is obese or overweight;

[0193] 2) a BMI > 24 kg / m 2 , for example a BMI > 28 kg / m 2 , for example a BMI of 28 kg / m 2 - 42 kg / m 2 ;

[0194] 3) in need of improved glycemic control;

[0195] 4) moderate, severe obstructive sleep apnea;

[0196] 5) an AHI > 5 / h, for example an AHI > 15;

[0197] 6) the subject is not using PAP therapy prior to and / or during administration;

[0198] 7) the subject has received or is receiving PAP therapy.

[0199] In some embodiments, the sleep apnea subject has obstructive sleep apnea and at the same time meets the characteristics of any one of the following groups:

[0200] A)

[0201] 1) Those who need improved weight management, such as subjects who are obese or overweight; or

[0202] 2) BMI ≥ 24 kg / m 2 For example, BMI ≥ 28 kg / m 2 For example, a BMI of 28 kg / m 2 -42kg / m 2 ;

[0203] B)

[0204] 1) Those who need to improve their blood sugar control;

[0205] C)

[0206] 1) Moderate to severe obstructive sleep apnea; or

[0207] 2) AHI ≥ 5 times / h, for example, AHI ≥ 15 times;

[0208] D)

[0209] 1) Subjects did not use PAP treatment before and / or during administration;

[0210] E)

[0211] 1) Those who need improved weight management, such as subjects who are obese or overweight; and

[0212] 2) Moderate to severe obstructive sleep apnea;

[0213] F)

[0214] 1) Those who need to improve their weight management, such as subjects who are obese or overweight;

[0215] 2) Moderate to severe obstructive sleep apnea; and

[0216] 3) Subjects did not use PAP treatment before and / or during administration;

[0217] G)

[0218] 1) BMI ≥ 24 kg / m 2 For example, BMI ≥ 28 kg / m 2 For example, a BMI of 28 kg / m 2 -42kg / m 2 ;and

[0219] 2) AHI ≥ 5 times / h, for example, AHI ≥ 15 times;

[0220] H)

[0221] 1) BMI ≥ 24 kg / m 2e.g., BMI > 28 kg / m2 2 e.g., BMI is 28 kg / m2 2 - 42 kg / m2 2 ;

[0222] 2) AHI > 5 events / h, e.g., AHI > 15 events; and

[0223] 3) the subject is not using PAP therapy prior to and / or during dosing;

[0224] I)

[0225] 1) the subject is receiving or has received PAP therapy;

[0226] J)

[0227] 1) in need of improved weight management, e.g., the subject is obese or overweight;

[0228] 2) moderate, severe obstructive sleep apnea; and

[0229] 3) the subject is receiving or has received PAP therapy;

[0230] K)

[0231] 1) BMI > 24 kg / m2 2 e.g., BMI > 28 kg / m2 2 e.g., BMI is 28 kg / m2 2 - 42 kg / m2 2 ;

[0232] 2) AHI > 5 events / h, e.g., AHI > 15 events; and

[0233] 3) the subject is receiving or has received PAP therapy.

[0234] In some embodiments, the GLP-1 analog or pharmaceutically acceptable salt thereof reduces the risk of the subject experiencing sleep apnea, reduces body weight, improves glycemia, and / or reduces blood lipids.

[0235] In some embodiments, the GLP-1 analog or pharmaceutically acceptable salt thereof improves at least one of the following:

[0236] 1) reduces body weight;

[0237] 2) reduces the proportion of subjects who reduce body weight by > 5%, > 10%, > 15%, or > 20% relative to baseline;

[0238] 3) improves body mass index;

[0239] 4) reduces the risk of developing sleep apnea, e.g., obstructive sleep apnea;

[0240] 5) reducing the apnea hypopnea index (AHI), for example, reducing the AHI of a subject to <20 / h, <15 / h, <10 / h, or <5 / h;

[0241] 6) improving the proportion of subjects with a reduction in AHI of >50% relative to baseline;

[0242] 7) improving the Epworth Sleepiness Scale score;

[0243] 8) improving the proportion of subjects with an AHI of 5-14 / h and an Epworth Sleepiness Scale score of <10;

[0244] 9) improving the Sleep Function Outcomes Questionnaire score;

[0245] 10) improving the risk of transient ischemic attack;

[0246] 11) improving cardiovascular risk factors;

[0247] 12) improving the risk of death;

[0248] 13) improving the PROMIS Sleep Disturbance Brief Form 8a and / or 8b score;

[0249] 14) improving the proportion of subjects with sleepiness, fatigue, and / or snoring.

[0250] GLP-1 analogue or pharmaceutically acceptable salt thereof

[0251] In some embodiments, the GLP-1 analogue or salt thereof comprises or is a structure as shown below:

[0252] In some embodiments, the GLP-1 analogue can activate both GLP-1 receptor and GIP receptor.

[0253] In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is selected from any GLP-1 analogue or pharmaceutically acceptable salt thereof, composition disclosed in WO2021239082. The present disclosure incorporates by reference the structures, preparation methods, etc. of the GLP-1 analogue or pharmaceutically acceptable salt thereof in the above-mentioned patent into the present disclosure.

[0254] In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered parenterally, including but not limited to intravenous injection, subcutaneous injection, intramuscular injection. In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is administered subcutaneously.

[0255] In some embodiments, the GLP-1 analogue or pharmaceutically acceptable salt thereof is formulated in an injectable form, for example, the pharmaceutical composition comprising the aforementioned GLP-1 analogue or pharmaceutically acceptable salt thereof further comprises at least one of a buffer, an osmotic pressure adjusting agent, a pH adjusting agent, a bacteriostatic agent.

[0256] In some embodiments, the buffer is selected from one or more of acetate buffer, histidine buffer, phosphate buffer, succinate buffer, and citrate buffer. In some embodiments, the buffer is phosphate buffer, for example, disodium hydrogen phosphate.

[0257] In some embodiments, the pharmaceutical composition further comprises an osmotic pressure adjusting agent. The osmotic pressure adjusting agent includes, but is not limited to, a salt (e.g., sodium chloride, phosphate, sodium citrate, boric acid, and sodium tartrate), a sugar or sugar alcohol (lactose, trehalose, sucrose, glucose, mannitol, sorbitol, xylitol), an amino acid (e.g., L-glycine, L-histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine), a polyol [e.g., glycerol, 1,2-propanediol (also referred to as propylene glycol in the present disclosure), 1,3-propanediol, 1,3-butanediol], polyethylene glycol (e.g., PEG 400), or a mixture thereof. In some embodiments, the osmotic adjusting agent is selected from one or more of propylene glycol, mannitol, sorbitol, xylitol, glycerol, lactose, trehalose, sucrose, glucose, sodium chloride, phosphate, sodium citrate, boric acid, and sodium tartrate. In some embodiments, the osmotic adjusting agent is sodium chloride. In some embodiments, the osmotic pressure adjusting agent is propylene glycol or mannitol.

[0258] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable bacteriostatic agent. In some embodiments, the pharmaceutically acceptable bacteriostatic agent includes, but is not limited to, phenol, o-cresol, m-cresol, p-cresol, methyl paraben, propyl paraben, 2-phenoxyethanol, butyl paraben, 2-phenylethanol, benzyl alcohol, ethanol, chlorobutanol, and thiomersal, bronopol, benzoic acid, imidurea, chlorhexidine, sodium dehydroacetate, chlorocresol, ethyl paraben, benzalkonium chloride, or a mixture thereof. In some embodiments, the pharmaceutically acceptable bacteriostatic agent is phenol.

[0259] In some embodiments, the pharmaceutical composition is a pharmaceutical composition comprising any component, concentration disclosed in WO2023083301, the composition, preparation method, etc. in the aforementioned patent are incorporated into the present disclosure by reference.

[0260] The term

[0261] For the purposes of the present disclosure, certain technical and scientific terms are specifically defined below. Unless specifically defined herein, all other technical and scientific terms used in the present disclosure have the meanings that are commonly understood by one of ordinary skill in the art in the field of the present disclosure.

[0262] Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", "include", "including", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

[0263] "About", "approximately", or "substantially" mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined (i.e., the limitations of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation, or about 20%, e.g., within 1% to 15%, within 1% to 10%, within 1% to 5%, within 0.5% to 5%, within 0.5% to 1%, of the stated value. Each instance of a number or a numerical range in this disclosure, unless specifically stated to the contrary, can be interpreted as an embodiment of a range that includes that number or the numerical range. When a particular value is recited, "about" or "substantially" should be assumed to be within an acceptable error range for that particular value, unless otherwise indicated.

[0264] The term "and / or", e.g., "X and / or Y" shall be understood to mean either "X and Y" or, in the alternative, "X or Y" and shall be used to provide explicit support for both usages.

[0265] The term "native GLP-1" refers to a naturally occurring molecule of the glucagon family of peptides or the exendin family of peptides, wherein: the glucagon family of peptides is encoded by the preproglucagon gene and includes three small peptides with high homology, i.e., glucagon (1-29), GLP-1 (1-37), and GLP-2 (1-33); the exendin is a peptide expressed in lizards and, like GLP-1, is insulinotropic. In some embodiments, the term "native GLP-1" also refers to human GLP-1 (7-37) and human GLP-1 (7-36). The term "native GIP" refers to a peptide comprising the sequence of human GIP sequence (1-42).

[0266] The term "GLP-1 analogue" means an amino acid modification of up to 25, up to 24, up to 23, up to 22, up to 21, up to 20, up to 19, up to 18, up to 17, up to 16, up to 15, up to 14, up to 13, up to 12, up to 11, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2, or 1 amino acid modification, which can be an amino acid substitution, addition and / or deletion, or a chemical modification, which can be a chemical modification selected from one or more of the following groups: amide, carbohydrate, alkyl, acyl, ester, polyethylene glycol (PEG) group, sialylation group, glycosylation group, and the like, compared to native GLP-1, in particular compared to human GLP-1 (7-37) and human GLP-1 (7-36).

[0267] In some embodiments, the GLP-1 analogue is a GLP-1 receptor agonist. In some embodiments, the GLP-1 analogue is a dual agonist of the GLP-1 receptor and the GIP receptor.

[0268] The term agonist is defined as a substance that activates the type of receptor in question, "activity", "activate", "activation" and the like mean as determined using detection methods known in the art.

[0269] An amino acid "substitution" as described herein means that one amino acid residue is replaced by a different one.

[0270] The term "peptide" as used herein encompasses the category of peptides having modified amino terminus and carboxy terminus. For example, an amino acid chain comprising a terminal carboxylic acid replaced with an amide group is also included within the designation of an amino acid sequence of natural amino acids.

[0271] The hydrogen atoms described herein can be replaced by isotopes thereof (protium, deuterium, tritium), and any of the hydrogen atoms in the compounds of the present disclosure are intended to be replaced by isotopic atoms.

[0272] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and this description includes situations where the event or circumstance occurs and situations where it does not. For example, "heterocyclic group optionally substituted with alkyl" means that alkyl can or can not be present, and this description includes situations where the heterocyclic group is substituted with alkyl and situations where the heterocyclic group is not substituted with alkyl.

[0273] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of the group are independently of each other replaced with a substituent. Substituents are only in their possible chemical positions, which can or cannot be determined (experimentally or theoretically) by one skilled in the art without undue effort. For example, an amino group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0274] "Pharmaceutical composition" means a mixture of a compound described herein or a physiologically / pharmaceutically acceptable salt or

[0275] a prodrug with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, to facilitate absorption of the active ingredient, and to facilitate biological activity.

[0276] "Buffer" means a buffering agent that resists changes in pH through the action of its acid-base conjugate components. Examples of buffers that control pH in an appropriate range include acetate, succinate, citrate, phosphate, gluconate, histidine, oxalate, lactate, phosphate, citrate, tartrate, fumarate, glycylglycine, and other organic acid buffers.

[0277] The three letter code and one letter code for amino acids used in the present disclosure are as described in J. Biol. Chem, 243, p 3558 (1968).

[0278] "Administering" and "treatment" when applied to an animal, human, test subject, cell, tissue, organ, or biological fluid means the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, test subject, cell, tissue, organ, or biological fluid. "Administering" and "treatment" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treatment of a cell includes contact of the agent with the cell, as well as contact of the agent with a fluid that is in contact with the cell. "Administering" and "treatment" also mean in vitro and ex vivo treatment of, for example, a cell by an agent, diagnostic, binding composition, or by another cell. "Treatment" when applied to a human, veterinary, or research subject means therapeutic treatment, prophylaxis or preventative measures, research, and diagnostic applications.

[0279] "Treatment" means the administration of an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the disclosure, to a patient having one or more symptoms of a disease, where the therapeutic agent is known to have a therapeutic effect on those symptoms. Generally, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated patient or population to induce regression of such symptoms or to inhibit the development of such symptoms to any clinically measurable extent. The amount of therapeutic agent effective to alleviate any particular symptom of a disease (also referred to as a "therapeutically effective amount") can vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired therapeutic effect in the patient. Whether a disease symptom has been alleviated can be assessed by any clinical test method used by a physician or other professional health care provider to evaluate the severity or progression of the symptom. While embodiments of the disclosure (e.g., methods of treatment or articles of manufacture) can not be effective in alleviating every symptom of a target disease, it is determined that a statistically significant number of patients should have alleviation of the target disease symptoms according to any statistical test method known in the art, such as the Student t-test, the Chi-square test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), the Jonckheere-Terpstra test, and the Wilcoxon test.

[0280] "Effective amount" includes an amount that is sufficient to ameliorate or prevent the symptoms or conditions of a medical disease. An effective amount also means an amount that is sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on such factors as the condition to be treated, the overall health status of the patient, the method route and dose of administration, and the severity of side effects. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0281] As used herein, "titration dose" or "escalating dose" means a dose that is less than the highest effective dose required by a patient. As used herein, the present disclosure contemplates that a "titration dose" or "escalating dose" can become the highest effective dose required by a patient, or if it is observed that this dose is the effective dose required by a patient, it can become a "maintenance dose."

[0282] As used herein, "maintenance dose" means a dose that is the highest effective dose required by a patient, and when the maintenance dose is less than the highest effective dose required, this maintenance dose can become an escalating dose. That is, if for a particular patient, the "about 2 mg" maintenance dose contemplated by the present disclosure is not the highest effective dose required, then the 2 mg maintenance dose will in turn become an escalating dose, as the dose for that particular patient will be increased until the next highest maintenance dose contemplated by the present disclosure is achieved, e.g., 6.0 mg for at least about 2 weeks.

[0283] As used herein, "pharmaceutically acceptable salts" are well known to the skilled person. In one embodiment the GLP-1 analogue is in the form of a pharmaceutically acceptable salt. In one embodiment the GLP-1 analogue is in the form of a non-salt.

[0284] The terms "subject", "patient" mean a mammal, especially a primate, and especially a human. DETAILED DESCRIPTION

[0285] The present disclosure is further described in connection with the following examples, which are not intended to limit the scope of the present disclosure. The experimental methods in the embodiments of the present disclosure, unless otherwise specified, are generally performed according to conventional conditions, such as in accordance with the Antibody Techniques Experiment Manual published by Cold Spring Harbor Laboratory, Molecular Cloning Manual, or in accordance with the conditions recommended by the manufacturer of the raw materials or products. Reagents not specified by source are commercially available reagents.

[0286] Example 1. Preparation of GLP-1 analogue

[0287] The GLP-1 analogue is compound 18# prepared in Example 1 of WO2023083301 (incorporated by reference in its entirety into the present disclosure),

[0288] The molecular structure of compound 18# is: H-YAibEGTFTSDYSIYK(OEG-OEG-γGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2

[0289] The structural formula is as follows:

[0290] Example 2. Multicenter, randomized, double-blind, placebo-controlled phase II clinical study to evaluate the effectiveness and safety of GLP-1 analogue injection in subjects with obesity combined with obstructive sleep apnea

[0291] 1. Test drug

[0292] 1) GLP-1 analogue prepared in Example 1, in the form of an injection.

[0293] 2. Enrolled subjects

[0294] The subjects must meet all the following criteria to enter the study:

[0295] 1) 18-65 years old (including both ends), male or female;

[0296] 2) Body mass index (BMI) of 28.0-42.0 kg / m 2 (including both ends) at the time of screening;

[0297] 3) Subjects who have been diet and exercise controlled for 3 months or more prior to screening, and whose body weight has changed (the difference between the maximum and minimum body weight in the 3 months) ≤ 5.0 kg in the last 3 months;

[0298] 4) Subjects who are suspected or have been diagnosed with obstructive sleep apnea (OSA) and whose polysomnography (PSG) results at screening are consistent with OSA and AHI (apnea-hypopnea index) ≥ 15.0 times / hour;

[0299] 5) Subjects who are not willing or suitable to receive positive airway pressure (PAP) treatment, and who have not received PAP treatment in the 4 weeks prior to screening.

[0300] 3. Dosing Regimen

[0301] The test drug is administered by subcutaneous injection in the abdomen, lateral thigh, or lateral upper arm, once a week, either before or after meals.

[0302] The study is designed with 2 doses of the test drug / placebo, 2.0 mg or 6.0 mg once a week, starting at 1.0 mg, titrating once every 4 weeks to reach the target dose of each group and maintaining the target dose for treatment, for a total of 32 weeks of treatment.

[0303] The specific dosing regimen is as follows:

[0304] Table 1. Dosing Regimen

[0305] 4. Outcome Evaluation

[0306] 4.1 Study Endpoints

[0307] Primary Endpoint

[0308] Percentage change from baseline in body weight after 32 weeks of administration.

[0309] Key Secondary Endpoint

[0310] Change from baseline in apnea-hypopnea index (AHI) after 32 weeks of administration.

[0311] Secondary Endpoint

[0312] Proportion of subjects with ≥ 5%, ≥ 10%, and > 15% reduction in body weight from baseline after 32 weeks of administration;

[0313] Change from baseline in body weight, BMI after 32 weeks of administration;

[0314] Change from baseline in neck circumference, waist circumference, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, fasting serum insulin, glycosylated hemoglobin (HbAlc), insulin resistance (HOMA model), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and high-sensitivity C-reactive protein, urinary albumin / creatinine ratio (UACR) after 32 weeks of administration;

[0315] Percentage of subjects with a change from baseline in AHI after 32 weeks of administration;

[0316] Percentage of subjects with a reduction of > 50% in AHI from baseline after 32 weeks of administration;

[0317] Change from baseline in Epworth Sleepiness Scale (ESS) score after 32 weeks of administration;

[0318] Percentage of subjects with an AHI < 5.0 events / h, or an AHI 5.0-14.0 events / h and an Epworth Sleepiness Scale (ESS) < 10 after 32 weeks of administration;

[0319] Change from baseline in Functional Outcomes of Sleep Questionnaire (FOSQ) score after 32 weeks of administration;

[0320] Safety endpoints: adverse events, laboratory parameters, 12-lead ECG, vital signs, physical examination, immunogenicity, etc.

[0321] Example 3. A multicenter, randomized, double-blind, placebo-controlled phase I / II clinical study to evaluate the effectiveness and safety of a GLP-1 analogue in subjects with obstructive sleep apnea combined with obesity without the use of positive airway pressure therapy

[0322] 1. Test drug

[0323] 1) The GLP-1 analogue prepared in Example 1, in the form of an injection, was provided by Jiangsu Hengrui Medicine.

[0324] 2. Inclusion criteria

[0325] A subject must meet all of the following criteria to be enrolled in this trial:

[0326] 1) 18 to 75 years of age (inclusive) at the time of signing the informed consent form, male or female;

[0327] 2) BMI ≥ 28.0 kg / m 2 at screening;

[0328] 3) Self-reported diet and exercise controlled for 3 months or more prior to screening, and a body weight change (difference between the maximum and minimum body weight in the last 3 months) of < 5.0 kg in the last 3 months;

[0329] 4) previously diagnosed or suspected obstructive sleep apnea (OSA) and screening polysomnography (PSG) results consistent with OSA and AHI≥15.0 events / h;

[0330] 5) subjects who are not willing or suitable to receive positive airway pressure (PAP) therapy and who have not received PAP therapy within 4 weeks prior to screening.

[0331] 3. Dosing Regimen

[0332] Subjects are administered GLP-1 analogue injection or placebo subcutaneously in the abdomen, lateral thigh, or lateral upper arm, once weekly, either before or after meals.

[0333] GLP-1 analogue injection or placebo is administered using a titration regimen, starting at 1 mg, with titration every 4 weeks until the target dose is reached. The specific dosing regimen is as follows:

[0334] Table 2. Dosing Regimen

[0335] 4. Outcome Assessment

[0336] 4.1 Study Endpoints

[0337] Primary Endpoint

[0338] Change from baseline in AHI after 52 weeks of treatment.

[0339] Key Secondary Endpoints

[0340] 1) percentage change from baseline in AHI after 52 weeks of treatment;

[0341] 2) proportion of subjects with a reduction in AHI of >50% from baseline after 52 weeks of treatment;

[0342] 3) proportion of subjects with an AHI <5.0 events / h, or an AHI between 5.0-14.0 events / h and an Epworth Sleepiness Scale (ESS) score of <10 after 52 weeks of treatment;

[0343] 4) percentage change from baseline in body weight after 52 weeks of treatment.

[0344] Secondary Endpoints

[0345] 1) change from baseline in ESS score after 52 weeks of treatment;

[0346] 2) change from baseline in Functional Outcomes of Sleep Questionnaire (FOSQ) total score and domain scores after 52 weeks of treatment;

[0347] 3) the proportion of subjects with a body weight reduction of >5%, >10%, >15%, and >20% relative to baseline after 52 weeks of administration;

[0348] 4) the changes in body weight, BMI relative to baseline after 52 weeks of administration;

[0349] 5) the changes in neck circumference, waist circumference, fasting plasma glucose, fasting serum insulin, HbAlc, insulin resistance (HOMA model), TC, LDL-C, HDL-C, non-high density lipoprotein cholesterol (non-HDL-C), TG, and high-sensitivity C-reactive protein (hsCRP) relative to baseline after 52 weeks of administration;

[0350] 6) the changes in systolic blood pressure, diastolic blood pressure relative to baseline after 52 weeks of administration;

[0351] 7) the changes in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep-Related Impairments Short Form 8a, PROMIS Sleep Disturbance Short Form 8b scores relative to baseline after 52 weeks of administration;

[0352] 8) the proportion of subjects with improvement in Patient Global Impression Scale (PGIS)-OSA Somnolence, Fatigue, Snoring classification changes after 52 weeks of administration;

[0353] Safety endpoints: adverse events, etc.

[0354] Example 4. A multicenter, randomized, double-blind, placebo parallel controlled phase I / II clinical study for evaluating the effectiveness and safety of GLP-1 analog in subjects with obstructive sleep apnea combined with obesity treated with positive airway pressure

[0355] 1. Test drug

[0356] 1) GLP-1 analog prepared in Example 1, in the form of injection, provided by Jiangsu Hengrui Medicine.

[0357] 2. Inclusion criteria

[0358] A subject must meet all the following criteria to be enrolled in this trial:

[0359] 1) 18 to 75 years of age (inclusive) at the time of signing the informed consent form, male or female;

[0360] 2) BMI > 28.0 kg / m 2 at screening;

[0361] 3) Self-reported diet and exercise controlled for 3 months or more before screening, and body weight change (the difference between the maximum body weight and the minimum body weight in the last 3 months) < 5.0 kg in the last 3 months;

[0362] 4) previously diagnosed or suspected obstructive sleep apnea (OSA) and screening polysomnography (PSG) results consistent with OSA and an AHI ≥ 15.0 events / h;

[0363] 5) received PAP therapy for at least 3 months prior to screening and plan to continue PAP therapy during the study and are willing to discontinue PAP therapy for at least one week prior to each PSG examination during the study.

[0364] 3. Dosing Regimen

[0365] Subjects are administered a subcutaneous injection of GLP-1 analogue injection or placebo once weekly, either before or after meals, in the abdomen, lateral thigh, or lateral upper arm.

[0366] The GLP-1 analogue injection or placebo is administered using a titration regimen, starting at 1 mg and titrating every 4 weeks until the target dose is reached. The specific dosing regimen is as follows:

[0367] Table 2. Dosing Regimen

[0368] 4. Outcome Assessments

[0369] 4.1 Study Endpoints

[0370] Primary Endpoint

[0371] Change from baseline in AHI after 52 weeks of treatment.

[0372] Key Secondary Endpoints

[0373] 1) Percentage change from baseline in AHI after 52 weeks of treatment;

[0374] 2) Proportion of subjects with a reduction in AHI of > 50% from baseline after 52 weeks of treatment;

[0375] 3) Proportion of subjects with an AHI < 5.0 events / h, or an AHI between 5.0-14.0 events / h and an Epworth Sleepiness Scale (ESS) score of < 10 after 52 weeks of treatment;

[0376] 4) Percentage change from baseline in body weight after 52 weeks of treatment.

[0377] Secondary Endpoints

[0378] 1) Change from baseline in ESS score after 52 weeks of treatment;

[0379] 2) Change from baseline in Functional Outcomes of Sleep Questionnaire (FOSQ) total score and domain scores after 52 weeks of treatment;

[0380] 3) The proportion of subjects with a decrease in body weight of >5%, >10%, >15%, and >20% relative to baseline after 52 weeks of administration;

[0381] 4) Changes in body weight, BMI relative to baseline after 52 weeks of administration;

[0382] 5) Changes in neck circumference, waist circumference, fasting plasma glucose, fasting serum insulin, HbAlc, insulin resistance (HOMA model), TC, LDL-C, HDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), TG, and high-sensitivity C-reactive protein (hsCRP) relative to baseline after 52 weeks of administration;

[0383] 6) Changes in systolic blood pressure, diastolic blood pressure relative to baseline after 48 weeks of administration;

[0384] 7) Changes in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep-Related Impairments Short Form 8a, PROMIS Sleep Disturbance Short Form 8b scores relative to baseline after 52 weeks of administration;

[0385] 8) The proportion of subjects with improvement in Patient Global Impression Scale (PGIS)-OSA Somnolence, Fatigue, Snoring classification changes after 52 weeks of administration;

[0386] Safety endpoints: adverse events, etc.

[0387] Example 5. Multicenter, randomized, double-blind, placebo-controlled phase III clinical study for evaluating the effectiveness and safety of GLP-1 analogue injection in overweight or obese subjects

[0388] 1. Test drug

[0389] 1) GLP-1 analogue prepared in Example 1, in the form of an injection, at a dosage of 3 ml: 12 mg, 3 ml: 24 mg, 3 ml: 30 mg.

[0390] 2. Subjects enrolled

[0391] Subjects must meet all of the following criteria to enter this study:

[0392] 1) Age of ≥ 18 years, regardless of gender;

[0393] 2) BMI at the time of screening meets the following criteria:

[0394] ≥ 28.0 kg / m 2 or

[0395] ≥ 24.0 kg / m 2 with at least one weight-related comorbidity:

[0396] 3). Self-reported diet and exercise controlled for 3 months or more before screening, and body weight change (the difference between the maximum weight and the minimum weight in the last 3 months) ≤ 5 kg in the last 3 months.

[0397] 3. Dosing Regimen

[0398] GLP-1 analogue injection or placebo was administered by subcutaneous injection in the abdomen, lateral thigh or lateral upper arm, either before or after meals. The specific dosing regimen is shown in Table 6 below:

[0399] Table 6. Dosing Regimen

[0400] 4. Outcome Assessment

[0401] 4.1. Efficacy Assessment

[0402] Efficacy assessment indicators include body weight, waist circumference, BMI, blood pressure (systolic and diastolic blood pressure), blood lipids (TG, TC, LDL-C, non-HDL-C, HDL-C), glucose metabolism (fasting plasma glucose, fasting serum insulin, HbA1c, HOMA-IR), physiological function score (SF-36v2), hsCRP, total fat mass, lean body mass, UACR.

[0403] *Note: Insulin resistance under the steady-state model evaluation (HOMA-IR) is calculated using the following formula:

[0404] HOMA-IR = [fasting plasma glucose level (FPG, mmol / L) x fasting insulin level (FINS, mIU / L)] / 22.5

[0405] 4.2. Safety Assessment

[0406] Safety assessment indicators include adverse events, vital signs, physical examination, laboratory indicators, 12-lead electrocardiogram, PHQ-9 score, etc.

[0407] 4.3. Results

[0408] At baseline, the average body weight was 93.0 kg, and the average BMI value was 33.3 kg / m 2The mean percent change in body weight from baseline to Week 48 was -10.7%, -16.4%, and -17.7% for the GLP-1 analogue 2 mg, 4 mg, and 6 mg groups, respectively; the treatment differences compared with placebo were -9.3%, -15.0%, and -16.3%, respectively, p<0.0001, based on the on-treatment strategy evaluation. The proportions of subjects with >5% reduction in body weight from baseline were 68.1%, 88.0%, and 85.7% for the GLP-1 analogue 2 mg, 4 mg, and 6 mg groups, respectively, and 16.0% for the placebo group, p<0.0001. Moreover, the proportions of subjects with >20% reduction in body weight from baseline were 37.1% and 44.4% for the GLP-1 analogue 4 mg and 6 mg groups, respectively, and 3.5% for the placebo group, p<0.0001.

[0409] Based on the as-treated strategy evaluation, the mean percent change in body weight was -19.2% (-17.7% placebo-adjusted) for the GLP-1 analogue 6 mg group; the proportion of subjects with >5% reduction in body weight from baseline was 90.8% for the GLP-1 analogue 6 mg group. In addition, the GLP-1 analogue groups were superior to the placebo group in improving cardiovascular risk factors: the mean change in systolic blood pressure from baseline to Week 48 was -8.2 to -9.8 mmHg for the GLP-1 analogue groups (placebo group: -1.2 mmHg); the geometric mean ratio of triglycerides at Week 48 relative to baseline was 0.61 to 0.69 for the GLP-1 analogue groups (placebo group: 1.0); and other lipids such as total cholesterol, LDL cholesterol, and non-HDL cholesterol were also reduced in the GLP-1 analogue groups relative to the placebo group.

[0410] Improvements in urinary albumin creatinine ratio and uric acid ranged from -27.3% to -39.0% (placebo group: -5.8%) and -17.7% to -23.1% (placebo group: -8.1%), respectively. A DXA sub-study showed that the body weight loss was mainly due to a reduction in fat mass. Most treatment-emergent adverse events (TEAEs) were mild or moderate, and the most common TEAEs were related to the gastrointestinal tract. In this 48-week trial in Chinese overweight or obese adults, the GLP-1 analogue significantly reduced body weight and provided comprehensive metabolic improvements with good tolerability and safety.

[0411] Example 6. A multicenter, randomized, double-blind, placebo-parallel-controlled clinical study to evaluate the efficacy and safety of GLP-1 analogue injection in overweight or obese subjects

[0412] 1. Test drug

[0413] 1) The GLP-1 analogue prepared in Example 1, in the form of an injection.

[0414] 2. Test population

[0415] Overweight subjects with poor diet and exercise control and at least one weight-related comorbidity or obese subjects.

[0416] 3. Enrolled subjects

[0417] Subjects must meet all of the following criteria to be enrolled in the study:

[0418] 1). Age 18-65 years (inclusive), gender unrestricted;

[0419] 2). Body mass index (BMI) at screening meets the following criteria:

[0420] - 28.0-40.0 kg / m 2 (inclusive), or

[0421] - 24.0 (inclusive) - 28.0 (not inclusive) kg / m 2 and with at least one weight-related comorbidity

[0422] 3). Self-reported diet and exercise control for 3 months or more prior to screening, and body weight change (difference between maximum and minimum body weight in the last 3 months) no more than 5 kg in the last 3 months;

[0423] 3. Dosing regimen

[0424] GLP-1 analogue injection or placebo is given by subcutaneous injection in the abdomen, once a week, either before or after meals. GLP-1 analogue injection or placebo starts from 1.0 mg QW, and the dose is increased every 4 weeks, gradually titrating to the target dose of 8.0 mg QW. The specific dosing regimen is shown in the following Table 7:

[0425] Table 7: Dosing regimen

[0426] 4. Outcome evaluation

[0427] 4.1 Evaluation of effectiveness

[0428] The evaluation indexes of effectiveness include body weight, waist circumference, BMI, blood pressure (systolic pressure, diastolic pressure), glucose metabolism (fasting plasma glucose, fasting serum insulin, HbA1c), blood lipids (TG, TC, LDL-C, non-HDL-C, HDL-C).

[0429] 4.2 Evaluation of safety

[0430] The evaluation indexes of safety include adverse events, laboratory indexes, 12-lead electrocardiogram, vital signs, physical examination, PHQ-9 score, etc.

[0431] 4.3 Results

[0432] Sixty-one subjects were enrolled and randomized to receive GLP-1 analog 8 mg (n=49) and placebo (n=12). Baseline characteristics were generally comparable between the two groups. Mean baseline BW was 84.6 kg and mean BMI was 31.3 kg / m2. 2 .

[0433] After 36 weeks of dosing, the percent change from baseline in body weight for subjects in the GLP-1 analog 8.0 mg group was -22.8% with a least squares mean difference of -21.1% compared to placebo. The proportion of subjects in the GLP-1 analog 8.0 mg group who had a >5%, >10%, >15%, >20%, and >25% reduction in body weight after 36 weeks of dosing was 93.9%, 91.8%, 87.8%, 59.2%, and 30.6%, respectively, compared to 16.7%, 8.3%, 0%, 0%, and 0% for the placebo group. In addition, the GLP-1 analog improved waist circumference, BMI, systolic blood pressure, fasting glucose, fasting serum insulin, HbAlc levels, and reduced triglyceride levels compared to placebo at Week 36. Most adverse events (TEAEs) were mild in severity and related to the gastrointestinal tract, with diarrhea, nausea, and vomiting being the most common. No subjects permanently discontinued treatment due to TEAEs.

[0434] For overweight or obese adults, once-weekly subcutaneous injection of GLP-1 analog significantly reduced body weight at 36 weeks compared to placebo and demonstrated a manageable safety profile with gastrointestinal adverse events as the main adverse effect.

Claims

1. Use of a GLP-1 analogue or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of sleep apnoea, or for delaying progression of sleep apnoea, wherein the GLP-1 analogue comprising the structure shown below: 18 #H-YAibEGTFTSDYSIYK(OEG-OEG-gGlu-C20-OH)EKIAAQEFVNWLLAGGPSSGAPPPS-NH2; (SEQ ID NO. 1) Preferably, the GLP-1 analogue comprises the structure shown below:

2. Use according to claim 1, wherein, the sleep apnoea is obstructive sleep apnoea, preferably mild, moderate and / or severe obstructive sleep apnoea, more preferably moderate and / or severe obstructive sleep apnoea.

3. Use according to claim 1 or 2, wherein, the subject with sleep apnoea has an AHI of > 5 events / h, preferably an AHI of > 15 events, more preferably an AHI of > 15 events / h and < 30 events / h, or an AHI of > 30 events / h.

4. Use according to any one of claims 1 to 3, wherein, the subject with sleep apnoea has a metabolic disease.

5. Use according to any one of claims 1 to 4, wherein, the subject with sleep apnoea is in need of improved body weight management, preferably the subject is obese or overweight.

6. Use according to any one of claims 1 to 5, wherein, The subject with sleep apnea has a BMI > 24 kg / m 2 , preferably a BMI > 28 kg / m 2 .

7. Use according to any one of claims 1 to 6, wherein, the subject with sleep apnoea has obstructive sleep apnoea and is obese or overweight.

8. Use according to any one of claims 1 to 7, wherein, The subject suffering from sleep apnea has an obstructive sleep apnea and an AHI > 5 and / or a BMI > 24 kg / m 2 Preferably, the subject suffering from sleep apnea has an AHI > 15 and / or a BMI > 28 kg / m 2 .

9. Use according to any one of claims 1 to 8, wherein, the subject with sleep apnoea has multiple cardiovascular risk factors without established cardiovascular disease, or has established cardiovascular disease.

10. Use according to any one of claims 1 to 9, wherein, the subject with sleep apnoea is not using PAP therapy prior to and / or during treatment.

11. Use according to any one of claims 1 to 10, wherein, the subject with sleep apnoea has obstructive sleep apnoea and is not using PAP therapy prior to and / or during treatment, preferably the subject with sleep apnoea has moderate and / or severe obstructive sleep apnoea and is not using PAP therapy prior to and / or during treatment.

12. The use according to any one of claims 1-9, wherein the subject with sleep apnoea has received or is receiving PAP therapy.

13. Use according to any one of claims 1 to 12, wherein, the subject with sleep apnoea has obstructive sleep apnoea and has received or is receiving PAP therapy, preferably the subject with sleep apnoea has moderate and / or severe obstructive sleep apnoea and has received or is receiving PAP therapy.

14. Use according to any one of claims 1 to 13, wherein, the GLP-1 analogue or a pharmaceutically acceptable salt thereof improves at least one of the following: 1) reduces body weight; 2) reduces the proportion of subjects with a reduction in body weight of > 5%, > 10%, > 15% or > 20% relative to baseline; 3) improves body mass index; 4) reduces the risk of developing sleep apnoea, for example obstructive sleep apnoea; 5) reduces the apnoea hypopnoea index, for example reduces the AHI of a subject to < 20 events / h, < 15 events / h < 10 events / h, or < 5 events / h, for example improves the proportion of subjects with a reduction in AHI of > 50% relative to baseline; 6) improves Epworth Sleepiness Scale score, for example improves the proportion of subjects with an AHI of 5-14 events / h and an Epworth Sleepiness Scale score of < 10; 7) improves Sleep Function Outcomes Questionnaire score; 8) improves risk of transient ischaemic attack; 9) improves cardiovascular risk factors; 10) improves risk of death; 11) improving PROMIS Sleep Disturbance Short Form 8a and / or 8b score; 12) improving the proportion of subjects with drowsiness, fatigue and / or snoring.

15. Use according to any one of claims 1 to 14, wherein, The GLP-1 analogue or pharmaceutically acceptable salt thereof is administered at a dose of 0.1-20 mg and / or is administered with a frequency of about once a week; Preferably, the dose is 1-10 mg, more preferably 2-8 mg, most preferably about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg or about 8 mg.

16. Use according to any one of claims 1 to 15, wherein, The GLP-1 analogue or pharmaceutically acceptable salt thereof is administered according to a regimen comprising: administering an initial dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof; subsequently, administering a maintenance dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof; optionally, between the initial dose and the maintenance dose, administering an escalation dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof.

17. Use according to any one of claims 1 to 16, wherein, The GLP-1 analogue or pharmaceutically acceptable salt thereof is administered according to a regimen comprising any of the following groups: 1) a) administering an initial dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof once a week for > 1 week, and subsequently, optionally, b) administering an escalation dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof once a week for > 1 week, and subsequently, c) administering a maintenance dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof once a week for > 2 weeks; 2) a) administering an initial dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof once a week for > 2 weeks, and subsequently, optionally, b) administering an escalation dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof once a week for > 2 weeks, and subsequently, c) administering a maintenance dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof once a week for > 4 weeks; 3) a) administering an initial dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof once a week for about 4 weeks, and subsequently, optionally, b) administering an escalation dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof once a week for about 4 weeks, and subsequently, c) administering a maintenance dose of the GLP-1 analogue or pharmaceutically acceptable salt thereof once a week for > 12 weeks.

18. The use according to claim 17, wherein, a) the initial dose is selected from the group consisting of 0.1 mg - 2.5 mg or 0.5 mg - 1.5 mg; preferably about 0.5 mg, about 1.0 mg and / or about 1.5 mg; b) the escalation dose is selected from the group consisting of 0.5 mg - 8.0 mg or 1.0 mg - 7.0 mg; preferably about 1.0 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg and / or about 6.0 mg; c) the maintenance dose is selected from the group consisting of 0.5 mg - 10.0 mg or 2.0 mg - 8.0 mg; preferably about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg and / or about 8.0 mg.

19. Use according to any one of claims 16-18, wherein, The escalation doses comprise 1-5 escalation doses, preferably the escalation doses comprise 4 or 5 escalation doses.

20. Use according to any one of claims 16-18, wherein, 1) The escalation doses comprise 4 escalation doses: the first escalation dose is selected from the group consisting of 1.0 mg - 4.0 mg or 1.0 mg - 3.0 mg; preferably about 1.5 mg, about 2.0 mg or about 2.5 mg; the second escalation dose is selected from the group consisting of 2.0 mg - 5.0 mg or 2.0 mg - 4.0 mg; preferably about 2.5 mg, about 3.0 mg or about 3.5 mg; the third escalation dose is selected from the group consisting of 3.0 mg - 6.0 mg or 3.0 mg - 5.0 mg; preferably about 3.5 mg, about 4.0 mg or about 4.5 mg; the fourth escalation dose is selected from the group consisting of 4.0 mg - 7.0 mg or 4.0 mg - 6.0 mg; preferably about 4.5 mg, about 5.0 mg or about 5.5 mg. the second escalation dose is selected from the group consisting of 1.0 mg - 4.0 mg or 2.0 mg - 4.0 mg; preferably about 2.5 mg, about 3.0 mg, or about 3.5 mg; the third escalation dose is selected from the group consisting of 2.0 mg - 5.0 mg or 3.0 mg - 5.0 mg; preferably about 3.5 mg, about 4.0 mg, or about 4.5 mg; the fourth escalation dose is selected from the group consisting of 3.0 mg - 6.0 mg or 4.0 mg - 6.0 mg; preferably about 4.5 mg, about 5.0 mg, or about 5.5 mg; or 2) the escalation doses comprise five escalation doses: the first escalation dose is selected from the group consisting of 1.0 mg - 4.0 mg or 1.0 mg - 3.0 mg; preferably about 1.5 mg, about 2.0 mg, or about 2.5 mg; the second escalation dose is selected from the group consisting of 1.0 mg - 4.0 mg or 2.0 mg - 4.0 mg; preferably about 2.5 mg, about 3.0 mg, or about 3.5 mg; the third escalation dose is selected from the group consisting of 2.0 mg - 5.0 mg or 3.0 mg - 5.0 mg; preferably about 3.5 mg, about 4.0 mg, or about 4.5 mg; the fourth escalation dose is selected from the group consisting of 3.0 mg - 6.0 mg or 4.0 mg - 6.0 mg; preferably about 4.5 mg, about 5.0 mg, or about 5.5 mg; the fifth escalation dose is selected from the group consisting of 4.0 mg - 7.0 mg or 5.0 mg - 7.0 mg, preferably about 5.5 mg, about 6.0 mg, or about 6.5 mg.

21. The use according to any one of claims 1 to 20, wherein, the dosing regimen of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, comprises any one of the following: 1) a) 0.1 mg - 2.5 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 1 week, followed by c) 0.5 mg - 10.0 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 2 weeks; 2) a) 0.5 mg - 1.5 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 2 weeks, followed by c) 2.0 mg - 8.0 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 4 weeks; 3) a) 1.0 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for about 4 weeks, followed by c) 2.0 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 12 weeks; 4) a) 0.1 mg - 2.5 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 1 week, followed by b-1) 1.0 mg - 4.0 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 1 week, followed by b-2) 1.0 mg - 4.0 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 1 week, followed by b-3) 2.0 mg - 5.0 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 1 week, followed by b-4) 3.0 mg - 6.0 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 1 week, followed by c) 0.5 mg - 10.0 mg of the GLP-1 analogue, or pharmaceutically acceptable salt thereof, once weekly for > 2 weeks; 5) a) 0.5 mg - 1.5 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by b-1) 1.0 mg - 3.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by b-2) 2.0 mg - 4.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by b-3) 3.0 mg - 5.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by b-4) 4.0 mg - 6.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by c) 2.0 mg - 8.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 4 weeks; 6) a) about 1.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for about 4 weeks, followed by b-1) about 2.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for about 4 weeks, followed by b-2) about 3.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for about 4 weeks, followed by b-3) about 4.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for about 4 weeks, followed by b-4) about 5.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for about 4 weeks, followed by c) about 6.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 12 weeks; 7) a) 0.1 mg - 2.5 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by b-1) 1.0 mg - 4.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by b-2) 1.0 mg - 4.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by b-3) 2.0 mg - 5.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by b-4) 3.0 mg - 6.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by b-5) 4.0 mg - 7.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 1 week, followed by c) 0.5 mg - 10.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks; 8) a) 0.5 mg - 1.5 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by b-1) 1.0 mg - 3.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by b-2) 2.0 mg - 4.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by b-3) 3.0 mg - 5.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by b-4) 4.0 mg - 6.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once a week for > 2 weeks, followed by b-5) 5.0 mg - 7.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once weekly for > 2 weeks, followed by c) 2.0 mg - 8.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once weekly for > 4 weeks; 9) a) about 1.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by b-1) about 2.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by b-2) about 3.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by b-3) about 4.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by b-4) about 5.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by b-5) about 6.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once weekly for about 4 weeks, followed by c) about 8.0 mg of a GLP-1 analog or a pharmaceutically acceptable salt thereof once weekly for > 12 weeks.

22. A method of preventing or treating, or delaying progression of, sleep apnoea comprising administering to a subject in need thereof an effective amount of a GLP-1 analogue or a pharmaceutically acceptable salt thereof; wherein, The GLP-1 analog or a pharmaceutically acceptable salt thereof is as defined in claim 1 ; Preferentially, the subject suffers from obstructive sleep apnea.

23. A method of (i) improving body weight and (ii) preventing or treating, or delaying progression of, sleep apnoea in an overweight or obese patient, comprising administering to a subject in need thereof an effective amount of a GLP-1 analogue, or a pharmaceutically acceptable salt thereof; wherein, The GLP-1 analog or a pharmaceutically acceptable salt thereof is as defined in claim 1 ; Preferentially, the subject suffers from obstructive sleep apnea.

24. A method of (i) improving body weight and (ii) preventing or treating, or delaying progression of, sleep apnoea in a patient with a metabolic disease, comprising administering to a subject in need thereof an effective amount of a GLP-1 analogue, or a pharmaceutically acceptable salt thereof; wherein, The GLP-1 analog or a pharmaceutically acceptable salt thereof is as defined in claim 1 ; Preferentially, the subject suffers from obstructive sleep apnea.

25. A method of reducing the risk of a subject experiencing sleep apnea, reducing body weight, improving glycemia, and / or reducing blood lipids in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a GLP-1 analog or a pharmaceutically acceptable salt thereof; wherein, The GLP-1 analog or a pharmaceutically acceptable salt thereof is as defined in claim 1 ; wherein the subject suffers from sleep apnea, preferably from obstructive sleep apnea and is overweight or obese. The GLP-1 analog or a pharmaceutically acceptable salt thereof is as defined in claim 1 ; Preferentially, the subject suffers from obstructive sleep apnea. The GLP-1 analog or a pharmaceutically acceptable salt thereof is as defined in claim 1 ; Preferentially, the subject suffers from obstructive sleep apnea. The GLP-1 analog or a pharmaceutically acceptable salt thereof is as defined in claim 1 ; wherein the subject suffers from sleep apnea, preferably from obstructive sleep apnea and is overweight or obese.

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