Compound or pharmaceutically acceptable salt thereof, composition and use for treatment of muscular dystrophy and for positive regulation of utrophin levels in muscle cells

Description

1 / 30 A pharmaceutically acceptable compound or salt thereof, with a composition and use for the treatment of muscular dystrophy and for the positive regulation of utrophin levels in muscle cells, and a method of application thereof. CROSS-REFERENCE TO RELATED REQUEST

[001] This application is based on and derives the benefit of Provisional Application No. IN 202341026707, the content of which is incorporated into this document in its entirety by way of reference. FIELD OF TECHNIQUE

[002] The embodiments disclosed herein generally relate to compounds for the treatment or management of muscular dystrophy. More specifically, the invention relates to DPP-IV inhibitors and their use to increase utrophin levels in muscle cells for the treatment of muscular dystrophy. BACKGROUND

[003] Muscular dystrophy (MD) is a collection of inherited disorders characterized by weakness and degeneration of skeletal muscle. Duchenne muscular dystrophy (DMD) is one of the most common forms of muscular dystrophy, caused by recessive C-linked mutations in the dystrophin gene. DMD affects approximately 1 in 5000 men worldwide.

[004] Mutations in the dystrophin gene prevent the production of the muscle isoform of dystrophin, a crucial component of the dystrophin-associated glycoprotein (DGC) complex that serves to connect the inner cytoskeleton to the surrounding extracellular matrix. Dystrophin plays a fundamental role in providing structural stability to skeletal muscle, thus preserving strength and flexibility and protecting the sarcolemma from injury induced by muscle contractions. Individuals with dystrophies exhibit low levels or complete absence of dystrophin expression, resulting in progressive muscle degeneration and disruption of neuromuscular junction organization. Petition 870250093128, dated 10 / 10 / 2025, page 37 / 171 2 / 30 The absence of dystrophin also leads to elevated levels of intracellular calcium and excessive production of nitric oxide, which initiates processes such as protein degradation, generation of free radicals, oxidative stress, inflammation, fibrosis, necrosis, and macrophage activation, ultimately culminating in a dystrophic state of skeletal muscle, respiratory impairment, and cardiomyopathy. Progressive muscle degeneration frequently leads to loss of ambulation between 8 and 12 years of age, with premature death between 20 and 30 years of age due to respiratory and cardiac complications.

[005] A comprehensive cure for the disease remains elusive, despite extensive research into the molecular mechanisms of muscular dystrophies, and currently available treatments mainly offer only supportive care. Management of muscular dystrophy relies primarily on symptomatic treatment involving physiotherapy and the use of corticosteroids. While corticosteroids may help slow disease progression, they are associated with significant side effects such as weight gain, hyperglycemia, insulin resistance, characteristic Cushing's syndrome, short stature, behavioral changes, osteoporosis, and bone fractures.

[006] Therapeutic strategies for muscular dystrophy primarily focus on restoring dystrophin expression using various gene therapy methods, such as antisense oligonucleotide-mediated exon skipping, AAV-mediated minidystrophin gene delivery, CRISPR / Cas9 genome editing, and stop codon suppression. However, these approaches are mutation-specific and restricted to only a subset of patients with dystrophy. Challenges, including concerns about adverse immunological events, toxicities, and the need for systemic delivery, further complicate their use. Thus, it is crucial to identify therapeutic strategies capable of mitigating muscle fiber damage and delaying the onset of disability in patients with muscular dystrophy, regardless of the mutation type. Petition 870250093128, dated 10 / 10 / 2025, page 38 / 171 3 / 30

[007] Upregulation of utrophin, an autosomal homolog that shares structural and functional similarities with dystrophin, offers an alternative therapeutic approach for the treatment of muscular dystrophy. Utrophin is expressed in fetal muscle and in various non-skeletal muscle tissues in adults, including the lungs, kidneys, and liver. Spontaneous compensatory upregulation of utrophin is frequently observed in individuals with muscular dystrophy, as well as in dystrophin-deficient animal models. Seminal studies conducted in animal models support the potential of utrophin as a functional substitute for dystrophin, suggesting its viability as a therapeutic approach for the treatment of muscular dystrophies.Furthermore, therapeutic interventions that use small molecules to raise utrophin levels in the muscles of individuals with muscular dystrophy are unlikely to trigger an immune response or cause adverse side effects.

[008] Utrophin can be upregulated by several signaling pathways, such as AHR-ARNT, TGF-β, HDAC, GLP-1-PGC-1α, GABPa / β, and CalcineurinNFAT-mediated signaling pathways. Proposed strategies to modulate utrophin expression include the use of small drugs to increase its expression at both transcriptional and translational levels. The long-term implications of utrophin-focused therapeutic approaches, however, remain uncertain and require further clinical evaluation. For example, the development program for the small molecule drug Ezutromide, designed to increase utrophin expression, was recently terminated due to its failure to meet endpoints in clinical trials, potentially because of the molecule's self-limiting pharmacokinetic profile.Thus, there is currently a lack of evidence for the availability of a therapeutic intervention to clinically increase utrophin levels in order to effectively treat patients with muscular dystrophies.

[009] Therefore, there is a critical need to identify therapeutic agents with high efficacy, ease of administration, and broad applicability. Petition 870250093128, dated 10 / 10 / 2025, page 39 / 171 4 / 30 and excellent safety and tolerability profiles for the prevention, treatment, and management of muscular dystrophy. OBJECTIVES

[010] The main objective of the modalities in this document is to provide a compound for the treatment or management or both of muscular dystrophy.

[011] Another objective of the modalities in this document is to provide a compound that can positively regulate utrophin levels in muscles.

[012] Another objective of the modalities in this document is to provide a compound that can activate muscle regeneration and repair.

[013] Another objective of the modalities in this document is to provide a compound that can prevent or delay muscle loss or degradation.

[014] Another objective of the modalities in this document is to provide a compound capable of reducing inflammation, oxidative stress, fibrosis, and necrosis in muscles.

[015] Another objective of the modalities disclosed in this document is to provide a compound that is readily available, economical, easy to use, therapeutically effective, sustainable, fast-acting, and with minimal side effects.

[016] Another objective of the modalities in this document is to provide a compound that confers potential protection against neuromuscular diseases.

[017] Another objective of the embodiments in the present document is to provide a compound for the preparation of a medicament for the treatment or management or both of muscular dystrophy by means of the mechanisms mentioned above.

[018] Another objective of the modalities in the present document is to provide a compound with Dipeptidyl Peptidase IV (DPP-IV) inhibitory activity for the treatment or management or both of muscular dystrophy.

[019] Another objective of the modalities in this document is to provide a composition for the treatment or management or both of the dystrophy. Petition 870250093128, dated 10 / 10 / 2025, page 40 / 171 5 / 30 muscular.

[020] Another objective of the modalities in this document is to provide a method for the treatment or management or both of muscular dystrophy.

[021] These and other aspects of the modalities in this document will be better appreciated and understood when considered in conjunction with the following description and the accompanying drawings. It should be understood, however, that the following descriptions, while indicating at least one modality and several specific details thereof, are given by way of illustration and not limitation. Many changes and modifications may be made within the scope of the modalities in this document without departing from their spirit, and the modalities in this document include all such modifications. BRIEF DESCRIPTION OF THE FIGURES

[022] The embodiments in this document are illustrated in the accompanying drawings, along which similar reference letters indicate corresponding parts in the various figures. The embodiments in this document will be better understood from the following description with reference to the following illustrative drawings. The embodiments in this document are illustrated by means of examples in the accompanying drawings, in which:

[023] Figure 1 shows the effect of DPP-IV inhibitors on utrophin levels in vitro, according to the modalities disclosed in this document.

[024] Figure 2 presents a comparison of the upregulation of utrophin by Sitagliptin and Ezutromide in skeletal muscle myoblasts of C2C12 mice, according to the modalities disclosed in this document.

[025] Figure 3 is a schematic diagram illustrating the protocol for in vivo studies in the D2.mdx mouse model of DMD, according to the modalities disclosed in this document. Petition 870250093128, dated 10 / 10 / 2025, p. 41 / 171 6 / 30

[026] Figure 4 shows the results of the treadmill test in D2.mdx mice, wherein Figure 4A depicts the effect of Sitagliptin in terms of distance covered and Figure 4B depicts the effect of Sitagliptin in terms of time to exhaustion, according to the modalities disclosed in this document.

[027] Figures 5A and 5B show the effect of Sitagliptin on normalized grip strength in D2.mdx mice pre-treadmill and post-treadmill, respectively, according to the modalities disclosed in this document.

[028] Figures 6A and 6B show the effect of Sitagliptin on the latency of D2.mdx mice in pre-treadmill and post-treadmill, respectively, according to the modalities revealed in this document.

[029] Figure 7 shows the effect of Sitagliptin on latency to fall in D2.mdx mice in the rotary bar test, according to the modalities disclosed in this document.

[030] Figure 8 shows the effect of Sitagliptin on serum creatine kinase levels in D2.mdx mice, according to the modalities described in this document.

[031] Figure 9 presents the summary of the 28th day of the treadmill test, in which Figure 9A describes the distance covered, Figure 9B describes the time to exhaustion, Figure 9C describes the normalized pre-treadmill grip strength, Figure 9D describes the normalized post-treadmill grip strength, Figure 9E describes the pre-treadmill suspension test, Figure 9F depicts the post-treadmill suspension test, according to the modalities revealed in this document. DETAILED DESCRIPTION

[032] The embodiments in this document and their various advantageous features and details are explained in more detail with reference to the non-limiting embodiments which are illustrated in the drawings that Petition 870250093128, dated 10 / 10 / 2025, p. 42 / 171 7 / 30 accompany and detail the description below. Descriptions of known components and processing techniques are omitted so as not to unnecessarily obscure the modalities in this document. The examples used in this document are intended only to facilitate understanding of the ways in which the modalities described herein can be practiced and to further enable those skilled in the field to practice the modalities presented herein. Thus, the examples should not be interpreted as limiting the scope of the modalities described herein.

[033] For the purposes of interpreting this descriptive report, the definitions (as defined in this document) apply and, where appropriate, terms used in the singular shall also include the plural and vice versa. It should be understood that the terminology used in this document is only for the purpose of describing specific modalities and is not intended to be limiting. The terms understand, have and include should be interpreted as open terms, unless otherwise indicated.

[034] The words / phrases exemplar, example, illustration, in an instance, and similar, and so forth, etc., etcetera, for example, i.e., are merely used in this document to signify that it serves as an example, instance, or illustration. Any embodiment or implementation of the present matter described in this document using the words / phrases exemplar, example, illustration, in an instance, and similar, and so forth, etc., etcetera, i.e., should not necessarily be interpreted as preferred or advantageous in relation to other embodiments. The terms comprise, have, and include should be interpreted as open terms, unless otherwise indicated. The terms individual, patient, subject, or cell line are used interchangeably in this document.

[035] It should be noted that the elements in the drawings are illustrated for the purposes of this description and to facilitate understanding of the aspects of the modalities. Petition 870250093128, dated 10 / 10 / 2025, p. 43 / 171 8 / 30 as disclosed in this document. The accompanying drawings are used to help easily understand various features of the technique and it should be understood that the embodiments presented herein are not limited by the accompanying drawings. As such, this disclosure should be interpreted as extending to any modifications, equivalents and substitutes, in addition to those specifically set forth in the accompanying drawings and the corresponding description. The use of words such as first, second, third, etc., or I, II, III, etc., to describe components / elements / steps is for the purposes of this description and should not be interpreted as sequential ordering / placement / occurrence, unless otherwise specified.

[036] The embodiments in this document disclose compounds for the preparation of a medicament for the treatment or management, or both, of muscular dystrophy. The inventors of this application have shown that, for the first time, inhibition of DPP-IV activity can increase utrophin levels in mouse skeletal muscle cell lines in vitro, as well as in vivo in Duchenne Muscular Dystrophy (DMD) D2-mdx model mice, resulting in an overall improvement in muscle function.The inventors further illustrated that DPP-IV inhibitors, such as sitagliptin, meloliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, retagliptin, cofrogliptin, fotagliptin, and prusogliptin, normally used for the treatment of type 2 diabetes, can be repurposed to increase utrophin levels in muscle cells and can be used for the treatment or management of muscular dystrophy. Consequently, the embodiments in the present document disclose the use of dipeptidyl peptidase-IV (DPP-IV) inhibitors for the treatment or management, or both, of muscular dystrophy. Specifically, the inventors showed that sitagliptin can increase utrophin levels in muscle cells, resulting in... Petition 870250093128, dated 10 / 10 / 2025, page 44 / 171 9 / 30 an overall improvement in muscle function. The modalities in this document also achieve a composition to positively regulate utrophin levels in muscle cells. The composition, according to the modalities in this document, includes at least one DPP-IV inhibitor or its pharmaceutically acceptable salt, solvate or analogue thereof and, optionally, at least one pharmaceutically acceptable excipient.

[037] The term muscular dystrophy refers to a genetically and clinically heterogeneous group of rare neuromuscular diseases caused by mutations in the dystrophin gene, dysferlin gene, and associated glycoprotein complex (DAPC / DGC). Muscular dystrophy, as used in this document, encompasses different categories of muscular dystrophies, including, but not limited to, dystroglycanopathy, dysferlinopathy, and dystrophinopathy.

[038] Dystroglycanopathy is a collective term that refers to muscular dystrophies with abnormal glycosylation of α-dystroglycan (DG), a glycoprotein that interacts with dystrophin, or mutations in genes related to the dystroglycan protein complex (DAPC / DGC). Dystroglycanopathies exhibit a broad clinical spectrum, ranging from severe to mild congenital muscular dystrophies, including Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy (LGMD, approximately 32 variants including (LGMDR9 / LGMD2I), Emery-Dreiffus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), calpainopathies or LGMD2A, and oculopharyngeal muscular dystrophy.

[039] Dystrophinopathy encompasses a spectrum of X-linked muscle diseases ranging from mild to severe, including Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DMD).

[040] Dysferlinopathy is a disease caused by a deficiency of dysferlin due to mutations in the DYSF gene. Dysferlin is a membrane protein in Petition 870250093128, dated 10 / 10 / 2025, page 45 / 171 10 / 30 sarcolemma and is involved in different functions, such as membrane repair and vesicle fusion, T-tubule development and maintenance, Ca2+ signaling, and regulation of various molecules. Dysferlinopathy includes Miyoshi myopathy type 1 (MMD1) and dysferlin-related limb-girdle muscular dystrophy R2 (LGMDR2).Thus, the compounds of the present invention can be used for the treatment or management or both of muscular dystrophy, including, but not limited to, Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emery-Dreiffus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), calpainopathies or LGMD2A, oculopharyngeal muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi myopathy type 1 (MMD1) and dysferlin R2-related muscular dystrophy (LGMDR2).

[041] In one form, muscular dystrophy is Duchenne Muscular Dystrophy (DMD). In another form, muscular dystrophy is Becker Muscular Dystrophy (BMD). Both DMD and BMD are characterized by progressive muscle weakness and skeletal degeneration. In patients with DMD, dystrophin is virtually absent, while patients with BMD have 10% to 40% of the normal amount. The increased permeability of the sarcolemma caused by dystrophy usually leads to the release of creatine kinase (CK) from muscle fibers. Therefore, an elevated serum CK level is the hallmark of muscle damage. In patients with DMD, CK is markedly elevated compared to the normal range, which has diagnostic value.

[042] Muscular dystrophy, as used in this document, also includes atrophy characterized by muscle degeneration or loss of mass, often attributed to aging or various diseases such as poliomyelitis, severe malnutrition, nerve damage, or other disorders. Petition 870250093128, dated 10 / 10 / 2025, page 46 / 171 11 / 30 neurogenic. Dystrophy usually results from genetic mutations and causes severe weakness due to insufficient muscle proteins, often with visible muscle weakness and atrophy. Although atrophy can be mitigated through exercise and lifestyle adjustments, dystrophy, being genetic in nature, is irreversible.

[043] DPP-IV inhibitors, as used in this document, refer to molecules that inhibit the activity of the enzyme dipeptidyl peptidase-IV (DPP-IV). DPP-IV is an enzyme expressed on the surface of most cell types and is associated with immune regulation, signal transduction, and apoptosis. The DPP-IV enzyme plays an important role in glucose metabolism and is responsible for the degradation of incretins such as glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (or gastric inhibitory polypeptide, GIP). The DPP-IV enzyme has five binding sites, namely S1, S2, S1', S2', and the S2 extensive site. The primary interaction with S1 and S2 is crucial for DPP-IV inhibition, with additional interactions at S1', S2', and the S2 extensive site potentially increasing inhibition.Examples of DPP-IV inhibitors include, but are not limited to, sitagliptin, meloliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, retagliptin, cofrogliptin, fotagliptin, and prusogliptin.

[044] DPP-IV inhibitors are categorized based on their interactions with the enzyme into Class 1, Class 2, and Class 3. Class 1 inhibitors, such as vildagliptin and saxagliptin, bind to S1 and S2, which represent fundamental inhibitors. Class 2 inhibitors (e.g., alogliptin and linagliptin) interact with additional sites (S1' and S2'), potentially leading to increased inhibition compared to Class 1. Class 3 inhibitors (e.g., sitagliptin and teneligliptin) bind to an additional, extensive S2 site, resulting in more extensive DPP-IV inhibition.

[045] The compound for the preparation of a medicine for the treatment or Petition 870250093128, dated 10 / 10 / 2025, page 47 / 171 12 / 30 management or both of muscular dystrophy, according to the modalities described in this document, includes at least one dipeptidyl peptidase-IV (DPP-IV) inhibitor, its salts or combinations thereof.

[046] In one embodiment, the compound is Sitagliptin. Sitagliptin or (R)-4-oxo4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5trifluorophenyl)butan-2-amine and its phosphate salt are the first oral DPP-IV inhibitors approved by the FDA. In one embodiment, the compound is sitagliptin phosphate monohydrate.

[047] In one embodiment, the compound is melogliptin. Melogliptin, or (2S,4S)-4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile, is a potent, selective, orally bioavailable, cyanopyrrolidine-based DPP-IV inhibitor with hypoglycemic activity.

[048] In one embodiment, the compound is linagliptin. Linagliptin, or 8-[(3R)3-Aminopiperidine-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]3,7-dihydro-1H-purine-2,6-dione, is an FDA-approved oral antidiabetic drug. Linagliptin differs from other DPP-IV inhibitors in that it has a non-linear pharmacokinetic profile, is not primarily eliminated by the renal system, and exhibits concentration-dependent protein binding.

[049] In one embodiment, the compound is vildagliptin. Vildagliptin or (S)1-[2-(3-hydroxyadamantane-1-ylamino)acetyl]pyrrolidine-2-carbonitrile is an FDA-approved oral antidiabetic agent that increases the responsiveness of pancreatic islet cells to glucose.

[050] In one embodiment, the compound is teneligliptin. Teneligliptin or {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}(1,3thiazolidin-3-yl)methanone is one of the newest antidiabetic drugs.

[051] It is also within the scope of the invention to use salts, solvates, derivatives or analogues of Sitagliptin, Melogliptin, Linagliptin, Vildagliptin, Teneligliptin, Saxagliptin, Alogliptin, Anagliptin, Gemigliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, Retagliptin, Cofrogliptin, Fotagliptin Petition 870250093128, dated 10 / 10 / 2025, page 48 / 171 13 / 30 and Prusogliptin. COMPOSITION

[052] The embodiments described herein also provide a composition for the treatment, management, or both of muscular dystrophy. In one embodiment, the composition contains at least one DPP-IV inhibitor or its pharmacologically acceptable salt, solvate, or analogue thereof. DPP-IV inhibitors include, but are not limited to, Sitagliptin, Meloliptin, Linagliptin, Vildagliptin, Teneligliptin, Saxagliptin, Alogliptin, Anagliptin, Gemigliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, Retagliptin, Cofrogliptin, Fotagliptin, and Prusogliptin.

[053] In one embodiment, the composition contains a pharmacologically acceptable salt of the DPP-IV inhibitor. The pharmaceutically acceptable salt, as used herein, refers to a salt that retains the biological efficacy of the free acids and bases of a specified compound and that is not biologically or otherwise undesirable. The pharmaceutically acceptable salt may also refer to a salt that may have unexpectedly superior biological efficacy or efficiency when compared to the actual or active pharmaceutical ingredient (API). According to the present invention, pharmacologically acceptable salts are produced from acidic inorganic or organic compounds, or alkaline inorganic or organic compounds. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like.Salts in solid form can exist in more than one crystalline structure and can also be in the form of hydrates. Pharmacologically acceptable salts derived from non-toxic organic bases include salts of primary, secondary, and tertiary amines, substituted amines (including naturally substituted amines), cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, and N-ethyl. Petition 870250093128, dated 10 / 10 / 2025, page 49 / 171 14 / 30 morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropilamine, tromethamine and the like. Salts of inorganic and organic acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. In one embodiment, the pharmaceutically acceptable salt is a phosphate salt. In one embodiment, the composition contains a pharmacologically acceptable sitagliptin salt. In one embodiment, the composition contains sitagliptin phosphate monohydrate.

[054] In one embodiment, the composition includes a solvate or analogue of the DPP-IV inhibitor. A solvate, as used herein, typically refers to a compound (or a salt thereof) in association with a solvent, such as water. Representative examples include hydrates, hemihydrates, trihydrates, and the like. As used herein, the term analogue is typically used to denote a compound that has a chemical structure substantially similar to the structure of the parent compound, while retaining at least some of the parent compound's biological function. Analogues also include pharmacologically acceptable salts.

[055] In one embodiment, the composition includes at least one pharmacologically acceptable excipient. Examples of pharmacologically acceptable excipients include, but are not limited to, mannitol, starch, xylitol, maltodextrin, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous dicalcium phosphate, glyceryl behenate, triethyl citrate, polyethylene glycol, croscarmellose sodium, stearic acid, talc, hydrogenated cottonseed oil, magnesium stearate, colloidal silicon dioxide, polysorbate, sodium lauryl sulfate, Petition 870250093128, dated 10 / 10 / 2025, page 50 / 171 15 / 30 anhydrous calcium hydrogen phosphate, sodium stearyl fumarate, propyl gallate, poly(vinyl alcohol), macrogol 3350, titanium dioxide, red iron oxide and yellow iron oxide or mixtures thereof. In one embodiment, the composition may further include a pharmacologically acceptable carrier, diluent and / or adjuvant. It is also within the scope of the invention that the composition may have additional additives selected from solvents, stabilizers or suspensions.

[056] The composition may be formulated together or separately with pharmacologically acceptable excipients or carriers. Preferably, a compound of the invention and the pharmacologically acceptable excipient or carrier are formulated together for simultaneous or near-simultaneous administration. In one embodiment, the pharmacologically acceptable excipient or carrier may be formulated separately with a compound of the invention.

[057] The concentration of the DPP-IV inhibitor in the composition can vary from as little as 0.1% of the total amount of the composition up to 100%. In some embodiments, the concentration of the DPP-IV inhibitor in the composition is from 1% to 90% by weight. In some embodiments, the concentration of the DPP-IV inhibitor in the composition is from 5% to 80% by weight. In some embodiments, the concentration of the DPP-IV inhibitor in the composition is from 10% to 70% by weight. The exact amount will depend on any additional materials chosen.

[058] The DPP-IV inhibitor or the composition comprising at least one DPP-IV inhibitor, according to the embodiments described herein, may be administered as monotherapy or in combination with one or more additional therapies. In one embodiment, the DPP-IV inhibitor, or the composition including the DPP-IV inhibitor, is administered as monotherapy. In another embodiment, the DPP-IV inhibitor or the composition including the DPP-IV inhibitor is administered as combination therapy with one or more additional therapeutic agents. Non-limiting examples of additional therapies that may be used for combination therapy include, but are not limited to, therapy Petition 870250093128, dated 10 / 10 / 2025, page 51 / 171 16 / 30 with corticosteroids, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy.

[059] In one embodiment, combination therapy comprises the administration of a DPP-IV inhibitor or a composition comprising at least one DPP-IV inhibitor with corticosteroids. Corticosteroid therapy includes the administration of corticosteroids to slow the progression of muscular dystrophy. Examples of corticosteroids used in the treatment of dystrophy include, but are not limited to, prednisone / prednisolone, deflazacort (an oxazoline derivative of prednisolone), vamorolone, and combinations thereof. Corticosteroids are administered by two common regimens – daily and intermittent.

[060] In one embodiment, combination therapy comprises the administration of the DPP-IV inhibitor or the composition comprising at least one DPP-IV inhibitor with exon-skipping therapies. Exon-skipping therapy refers to the use of antisense oligonucleotides to remove selected exons from pre-mRNA, at or near the site of the mutation, to generate a translatable transcript of the mutant dystrophin gene. Antisense oligonucleotides (AONs) are 20 to 30 nucleotides in length, designed to target specific pre-mRNA sequences and skip a specific DMD exon adjacent to the mutation region, so as to produce a frame-like but truncated transcript that translates a functional dystrophin protein. Examples of AON agents for exon-skipping therapy include, but are not limited to, Eteplirsen, Golodirsen, Viltolarsen, Casimersen, Drisapersen, tricycle-DNA (tcDNA), ASO-based therapy, and combinations thereof.

[061] In one embodiment, combination therapy comprises the administration of the DPP-IV inhibitor or the composition comprising at least one DPP-IV inhibitor with epigenetic agents. Epigenetic therapy involves the use of small molecules or epigenetic modifiers to modify gene activity without altering the gene's coding sequence. The main Petition 870250093128, dated 10 / 10 / 2025, page 52 / 171 17 / 30 Epigenetic mechanisms, such as DNA methylation or histone modification, play a crucial role in regulating muscle regeneration. Epigenetic therapy includes therapeutic approaches through the creation of epigenetic drugs designed to target specific chromatin elements within individual signaling pathways. Examples of epigenetic drugs include, but are not limited to, Givinostat, Trichostatin A (TSA), Pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof.

[062] In one embodiment, combination therapy comprises the administration of the DPP-IV inhibitor or the composition comprising at least one DPP-IV inhibitor with gene therapy agents. Gene therapy includes, but is not limited to, adeno-associated virus (AAV) vector-mediated gene therapy, with the microdystrophin gene being a preferred candidate.

[063] It is also within the scope of the invention to use the DPP-IV inhibitor, or the composition comprising at least one DPP-IV inhibitor, in combination with muscle regeneration therapies such as AAK1 inhibitors or cAMP boosting mechanisms, other utrophin regulators, muscle strengthening therapies such as aryl hydrocarbon receptor (AhR) antagonists, myostatin inhibitors, muscle Ca2+ overload inhibitors such as P2X7 antagonists, Storage-Operated Calcium Entry (SOCE) inhibitors / calcium release-activated calcium channel (CRAC) inhibitors, anti-inflammatory agents acting on the NF-kB signaling pathway at targets such as NF-κB inhibitors, IKK2 / β inhibitors, TBK1 inhibitors, Akt-mTOR pathway inhibitors and agents of the antifibrotic mechanism pathway such as TGF-β inhibitors, RIPK1 / 3 inhibitors, activin receptor inhibitors,Smad2 / 3 inhibitors and TAK1 inhibitors and other GLP-1 agonists and GLP-1 pathway activators.

[064] Combination therapy is administered in a manner and at a dosage that is effective in increasing utrophin production and improving muscle function and strength. Petition 870250093128, dated 10 / 10 / 2025, page 53 / 171 18 / 30

[065] The DPP-IV inhibitor, or the composition comprising at least one DPP-IV inhibitor of the present invention, may be used in combination with one or more other drugs in the treatment, suppression, or improvement of muscular dystrophy, where the combination of the drugs together is safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used for this purpose, contemporaneously or sequentially with the compounds of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing those other drugs in addition to the compound of the present invention is preferable. Thus, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients in addition to a compound of the present invention.Combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered in different overlapping regimens. It is also contemplated that, when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used at lower doses than when each is used alone.

[066] The DPP-IV inhibitor or the composition comprising at least one DPP-IV inhibitor, according to the embodiments described in this document, may be formulated for administration by any suitable route, including parenteral (e.g., intravenous, intramuscular), intradermal, cutaneous, subcutaneous, oral, transdermal, transmucosal, topical, nasal, vaginal, intrathecal, epidural, ocular and rectal administration or by injection or inhalation.

[067] Solutions or suspensions used for parenteral, intradermal or subcutaneous administration may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, Petition 870250093128, dated 10 / 10 / 2025, page 54 / 171 19 / 30 polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and tonicity adjusters such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be placed in ampoules, disposable syringes or multi-dose glass or plastic vials.

[068] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (when water-soluble) or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, New Jersey) or phosphate-buffered saline (PBS). In all cases, the composition is preferably sterile and should be flowable to the extent that easy syringeability exists. In some embodiments, it will be stable under manufacturing and storage conditions and will be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol or liquid polyethylene glycol and the like) and suitable mixtures thereof.Adequate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the necessary particle size in the case of a dispersion, or by using surfactants. Prevention of microbial action can be achieved by incorporating various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions can be obtained by including an absorption-delaying agent in the composition, for example, monostearate. Petition 870250093128, dated 10 / 10 / 2025, page 55 / 171 20 / 30 of aluminum or gelatin.

[069] Sterile injectable solutions can be prepared by incorporating the active compound in the required quantity into an appropriate solvent with one or a combination of ingredients listed above, as needed, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the other necessary ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization, which produce a powder of the active ingredient plus any desired additional ingredient from a previously filtered and sterile solution.

[070] The DPP-IV inhibitor or the composition including the DPP-IV inhibitor may be formulated as tablets, hard or soft capsules, chewable gums, syrups, elixirs, pills, lozenges, emulsions, dispersible powders or granules, liquids, gels, aqueous or oily suspensions, patches, nanoformulations or other forms suitable for oral, parenteral, topical or inhalation administration. The tablets, pills, capsules, lozenges and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.Suitable tablets can be obtained, for example, by mixing at least one of the compounds that can be used in the present invention with known excipients, for example, diluents such as microcrystalline cellulose, calcium carbonate, calcium phosphate or lactose, disintegrants such as croscarmellose sodium, HPMC, sodium starch glycolate, binders such as starch or gelatin, guar gum, xanthan gum, lubricants such as stearate. Petition 870250093128, dated 10 / 10 / 2025, p. 56 / 171 21 / 30 of magnesium or talc and / or agents. Shapes include round, small capsules, flat, oval and chamfered edges with and without relief.

[071] Capsules such as hard or soft gelatin containing the compounds that can be used in the present invention can, for example, be prepared by mixing the active compounds with inert carriers, such as lactose or sorbitol, and packaging them in gelatin capsules. The capsules may be printed or unprinted.

[072] Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oil suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[073] Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweeteners, flavorings and colorings, may also be present.

[074] The composition may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example, olive oil or aracis oil, or a mineral oil, for example, liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally occurring gums, for example, acacia gum or tragacanth gum, naturally occurring phosphatides, for example, soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example. Petition 870250093128, dated 10 / 10 / 2025, page 57 / 171 22 / 30 example, polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings.

[075] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain an emollient, a preservative, and flavoring and coloring agents.

[076] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated can be used in the formulation. These penetrants are generally known in the field and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be performed with nasal sprays or suppositories. The compounds can be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal administration.

[077] The dosage of the DPP-IV inhibitor, or the composition that includes the DPP-IV inhibitor, varies according to the specific compound employed, the metabolic stability and duration of action of the compound, the route and time of administration, the rate of excretion, the duration of treatment, the severity of the condition, the drug combination, the identity of any other therapeutic compounds administered, the age, body weight, general health, sex, diet, size and species of the subject, e.g., human patient, and similar factors. In general, the dosage of DPP-IV inhibitors in the present composition will be an amount that is the lowest effective dose to produce the desired effect with no or minimal side effects. The effective dose of DPP-IV inhibitors may also be administered in two, three, four, five, six or more subdoses, administered separately at appropriate intervals throughout the day.An appropriate dosage level will generally be around 10 to 250 mg per day, which can be administered in single or multiple doses. Petition 870250093128, dated 10 / 10 / 2025, page 58 / 171 23 / 30 Preferably, the dosage level will be from about 0.5 to about 100 mg / kg per day. An appropriate dosage level may be from about 0.01 to 250 mg / kg per day, from about 0.05 to 100 mg / kg per day, or from about 0.1 to 50 mg / kg per day. Within this range, the dosage may be from 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg per day. For oral administration, the compositions are preferably supplied in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient for symptomatic dosage adjustment to the patient being treated. The compounds can be administered in a regimen of 1 to 4 times a day, preferably once or twice a day. In one embodiment, the composition is administered at a dose between 30 mg / kg per day and 70 mg / kg per day in mice.In one embodiment, the composition is administered at a dose of 50 mg / kg per day in D2.mdx mice. In another embodiment, the widest human dosage range of the composition is 10 to 250 mg per day, administered in a single or multiple dosing regimen.

[078] In one embodiment, the DPP-IV inhibitor or the composition including the DPP-IV inhibitor is used for the treatment or management, or both, of muscular dystrophy. Treatment or management includes inhibiting the condition, i.e., halting the development or progression of clinical symptoms, and / or alleviating the condition, i.e., causing regression of clinical symptoms. The composition, according to the embodiments presented herein, may be used to control the symptoms of muscular dystrophy, such as muscle weakness and wasting, and to slow the progression of the disease. The composition may also be used to improve the quality of life in patients with dystrophy. In one embodiment, the composition provides a strategy for a dystrophy-specific therapy that, in principle, is applicable to all patients, i.e., it is not limited to restricted subsets of patients with mutation-specific muscular dystrophies. Petition 870250093128, dated 10 / 10 / 2025, page 59 / 171 24 / 30

[079] In one embodiment, the DPP-IV inhibitor or the composition that includes the DPP-IV inhibitor positively regulates utrophin expression in muscle cells. Utrophin expression is subject to regulation at multiple steps along its synthesis and degradation pathways. Different approaches to modulate utrophin expression include, but are not limited to, direct mechanisms such as gene or protein substitution, and indirect mechanisms such as transcriptional upregulation of the utrophin promoter, posttranscriptional regulation, and protein / mRNA stabilization. Utrophin can be positively regulated by several signaling pathways, but not limited to, AHRARNT, TGF-β, HDAC, GLP-1-PGC-1α, GABPa / β, and Calcineurin-NFAT-mediated signaling pathways. In one embodiment, the composition positively regulates utrophin expression through DPP-IV inhibition.

[080] In one embodiment, the DPP-IV inhibitor or the composition including the DPP-IV inhibitor activates the PI3K / Akt signaling pathway, which is known to play a role in muscle growth and regeneration. Inhibition of DPP-IV may activate the PI3K / Akt signaling pathway in muscle cells, which increases protein synthesis and muscle fiber size. Another mechanism by which the composition may exert its effects on muscular dystrophies is through stimulation of mitochondrial biogenesis. In one embodiment, the composition positively regulates myogenic factors such as myogenin (MyoG) and MyoD. In one embodiment, the composition inhibits inflammation, muscle atrophic factors, and thus reduces muscle mass loss. In one embodiment, the composition may reduce muscle fibrosis and necrosis. In one embodiment, the composition has potential therapeutic effects in animal models and clinical trials, indicating its efficacy in humans.

[081] The use of DPP-IV inhibitors as a repurposed drug for the upregulation of utrophin has several advantages. DPP-IV inhibitors are potent, well-tolerated, and orally bioavailable drugs with wide Petition 870250093128, dated 10 / 10 / 2025, page 60 / 171 25 / 30 applicability, excellent safety and tolerability profiles, which makes them suitable for long-term use. DPP-IV inhibitors are also proven safe for long-term use in the pediatric (adolescent) and adult population. DPP-IV inhibitors also demonstrate anti-inflammatory and antifibrotic properties, along with the ability to prevent muscle loss and degradation while strengthening myofibers.

[082] The embodiments in this document also disclose a method for increasing utrophin expression in an individual who needs it, wherein the method comprises administering to the subject a therapeutically effective amount of the DPP-IV inhibitor or of the composition comprising at least one pharmaceutically acceptable DPP-IV inhibitor or its salt, and at least one pharmaceutically acceptable excipient.

[083] The embodiments in this document also disclose a method for the treatment of muscular dystrophy. The method, according to the embodiments described in this document, includes administering to a subject in need a therapeutically effective amount of DPP-IV inhibitor or the composition comprising at least one DPP-IV inhibitor or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient. The term effective or therapeutically effective, as used in this document, refers to the amount of a compound that is not toxic but is present in sufficient quantity to provide the desired effect at a reasonable benefit / risk ratio for the performance of any medical treatment. The desired effect may be the relief of the signs, symptoms or causes of a disease, or any other desired outcome in a biological symptom.

[084] The subject is generally a mammal, preferably a human, male or female, in whom inhibition of dipeptidyl peptidase IV enzyme activity is desired. In one embodiment, the subject includes a mammal suffering from muscular dystrophy. In one embodiment, muscular dystrophy includes dystrophy Petition 870250093128, dated 10 / 10 / 2025, page 61 / 171 26 / 30 Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emery-Dreiffus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), calpainopathies or LGMD2A, oculopharyngeal muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi myopathy type 1 (MMD1), and dysferlin-related limb-girdle muscular dystrophy R2 (LGMDR2).

[085] The invention is further described by reference to the following examples by way of illustration only and should not be construed as limiting the scope of the embodiments disclosed herein. It will be evident to those skilled in the art that many modifications, both in materials and in methods, can be made without departing from the scope of the claimed embodiments. EXAMPLE 1 - UTROFIN UPREGULATION BY DPP-IV INHIBITORS IN VITRO

[086] C2C12 myoblast cells are seeded in well plates with growth medium (10% FBS and DMEM). After reaching 70% confluence, the cells are added to differentiation medium (2% HS and DMEM) and differentiated for seven days. Stock solutions are prepared for sitagliptin and other DPP-IV inhibitors, namely melogliptin, linagliptin, vildagliptin, and teneligliptin in DMSO. The cells are treated with a final stock solution concentration of 10 μM for 24 hours. RNA isolation is performed using the Qiagen assay kit and quantified using NanodropRT-PCR for Utrophin Upregulation.

[087] Figure 1 illustrates the fold change of utrophin at concentrations of 10 μM for Sitagliptin, Meloliptin, Linagliptin, Vildagliptin, and Teneligliptin. It is clear that all DPP-IV inhibitors are capable of increasing utrophin levels in myoblast cells. EXAMPLE 2 - COMPARISON OF UTROFIN POSITIVE REGULATION Petition 870250093128, dated 10 / 10 / 2025, page 62 / 171 27 / 30 By sitagliptin and ezutromide in vitro

[088] Using the same protocol as in Example 1, C2C12 myoblast cells are treated with sitagliptin for 24 hours. Ezuthromide is a known regulator of utrophin and is used as a positive control. RNA isolation and RT-PCR are performed to quantify the fold change in utrophin mRNA expression. Figure 2 shows the fold change in utrophin mRNA expression in C2C12 mouse skeletal muscle myoblasts at 10 µM sitagliptin compared to 10 µM ezuthromide. Sitagliptin exhibits superior upregulation of utrophin compared to ezuthromide. EXAMPLE 3 - IN VIVO STUDIES IN D2.MDX MOUSE MODELS

[089] Drug Administration and Efficacy Assessment Protocol:

[090] All functional experimental parameters are evaluated in wild-type mdx mice and in D2.mdx mice (D2.B10-DMD mdx / J mice acquired from Jackson Laboratories (Strain # 013141), Bar Harbor, Maine (ME), USA 04609.

[091] The test item, Sitagliptin 50 mg / kg, is administered orally (po) once daily (qd) at a dose volume of 10 ml / kg. Sitagliptin suspension in a formulation containing 0.1% Tween20 and 0.5% carboxymethylcellulose (CMC) is administered once daily for 28 days orally. Wild-type and mdx control groups received only the vehicle (0.5% carboxymethylcellulose (CMC) containing 0.1% Tween20). The body weight of the study animals is recorded before the study (pre-dose) and twice weekly / daily throughout the study. Animals are also monitored for clinical signs, mortality, and morbidity.

[092] Experimental procedure and efficacy assessment:

[093] D2.mdx and wild-type mice are trained for functional testing on a treadmill (Pan Lab, Harvard Instruments, USA) before recording their baseline performance (Day 0) on the treadmill for distance covered and functional parameters of time to exhaustion. D2.mdx mice are randomized into MDX-Control and MDX-Sitagliptin groups with Petition 870250093128, dated 10 / 10 / 2025, page 63 / 171 28 / 30 based on their body weights and their functional parameters on a treadmill.

[094] All three mice in the group (wild type, DMD-Control and DMD-Sitagliptin) underwent functional tests at week 0 (Baseline Day 0), week 2 (Day 14) and at the end of the study (week 4 or Day 28). Muscle function was assessed using grip strength testing with a grip strength meter (Orchid Scientific, Model No.: GSM02RS, India), suspension test, treadmill running and rotator bar test (Orchid Scientific, India) in response to Vehicle and Sitagliptin (50 mg / kg, po) treatments. Blood samples are collected for creatine kinase (CK) analysis 30 minutes after the treadmill function test on days 0, 14, and 28. Sitagliptin efficacy is assessed by comparing functional test parameters and serum CK levels of the treated group with those of the mdx control group compared to the baseline value of the wild-type group.

[095] Statistical analyses are performed using GraphPad Prism version 10 software which uses Two-Factor ANOVA (multiple comparisons method) followed by Tukey / Bonferroni t-test, where significance *** p < 0.001, ** p < 0.01 and * p < 0.05 vs DMD-Control (Treated Vehicle) are applied whenever applicable in the designs.

[096] Figure 3 illustrates the protocol adopted for in vivo studies in D2.mdx mouse models. The D2.mdx mouse is a superior DMD model that recapitulates several of the human characteristics of DMD myopathology, such as lower muscle weight in the hind limbs, fewer myofibers, increased fibrosis and fat accumulation, and muscle weakness compared to strains with this mutant allele in other genetic backgrounds. D2.mdx mice aged 6 to 7 weeks are selected for the 28-day in vivo study. Three cohorts of 10 animals each are selected - Group I comprising wild-type mice, Group II comprising D2.mdx control mice, Group III comprising D2.mdx mice treated with Sitagliptin (test item). Mice from all groups are subjected to training and randomization for 3 days (Baseline, Day -3), Petition 870250093128, dated 10 / 10 / 2025, p. 64 / 171 29 / 30 followed by 28 days of treatment (Days 0-28). Treadmill, grip strength, suspension, rotator bar, and creatine kinase tests are recorded on day 0, day 14, and day 28. Treadmill experiments are conducted on mouse treadmills (Pan Lab, Harvard Instruments, USA). The rotator bar test is used as a baseline to record overall improvement in muscle coordination.

[097] Figure 4 shows the results of the treadmill test in D2.mdx mice, where Figure 4A depicts the effect of Sitagliptin in terms of distance covered in 30 minutes and Figure 4B depicts the effect of Sitagliptin in terms of time to exhaustion, according to the modalities disclosed in this document. The results suggest that Sitagliptin provides significant and sustained improvement in distance covered and time to exhaustion over 28 days of treatment.

[098] Figures 5A and 5B show the effect of sitagliptin on normalized grip strength in D2.mdx mice pre- and post-treadmill, respectively, according to the modalities disclosed in this document. Sitagliptin-treated mice could grip as well as wild-type mice before being subjected to treadmill stress. Suspension tests also demonstrate that sitagliptin-treated mice perform comparably to wild-type mice, regardless of treadmill stress (Figures 6A and 6B). The latency to drop in a rotary bar test indicates that sitagliptin-treated mice exhibit sustained improvements in overall muscle coordination (Figure 7).

[099] Elevated serum creatine kinase (CK) levels in blood samples are indicative of muscle breakdown caused by muscular dystrophies. Serum creatine kinase levels are measured within 30 minutes after mice undergo treadmill testing. The pattern of creatine kinase changes in mdx control mice is consistent with published literature. Figure 8 shows that treatment with sitagliptin causes significant reductions in serum creatine kinase levels over 28 Petition 870250093128, dated 10 / 10 / 2025, page 65 / 171 Treatment every 30 days.

[100] Figure 9A-9F provides a summary of day 28 of distance covered, time to exhaustion, pre- and post-treadmill normalized grip strength, pre- and post-treadmill suspension test, tests in D2.mdx mouse models. Mice treated with sitagliptin show a robust improvement in all functional parameters compared to DMD control mice. The robust performance is indicative of an overall improvement in muscle function. These functional results suggest the potential utility of sitagliptin in the treatment of DMD.

[101] The preceding description of the specific modalities will reveal so completely the general nature of the modalities in the present document that others may readily modify and / or adapt, applying current knowledge, such specific modalities for various applications without departing from the generic concept and, therefore, such adaptations and modifications must and are intended to be understood within the meaning and range of equivalents of the modalities revealed. It should be understood that the phraseology or terminology employed in this document is for descriptive purposes and not for limitation. Therefore, although the modalities in the present document have been described in terms of modalities and examples, experts in the field will recognize that the modalities and examples revealed in the present document may be practiced with modifications within the scope of the modalities described in the present document. Petition 870250093128, dated 10 / 10 / 2025, p. 66 / 171

Claims

1 / 6 CLAIMS 1. A PHARMACEUTICALLY ACCEPTABLE COMPOUND OR SALT THEREOF characterized in being for the preparation of a medicament for the treatment or management or both of muscular dystrophy, wherein the compound is a DPP-IV inhibitor selected from a group consisting of Sitagliptin, Meloliptin, Linagliptin, Vildagliptin, Teneligliptin, Saxagliptin, Alogliptin, Anagliptin, Gemigliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, Retagliptin, Cofrogliptin, Fotagliptin, Prusogliptin and combinations thereof.

2. COMPOUND, according to claim 1, wherein the compound is characterized as being Sitagliptin.

3. COMPOUND, according to claim 1, wherein the compound is characterized by being sitagliptin phosphate monohydrate.

4. COMPOUND, according to claim 1, wherein the compound is characterized as being Meloliptin.

5. COMPOUND, according to claim 1, characterized in that the muscular dystrophy is selected from a group consisting of Duchenne muscular dystrophy, Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emery-Dreiffus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), Calpainopathis or LGMD2A, oculopharyngeal muscular dystrophy, DMD-associated dilated cardiomyopathy (CMD), Miyoshi myopathy type 1 (MMD1) and dysferlin-related limb-girdle muscular dystrophy R2 (LGMDR2).

6. COMPOUND, according to claim 1, wherein the compound is characterized by being administered in combination with at least one additional therapy selected from a group consisting of corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy and muscle strengthening therapy. Petition 870250093128, dated 10 / 10 / 2025, p. 67 / 171 2 / 6 7. COMPOUND, according to claim 6, characterized in that corticosteroid therapy comprises the administration of at least one corticosteroid selected from a group consisting of Prednisone, Prednisolone, Deflazacort, Vamorolone and combinations thereof.

8. COMPOUND, according to claim 6, characterized by the exon-skipping therapy comprising the administration of at least one agent selected from a group consisting of Eteplirsen, Golodirsen, ASO-based therapy and combinations thereof.

9. COMPOUND, according to claim 6, characterized by the epigenetic therapy comprising the administration of at least one agent selected from a group consisting of Givinostat, Pan-HDAC inhibitors, HDAC6 inhibitors and combinations thereof.

10. COMPOUND, according to claim 1, characterized in that the dosage of the compound is in the range of 10 to 250 mg / day, administered in a single or multiple dosing regimen.

11. COMPOUND, according to claim 1, characterized in that the compound is formulated for intravenous, intramuscular, inhalation, intradermal, cutaneous, subcutaneous, oral, transdermal, transmucosal, topical, nasal, vaginal, intrathecal, epidural, ocular or rectal administration.

12. COMPOSITION characterized by comprising the compound, as defined in claim 1, or its pharmaceutically acceptable salt, solvates or analogues thereof and, optionally, at least one pharmaceutically acceptable excipient.

13. COMPOSITION, according to claim 12, characterized in that the compound is a DPP-IV inhibitor selected from a group consisting of Sitagliptin, Meloliptin, Linagliptin, Vildagliptin, Teneligliptin, Saxagliptin, Alogliptin, Anagliptin, Gemigliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, Retagliptin, Cofrogliptin, Fotagliptin, Prusogliptin and combinations thereof.

14. COMPOSITION, according to claim 12, characterized by the compound being Sitagliptin.

15. COMPOSITION, according to claim 12, characterized in that the compound is sitagliptin phosphate monohydrate.

16. COMPOSITION, according to claim 12, characterized in that the pharmaceutically acceptable excipient is selected from a group consisting of mannitol, starch, xylitol, maltodextrin, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous dicalcium phosphate, glyceryl behenate, triethyl citrate, polyethylene glycol, croscarmellose sodium, stearic acid, talc, hydrogenated cottonseed oil, magnesium stearate, colloidal silicon dioxide, polysorbate, sodium lauryl sulfate, anhydrous calcium hydrogen phosphate, sodium stearyl fumarate, propyl gallate, poly(vinyl alcohol), macrogol 3350, titanium dioxide, red iron oxide and yellow iron oxide and mixtures thereof.

17. COMPOSITION, according to claim 12, wherein the composition is characterized by being administered in combination with at least one additional therapy selected from a group consisting of corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy and muscle strengthening therapy.

18. COMPOSITION, according to claim 17, characterized in that corticosteroid therapy comprises the administration of at least one corticosteroid selected from a group consisting of Prednisone, Prednisolone, Deflazacort, Vamorolone and combinations thereof.

19. COMPOSITION, according to claim 17, characterized by exon-skipping therapy comprising the administration of at least one agent selected from a group consisting of Eteplirsen, Golodirsen, ASO-based therapy and combinations thereof.

20. COMPOSITION, according to claim 17, characterized by the epigenetic therapy comprising the administration of at least one agent Petition 870250093128, dated 10 / 10 / 2025, page 69 / 171 4 / 6 selected from a group consisting of Givinostat, Pan-HDAC inhibitors, HDAC6 inhibitors and combinations thereof.

21. COMPOSITION, according to claim 12, characterized in that the dosage of the composition is in the range of 10 to 250 mg / day, administered in a single or multiple dosing regimen.

22. COMPOSITION, according to claim 12, wherein the composition is characterized by being formulated for intravenous, intramuscular, inhalation, intradermal, cutaneous, subcutaneous, oral, transdermal, transmucosal, topical, nasal, vaginal, intrathecal, epidural, ocular or rectal administration.

23. USE of the compound, as defined in claim 1, characterized by being for preparing a medicament for the treatment of muscular dystrophy.

24. USE, according to claim 23, characterized in that the compound is a DPP-IV inhibitor selected from a group consisting of Sitagliptin, Meloliptin, Linagliptin, Vildagliptin, Teneligliptin, Saxagliptin, Alogliptin, Anagliptin, Gemigliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, Retagliptin, Cofrogliptin, Fotagliptin, Prusogliptin and combinations thereof.

25. USE, according to claim 23, characterized in that the compound is Sitagliptin.

26. USE, according to claim 23, characterized in that the compound is sitagliptin phosphate monohydrate.

27. USE, according to claim 23, characterized in that the muscular dystrophy is selected from a group consisting of Duchenne muscular dystrophy, Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emery-Dreiffus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), Calpainopathis or LGMD2A, oculopharyngeal muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi myopathy type 1 (MMD1), and dysferlin-related limb-girdle muscular dystrophy R2 (LGMDR2). Petition 870250093128, dated 10 / 10 / 2025, p. 70 / 171 5 / 6 28. USE, according to claim 23, characterized in that the compound is administered in combination with at least one additional therapy selected from a group consisting of corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy.

29. USE, according to claim 28, characterized by corticosteroid therapy comprising the administration of at least one corticosteroid selected from a group consisting of Prednisone, Prednisolone, Deflazacort, Vamorolone and combinations thereof.

30. USE, according to claim 28, characterized by exon-skipping therapy comprising the administration of at least one agent selected from a group consisting of Eteplirsen, Golodirsen, ASO-based therapy and combinations thereof.

31. USE, according to claim 28, characterized by epigenetic therapy comprising the administration of at least one agent selected from a group consisting of Givinostat, Pan-HDAC inhibitors, HDAC6 inhibitors and combinations thereof.

32. USE, according to claim 23, characterized by the dosage of the compound being in the range of 10 to 250 mg / day, administered in a single or multiple dosing regimen.

33. USE, according to claim 23, characterized in that the compound is formulated for intravenous, intramuscular, inhalation, intradermal, subcutaneous, oral, transdermal, transmucosal or rectal administration.

34. USE of the compound, as defined in claim 1, characterized by being to prepare a medicament to positively regulate utrophin levels in muscle cells.

35. USE, according to claim 34, characterized in that the compound is a DPP-IV inhibitor selected from a group consisting of Sitagliptin, Meloliptin, Linagliptin, Vildagliptin, Teneligliptin, Saxagliptin, Alogliptin, Anagliptin, Gemigliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, Retagliptin, Cofrogliptin, Fotagliptin, Prusogliptin and combinations thereof.

36. USE, according to claim 34, characterized in that the compound is Sitagliptin.

37. USE, according to claim 34, characterized in that the compound is sitagliptin phosphate monohydrate.

38. USE, according to claim 34, characterized in that the compound is administered in combination with at least one additional therapy selected from a group consisting of corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy.

39. USE, according to claim 38, characterized by corticosteroid therapy comprising the administration of at least one corticosteroid selected from a group consisting of Prednisone, Prednisolone, Deflazacort, Vamorolone and combinations thereof.

40. USE, according to claim 38, characterized by exon-skipping therapy comprising the administration of at least one agent selected from a group consisting of Eteplirsen, Golodirsen, ASO-based therapy and combinations thereof.

41. USE, according to claim 38, characterized by epigenetic therapy comprising the administration of at least one agent selected from a group consisting of Givinostat, Pan-HDAC inhibitors, HDAC6 inhibitors and combinations thereof.

42. USE, according to claim 34, characterized by the dosage of the compound being in the range of 10 to 250 mg / day, administered in a single or multiple dosing regimen.

43. USE, according to claim 34, characterized by the compound being formulated for intravenous, intramuscular, inhalation, intradermal, subcutaneous, oral, transdermal, transmucosal or rectal administration. Petition 870250093128, dated 10 / 10 / 2025, pp. 72 / 171

Images