Mebeverine for its use in the treatment of autoimmune diseases

Abstract

The present invention relates to the use of compound I, namely mebeverine and its derivatives, for the prevention and / or treatment of autoimmune diseases, particularly systemic lupus erythematosus (SLE), in a subject in need. Specifically, the invention relates to the prevention and / or treatment of organ damage, flare-ups, exacerbation or worsening of the disease, or any adverse health consequences of SLE in a subject with systemic lupus erythematosus (SLE).

Description

Title of the invention: Mebeverine for its use in the treatment of autoimmune diseases technical field

[0001] The present invention relates to the use of mebeverine and its derivatives for the prevention and / or treatment of autoimmune diseases, particularly systemic lupus erythematosus (SLE), in a subject in need. In particular, the invention relates to the prevention and / or treatment of organ damage and flare-ups, exacerbation or worsening of the disease, or any adverse health consequences of SLE in a subject with systemic lupus erythematosus (SLE). State of the art

[0002] Autoimmune diseases constitute a heterogeneous group of pathologies characterized by an abnormal immune response directed against the body's own tissues. These diseases affect approximately 5 to 8% of the world's population and can affect virtually all organs and systems of the human body. Among the best-known autoimmune diseases are rheumatoid arthritis, type 1 diabetes, multiple sclerosis, Crohn's disease, and systemic lupus erythematosus (SLE).

[0003] Systemic lupus erythematosus (SLE) is a serious autoimmune disease affecting 2 million patients worldwide, with an annual incidence of approximately 3 per 100,000 in Europe and North America. The disease primarily affects young women, particularly those of childbearing age, with a typical onset at age 30 and a female-to-male ratio of 10:1. Although genetic and environmental risk factors have been reported to play a role, the etiology of SLE is undetermined. SLE is characterized by multiple organ lesions and episodic flares that exacerbate the disease and increase the risk of serious comorbidities, including renal failure, heart disease, lung disease, blood disorders, neurological disorders, and psychiatric illnesses. Some aspects of these conditions are related to both the disease itself and its aggressive treatments.

[0004] However, there is currently no curative treatment for SLE. Current therapeutic solutions rely primarily on treatments aimed at limiting exacerbations of the disease, such as the long-term use of hydroxychloroquine (HCQ), a synthetic antimalarial drug, as a primary treatment. Corticosteroids aim to limit inflammatory manifestations. These medications are administered either at high doses to manage acute flares or at lower doses to reduce disease activity. Some immunosuppressants, such as methotrexate, azathioprine, mecophenolic acid, and cyclophosphamide, are used as adjunctive, supplementary, or secondary replacement therapies in patients with more severe disease. Other immunosuppressants used in autoimmune diseases are also used, off-label, when patients do not respond to immunosuppressants specifically approved for SLE. Belimumab, a human monoclonal antibody that specifically targets the BLyS protein, has also been approved for severe SLE, including cases with chronic kidney disease.Finally, multiple medications are prescribed to treat the complications of the disease, whether organic and / or psychiatric, because lupus can cause damage to virtually all organs and systems in humans.

[0005] As a result, despite these existing treatments, SLE remains highly debilitating, with severe relapses and organ damage. More than 5% of mildly, moderately, or severely severe cases of SLE require hospitalization each year for relapses or morbid consequences of the disease, with this figure increasing to 10% to 20% and more in more severe cases, including those with chronic organ failure, not counting hospitalizations required for the administration of certain treatments. Nearly 40% of patients with SLE may face end-stage renal failure during their lifetime, requiring dialysis or transplantation, which underscores the ongoing need for advanced therapeutic options. Many others suffer from chronic heart failure, pulmonary insufficiency, extreme fatigue, or other systemic failures.

[0006] Thus, SLE remains to this day a very debilitating and serious condition, for which there is a need for new therapeutic solutions. This is the object of the present invention. Summary of the invention

[0007] To address this need, the invention proposes a family of compounds, namely mebeverine and its known derivatives, for which the inventors have, surprisingly, demonstrated efficacy in the prevention and / or treatment of systemic lupus erythematosus (SLE) in a subject in need. In particular, the present invention proposes mebeverine and its known derivatives for the prevention and / or treatment of organic lesions and / or SLE flares and / or exacerbations of SLE and / or worsening of the disease or any adverse health consequences of SLE in a subject with SLE.

[0008] Thus, the invention relates to a compound of formula I or a pharmaceutically acceptable salt and / or solvate of such a compound, for its use in the prevention and / or treatment of an autoimmune disease, in a subject in need.

[0009] [Formula I]

[0010] According to a preferred object of the invention, the compound of formula I, namely mebeverine and one of its known derivatives, is in the form of a salt.

[0011] When the compound according to the invention is in the form of a salt, it is very preferably in the form of a hydrochloride salt.

[0012] According to a variant of the present invention, the compound of formula I, namely mebeverine and one of its known derivatives, is in solvated form.

[0013] In the context of the present invention, the compound of formula I is particularly suitable for preventing and / or treating systemic lupus erythematosus (SLE). More preferably, the compound of formula I is intended for use in the secondary prevention and / or treatment of SLE. When said compound according to the invention is intended for use in the secondary prevention of SLE, it aims to prevent an exacerbation of the disease.

[0014] According to another object of the invention, the compound of formula I is advantageously used to prevent and / or treat organic lesions and / or flares of SLE and / or exacerbation of SLE and / or worsening of the disease or any adverse health consequence of SLE, in a subject suffering from SLE.

[0015] Most preferably, the invention aims at said compound of formula I for its use in LED, in particular for subjects with mildly severe, moderate, moderately severe or severe LED.

[0016] According to another aspect, the invention also relates to a pharmaceutical composition comprising at least one compound according to any one of the embodiments and at least one pharmaceutically acceptable excipient, for its use in the prevention and / or treatment of an autoimmune disease, preferably in the prevention and / or treatment of systemic lupus erythematosus (SLE).

[0017] According to a preferred object, the pharmaceutical composition further comprises another active ingredient selected from the group consisting of an antimalarial agent, a corticosteroid, an immunosuppressant and a non-steroidal anti-inflammatory drug (NSAID).

[0018] When the composition according to the invention further comprises an antimalarial agent, this is preferably chosen from the group consisting of hydroxychloroquine, chloroquine and their derivatives.

[0019] When the composition according to the invention further comprises a corticosteroid, this is preferably a corticosteroid of ATC Class H02.

[0020] Most preferably, the corticosteroid is chosen from the group consisting of prednisone, dexamethasone, triamcinolone, betamethasone, beclomethasone, flunisolide and fluticasone.

[0021] When the composition according to the invention further comprises an immunosuppressant, this is preferably an immunosuppressant of the ATC L04 class.

[0022] According to another preferred object, the immunosuppressant is chosen from the group consisting of cyclophosphamide, methotrexate, mycophenolic acid, azathioprine and belimumab.

[0023] In the context of the invention, the pharmaceutical composition may be in any form suitable for oral or injectable administration.

[0024] Thus, the present pharmaceutical composition is preferably in the form of a tablet, a capsule, a liquid dose, a gel or a powder.

[0025] The scope of the present invention is not limited by the specific embodiments described herein. These embodiments are illustrative only. Compounds, including known derivatives of the compound according to the invention, pharmaceutical compositions, and any equivalents, fall within the scope of the present invention as described herein.

[0026] Other features and advantages will become apparent from the detailed description of the invention, the examples and figures that will follow. Brief description of the Figures

[0027] [Fig.1] represents the selection of patients for the study in the form of a “Flowchart”, namely a flowchart of patient selection in the MELUSINE study.

[0028] [Fig.2] presents the results of the main analysis and stratified analyses in the form of a "Forest Plot". Detailed description of the invention

[0029] Definition

[0030] In the context of the present invention, the term "pharmaceutically acceptable" or "physiologically acceptable" means what is useful for the preparation of a pharmaceutical composition and what is generally safe, compatible, stable, non Irritant, non-allergic and non-toxic, for pharmaceutical use with a reasonable benefit / risk ratio.

[0031] For the purposes of the invention, "pharmaceutically acceptable salt and / or solvate" means a salt and / or solvate of a pharmaceutically acceptable compound, as defined above, and which has the pharmacological activity of the corresponding compound.

[0032] Pharmaceutically acceptable salts include, in particular, salts prepared from pharmaceutically acceptable non-toxic acids, such as hydrochloric, hydrobromic, phosphoric, and sulfuric acids. The most preferred salt is the hydrochloride salt (mebeverine hydrochloride).

[0033] Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. By way of example, solvates due to the presence of water (these solvates are also called hydrates) or ethanol may be cited.

[0034] By "prevention" or "prevent" in the sense of the invention, we mean the reduction to a lesser degree of the risk or the probability of occurrence of a given phenomenon, that is to say, in the context of the present invention, the partial or complete prevention or at least a delay of the appearance of organic lesions, flare-ups, exacerbation, aggravation of the disease or any adverse health consequence of SLE in a subject, or the prevention of the aggravation of the severity of the disease in particular of the symptoms and clinical signs characterizing the different clinical stages of SLE.

[0035] For the purposes of this invention, "treatment" means a reduction in disease progression, stabilization, reversal or regression, or even an interruption or inhibition of the progression of an autoimmune disease, particularly SLE. Specifically, in the context of the present invention, it means the production of a desired pharmacological and / or physiological effect on a subject. The treatment may be therapeutic in terms of: preventing the onset of organic lesions, disease flares, exacerbation or worsening of the disease, or any adverse health consequences of SLE, in a subject suffering from SLE.

[0036] For the purposes of this invention, "subject" or "patient" refers to a human subject. Thus, the present invention is intended for human pharmaceutical uses.

[0037] By "therapeutically effective quantity" within the meaning of the invention, is meant the administration of a quantity of a compound according to the present invention, namely the compound of formula I, namely mebeverine, of a known derivative of mebeverine and / or of one of its salts and / or of one of its solvates, enabling a desired therapeutic response to be obtained, for example to prevent and / or treat SLE, including its organic lesions and / or flare-ups, exacerbation or worsening of the disease, or any adverse health consequences of SLE in a subject with SLE. It is understood that the specific therapeutically effective amount will vary depending on a multitude of factors such as the particular condition being treated, the severity of the condition, the subject's physical state and clinical history, the duration of treatment, the nature of any concomitant treatment, the specific formulations used, and the composition structure. As an example, the therapeutically effective amount may be between 0.01 and 100 mg / kg of the subject's body weight, for example 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 mg / kg of body weight, and values ​​in between.

[0038] The invention described herein may include one or more ranges of values, for example, the administered quantity. A range of values ​​includes all values ​​within the range, including the values ​​defining the range, and values ​​adjacent to the range that lead to the same or substantially the same result as the values ​​immediately adjacent to the value defining the range boundary. In this description, unless the context otherwise requires, the word "includes" or variants such as "comprises" or "comprising" shall be interpreted as implying the inclusion of an integer or group of integers, but not the exclusion of another integer or group of integers.

[0039] Compound according to the invention

[0040] Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a poorly understood inflammatory cascade that contributes to its pathogenesis. Despite advances in therapeutic interventions, the specific triggers of inflammation and the autoimmune response in SLE remain largely enigmatic. The complexity of the pathological process, marked by an aberrant immune response against the body's own tissues, leads to a diverse range of clinical manifestations and an unpredictable disease course.

[0041] Now, the inventors of the present invention have surprisingly discovered that the administration of an agent used as an antispasmodic within the family of compounds comprising the compound of formula I, namely mebeverine, as well as its derivatives, makes it possible to prevent and / or treat autoimmune diseases, very preferentially systemic lupus erythematosus (SLE).

[0042] "Mebeverine" is well known for its pharmacological activity as an antispasmodic agent and designates compounds of formula I: 3,4-dimethoxybenzoic acid 4-(ethyl(2-(4-methoxyphenyl)-l-methylethyl)amino)butyl ester, its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or pharmaceutically acceptable polymorphs.

[0043] Thus, the invention relates to a compound of formula I, one of its derivatives, its salts and / or pharmaceutically acceptable solvates of such a compound, for its use in the prevention and / or treatment of an autoimmune disease, in a subject in need.

[0044] [Formula I]

[0045] According to a preferred object, the present invention is not limited to the compound of formula I alone, but also to its known derivatives. Advantageously, the mebeverine derivatives are chosen from the group consisting of mebeverine hydrochloride, mebeverine sulfate, polyethylene glycol-modified mebeverine (PEG-mebeverine), mebeverine esters, such as mebeverine acetate, mebeverine propionate, or mebeverine butyrate.

[0046] According to another object, the invention also relates to the salts of the compound according to the invention, namely mebeverine, said salts may be any known salts of mebeverine.

[0047] Indeed, the compounds of formula I of the invention are useful in the form of free base or acid addition salts. Acid addition salts are preferably pharmaceutically acceptable non-toxic addition salts with suitable acids, such as inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric and phosphoric acids, or organic acids, such as organic carboxylic acids, for example glycolic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, etc., for example glycolic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, salicylic, o-acetoxybenzoic, nicotinic or isonicotinic acids, or organic sulfonic acids, for example methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, toluene-p-sulfonic acid or naphthalene-2-sulfonic acid.

[0048] Most preferably, the mebeverine salts are chosen from the group consisting of mebeverine hydrochloride, mebeverine sulfate, mebeverine hydrobromide, mebeverine phosphate, mebeverine citrate, mebeverine tartrate, mebeverine maleate, mebeverine fumarate, mebeverine succinate, mebeverine oxalate, mebeverine benzoate, mebeverine acetate, mebeverine lactate, mebeverine gluconate and mebeverine salicylate.

[0049] These salts can be chosen to improve the solubility, stability, bioavailability, or formulation properties of the compound according to the present invention. The choice of a particular salt falls within the knowledge of a person skilled in the art and depends in particular on factors such as the intended route of administration, the desired physicochemical properties, and manufacturing and storage considerations.

[0050] Thus, according to a preferred object of the invention, the compound of formula I, namely mebeverine and one of its known derivatives, is in the form of a salt.

[0051] When the compound according to the invention is in the form of a salt, it is very preferably in the form of a hydrochloride salt.

[0052] According to another object of the present invention, the compound of formula I, namely mebeverine and one of its known derivatives, is in solvated form.

[0053] Preferably, mebeverine solvates are chosen from the group consisting of mebeverine hydrate (aqueous solvate), mebeverine ethanoate, mebeverine methanolate, mebeverine isopropanolate, mebeverine acetonide, mebeverine dioxanate, mebeverine tetrahydrofuranate, mebeverine solvated dimethylformamide (DMF), mebeverine solvated dimethyl sulfoxide (DMSO), and mebeverine solvated acetonitrile.

[0054] These solvates are formed when solvent molecules are incorporated into the crystal structure of mebeverine. The formation of solvates can affect the physicochemical properties of the compound, such as solubility, stability, and bioavailability. Consequently, solvates can offer advantages in terms of pharmaceutical formulation or therapeutic performance.

[0055] The compound according to the invention and its known derivatives contain at least one asymmetric carbon atom. Thus, the present invention also includes the use of isolated optical isomers and / or mixtures of these isomers.

[0056] Preferably, the preferred therapeutically effective amount of a compound of formula I, a known derivative of mebeverine and / or a salt and / or a solvate thereof, is between 0.01 and 100 mg / kg of the subject's body weight, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 mg / kg of body weight body mass index (BMI), and values ​​between those listed. In a preferred embodiment, it is used in an amount of approximately 5-25 mg / kg. The dose may vary from 100 to 600 mg / day in divided doses, for example 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, 400 mg, 500 mg.

[0057] The exact quantity of a compound of formula I, of a known derivative of mebeverine, and / or of one of its salts, and / or of one of its solvates in the composition will of course depend on the route of administration, the nature of the stage of SLE or of another complication of the SLE disease, the therapeutically effective amount of mebeverine required, and the general nature and health status of the subject to whom the composition is administered.

[0058] Preferably, the concentration of compound I, a known derivative of mebeverine, and / or one of its salts, and / or one of its solvates in the composition will be sufficient (qs) to deliver a therapeutically effective dose to the target cells. This therapy may be directed towards the treatment or prevention of organ damage or relapses, exacerbation or worsening of the disease, or any adverse health consequence of SLE in a subject with SLE. Preferably, the therapeutically effective dose is intended for the treatment or prevention of organ damage or relapses, exacerbation or worsening of the disease, or any adverse health consequence of SLE in a subject with mild, moderate, moderately severe, or severe SLE.

[0059] Composition according to the invention

[0060] The present invention also relates to a pharmaceutical composition comprising at least one compound according to the invention of formula I as described above and at least one pharmaceutically acceptable excipient, for use in the prevention and / or treatment of an autoimmune disease, preferably SLE.

[0061] The pharmaceutical compositions according to the invention can be formulated, in particular, for topical administration, oral administration, or injection, especially by oral, topical, parenteral, transdermal, transmucosal, intranasal, rectal, or vaginal routes, said compositions being intended for human use. The pharmaceutical composition can be administered orally by means of tablets, capsules, liquid doses, gels, or powders.

[0062] By way of example, when a solid composition is prepared in tablet form, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, acacia gum, and others. The tablets may be coated with sucrose or other suitable materials, or they may be treated, according to the knowledge of those skilled in the art, to have prolonged or delayed activity and to continuously release a predetermined amount of the active ingredient.

[0063] A preparation in gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

[0064] The pharmaceutical composition administered by injection is preferably injected in liquid form. Thus, for administration by injection, aqueous suspensions, isotonic saline solutions, or sterile and injectable solutions that contain pharmacologically compatible dispersing and / or wetting agents.

[0065] The pharmaceutical compositions according to the invention can also be administered topically by means of a cream, a gel, a stick or a serum.

[0066] The active ingredient can be administered in unit dose forms, mixed with standard pharmaceutical carriers, to humans.

[0067] The invention also proposes a pharmaceutical composition for the treatment of the prevention of organic lesions and flare-ups, exacerbation or aggravation of the disease or any adverse health consequence of SLE in a subject with SLE, the composition comprising a therapeutically effective amount of a compound of formula I, a known derivative of mebeverine, and / or a salt, and / or a solvate thereof and one or more pharmaceutically acceptable additives, excipients, carriers and / or diluents.

[0068] Preferably, said composition according to the invention comprises 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg of a compound of formula (1), a known derivative of mebeverine, and / or one of its salts, and / or one of its solvates. In a preferred embodiment, it is used in an amount of approximately 5–25 mg / kg. The dose can vary from 100 to 600 mg / day in divided doses, for example, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, 400 mg, 500 mg.

[0069] The composition of the present invention, comprising a compound of formula I, a known derivative of mebeverine, and / or a salt and / or a solvate thereof, is preferably suitable for administration to the subject who requires it more than once a day, once a day, or less frequently. For example, if the composition is suitable for oral administration, it is preferably administered once a day. However, the composition may be administered more frequently (for example, two or three times a day) or less frequently (for example, every two days, every three days, once a week). Furthermore, if the composition comprising a compound of formula I, a known derivative of mebeverine, and / or one of its salts, and / or one of its solvates, is in the form of an injectable formulation, it is preferable that the composition be suitable for administration once a week or once a month.

[0070] The additives, excipients, carriers and diluents to be used in the compositions of the present invention include, but are not limited to: water, saline solution, ethanol, dextrose, glycerol, glycerol and polyhydric alcohols, milk proteins, vitamins, animal and vegetable oils, polyethylene glycols, lactose, dextrose, sucrose, sorbitol, mannitol and other sugars, starches, the acacia gum, calcium phosphates, alginate, tragacanth gum, gelatin, calcium silicate, cellulose and its derivatives such as microcrystalline cellulose and methylcellulose, polyvinylpyrrolidone, water syrup, methylhydroxybenzoates and propylhydroxybenzoates, talc, magnesium carbonate, titanium dioxide, magnesium stearate and mineral oil or combinations thereof.

[0071] The composition may also include lubricating agents, dispersing media, pH buffers, wetting agents, emulsifying and suspending agents, solvents, preservatives, sweetening or flavoring agents, antifoaming agents, polymers, antioxidants, chelating agents, viscomodulators, tonics, flavorings, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, absorption promoters, and mixtures of these products. Preservatives include antimicrobial, antibacterial, and antifungal agents, antioxidants, chelating agents, and inert gases. The specific selection of components that may be included in the compositions described herein generally depends on the type of preparation.

[0072] In preferred embodiments, the composition is formulated to allow the localization and retention of the compound of formula I, a known derivative of mebeverine, and / or one of its salts, and / or one of its solvates in the area required to produce the desired therapeutic effect, without significantly interfering with the efficacy of the compound. It is therefore understood that the therapeutically effective composition can be formulated differently depending on the area to be treated and the manner in which the composition is to be administered.

[0073] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in oral, parenteral, sublingual, buccal, rectal, intravaginal, or inhaled compositions may include: ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems such as polyethylene glycol 1000 alpha-tocopherol succinate, or other similar polymeric matrices or delivery systems such as nanoparticles; serum proteins such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated fatty acids of vegetable origin; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate;polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethylcellulose; polyacrylates; polyethylene-polyoxypropylene block polymers; and wool grease.

[0074] The composition of the present invention, comprising a compound of formula I, a known derivative of mebeverine, and / or a salt, and / or a solvate thereof, may also contain one or more additives, provided that they do not impair the therapeutic effect of the compound of formula I, a known derivative of mebeverine, and / or a salt, and / or a solvate thereof. In one instance, the additive is a colorant. In other embodiments, the additive is a preservative such as a mold inhibitor or an antioxidant, a fragrance, or a stabilizer. Additional additives may also be agents that make the composition an emulsion, a microemulsion, or a nanoemulsion.

[0075] In a preferred embodiment, the compound of formula I, a known derivative of mebeverine, and / or one of its salts and / or one of its solvates, can therefore be administered orally. Mebeverine can thus be in the form of a tablet, a capsule, a gel, or a liquid composition. If the compound of formula I, a known derivative of mebeverine, and / or one of its salts, and / or one of its solvates, is in the form of a tablet, it may further comprise fillers such as: lactose (milk sugar), microcrystalline cellulose, corn starch, sugars (including sucrose, mannitol, sorbitol, fructose, and dextrose), whey, and yeast; and / or binders such as: povidone, xanthan gum, and carbopol.Additional ingredients may include: disintegrants such as crospovidone, croscarmellose sodium and gellan gum; coatings such as shellac; lubricants such as magnesium stearate, stearic acid, sodium stearyl fumarate and hydrogenated vegetable oil; colorants such as titanium dioxide and iron oxides; flavorings (in chewable tablets); and plasticizers.

[0076] Preferably, the compound of formula I, a known derivative of mebeverine, and / or one of its salts, and / or one of its solvates is administered in the form of a tablet comprising mebeverine, magnesium stearate, lactose, corn starch and povidone. Preferably, the tablet, capsule, gel or liquid composition comprises between 0.01 and 100 mg / kg of the subject's body weight, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 mg / kg of body weight, and values ​​in between.

[0077] The compound of formula I, a known derivative of mebeverine, and / or one of its salts, and / or one of its solvates can also be administered sublingually, buccally, rectally or intravaginally, for example by administration of a tablet, capsule, gel, powder or spray.

[0078] In another embodiment, the compound of formula I, a known derivative of mebeverine, and / or one of its salts, and / or one of its solvates, is administered by The parenteral route is preferably by injection, for example, subcutaneously or intramuscularly. However, administration may also be by intra-arterial or intraperitoneal route for the treatment or prevention of lupus flares in a patient. The composition may be presented as a sterile injectable preparation, for example, as a sterile injectable suspension for the treatment or prevention of lupus flares in a patient. This suspension may be formulated according to techniques known in the art using appropriate dispersing agents, surfactants, and suspending agents (e.g., Tween 80). The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent acceptable to parents (e.g., 1,2-propanediol).Acceptable vehicles and solvents may include mannitol, water, Ringer's solution, and isotonic saline solution with buffer. In addition, sterile fixed oils may be used as solvents or suspension media. For this purpose, any bland fixed oil may be used, including mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, and pharmaceutically acceptable natural oils, such as polyoxyethylated olive oil or castor oil, may also be used in the preparation of injectables. Preferably, the injectable composition comprises between 0.01 and 100 mg / kg of the subject's body weight, for example, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 mg / kg of body weight, and values ​​in between.

[0079] The pharmaceutical compositions according to the invention may further comprise at least one other active ingredient selected from the group consisting of an antimalarial agent, a corticosteroid, an immunosuppressant and a non-steroidal anti-inflammatory drug (NSAID).

[0080] The present invention therefore also relates to a pharmaceutical composition comprising: - (i) at least one compound of formula I as described above, and - (ii) at least one other active ingredient, chosen from the group consisting of an antimalarial agent, a corticosteroid, an immunosuppressant and a non-steroidal anti-inflammatory drug (NSAID) as a combination product for simultaneous, separate or sequential use.

[0081] When the active ingredient is an antimalarial agent, it is selected from hydroxychloroquine, chloroquine and their derivatives.

[0082] When the active ingredient is a corticosteroid, said corticosteroid is preferably a corticosteroid of ATC Class H02.

[0083] Most preferably, the corticosteroid is chosen from the group consisting of prednisone, prednisolone, methylprednisolone, dexamethasone, hydrocortisone, cortisone, triamcinolone, betamethasone, deflazacort, fludrocortisone, budesonide, cloprednol, cortivazol, fluocortolone, and paramethasone.

[0084] These corticosteroids can be used at different stages of the disease and depending on the severity of the symptoms. The choice of the specific corticosteroid often depends on factors such as the required potency, the desired duration of action, and the side effect profile; a person skilled in the art is thus able to define the corticosteroid according to the desired effect.

[0085] In a particularly preferential manner, the corticosteroid is chosen from the group consisting of prednisone, dexamethasone, triamcinolone, betamethasone, beclomethasone, flunisolide and fluticasone.

[0086] Prednisone is notably used to control acute flare-ups and severe manifestations of the disease due to its powerful anti-inflammatory effects.

[0087] When the active ingredient is an immunosuppressant, said immunosuppressant is preferably an immunosuppressant of ATC Class L04.

[0088] According to another preferred object, the immunosuppressant is chosen from the group consisting of cyclophosphamide, methotrexate, azathioprine, mycophenolate mofetil, tacrolimus, ciclosporin, belimumab, rituximab, abatacept, anifrolumab, voclosporin, leflunomide, sirolimus (rapamycin), ustekinumab, tofacitinib, baricitinib, ixekizumab, secukinumab, certolizumab pegol and fingolimod.

[0089] These immunosuppressants can be used alone or in combination with other treatments, depending on the severity of the disease, the organs affected, and the individual patient's response. The choice of treatment is thus tailored to each case, taking into account the benefit-risk ratio for the patient.

[0090] In a particularly preferential manner, the immunosuppressant is chosen from the group consisting of cyclophosphamide, methotrexate, mycophenolic acid, azathioprine and belimumab.

[0091] Finally, the second active ingredient may also be a biological product, such as Belimumab (Benlysta®), a monoclonal antibody targeting the B-cell stimulator (BLyS), particularly for subjects suffering from active SLE and positive for autoantibodies.

[0092] Each of these agents is thus selected according to the individual profile of the patient, the activity of the disease and the involvement of organs, thus reflecting the personalized approach necessary for the management of the heterogeneous manifestations of SLE.

[0093] Use

[0094] The invention therefore proposes the compound according to the invention or the composition comprising it to prevent and / or treat an autoimmune disease, preferably systemic lupus erythematosus (SLE).

[0095] Advantageously, the compound according to the invention or the composition comprising it is particularly suitable for preventing organic lesions and flare-ups, exacerbation or aggravation of the disease or any adverse health consequence of SLE in a subject with SLE, preferably at a mildly severe, moderate, moderately severe or severe stage.

[0096] Thus, very preferentially, LED is a mildly severe, moderate, moderately severe or severe lupus.

[0097] Even more preferably, said compound according to the invention or composition according to the invention are adapted for use in the prevention and / or treatment of LED.

[0098] Indeed, SLE is a complex pathology, defined by a plurality of clinical stages defined according to clinical symptoms. The clinical stages of systemic lupus erythematosus (SLE) can thus be described as follows.

[0099] Mildly severe lupus has the following characteristics: - Minor skin lesions - Mild arthritis - Moderate fatigue - Little or no damage to internal organs

[0100] Moderate lupus has the following characteristics: - More extensive skin lesions - More pronounced arthritis - Significant fatigue - Onset of damage to internal organs (kidneys, heart, lungs) - Mild to moderate anemia

[0101] Moderately severe lupus has the following characteristics: - Significant skin lesions - Debilitating arthritis - Severe fatigue - Moderate damage to internal organs - More pronounced anemia - Possible thrombocytopenia

[0102] Severe lupus has the following characteristics: - Severe skin damage - Severe arthritis - Extreme fatigue - Severe involvement of one or more internal organs (lupus nephritis, pericarditis, pleurisy) - Severe anemia - Marked thrombocytopenia - Possible neurological manifestations

[0103] Critical or fulminant lupus has the following characteristics: - Severe multi-organ involvement - Life-threatening situation - Need for intensive care

[0104] Lupus is therefore a fluctuating disease, with periods of flare-ups and remissions. Severity can vary over time in the same patient. The assessment of lupus severity takes into account not only clinical manifestations, but also the results of laboratory and imaging tests.

[0105] Preferably, the subject has lupus at a mildly severe, moderate, moderately severe or severe clinical stage.

[0106] Advantageously, the compound of formula I also prevents damage to several organs and flare-ups, exacerbation or worsening of the disease or any adverse health consequences of SLE in patients with SLE.

[0107] Preferably, the subject to whom the regimen is administered has lupus at a mildly severe, moderate, moderately severe or severe clinical stage and its treatments.

[0108] Methods

[0109] According to a final aspect, the present invention also relates to a method of prevention / treatment of systemic lupus erythematosus (SLE) in a subject who needs it, comprising administering to the subject a therapeutically effective amount of a compound of formula I according to the invention or of a pharmaceutically acceptable salt and / or solvate thereof.

[0110] Preferably, the method includes the treatment or prevention of morbid manifestations of SLE, even more preferably the prevention or treatment of organic lesions and / or flare-ups, exacerbation or aggravation of the disease or any adverse health consequences of SLE associated with lupus erythematosus.

[0111] The present invention therefore also relates to a method of treatment and / or prevention in a subject suffering from SLE, comprising the administration of a dose of 100 mg or 150 mg or 200 mg or 250 mg or 300 mg or 350 mg or 400 mg of a compound of formula (I), of a known derivative of mebeverine, and / or of one of its salts and / or of one of its solvates.

[0112] In a preferred embodiment, it is used in an amount of approximately 5-25 mg / kg. The dose can vary from 100 to 600 mg / day in divided doses, for example 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg.

[0113] Preferably, the present method is intended to prevent serious consequences, including organ damage and flare-ups, of exacerbation or worsening of the disease or any adverse health consequences of SLE in a subject with systemic lupus erythematosus, comprising administering a dose of 100 mg, 150 mg or 200 mg of a compound of formula I, of a known derivative of mebeverine, and / or of one of its salts and / or solvates once or twice daily.

[0114] Preferably, the treatment method of the present invention results in the treatment or prevention of one or more of the following events: a. organ damage: (i) renal disorders: nephritis, interstitial nephritis, glomerulonephritis, renal failure; (ii) cardiac disorders: myocarditis, pericarditis, endocarditis; (iii) pulmonary disorders: interstitial pneumonia, acute pulmonary failure, pleural effusion related to SLE; (iv) hematological disorders: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, hemorrhagic event on circulating anticoagulants; (v) neurological or psychiatric disorders; (vi) acute thromboembolic event such as: coronary syndrome, myocardial infarction, unstable angina, cardiac arrest; stroke (ischemic or hemorrhagic), transient ischemic attack; pulmonary embolism, deep vein thrombosis, arterial thrombosis, portal vein thrombosis; b. flares or exacerbations of multi-systemic LED. c. Worsening of the disease through the development of a more severe clinical stage.

[0115] The invention is now illustrated by non-limiting examples of compositions according to the invention and by results.

[0116] Examples - Study of the effectiveness of the compound according to the invention in the prevention and / or treatment of LED

[0117] A comparative efficacy study was conducted to evaluate whether mebeverine or its derivatives (compounds according to the invention) reduce the risk of organ damage or flares, exacerbations, or worsening of the disease in patients with objectively diagnosed SLE. The name of the study is MELUSINE (MEbeverine and LUPUS INjuriEs).

[0118] 1. Methods

[0119] The SLE cohort study was registered and received ethical approval from CESREES (Committee for the Evaluation of Ethics of Health Research Projects) and CNIL (National Commission for Information Technology and Freedoms) on January 14, 2021.

[0120] The study was conducted within the national cohort of patients with SLE registered with the French national health service between January 1, 2010, and December 31, 2020, for at least one year. Within this cohort, patients who received mebeverine treatment were compared to matched SLE patients who did not use mebeverine.

[0121] 1.1 Eligibility

[0122] Patients with chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) were excluded from the study to minimize confounding factors, as these diseases are associated with both mebeverine use and the occurrence of certain study outcomes. Patients were also excluded if they had a history of chronic organ failure (such as chronic renal failure, dialysis, kidney transplantation, lung transplantation, heart transplantation, chronic passive liver congestion, or pulmonary arterial hypertension) at the start of mebeverine exposure, due to the potential for confusion arising from the treatment of these conditions, which are considered critical states of the disease.

[0123] 1.2 Use of mebeverine

[0124] Patients were considered to be starting active treatment each time they obtained a mebeverine-based product dispensed by their pharmacist. This dispensing is recorded in the computerized registers kept by the national health insurance, which covers virtually all patients in the country.

[0125] Patients were able to undergo several mebeverine treatment sequences, provided that there was an interval of at least 90 days between the end of use of the drug in one given sequence and the start of use of the drug in the next sequence.

[0126] 1.3 Controls and matching

[0127] Patients treated with mebeverine were matched for sex and age (±1 year at the time of exposure, considered the "index date" in both groups) to non-mebeverine-using patients. To make the groups comparable in terms of co-administered SLE treatments, they were matched for use (or non-use), on the calendar day or in the 90 days preceding the index date, of one of the usual SLE treatments (HCQ, corticosteroids, immunosuppressants), each of these drug categories being matched individually.

[0128] In addition, a match was made on the use (or not), also on that date, of at least one NSAID, as well as on the use (or not) of a gastro-drug intestinal of the ATC class A03 (except mebeverine), or of the ATC classes A02 or A06. Finally, to take into account cardiac risk factors, a matching was carried out according to the use (or not) of a cardiovascular or antidiabetic treatment (drugs of the ATC classes C and A10 respectively).

[0129] Up to 10 mebeverine-unexposed controls were selected for each mebeverine treatment; high-density propensity scores were used for prioritization when too many controls were eligible. When a mebeverine user had multiple sequences of product use, an eligible control was matched for each sequence.

[0130] In a sensitivity analysis, patients who had previously used mebeverine were admitted as controls if they had not used it for at least 90 days.

[0131] 1.4 Outcomes

[0132] The primary outcome of the study was a composite outcome of the occurrence of one of the following events: (A) hospitalization for organ damage such as acute nephritis, interstitial nephritis, glomerulonephritis, acute renal failure; myocarditis, pericarditis, endocarditis, interstitial lung disease, acute pulmonary failure, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, hemorrhagic event under circulating anticoagulants, myocardial infarction, unstable angina pectoris, cardiac arrest; stroke, transient ischemic attack, pulmonary embolism, deep vein thrombosis, arterial thrombosis, portal vein thrombosis, or (B) severe flares or exacerbations leading to the administration of a very high dose of CS (> 1g) within 10 days of hospitalization with a diagnosis of SLE or a visit to a specialist physician (internal medicine, rheumatology, nephrology).Hospitalizations were documented in the comprehensive records of the national health services database, while medical visits and prescriptions were traced in the records held by the Health Insurance system, the two sources being linked. The primary effectiveness criterion is the composite criterion (A) or (B). The secondary criteria are the individual components (A) or (B) of the primary criterion.

[0133] 1.5 Study size and statistical power

[0134] The control group had an expected composite outcome rate of 7 per 100 person-years of cumulative follow-up, on the assumption of constant risk; the sample size required to have power >80% to detect a hazard ratio <0.50 with a confidence greater than or equal to 95% was at least 345 person-years in the mebeverine group, assuming an average of 4 unexposed controls followed similarly.

[0135] 1.6 Data Analysis

[0136] Descriptive statistics were performed, showing the mean and standard deviation for continuous variables and proportions for categorical variables, for the characteristics of the treatment groups at the index date or in the previous 90 days).

[0137] In the primary analysis known as the "intention-to-treat" analysis, a standard 90-day time window was applied after the index date, and the "time-to-event" (times to occurrence of censoring events) were calculated in days by subtracting the index date from: (1) the date of the first outcome in this time window or (2) the date of development of a chronic disease, or (3) the date of death or (4) the end of this 90-day time sequence, whichever occurred first in each case.

[0138] Subgroup analyses of this main analysis were carried out by matching strata and in particular according to the use of usual treatments for SLE: use of HCQ, use of CS, use of immunosuppressants and use of HCQ, CS or immunosuppressants.

[0139] A secondary "during treatment" analysis was performed to assess the occurrence of outcomes of interest during the duration of mebeverine use in each patient (rather than a fixed 90-day period), applying this time frame also to matched controls. To estimate this effective exposure period, the amount of mebeverine dispensed in milligrams was divided by the World Health Organization (WHO) defined daily dose (DDD) for this drug, which is 300 mg. A 50% grace period was applied to each prescription, also taking into account overlaps between drug dispensing episodes.

[0140] Efficacy was analyzed using a conditional Cox proportional hazards model, including the mebeverine treatment group and the control group for each treatment sequence. A conditional univariate analysis ("crude analysis") and a multivariate analysis were performed in each type of analysis. The multivariate analysis was adjusted, in each case, for the use, during follow-up, of gastrointestinal and psychiatric medications and also for propensity scores for using mebeverine.

[0141] In a secondary analysis, outcome categories (A) and (B) were analyzed separately and each outcome was examined independently.

[0142] 2. Results

[0143] The results of the study are as follows.

[0144] 2.1 Study population:

[0145] Fig. 1 presents the patient selection for the study (Flowchart). During the study period (between January 1, 2010 and January 31, 2010) As of December 2020, 51,674 patients participated in the French National Health Service's eligible cohort of patients with SLE; among them, 865 (1.7%) had been diagnosed with inflammatory bowel disease and were excluded from the mebeverine study. Of the remaining 50,809 patients, 1,920 used mebeverine at least once, of whom 204 (10.6%) did not meet the inclusion criteria, and 1,716 (89.4%) were eligible for the study. Among these, 1,605 found at least one "control" patient in the national SLE cohort, not using mebeverine on the same day and matchable to at least one of its treatment sequences, based on all matching criteria. The 1605 mebeverine users accumulated 2016 usage sequences during the follow-up (1.26 per user on average).Up to 10 controls were matched to each mebeverine use sequence, with a total of 13,244 controls [mean: 6.6 controls per treatment sequence]. All 14,849 patients were followed for at least 90 days (or until a censoring event occurred). Outcome data were obtained for all these patients.

[0146] The basic characteristics according to the treatment groups are presented in Table 1 below. The two groups were very similar with regard to the clinical characteristics considered.

[0147] [Tables] COMORBIDITIES AT ENTRY* Mebeverine N, [%] or (sd) Controls N, [% weighted**] or (sd) Total (sequences compared) 2016 [100%] 13244 [!00%] Mean Age (sd) 51.6(14.6) 51.6(13.4) Women 1915 [95%] 12969 [95%] CV & Diabetes Medications 1001 [49.7%] 6119 [49.7%] Cancers 122 [6.1%] 766 [6.4%] Dementias 9 [0.4%] 43 [0.5%] Liver Disorders 25 [1.2%] 177 [1.6%] Immunodepression 8 [0.4%] 85 [0.8%] Metabolic disorders 12 [0.6%] 51 [0.4%] Musculoskeletal disorders 9 [0.4%] 39 [0.4%] Neurological disorders 9 [0.4%] 108 [0.9%] Pancreatic disorders 5 [0.2%] 13 [0.1%] Psychiatric disorders or addictions 525 [26%] 2915 [25%] *Comorbidities reported during hospitalizations (or cardiovascular or antidiabetic treatments, or psychiatric treatments)

[0148] ** Weighted percentages for the number of controls per exposed patient.

[0149] Table 2 below represents the distribution of usual treatments for SLE (HCQ, CS, IS), NSAIDs and gastrointestinal drugs in the mebeverine and control groups.

[0150] Table 2 shows that over 80% of patients in each group also received at least one standard treatment for SLE: HCQ (61.3%), corticosteroids (54.3%), and / or immunosuppressants (11.6%) within the 90 days prior to or at the index date. Nearly half (49.6%) of patients received an NSAID during this period, and the majority received another gastrointestinal drug of the same class as mebeverine (63.5%) or of a different class (79%). The treatment and control groups were made perfectly similar with respect to these characteristics by matching.

[0151] [Tables2] CO-ADMINISTERED MEDICATION* Treatment Sequences [%] Controls [% weighted **] Total 2016 [100%] 13244 [100%] SLE Medications Hydroxychloroquine (HCQ) 1236 [61.3%] 18779 [61.3%] Corticosteroids (CS)2 1095 [54.3%] 17066 [54.3%] Immunosuppressants (IS)1 233 [11.6%] 944 [11.6%] At least one IS, HCQ or CS 1642 [82.0%] 10862 [82.0%] NSAID3 1000 [49.6%] 6375 [49.6%] Same class as mebeverine 4 1281 [63.5%] 7360 [63.5%] Other gastrointestinal drugs 5 1592 [79%] 10263 [79%] *Drug use at entry (index date or previous 90 days; drug categories in the table were all matching variables). **Proportions are weighted according to the number of matched controls per treatment sequence.1 Immunosuppressants: ATC L04, L01AA01, L01XC02 ATC + hospitalization code Z512 2 Corticosteroids: ATC H02AB 3 Non-steroidal anti-inflammatory drugs: ATC MOI 4 Same class as mebeverine: ATC A03 (except mebeverine) 5 Other gastrointestinal drugs: ATC A02 or A06.

[0152] Among mebeverine users, there were on average 1.26 drug treatment sequences (separated by more than 90 days without use) in the total follow-up of the national cohort.

[0153] Table 3 below presents the event rates by exposure group. A primary outcome (composite endpoint) occurred in 236 cases, including 17 during mebeverine exposure (with a rate of 3.4 outcomes per 100 person-years of mebeverine use) and 219 in the controls (with a rate of 6.7 outcomes per 100 person-years). Remarkably, mebeverine use was associated with a rate of serious events that was half (or less) that observed in the absence of mebeverine, regardless of the stratum of usual SLE treatments administered concurrently with mebeverine.

[0154] [Tables3] RESULT RATES Mebeverine Controls N Sequences* N p.-a. # N events Event Rate (per 100 p.-a.) N matched * N p.-a. # Events Event Rate (per 100 p.-y.) Overall 2016 500.6 17 3.40% 13244 3269.5 219 6.70% Without HCQ With HCQ 780 1236 194.1 306.6 7 10 3.60% 3.30% 4465 8779 1101.5 2168 89 130 8.10% 6.00% Without CS With CS 921 1095 229.1 271.5 4 13 1.70% 4.80% 6178 7066 1528.3 1741.2 70 149 4.60% 8.60% Without IS With IS 1783 233 442.9 57.7 13 4 2.90% 6.90% 12300 944 3039.2 230.3 183 36 6.00% 15.60% Without HCQ|CS|IS| 374 93.2 1 1.10% 2382 589.5 33 5.60% *90 days each # p.-a. = person-years

[0155] 2.2 Main analysis

[0156] The results of the primary analysis are presented in Table 4 below for both the overall model and the stratified analyses. The crude hazard ratio (HR) for use or non-use of mebeverine and the composite outcome endpoint was: 0.42, 95% CI 0.24–0.73; p < 0.01. The adjusted HR was very similar: 0.41, 95% CI 0.23–0.73; p < 0.01.

[0157] [Tables4] Cox model of event risk for the mebeverine and control (reference) groups, overall and stratified according to co-administered SLE drug. Crude Hazard Ratio [95% CI] Adjusted Hazard Ratio [95% CI] P Model Overall 0.42 [0.24-0.73] 0.41 [0.23-0.73] 0.0023 Stratified Analysis No HCQ 0.40 [0.17-0.92] 0.37 [0.15-0.88] 0.0304 With HCQ 0.43 [0.20-0.92] 0.46 [0.22-0.98] 0.0302 No CS 0.33 [0.11-0.97] 0.40 [0.13-1.25] 0.0445 With CS 0.46 [0.24 - 0.88] 0.41 [0.20-0.81] 0.0197 No SI 0.42 [0.23 - 0.79] 0.42 [0.22 - 0.78] 0.0064 With IS 0.40 [0.11-1.46] 0.38 [0.08- 1.69] 0.1652 No HCQ|CS| IS| 0.20 [0.03 - 1.49] 0.21 [0.03- 1.64] 0.1159

[0158] Table 4 also presents the results of the subgroup analysis according to usual treatments for systemic lupus erythematosus co-administered on the index date or in the preceding 90 days, in the form of a Forest Plot. The effect of mebeverine on the prevention of acute events was maintained according to the use of these treatments. In patients not receiving HCQ, the hazard ratio was 0.40, 95% CI 0.17–0.92 (p=0.03) and 0.43, 95% CI 0.20–0.92 (p=0.04) in patients using HCQ. In patients not receiving CS, the hazard ratio was 0.33, 95% CI; 0.11 - 0.97 (p=0.04) and 0.46, 95% CI; 0.24 - 0.88 (p=0.02) in patients using CS. In patients without IS, the risk ratio was 0.42, 95% CI; 0.23 - 0.79 (p<0.01) and it was 0.40, 95% CI; 0.11 - 1.46 (p=0.16) in patients using IS (small sample size group).It is interesting to note that only one subject who consumed mebeverine developed an outcome of interest in patients not using HCQ, CS, or IS.

[0159] Fig. 2 presents the raw results from Table 4 in the form of a " Forest Plot (Forest Diagram)

[0160] Table 5 presents the secondary and sensitivity results.

[0161] The results of the analysis examining the outcomes that occurred during the treatments The figures are consistent with those of the analysis (which used a 90% "ITT" window). days), perhaps even better [HR: 0.32 95% CI, 0.16 - 0.65; adjusted HR: 0.35, 95% CI, 0.17-0.71],

[0162] Analysis using only the first treatment sequence in mebeverine users gave results very comparable to analysis using all sequences [HR: 0.39 95% CI, 0.20-0.74; adjusted HR: 0.37, 95% CI, 0.19-0.71.

[0163] Sensitivity analysis allowing controls to have previously used mebeverine identified 775 such patients out of a total of 13,882 controls that were matched to 1,613 patients (2,029 sequences) who had used mebeverine. The results of this sensitivity analysis were very similar to those of the primary analysis [HR: 0.44, 95% CI; 0.25–0.72; adjusted HR: 0.45, 95% CI; 0.26–0.79].

[0164] When only organic lesions were considered, the hazard ratio was 0.43 [95% CI; 0.23 - 0.79] and the adjusted HR was 0.41 [95% CI: 0.22 - 0.77]; and when severe flares without specific organic lesions were considered, the HR was 0.40 [95% CI; 0.15 - 1.05] and the adjusted HR was 0.47 [95% CI: 0.17 - 1.28], with central estimates similar to those in the overall analysis, the small sample sizes explaining the width of the confidence intervals.

[0165] [Tables5] Overall Cox model for event risk, Secondary or sensitivity analyses Mebeverine analysis n events (sequences) Controls n events (sequences) HR [95% CI] Adjusted HR [95% CI] P Effective treatment * 11 (2016) 161 (13244) 0.32 [0.16-0.65] 0.35 [0.17-0.71] 0.004 First treatment sequences 13 (1605) 174 (10479) 0.39 [0.20 - 0.74] 0.37 [0.19-0.71] 0.003 Controls with possible prior mebeverine use 17 (2029) 225 (13882) 0.44 [0.25 - 0.77] 0.45 [0.26 - 0.79] 0.006 Outcome Components (a) Organ Lesions 15 (2016) 181 (13244) 0.43 [0.23 - 0.79] 0.41 [0.22-0.77] 0.005 (b) Severe Relapses without Specific Organ Lesion 5 (2016) 79 (13244) 0.40 [0.15-1.05] 0.47 [0.17-1.28] 0.142

[0166] 3. Conclusion

[0167] The MELUSINE study demonstrates that the use of mebeverine significantly reduces the risk of organ damage or flares or exacerbations in patients with SLE, these signs being indicators of disease progression. The benefits of mebeverine were observed in the context of widespread use of standard, effective SLE treatments, such as hydroxychloroquine (HCQ), corticosteroids (CS), or immunosuppressants (IS). It is noteworthy that mebeverine had the same effect whether or not patients were using these medications; therefore, mebeverine has a beneficial effect on SLE outcomes independently of the effect of all known SLE treatments. These surprising results have never been described in the prior art.

Claims

Demands

1. Composed of the following formula (I):

2.

3.

4.

5.

6.

7.

8.

9. or a pharmaceutically acceptable salt and / or solvate of such a compound, for its use in the prevention and / or treatment of an autoimmune disease, in a subject in need. Compound for its use according to claim 1, characterized in that the autoimmune disease is systemic lupus erythematosus (SLE) A compound for use according to claim 2, for use in the secondary prevention and / or treatment of SLE. A compound for use according to any one of claims 1 or 2, characterized in that the compound of formula (I) is in the form of a hydrochloride salt. Compound for use according to any one of claims 1 to 4, to prevent and / or treat organic lesions and / or flare-ups and / or exacerbation and / or aggravation or adverse consequences of SLE. Compound for use according to any one of claims 1 to 5, characterized in that the subject has SLE disease at a mildly severe, moderate, moderately severe or severe stage. Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 6 and at least one pharmaceutically acceptable excipient, for use in the prevention and / or treatment of an autoimmune disease. Pharmaceutical composition according to claim 7, for use in the prevention and / or treatment of systemic lupus erythematosus (SLE). Pharmaceutical composition for its use according to claim 7, further comprising another active ingredient selected from the group consisting of an antimalarial agent, a corticosteroid, an immunosuppressant and a non-steroidal anti-inflammatory drug (NSAID).

10. Pharmaceutical composition for its use according to claim 9, characterized in that the antimalarial agent is hydroxychloroquine, chloroquine and their derivatives.

11. Pharmaceutical composition for its use according to claim 9, characterized in that the corticosteroid is a corticosteroid of ATC Class H02.

12. Pharmaceutical composition for its use according to claim 9, characterized in that the corticosteroid is selected from the group consisting of prednisone, dexamethasone, triamcinolone, betamethasone, beclomethasone, flunisolide and fluticasone.

13. Pharmaceutical composition for its use according to claim 9, characterized in that the immunosuppressant is an immunosuppressant of ATC class L04.

14. Pharmaceutical composition for its use according to claim 9, characterized in that the immunosuppressant is cyclophosphamide or methotrexate.

15. Pharmaceutical composition for use according to any one of claims 7 to 14, characterized in that it is in a form suitable for oral or injectable administration.

16. Pharmaceutical composition for use according to any one of claims 7 to 15, characterized in that it is in the form of a tablet, a capsule, a liquid dose, a gel or a powder.

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