New GLP-1 receptor agonists for the treatment of joint diseases

Abstract

The present invention relates to GLP-1 receptor agonist compounds having an additional agonist activity over the GIP receptor and / or an agonist activity over the glucagon receptor and / or an antagonist activity over the GIP receptor for use in the treatment of joint diseases and / or joint pain and selected from the group comprising retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide and UBT251. The invention also relates to a pharmaceutical composition comprising at least one of the above mentioned GLP-1 receptor agonist compound, and a pharmaceutically acceptable excipient, for use in the treatment of joint diseases and / or joint pain.

Description

NEW GLP-1 RECEPTOR AGONISTS FOR THE TREATMENT OF JOINTDISEASESFIELD OF INVENTION

[0001] The present invention relates to a GLP-1 receptor agonist compound, such as retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide, UBT251 for use in the treatment of joint diseases and / or joint pain. The present invention also relates to a pharmaceutical composition comprising said GLP-1 receptor agonist compound for use in the treatment of joint diseases, the pharmaceutical composition being administered, for example, via intra-articular injection.BACKGROUND OF INVENTION

[0002] Glucagon Like Peptide- 1 (GLP-1) is a peptide hormone that binds to GLP-1 receptors notably expressed on the pancreatic beta cells, thus increasing the glucose transporter 2 expression and the secretion of insulin in response to increased blood glucose concentration. Moreover, GLP-1 reduces the secretion of some proinflammatory cytokines. GLP-1 receptor (GLP-1 R) agonists are commonly used as a treatment for type 2 diabetes and obesity.

[0003] Joint cartilage is a connective tissue composed of chondrocytes and an extracellular matrix mostly composed of water, proteoglycans, and collagen. Chondrocytes have a fundamental role in the homeostasis of the extracellular matrix, for which they ensure the synthesis and renewal.

[0004] Synovial tissue is a specialized connective tissue comprising macrophage-like and fibroblast-like synoviocytes, vessels and sensory nerves. Synoviocytes play a crucial role in maintaining the integrity and function of the synovial fluid, where they regulate its composition and turnover to facilitate joint lubrication and nourishment. Additionally,synoviocytes contribute to the modulation of inflammatory responses within the joint, influencing pain perception and overall joint health.

[0005] Among the chronic joint diseases, osteoarthritis (OA) is the most prevalent disease, affecting nearly 50% of people over the age of 65 and occurring in younger people in case of anatomical abnormality, following a joint injury or in case of obesity. Worldwide, about 590 million people suffer from OA; this disease has major economic and social impacts.

[0006] The treatments offered to patients suffering from joint diseases are mostly symptomatic since there is no currently available curative treatment for this pathological condition.

[0007] Known GLP-1R agonists, such as liraglutide, target relevant mechanisms associated with inflammatory, anti-degradative and regenerative processes relevant to joint diseases. In the recent years, several compounds having GLP-1R agonist activity and additional binding activity have been discovered and their efficacy to treat diabetes and / or obesity has been investigated. More precisely, these compounds are GLP-1R agonists which also have agonist or antagonist activity over the GIP (glucose-dependent insulinotropic polypeptide also known as gastric inhibitory polypeptide) receptor and / or glucagon receptor.

[0008] However, whether these new GLP- 1R agonists can have a positive effect on joint diseases is unknown. There is a need to find efficient treatment for joint diseases able to not only stop the progression of the disease but also to activate the regeneration of damaged cartilage tissue.

[0009] The present invention relates to a GLP- 1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain. The inventors demonstrated that several GLP-1 receptor agonists with simple, dual or triple binding activity, are able to significantly reduce the expression levels of inflammation markers and catabolic markers and that they have a regenerative effect on cartilage, as shown by the increase in the expression levels of anabolism markers, in an in vitro model of joint disease. Therefore, GLP-1 receptor agonist compounds such as retatrutide, tirzepatide, orforglipron,mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide, UBT251 may be used in the treatment of joint diseases and / or joint pain.SUMMARY

[0010] This invention relates to a GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain, selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide, UBT251 and combinations thereof.

[0011] The GLP-1 receptor agonist compound for use as described here above may inhibit or slow down the arthritic cartilage destruction.

[0012] The GLP-1 receptor agonist compound for use as described here above may stimulate the regeneration of cartilage or improves the rate of regeneration of the cartilage.

[0013] The GLP-1 receptor agonist compound for use as described here above may reduce inflammation and / or prevents the thickening of the synovial tissue.

[0014] The joint disease may be selected from the group consisting of osteoarthritis and / or cartilage diseases including inflammatory arthritis, in particular cartilage defects caused by external injuries or surgical treatment, osteochondritis dissecans, osteoarthritis, congenital cartilage disease, gout and any crystal-induced arthritis and cartilage injury, synovitis caused by rheumatoid arthritis, psoriatic arthritis.

[0015] The joint pain may be inflammatory joint pain.

[0016] The GLP-1 receptor agonist compound for use as described here above may be administered to a subject to be treated in combination with at least one further active substance selected from the group consisting of analgesics, non-steroidal antiinflammatory drugs, steroidal anti-inflammatory drugs, hyaluronic acids and symptomatic slow-acting anti-osteoarthritic agents.

[0017] The GLP-1 receptor agonist compound for use and the at least one further active substance as described here above may be administered to a subject to be treated simultaneously.

[0018] The GLP-1 receptor agonist compound for use and the at least one further active substance as described here above may be administered to a subject to be treated sequentially.

[0019] The GLP-1 receptor agonist compound for use as described here above may be administered in combination with local treatments for osteoarthritis or any other arthritis.

[0020] The GLP- 1 receptor agonist compound for use as described here above, may be administered orally, subcutaneously, intramuscularly, intravenously, intratendinously or intra-articularly.

[0021] Another aspect of the invention is a pharmaceutical composition for use in the treatment of joint diseases and / or joint pain comprising a GLP-1 receptor agonist compound as described here above, and a pharmaceutically acceptable excipient.

[0022] The pharmaceutical composition for use may be formulated as a gel.

[0023] The pharmaceutical composition formulated as a gel may comprise a polymer selected from the group consisting of non-ionic surfactant, cellulose, polyether, glucan, glycerophospholipids polysaccharides, proteins, and combinations thereof.

[0024] The subject to be treated may be a non-human animal, preferably a non-human mammal, more preferably an animal selected from the group consisting of a dog, a cat, a horse, a cow, a sheep, a pig and a non-human primate.

[0025] The subject to be treated may be a human being.DEFINITIONS

[0026] In the present invention, the following terms have the following meanings:

[0027] “Active agent” or “active substance” refers to an agent that has a therapeutic effect. The agent may be a chemical or a biological substance. The therapeutic effect may be the prevention, delay, reduction in severity and / or frequency or suppression of at least one symptom associated with a pathological condition, or the prevention, slowing down or suppression of the underlying cause of a pathological condition, or the improvement or repair of a damage.

[0028] “Acute disease” refers to a non-chronic disease.

[0029] “Administration in combination” refers to sequential, simultaneous or separate administration of at least two active agents. When the administration in combination is simultaneous, the active agents administered simultaneously may be present in the same pharmaceutical composition.

[0030] “Cartilage” refers to elastic, translucent connective tissue in mammals, including human. Cartilage comprises chondrocytes, type II collagen, small amounts of other collagen types, other noncollagenous proteins, proteoglycans and water. Although most cartilage becomes bone upon maturation, some cartilage remains in its original form in some locations, such as the nose, ears, knees. The cartilage has no blood or nerve supply. In the present application, the terms “cartilage matrix” or “articular cartilage” are equivalent to “cartilage”.

[0031] “Chronic disease” refers to a long-term, progressive illness, often associated with disability and the threat of serious complications. Chronic diseases evolve more or less rapidly for at least several months, in particular at least 3 months.

[0032] “Complex of GLP-1R agonist” refers to a polyatomic structure consisting of one or more independent entities (ions or molecules), in interaction, said structure comprising a GLP-1R agonist.

[0033] “Gel” refers to a non-fluid colloidal network or polymer network that is expanded throughout its whole volume by a fluid, the fluid being called “swelling agent”. “Hydrogel” refers to a gel in which the swelling agent is water.

[0034] “Colloidal’’ refers to a state of subdivision, implying that the molecules or polymolecular particles dispersed in a medium have at least in one direction a dimension roughly from 1 nm to 1 pm.

[0035] “Network” refers to a highly ramified structure in which essentially each constitutional unit is connected to each other constitutional unit and to the macroscopic phase boundary by many paths through the structure, the number of such paths increasing with the average number of intervening constitutional units; the paths must on average be co-extensive with the structure.

[0036] “GLP-1 ” or “glucagon-like peptide 1” refers to a 30- or 31-amino acid long peptide hormone deriving from the post-translational processing of the proglucagon peptide into “GLP-1 (1-37)”, which is further / V-tcrminally truncated by tissue- specific post-translational processing in the intestinal L cells resulting in the two truncated and equipotent biologically active forms, “GLP-1 (7-36) amide” and “GLP-1 (7-37)”. In the NCBI databases (https: / / www.ncbi.nlm.nih.gov), the reference human GLP-1 gene sequence corresponds to NCBI Gene ID: 2641, as updated on January 29, 2024. The human GLP-1 gene consists of 6 exons on chromosome 2q24.2, and encodes a 180 amino acid protein referenced as NP_002045.1, in the NCBI databases. Alternatives names for GLP-1 include “Glucagon-Like Peptide 1”, “GLP1”, as non- limiting examples.

[0037] “GLP-1 receptor” or “GLP-1R” refer to a G protein-coupled receptor which is a member of the glucagon receptor family. GLP-1R is involved in the control of blood sugar level by enhancing insulin secretion. In the NCBI databases, the reference human GLP-1R gene sequence corresponds to NCBI Gene ID: 2740, as updated on January 15, 2024. The human GLP- 1R gene consists of 14 exons on chromosome 6p21.2, and encodes a 463 amino acid protein referenced as NP_002053, in the NCBI databases. Alternatives names for GLP-1R include “Glucagon Like Peptide 1 Receptor”, “GLP1R”, “Glucagon- Like Peptide 1 Receptor”, “GLP-1 Receptor”, “GLP1 Receptor”, “GLP-l-R”, as nonlimiting examples.

[0038] “GLP-1R agonists” or “GLP-1 receptor agonists” refers to agonists of the GLP-1 receptor (GLP-1R). GLP-1R agonists may be GLP-1 analogues. GLP-1R agonistsmay be selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, danuglipron, lotiglipron, ecnoglutide, efocipegtrutide and UBT251. According to the present invention, the term “GLP-1R agonists” includes GLP-1R agonists enantiomers, GLP-1R agonists esters, GLP-1R agonists racemates, salts of GLP- 1R agonists, solvates of GLP-1R agonists, hydrates of GLP-1R agonists, polymorphs of GLP-1R agonists and complexes of GLP-1R agonists.

[0039] “Intra-articular injection” refers to the injection of a compound directly into the closed cavity of a joint. “Intra-articular injection”, with reference to a GLP-1R agonist compound of the invention, means that the GLP-1R agonist compound is injected directly into the closed cavity of a joint of the subject to be treated.

[0040] “Joint diseases” refers to a disease affecting at least one joint in a subject to be treated and which may include the structural deterioration of a joint tissue. The symptoms of this pathological condition can vary depending on the joint concerned but are generally characterized by persistent pain associated with a functional impairment, i.e., a limitation of the mobility of the joint concerned.

[0041] “Synovitis” refers to an inflammation of the connective tissue (called synovium) that lines the inside of the joint capsule.

[0042] “Osteoarthritis” or “OA” is a joint disease. Osteoarthritis is a disorder that can affect any moveable joint of the body, for example knees, hips, and / or hands. It can show itself as a breakdown of tissues and abnormal changes to cell structures of joints, which can be initiated by injury. As the joint tries to repair, it can lead to other problems. Osteoarthritis first shows itself as a change to the biological processes within a joint, followed by abnormal changes to the joint, such as the breakdown of cartilage, bone reshaping, bony lumps, joint inflammation, and loss of joint function. This can result in pain, stiffness and loss of movement. There are certain factors which make some people more vulnerable to developing osteoarthritis, such as genetic factors, other joint disorders (such as rheumatoid arthritis), injury to the joint from accidents or surgery, beingoverweight, metabolic disorders like diabetes, lipid abnormalities, hypertension, or doing heavy physical activity in some sports or a person’s job.

[0043] “Pharmaceutical composition” refers to the combination of at least one active agent and at least one pharmaceutically acceptable excipient.

[0044] “Pharmaceutically acceptable excipient” as used herein, includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. Said excipient does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a mammal, more preferably a human. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by regulatory offices, such as, for example, FDA Office or EMA.

[0045] “Subject” refers to an animal, in particular a mammal, preferably a human. In one embodiment, “subject” refers to an animal including, without limitation, a dog, a cat, a horse, a cow, a sheep, a goat, or a non-human primate. In one embodiment, “subject” refers to a human (man or woman). In one embodiment, the subject is an adult (for example a subject above the age of 18). In one embodiment, the subject is a child (for example a subject below the age of 18). In one embodiment, the subject is a male. In one embodiment, the subject is a female. According to a preferred embodiment, “subject” refers to a human over the age of 18, preferably over the age of 50, more preferably over the age of 65. In one embodiment, a subject may be a “patient”, i.e., a warm-blooded animal, more preferably a human, who / which is awaiting the receipt of, or is receiving medical care or was / is / will be the object of a medical procedure, or is monitored for the development of a disease.

[0046] “Therapeutically effective amount” of an active agent refers to a nontoxic but sufficient amount of said active agent to provide the desired therapeutic effect.

[0047] “Treating” or “treatment” refers to any action which makes it possible to prevent, delay, reduce in severity and / or frequency or suppress at least one symptom associated with a pathological condition, or to prevent, slow down or suppress the underlying cause of a pathological condition, or the improvement or remediation ofdamage. In particular, in the context of the present invention, the term “treating” or “treatment” may refer more particularly to the inhibition or the slowing down of the osteoarthritic destruction of cartilage. In particular, in the context of the present invention, the term “treating” or “treatment” may refer more particularly to the reduction or even the suppression of a joint pain. In one embodiment, “treatment” refers to a curative treatment. In another embodiment, “treatment” refers to a preventive treatment. In another embodiment, “treatment” refers to a preventive and / or curative treatment.DETAILED DESCRIPTION

[0048] This invention relates to a GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain, wherein the compound is selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide or pharmaceutically acceptable salts and / or solvates thereof, and combinations thereof.

[0049] This invention relates to a GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain, wherein the compound is selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide, UBT251 or pharmaceutically acceptable salts and / or solvates thereof, and combinations thereof.

[0050] In one embodiment, the GLP-1 receptor agonist compound is selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide and combinations thereof.

[0051] In one embodiment, the GLP-1 receptor agonist compound is selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide, UBT251 and combinations thereof.

[0052] In one embodiment, the GLP-1 receptor agonist compound is selected from the group consisting of orforglipron, efpeglenatide, froniglutide, danuglipron, lotiglipron and combinations thereof.

[0053] In one embodiment, the GLP-1 receptor agonist compound is orforglipron (CAS number 2212020-52-3).

[0054] In one embodiment, the GLP- 1 receptor agonist compound is efpeglenatide (CAS number 1296200-77-5).

[0055] In one embodiment, the GLP-1 receptor agonist compound is danuglipron (CAS number 2230198-02-2).

[0056] In one embodiment, the GLP-1 receptor agonist compound is lotiglipron (CAS number 2401892-75-7).

[0057] In one embodiment, the GLP-1 receptor agonist compound is froniglutide (CAS number 1234965-40-2).

[0058] In one embodiment, the GLP-1 receptor agonist compound is a dual GLP-1 receptor agonist and glucagon receptor agonist selected from the group consisting of mazdutide, efinopegdutide and survodutide and combinations thereof.

[0059] In one embodiment, the GLP-1 receptor agonist compound is mazdutide (CAS number 2259884-03-0).

[0060] As used herein, "mazdutide” refers to a dual GLP-1 receptor and glucagon receptor agonist.

[0061] In one embodiment, the GLP-1 receptor agonist compound is efinopegdutide (CAS number 2055640-93-0).

[0062] As used herein, “efinopegdutide” refers to a dual GLP-1 receptor and glucagon receptor agonist.

[0063] In one embodiment, the GLP-1 receptor agonist compound is survodutide (CAS number 2805997-46-8).

[0064] As used herein, “survodutide” refers to a dual GLP-1 receptor and glucagon receptor agonist.

[0065] In one embodiment, the GLP-1 receptor agonist compound is tirzepatide (CAS number 2023788-19-2).

[0066] As used herein, “tirzepatide” refers to a dual GLP-1 receptor and GIP receptor agonist.

[0067] In one embodiment, the GLP-1 receptor agonist compound is a triple GLP-1 receptor agonist, glucagon receptor agonist and GIP receptor agonist selected from the group consisting of retatrutide, efocipegtrutide, UBT251 and combinations thereof.

[0068] In one embodiment, the GLP-1 receptor agonist compound is retatrutide (CAS number 2381089-83-2).

[0069] As used herein, “retatrutide” refers to a triple GLP- 1 receptor, glucagon receptor and GIP receptor agonist.

[0070] In one embodiment, the GLP-1 receptor agonist compound is efocipegtrutide (CAS number 2513399-19-2).

[0071] As used herein, “efocipegtrutide” refers to a triple GLP-1 receptor, glucagon receptor and GIP receptor agonist.

[0072] In one embodiment, the GLP-1 receptor agonist compound is UBT251.

[0073] As used herein, “UBT251” refers to a triple GLP- 1 receptor, glucagon receptor and GIP receptor agonist.

[0074] In one embodiment, the GLP-1 receptor agonist compound is maridebart cafraglutide (CAS number 2760218-55-9).

[0075] As used herein, “maridebart cafraglutide” refers to a dual GLP-1 receptor and GIP receptor antagonist.

[0076] In the present invention, the mention of a GLP-1R agonist also encompasses any pharmaceutically acceptable ester, salt, complex, polymorph, hydrate, solvate, enantiomer or racemate of said GLP-1R agonist.

[0077] In one embodiment, the GLP-1 receptor agonist compound is selected from the group consisting of retatrutide, tirzepatide, orforglipron, or pharmaceutically acceptable salts and / or solvates thereof, and combinations thereof.

[0078] In one embodiment, the GLP-1 receptor agonist compound is selected from the group consisting of retatrutide, tirzepatide, orforglipron, ecnoglutide or pharmaceutically acceptable salts and / or solvates thereof, and combinations thereof.

[0079] In one embodiment, the GLP-1 receptor agonist compound is selected from the group consisting of AZD5004 / ECC5004, CT-996, GSBR-1290, HDM-1002, TERN-01, amicretin, VK2735, WB4-24, aleniglipron (GSBR-1290), MLX-7005, ID110521156, ECC5004, RGT075, GS-4571, OWL833, HD-7671, PB-119, BGM-0504, bofanglutide, efpeglenatide LA, GMA-102, GXG-6, HR- 17031, HRS-7535, HRS-9531, HS-20004, HS-20094, INB-00009, JY-09, SAL-015, SL-209, Uni-E4, VCT-220, AZD-9550, cotadutide, CT-388, CT-868, dapiglutide, DD-01, DR-10624, E-2HSA or pharmaceutically acceptable salts and / or solvates thereof, and combinations thereof.

[0080] The invention also relates to a GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain, having an additional binding (agonist or antagonist) activity: for a glucagon receptor, and / or for a glucose-dependent insulinotropic polypeptide also known as gastric inhibitory polypeptide receptor (GIP) receptor.

[0081] In one embodiment, the GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain, having an additional glucagon receptor agonist activity and a GIP receptor agonist activity is retatrutide.

[0082] In one embodiment, the GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain, having an additional may be glucagon receptor agonist activity is mazdutide, efinopegdutide or survodutide.

[0083] In one embodiment, the GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain, having an additional GIP receptor agonist activity is tirzepatide.

[0084] In one embodiment, the GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain, having an additional GIP receptor antagonist activity is maridebart cafraglutide.

[0085] The GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain may be a dual GLP-1 receptor agonist and glucagon receptor agonist.

[0086] The GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain may be a dual GLP-1 receptor agonist and GIP receptor agonist.

[0087] The GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain may be a dual GLP-1 receptor agonist and GIP receptor antagonist.

[0088] The GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain may be a triple GLP-1 receptor agonist, glucagon receptor agonist and GIP receptor agonist.

[0089] In one embodiment, the GLP-1 receptor agonist compound inhibits or slows down the arthritic cartilage destruction.

[0090] In one embodiment, the GLP-1 receptor agonist compound stops further arthritic cartilage destruction.

[0091] In one embodiment, the GLP-1 receptor agonist compound inhibits chondrocyte catabolism.

[0092] In one embodiment, the GLP-1 receptor agonist compound reduces an existing joint inflammation in a subject in need thereof.

[0093] In one embodiment, the GLP-1 receptor agonist compound decreases synovitis in a subject in need thereof.

[0094] In one embodiment, the GLP-1 receptor agonist compound stimulates the chondrocyte proliferation and / or chondrocyte differentiation.

[0095] In one embodiment, the GLP-1 receptor agonist compound stimulates the regeneration of cartilage.

[0096] In one embodiment, the GLP- 1 receptor agonist compound improves the rate of regeneration of cartilage.

[0097] In one embodiment, the GLP-1 receptor agonist compound activates the anabolism of chondrocytes.

[0098] In one embodiment, the GLP-1 receptor agonist compound reduces inflammation.

[0099] In one embodiment, the GLP-1 receptor agonist compound prevents the thickening of the synovial tissue.

[0100] As compared to the GLP-1R agonists of the prior art, the GLP-1R agonists as described herein may present one or several of the following advantages:In one embodiment, the GLP-1R agonists as described herein inhibit or slow down the arthritic cartilage destruction more efficiently / faster / at a lower dosage / more durably;In one embodiment, the GLP-1R agonists as described herein induce a stronger reduction of an existing joint inflammation in a subject, as compared to GLP-1R agonists of the prior art.In one embodiment, the GLP-1R agonists as described herein induce a stronger decrease in synovitis in a subject, as compared to GLP-1R agonists of the prior art.In one embodiment, the GLP-1R agonists as described herein do not need another active substance to elicit an anabolic effect;In one embodiment, the GLP-1R agonists as described herein do not need another active substance to elicit an anti-catabolic effect;In one embodiment, the GLP-1R agonists as described herein present an increased rate of regeneration as compared to the GLP-1R agonists of the prior art;In one embodiment, the GLP-1R agonists as described herein present a further reduction of cartilage degradation as compared to the GLP-1R agonists of the prior art;In one embodiment, the GLP-1R agonists as described herein are more suitable for therapeutic use, such as, for example, in humans;In one embodiment, the GLP-1R agonists as described herein induce a similar rate of regeneration of cartilage but with fewer side effects than the GLP-1R agonists of the prior art.

[0101] In one embodiment, the joint disease is a chronic disease. In one embodiment, the chronic disease may be osteoarthritis.

[0102] In one embodiment, the joint disease is an acute disease. In one embodiment, the acute disease may be an acute pain.

[0103] In one embodiment the joint disease is selected from the group comprising or consisting of osteoarthritis and / or cartilage diseases including inflammatory arthritis, in particular cartilage defect caused by external injuries (such as post-traumatic condition)or surgical treatment, osteochondritis dissecans, osteoarthritis, congenital cartilage disease, gout and any crystal-induced arthritis and cartilage injury, synovitis caused by rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis.

[0104] In one embodiment, the joint pain may be inflammatory joint pain or noninflammatory joint pain.

[0105] The invention also relates to a composition for use in the treatment of joint diseases in a subject comprising, consisting essentially of or consisting of a GLP-1 receptor agonist compound selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide and combinations thereof.

[0106] The invention also relates to a composition for use in the treatment of joint diseases in a subject comprising, consisting essentially of or consisting of a GLP-1 receptor agonist compound selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide, UBT251 and combinations thereof.

[0107] As used herein, “consisting essentially of’, with reference to a composition of the invention, means that the GLP- 1 receptor agonist compound as described herein, is the only agent with a biologic or therapeutic activity within said composition.

[0108] In one embodiment, said composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable excipient.

[0109] Consequently, another object of the present invention is a pharmaceutical composition for use in the treatment of joint diseases and / or joint pain in a subject comprising, consisting essentially of or consisting of a GLP-1 receptor agonist compound selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide and combinations thereof, and at least one pharmaceutically acceptable excipient.

[0110] Consequently, another object of the present invention is a pharmaceutical composition for use in the treatment of joint diseases and / or joint pain in a subject comprising, consisting essentially of or consisting of a GLP-1 receptor agonist compound selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide, UBT251 and combinations thereof, and at least one pharmaceutically acceptable excipient.

[0111] Examples of pharmaceutically acceptable excipients that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances (for example sodium carboxymethylcellulose), polyethylene glycol, poly acrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat.

[0112] The present invention further relates to a medicament for use in the treatment of joint diseases in a subject comprising, consisting essentially of or consisting of a GLP-1 receptor agonist compound selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide and combinations thereof.

[0113] The present invention further relates to a medicament for use in the treatment of joint diseases in a subject comprising, consisting essentially of or consisting of a GLP-1 receptor agonist compound selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide, UBT251 and combinations thereof.

[0114] In one embodiment, the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, is formulated for administration to a subject in need thereof.

[0115] In one embodiment, administration to a subject can be performed parenterally, orally, by inhalation, spray, rectally, nasally, or via an implanted reservoir. The term “administration” includes, inter alia, subcutaneous, intravenous, intramuscular, intraarticular, intra- synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In one embodiment, the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, is administered by injection, including, without limitation, subcutaneous, intravenous, intramuscular, intra- articular, intra- synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0116] In one embodiment, the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, is administered orally, subcutaneously, intramuscularly, intravenously, intratendinously or intraarticularly.

[0117] Examples of forms adapted for injection include, but are not limited to, solutions, such as, for example, sterile aqueous solutions, gels, dispersions, emulsions, suspensions, solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to use, such as, for example, powder, liposomal forms and the like.

[0118] In one embodiment, the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, is formulated as a gel.

[0119] In one embodiment, the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, is formulated as a gel comprising a polymer selected from the group comprising or consisting of nonionic surfactant, cellulose, polyether, glucan, glycerophospholipids polysaccharides, proteins, and combinations thereof.

[0120] In one embodiment, the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, is to be administered to a subject in need thereof in a therapeutically effective amount.

[0121] It will be however understood that the total daily usage of the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, will be decided by the attending physician within the scope of sound medical judgment. In particular, the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease being treated and the severity of the disease; activity of the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, employed; the age, body weight, general health, gender and diet of the subject; the time of administration, route of administration, and rate of excretion of the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, employed; the duration of the treatment; drugs used in combination or coincidental with the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as defined hereinabove, employed; and like factors well-known in the medical arts. The total dose required for each treatment may be administered by multiple doses or in a single dose.

[0122] In one embodiment, the subject to be treated with the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as described hereinabove, is a non-human animal, preferably a non-human mammal, more preferably an animal selected from the group consisting of a dog, a cat, a horse, a cow, a sheep, a pig and a non-human primate.

[0123] In one embodiment, the subject to be treated with the GLP-1 receptor agonist compound, the composition, the pharmaceutical composition, or the medicament, as described hereinabove, is a human.

[0124] In one embodiment, the GLP-1 receptor agonist compound is the only active substance administered in the treatment of joint diseases and / or joint pain.

[0125] In one embodiment, the GLP-1 receptor agonist compound is administered in combination with at least one further active substance used in the treatment of joint diseases, in particular of osteoarthritis.

[0126] In one embodiment, the at least one further active substance may be selected from the group consisting of incretins such as GIP (Glucose-dependent insulin releasing polypeptide also known as gastric inhibitory polypeptide), inhibitors of the dipeptidyl peptidase IV enzyme, growth factors or growth factors targeting agents (FGF-18, BMP7, anti-NGF agents), Wnt pathway molecules targeting agents (DYRK1A targeting agents, CLK2 targeting agents), metalloproteinases and / or aggrecanases targeting agents (ADAMTS4 targeting agents, ADAMTS5 targeting agents, MMPs targeting agents), senescence pathway targeting agents, bone resorption molecules targeting agents (cathepsin K targeting agents), analgesics (such as opioids, tramadol, acetaminophen, capsaicin), nonsteroidal anti-inflammatory drugs (such as ibuprofen, ketoprofen, diclofenac, celecoxib, indomethacin), anti- arthritic (such as modified angiopoietin-like 3 (ANGPTL3) protein, for example LNA043), anti-ILl (for example anakinra, canakinumab), steroidal anti-inflammatory drugs, symptomatic slow-acting anti- arthritic agents (SYSADOAs), hyaluronic acids, platelet rich plasmas (PRPs), alpha- 1 glycoprotein, albumin and cellular therapies (such as injection of stem cells and Mesenchymal Stromal Cells).

[0127] In one embodiment, the at least one further active substance may be selected from the group consisting of analgesics (such as opioids, tramadol, acetaminophen, capsaicin), non-steroidal anti-inflammatory drugs (such as ibuprofen, ketoprofen, diclofenac, celecoxib, indomethacin), steroidal anti-inflammatory drugs, hyaluronic acids and symptomatic slow-acting anti-arthritic agents (SYSADOAs).

[0128] In one embodiment, the inhibitor of the dipeptidyl peptidase IV enzyme may be selected from the group consisting of sitagliptin, saxagliptin, vildagliptin, alogliptin and linagliptin.

[0129] In one embodiment, the growth factor is selected from the group consisting of fibroblast growth factor (FGF-18 sprifermin), NGF and BMP7 protein.

[0130] In one embodiment, the growth factor targeting agent is selected from the group consisting of fibroblast growth factor targeting agents, anti-NGF agents (such as tanezumab) and BMP7 protein targeting agents.

[0131] In one embodiment, the Wnt pathway molecules targeting agent is selected from the group consisting of CLK2 inhibitors, DYRK1A inhibitors and lorecivivint.

[0132] In one embodiment, the metalloproteinases and aggrecanases targeting agent is selected from the group consisting of ADAMTS5 inhibitors and ADAMTS5 antibodies.

[0133] In one embodiment, the senescence pathway targeting agent is MDM2-p53 interaction inhibitors.

[0134] In one embodiment, the bone resorption molecules targeting agent is cathepsin K.

[0135] In one embodiment, the analgesics may be selected from the group consisting of acetylsalicylic acid, lysine acetylsalicylate, phenylbutazone, sulindac, diclofenac potassium or sodium, aceclofenac, tiaprofenic acid, ibuprofen, ketoprofen, alminoprofen, fenoprofen, naproxen, flurbiprofen, indomethacin, mefenamic acid, niflumic acid, tenoxicam, meloxicam, piroxicam, celecoxib, etoricoxib, betamethasone, dexamethasone, prednisone, prednisolone, tixocortol, triamcinolone, CNTX-4975 and bedin vetmab.

[0136] In one embodiment, the nonsteroidal anti-inflammatory drugs may be selected from the group consisting of acetylsalicylic acid, lysine acetylsalicylate, phenylbutazone, sulindac, diclofenac potassium or sodium, aceclofenac, tiaprofenic acid, ibuprofen, ketoprofen, alminoprofen, fenoprofen, naproxen, flurbiprofen, indomethacin, mefenamic acid, niflumic acid, tenoxicam, meloxicam, piroxicam, celecoxib and etoricoxib.

[0137] In one embodiment, the steroidal anti-inflammatory drugs may be selected from the group consisting of betamethasone, dexamethasone, prednisone, prednisolone, tixocortol and triamcinolone.

[0138] In one embodiment, the symptomatic slow-acting anti-arthritic agents may be selected from the group consisting of chondroitin, chondroitin sulphate, glucosamine, glucosamine sulphate, diacerein, and unsaponifiable extracts of avocado and soya (such as in the marketed product Piascledine®).

[0139] In some embodiment, the at least one further active agent used in the treatment of joint diseases is selected from the group consisting of hyaluronic acid, albumin and alpha- 1 glycoprotein.

[0140] In one embodiment, the GLP-1 receptor agonist compound and the at least one further active substance are administered simultaneously, separately or sequentially.

[0141] In one embodiment, the GLP-1 receptor agonist compound and the at least one further active substance are administered simultaneously.

[0142] In one embodiment, the GLP-1 receptor agonist compound and the at least one further active substance are administered separately.

[0143] In one embodiment, the GLP-1 receptor agonist compound and the at least one further active substance are administered sequentially.

[0144] In one embodiment, the GLP-1 receptor agonist compound is administered in combination with local treatments for osteoarthritis or any other arthritis.BRIEF DESCRIPTION OF THE DRAWINGS

[0145] Figure 1 is a histogram showing the relative mRNA levels of Mmp-13 (in fold change against control) in chondrocytes stimulated with interleukin- ip (IL-ip), and treated with tirzepatide. The graph presents 6 conditions, as indicated: vehicle (DMSO), IL-ip (2 ng / mL) + vehicle, IL-ip (2 ng / mL) + tirzepatide 1 nM, IL-ip (2 ng / mL) + tirzepatide 10 nM, IL-ip (2 ng / mL) + tirzepatide 100 nM, and IL-ip (2 ng / mL) + tirzepatide 1 pM. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0146] Figure 2 is a histogram showing the relative mRNA levels of Mmp-13 (in fold change against control) in chondrocytes stimulated with IL-ip, and treated with orforglipron. The graph presents 6 conditions, as indicated: vehicle (DMSO), IL-ip (2 ng / mL) + vehicle, IL-ip (2 ng / mL) + orforglipron 1 nM, IL-ip (2 ng / mL) + orforglipron 10 nM, IL-ip (2 ng / mL) + orforglipron 100 nM, and IL-ip (2 ng / mL) + orforglipron 1 pM. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0147] Figures 3A-B are a combination of histograms showing the relative mRNA levels of Mmp-13 (Fig. 3A) and Mmp-3 (Fig. 3B) (in fold change against control) in chondrocytes stimulated with IL-ip, and treated with retatrutide. Both graphs present 6 conditions, as indicated: vehicle (DMSO), IL-ip (2 ng / mL) + vehicle, IL-ip (2 ng / mL) + retatrutide 1 nM, IL-ip (2 ng / mL) + retatrutide 10 nM, IL-ip (2 ng / mL) + retatrutide 100 nM, and IL- ip (2 ng / mL) + retatrutide 1 M. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0148] Figures 4A-B are a combination of histograms showing the relative mRNA levels of Cox2 (Fig. 4A) and 11-6 (Fig. 4B) (in fold change against control) in chondrocytes stimulated with IL-ip, and treated with tirzepatide. Both graphs present 6 conditions, as indicated: vehicle (DMSO), IL-ip (2 ng / mL) + vehicle, IL-ip (2 ng / mL) + tirzepatide 1 nM, IL-ip (2 ng / mL) + tirzepatide 10 nM, IL-ip (2 ng / mL) + tirzepatide 100 nM, and IL-ip (2 ng / mL) + tirzepatide 1 pM. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0149] Figures 5A-B are a combination of histograms showing the relative mRNA levels of Cox2 (Fig. 5A) and 11-6 (Fig. 5B) (in fold change against control) in chondrocytes stimulated with IL-ip, and treated with orforglipron. Both graphs present 6 conditions, as indicated: vehicle (DMSO), IL-ip (2 ng / mL) + vehicle, IL-ip (2 ng / mL) + orforglipron 1 nM, IL-ip (2 ng / mL) + orforglipron 10 nM, IL-ip (2 ng / mL) + orforglipron 100 nM, and IL-ip (2 ng / mL) + orforglipron 1 pM. Statistical analysis wasperformed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0150] Figures 6A-B are a combination of histograms showing the relative mRNA levels of Cox2 (Fig. 6A) and 11-6 (Fig. 6B) (in fold change against control) in chondrocytes stimulated with IL-ip, and treated with retatrutide. The graph presents 6 conditions, as indicated: vehicle (DMSO), IL-ip (2 ng / mL) + vehicle, IL-ip (2 ng / mL) + retatrutide 1 nM, IL-ip (2 ng / mL) + retatrutide 10 nM, IL-ip (2 ng / mL) + retatrutide 100 nM, IL-ip (2 ng / mL) + retatrutide 1 pM. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0151] Figures 7A-B are a combination of histograms showing the relative mRNA levels of Col2 (in fold change against control) in chondrocytes treated with tirzepatide, in basal conditions (Fig. 7A), or after stimulation with IL-ip (Fig. 7B). Fig. 7A presents 5 conditions, as indicated: vehicle (DMSO), tirzepatide 1 nM, tirzepatide 10 nM, tirzepatide 100 nM, and tirzepatide 1 p M. Fig. 7B presents 6 conditions, as indicated: vehicle (DMSO), IL-ip 2 ng / mL + vehicle, IL-ip 2 ng / mL + tirzepatide 1 nM, IL-ip 2 ng / mL + tirzepatide 10 nM, IL-ip 2 ng / mL + tirzepatide 100 nM, IL-ip 2 ng / mL + tirzepatide1 pM. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0152] Figures 8A-B are a combination of histograms showing the relative mRNA levels of Col2 (in fold change against control) in chondrocytes treated with orforglipron, in basal conditions (Fig. 8A), or after stimulation with IL-ip (Fig. 8B). Fig. 8A presents 5 conditions, as indicated: vehicle (DMSO), orforglipron 1 nM, orforglipron 10 nM, orforglipron 100 nM, and orforglipron 1 pM. Fig. 8B presents 6 conditions, as indicated: vehicle (DMSO), IL-ip 2 ng / mL + vehicle, IL-ip 2 ng / mL + orforglipron 1 nM, IL-ip2 ng / mL + orforglipron 10 nM, IL-ip 2 ng / mL + orforglipron 100 nM, IL-ip 2 ng / mL + orforglipron 1 pM. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0153] Figures 9A-B are a combination of histograms showing the relative mRNA levels of Col2 (in fold change against control) in chondrocytes treated with retatrutide, in basal conditions (Fig. 9A), or after stimulation with IL-ip (Fig. 9B). Fig. 9A presents 5 conditions, as indicated: vehicle (DMSO), retatrutide 1 nM, retatrutide 10 nM, retatrutide 100 nM, and retatrutide 1 pM. Fig. 9B presents 6 conditions, as indicated: vehicle (DMSO), IL-ip 2 ng / mL + vehicle, IL-ip 2 ng / mL + retatrutide 1 nM, IL-ip 2 ng / mL + retatrutide 10 nM, IL-ip 2 ng / mL + retatrutide 100 nM, IL-ip 2 ng / mL + retatrutide 1 p M. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0154] Figures 10A-B are a combination of histograms showing the relative mRNA levels of Sox9 (in fold change against control) in chondrocytes treated with tirzepatide, in basal conditions (Fig. 10A), or after stimulation with IL-ip (Fig. 10B). Fig. 10A presents 5 conditions, as indicated: vehicle (DMSO), tirzepatide 1 nM, tirzepatide 10 nM, tirzepatide 100 nM, and tirzepatide 1 pM. Fig. 10B presents 6 conditions, as indicated: vehicle (DMSO), IL-ip 2 ng / mL + vehicle, IL-ip 2 ng / mL + tirzepatide 1 nM, IL-ip 2 ng / ml + tirzepatide 10 nM, IL-ip 2 ng / mL + tirzepatide 100 nM, IL-ip 2 ng / mL + tirzepatide 1 pM. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0155] Figures 11A-B are a combination of histograms showing the relative mRNA levels of Sox9 (in fold change against control) in chondrocytes treated with orforglipron, in basal conditions (Fig. HA), or after stimulation with IL-ip (Fig. 11B). Fig. 11A presents 5 conditions, as indicated: vehicle (DMSO), orforglipron 1 nM, orforglipron 10 nM, orforglipron 100 nM, and orforglipron 1 pM. Fig. 11B presents 6 conditions, as indicated: vehicle (DMSO), IL-ip 2 ng / mL + vehicle, IL-ip 2 ng / mL + orforglipron 1 nM, IL-ip 2 ng / mL + orforglipron 10 nM, IL-ip 2 ng / mL + orforglipron 100 nM, IL- ip 2 ng / mL + orforglipron 1 pM. Statistical analysis was performed using unpaired t- tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.000! (****).

[0156] Figures 12A-B are a combination of histograms showing the relative mRNA levels of Sox9 (in fold change against control) in chondrocytes treated with retatrutide, in basal conditions (Fig. 12A), or after stimulation with IL-ip (Fig. 12B). Fig. 12A presents 5 conditions, as indicated: vehicle (DMSO), retatrutide 1 nM, retatrutide 10 nM, retatrutide 100 nM, and retatrutide 1 pM. Fig. 12B presents 6 conditions, as indicated: vehicle (DMSO), IL-ip 2 ng / mL + vehicle, IL-ip 2 ng / mL + retatrutide 1 nM, IL-ip 2 ng / mL + retatrutide 10 nM, IL-ip 2 ng / mL + retatrutide 100 nM, IL-ip 2 ng / mL + retatrutide 1 p M. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0157] Figures 13A-B are a combination of histograms showing the relative mRNA levels of Acan (in fold change against control) in chondrocytes treated with tirzepatide, in basal conditions (Fig. 13A), or after stimulation with IL-ip (Fig. 13B). Fig. 13A presents 5 conditions, as indicated: vehicle (DMSO), tirzepatide 1 nM, tirzepatide 10 nM, tirzepatide 100 nM, and tirzepatide 1 pM. Fig. 13B presents 6 conditions, as indicated: vehicle (DMSO), IL-ip 2 ng / mL + vehicle, IL-ip 2 ng / mL + tirzepatide 1 nM, IL-ip 2 ng / mL + tirzepatide 10 nM, IL-ip 2 ng / mL + tirzepatide 100 nM, IL-ip 2 ng / mL + tirzepatide 1 pM. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0158] Figures 14A-B are a combination of histograms showing the relative mRNA levels of Acan (in fold change against control) in chondrocytes treated with orforglipron, in basal conditions (Fig. 14A), or after stimulation with IL-ip (Fig. 14B). Fig. 14A presents 5 conditions, as indicated: vehicle (DMSO), orforglipron 1 nM, orforglipron 10 nM, orforglipron 100 nM, and orforglipron 1 pM. Fig. 14B presents 6 conditions, as indicated: vehicle (DMSO), IL-ip 2 ng / mL + vehicle, IL-ip 2 ng / mL + orforglipron 1 nM, IL-ip 2 ng / mL + orforglipron 10 nM, IL-ip 2 ng / mL + orforglipron 100 nM, IL- ip 2 ng / mL + orforglipron 1 pM. Statistical analysis was performed using unpaired t- tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.000! (****).

[0159] Figures 15A-B are a combination of histograms showing the relative mRNA levels of Acan (in fold change against control) in chondrocytes treated with retatrutide, in basal conditions (Fig. 15A), or after stimulation with IL-ip (Fig. 15B). Fig. 15A presents 5 conditions, as indicated: vehicle (DMSO), retatrutide 1 nM, retatrutide 10 nM, retatrutide 100 nM, and retatrutide 1 pM. Fig. 15B presents 6 conditions, as indicated: vehicle (DMSO), IL-ip 2 ng / mL + vehicle, IL-ip 2 ng / mL + retatrutide 1 nM, IL-ip 2 ng / mL + retatrutide 10 nM, IL-ip 2 ng / mL + retatrutide 100 nM, IL-ip 2 ng / mL + retatrutide 1 p M. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).

[0160] Figures 16 A-B are a combination of histograms showing the secretion of nitrite oxide (NO) in supernatant of primary murine chondrocytes (Fig. 16A) stimulated with IL-ip and after treated with ecnoglutide and the secretion of nitrite oxide (NO) in supernatant of murine macrophages (RAW 264.7) (Fig. 16B) stimulated with LPS and after treated with ecnoglutide. Fig. 16A presents 10 conditions, as indicated: vehicle (water), IL-ip (2 ng / ml), IL-ip (2 ng / ml) + ecnoglutide 0.001 nM, IL-ip (2 ng / ml) + ecnoglutide 0.01 nM, IL-ip (2 ng / ml) + ecnoglutide 0.1 nM, IL-ip (2 ng / ml) + ecnoglutide 1 nM, IL-ip (2 ng / ml) + ecnoglutide 10 nM, IL-ip (2 ng / ml) + ecnoglutide 100 nM, IL-ip (2 ng / ml) + ecnoglutide 1 pM, and IL-ip (2 ng / ml) + ecnoglutide 10 pM. Fig. 16B presents 10 conditions, as indicated: vehicle (water), LPS (100 ng / ml), LPS (100 ng / ml) + ecnoglutide 0.001 nM, LPS (100 ng / ml) + ecnoglutide 0.01 nM, LPS (100 ng / ml) + ecnoglutide 0.1 nM, LPS (100 ng / ml) + ecnoglutide 1 nM, LPS (100 ng / ml) + ecnoglutide 10 nM, LPS (100 ng / ml) + ecnoglutide 100 nM, LPS (100 ng / ml) + ecnoglutide 1 pM, and LPS (100 ng / ml) + ecnoglutide 10 pM. Statistical analysis was performed using unpaired t-tests. Statistical significance is indicated as follows: P < 0.05 (*), P < 0.01 (**), P < 0.001 (***), P < 0.0001 (****).EXAMPLES

[0161] The present invention is further illustrated by the following examples.Materials and MethodsCulture of immature murine chondrocytes

[0162] Immature murine chondrocytes were derived from newborn pups (5-6 days old C57B1 / 6). After euthanizing the pups, the hind limbs were cut and the skin and muscles removed from the femoral heads to the paws. After isolation, femoral heads were placed in PBS. The knee joint was cleaned from the surrounding tissue, then cut in half to separate the two spheres, and then cut in half again, to facilitate digestion. The femoral condyles and the tibial plateau were also placed in PBS.

[0163] The pieces of cartilage were incubated twice in a digestion solution (DMEM, 2 mM L-Glutamine, 1 g / L of glucose + 1% P / S + Collagenase 3 mg / mL): for 45 min in an incubator at 37°C with 5% CO2 in Petri dish. After the two digestions, dispersion of the aggregates was performed and a suspension of isolated cells was obtained. The pieces of cartilage were then incubated in DMEM, 2 mM L-Glutamine, 1 g / L of glucose + 1% P / S with collagenase D solution at 0.5 mg / mL (diluted to 1 / 6) overnight in an incubator at 37°C with 5% CO2. The action of the collagenase D was stopped by adding cell culture medium to the Petri dish. After dispersion of the aggregates by using pipettes of decreasing sizes, a suspension of isolated cells was obtained and, filtered through a sterile 70 pm cell strainer, thus a single cells suspension of chondrocytes was obtained.

[0164] The suspended cells were centrifuged for 10 min at 400 g at 20°C. The medium was removed and the pellet resuspended in PBS to wash the cells. The cells were centrifuged again for 10 min at 400 g at 20°C, this time PBS was replaced by DMEM 2 mM L-Glutamine, 1 g / L of glucose + 10% LBS + 1% P / S + 0.5% Gentamicin. The chondrocytes were counted in a Neubauer hemocytometer and observed to assess the viability of extracted cells. The chondrocytes were seeded at a density of 40x103cells in 2 mL of DMEM 2 mM L-Glutamine, 1 g / L of glucose + 10% LBS + 1% P / S + 0.5% Gentamicin per well, in 12- well plates.

[0165] The culture of chondrocytes was maintained under sterile conditions in an incubator at 37°C with 5% CO2. Immature murine articular chondrocytes are expected to reach confluence by 6-7 days of culture. The culture medium was changed after 3 daysof culture. At day 7, the DMEM medium containing 10% FBS was removed, the wells were rinsed twice with PBS and DMEM, 2 mM L-Glutamine, 1 g / L of glucose + 1% P / S + 0.5% Gentamicin + 0.1% BSA was added. At day 8, the medium was removed. Fresh DMEM 2 mM L-Glutamine, 1 g / L of glucose + 1% P / S + 0.5% Gentamicin + 0.1% BSA containing either vehicle or treatment with GLP-1R agonists : tirzepatide (Fig. 1, Fig. 4A-B, Fig. 7A-B, Fig. 10A-B, Fig. 13A-B), orforglipron (Fig. 2, Fig. 5A-B, Fig. 8A-B, Fig. 11A-B, Fig. 14A-B) ,retatrutide (Fig. 3A-B, Fig. 6A-B, Fig. 9A-B, Fig. 12A-B, Fig. 15A-B) or ecnoglutide (Fig. 16A) was added in each well. The plates were incubated at 37 °C + 5% CO2 for 24 hours.Culture of immature murine macrophages

[0166] The murine macrophage cell line RAW 264.7 (TIB-71, American Type Culture Collection, Manassas, VA, USA) was cultured at 37°C and under 5% CO2 condition in Dulbecco’s modified Eagle’s medium (DMEM) containing 4.5 g / L glucose, 10% fetal bovine serum (FBS), and 1% penicillin-streptomycin (P / S) mixture. RAW 264.7 cells were plated, 100 000 cells per well in 96 well-plate, and treated in starving medium (DMEM containing 1% P / S) 24 hours after plating cells. The macrophage cell line was used before passage 20 for all the experiments.

[0167] At day 2, the DMEM medium containing 4.5 g / L glucose, 10% fetal bovine serum (FBS), and 1% penicillin-streptomycin (P / S) mixture was removed, the plate were rinsed twice with PBS and DMEM + 1% P / S was added containing LPS (100 ng / ml) and / or either vehicle or treatment with GLP-1R agonist: ecnoglutide (Fig. 16B) in each well. The plates were incubated at 37°C + 5% CO2 for 24 hours.Measure of mRN levels with RT-qPCR

[0168] Following supernatant harvesting, murine primary chondrocyte cells were harvested in a lysis buffer and stored at -70°C before RNA extraction. RNA extraction was performed according to the manufacturer instructions (Relia Prep RNA Cell Miniprep System, Promega) for RT-qPCR analyses.

[0169] The extracted RNAs were quantified using a N anodrop . The reverse transcription was performed on 1 pg of RNA, in 10 pL of water maximum, for each sample. The reactants used for the reverse transcription were: 4.2 pL of nuclease free water, 2 pL of RT buffer, 0.8 pL of dNTP mix, 2 pL of RT random primers and 1 pL of multiscribe Reverse transcriptase together with 10 pL of RNA. The reverse transcription final volume was 20 pL per tube. The program used for reverse transcription was 10 min at 25°C, 2 hours at 37°C followed by 10 minutes at 85°C. The samples were cooled to 4°C and then frozen at -20°C awaiting qPCR analyses.

[0170] The qPCR analyses were performed on 1 / 20 diluted cDNA samples. The program included 3 steps of amplification: 1st cycle 95°C for 2 min and 40 cycles: 95°C for 15 sec and 60°C 60 sec. The results were analyzed according to the delta-delta Ct method and the expression levels of catabolic markers Mmp-13 and Mmp-3 (Example 1, Fig. 1, 2, and 3A-B), markers of inflammation Cox2 and 11-6 (Example 2, Fig. 4A-B, 5A-B, and 6A-B) or anabolic markers Col2, Sox9 and Acan (Example 3, Fig. 7A-B, 8A-B, and 9A- B for Col2, Example 3, Fig. 10A-B, 11A-B, and 12A-B for Sox9 and Example 3, Fig. 13A-B, 14A-B, and 15A-B for Acan) in the different conditions were calculated.Quantification of inflammatory marker

[0171] The nitrite content of primary murine chondrocytes (pO) and murine macrophage cell line (p + 8) after 24 h of treatment was determined in supernatant by the Griess method (Giustarini D. el al. Nitrite and Nitrate Measurement by Griess Reagent in Human Plasma: Evaluation of Interferences and Standardization, Methods in Enzymology, Academic Press, Volume 440, 2008, Pages 361-380), using a Griess Reagent System kit according to the manufacturer’s instructions. No enzymatic treatment was performed prior to the assay. Concentrations were analysed using a spectrophotometer at 540 nm and determined by comparison against a standard.and retatrutide reduced the level of catabolic markers in an in vitro model of joint disease.Results

[0172] We measured the mRNA expression levels of Mmp-13 and Mmp-3, two markers of catabolism, which play key roles in development of osteoarthritis, in primary murine chondrocytes, after treatment with one of the following GLP-1R agonists: tirzepatide, orforglipron or retatrutide.

[0173] We used an in vitro model of joint disease induced inflammation by applying IL- ip.

[0174] Mmp-13 is a catabolic cytokine, involved in the cleavage of collagen type II, as such it is considered a major catabolic effector in osteoarthritis.

[0175] Thus, a reduction in the level of expression of Mmp-13 shows an anti-degradative effect of GLP-1R agonist family which represents a beneficial effect on joint structure.

[0176] Mmp-3 is a catabolic cytokine, capable of degrading wide array of extracellular molecules, including collagen types II, III, IV, IX, and X and various proteoglycans.

[0177] Thus, a reduction in the level of expression of Mmp-3 shows an anti-degradative effect of GLP-1R agonist family which represents a beneficial effect on joint structure.

[0178] We showed that tirzepatide greatly reduces the level of expression of Mmp-13 mRNA and in a dose dependent manner compared to the vehicle (Fig. 1), though not significatively.

[0179] We showed that orforglipron reduces the level of expression of Mmp-13 mRNA in a dose dependent manner compared to the vehicle (Fig. 2) and this decrease is statistically significant at the dose of 1 pM.

[0180] We showed that retatrutide reduces the level of expression of Mmp-13 mRNA in a dose dependent manner compared to the vehicle (Fig. 3A) and this decrease is statistically significant at the dose of 1 pM.

[0181] Given the strong effect of retatrutide on Mmp-13 (Fig. 3A), we also tested its effect on a second catabolic marker Mmp-3 (Fig. 3B). We showed that retatrutide has a similar effect on the level of expression of Mmp- mRNA and decreases the level ofexpression of Mmp-3 mRNA in a dose dependent manner, compared to the vehicle and this decrease is statistically significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM.Conclusion

[0182] Tirzepatide, orforglipron and retatrutide reduce the expression levels of catabolic markers in an in vitro model of joint diseases.Example 2: GLP-1R agonists tirzepatide, orforglipron and retatrutide reduced the inflammation in an in vitro model of joint diseaseResults

[0183] We measured the mRNA expression levels of Cox2 and 11-6, two markers of inflammation, in primary murine chondrocytes, after treatment with one of the following GLP-1 analogues: tirzepatide, orforglipron or retatrutide.

[0184] We used an in vitro model of joint disease and induced inflammation by applying IL-10.

[0185] Cox2 is a family of enzymes induced by multiple pro-inflammatory factors (such as cytokines, interferons, etc). They contribute to the proper functioning of the body if they are properly regulated. They are mainly responsible for inflammation activity, through overexpression.

[0186] Amongst interleukins, 11-6 is the most preeminent pro-inflammatory cytokine driving the disease. This mediator plays important roles in OA inflammation and pain.

[0187] We showed that tirzepatide reduces the level of expression of Cox2 mRNA in a dose dependent manner compared to the vehicle (Fig. 4A), and this decrease is statistically significant at the dose of 1 pM.

[0188] Tirzepatide also reduced the level of expression of 11-6 mRNA in a dose dependent manner compared to the vehicle (Fig. 4B), and this decrease is statistically significant at the doses of 100 nM and 1 pM.

[0189] We showed that orforglipron reduces the level of expression of Cox2 mRNA in a dose dependent manner compared to the vehicle (Fig. 5A), though not significantly.

[0190] Orforglipron also reduced the level of expression of 11-6 mRNA in a dose dependent manner compared to the vehicle (Fig. 5B), and this decrease is statistically significant at the doses of 10 nM, 100 nM and 1 pM.

[0191] We showed that retatrutide reduces the level of expression of Cox2 mRNA in a dose dependent manner compared to the vehicle (Fig. 6A) and this decrease is statistically significant at the dose of 1 pM.

[0192] Retatrutide also reduced the level of expression of mRNA expression of 11-6 in a dose dependent manner compared to the vehicle (Fig. 6B), and this decrease is statistically significant at the dose of 1 pM.Conclusion

[0193] Tirzepatide, orforglipron and retatrutide reduce the expression levels of the markers of inflammation in an in vitro model of joint diseases.Example 3: GLP-1R agonists tirzepatide, orforglipron and retatrutide increased the levels of markers of cartilage regenerationResults

[0194] We measured the mRNA expression levels of Col2, Sox9 and Acan, three markers of chondrocytes differentiation and regeneration of the cartilage, in primary murine chondrocytes, after treatment with one of the following GLP-1 analogues: tirzepatide, orforglipron or retatrutide.

[0195] We used an in vitro model of joint cells both in basal conditions (without inducing inflammation) and after stimulation with IL-ip (also called the stimulated condition or inflammatory condition), to better observe the pro-chondrogenic effects of GLP-1R agonists.

[0196] Col2 is a gene involved in the synthesis of the pro-alpha- 1 chain of type IIcollagen, the main macromolecule found in articular cartilage (representing 90 to 95% of total collagen content).

[0197] Col2 is a major component of the extracellular matrix, important for providing a smooth surface that supports pressure and facilitates movement while minimizing friction.

[0198] Thus, the increase of Col2 expression in chondrocyte is a sign of regeneration of cartilage.

[0199] We showed that tirzepatide increases the level of expression of Col2, as compared to the vehicle condition, in the basal condition (Fig. 7A), and this increase is statistically significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM. We also showed that tirzepatide increases the level of expression of Col2 after treatment with IL-ip (Fig. 7B) and this increase is significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM.

[0200] We showed that orforglipron increases the level of expression of Col2, as compared to the vehicle condition, in the basal condition (Fig. 8A) and this increase is statistically significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM. We also showed that orforglipron increases the level of expression of Col2 after treatment with IL-ip (Fig. 8B) and this increase is significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM.

[0201] We showed that retatrutide increases the level of expression of Col2, as compared to the vehicle condition, in the basal condition in a dose dependent manner (Fig. 9A) and this increase is statistically significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM. We also showed that retatrutide increases the level of expression of Col2 after treatment with IL-ip (Fig. 9B) and this increase is significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM.

[0202] Sox9 is a transcription factor essential for chondrocyte differentiation and cartilage formation.

[0203] Sox9 is a pivotal transcription factor in developing and adult cartilage. The Sox9 gene is expressed from the multipotent skeletal progenitor stage and remains active throughout chondrocyte differentiation. While it is repressed in hypertrophicchondrocytes in cartilage growth plates, it remains expressed throughout life in permanent chondrocytes of healthy articular cartilage. Sox9 is required for chondrogenesis: it secures chondrocyte lineage commitment, promotes cell survival, and transcriptionally activates the genes for many cartilage- specific structural components and regulatory factors.

[0204] We showed that tirzepatide increases the level of expression of Sox9, as compared to the vehicle condition, in the basal condition, although not statistically significantly (Fig. 10A). In this experiment, tirzepatide was not able to restore or increase the level of expression of Sox9 after treatment with IL-ip, compared to the IL-ip + vehicle condition (Fig. 10B).

[0205] We showed that orforglipron increases the level of expression of Sox9, as compared to the vehicle condition, in the basal condition, although not statistically significantly (Fig. 11A). We also showed that orforglipron increases the level of expression of Sox9 after treatment with IL-ip compared to the IL-ip + vehicle condition (Fig. 11B) and this increase is significant at the dose of 1 pM.

[0206] We showed that retatrutide increases the level of expression of Sox9, as compared to the vehicle condition, in the basal condition, although not statistically significantly (Fig.l2A). We also showed that retatrutide increases the level of expression of Sox9 after treatment with IL-ip, in a dose dependent manner (Fig. 12B) and this increase is significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM.

[0207] Acan is a gene which codes aggrecan, a protein from chondroitin sulfate proteoglycan family. This protein is an integral part of the extracellular matrix of cartilage tissue and helps cartilage resist compression.

[0208] Thus, an increase of Acan expression in chondrocytes provides the instruction for the production of aggrecan proteins, also known as proteoglycans, second largest component of the extracellular matrix.

[0209] We showed that tirzepatide increases the level of expression of Acan, as compared to the vehicle condition, in the basal condition (Fig. 13A), and this increase is statistically significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM. We also showedthat tirzepatide increases the level of expression of Acan after treatment with IL-ip (Fig. 13B) and this increase is significant at the doses of 10 nM, 100 nM and 1 pM.

[0210] We showed that orforglipron increases the level of expression of Acan, as compared to the vehicle condition, in the basal condition, in a dose dependent manner (Fig. 14A) and this increase is statistically significant at the doses of 1 nM, 10 nM, 100 nM and 1 p M. We also showed that orforglipron increases the level of expression of Acan after treatment with IL-ip (Fig. 14B) and this increase is significant at the doses of 100 nM and 1 pM.

[0211] We showed that retatrutide increases the level of expression of Acan, as compared to the vehicle condition, in the basal condition, in a dose dependent manner (Fig. 15A) and this increase is statistically significant at the dose of 1 pM. We also showed that retatrutide increases the level of expression of Acan after treatment with IL- ip, in a dose dependent manner (Fig. 15B) and this increase is significant at the doses of 1 nM, 10 nM, 100 nM and 1 pM.Conclusion

[0212] Tirzepatide, orforglipron and retatrutide increase the expression levels of markers of cartilage regeneration in an in vitro model of joint diseases both in basal conditions and in inflammatory condition.Example 4: GLP-1R agonist ecnoglutide reduced the inflammation in an in vitro model of joint diseaseResults

[0213] We measured the Nitrite Oxide (NO) secretion, by primary murine chondrocytes (Fig. 16A) and by murine macrophages (Fig. 16B), after 24 hours treatment with the following GLP-1 analogue: ecnoglutide at 8 different doses along with two control conditions.

[0214] For the primary murine chondrocytes, we used an in vitro model of joint disease and induced inflammation by stimulating cells with IL-IP; while for the murinemacrophages, we used an in vitro model of joint disease and induced inflammation by stimulating cells with LPS.

[0215] Macrophages produce and release NO as part of their inflammatory response, while in osteoarthritis models, where the chondrocytes were stimulated with IL-ip, an increased production of NO is associated to cartilage degradation, matrix metalloprotease activation and apoptosis.

[0216] In both in vitro models, an increased secretion of NO is associated with active inflammation and an inflammatory-mediated stress, associated with tissue damage.

[0217] We showed that ecnoglutide significantly reduces the level of NO secreted by primary murine chondrocytes in a dose dependent manner compared to the positive control (IL- 1 P) (Fig. 16A) and this decrease is relevant at the dose of 100 nM.

[0218] We showed that ecnoglutide significantly reduces the level of NO secreted by murine macrophages in a dose dependent manner compared to the positive control (LPS) (Fig. 16B) and this decrease is relevant at the dose of 0.1 nM. Conclusion

[0219] Ecnoglutide significantly reduces the secretion of the marker of inflammation in an in vitro model of joint diseases.

Claims

CLAIMS1. A GLP-1 receptor agonist compound for use in the treatment of joint diseases and / or joint pain, wherein the compound is selected from the group consisting of retatrutide, tirzepatide, orforglipron, mazdutide, efinopegdutide, froniglutide, maridebart cafraglutide, survodutide, efpeglenatide, ecnoglutide, efocipegtrutide, UBT251 and combinations thereof.

2. The GLP-1 receptor agonist compound for use according to claim 1, wherein the GLP-1 receptor agonist compound inhibits or slows down the arthritic cartilage destruction.

3. The GLP- 1 receptor agonist compound for use according to claim 1 or claim 2, wherein the GLP-1 receptor agonist compound stimulates the regeneration of cartilage or improves the rate of regeneration of the cartilage.

4. The GLP-1 receptor agonist compound for use according to any one of claims 1 to 3, wherein the GLP-1 receptor agonist compound reduces inflammation and / or prevents the thickening of the synovial tissue.

5. The GLP-1 receptor agonist compound for use according to any one of claims 1 to 4, wherein the joint disease is selected from the group consisting of osteoarthritis and / or cartilage diseases including inflammatory arthritis, in particular cartilage defects caused by external injuries or surgical treatment, osteochondritis dissecans, osteoarthritis, congenital cartilage disease, gout and any crystal-induced arthritis and cartilage injury, synovitis caused by rheumatoid arthritis, psoriatic arthritis and / or wherein the joint pain is inflammatory joint pain.

6. The GLP-1 receptor agonist compound for use according to any one of claims 1 to 5, wherein the GLP-1 receptor agonist compound is administered to a subject to be treated in combination with at least one further active substance selected from the group consisting of analgesics, non-steroidal anti-inflammatory drugs,steroidal anti-inflammatory drugs, hyaluronic acids and symptomatic slow-acting anti-osteoarthritic agents.

7. The GLP- 1 receptor agonist compound for use according to claim 6, wherein the GLP-1 receptor agonist compound and the at least one further active substance are administered to the subject to be treated simultaneously.

8. The GLP- 1 receptor agonist compound for use according to claim 6, wherein the GLP-1 receptor agonist compound and the at least one further active substance are administered to the subject to be treated sequentially.

9. The GLP-1 receptor agonist compound for use according to any one of claims 1 to 8, wherein the GLP-1 receptor agonist compound is administered in combination with local treatments for osteoarthritis or any other arthritis.

10. The GLP-1 receptor agonist compound for use according to any one of claims 1 to 9, wherein the GLP-1 receptor agonist compound is administered orally, subcutaneously, intramuscularly, intravenously, intratendinously or intraarticularly.

11. A pharmaceutical composition for use in the treatment of joint diseases and / or joint pain comprising a GLP-1 receptor agonist compound according to any one of claims 1 to 10, and a pharmaceutically acceptable excipient.

12. The pharmaceutical composition for use according to claim 11, formulated as a gel.

13. The pharmaceutical composition for use according to claim 12, wherein the gel comprises a polymer selected from the group consisting of non-ionic surfactant, cellulose, polyether, glucan, glycerophospholipids polysaccharides, proteins, and combinations thereof.

14. The GLP-1 receptor agonist compound for use according to any one of claims 1 to 10, or the pharmaceutical composition for use according to any one of claims 11 to 13, wherein the subject to be treated is a non-human animal, preferably anon-human mammal, more preferably an animal selected from the group consisting of a dog, a cat, a horse, a cow, a sheep, a pig and a non-human primate.

15. The GLP-1 receptor agonist compound for use according to any one of claims 1 to 10, or the pharmaceutical composition for use according to any one of claims 11 to 14, wherein the subject to be treated is a human.

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